UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
August
10,
2005
Jonathan
Wilkin,
M.
D.
Director,
Division
of
Dermatologic
and
Dental
Drug
Products
Center
for
Drug
Evaluation
and
Research
Food
and
Drug
Administration
Mail
Code
HFD­
540
9201
Corporate
Blvd.
Rockville,
MD
20850
Dear
Dr.
Wilkin:

As
you
know,
EPA
has
been
considering
how
to
include
in
its
safety
assessment
those
exposures
resulting
from
pharmaceutical
uses
of
pesticide
products.
The
Office
of
Pesticide
Programs
(
OPP)
has
completed
a
draft
document,
"
Determination
of
Permethrin
Pharmaceutical
and
Pesticide
Co­
Exposure,"
and
is
providing
it
to
FDA
for
review
and
comment.
The
ultimate
goal
of
this
draft
document
is
to
present
the
proposed
safety
findings
on
permethrin
as
a
pharmaceutical
and
pesticide
product
from
the
joint
perspective
of
FDA
and
EPA.
OPP
intends
to
release
the
document
for
public
comment
along
with
its
human
health
and
ecological
risk
assessments,
in
late
August,
as
part
of
the
public
participation
process
for
reregistering
pesticides.
Following
a
public
comment
period,
the
document
will
also
be
incorporated
into
the
Reregistration
Eligibility
Decision
for
Permthrin,
currently
scheduled
for
June
2006.

As
discussed
in
the
attached
document,
section
408
of
the
Federal
Food
Drug
and
Cosmetic
Act
requires
EPA
to
consider
potential
sources
of
exposure
to
a
pesticide
in
addition
to
the
dietary
sources
expected
to
result
from
a
pesticide
use
subject
to
the
tolerance.
The
statute
also
requires
that
in
order
to
set
or
maintain
a
pesticide
tolerance,
EPA
must
"
determine
that
there
is
a
reasonable
certainty
of
no
harm "
Under
FFDCA
section
505,
FDA
reviews
human
drugs
for
safety
and
effectiveness
and
may
approve
a
drug
notwithstanding
the
real
possibility
that
some
patients
may
experience
adverse
side
effects.
EPA
does
not
believe
that,
for
the
purposes
of
section
408
dietary
risk
assessment,
it
is
compelled
to
treat
a
pharmaceutical
patient
the
same
as
a
non­
patient,
or
to
assume
that
combined
exposures
to
pesticide
and
pharmaceutical
residues
that
lead
to
a
physiological
effect
constitutes
"
harm"
under
the
meaning
of
section
408.
Rather,
EPA
believes
the
appropriate
way
to
harmonize
sections
408
and
505
is
to
examine
the
impact
that
the
additional
non­
occupational
pesticide
exposures
would
have
to
a
pharmaceutical
patient
exposed
to
a
similar
(
or,
in
some
cases,
the
same)
compound.
Where
the
additional
pesticide
exposure
has
not
more
than
a
minimal
impact
on
the
pharmaceutical
patient,
EPA
could
make
a
reasonable
certainty
of
no
harm
finding
for
the
pesticide
tolerances
of
that
compound
under
section
408.
If
the
potential
impact
on
the
pharmaceutical
user
as
a
result
of
co­
exposure
from
pesticide
use
is
not
deemed
to
be
minimal,
then
the
Agencies
could
discuss
appropriate
measures
to
reduce
exposure
from
one
or
both
sources.

Under
this
approach,
EPA
must
consider
the
incremental
impact
of
exposure
to
permethrin
pesticide
residues
on
the
pharmaceutical
patient,
and
FDA's
authority
on
this
issue
is
clearly
important.
Accordingly,
EPA
has
prepared
the
following
attached
draft
documents:
"
Determination
of
Permethrin
Pharmaceutical
and
Pesticide
Co­
Exposure"
(
Attachment
1);
and
"
Permethrin
Pesticide
Co­
Exposure
Estimates
Worksheet."
(
Attachment
2),
which
describes
EPA's
rationale
and
assessment
of
potential
impact
on
the
pharmaceutical
user
as
a
result
of
co­
exposure
from
pesticide
use
of
permethrin.
This
information
is
being
provided
to
FDA
for
consideration
in
determining
whether
the
additional
pesticide
exposure
results
in
no
more
than
a
minimal
impact
on
the
pharmaceutical
patient.
EPA
requests
that,
following
your
review
of
this
information,
FDA
provide
a
letter
summarizing
your
conclusions,
as
this
will
be
an
important
part
of
EPA's
public
record
on
this
issue.
In
light
of
the
schedule
for
public
release
of
this
information,
we
request
FDA
to
provide
your
written
determination
to
EPA
by
August
23rd.
If
you
have
comments
on
the
attached
information,
please
let
us
know
and
we
will
schedule
a
conference
call
or
meeting
to
exchange
comments
and
discuss
FDA's
assessment.

