UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides
and
Toxic
Substances
July
31,
2002
MEMORANDUM
SUBJECT:
Lindane;
Chemical
No.
009001.
Revised
Assessment
of
Risk
from
Use
of
Lindane
for
Treatment
of
Lice
and
Scabies
DP
Barcode:
D284188;
Submission
No.
S605841
Reregistration
Case
#:
0315
FROM:
Becky
Daiss
Environmental
Health
Scientist
Reregistration
Branch
4
Health
Effects
Division
(7509C)

THROUGH:
Susan
Hummel
Branch
Senior
Scientist
Reregistration
Branch
4
Health
Effects
Division
(7509C)

TO:
Mark
Howard
Reregistration
Branch
3
Special
Review
&
Reregistration
Division
(7508C)

This
provides
HED's
revised
assessment
of
risk
from
use
of
lindane
for
treatment
of
scabies
and
lice.
The
revised
assessment
incorporates
additional
information
and
comments
provided
by
the
Food
and
Drug
Administration
(FDA).
2
1.0
ASSESSMENT
OF
RISK
FROM
USE
OF
LINDANE
TO
TREAT
SCABIES
HED's
assessment
of
risk
from
use
of
lindane
to
treat
scabies
uses
data
from
both
animal
and
human
studies
and
provides
a
range
of
risk
estimates.
EPA
conducted
analyses
using:
1)
a
Margin
of
Exposure
(MOE)
approach
based
on
animal
toxicity
data,
and
2)
a
comparison
of
lindane
blood
levels
from
one
study
which
documents
cases
of
accidental
lindane
ingestion
by
toddlers
in
which
blood
levels
were
determined
after
ingestion,
and
a
second
study
which
provides
data
on
blood
levels
of
lindane
following
application
of
lindane
to
treat
scabies.
HED
based
its
assessment
on
directions
provided
in
the
current
label
for
scabies
treatment.
It
is
important
to
note,
however,
that
FDA
is
planning
to
make
a
number
of
changes
to
the
label
including
statements
that
restrict
the
use
to
patients
who
have
attained
adult
stature
(i.
e.,
>
60
kg
body
weight).
Therefore,
HED
also
considered
pending
label
changes
in
its
assessment
of
lindane
as
a
scabies
treatment.

1.1
MOE
Approach
Under
this
approach,
an
estimated
MOE
is
calculated
based
on
a
toxicological
endpoint
recommended
by
HED's
Hazard
Identification
and
Assessment
Committee
(HIARC)
and
compared
with
the
target
MOE
for
short­
term
dermal
exposure/
risk
to
determine
whether
there
is
an
exposure
of
concern.
The
MOE
is
the
ratio
of
the
appropriate
No
Observed
Adverse
Effect
Level
(NOAEL)
to
estimated
exposure.
For
the
short­
term
dermal
endpoint,
a
NOAEL
of
6
mg/
kg/
day
was
selected
from
an
acute
oral
neurotoxicity
study
in
rats.
For
residential
exposures,
uncertainty
factors
are
used
to
determine
target
MOEs.
The
target
MOE
for
exposure
to
lindane
from
pharmaceutical
use
is
100
based
on
uncertainty
factors
(UF)
used
to
account
for
differences
among
humans
(intraspecies
variability
­
UF
of
10),
and
for
differences
between
the
test
animals
and
humans
(interspecies
extrapolation
­
UF
of
10).

Since
the
NOAEL
is
based
on
an
oral
toxicity
study,
dermal
absorption
data
are
required
to
adjust
the
oral
dose.
Two
different
dermal
absorption
factors
were
used
to
calculate
estimated
exposure.
One
was
taken
from
a
1989
article
published
in
Journal
of
Toxicological
and
Environmental
Health,
which
reported
data
from
a
dermal
absorption
study
on
rhesus
monkeys
to
determine
if
lindane
applied
for
treatment
of
lice
and
scabies
is
absorbed
into
the
blood
stream
(1).
A
second
was
taken
from
a
study
in
Toxicology
and
Applied
Pharmacology,
1974,
in
which
lindane
was
tested
on
human
subjects
to
quantify
dermal
penetration
(2).

The
monkey
study
involved
topical
application
of
1%
lotion,
at
label
prescribed
rates,
to
the
forehead,
forearm,
or
forepaw
of
monkeys
for
24
hours.
Percent
absorption
was
determined
based
on
urinary
excretion
of
14
C­
lindane.
Study
results
indicated
that
18,
34,
and
54%
of
the
applied
dose
was
absorbed
after
application
to
the
forearm,
forehead,
and
palm,
respectively.
A
weighted
average
of
20%
was
derived
based
on
the
body
surface
area
corresponding
to
the
applicable
dermal
absorption
factor
from
the
monkey
study.

For
the
human
study,
C
14
­labeled
lindane
was
applied
topically
(4    
g/
cm
2
)
to
the
forearm
and
via
the
intravenous
route
(1    
Ci).
Excretion
of
the
chemical
was
then
monitored
by
collecting
3
and
analyzing
urine
samples
during
the
5
day
testing
period.
All
results
were
calculated
as
percent
of
the
injected
or
applied
dose.
Data
from
the
IV
dosing
was
used
to
correct
the
skin
penetration
data
for
incomplete
urinary
recovery.
Lindane
was
shown
to
have
a
dermal
penetration
factor
of
9.3%
±
3.
7
(SD).

