UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
07/
11/
2003
TXR
No.
0052016
MEMORANDUM
DATE:
07/
11/
2003
SUBJECT:
ID
No.
109702.
Cypermethrin:
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
DP
Barcode:
D289429
Case#:
819433
Submission
#:
S632879
PC
Code:
109702
FROM:
Pamela
M.
Hurley,
Toxicologist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

TO:
William
Donovan,
Risk
Assessor
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

THRU:
Catherine
Eiden
Branch
Senior
Scientist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

Conclusions:

The
existing
toxicity
database
for
cypermethrin
supports
reregistration.
With
the
exception
of
the
developmental
neurotoxicity
study,
the
toxicology
database
for
cypermethrin
is
complete
and
there
are
no
data
gaps.
The
scientific
quality
is
relatively
high
and
the
toxicity
profile
of
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.

Action
Requested:

The
Health
Effects
Division
(
HED)
has
been
requested
to
prepare
the
disciplinary
toxicology
chapter
for
the
Reregistration
Eligibility
Decision
on
cypermethrin.
Results/
Discussion:
2
In
mammals,
cypermethrin
generally
affects
the
neuromuscular
system.
The
neuromuscular
effects
(
tremors,
gait
abnormalies
and
decreases
in
activity)
are
observed
across
species
(
dog
and
rat)
and
via
both
the
oral
and
inhalation
routes
of
administration.
As
with
other
pyrethroids,
the
neuromuscular
effects
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
a
long­
term
accumulated
dose.
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
(
Cancer
Peer
Review
Committee,
1988).
The
evidence
was
not
considered
strong
enough
to
warrant
a
quantitative
estimation
of
human
risk.
Structure­
activity
comparisons
with
the
pyrethroid
class
of
insecticides
indicate
that
lung
tumors
in
mice
were
induced
with
3
other
pyrethroids.
Cypermethrin
is
not
a
developmental/
reproductive
toxicant.
No
developmental
toxicity
is
observed
in
any
of
the
developmental
toxicity
studies
and
in
the
reproduction
studies.
Offspring
toxicity
was
observed
at
the
same
treatment
level
which
resulted
in
parental
systemic
toxicity.
There
did
not
appear
to
be
any
increases
in
severity
of
toxicity
for
the
pups.
With
the
available
toxicity
database
at
this
time,
there
is
no
evidence
that
cypermethrin
induces
any
endocrine
disruption.

Based
on
the
weight
of
evidence
presented,
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
is
requiring
a
developmental
neurotoxicity
(
DNT)
study.
This
study
is
to
be
conducted
with
z­
cypermethrin
(
see
below).
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
toxicological
endpoints
for
use
in
human
risk
assessment
for
cypermethrin
were
selected
from
the
most
sensitive
species
from
the
combined
databases
for
both
cypermethrin
and
zcypermethrin
z­
Cypermethrin
is
an
enriched
isomer
of
cypermethrin.
Cypermethrin
is
a
combination
of
8
isomers
and
z­
Cypermethrin
is
generally
a
combination
of
4
of
the
same
8
isomers,
with
the
two
most
insecticidally
active
isomers
present
at
a
concentration
of
24%
each.
The
following
endpoints
were
selected
for
estimation
of
risk:
acute
dietary
(
general
population):
a
NOAEL
of
10
mg/
kg
from
the
acute
neurotoxicity
study
in
the
rat
(
zcypermethrin
aPAD
=
0.01
mg/
kg);
chronic
dietary:
a
NOAEL
of
6
mg/
kg/
day
from
the
chronic
feeding
study
in
the
dog
(
cPAD
=
0.006
mg/
kg/
day);
short­
term
incidental
oral
exposure:
a
NOAEL
of
10
mg/
kg/
day
from
the
acute
neurotoxicity
study
in
the
rat
(
zcypermethrin
residential
MOE
=
1000);
intermediate­
term
incidental
oral
exposure:
a
NOAEL
of
5
mg/
kg/
day
from
the
subchronic
neurotoxicity
study
in
the
rat
(
z­
cypermethrin,
residential
MOE
=
1000);
short­
and
intermediate­
term
dermal
exposure:
no
hazard
was
identified
to
support
a
quantitation
of
risk;
long­
term
dermal
exposure:
a
NOAEL
of
6
mg/
kg/
day
from
the
chronic
feeding
study
in
the
dog
(
occupational
MOE
=
100
and
residential
MOE
=
1000)
with
an
estimated
dermal
absorption
factor
of
2.5%;
and
inhalation
exposure
(
any
time
period):
a
NOAEL
of
0.01
mg/
L
(
2.7
mg/
kg/
day)
from
the
21­
day
inhalation
study
in
the
rat
(
short­
and
intermediate­
term
occupational
MOE
=
100
and
long­
term
occupational
MOE
=
300;
short­
and
residential
MOE
(
all
durations)
=
1000).
The
extra
3x
for
long­
term
3
occupational
exposure
was
selected
because
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.
4
CYPERMETHRIN
PC
Code:
109702
and
129064
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
July
10,
2003
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Pamela
M.
Hurley,
Toxicologist
,
Date
Reregistration
Branch
3
(
7509C)

TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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3
2.0
REQUIREMENTS
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5
3.0
DATA
GAP(
S)
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7
4.0
HAZARD
ASSESSMENT
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7
4.1
Acute
Toxicity
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7
4.2
Subchronic
Toxicity
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9
4.3
Prenatal
Developmental
Toxicity
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12
4.4
Reproductive
Toxicity
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14
4.5
Chronic
Toxicity
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15
4.6
Carcinogenicity
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17
4.7
Mutagenicity
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18
4.8
Neurotoxicity
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18
4.9
Metabolism
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22
5.0
TOXICITY
ENDPOINT
SELECTION
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24
5.1
See
Section
8.2
for
Endpoint
selection
table.
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25
5.2
Dermal
Absorption
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25
5.3
Classification
of
Carcinogenic
Potential
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25
6.0
FQPA
CONSIDERATIONS
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25
6.1
Special
Sensitivity
to
Infants
and
Children
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26
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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26
7.0
REFERENCES
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28
8.0
APPENDICES
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37
8.1
Toxicity
Profile
Summary
Tables
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38
8.1.1
Acute
Toxicity
Table
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38
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Table
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38
8.2
Summary
of
Toxicological
Dose
and
Endpoints
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44
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
6
1.0
HAZARD
CHARACTERIZATION
With
the
exception
of
the
developmental
neurotoxicity
study,
the
toxicology
database
for
cypermethrin
is
complete
and
there
are
no
data
gaps.
The
scientific
quality
is
relatively
high
and
the
toxicity
profile
of
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.

The
toxicological
endpoints
for
use
in
human
risk
assessment
for
cypermethrin
were
selected
from
the
most
sensitive
species
from
the
combined
databases
for
both
cypermethrin
and
zcypermethrin
z­
Cypermethrin
is
an
enriched
isomer
of
cypermethrin.
Cypermethrin
is
a
combination
of
8
isomers
with
percentage
compositions
ranging
from
11­
14%.
z­
Cypermethrin
is
a
combination
of
the
same
8
isomers
with
the
4
insecticidally
less
active
ones
at
a
concentration
of
1%
each.
The
remaining
4
isomers,
two
of
which
are
regarded
as
being
the
most
insecticidally
active,
are
present
at
a
concentration
of
24%
each.
Summaries
of
the
pertinent
studies
from
the
z­
cypermethrin
toxicology
database
are
included
in
this
document.

Acute
toxicity
studies
conducted
with
cypermethrin
indicate
that
it
is
moderately
acutely
toxic
via
the
oral
route
(
Category
II);
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
cypermethrin
indicates
one
major
target
for
this
chemical:
the
neuromuscular
system.
The
liver
also
appears
to
be
affected
(
dermal
study
in
rabbits:
focal
necrosis,
abraded
animals
only)
and
mice
(
may
only
be
an
adaptive
response)).
The
neuromuscular
effects
(
tremors,
gait
abnormalies
and
decreases
in
activity)
occur
mainly
in
oral
studies
in
the
dog
and
the
rat,
but
similar
effects
were
also
observed
in
an
inhalation
study.
These
effects
do
not
occur
in
the
dermal
studies
in
either
rats
(
z­
cypermethrin)
or
rabbits
(
cypermethrin:
nonabraded
animals;
abraded
animals
did
exhibit
decreases
in
activity).
The
weight
of
the
evidence
indicates
that
the
dog
appears
to
be
the
most
sensitive
species
for
neuromuscular
effects.
In
general,
neither
sex
is
more
sensitive;
however,
in
both
the
rat
90­
day
neurotoxicity
study
(
z­
cypermethrin)
and
the
1­
year
feeding
study
in
the
dog
(
cypermethrin),
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.
The
effect
is
not
consistently
observed.
Therefore,
it
is
difficult
to
assess
dose­
response
and
any
differences
between
the
capsule/
gavage/
dietary
routes
of
administration.

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
(
z­
cypermethrin)
and
the
NOAEL
(
highest
dose
tested)
of
1000
mg/
kg/
day
from
the
21­
day
dermal
study
in
the
rat
(
z­
cypermethrin).
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.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
7
In
the
prenatal
developmental
toxicity
studies
in
rats
and
rabbits
with
both
cypermethrin
and
zcypermethrin
(
rat
only),
there
was
no
evidence
of
developmental
toxicity
at
the
highest
dose
tested.
Maternal
toxicity
was
observed
in
these
studies
in
the
form
of
decreased
body
weight
gain
and
food
consumption
and/
or
clinical
signs
of
neurotoxicity
such
as
gait
abnormalities.
In
the
multi­
generation
reproduction
studies
in
rats
conducted
with
both
of
the
cypermethrins,
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
did
not
appear
to
be
any
increases
in
severity
of
toxicity
for
the
pups.

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
(
Cancer
Peer
Review
Committee,
1988).
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).
Structureactivity
comparisons
with
the
pyrethroid
class
of
insecticides
indicate
that
lung
tumors
in
mice
were
induced
with
3
other
pyrethroids.
Cypermethrin
was
negative
in
all
mutagenicity
studies
available
to
the
Agency.

Cypermethrin
is
a
known
neurotoxicant.
It
is
a
member
of
the
pyrethroid
class
of
insecticides,
which
are
known
to
induce
transient
clinical
signs
of
neurotoxicity
in
mammals,
but
do
not
generally
induce
neuropathologic
lesions.
The
acute
neurotoxicity
studies
conducted
with
cypermethrin
indicated
gait
abnormalities,
splayed
hindlimbs,
decreased
motor
activity,
salivation,
lacrimation,
arousal,
urination
and/
or
soiled
fur.
Other
parameters
affected
included
abnormal
motor
movement,
forelimb
or
hindlimb
grip
strength,
righting
reflex,
touch
response
and
tail
pinch
response.
The
acute
neurotoxicity
study
conducted
with
z­
cypermethrin
indicated
similar
clinical
signs
plus
tremors,
convulsions
and
vocalization.
The
subchronic
neurotoxicity
study
with
both
cypermethrin
and
z­
cypermethrin
indicated
the
same
types
of
signs
and
symptoms
plus
decreased
body
weight
gain.
Similar
clinical
signs
of
neurotoxicity
were
observed
in
the
other
guideline
oral
and
inhalation
toxicity
studies
in
the
rat
and
dog
for
both
cypermethrin
and
z­
cypermethrin.

The
neuromuscular
effects
(
i.
e.
gait
abnormalities,
tremors,
reduced
motor
activity,
changes
in
FOB
parameters
and
convulsions)
occur
across
species,
sexes
and
routes
of
administration.
These
clinical
signs
appear
to
be
more
of
a
transient
acute
effect
as
opposed
to
an
effect
which
appears
after
an
accumulated
dose.