In
addition,
both
EPA
and
FDA
have
registrations
for
a
permethrin
impregnated
mattress
liner,
which
is
not
included
in
the
co­
exposure
assessment.
We
do
not
have
adequate
data
to
assess
the
exposure
from
this
product,
however,
given
the
application
rate
and
the
use
pattern
compared
to
the
topical
pharmaceutical
cremes,
we
assume
that
the
exposure
to
the
cremes
would
be
greater,
and
therefore
is
adequately
covered
in
our
co­
exposure
assessment
attached.
Please
confirm
this
assumption
in
your
response,
or
let
us
know
if
you
would
like
to
discuss
it
further.

Thank
you
for
your
continued
cooperation.
If
you
have
any
comments
or
questions,
please
do
not
hesitate
to
contact
me
or
Jacqueline
Guerry
of
my
staff
at
(
703)
305­
0024.

Sincerely,

Debra
Edwards,
Ph.
D.
Director
Special
Review
and
Reregistration
Division
Attachments:
Draft
Determination
of
Permethrin
Pharmaceutical
and
Pesticide
Co­
Exposure
Permethrin
Pesticide
Co­
Exposure
Estimates
Worksheet
2
ATTACHMENT
1
DETERMINATION
OF
PERMETHRIN
PHARMACEUTICAL
AND
PESTICIDE
CO­
EXPOSURE
Pharmaceutical
Use
of
Permethrin
In
addition
to
the
registered
pesticide
uses,
permethrin
is
also
produced
for
use
as
a
pharmaceutical
product
for
treating
scabies
and/
or
lice.
Permethrin
1%
is
indicated
for
lice,
under
the
trade
names
Nix
®
Cream
Rinse
and
Nix
®
over­
the­
counter,
by
Insight
Pharmaceuticals.
Permethrin
5%
is
indicated
for
scabies
under
the
trade
name
Elimite
®
and
Acticin
®
,
by
Allergan,
Inc.
and
Alpharma
Inc.
respectively.
Permethrin
1%
was
approved
as
a
prescription
in
1986,
and
over­
the­
counter
in
1990;
permethrin
5%
was
approved
as
a
prescription
in
1989.

Approximately
65
million
pounds
of
permethrin
have
been
sold
for
pharmaceutical
use
within
the
last
five
years
(
2000­
2004).
The
majority
of
permethrin
is
obtained
through
prescriptions.
In
2004,
prescriptions
constituted
81%
of
the
permethrin
market.

Permethrin
Nix
(
1%)
Labeling
Permethrin
1%
is
available
over
the
counter
to
treat
lice
on
children
and
adults.
Patients
are
directed
by
the
label
to
saturate
the
hair
and
scalp,
including
behind
the
ears
and
back
of
neck,
with
Nix
creme
rinse,
and
leave
it
on
for
a
maximum
of
10
minutes.
A
second
treatment
with
Nix
is
suggested
if
infestation
of
lice
persist
after
7
or
more
days.
Several
contraindications
and
warnings
appear
on
the
product
label
including:
information
and
directions
in
the
case
of
accidental
ingestion;
cautionary
statements
to
pregnant
or
nursing
mothers;
and
a
warning
that
possible
adverse
reactions
may
occur
as
a
result
of
labeled
use.
The
label
also
states
that
use
on
infants
under
2
months,
use
near
the
eyes,
inside
the
nose,
ear,
mouth
or
vagina,
and
use
on
the
eyebrows
or
eyelashes
is
prohibited.
It
also
states
that
for
those
allergic
to
ragweed,
the
product
may
cause
difficulty
breathing
or
an
asthmatic
episode.