Results
of
the
scabies
MOE
assessment
for
children
and
young
adults
using
both
monkey
and
human
dermal
absorption
data
are
provided
in
Tables
1
and
2
respectively.
The
analysis
indicates
MOEs
of
concern
(MOE<
100)
from
both
high
and
low­
end
treatment
scenarios.

Table
1.
Assessment
of
Use
of
Lindane
for
Scabies
­
DAF
from
Product
Specific
Monkey
Study
Age
Group
Oral
NOAEL
(mg/
kg/
d)
Applied
Dose
(mg)
1
Body
Weight
(kg)
2
Daily
Dermal
Dose
(mg/
kg/
d)
dermal
absorption
(%)
MOE
Target
MOE
3
Young
Adult
6
600
high
end
(1
oz)
60
10
20
3
100
Young
Adult
6
300
low
end
(2
oz)
60
5
20
6
100
Child
4­
6
6
250
high
end
22
11
20
3
100
Child
4­
6
6
150
low
end
22
7
20
4
100
Toddler
1­
3
6
200
high
end
13
15
20
2
100
Toddler
1­
3
6
100
low
end
13
8
20
4
100
MOE
=
Oral
NOAEL(
mg/
kg/
day)
daily
dermal
dose
(mg/
kg/
day)
x
dermal
absorption
factor
(%)
where:
Daily
Dermal
Dose
=
applied
dose
(mg)
÷
body
weight
(kg)
Applied
Dose
=
20­
60g
of
1%
lotion
(high­
end);
10­
30
g
of
1%
lotion
(low­
end)
depending
on
age
group
Dermal
Absorption
Factor
=
20%
(weighted
avg)
where:
Palm
Dermal
Absorption
Factor
=
54%
­­
DAF
from
monkey
study;
Used
for
hands
which
are
assumed
to
be
6%
of
Dosed
Body
Surface
Area
based
on
%
of
Surface
Area/
Body
Part
from
EPA
Exposure
Factor
Handbook
(EFH)
Vol
I
Forearm
Dermal
Absorption
Factor
=
18%
­­
DAF
from
monkey
study;
Used
for
94%
of
Dosed
Body
Surface
Area
(all
but
hands)
based
on
%
of
Total
Surface
Area/
Body
Part
from
EPA
EFH
Vol
I
Dosed
Body
Surface
Area
=
entire
body
from
neck
down
Table
2.
Assessment
of
Lindane
for
Scabies
­
DAF
from
Pesticide
Exposure
in
Human
Study
Age
Group
Oral
NOAEL
(mg/
kg/
d)
Applied
Dose
(mg)
1
Body
Weight
(kg)
2
Daily
Dermal
Dose
(mg/
kg/
d)
dermal
absorption
(%)
MOE
Target
MOE
3
Young
Adult
6
600
high
end
60
10
10
6
100
Young
Adult
6
300
low
end
60
5
10
12
100
Child
4­
6
6
250
high
end
22
11
10
5
100
Child
4­
6
6
150
low
end
22
7
10
9
100
Toddler
1­
3
6
200
high
end
13
15
10
4
100
Toddler
1­
3
6
100
low
end
13
8
10
8
100
MOE
=
Oral
NOAEL(
mg/
kg/
day)
daily
dermal
dose
(mg/
kg/
day)
x
dermal
absorption
factor
(%)
where:
Daily
Dermal
Dose
=
applied
dose
(mg)
÷
body
weight
(kg)
Applied
Dose
=
20­
60
g
of
1%
lotion
(high­
end);
10­
30
g
of
1%
lotion
(low­
end)
depending
on
age
group
Dermal
Absorption
Factor
=
10%
from
human
pesticide
application
dermal
absorption
study
1
Application
rates
are
based
on
pending
label
for
young
adults
and
current
label/
estimated
body
sizes
for
small
children.
2
Young
adult
BW
is
based
on
pending
label
changes.
Child
and
toddler
BW
is
avg
from
EPA
EFH
3
Does
not
include
an
FQPA
safety
factor
which,
if
applied,
would
increase
the
Target
MOE
to
300
for
infants
and
children
4
Uncertainties
Associated
with
the
MOE
Assessment
Toxicity
Endpoint
­
The
toxicity
endpoint
used
in
the
MOE
assessment
is
based
on
an
acute
oral
neurotoxicity
study
where
the
test
material
was
administered
by
gavage.
An
oral
gavage
dose
may
be
absorbed
more
rapidly
than
the
dermal
dose,
producing
a
higher
peak
concentration
of
lindane
in
the
blood
and
target
tissues
than
a
dermal
dose.
Use
of
a
toxicity
endpoint
based
on
an
oral
dose
(adjusted
to
reflect
10%
or
20%
dermal
absorption)
may
therefore
overestimate
toxicity
from
a
dermal
dose.

Since
adult
animals
were
used
in
the
acute
oral
study
and
children
are
more
susceptible
to
exposure
than
adults,
use
of
a
toxicity
endpoint
based
on
the
acute
study
may
underestimate
risks
to
children
who
are
exposed
to
lindane.