The
liver
effects
are
seen
in
the
mouse
oncogenicity
study
and
the
rabbit
dermal
study
(
abraded
animals
only).
The
effects
in
rabbits
would
be
significant,
except
that
the
Agency
does
not
generally
use
data
from
abraded
animals
in
a
dermal
toxicity
study.
The
effects
in
the
mouse
may
be
due
to
induction
of
microsomal
enzymes
in
the
liver
and
are
likely
more
of
a
physiological
response
as
opposed
to
a
toxicological
effect.
In
the
presence
of
a
xenobiotic,
certain
metabolic
pathways
are
stimulated
in
the
liver
to
increase
the
ability
of
the
animal
to
purge
itself
of
the
xenobiotic.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
8
Cypermethrin
is
a
type
II
pyrethroid
(
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,
it
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."

2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
Food/
Feed
use
for
cypermethrin
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
9
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
(
Non­
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
No
number
21­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
no
yes
yes
yes
N/
A
yes
870.3700a
Developmental
Toxicity
(
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity(
Non­
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
Non­
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
Mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
.
.
.
870.5375
Mutagenicity 
Structural
Chromosomal
Aberrations
.
.
.
.
870.5385
Mutagenicity 
Structural
Chromosomal
Aberrations
.
.
.
.
870.5550
Mutagenicity 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes1
yes1
yes1
yes1
yes1
yes
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
yes
yes
yes2
N/
A
N/
A
yes
yes
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
870.7200
Companion
Animal
Safety
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
Dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
N/
A
N/
A
N/
A
1Mutagenicity
requirements
are
under
the
new
guideline
requirements.
In
vitro
structural
chromosomal
aberration
study
conducted
with
z­
cypermethrin.
2Required
by
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
on
9/
19/
2000
and
is
to
be
conducted
with
zcypermethrin
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
10
3.0
DATA
GAP(
S)

The
toxicology
data
base
for
cypermethrin
is
not
complete,
but
it
is
adequate
to
support
reregistration
at
this
time.
A
requirement
for
a
developmental
neurotoxicity
study
was
recommended
by
HIARC
on
9/
19/
00.

4.0
HAZARD
ASSESSMENT
The
hazard
assessment
includes
toxicology
studies
conducted
with
cypermethrin
and
selected
studies
conducted
with
z­
cypermethrin..

4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
complete.
Acute
toxicity
studies
conducted
with
cypermethrin
indicate
that
it
is
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
acute
toxicity
data
on
cypermethrin
are
summarized
below
in
Table
2.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
11
Table
2.
Acute
Toxicity
Data
on
Cypermethrin
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1000
Acute
Oral
­
rat
00056800
LD
50
(
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
Rabbits
00056800
00056800
LD
50
>
4920
mg/
kg/
day.
Clinical
signs
of
neurotoxicity.

Abraded
skin:
LD
50
>
2460
mg/
kg.
Lacrimation,
discharge
from
the
eye
and
"
nervous
and
shaking".
III
III
870.1200
Acute
Inhalation
­
rat
42395702
LC
50
:
%
(
not
calculated
but
higher
than
&)
LC
50
:
&
2.5
(
1.6­
3.4)
mg/
L.
Clinical
signs
of
neurotoxicity.
IV
870.2400
Primary
Eye
Irritation
­
rabbit
00056800
Slight
redness
of
conjunctivae,
chemosis
&
discharge.
Persisted
to
day
7.
III
870.2500
Primary
Skin
Irritation
rabbit
00056800
Slight
to
mild
erythema
on
intact
&
abraded
skin.
Regressed
by
48
hours.
Primary
Irritation
Index:
0.71
IV
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
12
870.2600
Dermal
Sensitization
00056800
40377701
Not
a
sensitizer
in
Buehler
assay.
Moderate
sensitizer
in
Magnusson
Kligman
Maximization
method.
N/
A
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
incomplete,
however,
acceptable
chronic
oral
studies
are
available
to
fulfill
the
data
requirements
for
a
subchronic
oral
study
in
the
rat.
In
addition,
a
subchronic
feeding
study
is
available
with
zcypermethrin
No
additional
studies
are
required
at
this
time.
The
main
toxicological
effects
are
neuromuscular
effects
and
decreases
in
body
weight
and
body
weight
gain
in
both
rats
and
dogs..
No
effects
are
observed
when
z­
cypermethrin
is
administered
to
rats
via
the
dermal
route.
No
effects
are
observed
when
cypermethrin
is
administered
to
nonabraded
rabbits
at
dose
levels
up
to
200
mg/
kg/
day
via
the
dermal
route
either.
When
cypermethrin
is
administered
via
inhalation,
clinical
signs
of
neurotoxicity
and
decreases
in
body
weight
are
observed.

870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
subchronic
toxicity
study
(
MRID
00056802
and
92027034)
cypermethrin
(
92%
purity)
was
administered
to
four
groups
of
20
SPF
Alderley
Park
strain
rats/
sex
at
dose
levels
of
0,
75,
150
or
1500
ppm
(
corresponding
to
0,
3.75,
7.5
or
75
mg/
kg/
day)
for
90
days.
Groups
of
4/
sex/
dose
were
allowed
28
days
for
recovery.
The
male
rats
dosed
with
7.5
mg/
kg/
day
had
increases
(
260%)
in
hepatic
aminopyrine
demethylase.
This
was
increased
to
539%
in
the
75
mg/
kg/
day
dose
group.
Females
(
466%)
were
increased
in
the
75
mg/
kg/
day
dose
group
only.
Recovery
was
evident
after
28
days.
Body
weight
was
decreased
in
the
75
mg/
kg/
day
dose
groups
for
both
males
(
i.
e.
17%
at
week
9)
and
females
(
i.
e.
8%
at
week
9).
The
LOAEL
is
1500
ppm
(
75
mg/
kg/
day)
based
on
decreases
in
body
weight.
The
NOAEL
is
150
ppm
(
7.5
mg/
kg/
day).
The
increase
in
hepatic
aminopyrine
demethylase
is
considered
a
physiological
rather
than
toxicological
response
but
its
presence
is
indicated.
This
subchronic
toxicity
study
is
classified
as
supplementary
(
due
to
insufficient
tables)
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
oral
study
(
82­
1)
in
rats.
The
study
does
not
require
upgrading
because
an
acceptable
chronic
feeding
study
with
rats
is
available.

z­
Cypermethrin
(
88.2%
a.
i.)
was
tested
in
a
90­
day
feeding
study
in
groups
of
10
male
and
10
female
Fisher
344
(
CDF)
rats
at
the
following
dose
levels:
0,
10,
50,
150,
250,
500
or
900
ppm
(
0,
0.6,
2.7,
8.4,
13.8,
28.2
or
55.7
mg/
kg/
day
for
males
and
0,
0.6,
3.3,
9.6,
16.3,
32.2
or
65.2
mg/
kg/
day
for
females)
(
MRID
41776101).
At
500
ppm,
females
had
significantly
decreased
glucose
levels.
Clinical
chemistries
were
not
obtained
for
females
at
900
ppm
due
to
high
mortality.
This
was
attributed
to
decreased
food
consumption.
At
500
and
900
ppm,
both
sexes
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
13
had
significantly
decreased
body
weights
(
12
and
38%,
respectively
in
males,
9
and
35%,
respectively
in
females),
body
weight
gains
(
15
and
63%,
respectively
in
males
and
21%
in
females
at
500
ppm)
and
food
consumption
when
compared
to
controls.
At
900
ppm,
70
and
100
percent
of
the
males
and
females,
respectively
died.
The
deaths
were
attributed
to
"
inanition".
Food
efficiency
was
also
significantly
decreased
(
48%
in
males
and
65%
in
females).
These
animals
exhibited
abdominal­
genital
staining,
ataxia,
clonic
convulsions,
chromodacryorrhea,
chromorhinorrhea,
decreased
feces,
decreased
locomotion,
dehydration,
hypersensitivity
to
touch
and
sound,
splayed
hindlimbs
and
unthriftiness.
Females
also
exhibited
abdominal
recumbency
and
walking
on
toes.
Males
had
significant
decreases
in
erythrocyte
and
leukocyte
counts
when
compared
to
controls.
Hemoglobin
and
hematocrit
were
also
decreased
in
males
as
well
as
increases
in
BUN.
The
NOAEL
is
250
ppm
(
13.9
mg/
kg/
day)
and
the
LOAEL
is
500
ppm
(
28.2
mg/
kg/
day)
based
on
decreases
in
body
weight
and
body
weight
gains
and
food
consumption
at
28.2
mg/
kg/
day
and
above
and
deaths;
clinical
signs
of
neurotoxicity;
decreases
in
erythrocyte
and
leukocyte
counts,
hemoglobin
and
hematocrit
and
increases
in
BUN
at
55.7
mg/
kg/
day.
The
study
is
acceptable.

870.3150
90­
Day
Oral
Toxicity
­
Dog
There
are
two
available
subchronic
dog
studies
with
cypermethrin;
only
one
study
is
acceptable.

In
a
subchronic
toxicity
study
(
MRID
44527002),
cypermethrin
(
95.7%
a.
i.)
was
administered
to
beagle
dogs
(
4/
sex/
group)
at
concentrations
of
0,
300,
600,
800,
or
1100
ppm
in
the
diet
(
achieved
doses
0/
0,
10.4/
12.2,
20.7/
25.4,
24.6/
34.3,
and
37.0/
45.2
mg/
kg/
day
[
M/
F],
respectively)
for
3
months.
No
deaths
occurred
during
the
study.
In
the
1100
ppm
group,
two
males
and
one
female
exhibited
slight
tremor
activity
beginning
on
day
49
(
female),
60,
or
71
through
study
termination,
and
one
male
and
one
female
exhibited
moderate
tremor
activity
either
on
two
occasions
(
male)
or
during
the
week
8,
9,
and
12
detailed
physical
examinations
(
female).
Males
and
females
displayed
decreases
in
body
weights
throughout
the
study,
reduced
body
weight
gains
and
gained
little
or
no
weight
during
the
study.
No
treatment­
related
differences
in
food
consumption,
hematological,
clinical
chemistry,
or
urinalysis
parameters,
ophthalmoscopic
abnormalities,
organ
weight,
or
gross
or
microscopic
pathology
were
observed.
No
neoplastic
tissue
was
observed.
The
LOAEL
is
1100
ppm
(
equivalent
to
37.0/
45.2
mg/
kg/
day
[
M/
F]),
based
on
tremor
activity
in
both
sexes
and
decreased
body
weight
and
body
weight
gains
in
the
males
and
females.
The
NOAEL
is
800
ppm
(
equivalent
to
24.6/
34.3
mg/
kg/
day
[
M/
F]).
This
study
is
classified
acceptable
(
§
82­
1b)
and
satisfies
the
guideline
requirements
for
a
subchronic
toxicity
study
in
the
dog.

In
a
subchronic
toxicity
study
(
MRID
00112929,
42068502)
cypermethrin
(
98%
purity)
was
administered
to
four
groups
of
4
beagle
dogs/
sex
at
dose
levels
of
0,
5,
50,
500
or
1500
ppm
(
corresponding
to
0..
125,
1.25,
12.5
and
37.5
mg/
kg/
day)
for
13
weeks.
Responses
to
treatment
were
noted
at
37.5
mg/
kg/
day
in
both
sexes
and
consisted
of
whole
body
tremors,
exaggerated
gait,
ataxia,
incoordination,
hyperaesthesia,
licking
and
chewing
of
paws
as
well
as
diarrhea
and
anorexia
and
decreased
body
weight.
The
LOAEL
is
1500
ppm
(
37.5
mg/
kg/
day,
based
on
clinical
signs
indicating
neurotoxicity.
The
NOAEL
is
500
ppm
(
12.5
mg/
kg/
day).
This
subchronic
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
14
toxicity
study
is
classified
as
unacceptable
guideline
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
oral
study
(
82­
1b)
in
dogs.
The
limiting
factors
include
no
data
tables
for
clinical
signs
to
determine
their
onset
and
duration,
there
is
no
discussion
of
the
body
weight
effect
at
1500
ppm
and
the
copy
available
is
unreadable
in
most
places.

