UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
NO.
0051578
DATE:
February
19,
2003
MEMORANDUM
SUBJECT:
CYPERMETHRIN
AND
ZETA­
CYPERMETHRIN
­
5th
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Brenda
Tarplee,
Senior
Scientist
Science
Information
Management
Branch
Health
Effects
Division
(
7509C)

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

TO:
Yan
Donovan,
Risk
Assessor
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

PC
Code:
109702
and
129064
On
January
22,
2003
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reassessed
FQPA
requirements
in
response
to
questions
posed
by
the
Natural
Resources
Defense
Council
(
NRDC).
HIARC
also
reviewed
the
previous
recommendation
for
a
developmental
neurotoxicity
study
in
rats
and
subsequent
need
for
a
data
base
factor
to
account
for
this
data
gap.
No
new
data
have
been
reviewed
and
no
changes
were
made
to
the
toxicology
endpoints
previously
selected
for
cypermethrin
and
zeta­
cypermethrin.
This
document
revises
the
previous
HIARC
report
dated
January
17,
2001
(
TXR
NO.
014445).
2
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Paula
Deschamp,
Elizabeth
Doyle,
Pamela
Hurley,
John
Liccione,
Susan
Makris,
Elizabeth
Mendez,
David
Nixon,
Jess
Rowland,
PV
Shah
(
for
Jonathan
Chen),
and
Brenda
Tarplee
(
Executive
Secretary).

Member(
s)
in
absentia
were:
Jonathan
Chen
Also
in
attendance
were:
Karen
Whitby
(
RAB1)
and
Ed
Zager
(
HED
IO).

Meeting
materials
prepared
by:
Brenda
Tarplee,
Senior
Scientist,
SIMB
3
INTRODUCTION
On
November
16
and
December
19,
2000,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
both
cypermethrin
and
z­
cypermethrin
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
This
was
a
re­
evaluation
of
previous
HIARC
(
2000
and
1997)
and
RfD
(
1996)
Committee
decisions.
The
December
19
meeting
was
a
re­
evaluation
of
the
dermal
absorption
value
determined
on
November
16.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
either
cypermethrin
and/
or
z­
cypermethrin
was
previously
evaluated
on
September
19,
2000
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

On
January
22,
2003
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reassessed
FQPA
requirements
in
response
to
questions
posed
by
the
Natural
Resources
Defense
Council
(
NRDC).
HIARC
also
reviewed
the
previous
recommendation
for
a
developmental
neurotoxicity
study
in
rats
and
subsequent
need
for
a
data
base
factor
to
account
for
this
data
gap.
No
new
data
have
been
reviewed
and
no
changes
were
made
to
the
toxicology
endpoints
previously
selected
for
cypermethrin
and
zeta­
cypermethrin.
This
document
revises
the
previous
HIARC
report
dated
January
17,
2001
(
TXR
NO.
014445).

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

On
November
16
and
December
19,
2000,
the
HIARC
requested
that
a
developmental
neurotoxicity
study
in
rats
be
conducted
with
zeta­
cypermethrin.

2.
Evidence
of
Neurotoxicity
The
HIARC
concluded
that
there
is
a
concern
for
neurotoxicity
resulting
from
exposure
to
zetacypermethrin
The
following
data
are
available.

a.
Acute
Delayed
Neurotoxicity
­
Hen
(
Cypermethrin)

Cypermethrin
is
not
an
organophosphate
insecticide
and
this
study
is
not
required.
However,
cypermethrin
was
tested
in
the
hen
following
a
protocol
similar
to
the
series
81­
7
guideline.
The
dose
levels
tested
were
0,
2500,
5000
and
10000
mg/
kg
but
there
was
no
indication
of
the
delayed
type
neurotoxicity
noted
(
MRID
No.:
00070564).

b.
Acute
Neurotoxicity
Screening
Battery
­
Rat
(
Cypermethrin)

In
an
acute
neurotoxicity
screen,
cypermethrin
(
95.5/
95.7%
purity,
1:
1
cis:
trans)
was
administered
once
by
gavage
in
corn
oil
to
four
groups
of
12­
hour
fasted
Sprague­
Dawley
rats
(
10/
sex/
group)
at
4
doses
of
0
(
corn
oil
only),
30,
100
or
200
mg/
kg.
The
rats
were
assessed
at
pretest,
four
hours
after
treatment
and
on
days
7
and
14
for
FOB
and
motor
activity.
After
day
14,
5/
sex/
dose
were
prepared
for
neurohistopathology.
(
MRID
43152001).

At
100
mg/
kg,
on
days
0,
1
or
2
only,
ataxia
(
2
males
and
2
females)
and
related
conditions
(
staggered
or
impaired
gait,
decreased
activity,
splayed
hindlimbs
and
limp
condition)
and
decreased
motor
activity
(
49%,
p<
0.001
for
males
and
33%,
p<
0.01
for
females)
resulted.
In
addition,
some
females
had
salivation,
lacrimation
and/
or
soiled
fur.
At
200
mg/
kg,
one
male
and
two
females
died
on
day
0;
the
majority
of
the
following
clinical
signs
were
noted
on
day
0
in
one
or
more
of
7/
10
males
and
9/
10
females:
ataxia,
staggered
gait,
abdominogenital
staining,
oral
discharge
and
decreased
locomotion.
Neurohistopathologically,
no
treatment
related
lesions
in
any
of
the
various
structures
were
reported.
Acceptable
positive
control
data
were
provided
by
the
sponsor.
The
LOAEL
is
100
mg/
kg
based
primarily
on
ataxia
and
related
conditions
(
staggered
or
impaired
gait,
decreased
activity,
splayed
hindlimbs
and
limp
conditions
in
addition
to
decreased
motor
activity
in
males
and
females
on
days
0,
1
or
2).
The
NOAEL
is
30
mg/
kg.
This
study
is
ACCEPTABLE
and
satisfies
the
requirement
for
an
acute
neurotoxicity
screen
(
81­
8,
870.6200)
in
rats.

c.
Acute
Neurotoxicity
Screening
Battery
­
Rat
(
Cypermethrin)

THIS
EXECUTIVE
SUMMARY
IS
BASED
UPON
A
PUBLICATION
Katherine
L.
McDaniel
and
Virginia
C.
Moser,
"
Utility
of
a
Neurobehavioral
Screening
Battery
for
Differentiating
the
Effects
of
Two
Pyrethroids,
Permethrin
and
Cypermethrin",
Neurotoxicology
and
Teratology
15:
71­
83
(
1993).
MRID
none.

The
Executive
Summary
will
include
information
pertaining
only
to
cypermethrin.

Four
groups
of
8/
sex
Charles
River
Long
Evans
rats
were
administered
by
gavage
cypermethrin
(
97%
a.
i.,
1:
1
ratios
of
cis
and
trans
isomers)
at
single
doses
of
0
(
corn
oil),
20,
60
or
120
(
FOB
experiment)/
100
(
motor
activity)
mg/
kg.
Separate
sets
of
animals
were
treated
for
the
FOB
and
motor
assessments.
FOB
was
examined
1.5
and
3
hours
post­
dosing.
Motor
activity
was
examined
3
hours
post­
dosing.
Both
FOB
and
motor
activity
were
also
examined
pretest
as
well
as
after
24
and
48
hours
post­
dosing.
During
the
FOB
assessments,
one
male
and
6
of
12
(
8
original
and
4
replacements)
female
rats
dosed
with
120
mg/
kg
died.
The
dose
was
then
reduced
to
100
mg/
kg
for
the
motor
assessments
and,
at
this
level,
two
males
and
one
female
died
(
symptoms
prior
to
death
not
described).

Transient
weight
losses
of
7.5
and
9%
for
males
and
females
were
observed
24
hours
postdosing
in
the
highest
dose
(
persisted
to
48
hours).
No
body
weight
effects
at
lower
doses.
There
were
gait
and
muscle
effects
as
well
as
choreoathetosis.
Motor
activity
was
decreased
for
all
dose
groups
for
males
(
estimated
45%,
66%
and
85%
for
the
20,
60
and
100
mg/
kg
groups,
respectively).
Gait
abnormalities
were
noted
in
all
dose
groups
(
males
only
at
20
mg/
kg)
at
1.5
hours
post
dosing
with
the
60
and
100
mg/
kg
rats
showing
progressively
higher
median
scores.
The
high­
dose
males
and
females
showed
gait
abnormalities
at
24
and
possibly
48
hours.
Effects
were
reported
for
males
5
and
females
regarding
the
following
parameters
at
60
and
100
mg/
kg:
salivation,
urination,
arousal,
abnormal
motor
movement,
forelimb
or
hindlimb
grip
strength,
landing
foot
splay,
righting
reflex,
touch
response
and
tail
pinch
response.
[
Details
of
these
effects
were
not
included
in
the
DER.]
Regarding
body
temperature,
the
20
mg/
kg
males
had
statistically
significant
increased
temperature
at
1.5
hours
(
38.5
to
slightly
over
39
°
C;
male
and
female
100
mg/
kg
as
well
as
male
60
mg/
kg
had
temperature
decreased
to
below
37
°
C
at
1.5
hours
for
females
and
3
hours
for
males;
and
females
were
still
decreased
after
24
and
48
hours.
No
histopathology
or
perfusion
data
were
included.

The
LOAEL
for
neurotoxicity
was
20
mg/
kg
based
on
decreased
motor
activity
and
gait
abnormalities.
The
NOAEL
was
<
20
mg/
kg.
This
single­
dose
neurotoxicity
study
is
classified
as
SUPPLEMENTARY.
It
was
in
the
form
of
a
literature
reprint
and
was
not
designed
to
meet
a
specific
guideline
protocol.
[
Most
of
the
data
were
presented
in
a
semi­
quantitative
manner
and
no
individual
animal
data
were
presented
to
verify
the
observations.]

d.
Acute
Neurotoxicity
Screening
Battery
­
Rat
(
z­
Cypermethrin)

In
an
acute
neurotoxicity
screening
battery
study
(
MRID
44962201),
male
and
female
Long
Evans
rats
(
10
animals/
sex/
group)
were
dosed
once
orally
by
gavage
with
undiluted
z­
cypermethrin
(
84.4%
a.
i.)
at
levels
of
0
(
water
only),
10,
50
or
250
mg/
kg.
The
functional
observational
battery
(
FOB)
and
motor
activity
were
evaluated
prior
to
treatment
and
on
study
days
0,
7
and
14
postdosing
At
study
termination,
5
animals/
sex/
dose
were
perfused
in
situ,
and
animals
from
the
control
and
250
mg/
kg
dose
groups
were
subjected
to
neuropathological
examinations.

No
treatment­
related
findings
were
observed
in
the
10
mg/
kg
group.
Body
weights,
body
weight
gains,
motor
activity,
gross
pathology
and
neuropathology
were
unaffected
by
the
test
substance.
At
50
mg/
kg,
noted
clinical
observations
included
the
following
(
data
presented
as
total
occurrences/
number
of
animals):
(
i)
abdominogenital
staining
(
1/
1,
both
sexes);
(
ii)
oral
discharge
(
1/
1,
males);
(
iii)
splayed
hindlimbs
(
1/
1,
males);
(
iv)
staggered
gait
(
2/
2,
males);
and
(
v)
tremors
(
1/
1,
males).
On
day
0
during
the
homecage
portion
of
the
FOB,
treatment­
related
observations
included
the
following:
(
i)
abnormal
mobile
posture
(
1/
10,
females);
(
ii)
splayed
hindlimbs
(
1/
10,
females);
(
iii)
soiled
fur
(
males­
2/
10,
females­
1/
10);
and
(
iv)
unable
to
walk
(
1/
10,
females).
All
groups
were
comparable
during
the
pretest
evaluation
and
on
test
days
7
and
14.
On
day
0
during
the
open
field
portion
of
the
FOB,
treatment­
related
observations
noted
in
the
females
included
the
following:
(
i)
abnormal
mobile
posture
(
1/
10);
(
ii)
unusual
immobile
posture
(
1/
10);
(
iii)
severely
impaired
gait
(
1/
10);
(
iv)
splayed
hindlimbs
(
1/
10);
(
v)
lands
on
back
(
1/
10);
(
vi)
whole
body
tremors
(
1/
10);
and
(
vii)
convulsions
(
1/
10).
All
female
groups
were
comparable
during
the
pretest
evaluation
and
on
test
days
7
and
14.
None
of
these
findings
were
observed
in
the
controls.