Dermal
Absorption
­
HED
calculated
MOEs
assuming
20%
and
10%
dermal
absorption.
The
20%
absorption
value
is
derived
from
a
study
of
the
absorption
of
the
scabies
lotion
applied
to
monkeys.
The
lotion
was
left
on
for
24
hours
in
the
monkey
assessment
and
therefore
may
overestimate
dermal
absorption
for
scabies
treatment,
which
has
a
12
hour
exposure
duration
limit
based
on
label
restrictions.
In
addition,
monkeys
may
not
absorb
the
scabies
lotion
in
the
same
manner
as
humans.
The
10%
absorption
values
is
from
a
study
of
absorption
of
pesticides
applied
to
humans.
Humans
may
absorb
the
pesticide
and
lotion
formulations
at
different
rates.
Since
there
are
no
data
to
evaluate
the
relative
absorption
of
the
scabies
lotion
by
monkeys
vs.
humans
or
the
relative
absorption
by
humans
of
the
pesticide
vs.
scabies
lotion,
it
is
not
possible
to
assess
whether
these
dermal
absorption
factors
tend
to
overstate
or
understate
potential
risk.
However,
use
of
both
studies
provides
a
range
of
dermal
absorption
and
probably
provides
an
adequate
bounding
of
potential
exposure.

Anticipated
Label
Changes
­
According
to
the
FDA,
the
label
for
the
1%
scabies
treatment
lotion
will
be
revised
to
restrict
use
to,
"patients
who
have
attained
adult
stature,
or
approximately
60
kg".
The
label
will
also
be
revised
to
recommend
only
that
a
thin
layer
of
lotion
be
applied.
The
current
label
prescribes
the
following;
"Use
only
enough
to
cover
the
body
in
a
thin
layer.
1
ounce
(half
a
2
ounce
container)
should
be
all
that
is
needed
for
children
under
6
years
of
age:
1­
2
ounces
for
older
children
and
adults".
HED
conducted
its
scabies
MOE
assessment
based
on
directions
provided
in
the
current
label.
Given
anticipated
label
changes,
use
in
accordance
with
the
revised
label
would
eliminate
risks
to
young
children
(less
than
60
kg).
Also,
according
to
FDA,
pending
label
changes
to
the
amount
of
lotion
required
should
result
in
lower
application
rates
for
both
older
children
and
adults.

1.
2
Blood
Level
Comparison
in
Children
HED
also
analyzed
potential
risk
from
lindane
used
as
a
scabies
treatment
based
on
data
on
lindane
blood
levels
provided
in
two
published
literature
studies.
One
study
documents
cases
of
accidental
lindane
ingestion
by
toddlers
in
which
blood
levels
were
determined
after
ingestion.
The
second
study
provides
data
on
blood
levels
of
lindane
in
children
after
application
of
1%
5
lindane
lotion
to
treat
scabies.
The
blood
level
associated
with
acute
accidental
ingestion
which
resulted
in
short­
term
adverse
effects
according
to
the
accidental
ingestion
case
study
is
0.32
ug/
mL.
The
highest
measured
blood
concentration
from
the
clinical
study
of
levels
associated
with
prescribed
uses
of
lindane
to
treat
scabies
was
0.064
ug/
mL.
The
studies
are
described
in
more
detail
below.

Acute
Accidental
Lindane
Ingestion
Case
reports
published
in
the
November,
1995,
edition
of
the
Annals
of
Emergency
Medicine
provide
data
on
blood
levels,
adverse
effects,
and
time
and
level
of
recovery
resulting
from
acute
accidental
lindane
ingestion
in
toddlers.(
3)
As
noted
in
the
Annals
publication,
most
cases
reported
in
the
literature
involve
dermal
lindane
toxicity;
ingestion
toxicity
is
infrequently
documented
and
data
on
blood
levels
associated
with
ingestion
are
rare.
The
article
presents
three
cases
in
which
blood
levels
were
obtained
and
documented
after
ingestion.
The
highest
lindane
blood
concentrations
documented
in
the
case
studies
in
which
the
patient
exhibited
full
recovery
was
0.
32
ug/
mL
(Case
1).
This
case
involved
a
13
month
old
boy
who
accidently
ingested
part
of
the
contents
of
a
bottle
of
Kwell
lotion.
The
following
description
of
Case
1
is
excerpted
from
the
1995
article.

In
this
case,
a
13
month
old
boy
was
brought
to
a
local
emergency
department
after
being
found
with
an
open
bottle
of
Kwell
lotion.
He
was
described
as
glassy
eyed,
he
vomited
twice,
and
had
a
generalized
tonic­
clonic
seizure.
The
child
was
transported
to
the
hospital
where
he
was
somnolent.
Shortly
after
arrival,
he
had
another
seizure.
He
was
treated
and
laboratory
analyses
were
conducted.

Blood
lindane
concentrations
were
determined
with
the
method
of
Dale
et
al
in
accordance
with
Environmental
Protection
Agency
procedures.
The
lindane
level
was
0.
32
ug/
mL
(4
hours
after
ingestion)
and
0.
02
ug/
mL
(20
hours
after
ingestion).
The
child
was
transferred
to
a
children's
hospital
ICU,
where
his
mental
status
progressively
improved.
The
next
day
the
child
had
slightly
decreased
activity.
During
observation
over
the
next
2
days
his
condition
progressively
improved,
and
he
was
discharged
home.

