Document ID: EPA-HQ-OPP-2002-0202-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-08-14T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
September
28,
2000
MEMORANDUM
SUBJECT:
Lindane;
P.
C.
Code
009001.
The
HED
Toxicology
Chapter
for
the
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
Document
(RED),
Case
#
818566.
DP
Barcode:
D269338
From:
Suhair
Shallal,
Toxicologist
Reregistration
Branch
4
Health
Effects
Division
(7509C)

Thru:
Sanjivani
Diwan,
Senior
Toxicologist
Reregistration
Branch
4
Health
Effects
Division
(7509C)
and
Susan
V.
Hummel,
Branch
Senior
Scientist
Reregistration
Branch
4
Health
Effects
Division
(7509C)

To:
Suhair
Shallal,
Risk
Assessor
Reregistration
Branch
4
Health
Effects
Division
(7509C)

Attached
is
the
Toxicology
Chapter
for
lindane,
for
purposes
of
issuing
a
Reregistration
Eligibility
Decision
(RED)
Document.
2
LINDANE
PC
Code:
009001
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date:
September
28,
2000
TABLE
OF
CONTENTS
1.
0
HAZARDCHARACTERIZATION........................................
4
2.
0
REQUIREMENTS
....................................................
5
3.
0
DATAGAP(
S)
.......................................................
6
4.
0
HAZARDASSESSMENT...............................................
6
4.
1
AcuteToxicity...............................................
6
4.
2
SubchronicToxicity...........................................
6
4.
3
PrenatalDevelopmentalToxicity................................
10
4.
4
ReproductiveToxicity........................................
14
4.
5
ChronicToxicity
............................................
16
4.
6
Carcinogenicity
.............................................
21
4.
7
Mutagenicity
...............................................
23
4.
8
Neurotoxicity
..............................................
24
4.
9
Metabolism................................................
28
5.
0
TOXICITYENDPOINTSELECTION....................................
30
5.
1
SeeSection9.
2for
EndpointSelectionTable.
......................
30
5.
2
DermalAbsorption..........................................
30
5.
3
ClassificationofCarcinogenicPotential
...........................
30
6.
0
FQPACONSIDERATIONS
............................................
31
6.
1
SpecialSensitivitytoInfantsandChildren.........................
31
6.
2
RecommendationforaDevelopmentalNeurotoxicityStudy............
32
7.
0
REFERENCES
......................................................
33
8.
0
APPENDICES.......................................................
36
8.
1ToxicityProfileSummaryTables
................................
37
8.
1.
1AcuteToxicityTable
............................
37
8.
1.
2
Subchronic,
ChronicandOther
ToxicityTables
........
37
Lindane/
September
2000
RED
Toxicology
Chapter
4
1.0
HAZARD
CHARACTERIZATION
Lindane
is
a
moderately
toxic
compound
in
EPA
toxicity
class
II.
Labels
for
products
containing
it
must
bear
the
Signal
Word
WARNING.
It
is
neither
an
eye
nor
dermal
sensitizer.
Some
formulations
of
lindane
are
classified
as
Restricted
Use
Pesticides
(RUP),
and
as
such
may
only
be
purchased
and
used
by
certified
pesticide
applicators.
Lindane
is
no
longer
manufactured
in
the
U.
S.,
and
most
agricultural
and
dairy
uses
have
been
canceled
by
the
EPA
because
of
concerns
about
the
compound's
potential
to
cause
cancer.

The
primary
effect
of
lindane
is
on
the
nervous
system;
as
seen
in
both
acute,
subchronic,
and
developmental
neurotoxicity
studies,
as
well
as,
combined
chronic
and
carcinogenicity
study,
lindane
appears
to
cause
neurotoxic
effects
including
tremors,
convulsions
and
hypersensitivityto
touch.
This
is
further
corroborated
by
the
published
literature
in
which
human
exposure
has
been
seen
to
produce
neurologic
effects.
Lindane
also
causes
renal
and
hepatic
toxicity
via
the
oral,
dermal
and
inhalation
routes
of
exposure
as
seen
in
subchronic,
reproduction
and
chronic
toxicity
studies
in
the
rat.