At
250
mg/
kg,
one
female
died
on
the
day
following
test
substance
administration
(
no
cause
of
death
determined).
Clinical
observations
included
the
following
(
data
presented
as
total
occurrences/
number
of
animals):
(
i)
abdominal
gripping
(
1/
1,
females):
(
ii)
abdominogenital
staining
(
males­
6/
4,
females­
4/
3);
(
iii)
ataxia
(
1/
1,
females);
(
iv)
decreased
locomotion
(
males­
2/
2,
6
females­
1/
1);
(
v)
lacrimation
(
1/
1,
females);
(
vi)
loss
of
muscle
control
(
1/
1,
females);
(
vii)
oral
discharge
(
males­
3/
3,
females­
2/
1);
(
viii)
splayed
hindlimbs
(
males­
2/
2,
females­
3/
2);
(
ix)
staggered
gait
(
4/
4,
males);
(
x)
tremors
(
2/
2,
both
sexes);
(
xi)
tonic­
clonic
convulsions
(
2/
2,
females);
and
(
xii)
vocalization
(
1/
1,
both
sexes).
These
findings
were
not
observed
in
concurrent
controls.
The
only
statistically
significant
(
p<
0.05)
finding
noted
during
the
home
cage
portion
of
the
FOB
on
day
0
was
soiled
fur
in
the
males
(
4/
10);
this
finding
was
not
observed
in
any
control
animal.
Other
treatment­
related
observations
included
the
following:
(
i)
staggered
gait
(
2/
10,
males);
(
ii)
abnormal
mobile
posture
(
males­
1/
10,
females­
3/
10);
(
iii)
splayed
hindlimbs
(
males­
1/
10,
females­
2/
10);
(
iv)
soiled
fur
(
2/
10,
females);
and
(
v)
inability
to
walk
(
1/
10,
females).
Treatment­
related
effects
noted
on
day
0
during
the
open
field
portion
of
the
FOB
included
the
following:
(
i)
abnormal
mobile
posture
(
males­
1/
10,
females­
3/
10);
(
ii)
unusual
immobile
posture
(
1/
10,
females
only);
(
iii)
staggered
gait
(
males­
2/
10,
females­
1/
10);
(
iv)
splayed
hindlimbs
(
males­
1/
10,
females
­
2/
10);
(
v)
slightly
impaired
gait
(
1/
10,
both
sexes);
(
vi)
moderately
impaired
gait
(
1/
10,
males
only);
(
vii)
severely
impaired
gait
(
1/
10,
females
only);
(
viii)
dragging
hindlimbs
(
1/
10,
females
only);
(
ix)
incoordinated
landing
(
1/
10,
both
sexes);
(
x)
lands
on
back
(
1/
10,
females
only);
(
xi)
whole
body
tremors
(
3/
10,
females
only);
(
vii)
convulsions
(
1/
10,
females
only);
and
(
xiii)
decreased
activity
(
1/
10,
both
sexes).
None
of
these
findings
were
observed
in
the
controls.
Acceptable
positive
control
data
were
provided
by
the
sponsor.

The
acute
neurotoxicity
LOAEL
is
50
mg/
kg
based
on
clinical
signs
of
toxicity
and
FOB
findings.
The
acute
neurotoxicity
NOAEL
for
this
study
is
10
mg/
kg.
This
submitted
study
is
classified
as
acceptable/
guideline
(
81­
8[
a];
870.6200)
and
satisfies
the
guideline
requirements
for
an
acute
neurotoxicity
screening
battery
in
rats.

e.
Subchronic
Neurotoxicity
Screening
Battery
­
Rat
(
Cypermethrin)

Cypermethrin
(
95.7%
purity)
was
administered
by
dietary
admix
to
four
groups
of
10/
sex
Sprague­
Dawley
strain
rats
at
doses
of
0,
500,
1300
or
1700
ppm
(
mg/
kg/
day:
0,
31,
77
or
102
for
males
and
0,
37,
95
or
121
for
females)
for
90
days
in
a
subchronic
neurotoxicity
study.
Rats
were
assessed
twice
daily
for
clinical
signs
and
mortality;
FOB
and
motor
activity
were
examined
pretest
as
well
as
at
weeks
4,
8
and
13.
Neurohistopathology
was
performed.
MRID
43152002.
At
1300
ppm,
females
displayed
the
following
(
number
of
rats
with
sign/
total
number
of
rats
in
the
group):
ataxia
(
1/
10),
splayed
hindlimbs
(
5/
10),
impaired
gait
(
4/
10)
and
decreased
feces
(
4/
10)
as
well
as
decreased
body
weight
gain
(­
41%).
Males
had
only
decreased
body
weight
gain
(­
27%)
and
increased
landing
foot
splay.
At
1700
ppm,
males
showed
ataxia
(
8/
10)
and
additional
related
symptoms;
females
had
decreased
motor
activity
(­
27%).
No
test
article
related
neurohistopathological
lesions
were
reported.
Acceptable
positive
control
data
were
included.
The
LOAEL
is
1300
ppm
(
77
mg/
kg/
day)
based
on
the
following:
males
=
decreased
body
weight
gain
and
increased
landing
foot
splay;
females
=
ataxia,
splayed
hindlimbs,
impaired
gait
and
decreased
feces
as
well
as
decreased
body
weight
gain.
The
NOAEL
is
500
ppm
(
31
mg/
kg/
day).
This
study
is
ACCEPTABLE
and
satisfies
the
guideline
(
82­
7,
870.6200)
requirements
for
a
subchronic
neurotoxicity
study
in
rats.
7
f.
Subchronic
Neurotoxicity
Screening
Battery
­
Rat
(
z­
Cypermethrin)

In
this
subchronic
neurotoxicity
screening
battery,
z­
cypermethrin,
purity
of
86.0%
(
MRID
44962202),
was
administered
continuously
in
the
diet
for
13
weeks
to
10
Charles
River
Long
Evans
rats/
sex/
group
at
doses
of
0,
75,
400
or
750
ppm
(
equivalent
to
[
M/
F]
0/
0,
5.0/
5.9,
26.3/
31.5,
or
47.2/
55.6
mg/
kg/
day).
Five
animals/
sex/
group
were
perfused
for
neurohistological
examination,
and
the
control
and
high­
dose
animals
were
examined
microscopically.
Functional
observational
battery
(
FOB)
and
motor
activity
were
evaluated
during
the
pretest
interval,
and
following
weeks
4,
8,
and
13.

No
treatment­
related
deaths
occurred.
Clinical
signs,
gross
pathology
and
neuropathology
were
unaffected
by
the
test
substance;
furthermore,
no
treatment­
related
findings
were
noted
in
the
home
cage
observations
of
the
FOB
at
any
dose.
No
treatment­
related
findings
were
observed
in
the
75
ppm
group.
In
the
400
ppm
males,
statistically
significant
decreases
in
body
weights
were
observed
at
all
intervals
except
week
3
(
95­
8%),
p
#
0.05);
overall
(
weeks
0­
13)
body
weight
gains
were
also
decreased
relative
to
concurrent
controls
in
these
animals
(
915%,
p
#
0.05).
Decreased
food
consumption
was
observed
throughout
the
study,
but
statistical
significance
was
sporadic
(
96­
17%,
p
#
0.01
or
0.05).
During
the
open
field
portion
of
the
FOB,
increased
landing
foot
splay
was
observed
at
week
13
(
833%,
p
#
0.01).
In
addition,
mean
motor
activity
was
decreased
(
p
#
0.01
or
0.05)
at
weeks
8
(
936%)
and
13
(
951%).
At
750
ppm,
one
female
was
sacrificed
in
extremis
on
day
51
following
mechanical
injury;
this
death
was
considered
not
to
be
treatmentrelated
Body
weights
were
decreased
throughout
the
study
(
912­
17%,
p
#
0.01)
in
the
males.
In
the
females,
body
weights
were
decreased
sporadically
for
the
first
9
weeks
of
the
study,
and
continually
at
weeks
10­
13
(
95­
10%,
p
#
0.05
or
0.01).
Overall
(
weeks
0­
13)
body
weight
gains
were
decreased
(
p
#
0.01)
in
both
sexes
(
928­
31%)
as
was
food
consumption
(
98­
29%).
During
the
open
field
portion
of
the
FOB,
increased
landing
foot
splay
was
observed
in
the
males
at
week
13
(
841%,
p
#
0.01).
Mean
motor
activity
was
decreased
(
p
#
0.05
or
0.01)
in
the
males
at
weeks
8
(
925%)
and
13
(
942%).

The
LOAEL
for
this
study
is
400
ppm
for
males
(
equivalent
to
26.3
mg/
kg/
day),
based
on
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption;
and
750
ppm
for
females
(
equivalent
to
55.6
mg/
kg/
day)
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
The
NOAEL
for
this
study
is
75
ppm
for
males
(
equivalent
to
5.0
mg/
kg/
day)
and
400
ppm
for
females
(
equivalent
to
31.5
mg/
kg/
day).
The
submitted
study
is
classified
as
acceptable/
guideline
(
§
82­
7[
a];
870.6200)
and
satisfies
the
guideline
requirements
for
a
subchronic
neurotoxicity
screening
battery
in
rats.

g.
Evidence
of
neurotoxicity
from
studies
other
than
the
neurotoxicity
studies
Clinical
signs
of
neurotoxicity
(
i.
e.
tremors
and
gait
abnormalities)
were
observed
in
dog
(
subchronic
and
chronic)
and
rat
(
subchronic,
developmental,
and
reproduction)
oral
studies
conducted
with
both
cypermethrin
and
z­
cypermethrin.
Similar
clinical
signs
were
also
observed
in
the
rat
inhalation
study
conducted
with
cypermethrin.
Increased
relative
brain
weights
were
noted
8
in
the
z­
cypermethrin
rat
reproduction
study.
In
the
cypermethrin
subchronic
rat
study
(
1980),
electron
microscopic
examination
of
the
central
and
peripheral
nervous
system
revealed
some
possible
splitting
and/
or
vacuolation
(
not
specified
which
tissue;
7/
16
high
dose
males
versus
2/
12
control
males;
this
was
not
specifically
listed
as
a
treatment­
related
effect
in
the
DER).