The
Physicians
Desk
Reference
(PDR)
provides
the
following
statement
on
clinical
pharmacology
regarding
1%
lindane
cream,
"Dale,
et
al
reported
a
blood
level
of
290
ng/
ml
associated
with
convulsions
following
the
accidental
ingestion
of
a
lindane
containing
product".

Lindane
Blood
Levels
in
Children
Following
Application
of
1%
Lotion
for
Scabies
A
1977
article
in
The
Journal
of
Pediatrics
provides
data
from
a
study
conducted
in
the
Acute
Care
Clinic
of
Children's
Medical
Center,
Dallas,
Texas
which
documents
blood
levels
of
lindane
in
infants
and
children
who
were
treated
with
1%
lindane
lotion
for
scabies.
(4)
6
In
this
study,
serum
concentrations
of
lindane
were
determined
in
infants
and
children
with
and
without
scabies
infection
following
application
of
1%
lindane
lotion.
Studies
were
performed
in
20
infected
and
noninfected
patients
who
averaged
33
to
64
months
of
age
with
average
weights
ranging
from
13
to
17
kg.
After
a
pretreatment
blood
sample
was
obtained,
1%
lindane
product
was
applied
to
the
body
surface
area
prescribed
by
the
label.
Twenty
four
hours
after
application
of
the
lotion,
all
patients
were
given
a
warm
soapy
bath.
The
current
label
for
lindane
lotion
applied
for
scabies
specifies
that
the
lotion
should
not
be
left
on
for
more
than
12
hours.
This
may
result
in
an
overestimation
of
blood
concentrations,
however,
it
is
likely
not
relevant
to
the
risk
assessment
since
the
blood
level
measured
at
6
hours
was
used
for
risk
assessment
purposes.
Specimens
of
blood
for
determination
of
lindane
concentrations
were
obtained
at
0,
2,
4,
6,
8,
12,
24,
and
48
hours
after
topical
application
of
1%
lotion.
Patient
characteristics
are
presented
in
Table
3
and
results
are
presented
in
Table
4.

TABLE
3.
Characteristics
of
Scabies
Treatment
Patients
Infected
Non­
Infected
No.
patients
12
8
Mean
Age
(months)
33
64
Mean
Weight
(kg)
13
17
Dose
of
1%
lotion
(mg)
44
57
TABLE
4.
Blood
Concentrations
of
Lindane
After
Scabies
Treatment
Concentrations
of
Lindane
in
Blood
(ug/
ml)

Time
(hr)
Infected
Noninfected
Avg
Range
Avg
Range
2
0.
013
0.005­
0.038
0.007
0.001­
0.017
4
0.
025
0.007­
0.048
0.013
0.008­
0.027
6
0.
028
0.013­
0.039
0.024
0.007­
0.064
8
0.
026
0.010­
0.037
0.019
0.009­
0.040
12
0.023
0.002­
0.043
0.015
0.002­
0.033
24
0.010
0.003­
0.019
0.013
0.006­
0.024
36
0.008
0.002­
0.012
0.009
0.004­
0.018
48
0.006
0.001­
0.021
0.005
0.002­
0.008
Blood
half­
life
17.9
hr
21.4
hr
Discussion
of
Uncertainties
Associated
with
Blood
Level
Analysis
Allowable
Blood
Level
in
Children
(i.
e.,
non­
exceedance
levels
based
on
evidence
of
adverse
effects)
­
It
is
uncertain
whether
the
levels
of
320
ng/
mL
and
290
ng/
mL
represent
the
maximum
levels
of
lindane
in
the
subjects'
blood.
Given
that
the
measured
level
of
320
ng/
mL
in
the
cited
clinical
study
was
taken
at
least
4
hours
after
ingestion,
it
is
likely
that
initial
blood
levels
were
higher.
It
is
also
uncertain
what
blood
level
is
associated
with
the
effects
observed
in
the
case
study
patient.
To
the
extent
that
observed
effects
are
attributable
to
higher
than
measured
lindane
blood
levels,
the
assessment
tends
to
overstate
potential
risk.
To
the
extent
that
adverse
effects
may
be
associated
with
lindane
blood
levels
lower
than
320
ng/
mL,
the
assessment
may
tend
to
underestimate
risk.
7
The
subjects
in
the
clinical
study
received
a
bath
with
warm
soapy
water
prior
to
application
of
the
lindane
lotion.
Wet
skin
tends
to
exhibit
greater
dermal
absorption
than
dry
skin.
Use
of
the
blood
levels
from
the
study
may
therefore
overstate
potential
exposure
for
individuals
who
have
dry
skin
at
the
time
of
application.

In
the
clinical
study,
the
lindane
lotion
was
left
on
for
24
hours
after
application.
The
current
label
for
scabies
treatment
specifies
that
the
lotion
should
not
be
left
on
for
more
than
12
hours.
This
prolonged
exposure
may
result
in
an
overestimation
of
blood
concentrations
seen
after
12
hours.
However,
it
should
not
effect
the
6
hour
peak
level
used
in
the
risk
assessment.

The
potential
contribution
of
other
lotion
components
to
observed
effects
is
not
known.