Indevelopmental
toxicitystudies,
no
developmental
effects
were
seen
at
levels
where
maternal
toxicity
was
evident.
In
the
rat
developmental
study,
the
developmental
effects
(extra
rib
and
total
skeletal
variations)
were
seen
at
dose
levels
(20
mg/
kg/
day)
greater
than
those
that
elicit
maternal
toxicity
(10
mg/
kg/
day).
In
the
reproduction
study,
both
systemic
and
developmental
LOAELs
are
13
mg/
kg;
however
a
qualitative
difference
in
maternal
and
offspring
effects
(reduced
body
weight
of
maternal
animals
and
reduced
viability
and
delayed
maturation
in
pups)
indicates
an
increased
pup
susceptibility
to
exposure
to
lindane.
This
is
further
corroborated
by
a
developmental
neurotoxicity
study
in
which
a
qualitative
and
quantitative
increase
in
susceptibility
is
seen.
At
the
high
dose
(13.
7
mg/
kg/
day)
,
parental
animals
have
a
reduced
body
weight
and
body
weight
gain
while
at
the
mid­
dose
(5.6
mg/
kg/
day)
offspring
have
a
reduced
survival
rate,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation
as
compared
to
controls.
The
FQPA
factor
was
therefore
reduced
to
3X.

The
toxicity
endpoints
have
been
selected
by
the
Hazard
Identification
Assessment
Review
Committee
(HIARC,
7/
00)
and
can
be
found
in
Section
8­
Appendices.
They
include
acute
and
chronic
reference
doses
(RfDs),
and
short­,
intermediate­
and
long­
term
dermal
and
inhalation
no
observable
adverse
effect
levels
(NOAELs).
A
reassessment
of
the
cancer
classification
will
occur
after
a
review
of
the
new
mouse
carcinogenicity
report
due
in
December
2000.
Currently,
according
to
the
TES
committee
report
(1994),
lindane
has
not
been
classified
by
the
HED
Cancer
Peer
Review
Committee.
The
RfD/
Peer
Review
Committee
(1993)
concluded
that:
"The
mouse
carcinogenicity
data
were
considered
insufficient
because
of
major
deficiencies
associated
with
all
studies
available."
Lindane
however
had
been
previously(
1985)
classified
bythe
Cancer
Assessment
Group
of
the
Office
of
Research
and
Development
as
a
group
B2/
C
carcinogen
based
on
increased
incidence
of
mouse
liver
tumors.
The
upper­
bound
slope
of
the
dose­
response
as
reported
in
the
memorandum
is
Q1*
=
1.
1
(mg/
kg/
day)
­1
.

Lindane
does
not
appear
to
be
mutagenic.
The
available
mutagenicity
studies
are
negative;
they
include
a
dominant
lethal
mutation
assay,
sister
chromatid
exchange
assay
and
mammalian
cell
culture
gene
mutation
in
V79
cells.
IPCS
(1991)
reported
that
lindane
does
not
appear
to
have
Lindane/
September
2000
RED
Toxicology
Chapter
5
mutagenic
potential.
There
is
some
evidence
that
lindane
may
act
as
an
endocrine
disruptor;
further
investigation
is
necessary
to
ascertain
the
relevance
and
impact
of
such
findings
on
public
health.

2.0
REQUIREMENTS
The
requirements
(CFR
158.340)
for
food­
use
for
LINDANE
are
in
Table
1.

Table
1.
A
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)
.........................
Oral
Subchronic
(nonrodent)
......................
870.3200
21­
Day
Dermal
................................
870.3250
90­
Day
Dermal
................................
870.3465
90­
Day
Inhalation
...............................
yes
yes
yes
yes
870.3150