3.
Developmental
Toxicity
Study
Conclusions
a.
Developmental
Toxicity
Study,
Rat
(
Cypermethrin)

In
a
developmental
toxicity
study
(
MRID
00056804,
92027039
or
92027061),
cypermethrin
(
98.2%
purity)
in
corn
oil
was
administered
by
gavage
to
four
groups
of
25
mated
CD
strain
Charles
River
rats
at
dose
levels
of
0,
17.5,
35
or
70
mg/
kg/
day
on
days
6­
15
of
gestation.
The
rats
were
sacrificed
at
day
21
of
gestation.
Dose
levels
of
35
(
12%)
and
70
(
28%)
mg/
kg/
day
resulted
in
decreased
body
weight
gain.
The
dams
dosed
with
70
mg/
kg/
day
displayed
neurological
signs
such
as
splayed
limbs,
spasms,
and
hypersensitivity
to
noise
and
convulsions.
The
maternal
LOAEL
is
35
mg/
kg/
day,
based
on
decreased
body
weight
gain.
The
maternal
NOAEL
is
17.5
mg/
kg/
day.
There
were
no
effects
on
either
skeletal
or
visceral
structures
reported.
The
developmental
LOAEL
is
>
70
mg/
kg/
day.
The
developmental
NOAEL
is
>
70
mg/
kg/
day.
This
developmental
toxicity
study
in
the
rat
is
classified
as
ACCEPTABLE
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700,
83­
a).

b.
Developmental
Toxicity
Study,
Rat
(
z­
Cypermethrin)

In
a
developmental
toxicity
study
(
MRID
41776102)
z­
cypermethrin
(
89.6%
purity)
in
corn
oil
was
administered
by
gavage
to
five
groups
of
25
Charles
River
Crl:
CD
(
SD)
rats
at
dose
levels
of
0,
5,
12.5,
25
or
35
mg/
kg/
day
on
days
6
through
15
of
gestation.
Clinical
signs
of
toxicity
were
observed
in
the
25
and
35
mg/
kg/
day
groups.
In
the
25
mg/
kg/
day
group,
there
was
ataxia,
urinestained
abdominal
fur
and
fecal­
stained
perineal
fur.
In
the
35
mg/
kg/
day
group
there
was
a
significant
(
p#
0.01)
increase
in
ataxia,
hypersensitivity,
urine
stained
abdominal
fur,
emaciated
appearance,
excess
salivation
and
soft
or
liquid
feces.
These
symptoms
started
about
8­
10
days
after
initiation
of
treatment
and
lasted
through
gestation.
Chromorhinorrhea
was
observed
in
0,
3,
3,
4
and
4
rats
at
0,
12.5,
25
and
35
mg/
kg/
day
groups.
There
was
a
decrease
in
body
weight
gains
(
p#
0.01)
during
the
dosing
period
in
the
25
mg/
kg/
day
group
(
23%)
and
the
35
mg/
kg/
day
group
(
51%).
During
dosing,
food
consumption
was
also
decreased
(
p#
0.01)
at
both
25
and
35
mg/
kg/
day.
There
were
no
effects
noted
regarding
any
developmental
parameters.
The
maternal
LOAEL
was
25
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
as
well
as
ataxia,
urine­
stained
abdominal
fur
and
fecal­
stained
perineal
fur.
The
maternal
NOAEL
was
12.5
mg/
kg/
day.
The
developmental
LOAEL
was
>
35
mg/
kg/
day.
The
developmental
NOAEL
was
35
mg/
kg/
day.
This
developmental
toxicity
study
in
the
rat
is
classified
ACCEPTABLE
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700,
83­
a).

c.
Developmental
Toxicity
Study,
Rabbit
(
Cypermethrin)
9
In
a
developmental
toxicity
study
(
MRID
00056805),
cypermethrin
(
98.5%
purity)
in
corn
oil
was
administered
to
banded
Dutch
rabbits
by
gelatin
capsule
at
dose
levels
of
0
(
empty
capsule),
0
(
capsule
plus
corn
oil),
3,
10
or
30
mg/
kg/
day
on
days
6
to
18
inclusive
of
gestation.
There
were
no
effects
on
the
does
of
any
kind
reported.
The
maternal
LOAEL
is
>
30
mg/
kg/
day.
The
maternal
NOAEL
is
>
30
mg/
kg/
day.
There
were
no
treatment
related
effects
on
either
the
skeletal
or
visceral
structures
reported.
The
developmental
LOAEL
is
>
30
mg/
kg/
day.
The
developmental
NOAEL
is
>
30
mg/
kg/
day.
This
developmental
toxicity
study
in
the
rabbit
is
classified
SUPPLEMENTARY
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
83­
3b)
in
the
rabbit.
The
study
is
not
considered
upgradeable
because
the
dose
levels
selected
are
too
low.

d.
Developmental
Toxicity
Study,
Rabbit
(
Cypermethrin)

In
a
developmental
toxicity
study
(
MRID
43776302)
cypermethrin
(
94­
96%
pure,
cis/
trans
ratio
approximately
1:
1)
was
administered
to
20
New
Zealand
White
rabbits
per
dose
group
by
gavage
at
dose
levels
of
0,
100,
450
or
700
mg/
kg/
day
from
days
7
through
19
of
gestation.
The
does
were
sacrificed
on
day
29
of
gestation.
Cypermethrin
was
administered
as
a
50%
w/
v
solution
in
corn
oil
at
varying
volumes
and
corn
oil
was
administered
to
the
control
group.
Body
weight
gain
was
decreased
during
dosing
at
450
(
25%)
and
700
(
30%)
mg/
kg/
day
and
this
was
followed
by
compensatory
increases.
Exacerbation
of
some
clinical
signs
such
as
anorexia,
abdominogenital
staining
and
decreased
feces
and
red
or
pink
material
in
the
pan
also
resulted
in
the
700
mg/
kg/
day
dose
group
and
in
a
few
does
in
the
450
mg/
kg/
day
group.
The
maternal
LOAEL
is
450
mg/
kg/
day,
based
on
decreased
body
weight
gain.
The
maternal
NOAEL
is
100
mg/
kg/
day.
There
were
no
indications
of
developmental
toxicity.
The
NOAEL
and
LOAEL
for
developmental
toxicity
are
>
700
mg/
kg/
day.
This
developmental
toxicity
study
in
the
rabbit
is
classified
ACCEPTABLE
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
83­
3b).

4.
Reproductive
Toxicity
Study
Conclusions
a.
3­
Generation
Reproduction
Study,
Rat
(
Cypermethrin)

In
a
3
generation
(
2
litters/
generation)
reproduction
study
(
MRID
00090040)
cypermethrin
(
98%
purity)
was
administered
to
four
groups
of
30/
sex
Wistar
SPF
strain
rats/
sex/
dose
group
in
their
diets
at
dose
levels
of
0,
10,
100
or
500
ppm
(
0,
0.5,
5
or
25
mg/
kg/
day).
The
first
parental
group
produced
two
litters
(
F1A
and
F1B),
the
F1B
litter
was
culled
to
produce
the
F2A
and
F2B
litters
and
the
F2B
litter
was
culled
to
produce
the
F3A
and
F3B
litters.
At
25
mg/
kg/
day
there
was
decreased
parental
weight
gain
(
i.
e.
about
3%
for
males
and
7%
for
females
for
the
F1
generation)
and
pup
weight
at
day
21
of
lactation
for
one
or
both
litters
of
one
or
both
sexes
(
about
4%
but
p<
0.01).
The
parental
LOAEL
is
25
mg/
kg/
day
based
on
decreased
body
weight
gain.
The
NOAEL
is
5
mg/
kg/
day.
The
offspring
LOAEL
is
25
mg/
kg/
day
based
on
a
decrease
in
pup
body
weight
gain
on
lactation
day
21
for
one
or
both
sexes
of
one
or
both
litters
of
each
generation.
The
offspring
NOAEL
is
5
mg/
kg/
day.
Regarding
the
lactation
day
21
pup
body
weights/
gains,
there
was
a
small
but
statistically
significant
decrease
(
p<
0.01)
in
body
weight
at
100
(
3%)
and
500
(
4%)
ppm.
The
small
decrement
at
100
ppm
is
not
considered
of
sufficient
10
magnitude
to
be
included
in
the
LOAEL
as
the
pups
in
the
100
ppm
dose
group
matured
to
be
the
parental
groups
and
there
was
no
statistical
difference
regarding
the
parental
body
weights.
This
reproductive
study
in
the
rat
is
classified
as
SUPPLEMENTARY
and
does
not
satisfy
the
guideline
requirement
for
a
3
generation
reproductive
study
(
OPPTS
870.3800,
83­
4)
in
the
rat.
The
study
is
in
summary
form
only
and
is
not
supported
by
the
individual
animal
data.

b.
3­
Generation
Reproduction
Study,
Rat
(
Cypermethrin)

In
a
3
generation
(
2
litters/
generation)
reproduction
study
(
MRID
00112912,
42068504
and
92027040)
cypermethrin
(
90.6
to
93.1%
purity)
was
administered
to
four
groups
of
15
male
and
30
female
Wistar
derived
SPF
strain
rats
at
dose
levels
of
0,
50,
150
or
1000/
750
ppm
(
reduced
to
750
ppm
after
12
weeks
because
of
severe
neurological
signs).
These
dose
levels
correspond
to
0,
2.5,
7.5
or
50/
37.5
mg/
kg/
day.
Three
successive
generations
were
produced,
each
consisting
of
2
separate
breedings
to
produce
six
sets
of
litters.
At
150
ppm
(
7.5
mg/
kg/
day),
parental
weight
gain
was
decreased
in
males
(
i.
e.
about
7%
for
F2
at
week
5)
and
females
(
i.
e.
about
4.5%
for
F0
at
week
8
and
about
10%
for
F2
at
week
8).
At
1000/
750
ppm
(
50/
37.5
mg/
kg/
day)
parental
body
weight
gain
was
typically
10%
decreased
for
both
males
and
females
and
there
was
decreased
mean
litter
weight
gain
during
lactation
(
i.
e.
12%
to
21%
for
F1B
and
12
to
17%
for
F1B
females
for
days
10
to
28).
At
1000
ppm
(
50
mg/
kg/
day)
there
were
obvious
clinical
signs
of
neurotoxicity
(
i.
e.
ataxia,
increased
sensitivity
to
sound
and
high
stepping
gait).
The
LOAEL
is
1000/
750
ppm
(
50/
37.5
mg/
kg/
day)
based
on
consistent
decreased
body
weight
gain
in
both
sexes.
The
NOAEL
is
150
ppm
(
7.5
mg/
kg/
day).
This
reproduction
study
is
classified
ACCEPTABLE
and
satisfies
the
requirement
for
a
multigeneration
reproduction
study
(
OPPTS
870.3800,
83­
4)
in
the
rat.

c.
2­
Generation
Reproduction
Study,
Rat
(
z­
Cypermethrin)

In
a
2
generation
reproduction
(
1
litter/
generation)
study
(
MRID
41968204)
z­
cypermethrin
(
89.6%
purity)
was
administered
to
six
groups
of
30
male
and
30
female
Charles
River
Crl:
CD
(
SD)
BR
rats
at
dose
levels
of
0,
7.5,
25,
100,
375
or
750
ppm
(
750
ppm
one
generation
only
due
to
death
of
pups).
For
the
ppm
groups,
approximately
0,
0.5,
1.8,
7,
27
or
45
mg/
kg/
day.
At
750
ppm,
two
P1
females
died
on
lactation
days
18
or
21.
There
was
no
750
ppm
P2
generation
due
to
the
death
of
the
pups.
Three
750
ppm
males
had
soft/
liquid
stools.
Regarding
the
two
females
which
died,
one
or
both
displayed
signs
of
emaciation,
ataxia
and
hypersensitivity
to
sound
as
well
as
chromodacryorrhea
or
chromorhinorrhea
prior
to
death.
Hypersensitivity
to
sound
was
reported
for
one
male
(
8
incidents)
and
one
female
(
6
incidences)
in
the
375
ppm
group.
In
P1
males,
there
was
no
decrease
in
body
weights
or
weight
gains
in
groups
through
375
ppm
(­
26%
at
750
ppm).
For
P2
males,
there
was
a
slight
(
5.1%)
decrease
in
body
weight
gains.
For
females,
the
only
body
weight
differences
were
for
gains
during
lactation
in
P1
and
P2
at
375
ppm
(
p<
0.01),
8.7­
9.3%
decrease.
For
males
and
females,
food
consumption
was
decreased
8­
12%
(
p<
0.05
or
0.01)
in
the
375
ppm
groups.
There
was
increased
relative
brain
weight
in
both
sexes
(+
7.8%
or
+
7.9%,
p<
0.01)
in
the
375
ppm
group
only.
There
were
decreases
in
pup
body
weight
gains
(
lactation
day
21)
for
the
F1
(­
13.4%,
p<
0.01))
and
the
F2
(­
11.1%,
p<
0.01)
at
375
ppm.
At
750
ppm
(
F1
group
only,
no
F2
generation),
132/
332
pups
died
during
lactation.
The
parental
LOAEL
is
375
ppm
(
27
mg/
kg/
day)
based
on
a
threshold
for
clinical
signs
(
hypersensitivity
to
sound)
and
decreased
body
weight
gain
in
females
during
lactation.
The
parental
11
NOAEL
is
100
ppm
(
7
mg/
kg/
day).
The
offspring
LOAEL
is
375
ppm
(
27
mg/
kg/
day)
based
on
a
decrease
in
pup
weight
gain
during
lactation.
The
offspring
NOAEL
is
100
ppm
(
7
mg/
kg/
day).
This
2­
generation
reproduction
study
is
classified
ACCEPTABLE
and
satisfies
the
requirement
for
an
83­
4
(
870.3800)
multigeneration
reproduction
study
in
rats.