Anticipated
Label
Changes
­
Based
on
the
average
age,
the
clinical
scabies
study
looked
only
at
infants
and
small
children
(up
to
8
yrs
old).
Average
amounts
of
lindane
applied
in
the
study
were
129­
158
mg.
Given
that
the
current
label
prescribes
up
to
300
mg
(1
oz)
for
infants
and
up
to
600
mg
(2
oz)
for
children
6
and
older,
the
amount
of
product
applied
in
the
study
was
2­
4
times
less
than
the
currently
allowable
amount.
However,
the
label
for
the
1%
scabies
lotion
will
be
revised
to
prescribe
against
use
of
the
product
for
small
children
(i.
e.,
children
less
than
60
kg).
Given
anticipated
label
changes,
use
in
accordance
with
the
revised
label
would
eliminate
risks
to
young
children
(<
60
kg).
Also,
according
to
FDA,
pending
label
changes
on
the
amount
of
lotion
required
should
result
in
lower
application
rates
for
both
older
children
and
adults.
Although
there
is
insufficient
data
to
indicate
a
correlation
between
amount
applied
dermally
and
corresponding
blood
levels,
it
is
reasonable
to
assume
that
use
of
a
lower
amount
of
product
will
produce
lower
lindane
blood
levels.
Finally,
the
new
label
will
direct
that
lindane
be
applied
to
dry
skin
which
will
reduce
the
amount
of
lindane
absorbed
into
the
blood
stream.

Children
vs.
Adults
­
The
blood
level
comparison
analysis
pertains
and
is
applicable
only
to
small
children.
HED
has
no
data
on
blood
levels
associated
with
adverse
effects
in
adults
nor
do
we
have
data
on
blood
levels
associated
with
prescribed
use
of
lindane
to
treat
scabies
in
adults.
Based
on
available
toxicity
data,
children
are
more
sensitive
than
adults.
Therefore
adverse
effects
would
occur
at
higher
blood
levels
in
adults
and
older
children
than
in
young
children.
In
addition,
blood
levels
associated
with
prescribed
use
(under
both
current
and
revised
labels)
would
be
lower
in
older
children
and
adults
due
to
differences
in
weight
to
body
surface
area
ratios
between
young
children
and
adults/
young
adults.

1.3
HED
Conclusions
HED's
analysis
using
the
MOE
approach
indicates
MOEs
of
concern
from
both
high
and
low­
end
treatment
scenarios
for
all
ages
assessed
using
either
monkey
or
human
dermal
absorption
data.
For
the
blood
concentration
analysis,
HED
compared
blood
concentrations
from
the
scabies
study
with
the
blood
concentration
associated
with
short­
term
adverse
effects
in
children.
HED
is
concerned
that
there
is
an
inadequate
margin
of
safety
between
the
blood
levels
associated
with
scabies
treatment
(0.
064
ug/
mL)
and
the
blood
levels
resulting
in
short
term
8
effects
in
children
(0.
29
­
0.
32
ug/
mL).
Given
variability
of
responses
in
humans,
an
uncertainty
factor
of
10
is
considered
reasonable
for
this
risk
assessment.
There
is
a
4­
5
fold
difference
between
blood
levels
in
treated
patients
and
allowable
blood
levels
identified
based
on
evidence
of
adverse
effects.
While
this
assessment
does
consider
mitigation
efforts
being
undertaken
by
FDA,
it
is
important
to
note
that
it
does
not
consider
the
medical
benefits
of
scabies
treatment.

1.
4
FDA
Assessment
and
Conclusions
FDA
will
approve
a
drug
that
it
finds
is
safe
and
effective
for
a
specific
population
with
a
specific
condition
when
the
drug
is
used
in
accordance
with
its
proposed
labeling.
Safe
and
effective
does
not
mean
without
risks,
it
means
that
the
benefit
of
the
treatment
outweighs
the
risk
for
the
patient
group
specified
in
the
label.
As
described
below,
FDA
conducted
a
risk/
benefit
analysis
of
the
use
of
lindane
as
second
line
prescription
medication
for
scabies
and
concluded,
based
on
that
analysis,
that
lindane
is
safe
and
effective
for
treatment
of
scabies
when
used
in
a
manner
consistent
with
its
labeling.
Second
line
therapy
is
defined
as
a
product
that
should
be
used
only
if
another
treatment
has
already
failed,
or
if
the
patient
cannot
tolerate
another
available
therapy.

Risks
Lindane
has
been
on
the
market
since
1947,
but
was
labeled
a
second
line
therapy
in
1995
after
review
by
the
FDA.
It
is
similar
in
action
to
other
approved
therapies,
but
has
a
higher
percutaneous
absorption
than
other
approved
scabicides
and
pediculocides.
This
greater
systemic
exposure
may
translate
to
a
greater
potential
for
serious
adverse
events,
such
as
seizure.
This
systemic
exposure
can
be
exaggerated
in
patients
with
an
immature
or
compromised
cutaneous
barrier.
Animal
data
have
demonstrated
that
the
young
are
more
sensitive
to
the
neurotoxic
effects
of
lindane.