yes
yes
870.3700a
Developmental
Toxicity
(rodent)
...................
870.3700b
Developmental
Toxicity
(nonrodent)
................
870.3800
Reproduction
..................................
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(rodent)
.........................
870.4100b
Chronic
Toxicity
(nonrodent)
......................
870.4200a
Oncogenicity
(rat)
..............................
870.4200b
Oncogenicity
(mouse)
............................
870.4300
Chronic/
Oncogenicity
............................
yes
yes
yes
yes
yes

yes
no
870.5100
Mutagenicity
C
GeneMutation­
bacterial
.............
870.5300
Mutagenicity
C
GeneMutation­
mammalian...........
870.5915
Mutagenicity
C
Other
GenotoxicEffects
..............
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
yes

yes
yes
yes
870.7485
General
Metabolism
.............................
870.7600
Dermal
Penetration
.............................
yes
yes
Special
Studies
for
Ocular
Effects
AcuteOral
(rat)
................................
SubchronicOral(
rat)
............................
Six­
monthOral
(dog)
............................
no
no
no

A
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(1998)
guideline
protocols
were
used.

3.0
DATA
GAP(
S)

A
Mouse
Carcinogenicity
Study
is
expected
in
December
2000.
Lindane/
September
2000
RED
Toxicology
Chapter
6
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Lindane
is
a
moderately
toxic
compound
in
EPA
toxicity
class
II.
It
is
neither
an
eye
nor
dermal
sensitizer.
The
vehicle
used
when
administering
lindane
can
determine
its
toxicity.
It
appears
that
oily
solutions
of
lindane
are
more
toxic
than
ones
suspended
in
water.
Clinical
signs
including
convulsions,
spasms
as
well
as
death
have
been
found
to
occur
after
administration
of
lindane.
The
acute
toxicity
data
on
LINDANE
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
LINDANE
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
00049330
LD50
88
mg/
kg
­
males
91
mg/
kg
­
females
II
870.1200
Acute
dermal
toxicity
00109141
LD50
1000
mg/
kg
­
males
900
mg/
kg
­
females
II
870.1300
Acute
inhalation
toxicity
Acc.
263946
LC50
1.56
mg/
L
both
sexes
III
870.2400
Acute
eye
irritation
Acc.
263946
PIS
=
0.6
no
corneal
involvement
irritation
cleared
after
24
hours
III
870.2500
Acute
dermal
irritation
Acc.
263946
PIS
=
0
not
an
irritant
IV
870.2600
Skin
sensitization
Acc.
263946
not
a
sensitizer
NA
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete
due
to
the
availability
of
chronic
studies
and
subchronic
neurotoxicitystudy.
No
additional
studies
are
required
at
this
time.
Lindane
appears
to
affect
the
liver
and
kidneyin
male
rats
when
administered
through
the
oral,
dermal
or
inhalation
routes
of
exposure.
In
addition,
in
an
oral
neurotoxicity
study,
hypersensitivity
to
touch
and
hunched
posture
were
the
basis
for
a
neurotoxicity
LOAEL
of
28.1
mg/
kg.

870.3100
90­
Day
Oral
Toxicity
­
Rat
The
requirements
for
subchronic
oralstudies
are
satisfied
by
chronic
oral
studies.
See
chronic
oral
section
for
executive
summaries.
Lindane/
September
2000
RED
Toxicology
Chapter
7
870.3100
90­
Day
Oral
Toxicity
­
Mouse
The
requirements
for
subchronic
oral
studies
are
satisfied
by
chronic
oral
studies.
See
chronic
oral
section
for
executive
summaries.

870.3150
Oral
Toxicity
­
Dog
Chronic
studies
in
two
species,
rat
and
rabbit,
are
available.
See
chronic
oral
section
for
executive
summaries.