5.
Additional
Information
from
Literature
Sources
None
6.
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
concluded
that
there
is
not
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
zeta­
cypermethrin.

A.
Determination
of
Susceptibility
Based
on
the
results
in
a
developmental
toxicity
study
in
rats
and
in
a
developmental
toxicity
study
in
rabbits,
there
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
to
in
utero
exposure
to
zeta­
cypermethrin.

Based
on
the
results
in
a
2­
generation
reproduction
study
in
rats,
there
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
neonates
(
as
compared
to
adults)
to
zeta­
cypermethrin.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
There
are
no
concerns
or
residual
uncertainties
for
pre
and/
or
post­
natal
toxicity
following
exposure
to
zeta­
cypermethrin.

C.
Special
FQPA
Safety
Factor(
s):

The
special
FQPA
safety
factor
should
be
1X
since
there
are
no
residual
uncertainties
for
pre
and/
or
post
natal
toxicity.

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.

7.
Recommendation
for
a
Developmental
Neurotoxicity
Study
12
The
HIARC
concluded
that
there
is
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
zeta­
cypermethrin.

On
November
16
and
December
19,
2000,
HIARC
recommended
that
a
developmental
neurotoxicity
study
in
rats
be
conducted
with
zeta­
cypermethrin
based
on
the
following
considerations:

C
The
cypermethrins
induce
clinical
signs
of
neurotoxicity
in
at
least
two
species
(
rats
and
dogs).

C
There
was
suggestive
evidence
of
neuropathology
(
electron
microscope)
in
a
subchronic
feeding
study
in
rats
conducted
with
cypermethrin.
This
study
was
conducted
in
1980.
Electron
microscopy
is
not
the
usual
method
of
examination
of
tissues.

C
In
the
acute
neurotoxicity
study
conducted
with
z­
cypermethrin,
there
were
symptoms
related
to
loss
of
muscle
control,
gait
abnormalities,
decreased
motor
activity,
convulsions,
tremors,
abdominal
gripping
and
vocalization.
In
the
acute
neurotoxicity
study
conducted
with
cypermethrin,
ataxia
and
related
conditions
(
staggered
or
impaired
gait,
decreased
activity,
splayed
hindlimbs
and
limp
condition)
and
decreased
motor
activity
were
observed.

C
In
the
subchronic
neurotoxicity
study
conducted
with
z­
cypermethrin,
there
was
increased
landing
foot
splay
and
decreases
in
mean
motor
activity.
In
the
subchronic
neurotoxicity
study
with
cypermethrin,
ataxia,
splayed
hindlimbs,
impaired
gait,
increased
landing
foot
splay,
and
decreased
motor
activity
were
observed.

C
The
cypermethrins
are
members
of
the
synthetic
pyrethroid
class
of
insecticides,
which
are
known
to
induce
transient
tremors
in
mammals.
Evidence
to
the
contrary
included:

C
There
was
no
indication
of
increased
sensitivity
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
either
z­
cypermethrin
or
cypermethrin.

C
With
the
exception
of
fenvalerate/
esfenvalerate
in
which
neuropathology
was
cited
in
a
literature
study
at
dose
levels
close
to
the
LD
50
,
at
this
time,
there
is
no
indication
of
light
microscopy
neuropathology
with
at
least
15
other
pyrethroids
in
standard
toxicity
studies.
Mammalian
neurotoxicity
testing
with
this
group
of
chemicals
has
only
recently
been
initiated.

C
No
neuropathology
has
been
observed
in
either
the
acute
or
subchronic
mammalian
neurotoxicity
studies.

C
No
malformations
of
the
central
nervous
system
were
observed
in
the
developmental
and
reproduction
studies.

On
January
22,
2003,
based
on
the
weight
of
evidence
presented,
the
HIARC
reaffirmed
the
previous
conclusion
that
a
developmental
neurotoxicity
(
DNT)
study
conducted
with
zetacypermethrin
in
rats
is
required.
HIARC
determined
that
a
10X
database
uncertainty
factor
(
UF
DB
)
is
needed
to
account
for
the
lack
of
the
DNT
since
the
available
data
provide
no
basis
to
support
reduction
or
removal
of
the
default
10X
factor.
The
following
points
were
considered
in
this
determination:
°
It
is
assumed
that
the
DNT
study
will
be
conducted
at
dose
levels
similar
to
those
used
in
the
rat
reproduction
study
with
zeta­
cypermethrin
(
0.5,
1.8,
7,
27,
45
mg/
kg/
day)
wherein
the
offspring
NOAEL
/
LOAEL
was
7
/
27
mg/
kg/
day,
13
respectively.
°
It
is
possible
that
the
results
of
the
DNT
study
could
impact
the
current
selected
regulatory
doses
since
the
NOAELs
used
for
risk
assessment
endpoints
(
e.
g.,
10
mg/
kg/
day
for
acute
and
6
mg/
kg/
day
for
chronic)
are
approximately
the
same
order
of
magnitude
as
the
offspring
NOAEL
in
the
rat
reproduction
study
conducted
with
zeta­
cypermethrin
(
7
mg/
kg/
day).

Therefore,
a
UF
DB
of
10X
will
be
applied
to
account
for
the
lack
of
the
DNT
study
with
zetacypermethrin

II.
HAZARD
IDENTIFICATION
1.
Acute
Reference
Dose
(
RfD)
­
General
Population,
Including
Infants
and
Children
Study
Selected:
Acute
rat
neurotoxicity
study
with
z­
cypermethrin
§
870.6200
MRID
No.:
44962201
Executive
Summary:
In
an
acute
neurotoxicity
screening
battery
study
(
MRID
44962201),
male
and
female
Long
Evans
rats
(
10
animals/
sex/
group)
were
dosed
once
orally
by
gavage
with
undiluted
z­
cypermethrin
(
84.4%
a.
i.)
at
levels
of
0
(
water
only),
10,
50,
or
250
mg/
kg.
The
functional
observational
battery
(
FOB)
and
motor
activity
were
evaluated
prior
to
treatment
and
on
study
days
0,
7
and
14
post­
dosing.
At
study
termination,
5
animals/
sex/
dose
were
perfused
in
situ,
and
animals
from
the
control
and
250
mg/
kg
dose
groups
were
subjected
to
neuropathological
examinations.

No
treatment­
related
findings
were
observed
in
the
10
mg/
kg
group.
Body
weights,
body
weight
gains,
motor
activity,
gross
pathology
and
neuropathology
were
unaffected
by
the
test
substance.
At
50
mg/
kg,
noted
clinical
observations
included
the
following
(
data
presented
as
total
occurrences/
number
of
animals):
(
i)
abdominogenital
staining
(
1/
1,
both
sexes);
(
ii)
oral
discharge
(
1/
1,
males);
(
iii)
splayed
hindlimbs
(
1/
1,
males);
(
iv)
staggered
gait
(
2/
2,
males);
and
(
v)
tremors
(
1/
1,
males).
On
day
0
during
the
homecage
portion
of
the
FOB,
treatment­
related
observations
included
the
following:
(
i)
abnormal
mobile
posture
(
1/
10,
females);
(
ii)
splayed
hindlimbs
(
1/
10,
females);
(
iii)
soiled
fur
(
males­
2/
10,
females­
1/
10);
and
(
iv)
unable
to
walk
(
1/
10,
females).
All
groups
were
comparable
during
the
pretest
evaluation
and
on
test
days
7
and
14.
On
day
0
during
the
open
field
portion
of
the
FOB,
treatment­
related
observations
noted
in
the
females
included
the
following:
(
i)
abnormal
mobile
posture
(
1/
10);
(
ii)
unusual
immobile
posture
(
1/
10);
(
iii)
severely
impaired
gait
(
1/
10);
and
(
iv)
convulsions
(
1/
10).
All
female
groups
were
comparable
during
the
pretest
evaluation
and
on
test
days
7
and
14.
None
of
these
findings
were
observed
in
the
controls.
At
250
mg/
kg,
one
female
died
on
the
day
following
test
substance
administration
(
no
cause
of
death
determined).
Clinical
observations
included
the
following
(
data
presented
as
total
occurrences/
number
of
animals):
(
i)
abdominal
gripping
(
1/
1,
females);
(
ii)
abdominogenital
staining
(
males­
6/
4,
females­
4/
3);
(
iii)
ataxia
(
1/
1,
females);
(
iv)
decreased
locomotion
(
males­
2/
2,
females­
1/
1);
(
v)
lacrimation
(
1/
1
females);(
vi)
loss
of
muscle
control
(
1/
1,
females);
(
vii)
oral
14
discharge
(
males­
3/
3,
females­
2/
1);
(
viii)
splayed
hindlimbs
(
males­
2/
2,
females­
3/
2);
(
ix)
staggered
gait
(
4/
4,
males);
(
x)
tremors
(
2/
2,
both
sexes);
(
xi)
tonic­
clonic
convulsions
(
2/
2,
females);
and
(
xii)
vocalization
(
1/
1,
both
sexes).
These
findings
were
not
observed
in
concurrent
controls.
The
only
statistically
significant
(
p<
0.05)
finding
noted
during
the
home
cage
portion
of
the
FOB
on
day
0
was
soiled
fur
in
the
males
(
4/
10);
this
finding
was
not
observed
in
any
control
animal.
Other
treatment­
related
observations
included
the
following:
(
i)
staggered
gait
(
2/
10,
males);
(
ii)
abnormal
mobile
posture
(
males­
1/
10,
females­
3/
10);
(
iii)
splayed
hindlimbs
(
males­
1/
10,
females­
2/
10);
(
iv)
soiled
fur
(
males
­
2/
10,
females
­
2/
10);
and
(
v)
inability
to
walk
(
1/
10,
females).
Treatment­
related
effects
noted
on
day
0
during
the
open
field
portion
of
the
FOB
included
the
following:
(
i)
abnormal
mobile
posture
(
males­
1/
10,
females­
3/
10);
(
ii)
unusual
immobile
posture
(
1/
10,
females
only);
(
iii)
staggered
gait
(
males­
2/
10,
females­
1/
10);
(
iv)
splayed
hindlimbs
(
males­
1/
10,
females­
2/
10);
(
v)
slightly
impaired
gait
(
1/
10,
both
sexes);
(
vi)
moderately
impaired
gait
(
1/
10,
males
only);
(
vii)
severely
impaired
gait
(
1/
10,
females
only);
(
viii)
dragging
hindlimbs
(
1/
10,
females
only);
(
ix)
uncoordinated
landing
(
1/
10,
both
sexes);
(
x)
lands
on
back
(
1/
10,
females
only);
(
xi)
whole
body
tremors
(
3/
10,
females
only);
(
xii)
convulsions
(
1/
10,
females
only);
and
(
xiii)
decreased
activity
(
1/
10,
both
sexes).
None
of
these
findings
were
observed
in
the
controls.
Acceptable
positive
control
data
were
provided
by
the
sponsor.

The
acute
neurotoxicity
LOAEL
is
50
mg/
kg
based
on
clinical
signs
of
toxicity
and
FOB
findings.
The
acute
neurotoxicity
NOAEL
for
this
study
is
10
mg/
kg.
The
submitted
study
is
classified
as
acceptable/
guideline
(
81­
8[
a];
870.6200)
and
satisfies
the
guideline
requirements
for
an
acute
neurotoxicity
screening
battery
in
rats.

Dose
and
Endpoint
for
Establishing
RfD:
10
mg/
kg
based
on
clinical
signs
of
neurotoxicity
and
changes
in
the
FOB
in
the
acute
neurotoxicity
study
observed
at
50
mg/
kg.