FDA
assessed
the
safety
and
potential
risks
from
use
of
lindane
as
a
drug
based
on
safety
information
from
the
spontaneous
adverse
event
reporting
system
(AERS)
and
current
literature.
The
AERS
database
is
a
collection
of
spontaneous,
voluntarily
submitted
reports
of
adverse
events
associated
with
drug
products
submitted
by
consumers,
healthcare
professionals,
manufacturers,
and
others.
One
of
the
limitations
of
a
voluntary
system
of
reporting
is
a
substantial
amount
of
under­
reporting.
FDA
estimates
that
between
one
and
10%
of
all
adverse
events
are
reported
to
FDA.
Other
limitations
include
the
variability
in
the
quality
and
quantity
of
information
reported.
In
spite
of
known
limitations,
the
spontaneous
system
has
value.
The
system
is
sensitive
to
rare,
unexpected
events,
is
simple
to
use,
and
is
relatively
inexpensive.
However,
the
AERS
database
does
not
include
the
total
number
of
patients
who
have
been
treated,
with
or
without
adverse
events.
Because
of
this,
it
is
not
possible
to
quantify
the
percentage
of
patients
who
have
had
adverse
events.
Most
of
the
serious
adverse
events
in
the
AERs
database
occurred
in
patients
who
had
already
labeled
contraindications
to
the
use
of
lindane,
who
used
lindane
in
excessive
amounts,
or
who
ingested
lindane.
9
Moreover,
even
though
there
appears
to
be
a
narrow
therapeutic
index,
there
isn't
much
evidence
that
labeled
use
leads
to
serious
adverse
events.
The
290
ng/
ml
plasma
level
in
the
Physician's
Desk
Reference
(PDR)
and
the
320
ng/
ml
plasma
level
from
the
Aks
article
are
plasma
levels
that
were
obtained
several
hours
after
acute
ingestion
of
the
lindane
product.
The
two
levels
are
from
pediatric
patients
who
ingested
lindane
and
had
seizures.
This
information
is
helpful
to
a
physician
in
determining
if
the
patient's
seizure
was
secondary
to
lindane
ingestion,
or
if
there
is
another
etiology.
The
plasma
levels
may
provide
a
tool
to
determine
the
etiology
of
a
patient's
seizure
upon
presentation
to
the
Emergency
Room
but
are
not
a
"No
observed
adverse
event
level
(NOAEL)."

The
data
for
lindane
indicate
that
there
is
a
two­
compartment
pharmacokinetic
model.
After
ingestion,
there
is
a
steep
rise
in
the
serum
level,
followed
by
a
rapid
decline
during
the
disposition
phase
when
some
lindane
distributes
to
lipid
tissues
and
some
is
excreted.
The
disposition
phase
is
followed
by
a
prolonged
beta
elimination
phase.
Based
on
this
model,
it
is
probable
that
the
patients'symptoms
(seizure)
occurred
at
a
higher
serum
level
than
those
levels
obtained
4
hours
after
the
initial
ingestion.
In
addition,
the
marketed
formulation
contains
other
ingredients
that
may
contribute
to
the
toxicity
in
acute
ingestions.
Ingredients
for
lotion
include:
glycerol
monostearate,
cetyl
alcohol,
stearic
acid,
trolamine,
carrageenan,
2­
amino­
2­
methyl­
1propanol
methylparaben,
butylparaben,
perfume
and
water.
Ingredients
for
shampoo
include:
trolamine
lauryl
sulfate,
polysorbate
60,
acetone
and
water
It
is
important
to
emphasize
that
the
blood
levels
listed
in
the
PDR
and
the
article
by
Aks
are
single
cases
following
ingestion
by
toddlers
of
an
unknown
quantity
of
lindane.
The
young
do
appear
to
be
more
sensitive
to
the
neurotoxic
effects
of
lindane,
as
seen
in
studies
across
species.
The
serum
lindane
level
that
may
lead
to
a
seizure
in
a
small
child
is
most
likely
lower
than
the
level
that
would
cause
an
equal
effect
in
an
adult.
The
labeling
is
being
changed
to
reflect
this
concern,
indicating
that
lindane
should
be
used
only
in
patients
who
have
achieved
adult
stature,
or
approximately
60
kilograms.

Benefits
FDA
recognizes
that
all
drugs
have
associated
risks.
Therefore,
FDA
must
determine
if
the
potential
risks
of
adverse
side
effects
associated
with
a
drug
treatment
outweigh
the
overall
health
benefits
of
treating
the
condition.
Although
not
life
threatening,
scabies
can
pose
significant
problems
if
left
untreated,
including
severe
itching
and
secondary
infections.
In
underdeveloped
areas
of
the
world
where
treatments
are
not
available
or
medical
care
is
inaccessible,
scabies
can
be
pandemic
and
accounts
for
significant
morbidity.
FDA
has
concluded
that
there
is
no
question
that
the
standard
of
care
for
these
patients
is
to
administer
scabicidal
treatment
for
their
infestation.

FDA
considers
alternative
therapies
when
evaluating
the
benefit
of
a
drug.
Although
the
FDA
has
determined
that
there
are
other
products
for
the
treatment
of
scabies
that
may
have
less
risk
and
should
be
used
first
in
a
patient,
FDA
also
recognizes
that
there
are
patients
"who
have
10
either
failed
to
respond
to
adequate
doses,
or
are
intolerant
of,
other
approved
therapies."
These
patients
would
have
documented
failed
prior
treatment
with
other
approved
products,
or
documented
reactions
–
either
local
or
systemic,
to
those
products
or
drugs
that
would
be
expected
to
cross­
react
with
those
products.
Although
there
are
other
therapies
available
for
first­
line
use
in
the
treatment
of
scabies,
FDA
believes
it
is
in
the
best
interest
of
public
health
to
have
several
alternatives
available
for
this
subset
of
patients.
The
approved
treatment
options
for
scabies
are
limited.
They
are:

­
permethrin
cream,
5%
(Acticin
and
Elimite),
­
lindane
cream
1%
(not
marketed
in
the
U.
S.),
lindane
lotion
1%,
and
­
crotamiton
cream
(Eurax).
­
Precipitated
sulfur
ointment,
5­
10%,
is
occasionally
compounded
and
used
for
scabies.
For
safety
reasons,
crotamiton
and
precipitated
sulfur
ointment
are
reasonable
options
for
young
children
and
pregnant
women,
but
the
efficacy
of
these
products
is
much
lower
than
other
products,
and
re­
treatment
is
frequently
necessary.
There
is
information
available
on
the
internet
about
other
alternative
treatments
that
include
soaking
in
borax.
The
efficacy
of
these
therapies
is
unknown.

Resistance
to
products
must
also
be
considered
when
evaluating
drugs.
There
are
currently
only
three
approved
treatments
for
scabies,
and
as
mentioned
earlier,
crotamiton
is
not
as
effective
as
lindane
or
permethrin.
Lindane
is
labeled
for
second
line
therapy
and
should
only
be
used
in
the
event
that
there
is
treatment
failure
or
if
the
patient
is
intolerant
to
the
other
two
treatments.
If
a
patient
has
persistent
infestation
after
one
form
of
treatment,
there
should
first
be
an
assessment
for
appropriate
use,
and
if
it
is
determined
that
the
failure
wasn't
due
to
misuse,
then
the
patient
should
be
retreated
with
an
alternative
agent.
There
is
a
public
health
benefit
to
having
several
treatment
options
for
a
condition
where
a
patient
may
require
re­
treatment
with
a
different
therapy,
especially
when
there
may
be
emerging
or
transient
resistance.

Lindane
has
been
available
since
1947,
and
there
are
some
case
reports
that
the
scabies
mite
has
recently
developed
resistance
to
it.
A
literature
search
did
not
reveal
any
reports
of
scabies
mite
resistance
to
permethrin,
but
it
has
been
on
the
market
for
a
much
shorter
period
of
time
than
lindane.
There
is
one
case
report
in
the
literature
of
resistance
to
crotamiton.
It
is
not
unreasonable
to
expect
that
resistance
to
permethrin
will
develop
over
time.
If
this
resistance
does
occur,
and
lindane
is
not
available,
physicians
would
not
have
alternative
approved
and
effective
therapies
for
patients
infested
with
scabies.

Conclusions
FDA
has
concluded
that
lindane
is
safe
and
effective
for
treatment
of
scabies
when
used
in
a
manner
consistent
with
its
labeling.
Although
lindane
is
already
labeled
as
a
second
line
therapy,
the
current
label
is
being
revised
to
indicate
that
lindane
is
for
use
only
in
patients
who
have
attained
adult
stature
(approximately
60
kilograms).
This
emphasizes
that
it
should
not
be
used
in
young
pediatric
patients,
and
that
patients
should
be
post­
pubescent.
In
addition,
physicians
are
11
instructed
to
use
caution
when
they
are
prescribing
this
product
to
patients
who
have
underlying
conditions
(HIV/
AIDS)
or
are
on
medications
that
may
result
in
a
lowered
seizure
threshold,
and
patients
who
have
skin
conditions
that
may
allow
enhanced
absorption.

Extensive
information
will
be
provided
for
the
physician
and
the
patient
regarding
the
potential
risk
of
applying
the
product
more
than
once.
The
new
label
also
includes
a
medication
guide
that
must,
by
law,
be
given
to
each
patient
with
the
lindane
prescription.
This
medication
guide
explains
in
plain
language
the
potential
for
harm
if
the
lindane
is
used
other
than
as
instructed.
It
also
includes
clear
instructions
for
use.
The
high
volume
container
sizes
are
being
discontinued
to
limit
the
amount
per
prescription.
It
is
anticipated
that
this
will
decrease
over­
use
the
product.

2.0
ASSESSMENT
OF
RISK
FROM
USE
OF
LINDANE
TO
TREAT
LICE
HED's
assessment
of
risk
from
use
of
lindane
to
treat
head
lice
relies
on
data
provided
in
two
published
literature
studies.
One
study
documents
cases
of
accidental
lindane
ingestion
by
toddlers
in
which
blood
levels
were
determined
after
ingestion.
The
second
study
provides
data
on
blood
levels
of
lindane
in
children
and
young
adults
following
application
of
Kwell
Shampoo
to
treat
head
lice.