870.3200
90­
Day
Dermal
Toxicity
B
Rat
EXECUTIVESUMMARY:
Ina
subchronic
dermal
toxicitystudy(
MRID41427601),
groups
of
40
male
and
40
female
New
Zealand
white
rabbits
were
treated
with
lindane
(99.5%
a.
i.)
in
5%
aqueous
carboxymethyl
cellulose
at
doses
of
0,
10,
60,
or
400
mg/
kg/
day.
Due
to
excessive
toxicity
the
high
dose
was
reduced
to
350
mg/
kg/
day
from
week
nine
and
to
320
mg/
kg/
day
from
week
eleven.
Animals
were
treated
by
dermal
occlusion
for
6
hours/
day,
5
days/
week.
Within
each
dose
group,
10
animals/
sex
were
used
for
interim
sacrifice
at
week
6,
20
animals/
sex
were
used
for
the
main
study
and
dosed
for
13
weeks,
and
10
animals/
sex
were
dosed
for
13
weeks
and
allowed
a
6
week
recovery
period.

Tremors
and
convulsions
were
observed
in
high­
dose
animals
beginning
after
day
16
in
males
and
after
day
19
in
females.
One
mid­
dose
female
displayed
these
clinical
signs
on
day
50
only.
Clinical
signs
of
toxicity
were
not
observed
in
low­
dose
animals.
Reactions
at
the
site
of
application
were
not
reported.
In
the
high­
dose
group,
17
males
and
8
females
died
prior
to
scheduled
sacrifice.
Deaths
were
first
observed
after
week
5.
All
animals
in
the
control,
low­,
and
mid­
dose
groups
survived
to
scheduled
sacrifice.

Body
weights
and
body
weight
gains
by
the
low­
and
mid­
dose
males
and
females
were
similar
to
the
controls
throughout
the
study.
High­
dose
males
and
females
began
to
lose
weight
after
the
first
week
of
the
study
resulting
in
absolute
body
weights
3­
7%
and
3­
10%,
respectively,
lower
than
the
controls
during
the
13
weeks
of
treatment.
During
recovery,
body
weights
of
the
males
remained
3­
8%
below
the
controls
while
females
recovered
to
1­
3%
lower
than
the
controls.
Body
weight
data
were
not
analyzed
statistically.
Body
weight
loss
by
the
high­
dose
groups
correlated
with
generally
reduced
food
consumption
during
treatment.

No
treatment­
related
effects
were
observed
on
ophthalmology,
urinalysis,
or
white
blood
cell
parameters.
Alkaline
phosphatase
activity
was
significantly
increased
in
high­
dose
animals
at
interim
sacrifice
for
females
(+
34%;
p

0.
05),
and
at
main
study
sacrifice
for
males
(+
44%;
p

0.01)
and
females
(+
53%;
p

0.
01).
High­
dose
females
also
had
significantly
increased
­
glutamyl
transferase
activity
(+
38%;
p

0.
01)
at
main
study
sacrifice.
For
high­
dose
males,
significant
(p

0.05
or
0.01)
reductions
in
hemoglobin
(­
7%),
RBC
(­
8.
6%),
and
PCV
(­
5.
7%)
were
observed
at
main
study
sacrifice.
These
red
cell
parameters
were
comparable
to
the
controls
after
recovery.
Red
cell
parameters
in
females
were
not
affected.

At
main
study
sacrifice,
high­
dose
males
and
females
had
slightly
increased
absolute
kidney
weights
and
significantly
(p

0.01)
increased
relative
kidney
weights
as
compared
with
the
controls.
Lindane/
September
2000
RED
Toxicology
Chapter
8
Absolute
and
relative
kidney
(left
and
right)
weights
were
104­
106%
and
112­
114%,
respectively,
for
males
and
105­
106%
and
115­
116%,
respectively,
for
females.
High­
dose
females
also
had
significantly
(p

0.01)
increased
absolute
(+
27.01
to
27.24%)
and
relative
(+
30.53
to
44.985)
liver
weights
at
both
interim
and
main
study
sacrifice
which
remained
slightly
(+
13
to
17.31%;
n.
s.)
elevated
after
recovery.
Relative
liver
weights
were
significantly
(+
36.77%;
p

0.01)
increased
for
high­
dose
males
at
main
study
sacrifice.
Absolute
adrenal
weights
(left
and
right)
were
significantly
(p

0.05
or
0.01)
increased
at
main
study
sacrifice
for
mid­
dose
males
(+
19.5
to
23.4%),
high­
dose
males
(+
40.5
to
46.3%),
and
high­
dose
females
(+
33
to
34%).
Relative
adrenal
weights
were
increased
(p

0.05
or
0.01)
+19
to
21.6%
for
mid­
dose
males
and
+46
to
56.9%
for
high­
dose
males
and
females.
Following
the
recovery
period,
organ
weights
of
the
treated
groups
were
similar
to
the
control
group.