Uncertainty
Factor
(
UF):
1000
(
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variations,
and
10x
for
an
incomplete
database
for
lack
of
developmental
neurotoxicity
study).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
In
1997,
the
HIARC
selected
the
acute
dietary
endpoint
for
z­
cypermethrin
and
cypermethrin
from
a
chronic
dog
study
conducted
with
cypermethrin,
in
which
the
test
article
was
administered
in
corn
oil
via
capsules.
The
observed
effects
were
an
increased
incidence
of
loose
stools,
starting
on
the
first
week
of
the
study
at
5
mg/
kg/
day
with
a
NOAEL
of
1
mg/
kg/
day.
Since
1997,
an
acute
neurotoxicity
study
was
conducted
with
z­
cypermethrin.
The
current
HIARC
determined
that
the
new
acute
neurotoxicity
study
is
more
appropriate
because
loose
stools
in
the
dog
study
with
capsules
as
the
route
of
administration
are
of
questionable
regulatory
significance
to
the
acute
dietary
endpoint
and
because
one
can
definitively
state
that
the
observed
effects
in
the
neurotoxicity
study
are
due
to
a
single
dose.
In
addition,
the
acute
neurotoxicity
study
is
conducted
with
z­
cypermethrin,
an
enriched
isomer
of
cypermethrin
and
is
thus
anticipated
to
be
protective
of
any
effects
observed
following
acute
dietary
exposure
to
cypermethrin.

Acute
RfD
=
NOAEL:
10
mg/
kg
=
0.01
mg/
kg
UF:
1000
15
2.
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
53­
Week
chronic
toxicity
[
feeding]
­
dog
­
cypermethrin
§
870.4100
MRID
No.:
44536801
Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
44536801),
cypermethrin
(
95.7%
a.
i.)
in
corn
oil
was
administered
to
beagle
dogs
(
4/
sex/
dose)
in
the
diet
at
dose
levels
of
0,
100,
200,
600,
or
1100
ppm
(
achieved
doses
0/
0,
2.9/
3.3,
6.0/
5.7,
20.4/
18.1,
or
33.9/
38.1
mg/
kg/
day
[
M/
F],
respectively)
for
12
months.
One
600
ppm
male
died
and
two
1100
ppm
males
were
sacrificed
moribund
during
the
study
interval.

At
600
ppm,
one
male
exhibited
tremors,
irregular
gait,
and
excessive
salivation
on
two
occasions
each
prior
to
death
(
day
133).
A
second
male
exhibited
irregular
gait
and
tremors
during
weeks
39
or
44
(
1
or
2
incidents).
Females
had
reduced
body
weights
(
91­
16%,
not
statistically
significant
[
NS])
beginning
at
week
9
and
reduced
body
weight
gains
throughout
the
study
(
week
52:
0,
100,
200,
600
and
1100
ppm
=
2.0,
1.8,
2.6,
0.7
and
­
0.2
kg).

In
the
1100
ppm
group,
two
males
were
sacrificed
moribund
on
day
276
or
324.
Males
exhibited
the
following
clinical
signs:
tremors
in
four
males
during
weeks
16­
51
(
47/
276,
54/
324,
6/
368,
or
53/
367
incidents);
irregular
gait
in
four
males
during
weeks
11­
52
(
47/
276,
90/
324,
2/
368,
or
94/
367
incidents);
excessive
salivation
in
one
male
during
week
8
(
1/
368
incidents);
prostration
in
one
male
during
week
27
(
3/
368
incidents);
uncoordination,
characterized
by
difficulty
in
supporting
own
weight,
in
one
male
during
weeks
37­
40
(
6/
276
incidents);
decreased
activity
in
one
male
during
week
39
(
1/
276
incidents);
and
clonic
convulsions
in
one
male
during
week
32
(
1/
324
incidents).
Two
females
exhibited
the
following
clinical
signs:
tremors
during
weeks
33­
54
(
63/
368
or
132/
372
incidents);
irregular
gait
during
weeks
33­
54
(
93/
368
or
140/
372
incidents);
unthrifty
coat
during
weeks
23­
52
(
incidents
could
not
be
deduced
from
data
provided);
and
moderate
alopecia
during
weeks
15­
52
(
incidents
could
not
be
deduced
from
data
provided).
One
female
also
exhibited
excessive
salivation
during
week
27
(
1/
372
incidents).
Females
had
progressively
reduced
mean
body
weights
throughout
the
study
(
92­
24%,
p#
0.05
during
weeks
43­
47),
with
maximum
decreases
beginning
at
week
31
(
917­
24%)
and
reduced
mean
body
weight
gains
throughout
the
study
(
week
52
body
weight
gains
in
kg
for
0,
100,
200,
600
and
1100
ppm
=
2.0,
1.8,
2.6,
0.7
and
­
0.2).

When
compared
to
concurrent
controls,
no
treatment­
related
changes
were
noted
regarding
food
consumption,
ophthalmoscopic
abnormalities,
hematological,
clinical
chemistry,
or
urinalysis
parameters,
organ
weights,
or
gross
or
microscopic
pathological
findings.
No
neoplastic
tissue
was
observed
in
dogs
from
any
test
group.

The
LOAEL
is
600
ppm
(
equivalent
to
20.4/
18.1
mg/
kg/
day
[
M/
F]),
based
on
mortality
and
abnormal
clinical
signs
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females.
The
NOAEL
is
200
ppm
(
equivalent
to
6.0/
5.7
mg/
kg/
day
[
M/
F]).
16
This
study
is
classified
acceptable
(
§
83­
1b;
870.4100)
and
satisfies
the
guideline
requirements
for
a
chronic
toxicity
study
in
dogs.

Dose
and
Endpoint
for
Establishing
RfD:
6.0/
5.7
mg/
kg/
day
based
on
mortality
and
abnormal
clinical
signs
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females
at
20.4/
18.1
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor(
s):
1000
(
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variations,
and
10x
for
an
incomplete
database
for
lack
of
developmental
neurotoxicity
study).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
In
1997,
the
HIARC
selected
the
chronic
dietary
endpoint
for
z­
cypermethrin
from
a
chronic
dog
study
conducted
with
cypermethrin,
in
which
the
test
article
was
administered
in
corn
oil
via
capsules.
The
NOAEL
was
1
mg/
kg/
day
based
on
an
increased
incidence
of
loose
stools,
starting
on
the
first
week
of
the
study
at
5
mg/
kg/
day.
Since
1997,
a
dog
chronic
feeding
study
was
conducted
with
cypermethrin.
The
current
HIARC
determined
that
the
new
chronic
feeding
study
in
the
dog
is
more
appropriate
for
the
chronic
dietary
endpoint
because
dietary
exposure
is
more
relevant
for
the
expected
exposure
and
the
gastrointestinal
effects
in
the
capsule
dog
study
may
be
due
to
focal
exposure
(
bolus
dose
with
corn
oil).
Although
no
chronic
studies
are
available
on
z­
cypermethrin
which
is
anticipated
to
be
protective
of
any
effects
observed
following
chronic
dietary
exposure
to
cypermethrin,
the
parental
NOAEL
and
LOAEL
for
the
2­
generation
reproduction
study
conducted
with
zcypermethrin
are
7
and
27
mg/
kg/
day,
respectively,
which
are
comparable
to
the
parental
NOAEL
(
7.5
mg/
kg/
day)
and
LOAEL
(
50/
37.5
mg/
kg/
day)
observed
with
the
acceptable
rat
reproduction
study
conducted
with
cypermethrin.
The
NOAEL/
LOAEL
(
7.5/
75
mg/
kg/
day)
in
the
chronic
rat
study
conducted
with
cypermethrin
provide
additional
support
to
the
critical
study
selected.
In
addition,
the
endpoint
(
clinical
signs
of
neurotoxicity)
is
of
particular
relevance
to
pyrethroid
toxicity.

3.
Incidental
Oral
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
Acute
neurotoxicity
study
in
the
rat­
z­
cypermethrin
§
870.6200
MRID
No.:
44962201
Executive
Summary:
See
acute
dietary
endpoint
Dose
and
Endpoint
for
Risk
Assessment:
10
mg/
kg
based
on
clinical
signs
of
neurotoxicity
and
changes
in
the
FOB
observed
at
50
mg/
kg.
Chronic
RfD
=
NOAEL:
6
mg/
kg/
day
=
0.006
mg/
kg/
day
UF:
1000
17
Comments
about
Study/
Endpoint:
Although
the
endpoint
is
selected
from
a
single
dose
study,
it
is
supported
by
the
developmental
rat
study
conducted
with
z­
cypermethrin
with
a
maternal
NOAEL
of
12.5
mg/
kg/
day
based
on
ataxia,
urine­
stained
abdominal
fur,
fecal­
stained
perineal
fur,
decreased
food
consumption
and
decreased
body
weight
gain
at
25
mg/
kg/
day.
This
endpoint
is
appropriate
for
the
population
(
toddlers)
of
concern
and
is
considered
to
be
protective
of
any
effects
observed
following
short­
term
oral
exposure
to
cypermethrin.

4.
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
Subchronic
neurotoxicity
study
in
the
rat
­
z­
cypermethrin
§
870.6200
MRID
No.:
44962202
Executive
Summary:
In
this
subchronic
neurotoxicity
screening
battery,
z­
cypermethrin,
purity
of
86.0%
(
MRID
44962202),
was
administered
continuously
in
the
diet
for
13
weeks
to
10
Charles
River
Long
Evans
rats/
sex/
group
at
doses
of
0,
75,
400
or
750
ppm
(
equivalent
to
[
M/
F]
0/
0,
5.0/
5.9,
26.3/
31.5,
or
47.2/
55.6
mg/
kg/
day).
Five
animals/
sex/
group
were
perfused
for
neurohistological
examination,
and
the
control
and
high­
dose
animals
were
examined
microscopically.
Functional
observational
battery
(
FOB)
and
motor
activity
were
evaluated
during
the
pretest
interval,
and
following
weeks
4,
8,
and
13.

No
treatment­
related
deaths
occurred.
Clinical
signs,
gross
pathology
and
neuropathology
were
unaffected
by
the
test
substance;
furthermore,
no
treatment­
related
findings
were
noted
in
the
home
cage
observations
of
the
FOB
at
any
dose.
No
treatment­
related
findings
were
observed
in
the
75
ppm
group.
In
the
400
ppm
males,
statistically
significant
decreases
in
body
weights
were
observed
at
all
intervals
except
week
3
(
95­
8%),
p
#
0.05);
overall
(
weeks
0­
13)
body
weight
gains
were
also
decreased
relative
to
concurrent
controls
in
these
animals
(
915%,
p
#
0.05).
Decreased
food
consumption
was
observed
throughout
the
study,
but
statistical
significance
was
sporadic
(
96­
17%,
p
#
0.01
or
0.05).
During
the
open
field
portion
of
the
FOB,
increased
landing
foot
splay
was
observed
at
week
13
(
833%,
p
#
0.01).
In
addition,
mean
motor
activity
was
decreased
(
p
#
0.01
or
0.05)
at
weeks
8
(
936%)
and
13
(
951%).
At
750
ppm,
one
female
was
sacrificed
in
extremis
on
day
51
following
mechanical
injury;
this
death
was
considered
not
to
be
treatmentrelated
Body
weights
were
decreased
throughout
the
study
(
912­
17%,
p
#
0.01)
in
the
males.
In
the
females,
body
weights
were
decreased
sporadically
for
the
first
9
weeks
of
the
study,
and
continually
at
weeks
10­
13
(
95­
10%,
p
#
0.05
or
0.01).
Overall
(
weeks
0­
13)
body
weight
gains
were
decreased
(
p
#
0.01)
in
both
sexes
(
928­
31%)
as
was
food
consumption
(
98­
29%).
During
the
open
field
portion
of
the
FOB,
increased
landing
foot
splay
was
observed
in
the
males
at
week
13
(
841%,
p
#
0.01).
Mean
motor
activity
was
decreased
(
p
#
0.05
or
0.01)
in
the
males
at
weeks
8
(
925%)
and
13
(
942%).