2.
1
Blood
Level
Comparison
in
Children
Acute
Accidental
Lindane
Ingestion
in
Toddlers
See
case
study
and
PDR
data
described
above
for
scabies
assessment.
(3)

Absorption
of
Lindane
Following
Application
of
Kwell
Shampoo
to
Treat
Lice
EPA
has
a
published
study
on
blood
levels
of
lindane
in
children
and
young
adults
following
standard
application
of
Kwell
Shampoo.
An
1983
article
in
Pediatric
Dermatology
provides
data
from
a
study
conducted
in
the
Outpatient
Clinic
of
Children's
Medical
Center,
Dallas,
Texas.
(4)

In
this
study,
serum
concentrations
of
lindane
were
determined
in
children
with
pediculosis
capititis
following
application
of
1%
Kwell
shampoo.
Studies
were
performed
in
9
patients
who
were
from
3.5
to
18
years
of
age
with
weights
ranging
from
13.6
to
35
kg,
and
heights
ranging
from
99
to
163
cm.
After
a
pretreatment
blood
sample
was
obtained,
1%
lindane
product
was
applied
to
dry
hair
using
a
sufficient
amount
of
medication
to
thoroughly
saturate
the
hair
and
scalp.
After
10
minutes,
small
quantities
of
water
were
added
until
a
lather
formed.
Shampooing
was
continued
for
an
additional
4
minutes
after
which
the
hair
was
rinsed
and
blown
dry
with
a
hair
dryer.
The
current
label
for
Kwell
shampoo
specifies
that
the
shampoo
should
remain
in
place
on
dry
hair
for
4
minutes
only
before
water
is
added
to
form
lather.
Consequently,
the
study
may
result
in
higher
absorption
than
would
occur
following
label
directions.
Four
patients
were
12
retreated
because
of
persistence
of
living
lice
after
5
days.
Specimens
of
blood
were
obtained
at
0,
2,
4,
6,
and
24
hours
after
topical
application
of
Kwell
shampoo.
Patient
characteristics
are
presented
in
Table
5
and
results
are
presented
in
Table
6.

TABLE
5.
Characteristics
of
the
Lice
Patients
Initial
Treatment
Retreatmemt
No.
patients
8
4
Mean
Age
(years)
7.8
8.
1
Mean
Weight
(kg)
27
29
Mean
Height
(cm)
122
124
Dose
of
1%
GBH
Shampoo
(mL)
44
57
Calculated
Dose
of
lindane
(mg)
420
530
TABLE
6.
Blood
Concentrations
of
Lindane
After
Lice
Treatment
Mean
Concentrations
of
Lindane
in
Blood
(ng/
mL)

Time
(hr)
Initial
Treatment
Retreatment
Avg
Range
Avg
Range
0
0
0.29
0.25­
0.3
2
1.
4
0.43­
2.53
3.6
3.
26­
3.88
4
0.
96
0.
38­
1.52
3.3
1.
75­
6.13
6
0.
72
0.
29­
1.05
2.1
1.
64­
2.64
24
0.41
0.26­
0.69
1.1
0.
81­
1.33
Discussion
of
Uncertainties
Associated
with
Blood
Level
Analysis
It
is
uncertain
whether
the
levels
of
320
ng/
mL
and
290
ng/
mL
represent
the
maximum
levels
of
lindane
in
the
subjects'
blood.
Given
that
the
measured
level
of
320
ng/
mL
in
the
cited
clinical
study
was
taken
at
least
4
hours
after
ingestion,
it
is
likely
that
initial
blood
levels
were
higher.
It
is
uncertain
what
blood
level
is
associated
with
the
effects
observed
in
the
case
study
patient.
To
the
extent
that
observed
effects
are
attributable
to
higher
than
measured
lindane
blood
levels,
the
assessment
tends
to
overstate
potential
risk.
To
the
extent
that
adverse
effects
may
be
associated
with
lindane
blood
levels
of
320
ng/
mL
or
lower,
the
assessment
may
tend
to
underestimate
risk.

The
current
label
for
Kwell
shampoo
specifies
that
the
shampoo
should
remain
in
place
on
dry
hair
for
4
minutes
only
before
water
is
added
to
form
lather.
In
the
clinical
study,
the
shampoo
was
left
in
place
for
10
minutes
before
water
was
added.
Consequently,
the
study
may
result
in
higher
absorption
than
would
occur
following
label
directions.

2.2
HED
Conclusions
The
highest
measured
blood
concentration
obtained
following
single
and
double
treatments
of
head
lice
at
label
rates
but
at
longer
than
label
specified
treatment
durations
was
0.00613
ug/
mL.
This
is
significantly
lower
than
0.32
ug/
mL,
the
blood
level
associated
with
acute
accidental
ingestion
which
resulted
in
short­
term
adverse
effects
according
to
the
cited
case
study
13
article.
Therefore,
HED
does
not
believe
that
lindane
pharmaceutical
products
used
for
treatment
of
lice
pose
human
health
risks
of
concern
when
used
in
accordance
with
directions
provided
on
the
label.

2.
3
FDA
Assessment
Based
on
its
assessment
of
safety
and
potential
risks
from
use
of
lindane
as
a
prescription
medication
for
scabies
and
lice,
FDA
has
concluded
that
lindane
is
safe
and
effective
for
treatment
of
lice
when
used
as
labeled.
14
References
(1)
Moody,
R.
P.,
and
Ritter,
L.,
J.
Tox
and
Env
Hlth,
28:
161­
169,
1989
(2)
Feldman,
R.
J.
and
Maibach,
H.
I.,
Tox
and
Applied
Pharmacology
28,
126­
132,
1974
(3)
Aks,
S.
E.,
KrantzA.,
Hryhorczuk,
D.
O.,
Wagner,
S.,
andMock,
J.,
AnnEmergMed,
26:
647­
651,
1995
(4)
Ginsburg,
C.
M.
and
Lowry,
W.,
Pediatric
Dermatology
Vol
1.
No.
1
74­
76,
1983