Several
other
pharmaceutical
products
are
available
to
treat
head
lice.
There
is
another
over­
thecounter
product
(
no
prescription
needed)
available,
which
contains
pyrethrum
(
0.33%)
and
piperonyl
butoxide
as
a
shampoo
and
cream
rinse
(
Rid
®
)
.
There
are
two
additional
pharmaceuticals
available
by
prescription
only,
one
contains
malathion
(
0.5%)
as
a
lotion
(
Ovide),
and
the
other
contains
lindane
(
1%)
as
a
shampoo.

Permethrin
5%
Labeling
Elimite
®
5%
cream
is
a
prescription
topical
scabicide
agent
for
use
on
adults
and
children.
The
labeling
directs
the
patient
to
massage
Elimite
®
into
the
skin
from
the
head
to
the
soles
of
the
feet.
Although
scabies
rarely
infests
the
scalp
of
adults,
they
may
infect
the
hairline,
neck,
temple,
and
forehead
of
infants
and
geriatric
patients;
therefore,
the
label
specifies
applying
Elimite
®
on
the
scalp,
temples,
and
forehead
of
infants.
The
label
suggests
that
30
grams
is
3
sufficient
for
the
average
adult,
but
does
not
specify
a
dosage
for
children.
The
cream
should
be
left
on
the
skin
for
8
to
14
hours,
and
then
removed
by
washing
(
shower
or
bath).
One
dose
should
be
curative;
however,
if
living
mites
are
found
after
14
days
a
retreatment
is
necessary.
The
label
contraindicates
patients
with
known
hypersensitivities
to
any
of
its
components,
synthetic
pyrethroids,
or
pyrethrin.
Several
warnings
appear
on
the
labels
including
cautionary
statements
to
pregnant
woman
and
nursing
mothers,
children
less
then
2
months
of
age,
and
to
geriatric
patents
with
impaired
renal
function.
Additionally,
pre­
cautions
and
potential
adverse
reactions
are
listed
on
the
labels.
No
maximum
dose
is
specified.
The
label
claims
that
no
instances
of
overdosing
(
accidental
ingestion
of
Elimite
®
)
have
been
reported.
However,
directions
for
what
to
do
following
accidental
ingestion,
should
it
occur,
is
on
the
label.

Both
Lindane
Lotion
®
1%
and
Eurax
®
,
which
contains
crotamiton,
are
prescribed
as
topical
scabicides.
Lindane
Lotion
®
1%,
however,
is
recommended
for
use
only
for
after
patients
have
failed
first
line
treatment
with
safer
medications.

Risk
Management
Before
establishing
a
tolerance,
FFDCA
section
408(
b)(
2)(
D)(
vi)
requires
EPA
to
"
consider,
among
other
relevant
factors,
...
available
information
concerning
the
aggregate
exposure
levels
of
consumers
(
and
major
identifiable
subgroups
of
consumers)
to
the
pesticide
chemical
residue
and
to
other
related
substances...."
Accordingly,
EPA
must
consider
other
potential
sources
of
exposure
in
addition
to
the
dietary
exposure
to
residues
that
would
be
expected
to
result
from
the
pesticide
use
subject
to
the
tolerance.
Therefore,
in
considering
whether
a
dietary
exposure
to
a
pesticide
chemical
residue
is
safe,
EPA
will
consider
exposures
to
the
same
or
similar
substances
that
result
from
their
pharmaceutical
use.
Such
exposures
may
include
direct
exposure
to
the
person
being
treated
and
secondary
exposures
to
other
persons.

FFDCA
section
408(
b)(
2)(
A)(
i)
provides
that
EPA
may
establish
a
new
pesticide
chemical
tolerance
"
only
if
...
the
tolerance
is
safe."
Section
408(
b)(
2)(
A)(
i)
requires
that
in
order
to
make
this
safety
finding,
the
Agency
must
"
determine
that
there
is
a
reasonable
certainty
of
no
harm...."
Thus
"
harm"
is
the
central
focus
of
a
section
408
analysis.
For
its
part,
FDA
reviews
human
drugs
to
assure
that
drugs
are
safe
and
effective
under
section
505
of
the
FFDCA.