The
LOAEL
for
this
study
is
400
ppm
for
males
(
equivalent
to
26.3
mg/
kg/
day),
based
on
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption;
and
750
ppm
for
females
(
equivalent
to
55.6
mg/
kg/
day)
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
The
NOAEL
for
this
study
is
75
ppm
for
males
(
equivalent
to
5.0
mg/
kg/
day)
and
400
ppm
18
for
females
(
equivalent
to
31.5
mg/
kg/
day).
The
submitted
study
is
classified
as
acceptable/
guideline
(
§
82­
7[
a];
870.6200)
and
satisfies
the
guideline
requirements
for
a
subchronic
neurotoxicity
screening
battery
in
rats.

Dose
and
Endpoint
for
Risk
Assessment:
5.0
mg/
kg/
day
based
on
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption
observed
in
males
at
26.3
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
subchronic
neurotoxicity
study
is
considered
to
be
appropriate
for
the
intermediate­
term
incidental
exposure
endpoint
and
the
population
(
toddlers)
of
concern
because
it
is
of
an
appropriate
route
of
administration
and
duration
of
exposure.
See
the
comments
under
the
chronic
dietary
endpoint
as
to
why
the
chronic
capsule
dog
study
was
not
selected
for
this
endpoint.
In
addition,
it
is
recognized
that
the
NOAEL
of
5.0
mg/
kg/
day
selected
for
this
endpoint
is
less
than
the
NOAEL
of
6.0
mg/
kg/
day
selected
for
the
chronic
dietary
endpoint.
This
is
due
to
dose
selection
and
spacing.

5.
Dermal
Absorption
Dermal
Absorption
Factor:
2.5%

There
is
no
series
85­
2
dermal
penetration/
absorption
study
available.
In
1997,
the
HIARC
estimated
a
dermal
absorption
rate
of
25%
based
on
the
6­
45%
dermal
absorption
observed
with
the
structurally
related
pyrethroids
permethrin
(
22­
45%),
deltamethrin
(
15%)
and
tralomethrin
(
6­
25%).
A
range
of
dermal
absorption
factors
was
presented
for
permethrin
and
tralomethrin,
but
not
for
deltamethrin
because
the
studies
indicated
higher
absorption
at
lower
exposure
doses.
Since
no
study
was
available
with
either
cypermethrin
or
z­
cypermethrin,
a
value
of
25%
was
assumed.
In
the
case
of
z­
cypermethrin,
the
current
HIARC
estimated
a
dermal
absorption
value
by
comparing
the
developmental
rat
study
with
the
21­
day
dermal
study
in
the
rat
and
determined
that
the
dermal
absorption
rate
would
probably
be
an
order
of
magnitude
less.
Using
a
comparison
of
the
maternal
LOAEL
of
25
mg/
kg/
day
from
the
developmental
study
in
the
rat
and
the
NOAEL
(
highest
dose
tested)
of
1000
mg/
kg/
day
from
the
21­
day
dermal
study
in
the
rat,
dermal
absorption
would
be
estimated
to
be
less
than
2.5%.
Since
there
was
no
common
endpoint
because
no
effects
were
observed
in
the
21­
day
dermal
study
in
the
rat,
this
is
considered
to
be
a
worst­
case
estimate
(
i.
e.
the
dose
level
of
1000
mg/
kg/
day
was
considered
to
be
the
LOAEL).

6.
Dermal
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
None
MRID
No.:
None
Executive
Summary:
None
Dose
and
Endpoint
for
Risk
Assessment:
Not
Applicable
19
Comments
about
Study/
Endpoint:
No
hazard
has
been
identified
to
support
quantitation
of
risk.
No
systemic
effects
were
observed
in
the
21­
day
dermal
study
in
the
rat
at
dose
levels
up
to
1000
mg/
kg/
day.
In
addition,
no
developmental
effects
were
observed
in
any
of
the
available
developmental
studies.

For
the
dermal
risk
assessments,
HIARC
determined
the
following:

The
observed
systemic
effects
in
the
21­
day
dermal
study
conducted
with
cypermethrin
in
rabbits
(
focal
necrosis
of
the
liver,
decrease
in
testicular
weights
and
body
weight
loss
(
females))
were
noted
only
in
animals
with
abraded
skin.
No
effects
were
observed
in
animals
with
nonabraded
skin
up
to
the
highest
dose
tested
(
200
mg/
kg/
day).
These
effects
are
discounted
because
1)
the
method
does
not
simulate
actual
exposure,
2)
the
test
conditions
are
compromised,
3)
there
would
be
physiological
differences
between
the
abraded
and
nonabraded
animals
and
4)
the
rat
is
the
more
sensitive
species
for
z­
cypermethrin
in
the
oral
studies
(
comparison
of
maternal
toxicity
in
the
developmental
studies).
However,
the
dermal
study
in
the
rat
was
not
selected
because
no
systemic
toxicity
was
seen
at
the
limit
dose.

7.
Dermal
Exposure:
Intermediate­
Term
(
1­
6
months)

Study
Selected:
None
MRID
No.:
None
Executive
Summary:
None
Dose/
Endpoint
for
Risk
Assessment:
Not
applicable
Comments
about
Study/
Endpoint:
No
hazard
has
been
identified
to
support
quantitation
of
risk.

8.
Dermal
Exposure:
Long­
Term
(>
6
months)

Selected:
53­
Week
chronic
toxicity
[
feeding]
­
dog
­
cypermethrin
§
870.4100
MRID
No.:
44536801
Executive
Summary:
See
chronic
dietary
endpoint
Dose
and
Endpoint
for
Risk
Assessment:
6.0/
5.7
mg/
kg/
day
based
on
mortality
and
abnormal
clinical
signs
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females.
The
estimated
percent
dermal
absorption
value
will
be
2.5%
(
see
dermal
absorption
section).

Comments
about
Study/
Endpoint:
See
comments
under
chronic
dietary
endpoint.

9.
Inhalation
Exposure:
All
Durations
20
Study
Selected:
21­
Day
Inhalation
Study
in
the
Rat
(
Cypermethrin)
§
870.3465
MRID
No.:
43507101
Executive
Summary:
In
a
21­
day
subchronic
inhalation
toxicity
study
(
MRID
43507101)
cypermethrin
(
87.1%
purity,
1:
1
cis:
trans)
was
administered
to
five
Alpk:
Apfsd,
Wistar
derived
rats/
sex/
dose
group
by
nose­
only
exposure
at
concentrations
of
0,
0.01,
0.05
or
0.25
mg/
L
for
six
hours
per
day,
5
days
per
week
for
a
total
of
15
exposures.
The
analytical
concentrations
were
0,
0.0096,
0.0463,
0.229
mg/
L/
day.
Additional
satellite
groups
of
5/
sex
were
included
for
recovery
assessment
and
analysis
of
cypermethrin
in
the
brain.
The
MMAD
was
determined
to
be
2.63
to
2.86
µ
M.
At
0.05
mg/
L/
day
there
was
slight
but
consistently
statistically
significant
(<
5%
body,
p<
0.05)
body
weight
loss
also
reflected
as
a
16%
decrease
in
body
weight
gain.
All
males
and
4
females
had
occasional
salivation.
At
0.25
mg/
L,
clinical
signs
were
evident
from
day
10
on
(
particularly
including
decreased
activity,
salivation,
lacrimation,
tail
erection,
head
and/
or
paw
flicking
and
tip
toe
gait
and
others,
see
results).
Changes
in
RBC
parameters
were
slight
and
equivocal.
Cypermethrin
was
not
detected
in
the
brain
at
day
10
or
22.
The
LOAEL
is
0.05
mg/
L/
day
based
mainly
on
body
weight
decrease
and
salivation.
The
NOAEL
is
0.01
mg/
L/
day.
This
study
is
classified
as
ACCEPTABLE.

Dose/
Endpoint
for
Risk
Assessment:
0.01
mg/
L
(
2.7
mg/
kg/
day)
based
on
decreases
in
bodyweight
and
salivation
at
0.05
mg/
L/
day.

Comments
about
Study/
Endpoint:
This
is
an
appropriate
study
and
route
of
exposure
for
this
endpoint.
The
target
MOE's
are
100
for
short­
and
intermediate­
term
exposure
and
300
for
longterm
exposure.
Based
on
the
inhalation
study,
it
appears
that
the
most
sensitive
route
of
administration
is
inhalation.
The
additional
3x
for
long­
term
exposure
is
for
the
lack
of
an
alternative
study
on
which
to
make
an
endpoint
selection.
If
one
uses
an
oral
study
and
conducts
a
route­
to­
route
estimation,
the
result
would
be
a
less
protective
endpoint.

10.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

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

Occupational
(
Worker)
Exposure
Dermal
NA
NA
100
Inhalation
100
100
300
21
Residential
(
Non­
Dietary)
Exposure
Oral
1000
1000
1000
Dermal
NA
NA
1000
Inhalation
1000
1000
1000
For
Occupational
and
Residential
exposure:
short­
term
(
1
day
to
1
month)
and
intermediate­
term
(
1
to
6
months)
dermal
quantitative
risk
assessments
are
not
required
since
no
systemic
effects
were
observed
at
1000
and
there
are
no
developmental
concern.
MOE
is
not
applicable
(
NA)

For
Occupational
exposure:
short­
term
(
1
day
to
1
month)
and
intermediate­
term
(
1
to
6
months)
inhalation
risk
assessments,
and
for
long­
term
(
longer
than
6
months)
dermal
exposure
risk
assessments,
a
MOE
of
100
is
required.
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation).

For
occupational
exposure:
long­
term
(
longer
than
6
months)
inhalation
risk
assessment,
a
MOE
of
300
is
required.
This
requirement
is
due
to
lack
of
an
alternative
study
on
which
to
make
an
endpoint
selection:
inhalation
appears
to
be
the
most
sensitive
endpoint
and
using
the
existing
oral
studies
with
a
route­
to­
route
extrapolation
would
result
in
a
less
protective
endpoint.
For
Residential
incidental
oral
exposure:
short­
term
(
1
day
to
1
month)
and
intermediateterm
(
1
to
6
months)
risk
assessments,
a
MOE
of
1000
is
required.
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)
and
10X
for
an
incomplete
database
(
lack
of
developmental
neurotoxicity
study).

For
Residential
exposure:
short­
term
(
1
day
to
1
month),
intermediate­
term
(
1
to
6
months)
inhalation
risk
assessments
and
long­
term
(
longer
than
6
months)
dermal
and
inhalation
risk
assessments,
a
MOE
of
1000
is
required.
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)
and
10X
for
an
incomplete
database
(
lack
of
developmental
neurotoxicity
study).

11.
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows.
For
the
acute
and
chronic
dietary
aggregate
risks,
the
recommendation
is
food
plus
water.
For
short­
and
intermediate­
term
aggregate
risk,
the
recommendation
is
food
plus
water,
incidental
oral,
and
inhalation
(
dermal
is
not
required
for
these
scenarios).
For
long
term
aggregate
risk,
the
recommendation
is
food
plus
water,
dermal
and
inhalation
exposure.
The
ARI
method
needs
to
be
22
employed
because
the
target
MOEs
are
different
for
intermediate
dermal
and
inhalation
exposure
scenarios.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
Nos.
00112910
and
9202741
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
study
(
MRID
00112910),
cypermethrin
(
88­
93%
purity,
55%
cis
and
45%
trans)
was
administered
to
5
groups
of
52/
sex
Wistar
derived
Alderley
Park
SPF
strain
rats
at
dose
levels
of
control­
1,
control­
2,
20,
150
or
1500
ppm
(
corresponding
to
0,
0,
1,
7.5
or
75
mg/
kg/
day)
for
2
years.
Satellite
groups
of
12/
sex
were
sacrificed
after
one
year
of
dosing.
Definite
signs
of
toxicity
were
evident
at
75
mg/
kg/
day
and
these
consisted
of
body
weight
gain
decrease
throughout
the
study
(
i.
e.
about
10%
for
males
and
13%
for
females
at
week
13),
slight
effects
on
several
hematological
parameters
(
both
red
and
white
cells),
slight
effects
on
clinical
chemistry
parameters
(
decreased
cholesterol
and
triglycerides
and
glucose
and
increased
urea).
Decreases
in
urine
volume,
pH
and
an
increase
in
specific
gravity
were
noted.
Liver
weight
was
increased
in
females.
The
LOAEL
is
1500
ppm
(
75
mg/
kg/
day)
based
on
decreases
in
body
weight
gains.
The
NOAEL
is
150
ppm
(
7.5
mg/
kg/
day).
This
chronic
toxicity/
carcinogenicity
study
is
classified
ACCEPTABLE
and
satisfies
the
guideline
requirement
for
a
chronic
oral
feeding/
carcinogenicity
study
in
rats.