870.3200
21/
28­
Day
Dermal
Toxicity
 
Rat
or
Rabbit
In
a
21­
day
dermal
toxicity
study,
cypermethrin
(
91.5%
purity)
was
applied
to
the
skin
of
10
New
Zealand
White
rabbits/
sex/
dose
at
doses
of
0
(
polyethylene
glycol,
PEG
300),
2,
20
or
200
mg/
kg/
day
for
approximately
6
hours/
day,
5
days/
week,
for
a
total
of
15
applications
during
a
21­
day
period
(
MRID
00090035,
92027036).
The
skin
of
five/
sex/
dose
was
abraded
weekly.
There
were
no
apparent
effects
on
mortality,
food
consumption,
hematology
parameters,
clinical
chemistry
parameters
or
macroscopic
pathology.
At
200
mg/
kg/
day,
increased
incidences
in
subdued
behavior,
flacidity
and
possibly
fecal
incontinence
were
observed
when
compared
to
the
control
or
lower
dose
groups.
With
the
exception
of
fecal
incontinence,
the
increased
incidence
of
clinical
signs
were
observed
in
the
abraded
animals.
A
decrease
in
body
weight
was
observed
in
abraded
females
(­
0.35
kg
versus
­
0.05
kg
in
the
control
group,
p
<
0.01)
and
possibly
the
abraded
males
(
not
statistically
significant,
loss
of
0.26
kg
compared
to
loss
of
0.04
kg
in
the
control
group).
There
was
an
increased
incidence
of
microscopic
liver
focal
necrosis
in
the
abraded
females
(
1/
5
in
controls
versus
4/
5
for
abraded
and
1/
5
in
controls
versus
2/
5
for
nonabraded
and
possibly
abraded
males
(
1/
5
in
controls
versus
3/
5
for
abraded
and
1/
5
in
controls
versus
0/
5
for
non­
abraded).
Testicular
weights
were
also
decreased
(
absolute
19%
less
(
p<
0.05),
relative
15%
less
(
statistics
not
calculated).
Individual
animal
data
indicate
that
most
of
the
animals
with
decreased
testicular
weights
were
in
the
abraded
group.
Increased
incidences
and
severity
of
skin
changes
were
noted
(
erythema,
edema,
desquamation,
flaking/
sloughing,
redness,
scabbing,
cracking
and
wrinking),
particularly
in
females.
Microscopically,
there
was
an
increased
incidence
of
dermal
leucocyte
infiltration
in
males.
Combining
abraded
and
nonabraded
there
were
0/
10
in
the
control
group
and
3/
10,
3/
10
and
5/
10
in
the
2,
20
and
200
mg/
kg/
day,
respectively.
For
females,
there
were
3/
10
in
the
control
group
and
no
more
than
4/
10
in
any
treated
group.
There
were
no
parameters
which
seemed
to
clearly
distinguish
the
abraded
from
the
non­
abraded
animals.
At
lower
doses,
the
number
of
animals
involved
and
the
severity
of
the
findings
in
the
skin
was
considerably
reduced
and
were
not
considered
to
be
sufficient
to
be
related
to
treatment.
The
combined
abraded
&
nonabraded
animal
systemic
LOAEL
was
200
mg/
kg/
day
based
on
female
body
weight
loss
(
abraded
only),
a
decrease
in
testicular
weights
(
absolute
and
possibly
relative,
attributed
to
abraded
group)
and
liver
pathology
in
females
and
possibly
males
(
focal
necrosis,
abraded
only).
The
combined
abraded
&
nonabraded
animal
systemic
NOAEL
was
20
mg/
kg/
day.
The
non­
abraded
animal
systemic
LOAEL
was
greater
than
200
mg/
kg/
day
and
the
non­
abraded
animal
systemic
NOAEL
was
200
mg/
kg/
day,
the
highest
dose
tested.
The
dermal
LOAEL
was
200
mg/
kg/
day
based
on
male
and
female
clinical
signs
(
erythema,
edema
and
other
skin
lesions)
as
well
as
dermal
leucocyte
infiltration
in
both
sexes.
The
dermal
NOAEL
was
20
mg/
kg/
day.
This
study
is
classified
as
acceptable
(
82­
2b;
870.3200)
and
satisfies
the
guideline
for
a
repeated
dose
dermal
toxicity
study
in
rabbits.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
15
In
a
repeated­
dose
dermal
toxicity
study
(
MRID
45010401),
z­
cypermethrin
(
86%
a.
i.,
Lot/
Batch
#:
FMC­
T#
1517)
was
applied
to
the
clipped
intact
skin
of
10
Sprague­
Dawley
rats/
sex/
dose
at
nominal
doses
of
0
(
untreated
control),
100,
500,
or
1000
mg/
kg/
day
(
limit
dose)
for
6
hours/
day,
7
days/
week,
for
a
total
of
21
applications
during
a
21­
day
period.
On
day
21,
all
surviving
rats
underwent
Functional
Observational
Battery
(
FOB)
and
motor
activity
testing.
All
animals
survived
to
the
end
of
the
study
and
no
treatment­
related
clinical
signs
were
observed.
No
treatment­
related
differences
in
body
weights,
organ
weights,
food
consumption,
FOB,
motor
activity,
ophthalmology,
hematology,
clinical
chemistry,
or
pathology
(
gross
or
microscopic)
between
the
treatment
and
control
groups
were
observed.
At
the
site
of
application,
erythema
and/
or
eschar,
desquamation,
and
ulcerations
were
observed
in
both
males
and
females.
After
pathological
evaluation,
it
was
concluded
that
these
findings
were
due
to
clipping
and/
or
scratching
by
the
animals.
The
systemic
LOAEL
was
not
established.
The
systemic
NOAEL
is
1000
mg/
kg/
day
(
limit
dose).
The
dermal
LOAEL
was
not
established.
The
dermal
NOAEL
is
1000
mg/
kg/
day
(
limit
dose).
This
study
is
classified
acceptable
(
§
82­
2a)
and
does
satisfy
the
guideline
requirement
for
a
repeated­
dose
dermal
toxicity
study.
Although
a
LOAEL
was
not
observed,
the
test
substance
was
tested
up
to
the
limit
dose.

870.34xx
21/
28­
Day
Inhalation
Toxicity
 
Rat
In
a
21­
day
subchronic
inhalation
toxicity
study
(
MRID
43507101)
cypermethrin
(
87.1%
purity,
1:
1
cis:
trans)
was
ad­
ministered
to
5/
sex
rats
(
Alpk:
Apfsd,
Wistar
Derived)/
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.
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
uM.
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,
lachrymation,
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
based
mainly
on
body
weight
decrease.
The
NOAEL
is
0.01
mg/
L.
Classification:
This
study
is
classified
as
acceptable.
Histopathology
was
assessed
for
only
5
rats/
sex
and
10
rats/
sex
should
have
been
assessed.
Future
studies
should
assess
10/
sex/
group.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Maternal
toxicity
in
rats
was
evident
and
included
clinical
signs
of
toxicity
(
especially
neurotoxicity);
stained
abdominal
and
perineal
fur;
decreased
body
weights,
body
weight
gains,
and
food
consumption;
and
soft
or
liquid
feces.
Maternal
toxicity
in
rabbits
included
decreased
body
weight
gain,
clinical
signs
of
toxicity,
red
or
pink
material
in
the
pan
and
decreased
feces.
No
developmental
effects
were
observed
in
either
rats
or
rabbits.
Developmental
NOAELs
were
greater
than
the
maternal
NOAELs.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
16
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
In
a
developmental
toxicity
study
(
MRID
00056804,
42068505,
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).

z­
Cypermethrin
(
89.6%
a.
i.)
was
tested
in
a
developmental
toxicity
study
in
Charles
River
Crl:
CD
(
SD)
BR
rats
at
the
following
dose
levels:
0,
5,
12,5,
25,
or
35
mg/
kg/
day
(
MRID
41776102).
Groups
of
25
females
were
administered
the
test
chemical
by
gavage
on
gestation
days
6
through
15
in
a
volume
of
5
ml/
kg
bodyweight.
At
25
mg/
kg/
day
and
above,
ataxia
and
urine
stained
abdominal
fur
was
observed
as
well
as
reduced
body
weight
gains
and
food
consumption.
Fecal
stained
perineal
fur
was
also
observed
at
25
mg/
kg/
day.
At
35
mg/
kg/
day,
hypersensitivity,
emaciated
appearance,
excessive
salivation
and
soft
or
liquid
feces
were
observed.
One
rat
had
tremors,
red
exudate
on
the
snout,
front
limbs
and
abdomen,
chromorhinorrhea,
clonic
convulsions,
swollen
snout
and
a
nasal
lesion.
No
developmental
toxicity
was
observed
at
any
dose
level.
The
maternal
NOAEL
is
12.5
mg/
kg
and
the
maternal
LOAEL
is
25
mg/
kg
based
on
decreases
in
bodyweight
and
bodyweight
gain
and
food
consumption
and
clinical
signs
of
toxicity,
particularly
neurotoxicity.
The
developmental
NOAEL
is
35
mg/
kg/
day
(
HDT).
The
LOAEL
was
not
established.
The
study
is
classified
as
acceptable.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
There
are
two
developmental
rabbit
studies
conducted
with
cypermethrin.
One
study
was
not
tested
at
a
sufficiently
high
dose
level.

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.
The
developmental
toxicity
study
in
the
rabbit
is
classified
as
unacceptable
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.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
17
In
a
developmental
toxicity
study
(
MRID
No.:
43776302)
cypermethrin
(
94­
96%
pure,
cis/
trans
ration
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
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
is
>
700
mg/
kg/
day.
classification:
This
developmental
toxicity
study
in
the
rabbit
is
classified
acceptable
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
§
83­
3(
b).

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Two
reproduction
studies
are
available
with
cypermethrin.
In
these
studies,
decreased
body
weight
gain
was
observed
in
both
the
parents
and
pups.
The
offspring
NOAELs
were
equivalent
to
the
parental
NOAELs.
In
a
two­
generation
reproduction
study
conducted
with
z­
cypermethrin
in
rats,
decreased
body
weight
gains,
mortality
and
clinical
signs
of
neurotoxicity
were
observed
in
the
parents.
In
the
pups,
decreased
body
weight
gain
and
mortality
were
also
observed.
The
offspring
NOAEL
was
also
equivalent
to
the
parental
NOAEL.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
3
generation
reproduction
study
(
MRID
00112912,
42068504,
92027040)
cypermethrin
(
90.6
to
93.1%)
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
symptoms).
These
dose
levels
correspond
to
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
F
2
at
week
5)
and
females
(
i.
e.
about
4.5%
for
F
o
at
week
8
and
about
10%
for
F
2
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
F
1
B
and
12
to
17%
for
F
1
B
females
for
days
10
to
28).
At
1000
ppm
(
50
mg/
kg/
day)
there
were
obvious
clinical
signs
of
neurotoxicity
(
i.
e.
ataxia
etc).
The
parental/
offspring
LOAEL
is
750
ppm
(
50/
37.5
mg/
kg/
day)
based
on
consistent
decreased
body
weight
gain
in
both
sexes
in
the
parents
and
decreased
mean
litter
weight
gain
during
lactation.
The
parental/
offspring
NOAEL
is
150
ppm
(
7.5
mg/
kg/
day;
the
decreases
in
mean
body
weight
and
body
weight
gain
at
150
ppm
are
not
considered
to
be
toxicologically
significant).
The
reproductive
study
in
the
rat
is
classified
ACCEPTABLE
and
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
18
satisfies
the
guideline
requirement
for
a
3­
generation
reproductive
study
(
OPPTS
870.3800,
§
83­
4)
in
the
rat.

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
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.

z­
Cypermethrin
(
89.6%
a.
i.)
was
tested
in
a
2­
generation
reproduction
study
in
groups
of
30
male
and
30
female
Charles
River
Crl:
CD
(
SD)
BR
rats
at
the
following
dose
levels:
0,
7.5,
25,
100,
375
or
750
ppm
(
0,
0.5,
1.8,
7,
27
or
45
mg/
kg/
day;
MRID
41968204).
At
27
mg/
kg/
day,
decreased
parental
weight
(
particularly
during
lactation),
increased
relative
brain
weight,
clinical
signs
of
toxicity
(
particularly
neurotoxicity)
and
decreased
pup
weight
gain
during
lactation
were
observed.
At
45
mg/
kg/
day,
pup
and
parental
deaths
and
more
severe
clinical
signs
of
toxicity
were
observed.
The
parental
and
offspring
NOAELs
are
7
mg/
kg/
day
and
LOAELs
are
27
mg/
kg/
day
based
on
decreased
parental
and
pup
weight,
particularly
during
lactation,
clinical
signs
of
toxicity
and
death
at
45
mg/
kg/
day.
This
study
is
classified
as
Acceptable.