EPA
ordinarily
considers
any
physiological
effect
caused
by
a
pesticide
chemical
residue
to
be
a
harm,
for
purposes
of
section
408.
FDA
uses
a
different
approach
in
evaluating
the
safety
of
human
drugs
under
section
505
(
21
U.
S.
C.
§
355).
Many
drugs
are
designed
to
cause
physiological
effects
in
patients,
and
many
drugs
are
approved
notwithstanding
the
real
possibility
that
at
least
some
patients
are
expected
to
experience
unwelcome
side
effects.
EPA
has
considered
the
appropriate
way
of
assessing
whether
pharmaceutical
users
are
"
harmed"
under
the
meaning
of
the
section
408
when
those
users
are
exposed
to
pesticide
residues
that
could
conceivably
have
an
additive
impact
with
the
pharmaceutical
exposures.
The
Agency
has
concluded
that
it
is
not
compelled
under
the
FFDCA
to
treat
pharmaceutical
patients
the
same
as
it
treats
non­
patients,
or
to
automatically
assume
that
any
combined
exposure
of
pesticide
and
pharmaceutical
residues
that
may
result
in
a
physiological
effect
constitutes
harm
under
the
meaning
of
section
408.
To
do
so
would
lead
to
the
anomalous
result
that
pharmaceutical
4
exposures
alone
could
be
considered
"
safe"
for
pharmaceutical
users
under
section
505
of
the
FFDCA
and
"
unsafe"
at
the
same
time
for
the
same
users
under
section
408
(
since
the
desired
pharmaceutical
exposures
often
will
exceed
the
pesticide
"
risk
cup"
level
on
their
own).
Instead,
EPA
believes
the
appropriate
way
of
harmonizing
sections
408
and
505
when
determining
whether
exposures
to
pesticides
are
"
unsafe"
for
pharmaceutical
users
is
to
examine
the
impact
that
the
additional
non­
occupational
pesticide
exposures
will
have
on
pharmaceutical
patients
who
may
be
exposed
to
a
similar
substance
(
or,
in
some
cases,
the
same
substance)
through
the
use
of
a
human
drug.
Where
the
additional
non­
occupational
pesticide
exposures
have
no
more
than
a
minimal
impact
on
the
pharmaceutical
patient,
EPA
could
make
the
reasonable
certainty
of
no
harm
finding
for
pesticide
tolerances
under
section
408
(
provided,
of
course,
that
the
section
408
finding
can
be
made
for
all
other
populations
as
well).
Where,
however,
the
additional
non­
occupational
pesticide
exposure
would
result
in
non­
negligible
additional
risks
to
the
pharmaceutical
patients,
EPA
would
not
be
able
to
make
the
necessary
finding
under
section
408
unless
appropriate
risk
mitigation
measures
could
be
implemented.
Such
measures
could
involve
changes
to
the
pesticide
label,
to
the
drug
label,
or
both.

Although
both
EPA
and
FDA
exercise
authority
under
the
FFDCA,
their
authorities
come
from
different
provisions,
which
is
reflected
in
the
different
standards
and
processes
used
by
the
two
agencies
when
carrying
out
their
respective
roles.
EPA
regulates
pesticide
chemicals
in
such
a
way
that
there
is
reasonable
certainty
that
no
harm
will
result
from
dietary
exposures
to
the
pesticide
chemical
residues.
Because
EPA
must
regulate
to
a
standard
of
"
no
harm,"
it
incorporates
uncertainty
and/
or
safety
factors
into
its
quantitative
risk
characterization
to
ensure,
to
the
extent
possible,
that
exposure
to
a
pesticide
chemical
is
below
the
level
expected
to
result
in
an
adverse
effect
in
a
sensitive
population.
In
regulating
human
drugs
on
the
other
hand,
FDA
recognizes
that
a
human
drug
may
have
associated
adverse
effects
and,
therefore,
determines
if
the
risk
from
a
drug
is
acceptable
when
compared
to
non­
treatment
of
the
condition.
Hence,
FDA
does
not
employ
a
quantitative
risk
assessment
similar
to
that
of
the
EPA,
nor
does
it
incorporate
large
safety
margins.
Rather,
FDA
considers
other
factors,
in
addition
to
the
benefits
of
a
compound,
such
as
the
type
and
reversibility
of
potential
side­
effects
from
a
product
when
reaching
its
regulatory
decision.