Discussion
of
Tumor
Data:
Cypermethrin
was
not
considered
to
be
carcinogenic
in
this
study.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
were
adequate
for
testing
of
carcinogenicity.
Body
weight
gains
were
reduced
10­
13%
(
both
sexes).

2.
Carcinogenicity
Study
in
Mice
MRID
No.
00112911
and
92027038
Executive
Summary:
In
a
carcinogenicity
study
(
MRID
00112911
and
92027038),
cypermethrin
(
53­
54%
cis
and
46­
47%
trans)
was
administered
to
groups
of
70/
sex
Swiss
derived
Alderley
Park
strain
SPF
mice
at
dose
levels
of
control­
1,
control­
2,
100,
400
and
1600
ppm
(
corresponding
to
0,
0,
14,
57
or
229
mg/
kg/
day)
for
97
weeks
for
males
and
101
weeks
for
females.
Liver
weight
was
increased
at
57
mg/
kg/
day
(
20%
absolute
weight)
and
above
in
males
and
for
females
at
the
high
dose
only
(
15%
for
relative
weight)
at
the
interim
sacrifice
but
not
at
the
terminal.
Other
systemic
effects
noted
at
229
mg/
kg/
day
included
reduction
in
RBC
parameters
(
hemoglobin,
hematocrit
and
RBC
count
in
males,
mean
cell
volume
and
hemoglobin)
and
platelet
counts
(
for
males
at
interim
but
not
terminal
sacrifice)
and
neutrophils
and
body
weight
gain
(
i.
e.
about
9%
at
week
6
for
males
and
22%
for
females
at
week
11).
The
LOAEL
is
57
mg/
kg/
day
based
on
increased
liver
weight.
The
NOAEL
is
14
mg/
kg/
day.
This
study
was
determined
to
be
positive
for
induction
of
benign
lung
adenomas.
This
carcinogenicity
study
is
classified
23
ACCEPTABLE
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
(
83­
2)
in
mice.

Discussion
of
Tumor
Data:
Cypermethrin
produced
a
statistically
significant
increase
in
lung
adenomas,
and
in
adenomas
plus
carcinomas
combined,
in
female
mice
at
the
highest
dose
level
(
1600
ppm,
229
mg/
kg/
day)
tested.
There
were
also
significant
positive
dose­
related
trends
for
these
tumor
combinations
in
female
mice.
No
significant
increases
in
carcinomas
were
observed.
The
Cancer
Peer
Review
Committee
(
1988)
noted
the
following
additional
information
in
regard
to
the
increased
lung
tumorigenic
response
in
female
mice:
(
a)
most
of
the
adenomas
were
observed
at
terminal
sacrifice
and
there
was
no
decrease
in
latency
for
the
time­
to­
tumor
occurrence
(
tumors
were
first
seen
at
week
53
in
the
control
females
and
at
weeks
52
to
53
in
the
high
dose
females);
(
b)
the
incidences
of
lung
tumors
produced
at
the
highest
dose
level
of
cypermethrin
exceeded
the
historical
control
incidences
for
lung
adenomas
(
mean
=
9.6%,
range
=
0
to
15.7),
and
adenomas/
carcinomas
combined
(
mean
11.3%,
range
=
0
to
15.7%),
in
several
contemporary
studies
conducted
in
female
Swiss
Alderley
Park
mice
at
ICI
Laboratories
between
1977
to
1985;
no
compound­
related
nonneoplastic
changes
were
observed
in
the
lungs
of
treated
female
mice;
(
d)
alveolar
adenoma
is
a
relatively
common
tumor
in
mice;
(
e)
there
were
more
malignant
lung
tumors
in
the
control
female
mice
than
there
were
in
the
treated
female
mice
(
i.
e.
2
carcinomas
occurred
in
controls
vs.
1
carcinoma
in
the
treated
groups);
and
(
f)
the
highest
dose
level
of
cypermethrin
tested
(
i.
e.
1600
ppm)
was
considered,
based
on
weight
gain
decrements,
to
approximate
(
but
not
to
exceed)
a
MTD
level
in
both
male
and
female
mice.

Adequacy
of
the
Dose
Levels
Tested:
Adequacy
of
dosing
for
carcinogenicity
is
based
upon
decreases
in
body
weight
gains
typically
of
9%
in
males
and
12%
in
females.

Classification
of
Carcinogenic
Potential:
The
Committee
classified
cypermethrin
as
a
category
C
oncogen
(
possible
human
carcinogen).
The
evidence
(
common
tumor,
one
species
(
mice),
one
sex
(
female),
no
increase
in
the
proportion
of
malignant
tumors
or
decrease
in
the
time­
to­
tumor
occurrence,
and
lack
of
mutagenic
activity)
was
not
considered
strong
enough
to
warrant
a
quantitative
estimation
of
human
risk
(
Cancer
Peer
Review
Committee,
1988).

IV.
MUTAGENICITY
Z­
cypermethrin
is
considered
a
possible
weak
mutagen
under
the
conditions
of
the
Ames
assay.
There
was
no
evidence
of
mutagenicity
in
any
of
the
other
assays.
Cypermethrin
tested
negatively
in
all
of
the
assays
available
to
the
Agency.

Z­
Cypermethrin
SALMONELLA/
MAMMALIAN
ACTIVATION
GENE
MUTATION
ASSAY
24
Doses:
0,
100,
333,
1000,
3333,
5000
and
10000
µ
g/
plate.
FMC
56701
gave
a
very
weak
positive
response
(
2­
fold
increase
in
revertants/
plate)
in
S.
typhimurium
strain
TA100
at
10000
µ
g/
plate
without
S­
9
activation
in
two
separate
experiments.
Doses
of
3333
and
5000
µ
g/
plate
gave
1.5
and
1.6­
fold
increases
in
revertants/
plate,
respectively.
Strains
TA98,
TA1535,
TA1537
and
TA1538
treated
in
the
presence
and
absence
of
mammalian
S­
9
activation
were
not
affected.
FMC
56701
is,
therefore,
considered
a
possible
weak
mutagen
under
the
conditions
of
this
assay.
(
MRID
41968205)

IN
VITRO
MAMMALIAN
GENE
MUTATION
ASSAY
Doses:
0,
1,
10,
25,
50,
100,
400,
700
and
1000
µ
g/
ml
in
the
absence
and
presence
of
S­
9
activation.
Doses
were
administered
to
Chinese
hamster
ovary
cells
(
CHO­
K1­
BH
4
,
subclone
D1).
No
evidence
of
increased
forward
mutation
rate
at
the
HGPRT
locus
was
observed
at
any
dose
tested
under
the
conditions
of
these
assays.
The
solubility
limit
of
the
test
compound
in
culture
media
was
about
100
µ
g/
ml.
(
MRID
41968206)

MOUSE
LYMPHOMA
IN
VITRO
ASSAY
Doses:
12.5,
25,
50,
100
and
150
µ
g/
ml
in
vitro
with/
without
metabolic
activation.
The
study
demonstrates
that
cypermethrin
is
not
mutagenic
in
the
mouse
lymphoma
assay
(
L5178Y
cell
line)
at
the
above
doses
with
or
without
metabolic
activation.
(
MRID
41551101)

CHROMOSOME
ABERRATIONS
IN
VIVO
IN
RAT
BONE
MARROW
Doses:
0,
31.25,
62.5
and
125
mg/
kg
in
corn
oil.
No
evidence
of
structural
chromosomal
aberrations
was
demonstrated
at
either
6,
18
or
30
hours
post
dosing.
(
MRID
42758601)

UNSCHEDULED
DNA
SYNTHESIS
ASSAY
IN
MALE
RAT
PRIMARY
HEPATOCYTE
CELLS
Doses:
14,
45,
140,
450,
1400
and
4500
µ
g/
ml.
No
unscheduled
DNA
synthesis
was
observed
at
any
dose
level
up
to
4500
µ
g/
ml
in
male
rat
(
Fischer
344)
liver
primary
hepatocyte
cultures
under
the
conditions
of
this
assay.
Minimal
cytotoxicity
was
observed
at
the
highest
doses.
Incomplete
solubility
of
the
test
compound
in
culture
media
was
observed,
particularly
at
higher
doses.
(
MRID
41968207)

Cypermethrin
SALMONELLA/
MAMMALIAN
ACTIVATION
GENE
MUTATION
ASSAY
Doses:
4,
20,
100,
500
or
2500
ug/
plate.
No
evidence
of
bacterial
mutations
in
S.
typhimurium
strains
TA­
1535,
TA­
1537,
TA­
1538,
TA­
98
or
TA­
100
with
and
without
metabolic
activation
(
S­
9)
at
dose
levels
of
4,
20,
100,
500
or
2500
ug/
plate.
Strains
of
yeast
(
S.
cerevisiae)
also
assessed
and
negative.
(
MRIDs
00090037,
92027042,
and
92027062;
00090036
and
00126834)

IN
VITRO
MAMMALIAN
GENE
MUTATION
ASSAY
In
an
in
vitro
gene
mutation
assay,
Chinese
hamster
ovary
cells
(
CHO­
K1­
BH
4
subclone
D1)
were
25
exposed
to
dose
levels
of
0,
1,
10,
25,
50
100,
400,
700
or
1000
ug/
ml
in
the
presence
or
absence
of
S9
activation
medium.
No
evidence
of
increased
forward
mutation
rate
at
the
HGPRT
locus
was
observed
at
any
dose
tested
under
the
conditions
of
these
assays.
The
solubility
limit
of
cypermethrin­
s
in
the
culture
media
was
about
100
ug/
ml.
(
MRID
41968206)

CHROMOSOME
ABERRATIONS
IN
VIVO
IN
CHINESE
HAMSTER
BONE
MARROW
There
was
no
evidence
of
increased
chromosome
aberrations
in
chinese
hamster
bone
marrow
cells
following
gavage
dosing
with
0,
20
or
40
mg/
kg.
(
MRID
00090038
and
92027043)

DOMINANT
LETHAL
ASSAY
IN
MALE
MICE
There
was
no
evidence
of
dominant
lethal
activity
in
CD­
1
strain
mice
at
dose
levels
of
control,
2.5,
5,
7.5
or
10
mg/
kg/
day
for
five
consecutive
days.
An
initial
observation
of
a
possible
effect
in
a
preliminary
experiment
with
animals
dosed
at
2.5
or
5
mg/
kg
for
5
days
was
not
repeated
at
higher
doses.
(
MRID
00090039)

UNSCHEDULED
DNA
SYNTHESIS
­
RAT
PRIMARY
HEPATOCYTES
IN
VIVO
No
evidence
of
induction
of
unscheduled
DNA
synthesis
in
vivo
at
dose
levels
of
100
and
200
mg/
kg
by
gavage
in
corn
oil)
in
Alpk:
APfSD
strain
rats
(
males
only)
assessed
4
and
12
hours
post
dosing.
The
200
mg/
kg
dose
was
considered
near
the
MTD
and
displayed
toxic
behavioral
reactions.
(
MRID
41599801)

V.
HAZARD
CHARACTERIZATION
With
the
exception
of
some
of
the
acute
toxicity
studies
and
the
developmental
neurotoxicity
study,
the
toxicology
database
for
z­
cypermethrin,
when
bridged
with
cypermethrin,
is
complete
and
there
are
no
data
gaps.
The
scientific
quality
is
relatively
high
and
the
toxicity
profile
of
z­
cypermethrin
can
be
characterized
for
all
effects,
including
potential
developmental,
reproductive
and
neurotoxic
effects.
The
data
provided
no
indication
of
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
the
cypermethrins.
At
the
present
time,
there
does
not
appear
to
be
increased
susceptibility
to
the
synthetic
pyrethroids
as
a
whole.
Exceptions
include
cyfluthrin
and
fenvalerate
and
esfenvalerate
(
at
dose
levels
approaching
the
LD
50
).