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.
The
main
effects
from
chronic
exposure
are
decreases
in
body
weight
gain
in
rats
and
clinical
signs
of
neurotoxicity
and
gastrointestinal
effects
in
dogs.

870.4100a
(
870.4300)
Chronic
Toxicity
 
Rat
In
a
chronic
toxicity/
carcinogenicity
study
(
MRID
00112910,
92027041)
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
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
19
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
decrease
in
body
weight
gain.
The
NOAEL
is
150
ppm
(
7.5
mg/
kg/
day).
Cypermethrin
was
not
considered
to
be
oncogenic
in
this
study.
A
possible
association
with
increased
testicular
interstitial
tumors
was
not
considered
definite.
This
chronic
toxicity/
carcinogenicity
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
oral
feeding/
carcinogenicity
study
(
83­
5)
in
rats.

870.4100b
Chronic
Toxicity
­
Dog
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
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
20
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]).
This
study
is
classified
acceptable
(
§
83­
1b;
870.4100)
and
satisfies
the
guideline
requirements
for
a
chronic
toxicity
study
in
dogs.

In
a
chronic
toxicity
study
(
MRID
00112909,
42068503,
92027037)
cypermethrin
(
90.6%)
dissolved
in
corn
oil
was
administered
to
4
groups
of
6/
sex
beagle
dogs
in
gelatin
capsules
at
dose
levels
of
0,
1,
5
or
15
mg/
kg/
day
for
52
weeks.
The
males
(
4.75
fold)
and
females
(
10
fold)
dosed
with
5
mg/
kg/
day
had
increased
incidence
of
passage
of
liquid
stools
starting
in
the
first
week
of
dosing
and
the
incidence
of
this
condition
greatly
increased
to
31
fold
at
the
15
mg/
kg/
day
dose
level
compared
to
controls.
At
15
mg/
kg/
day,
body
tremors,
gait
abnormalities,
uncoordination,
disorientation
and
hyper­
sensitivity
to
noise
were
evident
in
the
first
week
in
addition
to
body
weight
decrease.
The
LOAEL
is
5
mg/
kg/
day
based
on
gastrointestinal
effects.
The
NOAEL
is
1
mg/
kg/
day.
This
chronic
toxicity
study
is
classified
acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
(
82­
1)
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.
No
evidence
of
carcinogenicity
was
observed
in
rats.
In
mice,
cypermethrin
produced
a
statistically
significant
increase
in
lung
adenomas,
and
in
adenomas
plus
carcinomas
combined,
in
female
mice
at
the
highest
dose
level
tested.
There
were
also
significant
positive
dose­
related
trends
for
these
tumor
combinations
in
female
mice.
No
significant
increases
in
carcinomas
were
observed.

870.4200a
Carcinogenicity
Study
­
rat
This
study
(
MRID
No.
00112910)
is
presented
in
the
Chronic
Toxicity
Section
(
see
870.4100a)
above.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
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
were
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
12%
for
females
at
week
11).
The
LOAEL
is
400
ppm
(
57
mg/
kg/
day)
based
on
liver
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
21
weight.
The
NOAEL
is
100
ppm
(
14
mg/
kg/
day).
This
study
was
determined
to
be
positive
for
induction
of
benign
alveologenic
neoplasms.
Adequacy
of
dosing
for
carcinogenicity
is
based
upon
typically
9%
decreases
in
males
and
12%
in
females
in
the
first
months
of
the
study.
This
carcinogenicity
study
is
classified
acceptable
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
(
83­
2)
in
mice.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
1991
mutagenicity
guidelines.
Data
requirements
are
satisfied
by
these
submissions
and
no
further
studies
are
required.
There
was
no
evidence
of
mutagenic
activity
in
any
of
the
assays
conducted
with
cypermethrin.

Gene
Mutation
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)

Cytogenetics
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,
92027043,
92027063)

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
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)

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
The
data
base
for
neurotoxicity
is
considered
incomplete.
A
developmental
neurotoxicity
study
is
required.
Gait
abnormalities
were
observed
in
acute
neurotoxicity
studies
conducted
with
cypermethrin.
In
an
acute
study
with
zcypermethrin
evidence
of
neurotoxicity
was
also
noted
as
clinical
signs
and
treatment­
related
changes
in
the
FOB.
In
the
subchronic
mammalian
neurotoxicity
study
conducted
with
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
22
cypermethrin,
gait
abnormalites,
increased
landing
foot
splay,
splayed
hindlimbs
and
decreased
body
weight
gains
were
observed.
In
a
subchronic
mammalian
neurotoxicity
study
conducted
with
z­
cypermethrin,
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption
were
observed.

870.6200
Acute
Neurotoxicity
Screening
Battery
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
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.

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
doses
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
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
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
23
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.]

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
zcypermethrin
(
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);
(
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,
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,
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
24
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.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
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
(
MRID
43152002).
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.

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.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
25
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
treatment­
related.
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.

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.
Several
studies
with
both
rats,
dogs,
humans
and
mice
are
available
to
support
the
requirement
for
metabolism
in
mammals.
Some
of
these
studies
assess
individual
cis
and
trans
radiolabelled
isomers
and
other
studies
assess
the
metabolism
of
cypermethrin
with
the
label
in
either
the
cyclopropyl
of
the
phenoxybenzyl
ring.
Cypermethrin
is
readily
absorbed
from
the
gastrointestinal
tract
and
extensively
metabolized.
It
mostly
excreted
in
the
urine
that
contains
several
characterized
metabolites
derived
from
conjugation
of
the
hydrolysis
products
of
the
parent
compound
following
cleavage
of
the
esteratic
linkage
site.

870.7485
Metabolism
­
Rat
First
Study.
First
group.
Six/
sex
rats
Wistar
strain
rats
were
dosed
with
a
single
dose
0.61
mg/
animal
of
labelled
cis­
cypermethrin
isomers
in
0.5
ml
of
corn
oil.
The
rats
were
individually
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
26
housed
in
metabolism
cages
and
their
urine
and
fecal
matter
collected
daily
until
sacrifice.
Two
rats
of
each
sex
were
sacrificed
after
24
and
72
hours
and
after
eight
days.
Samples
of
the
blood
and
selected
tissues
were
assessed
for
radioactivity
content.
Second
group.
Three/
sex
rats
were
dosed
with
0.615
mg/
animal
of
labelled
trans
cypermethrin
in
0.8
ml
of
corn
oil.
In
addition
to
the
urine
and
fecal
collections,
expired
air
was
also
collected
from
one
male
and
one
female.
MRID
No.
41551102.
Total
recovery
was
from
97.2
to
100.5%.
About
70%
of
cis
and
80%
of
trans
cypermethrin
was
excreted
in
24
hours.
Essentially
all
was
excreted
in
8
days.
Most
of
the
label
was
excreted
in
the
urine
(>
53%)
with
less
in
the
feces
and
(<
20%)
for
the
trans
(
males
and
females)
and
cis
(
males
only)
groups
and
<
1%
in
the
air
for
all
groups.
A
sex
difference
with
respect
to
excretion
in
the
urine
from
the
cis
isomer
was
noted
for
females
since
about
equal
amounts
(
35%)
were
found
in
both
the
urine
and
feces.
Several
urinary
and
fecal
metabolites
were
tentatively
characterized.

Second
Study.
One
group
of
three/
sex
Wistar
strain
rats
was
dosed
with
a
single
oral
dose
(
approximately
1.3
mg/
kg)
of
14C­
cyclopropyl
labelled
cypermethrin
in
corn
oil
(
0.8
ml).
The
rats
were
then
placed
in
glass
metabolism
cages
and
their
urine
and
feces
were
collected.
Special
metabolism
cages
for
trapping
any
radioactivity
expired
through
their
respiratory
system
were
used
for
one
male
and
female
rat.
The
rats
were
sacrificed
after
three
days
and
their
blood
and
selected
tissues
were
assessed
for
radioactivity.
MRID
No.
41551103.
85.5%
for
males
and
97.2%
for
females
of
14C
was
excreted
in
72
hours.
The
urine
(
55.8%
for
males
and
69.4%
for
females)
was
the
major
route
of
excretion
with
the
feces
containing
the
balance.
The
air
contained
only
0.1%
or
less.
Tissue
retention
was
highest
in
the
skin
(
1.2%)
and
liver
(
0.74%
for
males
but
only
0.18%
for
females)
and
fat
(
0.57
to
0.66%).

Third
Study.
In
a
series
of
nine
different
studies,
labelled
cypermethrin
(
1
mg/
kg
or
less)
in
corn
oil
or
separated
cis
or
trans
cypermethrin
isomers
were
given
by
gavage
to
single
or
groups
of
two
or
three
Wistar
strain
rats.
Their
urine
and
in
some
cases
fecal
matter
were
collected
at
various
intervals
such
as
18
hours
to
3
days.
In
another
set
of
experiments,
labelled
cypermethrin
was
administered
to
rats
that
were
fitted
with
bile
duct
cannalulas
and
their
bile
collected
for
4­
5
hours
while
the
rat
was
under
anesthesia.
MRID
No.
41551104.
cis
and
trans
14C­
cyclopropyl
labelled
cypermethrin
was
demonstrated
to
form
glucuronide
conjugations
of
cis
and
trans
acids
and
hydroxyacids.
Only
1.6%
or
less
of
the
total
dose
is
excreted
in
the
bile.
Most
of
the
cypermethrin
in
the
feces
was
unmetabolized.
The
glucuronide
conjugates
in
the
urine
were
found
to
be
unstable
and
subject
to
hydrolysis.

In
addition
to
the
above
studies,
other
data
on
the
metabolism
of
cypermethrin
in
rats
can
be
found
in
MRID
Nos.:
00056806,
00056807,
00056809,
00056810
and
00056812
and
in
00089002,
00089003
and
00089004
that
supports
the
observations
reported
above.
Also
other
studies
demonstrate
the
metabolism
and
pharmacokinetics
in
mice
is
similar
to
that
of
the
rat
(
MRID
Nos.:
00089007,
00089008
and
00089009)
and
dogs
(
00089010,
00089011,
00089012
and
00089013).

870.7485
Metabolism
­
Human
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
27
This
dermal
metabolism
study
in
the
human
was
designed
to
determine
the
quantitative
urinary
excretion
of
three
cypermethrin
metabolites
following
dermal
application
to
six
male
human
subjects
(
MRID
43261603).
The
metabolites
analyzed
were
dichlorovinyldimethylcyclopropanecarboxylic
acid
(
DCVA),
3­
phenoxybenzoic
acid
(
3PBA)
and
3­(
4'­
hydroxy)­
phenoxybenzoic
acid
(
4OH3PBA).

Mean
total
DCVA
excretion
was
0.33%
of
the
administered
dose.
However,
considering
that
DCVA
is
further
metabolized
this
value
would
under
estimate
dermal
absorption.
The
sum
of
3PBA
and
4OH3PBA
excretion
ranged
from
0.85
to
1.77%
(
mean
1.23%).
Because
cypermethrin
is
hydrolized
to
yield
equimolar
quantities
of
DCVA
and
3PBA
these
values
are
not
additive.

870.7600
Dermal
Absorption
­
Rat
There
is
no
series
85­
2
dermal
penetration/
absorption
study
available.
Dermal
absorption
was
estimated
by
comparing
the
developmental
rat
study
with
the
21­
day
dermal
study
in
the
rat,
both
with
z­
cypermethrin
(
see
Section
5.2
below).

5.0
TOXICITY
ENDPOINT
SELECTION
On
November
16
and
December
19,
2000
(
HED
Doc.
No.
014445),
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
both
cypermethrin
and
zcypermethrin
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
z­
cypermethrin.