No
treatment­
related
gross
or
histopathological
lesions
were
observed
in
the
kidneys,
adrenals,
or
skin.
The
incidence
and
severity
of
centrilobular
hypertrophy
of
the
liver
was
increased
in
mid­
and
high­
dose
males
and
females
at
the
interim,
main,
and
recovery
sacrifice
times.
At
both
the
interim
and
main
sacrifices,
centrilobular
hypertrophy
was
observed
in
20%
of
mid­
dose
males,
25­
30%
of
mid­
dose
females,
80­
100%
of
high­
dose
males
and
73­
90%
of
high­
dose
females.
Following
recovery
this
lesion
was
seen
in
30%
and
40%
of
mid­
dose
males
and
females,
respectively,
and
in
50%
and
29%
of
high­
dose
males
and
females,
respectively.

Therefore,
the
dermal
toxicity
LOAEL
is
>400
mg/
kg/
day
and
the
dermal
toxicity
NOAEL
is
not
identified.
The
systemic
toxicity
LOAEL
is
60
mg/
kg/
day
based
on
histopathological
lesions
of
the
liver
in
males
and
females
and
increased
adrenal
weights
of
males.
The
systemic
toxicity
NOAEL
is
10
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
guideline
and
does
satisfy
the
guideline
requirements
for
a
repeated­
dose
dermal
study
(82­
2)
in
rabbits.

870.3465
90­
Day
Inhalation
B
Rat
EXECUTIVE
SUMMARY:
In
a
subchronic
inhalation
toxicity
study
(Accession
No.
255003),
lindane
(99.9%
a.
i.,
Batch
no.
79044/
174)
was
administered
by
inhalation
to
groups
of
12
male
and
12
female
Wistar
rats
at
nominal
concentrations
of
0,
0.02,
0.10,
0.50,
or
5.0
mg/
m
3
,6
h/
day
for
90
days.
Additional
control
and
high
concentration
groups,
12
rats/
sex,
were
treated
for
90
days
and
allowed
to
recover
for
6
weeks
before
sacrifice.
Analytically
measured
atmospheric
concentrations
were
0,
0.02,
0.12,
0.60,
and
4.
54
mg/
m
3
,
respectively.
The
arithmetic
mean
particle
size
of
the
aerosol
was
1.
11±
0.39
µm
and
the
geometric
mean
was
1.
03±
1.45
µm.

Lindane
was
detected
in
the
brain,
liver,
fat,
and
serum
of
all
exposed
rats.
The
chemical
accumulated
in
fat
with
levels
reaching
127,120
µg/
g
and
58,
260
µg/
g
in
high­
dose
females
and
males,
respectively.
After
the
recovery
period,
traces
of
lindane
were
still
detectable
in
the
tissues.

All
rats
survived
to
scheduled
sacrifice.
"Slight"
diarrhea
and
piloerection
were
observed
in
all
males
and
females
exposed
to
the
highest
concentration,
but
the
time
to
onset
and
duration
were
Lindane/
September
2000
RED
Toxicology
Chapter
9
not
included.
No
exposure­
related
effects
were
noted
for
bodyweight
gain,
food
consumption,
water
consumption,
or
urinalysis
parameters.
Although
hematology
parameters
did
not
appear
to
be
affected
by
treatment,
no
individual
animal
data
were
included
and
the
statistics
could
not
be
verified.
Clinical
chemistry
results,
especially
for
Na
+
,K
+
,andCa
++
,
were
highly
variable.
Cytochrome
p­
450
in
males
and
females
exposed
to
5
mg/
m
3
was
338%
and
174%,
respectively,
of
the
control
values
after
90
days,
but
similar
to
the
control
levels
after
the
recovery
period.