Z­
Cypermethrin
is
moderately
acutely
toxic
via
the
oral
route
(
Category
II).
No
other
acute
toxicity
studies
are
available
on
technical
z­
cypermethrin.
Acute
toxicity
studies
conducted
with
cypermethrin
indicate
that
it
is
also
Category
II
via
the
oral
route;
however,
it
is
not
very
toxic
via
the
dermal
and
inhalation
routes
(
Categories
III
and
IV).
It
is
mildly
irritating
to
the
eyes
and
skin
and
is
a
dermal
sensitizer.

The
database
on
z­
cypermethrin
(
including
cypermethrin)
indicates
one
major
target
for
this
chemical:
the
neuromuscular
system.
The
liver
also
appears
to
be
affected
(
rabbits
(
focal
necrosis,
abraded
animals
only)
and
mice
(
may
only
be
an
adaptive
response)).
The
neuromuscular
effects
(
tremors,
gait
abnormalies
and
26
decreases
in
activity)
occur
mainly
in
oral
studies
in
the
dog
and
the
rat,
but
similar
effects
were
also
observed
in
an
inhalation
study
conducted
with
cypermethrin.
There
appears
to
be
a
dose­
response
for
these
effects.
In
the
subchronic
feeding
studies,
the
rat
appears
to
be
the
most
sensitive
species;
however,
in
the
chronic
feeding
studies,
the
dog
appears
to
be
more
sensitive
to
the
neuromuscular
effects.
In
general,
neither
sex
is
more
sensitive;
however,
in
both
the
rat
90­
day
neurotoxicity
study
and
the
1­
year
feeding
study
in
the
dog,
the
male
appears
to
be
more
sensitive
to
these
effects.
As
with
other
pyrethroids,
the
tremors
do
not
appear
to
increase
in
severity
with
increasing
duration
of
exposure.
They
appear
to
be
more
of
a
transient
acute
effect
as
opposed
to
an
effect
which
appears
after
an
accumulated
dose.

No
dermal
penetration/
absorption
studies
are
available
for
z­
cypermethrin.
A
dermal
absorption
value
of
2.5%
may
be
estimated
by
comparing
the
maternal
LOAEL
of
25
mg/
kg/
day
from
the
developmental
study
in
the
rat
and
the
NOAEL
(
highest
dose
tested)
of
1000
mg/
kg/
day
from
the
21­
day
dermal
study
in
the
rat.
Since
there
was
no
common
endpoint
because
no
effects
were
observed
in
the
21­
day
dermal
study
in
the
rat,
this
is
considered
to
be
a
worst­
case
estimate.

The
data
demonstrated
no
indication
of
increased
sensitivity
or
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
either
z­
cypermethrin
or
cypermethrin.
In
the
prenatal
developmental
toxicity
studies
in
rats
and
rabbits
with
both
cypermethrin
and
z­
cypermethrin,
there
was
no
evidence
of
developmental
toxicity
at
the
highest
dose
tested.
In
the
multi­
generation
reproduction
studies
in
rats
conducted
with
both
of
these
chemicals,
offspring
toxicity
was
observed
either
at
the
same
treatment
level
which
resulted
in
parental
systemic
toxicity
or
at
higher
dose
levels
than
the
dose
levels
which
induced
parental
toxicity.

There
is
no
evidence
that
z­
cypermethrin
induces
any
endocrine
disruption.

Cypermethrin
has
been
classified
as
a
Category
C,
possible
human
carcinogen,
based
on
an
increased
incidence
of
lung
adenomas
and
adenomas
plus
carcinomas
combined
in
female
mice.
The
evidence
was
not
considered
strong
enough
to
warrant
a
quantitative
estimation
of
human
risk.
Cypermethrin
has
not
been
classified
under
the
more
current,
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
April
10,
1996).
Z­
Cypermethin
is
considered
a
weak
mutagen
under
the
conditions
of
the
Salmonella
typhimurium
(
Ames)
assay;
however,
cypermethrin
was
negative
in
all
mutagenicity
studies
available
to
the
Agency.
Structure­
activity
comparisons
with
the
other
pyrethroids
reveal
indications
of
lung
tumors
in
mice
with
3
other
pyrethroids.

Cypermethrin
and
z­
cypermethrin
are
type
II
pyrethroids
(
i.
e.
it
has
a
cyano
group
at
the
"
carbon
position
of
the
alcohol
moiety
and
it
is
more
effective
when
the
ambient
temperature
is
raised).
Ware
states,
"
pyrethroids
initially
stimulate
nerve
cells
to
produce
repetitive
discharges
and
eventually
cause
paralysis.
Such
effects
are
caused
by
their
action
on
the
sodium
channel,
a
tiny
hole
through
which
sodium
ions
are
permitted
to
enter
the
axon
to
cause
excitation.
These
effects
are
produced
in
insect
nerve
cord,
which
contains
ganglia
and
synapses,
as
well
as
in
giant
nerve
fiber
axons.
The
stimulating
effect
of
pyrethroids
is
much
more
pronounced
than
that
of
DDT.
The
exact
sites
of
action
of
pyrethroids
at
synapses
are
not
known.
It
is
probable
that
the
toxic
action
of
pyrethroids
is
primarily
due
to
its
blocking
action
on
the
nerve
axon
since
this
action
shows
a
negative
temperature
coefficient.
But
because
the
cockroach
ganglion
is
affected
by
pyrethroid
concentrations
many
fold
less
than
are
required
to
block
conduction
in
giant
fibers,
27
its
also
seems
likely
that
pyrethroids
act
on
some
aspect
of
synaptic
function.
The
fast
knockdown
of
flying
insects
could
be
the
result
of
rapid
muscular
paralysis,
suggesting
that
the
ganglia
of
the
insect
central
nervous
system
are
affected."

VI.
DATA
GAPS
/
REQUIREMENTS
z­
Cypermethrin
Acute
dermal
toxicity
study
(
81­
2,
870.1200)
Acute
inhalation
toxicity
study
(
81­
3,
870.1300)
Primary
eye
irritation
study
(
81­
4,
870.2400)
Primary
dermal
irritation
study
(
81­
5,
870.2500)
Dermal
sensitization
study
(
81­
6,
870.2600)
Developmental
neurotoxicity
study
(
83­
6,
870.6300)

Cypermethrin
None
28
VII.
ACUTE
TOXICITY
Acute
Toxicity
of
z­
Cypermethrin
and
Cypermethrin
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1000
Acute
Oral
­
z­
Cypermethrin
41776115
LD50
(
M):
134.4
mg/
kg
(
F):
86.0
mg/
kg
Clinical
signs
of
neurotoxicity
observed.
II
870.1000
Acute
Oral
­
Cypermethrin
00056800
LD50
(
M):
247
mg/
kg
(
F):
309
mg/
kg
females
Deaths:
$
150
mg/
kg,
usually
in
first
day.
Clinical
signs
of
neurotoxicity,
gait
abnormalities;
some
persisting
to
14
days.
II
870.1100
Acute
Dermal
Rats
­
Cypermethrin
Rabbits
­
Cypermethrin
00056800
00056800
LD50
>
4920
mg/
kg/
day.
Clinical
signs
of
neurotoxicity.

Abraded
skin:
LD50
>
2460
mg/
kg.
Lacrimation,
discharge
from
the
eye
and
"
nervous
and
shaking".
III
III
870.1200
Acute
Inhalation
­
Cypermethrin
42395702
LC50:
%
(
not
calculated
but
higher
than
&)
LC50:
&
2.5
(
1.6­
3.4)
mg/
L.
Clinical
signs
of
neurotoxicity.
IV
870.2400
Primary
Eye
Irritation
­
Cypermethrin
00056800
Slight
redness
of
conjunctivae,
chemosis
&
discharge.
Persisted
to
day
7.
III
870.2500
Primary
Skin
Irritation
­
Cypermethrin
00056800
Slight
to
mild
erythema
on
intact
&
abraded
skin.
Regressed
by
48
hours.
Primary
Irritation
Index:
0.71
IV
870.2600
Dermal
Sensitization
­
Cypermethrin
00056800
40377701
Not
a
sensitizer
in
Buehler
assay.
Moderate
sensitizer
in
Magnusson
Kligman
Maximization
method.
N/
A
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
29
Summary
of
Toxicology
Endpoint
Selection
for
Cypermethrin
and
Zeta­
cypermethrin
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
=
10
mg
ai/
kg
UF
=
1000
Acute
RfD
=
0.01
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.01
mg/
kg/
day
Acute
mammalian
neurotoxicity
study
Clinical
signs
of
neurotoxicity
and
changes
in
the
FOB
at
the
LOAEL
of
50
mg/
kg.

Chronic
Dietary
(
All
populations)
NOAEL
=
6
mg
ai/
kg/
day
UF
=
1000
Chronic
RfD
=
0.006
mg/
kg/
day
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.006
mg/
kg/
day
Chronic
feeding
study
­
dog
Clinical
signs
of
neurotoxicity
and
mortality
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females
at
the
LOAEL
of
20.4
mg/
kg/
day.

Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
10
mg
ai/
kg/
day
Residential
MOE
=
1000
Occupational
=
NA
Acute
mammalian
neurotoxicity
study
Clinical
signs
of
neurotoxicity
and
changes
in
the
FOB
at
the
LOAEL
of
50
mg/
kg.

Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL=
5
mg
ai/
kg/
day
Residential
MOE
=
1000
Occupational
=
NA
Subchronic
mammalian
neurotoxicity
study
Decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption
at
the
LOAEL
of
26.3
mg/
kg/
day.

Short­
Term
Dermal
(
1­
30
days)
None
Residential
MOE
=
NA
Occupational
MOE
=
NA
None
­
No
systemic
effects
observed
at
1000.
No
developmental
concern.
No
hazard
identified
to
support
a
quantitation
of
risk.

Intermediate­
Term
Dermal
(
1­
6
months)
None
Residential
MOE
=
NA
Occupational
MOE
=
NA
None
­
No
systemic
effects
observed
at
1000.
No
developmental
concern.
No
hazard
identified
to
support
a
quantitation
of
risk.

Long­
Term
Dermal
(>
6
months)
Oral
NOAEL=
6
mg
ai/
kg/
day
with
2.5%
dermal
absorption
factor.
Residential
MOE
=
1000
Occupational
MOE
=
100
Chronic
feeding
study
­
dog
Clinical
signs
of
neurotoxicity
and
mortality
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females
at
the
LOAEL
of
20.4
mg/
kg/
day.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
30
Short­
Term
Inhalation
(
1­
30
days)
Inhalation
NOAEL=
0.01
mg/
L
Residential
MOE
=
1000
Occupational
MOE
=
100
21­
day
inhalation
study
with
cypermethrin
Decrease
in
bodyweight
gain,
salivation.

Intermediate­
Term
Inhalation
(
1­
6
months)
Inhalation
NOAEL=
0.01
mg/
L
Residential
MOE
=
1000
Occupational
MOE
=
100
21­
day
inhalation
study
with
cypermethrin
Decrease
in
bodyweight
gain,
salivation.

Long­
Term
Inhalation
(>
6
months)
Inhalation
NOAEL=
0.01
mg/
L
Residential
MOE
=
1000
Occupational
MOE
=
300
21­
day
inhalation
study
with
cypermethrin
Decrease
in
bodyweight
gain,
salivation.

Cancer
(
oral,
dermal,
inhalation)
Classification:
Category
C
(
possible
human
carcinogen)
No
quantitation
required.

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.