5.1
See
Section
8.2
for
Endpoint
selection
table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
2.5%
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
28
A
dermal
absorption
value
was
estimated
by
comparing
the
developmental
rat
study
with
the
21­
day
dermal
study
in
the
rat,
both
conducted
with
z­
cypermethrin.
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).

The
dermal
absorption
factor
is
required
for
the
long­
term
dermal
risk
assessment
since
an
endpoint
from
an
oral
study
was
selected
for
this
exposure
period.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
The
HIARC
Concluded
Carcinogenicity
studies
in
rats
(
MRID
00112910,
09202741)
and
mice
(
MRID
00112911,
092027038)
were
acceptable.
Cypermethrin
produced
a
statistically
significant
increase
in
lung
adenomas,
and
in
adenomas
plus
carcinomas
combined,
in
female
mice
at
the
highest
dose
level
tested.
There
were
also
significant
positive
dose­
related
trends
for
these
tumor
combinations
in
female
mice.
No
significant
increases
in
carcinomas
were
observed.
No
evidence
of
carcinogenicity
was
observed
in
rats.

5.3.2
Classification
of
Carcinogenic
Potential
The
HED
Cancer
Peer
Review
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).

5.3.3
Quantification
of
Carcinogenic
Potential
The
quantification
of
cancer
risk
will
not
be
conducted
(
see
Section
5.3.2).

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
The
FQPA
Safety
Factor
Committee
evaluated
the
available
hazard
and
exposure
data
for
cypermethrin
and
z­
cypermethrin
on
October
23,
2000
and
made
the
recommendation
for
the
FQPA
safety
factor
to
be
used
in
human
health
risk
assessments
(
as
required
by
Food
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
29
Quality
Protection
Act
of
August
3,
1996).
The
committee
concluded
that
the
FQPA
safety
factor
could
be
removed
(
1x)
in
assessing
the
risk
posed
by
these
chemicals.
The
data
demonstrated
no
indication
of
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
either
cypermethrin
or
z­
cypermethrin.

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
had
been
reviewed
and
no
changes
were
made
to
the
toxicology
endpoints
previously
selected
for
cypermethrin
and
zeta­
cypermethrin.
The
HIARC
reaffirmed
that
the
special
FQPA
safety
factor
should
be
1X
since
there
are
no
residual
uncertainties
for
pre
and/
or
post
natal
toxicity.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
cypermethrin
and/
or
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:
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
30
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
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
zeta­
cypermethrin
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,
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
zeta­
cypermethrin.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
31
7.0
REFERENCES
No
MRID
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).

00056800
Henderson,
C.;
Oliver,
G.
A.;
Smith,
I.
K.;
et
al.
(
1980)
Cypermethrin
(
PP383):
Acute
Toxicity
and
Local
Irritation:
Report
No.
CTL/
P/
537.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Imperial
Chemical
Industries,
Ltd.,
United
Kingdom,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
B)

00056802
Glaister
et.
al.
(
1980)
PP383:
90­
Day
Feeding
Study
in
Rats:
Study
No.:
CTL/
P/
327.
Unpublished
Study
Prepared
by
ICI
Central
Toxicology
Laboratory.

00056804
Tesh,
J.
M.;
Tesh,
S.
A.;
Davies,
W.
(
1978)
WL
43467:
Effects
upon
the
Progress
and
Outcome
of
Pregnancy
in
the
Rat:
LSR
Report
No.
78/
SHL2/
364.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Life
Science
Research,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
F)

00056805
Dix,
K.
M.;
Van
der
Pauw,
C.
L.;
Whitaker,
J.;
et
al.
(
1978)
Toxicity
of
WL
43467:
Teratological
Studies
in
Rabbits
Given
WL
43467Orally:
Group
Research
Report
TLGR.
0010.78.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
G)

00056806
Crawford,
M.
J.;
Croucher,
A.;
Hutson,
D.
H.;
et
al.
(
1980)
The
Metabolism
of
WL
43467
in
Mammals
(
1).
The
Fate
of
a
Single
Oral
Dose
of
¢
¬
14æC­
Benzyl|
WL
43481
(~
Cis~­
WL
43467)
in
the
Rat:
Group
Research
Report
TLGR.
0046.76.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
H)

00056807
Crawford,
M.
J.;
Croucher,
A.;
Stevenson,
D.
E.;
et
al.
(
1980)
The
Metabolism
of
WL
43467
in
Mammals.
The
Fate
of
a
Single
Oral
Dose
of
¢
¬
14æC|
WL
42641
(~
trans~
WL
43467)
in
the
Rat:
Group
Research
Report
TLGR.
0077.76.
(
Unpublished
study
received
Dec
29
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
I)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
32
00056808
Crawford,
M.
J.;
Hutson,
D.
H.;
Bryant,
P.;
et
al.
(
1980)
The
Metabolic
Fate
of
the~
cis~
and~
trans~
Isomers
of
WL
43467
(
Cypermethrin).
Metabolism
and
Elimination
of
¬
14æC­
Aryl­
Labelled
'~
cis~
and~
trans~­
isomers
in
rats:
Group
Research
Report
TLGP.
0131.77.
(
Unpublished
study
received
Dec
19,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
J)

00056809
Crawford,
M.
J.;
Croucher,
A.;
Stevenson,
D.
E.;
et
al.
(
1980)
The
Metabolism
of
WL
43467
in
Mammals.
The
Fate
of
a
Single
Oral
Dose
of
¢
¬
14æCCyclopropyl
WL
43467
in
the
Rat:
Group
Research
Report
TLGR.
0004.77.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
K)

00056810
Crawford,
M.
J.;
Hutson,
D.
H.;
Croucher,
A.;
et
al.
(
1980)
The
Metabolic
Fate
of
the~
cis~
and~
trans~­
Isomers
of
Cypermethrin
in
the
Rat.
Metabolites
Derived
from
the
¬
14æC­
Labelled
Cyclopropyl
Ring:
Group
Research
Report
TLGR.
0183.78.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
L)

00056811
Crawford,
M.
J.;
Hutson,
D.
H.;
Moss,
P.
A.;
et
al.
(
1980)
The
Elimination
of
Residues
from
the
Fat
of
Rats
following
the
Oral
Administration
of
¢
¬
14æCBenzyl
WL
43481
(~
cis~­
WL
43467):
Group
Research
Report
TLGR.
0078.78.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
M)

00056812
Crayford,
J.
V.;
Fish,
A.;
Hutson,
D.
H.
(
1980)
A
Study
of
the
Metabolism
of
3­
phenoxybenzoic
acid
and
Its
Glucoside
Conjugate
in
Rats:
Group
Research
Report
TLGR.
0186.78.
(
Unpublished
study
received
Dec
29,
1980
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
099855­
N)

00089002
Logan,
C.
J.;
Hutson,
D.
H.
(
1980)
Cypermethrin:
Excretion
and
Retention
of
Cypermethrin
and
Its
Metabolites
in
Rats
following
a
Single
Oral
Dose
(
1~
ca~
1200
mg/
kg):
TLER.
80.083;
UR
0126.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
A)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
33
00089003
Hall,
B.
E.;
Vickers,
J.
A.;
Hopkins,
R.
(
1981)
(
¼
14:
C)­
Cypermethrin:
A
Study
To
Determine
the
Bioaccumulation
of
Radioactivity
in
the
Rat
Following
Repeated
Oral
Administration:
Report
No.
2487­
72/
201;
CTL/
C/
1059.
Final
rept.
(
Unpublished
study
received
Dec30,
1981
under
10182­
64;
prepared
by
Hazleton
Laboratories
Europe,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
B)

00089004
Jones,
B.
K.;
Rhodes,
C.
(
1981)
Cypermethrin:
Bioaccumulation
Study
in
the
Rat:
Report
No.
CTL/
P/
599.
Final
rept.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
ImperialChemical
Industries,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
C)

00089007
Hutson,
D.
H.;
Fish,
A.
(
1978)
The
Elimination
of
Radioactivity
by
Mice
following
Oral
Dosing
with
¼
14:
C­
1~
cis~
1­
and
¼
14:
C­
1~
trans~
1­
WL
43467
(
Cypermethrin):
TLRG.
0079.78.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
H)

00089008
Crawford,
M.
J.;
Hutson,
D.
H.;
Moss,
P.
A.;
et
al.
(
1978)
The
Elimination
of
Residues
from
the
Fat
of
Mice
following
the
Oral
Administration
of
ó
¼
14:
C­
Benzyl|
WL
43481
(
1~
cis~
1­
WL
43467):
TLGR.
0080.78.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
I)

00089009
Hutson,
D.
H.;
Casida,
J.
E.;
Fish,
A.
(
1978)
The
Metabolites
of
1~
cis~
1­
and1~
trans~
1­
cypermethrin
(
WL
43467)
in
Mice:
TLGR.
0102.78.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England
and
Univ.
of
California­­
Berkeley,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
J)

00089010
Crawford,
M.
J.;
Crayford,
J.
V.;
Croucher,
A.;
et
al.
(
1979)
The
Metabolism
of
Cypermethrin
(
WL
43467)
in
Mammals:
The
Fate
of
Single
Oral
Doses
of~
cis~
and~
trans~
ó
¼
14:
C­
Benzyl|
cypermethrin
in
the
Dog:
TLGR.
0011.79.
(
Unpublished
study
received
Dec
30,
1981under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
L)

00089011
Crawford,
M.
J.;
Croucher,
A.;
Cheeseman,
M.
E.;
et
al.
(
1979)
The
Metabolic
Fate
of
the1~
cis~
1­
and1~
trans~
1­
Isomers
of
WL
43467
(
cypermethrin)
and
of
3­
Phenoxybenzoic
Acid
in
Dogs:
TLGR.
79.012.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
M)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
34
00089012
Crawford,
M.
J.;
Cheeseman,
M.
E.;
Crayford,
J.
V.;
et
al.
(
1979)
The
Metabolism
of
Cypermethrin
(
WL
43467)
in
Mammals:
The
Fate
of
a
Single
Oral
Dose
of
ó
¼
14:
C­
Cyclopropyl|
cypermethrin
in
the
Dog:
TLGR.
79.029.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
N)

00089013
Crawford,
M.
J.;
Croucher,
A.;
Fish,
A.;
et
al.
(
1979)
The
Metabolism
of
Cypermethrin
(
WL
43467)
in
Mammals:
Metabolites
Derived
from
a
Single
Oral
Dose
of
ó
¼
14:
C­
Cyclopropyl|
cypermethrin
in
the
Dog:
TLGR.
79.096.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070565­
O)

00090035
Henderson,
C.;
Parkinson,
G.
R.;
Smith,
I.
K.
(
1981)
Cypermethrin
Technical:
Subacute
Dermal
Toxicity
Study
in
Rabbits:
Report
No.
CTL/
P/
588.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Imperial
Chemical
Industries,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
C)

00090036
Brooks,
T.
M.;
Dean,
B.
J.;
Gonzalez,
L.
P.;
et
al.
(
1980)
Toxicity
Studies
with
Agricultural
Chemicals:
Mutagenicity
Studies
with
Ripcord
in
Microorganisms~
in
vitro~
and
in
the
Host­
mediated
Assay:
Group
Research
Report
TLGR.
80.059.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
D)

00090037
Trueman,
R.
W.;
Longstaff,
E.
(
1981)
An
Examination
of
Cypermethrin
for
Potential
Mutagenicity
Using
the~
Salmonella~
1/
Microsome
Reverse
Mutation
Assay:
Report
No.
CTL/
P/
595.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Imperial
Chemical
Industries,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
E)

00090038
Dean,
B.
J.;
Thorpe,
E.;
Stevenson,
D.
E.
(
1980)
Toxicity
Studies
with
WL
43467:
Chromosome
Studies
on
Bone
Marrow
Cells
of
Chinese
Hamsters
after
Two
Daily
Oral
Doses
of
WL
43467:
Group
Research
Report
TLGR.
0136.77.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
F)