EPA
and
FDA
have
been
working
together
to
strengthen
their
respective
regulatory
decisions
while
bearing
in
mind
their
regulatory
and
normative
differences.
Both
EPA
and
FDA
have
considered
the
safety
of
individuals
who
may
be
exposed
to
both
pesticidal
and
pharmaceutical
permethrin
to
determine
whether
any
measures
need
to
be
taken
to
reduce
exposure.
In
addition,
EPA
and
FDA
have
been
sharing
information
and
expertise
in
order
that
each
may
gain
a
broader,
more
considered
regulatory
position
regarding
permethrin
products,
and
strengthen
the
technical
and
policy
analyses
of
each
agency.
Consideration
of
the
population
which
may
be
coexposed
and
cooperative
exchange
between
the
two
agencies
serves
to
augment,
not
undermine,
the
findings
of
each
agency
whose
objectives
are
to
protect
and
enhance
public
health.

FDA
Safety
Review
5
In
November
2003
the
FDA
Office
of
Drug
and
Safety
(
ODS)
completed
an
ODS
Postmarketing
Safety
Review
for
both
Elimite
5%
and
Nix
1%,
which
evaluated
the
reported
adverse
events
associated
with
permethrin
use
since
its
marketing
in
1989.
The
incident
data
base
(
the
Adverse
Exposure
Reporting
System,
AERS)
found
6843
reports
of
adverse
effect,
of
which
90%
(
6131
cases)
reported
drug
ineffectiveness.
Dermatitis
(
181),
pruritus
(
181),
alopecia
(
131),
and
pain
not
otherwise
specified
followed
as
the
most
commonly
reported
adverse
effects.
The
FDA
also
reviewed
in
detail
78
cases
coded
as
death
(
8),
hospitalization
(
36),
life­
threatening
(
2),
congenital
anomaly
(
4),
and
seizure
(
28)
adverse
events.
The
majority
of
these
cases
(
77%)
used
permethrin
to
treat
head
lice
or
scabies
treatment.
Seventy
percent
of
these
cases
associated
with
permethrin
were
reported
in
children
16
years
of
age
or
younger.
Additionally,
35%
of
the
serious
and/
or
seizure
cases
reported
misusing
permethrin.

The
FDA
review
concluded
that
the
number
of
adverse
events
reported
associated
with
permethrin
use
is
large
compared
with
lindane
or
crotamiton.
However,
unlike
lindane,
where
there
were
cases
of
death
directly
attributed
to
use
of
lindane,
there
were
no
cases
of
death
directly
attributed
to
permethrin
diagnosed
and/
or
autopsied.
Further,
the
cases
of
seizure
activity,
an
adverse
effect
currently
on
the
Elimite
5%
label,
ranked
low
compared
to
lindane
where
convulsion
and
grand
mal
convulsion
ranked
2nd
and
12th
respectively.
Eight
of
the
twenty
most
common
adverse
effects
appear
on
the
permethrin
labels,
and
the
reactions
leading
to
death,
hospitalization,
and
congential
anomaly
associated
with
permethrin
use
do
not
appear
to
represent
new
signals.

EPA's
Exposure
Information
EPA
has
estimated
potential
dietary
exposure
to
residues
in
or
on
food
commodities
and
in
drinking
water
which
occur
as
a
result
of
the
pesticide
uses
of
permethrin.
Non­
occupational
exposure
to
permethrin
can
also
occur
from
its
use
on
outdoor
and
indoor
areas,
pets,
impregnated
clothing,
and
as
part
of
mosquito
abatement
programs
where
applications
may
result
in
additional
exposure
at
residential
and
recreational
settings,
such
as
parks
and
school
playgrounds.