Bone
marrow
myelograms
from
animals
exposed
to
5
mg/
m
3
showed
significantly
(p

0.05)
increased
reticulocytes
(+
108%),
stemcells
(+
31%),
and
myeloblasts
(+
33%)
in
males,
and
increased
reticulocytes
(+
55)
in
females,
and
decreased
(­
45%)
lymphocytes
in
females.
However,
these
changes
in
bone
marrow
cannot
be
definitively
attributed
to
treatment
since
bone
marrow
from
the
other
exposed
groups
was
not
assayed.

Males
exposed
to
5
mg/
m
3
had
significantly
(p

0.05
or
0.01)
increased
absolute
(+
7.8%
to
+11.7%)
and
relative
(+
19.1%
to
19.2%)
kidney
weights
as
compared
with
the
controls.
Absolute
and
relative
kidney
weights
in
the
males
exposed
to
0.
5
mg/
m
3
were
increased
by
8­
9.8%
and
6.
98.2
respectively.
Although
not
statistically
significant,
the
increases
in
kidney
weights
for
these
groups
were
considered
biologically
significant.
After
the
recovery
phase,
kidney
weights
from
the
exposed
males
were
similar
to
the
controls.
In
females
exposed
to
5
mg/
m
3
absolute
and
relative
kidney
weights
were
increased
(p

0.05)
by
9.2­
9.9%
and
7.
9­
8.
2%,
respectively,
as
compared
with
the
controls.

In
high­
dose
males,
absolute
liver
weights
were
not
affected,
but
relative
liver
weights
were
slightly
(6.
9%)
higher
than
the
controls.
For
females
exposed
to
the
highest
dose,
absolute
and
relative
liver
weights
were
12.2%
and
11.0%
higher,
respectively,
than
the
controls.
No
differences
in
absolute
and
relative
liver
weights
were
noted
between
the
exposed
and
control
groups
after
the
recovery
period.

Kidney
lesions
in
males
exposed
to
0,
0.
02,
0.10,
0.50,
or
5.0
mg/
m
3
,
were
observed
in
17%,
0,
25%,
83%
and
82%,
respectively,
of
the
animals.
These
lesions
included
cloudy
swelling
of
the
tubule
epithelia,
dilated
renal
tubules
with
protein
containing
contents,
and
proliferated
tubules.
After
the
recovery
phase,
only
cloudy
swelling
of
the
tubule
epithelia
was
observed
in
two
control
animals
and
one
high­
concentration
animal.

Therefore,
the
systemic
toxicity
LOAEL
is
0.50
mg/
m
3
(0.
13
mg/
kg)
based
on
transient
microscopic
lesions
in
the
kidney
and
increased
kidney
weights
of
male
rats.
The
systemic
toxicity
NOAEL
is
0.
1
mg/
m
3
(0.
025
mg/
kg).
This
study
is
considered
Acceptable/
guideline
and
satisfies
the
requirement
for
a
subchronic
inhalation
toxicity
study
in
rats
[82­
4].

870.6200
Subchronic
oral
neurotoxicity
B
Rat
See
Section
4.
8
Neurotoxicity
for
Executive
Summary
Lindane/
September
2000
RED
Toxicology
Chapter
10
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.
Lindane
is
not
considered
teratogenic
when
administered
orally
or
subcutaneously.
Developmental
NOAELs
were
found
to
be
at
levels
equal
to
or
greater
than
maternal
NOAELs,
except
in
the
Developmental
Neurotoxicity
Study.
The
neurotoxicity
LOAEL
was
5.
6
mg/
kg/
day
(NOAEL
is
1.2
mg/
kg/
day)
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation
compared
to
a
maternal
toxicity
LOAEL
of
13.7
mg/
kg/
day
(NOAEL
is
5.6
mg/
kg/
day)
based
on
decreased
body
weight
gains,
decreased
food
consumption,
and
increased
reactivity
to
handling.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
42808001),
20
presumed
pregnant
CFY(
derived
fromCharles
River
CD)
rats
per
group
were
administered
technical
lindane
(purity
not
given;
Batch
No.
6801/
403)
by
gavage
in
0.5%
carboxymethyl­
cellulose
at
doses
of
0,
5,
10,
and
20
mg/
kg/
day
on
gestation
days
(GD)
6­
15,
inclusive.
On
GD
20,
dams
were
sacrificed
by
CO2
,
subjected
to
gross
necropsy,
and
all
fetuses
examined
externally.
Approximately
one­
third
of
each
litter
was
processed
for
visceral
examination
and
the
remaining
two­
thirds
was
processed
for
skeletal
examination.