00090039
Dean,
B.
J.;
Van
der
Pauw,
C.
L.;
Butterworth,
S.
T.
G.;
et
al.
(
1980)
Toxicity
Studies
with
WL
43467:
Dominant
Lethal
Assay
in
Male
Mice
after
Single
Oral
Doses
of
WL
43467:
Group
Research
Report
TLGR.
0042.77.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Toxicology
Laboratory,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
G)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
35
00090040
Hend,
R.
W.;
Hendy,
R.;
Fleming,
D.
J.
(
1972?)
Toxicity
Studies
on
the
Insecticide
WL
43467:
A
Three
Generation
Reproduction
Study
in
Rats:
Group
Research
Report
TLGR.
0188.78.
(
Unpublished
study
received
Dec
30,
1981
under
10182­
64;
prepared
by
Shell
Research,
Ltd.,
England,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
Del.;
CDL:
070564­
H)

00112909
Ishmael,
J.;
Kalinowski,
A.;
Banham,
P.;
et
al.
(
1982)
Cypermethrin:
One
Year
Oral
Dosing
Study
in
Dogs:
Report
No.
CTL/
P/
703.
(
Unpublished
study
received
Sep
1,
1982
under
2F2623;
prepared
by
Imperial
Chemical
Industries
PLC,
Eng.,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
DE;
CDL:
071069­
B)

00112910
Milburn,
G.;
Forbes,
D.;
Banham,
P.;
et
al.
(
1982)
Cypermethrin:
2
Year
Feeding
Study
in
Rats:
Report
No.
CTL/
P/
669.
(
Unpublished
study
received
Sep
1,
1982
under
2F2623;
prepared
by
Imperial
Chemical
Industries
PLC,
Eng.,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
DE;
CDL:
071070­
A;
071071)

00112911
Lindsay,
S.;
Banham,
P.;
Chart,
I.;
et
al.
(
1982)
Cypermethrin:
Lifetime
Feeding
Study
in
Mice:
Report
No.
CTL/
P/
687.
(
Unpub
lished
study
received
Sep
1,
1982
under
2F2623;
prepared
by
Imperial
Chemical
Industries
PLC,
Eng.,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
DE;
CDL:
071072­
A;
071073)

00112912
Milburn,
G.;
Banham,
P.;
Birtley,
R.;
et
al.
(
1982)
Cypermethrin:
Three
Generation
Reproduction
Study
in
the
Rat:
Report
No.
CTL/
P/
683.
(
Unpublished
study
received
Sep
1,
1982
under
2F2623;
prepared
by
Imperial
Chemical
Industries
PLC,
Eng.,
submitted
by
ICI
Americas,
Inc.,
Wilmington,
DE;
CDL:
071074­
A;
071075)

00112929
Buckwell,
A.;
Butterworth,
S.;
Stevenson,
D.
(
1977)
Toxicity
Stud
ies
on
the
Pyrethroid
Insecticide
WL
43467:
A
13­
week
Feeding
Study
in
Dogs:
TLGR.
0127.77,
Experiment
No.
1112.
(
Unpublished
study
received
Apr
15,
1981
under
10182­
EX­
19;
prepared
by
Shell
Research,
Ltd.,
Eng.,
submitted
by
ICI
Americas,
Inc.,
Wilming
ton,
DE;
CDL:
071077­
A)

00164942
Barnham,
J.
(
1986)
Cypermethrin
90
Day
Dog
Study:
Dietary
Analysis:
TLGR.
0127.77.
Unpublished
study
prepared
by
Shell
Inter
national
Chemical
Co.
Limited.
5
p.

40377701
Barber,
J.
(
1984)
Cypermethrin
70%
Technical
Material:
Acute
Oral
Toxicity,
Acute
Dermal
Toxicity,
Skin
and
Eye
Irritation
and
Skin
Sensitization
Studies:
Laboratory
Project
ID
CTL/
P/
866.
Unpublished
study
prepared
by
ICI
Central
Toxicology
Laboratory.
107
p.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
36
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McGregor,
D.;
Riach,
C.
(
1982)
Cypermethrin:
Assessment
of
Mutagenic
Potential
in
the
Mouse
Lymphoma
Assay:
Lab
Project
Number:
TL/
C/
1201.
Unpublished
study
prepared
by
Inversek
Research
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32
p.

41551102
Crawford,
M.;
Huston,
D.
(
1977)
Cypermethrin:
The
Metabolic
Fate
of
the
Cis
and
Trans
Isomers
of
WL
43467
(
Cypermethrin):
Metabolism
and
Elimination
of
óCarbon
14|­
Aryl
Labelled
Cis
and
Trans
Isomers
in
Rats:
Lab
Project
Number:
CTL/
C/
1146.
Unpublished
study
prepared
by
Shell
Research
Ltd.
25
p.

41551103
Crawford,
M.
(
1977)
Cypermethrin:
The
Metabolism
of
WL
43467
in
Animals:
The
Fate
of
a
Single
Oral
Dose
of
ó14­
Cyclopropyl|
WL
43467
in
the
Rat:
Lab
Project
Number:
CTL/
C/
1147.
Unpublished
study
prepared
by
Shell
Research
Ltd.
14
p.

41551104
Crawford,
M.;
Hudson,
D.
(
1978)
Cypermethrin:
The
Metabolic
Fate
of
Cis
and
Trans
Isomers
of
Cypermethrin
in
the
Rat::
Lab
Project
Number:
CTL/
C/
1154.
Unpublished
study
prepared
by
Shell
Research
Ltd.
30
p.

41599801
Kennelly,
J.
(
1990)
Cypermethrin:
Assessment
for
the
Induction
of
Unscheduled
DNA
Systhesis
in
Rat
Hepatocytes
in
vivo:
Lab
Project
Number:
CTL/
P/
3080;
SR0449.
Unpublished
study
prepared
by
ICI
Central
Toxicology
Laboratory.
44
p.

41776101
McCarty,
J.
(
1990)
FMC
56701
Technical:
Ninety­
Day
Feeding
Study
in
Rats:
Lab
Project
Number:
A89­
2880.
Unpublished
study
prepared
by
FMC
Corp.
511
p.

41776102
Hoberman.
A.
(
1990)
Developmental
Toxicity
(
Enbryo­
Fetal
Toxicity
and
Teratogenic
Potential)
Study
of
FMC
56701
Technical
Administered
Orally
via
Gavage
to
Crl:
CD
(
SD)
BR
Presumed
Pregnant
Rats:
Lab
Project
Number:
106­
006:
FMC
A89­
2958.
Unpublished
study
prepared
by
Angus
Research
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Inc.
210
p.

41968204
Hoberman,
A.
(
1991)
Multigeneration
Study
with
FMC
56701
Technical
Administered
Orally
via
Diet
to
Crl:
CD
(
SD)
BR
Rats:
Lab
Project
Number:
A89­
2959:
106­
007.
Unpublished
study
prepared
by
Argus
Research
Laboratories,
Inc.
1211
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42068502
Berry,
D.
(
1991)
Addendum
to
Phase
3
Summary
of
MRID
No.
112929
and
164942,
Toxicity
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on
the
Pyrethroid
Insecticide
Cypermethrin
(
WL43467):
A
13
Week
Feeding
Study
in
Dogs:
Lab
Project
Number:
TLGR.
0127.77.
Unpublished
study
prepared
by
Shell
Toxicology
Laboratory.
6
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CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
37
42068503
Berry,
D.
(
1991)
Addendum
to
Phase
3
Summary
of
MRID
No.
112909,
Cypermethrin:
One
Oral
Dosing
in
Dogs:
Lab
Project
Number:
CTL/
P/
703.
Unpublished
study
prepared
by
ICI
Central
Toxicology
Lab.
5
p.

42068504
Berry,
D.
(
1991)
Addendum
to
Phase
3
Summary
of
MRID
No.
112912,
Cypermethrin:
Three
Generation
Reproduction
Study
in
the
Rat:
Lab
Project
Number:
CTL/
P/
683.
Unpublished
study
prepared
by
ICI
Central
Toxicology
Lab.
6
p.

42068505
Berry,
D.
(
1991)
Addendum
to
Phase
3
Summary
of
MRID
No.
56804,
Cypermethrin
(
WL43467):
Effect
Upon
the
Progress
and
Outcome
of
Pregnancy
in
the
Rat:
Lab
Project
Number:
CTL/
C/
1054.
Unpublished
study
prepared
by
Life
Science
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4
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42395702
Mount,
E.
(
1992)
Cypermethrin
Technical:
Acute
Inhalation
Toxicity
Study
in
Rats:
Lab
Project
Number:
A91­
3534.
Unpublished
study
prepared
by
FMC
Corp.
53
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43152001
Freeman,
C.
(
1994)
Cypermethrin
Technical:
Acute
Neurotoxicity
Screen
in
Rats:
Lab
Project
Number:
A92/
3542.
Unpublished
study
prepared
by
FMC
Corp.
571
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43152002
Freeman,
C.
(
1993)
Cypermethrin
Technical:
Subchronic
Neurotoxicity
Screen
in
Rats:
Lab
Project
Number:
A92/
3543.
Unpublished
study
prepared
by
FMC
Corp.
608
p.

43261603
Woollen,
B.
H..;
Marsh,
J.
R.;
Thomley,
K.
F.
(
1992)
Cypermethrin:
Pharmacokinetics
in
Man
Following
a
Single
Dermal
Dose:
Lab
Project
Number:
CTL/
R/
1077.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Laboratory.

43507101
Parr­
Dobrzanski,
R.
(
1994)
Cypermethrin:
21
Day
Sub­
acute
Inhalation
Toxicity
Study
in
the
Rat:
Lab
Project
Number:
CTL/
P/
4534:
MR0165.
Unpublished
study
prepared
by
Zeneca
Central
Toxicology
Lab.
401
p.

43776301
Freeman,
C.
(
1994)
Cypermethrin
Technical:
Pilot
OralTeratology
Study
in
Rabbits:
Lab
Project
Number:
A93­
3823:
ATM­
0179:
GQA
82­
1.
Unpublished
study
prepared
by
FMC
Corp.
150
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43776302
Freeman,
C.
(
1994)
Cypermethrin
Technical:
Oral
Teratology
Study
in
Rabbits:
Lab
Project
Number:
93­
4063:
A93­
3822:
93­
8242.
Unpublished
study
prepared
by
FMC
Corp.
335
p.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
38
44527002
Daly,
I.
(
1994)
A
Subchronic
(
3­
month)
Oral
Toxicity
Study
of
FMC
30980
Technical
in
the
Dog
Via
Dietary
Administration:
Final
Report:
Lab
Project
Number:
92­
3114:
A92­
3706:
92­
8122.
Unpublished
study
prepared
by
Pharmaco
LSR
Inc.
480
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44536801
Daly,
I.
(
1995)
A
Chronic
(
12­
Month)
Oral
Toxicity
Study
of
FMC
30980
Technical
in
the
Dog
via
Dietary
Administration:
Final
Report:
Lab
Project
Number:
92­
3115:
A93­
3821:
92­
8123.
Unpublished
study
prepared
by
Pharmaco
LSR,
Inc.
876
p.

44962201
Watt,
B.
(
1998)
FMC
56701
Technical:
Acute
Neurotoxicity
Screen
in
Rats:
Lab
Project
Number:
A97­
4642:
P97­
0141:
P­
3261.
Unpublished
study
prepared
by
FMC
Corporation.
336
p.

44962202
Freeman,
C.
(
1999)
Zeta­
cypermethrin
Technical:
Subchronic
Neurotoxicity
Screen
in
Rats:
Lab
Project
Number:
A98­
4874:
P98­
0166:
194TST98403.
Unpublished
study
prepared
by
FMC
Corporation.
377
p.

45010401
Freeman,
C.
(
1999)
Zeta­
cypermethrin
Technical
21­
Day
Repeated­
Dose
Dermal
Study
in
Rats:
Lab
Project
Number:
A98­
4885:
194TST98403:
240.
Unpublished
study
prepared
by
FMC
Corp.
297
p.

92027034
Barber,
J.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00056802.
Cypermethrin
(
PP383):
90
Day
Feeding
Study
in
Rats:
CTL
Report
No.:
CTL/
P/
327;
CTL
Study
No.:
PR0044.:
10
p.

92027036
McCall,
J.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00090035.
Cypermethrin
Technical:
Subacute
Dermal
Toxicity
Study
in
Rabbits:
CTL
Report
No.:
P/
588;
CTL
Study
No.:
LB0019.
Prepared
by
ICI
Central
Toxicology
Laboratory.
8
p.