Human
Incident
Reporting
of
Permethrin
EPA
reviewed
several
different
data
bases
for
adverse
incidents
related
to
the
pesticide
use
of
a
compound.
The
sources
of
adverse
incidents
used
by
EPA
are
not
the
same
as
those
used
by
FDA,
and
while
some
duplication
of
reporting
may
occur
because
of
the
communication
between
reporting
centers,
it
is
not
enough
to
confound
any
conclusions
drawn
from
the
data
by
either
agency.
Of
the
many
reported
incidents
involving
permethrin,
none
refer
to
exposure
from
either
permethrin
1%
or
5%
pharmaceuticals.
The
adverse
incident
reports
gathered
by
EPA
involving
young
adults
and
children
mainly
involve
non­
occupational
pesticide
products,
and
most
are
likely
attributed
to
misuse
of
the
product.

Concurrent
Exposure
Scenarios
6
In
addition
to
the
information
and
review
provided
by
FDA,
EPA
examined
exposure
to
both
the
pharmaceutical
and
pesticide
uses
to
determine
whether
any
additional
measures
were
needed
to
protect
and
promote
the
health
of
those
who
may
be
concurrently
exposed
to
both
the
pesticide
and
pharmaceutical
sources
of
permethrin.
Limited
usage
data
on
permethrin
prescriptions
provided
by
FDA
indicates
that
children
ages
6­
16
years
received
approximately
37%
of
the
prescriptions,
and
approximately
27%
of
prescriptions
were
for
children
younger
than
5
years
old.
While
detailed
information
on
permethrin
usage
by
children
between
1
and
5
years
old
is
unknown,
the
labels
contraindicates
use
on
neonates
and
infants.

Incident
data
collected
by
FDA
indicates
that
the
majority
of
adverse
events
involving
permethrin
occurred
in
children
between
6
and
16
years
of
age.
Of
the
4,032
reports
with
submitted
age
information,
2200
(
55%)
involved
this
age
group.
A
smaller
percentage
involved
newborns
and
children
up
to
5
years
of
age,
845
cases
were
reported
(
21%).
Based
upon
the
usage
data
and
FDA's
incident
data,
EPA
believes
children
3
­
16
years
are
the
primary
subpopulation
exposed
to
permethrin
through
use
of
the
pharmaceutical
product.
EPA
then
considered
the
exposure
this
subpopulation
may
receive
from
both
pharmaceutical
and
pesticide
sources
of
permethrin
to
better
understand
the
potential
co­
exposure
event.

As
previously
mentioned,
EPA
estimates
potential
exposure
to
a
compound
from
both
occupational
and
non­
occupational
sources.
Non­
occupational
sources
include
dietary
sources
of
exposure
(
food
+
drinking
water)
and
non­
dietary
sources
such
as
residential
uses
or
wide
area
application
scenarios.
EPA
further
characterizes
dietary
exposure
as
either
acute
or
chronic.
The
EPA
considered
the
potential
exposure
from
two
non­
occupation
pesticide
scenarios:
1)
exposure
from
permethrin's
wide
area
applications
as
a
mosquitocide,
and
2)
use
by
homeowners
on
lawns
and
turf.
From
wide­
area
mosquitocide
applications,
pesticide
drift
can
deposit
onto
residential
settings
where
exposure
can
occur.
Additionally,
residential
use
of
permethrin
for
lawn
care
was
identified
by
the
Residential
Exposure
Joint
Venture
(
REJV)
survey
as
one
of
the
most
frequent
homeowner
uses
of
permethrin.
The
EPA
estimated
that
the
potential
exposure
from
the
lawn
care
scenario
would
result
in
a
greater
exposure
to
permethrin
than
the
mosquito
abatement
scenario.
Therefore,
the
lawn
care
scenario
was
selected
as
the
high­
end,
most
likely
coexposure
event.