92027037
Guttmann,
E.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00112909.
Cypermethrin:
One
Year
Oral
Dosing
Study
in
Dogs:
CTL
Report
No.:
CTL/
P/
703;
CTL
Study
No.:
PD0398.:
8
p.

92027038
Barber,
J.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00112911
and
Related
MRIDs
00133338,
00163497.
Cypermethrin:
Lifetime
Feeding
Study
in
Mice:
CTL
Report
Nos.:
CTL/
P/
687,
CTL/
P/
687A,
CTL/
P/
1614;
CTL
Study
No.:
PM0366.:
8
p.

92027039
Guttmann,
E.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00056804.
Cypermethrin
(
WL43467):
Effects
Upon
the
Progress
and
Outcome
of
Pregnancy
in
the
Rat:
Life
Science
Report
No.:
78/
SHL2/
364;
CTL
Report
No.:
CTL/
C/
1054.:
7
p.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
39
92027040
Guttmann,
E.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00112912.
Cypermethrin:
Three
Generation
Reproduction
Study
in
the
Rat:
CTL
Report
No.:
CTL/
P/
683;
CTL
Study
No.:
RR0143.:
9
p.

92027041
Barber,
J.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00112910.
Cypermethrin:
2
Year
Feeding
Study
in
Rats:
CTL
Report
No.:
CTL/
P/
669;
CTL
Study
No,:
PR0352.:
9
p.

92027042
Callander,
R.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00090037.
An
Examination
of
Cypermethrin
for
Potential
Mutagenicity
Using
the
Salmonella/
Microsome
Reverse
Mutation
Assay:
CTL
Report
No.:
CTL/
P/
595;
CTL
Study
Nos.:
YV0017,
YV0026,
YV0199.
Prepared
by
ICI
Central
Toxicology
Laboratory.
7
p.

92027043
Mackay,
J.
(
1990)
ICI
Americas
Inc.
Phase
3
Summary
of
MRID
00090038.
Toxicity
Studies
with
WL
43467:
Chromosome
Studies
on
Bone
Marrow
Cells
of
Chinese
Hamsters
after
Two
Daily
Oral
Doses
of
WL
43467:
Report
No.:
TLGR.
0136.77;
Study
No.:
1110;
CTL
Report
No.:
CTl/
C/
1052.
Prepared
by
Shell
Research
Ltd.
6
p.

92027061
Tesh,
J.;
Tesh,
S.;
Davies,
W.
(
1990)
ICI
Americas
Inc.
Phase
3
Reformat
of
MRID
00056804.
Cypermethrin
(
WL43467):
Effects
upon
the
Progress
and
Outcome
of
Pregnancy
in
the
Rat:
Life
Science
Research
Report
No.
78/
SHL2/
364;
CTL
Report
No.:
CTL/
C/
1054.
Prepared
by
Life
Science
Research
Ltd.
40
p.

92027062
Trueman,
R,
(
1990)
ICI
Americas
Inc.
Phase
3
Reformat
of
MRID
00090037.
An
Examination
of
Cypermethrin
for
Potential
Mutagenicity
Using
the
Salmonella/
Microsome
Reverse
Mutation
Assay:
CTL
Report
No.:
CTL/
P/
595;
CTL
Study
Nos.:
YV0017,
YV0199,
YV0026.
Prepared
by
ICI
Central
Toxicology
Laboratory.
40
p.

92027063
Dean,
B.
(
1990)
ICI
Americas
Inc.
Phase
3
Reformat
of
MRID
00090038.
Toxicity
Studies
with
WL
43467:
Chromosome
Studies
on
Bone
Marrow
Cells
of
Chinese
Hamsters
After
Two
Daily
Oral
Doses
of
WL
43467:
Shell
Report
No.:
TLGR.
0136.77;
Shell
Study
No.:
1110;
CTL
Report
No.:
CTL/
C/
1052.
Prepared
by
Shell
Toxicology
Laboratory,
Shell
Research
Centre.
23
p.
8.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
41
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Table
­
See
Section
4.1
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Table*

Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
870.3100
90­
Day
oral
toxicity
­
rat
MRID
00056802
&
92027034
(
1980)/
Unacceptable
ppm
=
0,
75,
150
or
1500
mg/
kg/
day
=
0,
3.75,
7.5
or
75
NOAEL
=
7.5
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body
weight
in
both
sexes.

870.3100
90­
Day
oral
toxicity
­
rat:
zcypermethrin
MRID
41776101
(
1990)/
Acceptable
ppm
=
0,
10,
50,
150,
250,
500
or
900
mg/
kg/
day
=
M:
0,
0.6,
2.7,
8.4,
13.8,
28.2
or
55.7;
F:
0,
0.6,
3.3,
9.6,
16.3,
32.2
or
65.2
NOAEL
=
M
=
13.8
(
M),
16.3
(
F)
mg/
kg/
day
LOAEL
=
28.2
mg/
kg/
day
(
M)
based
on
decreased
body
wt,
body
wt
gain
and
food
consumption;
at
55.7
mg/
kg/
day,
mortality
as
well
as
decreased
RBC,
WBC,
HGB
&
HCT
plus
increase
in
BUN.
32.2
mg/
kg/
day
(
F)
based
on
decreased
body
wt,
body
wt
gain
and
food
consumption
as
well
as
interference
with
estrous
cycle
and
decreased
glucose;
mortality
at
65.2
mg/
kg/
day.

870.3150
90­
Day
oral
toxicity
in
dogs
(
feeding)
MRID
44527002
(
1994)/
Acceptable
ppm
=
0,
300,
600,
800
or
1100
mg/
kg/
day
=
M:
0,
10.4,
20.7,
24.6
or
37.0
F:
0,
12.2,
25.4,
34.3
or
45.2
NOAEL
=
24.6
(
M),
34.3
(
F)
mg/
kg/
day
LOAEL
=
37.0
(
M),
45.2
(
F)
mg/
kg/
day
based
on
tremors
as
well
as
decreased
body
wt
and
body
wt
gains
in
both
sexes.

870.3150
90­
Day
oral
toxicity
in
dogs
(
feeding)
MRID
00112929
(
1977)/
Unacceptable
ppm
=
0,
5,
50,
500
or
1500
mg/
kg/
day
=
0,
0.125,
1.25,
12.5
or
37.5
NOAEL
=
12.5
mg/
kg/
day
LOAEL
=
37.5
mg/
kg/
day
based
on
clinical
signs
(
whole
body
tremors,
exaggerated
gait,
ataxia,
incoordination,
hyperaesthesia,
licking
&
chewing
of
paws;
diarrhea,
anorexia)
&
decreased
body
wt
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
42
870.3200
21­
Day
dermal
toxicity
­
rat:
zcypermethrin
MRID
45010401
(
1999)/
Acceptable
mg/
kg/
day
=
0,
100,
500
or
1000
NOAEL
=
systemic:
1000
mg/
kg/
day.
Dermal:
<
100
mg/
kg/
day
LOAEL
=
systemic:
>
1000
mg/
kg/
day
(
LIMIT
DOSE).
Dermal:
100
mg/
kg/
day,
based
on
erythema
&/
or
eschar
1/
10
M
&
6/
10
F;
desquamation
0/
10
M
&
2/
10
F
(
no
effects
in
any
M
or
F
controls).

870.3200
21­
Day
dermal
toxicity
­
rabbit
MRID
00090035
(
1981)/
Acceptable
mg/
kg/
day
=
0,
2,
20,
200
NOAEL
=
Systemic
nonabraded
animals:
200
mg/
kg/
day
(
HDT)
Dermal:
20
mg/
kg/
day
LOAEL
=
Systemic
nonabraded
animals:
>
200
mg/
kg/
day
(
HDT).
Dermal:
200
mg/
kg/
day
based
on
signs
of
dermal
irritation.

870.3465
21­
Day
inhalation
toxicity
MRID
43507101
(
1994)/
Acceptable
mg/
L
=
0,
0.01,
0.05
or
0.25
(
nose
only)
NOAEL
=
0.01
mg/
L
LOAEL
=
0.05
mg/
L
based
on
decreases
in
body
weight.

870.3700a
Prenatal
developmental
in
rats
MRID
00056804,
92027039
&
92027601
(
1978)/
Acceptable
mg/
kg/
day
=
0,
17.5,
35
or
70
Maternal
NOAEL
=
17.5
mg/
kg/
day
LOAEL
=
35
mg/
kg/
day
based
on
decreased
body
wt
gain;
at
70mg/
kg/
day,
splayed
limbs,
spasms
&
hypersensitivity
to
noise
&
convulsions.
Developmental
NOAEL
=
70
mg/
kg/
day
(
HDT).
LOAEL
=
>
70
mg/
kg/
day
.

870.3700a
Prenatal
developmental
in
rats
­
zcypermethrin
MRID
41776102
(
1990)/
Acceptable
mg/
kg/
day
=
0,
5,
12.5,
25
or
35
Maternal
NOAEL
=
12.5
mg/
kg/
day
LOAEL
=
25
mg/
kg/
day,
based
on
ataxia,
urinestained
abdominal
fur,
fecal­
stained
perineal
fur,
decreased
food
consumption
&
decreased
body
wt
gain.
Developmental
NOAEL
$
35
mg/
kg/
day
LOAEL
=
>
35
mg/
kg/
day
870.3700b
Prenatal
developmental
in
rabbits
MRID
43776301
&
43776302
(
1994)/
Acceptable
mg/
kg/
day
=
0,
100,
450
or
700
Maternal
NOAEL
=
100
mg/
kg/
day
LOAEL
=
450
mg/
kg/
day
based
on
decreased
body
wt
gain;
anorexia,
abdomino­
genital
staining,
decreased
feces
&
red
or
pink
material
in
the
pan
(
few
does).
At
700,
anorexia,
abdomino­
genital
staining,
decreased
feces
&
red
or
pink
material
in
the
pan
were
observed.
Developmental
NOAEL
=
700
mg/
kgday
LOAEL
=
>
700
mg/
kg/
day
(
highest
dose
tested)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
43
870.3700b
Prenatal
developmental
in
rabbits
MRID
00056805
(
1978)/
Unacceptable
[
dosed
by
capsule]
mg/
kg/
day
=
0
(
empty),
0
(
corn
oil),
3,
10
or
30
Maternal
NOAEL
=
30
mg/
kg/
day
LOAEL
>
30
mg/
kg/
day
(
HDT)
Developmental
NOAEL
=
30
mg/
kg/
day
LOAEL
=
>
30
mg/
kg/
day
(
highest
dose
tested)

870.3800
Reproduction
and
fertility
effects
MRID
00112912,
42068504
&
92027040
(
1982)/
Acceptable
ppm
=
0,
50,
150
or
1000/
750
(
to
750
after
wk
12
due
to
severe
neurological
signs)
mg/
kg/
day
=
0,
2.5,
7.5
or
50/
37.5
[
2
litters/
generation]
Parental/
Offspring
NOAEL
=
7.5
mg/
kg/
day
LOAEL
=
50/
37.5
mg/
kg/
day
based
on
decreased
body
wt
gain
in
both
sexes
and
decreased
mean
litter
weight
gain
during
lactation.

870.3800
Reproduction
and
fertility
effects
MRID
00090040
(
1979)/
Unacceptable
ppm
=
0,
10,
100
or
500
mg/
kg/
day
=
0,
0.5,
5
or
25
[
2
litters/
generation]
Parental/
Systemic
NOAEL
=
5
mg/
kg/
day
LOAEL
=
25:
based
on
decreased
body
wt
gain.
Offspring
NOAEL
=
5
mg/
kg/
day
LOAEL
=
25:
based
on
decreased
body
wt
gain
(
lactation
day
21).