Using
the
permethrin
1%
and
5%
registered
pharmaceutical
labels,
EPA
estimated
exposure
from
a
typical
treatment
of
both
products,
and
compared
those
to
the
potential
exposure
an
individual
would
receive
from
the
pesticide
uses
of
permethrin.
Because
Nix
and
Elimite
are
used
over
a
10
minute
period
and
an
8
­
14
hour
period,
respectively,
EPA
characterizes
the
pharmaceutical
use
as
a
short­
term
exposure.
To
estimate
combined
pesticide
exposure
for
a
7
short­
term
scenario,
EPA
integrates
average
dietary
exposure
estimates
(
food
+
drinking
water)
with
one
of
the
non­
occupational
exposure
scenarios
(
i.
e.
permethrin
used
on
residential
lawns).
EPA
estimates
that
the
combined
exposure
from
the
non­
occupational
sources
of
permethrin
is
approximately
450
to
2300
times
smaller
than
the
permethrin
exposure
a
patient
is
expected
to
receive
from
a
typical
single
application
of
Nix
and
Elimite
cremes,
respectively.
(
See
the
Attachment
2:
Permethrin
Pesticide
Co­
Exposure
Estimate
Worksheet.)
1
ATTACHMENT
2
Permethrin
Pesticide
Co­
Exposure
Estimates
Worksheet
A
core
part
of
FDA/
EPA
pharmaceutical
assessment
for
permethrin
reregistration
decision
is
a
determination
by
FDA
on
the
significance
of
the
additional
exposure
to
permethrin
a
pharmaceutical
user
would
receive
from
the
pesticide
uses
of
permethrin.

The
exposure
estimates
provided
below
reflect
the
external
dose
of
permethrin
an
individual
would
receive
in
a
reasonable
worst­
case
scenario.
EPA
has
taken
into
consideration
the
appropriate
population,
exposure
route,
and
exposure
duration
for
comparison
with
exposure
to
the
pharmaceutical
use
of
permethrin.

Population
of
Concern
Based
on
incident
data
(
AERS)
and
Nix
Cream
Rinse/
Elimite
Cream
usage
data1,
EPA
believes
that
the
primary
population
of
concern
is
children
ages
3
 
16
years.

Exposure
Route
and
Pathway
Because
Nix
Cream
Rinse
(
used
to
treat
head
lice)
is
indicated
for
use
over
a
10
minute
period
and
Elimite
Cream
(
used
to
treat
scabies)
is
indicated
for
use
over
an
8
to
14
hour
period,
EPA
would
characterize
both
these
uses
as
"
short­
term"
exposure
scenarios.
When
calculating
shortterm
pesticide
exposure
scenarios,
EPA
combines
the
following
exposure
scenarios:
1.
Chronic
dietary
exposure
(
food
+
drinking
water),
and
2.
Short­
term
(
1­
30
days)
non­
occupational
exposure,
which
include:
a)
dermal,
inhalation,
and
incidental
oral
(
toddler
only)
exposure
from
permethrin
use
in
the
residential
setting,
or
b)
dermal,
inhalation,
and
incidental
oral
(
toddler
only)
exposure
from
wide
area
applications
such
as
mosquitocide
use.

When
aggregating
non­
occupational
pesticide
exposure,
EPA
believes
a
reasonable
high­
end
exposure
scenario
would
combine
dietary
exposure
with
the
exposure
from
either
the
residential
use
of
permethrin
or
the
wide
area
treatment
uses,
such
as
the
mosquitocide
use.
The
Agency
believes
the
likelihood
is
low
that
an
individual
exposed
to
dietary
residues
(
food
+
drinking
water)
would
simultaneously
be
exposed
to
pesticide
residues
from
residential
uses
and
additionally
be
exposed
to
residues
from
wide
area
treatment
uses.
In
this
case,
EPA
combined
dietary
exposure
with
the
residential
lawn
care
uses
of
permethrin
as
these
uses
result
in
higher
permethrin
exposures
than
the
mosquitocide
uses.

Reasonable
High­
End
Exposure
Scenario
dietary
sources
residential
applications
Aggregate
(
food
+
drinking
water)
+
or
=
non­
occupational
wide
area
applications
exposure
1
According
to
the
November
3,
2003,
FDA
document
"
ODS
Postmarketing
Safety
Review
(
PID
030133),"
from
1997
to
2002
children
between
6
and
16
constitute
the
largest
user
group.
Additionally,
the
majority
of
incidents
reported
in
the
AERS
database
from
permethrin
use
involve
children
16
years
of
age
and
younger.
2
Choosing
Representative
Non­
Occupational
Exposure
Scenario
Although
Nix
Cream
Rinse/
Elimite
Cream
are
primarily
used
on
children
6
 
16
years,
EPA
chose
to
use
the
toddler
exposure
from
residential
pesticide
application
use
because
to
the
extent
toddlers
could
be
occasionally
co­
exposed,
their
predicted
total
exposure
(
mg/
kg/
day)
would
be
greater
than
other
population
subgroups.