870.3800
Reproduction
and
fertility
effects
­
zcypermethrin
MRID
41968204
(
1991)/
Acceptable
ppm
=
0,
7.5,
25,
100,
375
or
750
mg/
kg/
day
=
0,
0.5,
1.8,
7,
27
or
45
[
1
litter/
generation]
Parental/
Systemic
NOAEL
=
7
mg/
kg/
day
LOAEL
=
27
mg/
kg/
day
based
on
decreased
body
wt
gain
(
most
noticeable
during
lactation)
and
increased
relative
brain
wts
M
&
F;
at
45
mg/
kg/
day,
some
neurotoxic
clinical
signs
in
a
few
animals
(
some
mortality)
.
Offspring
NOAEL
=
7
mg/
kg/
day
LOAEL
=
27
mg/
kg/
day,
based
on
decreased
body
wt
gain
during
lactation;
at
45
mg/
kg/
day,
pup
mortality.

870.4100a
Chronic
toxicity
rats
MRID
00112910
&
9202741
(
1982)/
Acceptable
ppm
=
0
#
1,
0
#
2,
20,
150
or
1500
mg/
kg/
day
=
0,
0,
1,
7.5
or
75
NOAEL
=
7.5
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreases
in
body
wt
gain
(
both
sexes)
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
44
870.4100b
Chronic
toxicity
dogs
(
capsule)
MRID
00112909,
42068503
&
92027037
(
1982)/
Acceptable
mg/
kg/
day
=
0,
1,
5
or
15
NOAEL
=
1
mg/
kg/
day
LOAEL
=
5
mg/
kg/
day
based
on
gastrointestinal
effects
(
liquid
stool);
at
15
mg/
kg/
day,
body
tremors,
gait
abnormalities,
uncoordination,
disorientation
&
hypersensitivity
to
noise
plus
decrease
in
body
weight.

870.4100b
Chronic
toxicity
dogs
(
feeding)
MRID
44536801
(
1995)/
Acceptable
ppm
=
0,
100,
200,
600
or
1100
mg/
kg/
day
=
M:
0,
2.9,
6.0,
20.4,
33.9
F:
0,
3.3,
5.7,
18.1,
38.1
NOAEL
=
6
mg/
kg/
day
(
M),
5.7
mg/
kg/
day
(
F)
LOAEL
=
20.4
mg/
kg/
day
(
M)
based
on
abnormal
clinical
signs
(
tremors,
excessive
salivation,
irregular
gait);
at
33.9
mg/
kg/
day,
mortality.
18.1
mg/
kg/
day
(
F)
based
on
decreased
body
wt
&
wt
gains.

870.4200
Carcinogenicity
rats
MRID
00112910
&
9202741
(
1982)/
Acceptable
ppm
=
0
#
1,
0
#
2,
20,
150
or
1500
mg/
kg/
day
=
0,
0,
1,
7.5
or
75
NOAEL
=
7.5
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreases
in
body
wt
gain
(
both
sexes).
No
evidence
of
carcinogenicity
870.4300
Carcinogenicity
mice
MRID
00112911
&
92027038
(
1982)/
Acceptable
ppm
=
0
#
1,
0
#
2,
100,
400
or
1600
mg/
kg/
day
=
0,
0,
14,
57
or
229
[
M
=
97
weeks;
F
=
101
weeks]
NOAEL
=
14
mg/
kg/
day
LOAEL
=
57
mg/
kg/
day
(
M)
based
on
increased
absolute
(
20%)
liver
wts
Females,
there
was
a
15%
increase
in
relative
liver
wts
only
at
229
mg/
kg/
day.
CANCER:
positive
for
induction
of
benign
alveologenic
neoplasms.

870.5265
Salmonella
typhimurium
&
S.
cerevisiae
reverse
mutation
assay
MRIDs
00090037,
92027042,
92027062,
00090036,
00126834
(
1981)/
Acceptable
4,
20,
100,
500,
2500
µ
g/
plate
Negative
up
to
doses
of
2500
µ
g/
plate.

870.5380
in
vivo
cytogenetics
MRIDs
0090038,
92027043
(
1980)/
Acceptable
0,
20,
40
mg/
kg
No
evidence
of
structural
chromosomal
aberrations
in
rat
bone
marrow
at
20
or
40
mg/
kg.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
45
870.5450
Dominant
lethal
assay
in
the
rodent
MRID
00090039
1980/
Acceptable
0,
2.5,
5,
7.5,
10
mg/
kg/
day
for
5
days
No
evidence
of
dominant
lethal
activity
in
CD­
1
strain
mice
up
to
10
mg/
kg/
day
for
five
consecutive
days.

870.5550
Unscheduled
DNA
synthesis
in
mammalian
cells
in
culture
MRID
41599801
(
1990)/
Acceptable
100,
200
mg/
kg
No
unscheduled
DNA
synthesis
was
observed
at
any
dose
level
up
to
200mg/
kg
in
corn
oil
in
Alpk:
APfSD
strain
rats
(
males)
assessed
4
and
12
hours
post
dosing.
200
mg/
kg
dose
was
considered
near
the
MTD.

870.6200a
Acute
neurotoxicity
screening
battery
MRID
43152001
(
1994)/
Acceptable
mg/
kg
=
0,
30,
100
or
200
NOAEL
=
30
mg/
kg/
day
LOAEL
=
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).

870.6200a
Acute
neurotoxicity
screening
battery
MRID
N/
A
1993/
Acceptable
mg/
kg
=
0,
20,
60,
120
LITERATURE
STUDY
NOAEL
=
<
20
mg/
kg/
day
LOAEL
=
20
mg/
kg
based
on
decreased
motor
activity
and
gait
abnormalities.
(
Conducted
at
RTP).

870.6200a
Acute
neurotoxicity
screening
battery
­
z­
cypermethrin
MRID
44962201
(
1998)/
Acceptable
mg/
kg/
day
=
0,
10,
50
or
250
NOAEL
=
10
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day
based
on
clinical
signs
(
abdominogenital
staining,
oral
discharge,
splayed
hindlimbs,
staggered
gait
&
tremors);
FOB
findings
(
abnormal
mobile
posture,
splayed
hindlimbs,
soiled
fur
&
unable
to
walk);
at
250,
more
severe
findings.

870.6200b
Subchronic
neurotoxicity
screening
battery
MRID
43152002
1993/
Acceptable
ppm
=
0,
500,
1300
or
1700
mg/
kg/
day
=
M:
0,
31,
77
or
102;
F:
0,
37,
95
or
121
NOAEL
=
31
mg/
kg/
day
LOAEL
=
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.

870.6200b
Subchronic
neurotoxicity
screening
battery
­
z­
cypermethrin
MRID
44962202
(
1999)/
Acceptable
ppm
=
0,
75,
400
or
750
mg/
kg/
day
=
M:
0,
5.0,
26.3
or
47.2;
F:
0,
5.9,
31.5
or
55.6
NOAEL
=
5.0
mg/
kg/
day
(
M);
31.5
mg/
kg/
day
(
F)
LOAEL
=
26.3
mg/
kg/
day
(
M)
based
on
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption;
55.6
mg/
kg/
day
(
F)
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Resultsa
46
870.7485
Metabolism
and
pharmacokinetics
41551102
­
04
(
1977­
78)/
Acceptable
0.61
mg/
animal;
1.3mg/
kg;
1
mg/
kg
or
less
Several
studies
with
both
rats,
dogs
and
mice
are
available
to
support
the
requirement
for
metabolism
in
mammals.
Some
of
these
studies
assess
individual
cis
and
trans
radiolabelled
isomers
and
other
studies
assess
the
metabolism
of
cypermethrin
with
the
label
in
either
the
cyclopropyl
of
the
phenoxybenzyl
ring.
In
general
the
following
has
been
demonstrated
from
these
studies:
cypermethrin
is
readily
absorbed
from
the
gastrointestinal
tract
and
extensively
metabolized.
It
mostly
excreted
in
the
urine
that
contains
several
characterized
metabolites
derived
from
conjugation
of
the
hydrolysis
products
of
the
parent
compound
following
cleavage
of
the
esteratic
linkage
site.

870.7485
Metabolism
and
pharmacokinetics
43261603
(
1992)/
Acceptable
31.03
mg
Mean
total
DCVA
excretion
was
0.33%
of
the
administered
dose.
However,
considering
that
DCVA
is
further
metabolized
this
value
would
under
estimate
dermal
absorption.
The
sum
of
3PBA
and
4OH3PBA
excretion
ranged
from
0.85
to
1.77%
(
mean
1.23%).
Because
cypermethrin
is
hydrolized
to
yield
equimolar
quantities
of
DCVA
and
3PBA
these
values
are
not
additive.

870.7600
Dermal
penetration
N/
A
No
study
is
available.

aStudies
conducted
with
cypermethrin
unless
specified
otherwise.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
47
8.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Cypermethrin
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
Effectsb
Acute
Dietary
general
population
including
infants
and
children
NOAEL
=
10
mg
a.
i./
kg
UF
=
1000a
Acute
RfD
=
0.01
mg/
kg
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.01
mg/
kg
Acute
neurotoxicity
study
in
the
rat
(
z­
cypermethrin).
LOAEL
=
50
mg/
kg
based
on
clinical
signs
of
toxicity
and
FOB
findings.

Chronic
Dietary
all
populations
NOAEL=
6
mg
a.
i./
kg/
day
UF
=
1000a
Chronic
RfD
=
0.006
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.006
mg/
kg/
day
Chronic
feeding
study
in
the
dog.
LOAEL
=
20.4/
18.1
mg/
kg/
day
based
on
clinical
signs
of
neurotoxicity
and
mortality
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females.

Short­
Term
Incidental
Oral
(
1
to
30
days)
NOAEL=
10
mg
a.
i./
kg/
day
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
N/
A
Acute
neurotoxicity
study
in
the
rat
(
z­
cypermethrin).
LOAEL
=
50
mg/
kg/
day
based
on
clinical
signs
of
neurotoxicity
and
changes
in
the
FOB
Intermediate­
Term
Incidental
Oral
(
1
­
6
months)
NOAEL=
5.0
mg
a.
i./
kg/
day
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
N/
A
Subchronic
neurotoxicity
study
in
the
rat
(
z­
cypermethrin).
LOAEL
=
26.3
mg/
kg/
day
based
on
decreased
motor
activity,
increased
landing
foot
splay,
and
decreased
body
weights,
body
weight
gains,
and
food
consumption
Short­
and
Intermediate­
Term
Dermal
(
1
day
to
6
months
None
Residential
LOC
for
MOE
=
N/
A
Occupational
LOC
for
MOE
=
N/
A
No
systemic
effects
in
21­
day
dermal
study
(
z­
cypermethrin)
up
to
1000
mg/
kg/
day&
no
developmental
concern.
No
hazard
identified
to
support
quantitation
of
risk.
CYPERMETHRIN/
March/
2003
RED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effectsb
48
Long­
Term
Dermal
(>
6
months)
Oral
NOAEL=
6
mg
a.
i./
kg/
day
(
dermal
absorption
factor
=
2.5%)
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
100
Chronic
feeding
study
in
the
dog.
LOAEL
=
20.4/
18.1
mg/
kg/
day
based
on
clinical
signs
of
neurotoxicity
and
mortality
in
males,
and
decreased
body
weights
and
body
weight
gains
in
females.

Short­
and
Intermediate­
Term
Inhalation
(
1
day
to
6
months)
Inhalation
NOAEL=
0.01
mg
a.
i./
L/
day
(
2.7
mg/
kg/
day)
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
100
21­
day
inhalation
study
in
the
rat.
LOAEL
=
0.05
mg/
L/
day
(
13.5
mg/
kg/
day)
based
on
decrease
in
body
weight
and
salivation.

Long­
Term
Inhalation
(>
6
months)
Inhalation
NOAEL=
0.01
mg
a.
i./
L
(
2.7
mg/
kg/
day)
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
300
for
the
lack
of
alternative
study.
Route­
to­
route
estimation
would
result
in
less
protective
endpoint.
21­
day
inhalation
study
in
the
rat.
LOAEL
=
0.05
mg/
L/
day
(
13.5
mg/
kg/
day)
based
on
decrease
in
body
weight
and
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
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,
N/
A
=
not
applicable
aAdditional
10x
database
uncertainty
factor
for
lack
of
a
developmental
neurotoxicity
study.
bStudies
conducted
with
cypermethrin
unless
specified
otherwise.

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.