EPA
estimated
the
exposure
from
the
residential
lawn
care
pesticide
application
scenarios
of
permethrin.
EPA
chose
the
residential
lawn
care
exposure
scenario
because
this
application
is
a
reasonable
high­
end
scenario
(
residential
lawn
care
uses
of
permethrin
result
in
higher
permethrin
exposures
than
the
mosquitocide
uses),
and
is
likely
to
result
in
the
greatest
number
of
individuals
exposed.
Toddler
exposure
estimates
for
permethrin
by
route
from
the
residential
lawn
care
application
use
are
provided
below.
(
EPA
defines
toddlers
as
individuals
of
approximately
15
kg
of
weight).

Exposure
to
Permethrin
(
mg/
kg/
day)
for
Toddlers
from
Residential
Lawn
Care
Use
Dermal
Incidental
Oral
Inhalation
Total
Permethrin
Exposure
Permethrin
 
Outdoor
Residential
0.042
0.0017
N/
A
0.044
Permethrin­
Outdoor
Residential
includes
dermal
from
lawn,
hand­
to­
mouth
from
lawn,
object­
to­
mouth
from
lawn,
and
soil
ingestion.

Chronic
Dietary
Exposure
Values
Dietary
exposure
values
account
for
permethrin
in
food
and
drinking
water.
Numerous
variables
contribute
to
the
predicted
pesticide
concentrations
in
drinking
water.
EPA
has
presented
a
dietary
exposure
for
the
subgroup
population
of
children
3
 
5
years
of
age.
To
these
values,
EPA
added
the
total
exposure
estimates
from
the
residential
lawn
care
use.

Total
Combined
Permethrin
Exposure
to
Toddler
(
mg/
kg/
day)
Dietary
exposure
0.000284
Exposure
from
residential
lawn
care
use
0.044
Total
permethrin
exposure
0.044
Summary
The
potential
dietary
exposure
(
food
+
drinking
water)
children
3
 
5
years
old
receive
from
the
pesticide
use
of
permethrin
is
small
in
comparison
to
the
potential
exposure
to
permethrin
from
the
residential
lawn
care
use.
The
total
additional
estimated
exposure
a
Nix
Cream
Rinse/
Elimite
Cream
patient
would
receive
from
the
combined
pesticide
uses
of
permethrin
is
approximately
0.044
mg/
kg/
day.

Lice/
Scabies
Exposure
From
FDA
labels
for
Nix
Cream
Rinse
(
1%)
used
to
treat
lice
and
Elimite
Cream
(
5%)
used
to
treat
scabies,
EPA
selected
the
maximum
allowable
dose
applied
(
30
grams
for
children),
and
then
converted
g
to
mg
and
adjusted
for
body
weight
(
using
15
kg
and
body
weight
of
population
of
concern)
to
obtain
the
following
lice/
scabies
dose:

Nix
Cream
Rinse
=
20
mg/
kg
Elimite
Cream
=
100
mg/
kg
3
The
additional
exposure
a
Nix
Cream
Rinse
1%
patient
may
receive
in
a
reasonable
high­
end
scenario
from
the
pesticide
uses
represents
approximately
0.22%
of
the
Nix
Cream
Rinse
dose.
In
other
words,
our
calculations
indicate
that
the
Nix
Cream
Rinse
dose
is
currently
450x
that
of
the
high­
end
exposures
predicted
for
toddlers
(
ages
3
 
5
years)
as
a
result
of
potential
exposure
from
both
dietary
sources
(
food
+
drinking
water)
and
from
residential
lawn
care
applications.

The
additional
exposure
a
Elimite
Cream
5%
patient
may
receive
in
a
reasonable
high­
end
scenario
from
the
pesticide
uses
represents
approximately
0.044%
of
the
Elimite
Cream
dose.
In
other
words,
our
calculations
indicate
that
the
Elimite
Cream
dose
is
currently
2,300x
that
of
the
high­
end
exposures
predicted
for
toddlers
(
ages
3
 
5
years)
as
a
result
of
potential
exposure
from
both
dietary
sources
(
food
+
drinking
water)
and
from
residential
lawn
care
applications.