Deaths
of
two
high­
dose
dams
were
attributed
bythe
authors
to
treatment
although
the
cause
of
death
was
not
reported.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
any
animal.
Body
weight
gains
and
food
consumption
by
the
mid­
and
high­
dose
groups
were
decreased
during
the
treatment
interval
as
compared
with
the
controls.
Body
weight
gains
by
the
mid­
and
high­
dose
dams
were
70%
and
46%,
respectively,
of
the
control
values
during
GD
6­
14.
Food
consumption
by
the
mid­
and
high­
dose
groups
was
72%
of
the
control
level
during
GD
7­
10
and
92%
and
65%,
respectively,
during
GD
11­
14.
It
should
be
noted
that
data
were
not
available
for
the
entire
dosing
interval
and
that
statistical
analyses
were
not
provided
for
these
data.

Maternal
necropsy
was
unremarkable.
Organ
weights
were
similar
between
the
treated
and
control
groups.
Therefore,
the
maternal
toxicity
LOAELis
10
mg/
kg/
day
based
on
reduced
body
weight
gain
and
food
consumption.
The
maternal
toxicity
NOAEL
is
5
mg/
kg/
day.

No
significant
differences
were
observed
between
the
control
group
and
the
treated
groups
for
number
of
corpora
lutea,
number
of
implantation
sites,
live
fetuses/
dam,
pre­
and
postimplantation
losses,
fetal
body
weights,
or
fetal
sex
ratios.
No
treatment­
related
effects
were
found
at
external
or
visceral
examination
of
the
fetuses.

The
percentage
of
litters
in
the
control,
low­,
mid­,
and
high­
dose
groups
containing
fetuses
with
extra
(14th)
ribs
was
12.7,
21.0,
31.7,
and
40.6%
(p

0.05),
respectively.
The
total
incidences
of
litters
containing
fetuses
with
skeletal
variants
were
43.4,
52.7,
59.5,
and
68.
0%
(p

0.01),
respectively.
Although
the
response
rates
in
the
high­
dose
group
for
extra
ribs
and
total
variants
are
Lindane/
September
2000
RED
Toxicology
Chapter
11
within
the
upper
limit
of
historical
control
data,
they
were
considered
treatment­
related
due
to
the
dose­
related
manner
of
increase.

Therefore,
the
developmental
toxicity
LOAEL
is
20
mg/
kg/
day
based
on
increases
in
extra
ribs
and
total
skeletal
variants;
a
trend
for
increases
in
these
endpoints
at
the
lower
doses
is
recognized.
The
developmental
toxicity
NOAEL
is
10
mg/
kg/
day.

Although,
this
study
was
conducted
prior
to
implementation
of
current
guidelines
but
is
considered
sufficient
for
the
purpose
for
which
it
was
intended.
This
study
is
classified
as
Acceptable/
nonguideline
and
satisfies
the
requirements
for
a
developmental
toxicity
study
(83­
3a)
in
rats.
Several
deficiencies
were
noted
in
the
conduct
of
this
study:
percent
purity
of
the
test
article
wast
not
given,
less
than
20
litters/
group
were
available,
dosing
solutions
were
not
analyzed
for
concentration,
stability,
or
homogeneity,
and
much
of
the
individual
animal
data
were
not
included.

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
00062656),
groups
of
presumed
pregnant
Sprague­
Dawley
rats
were
administered
lindane
(purity
not
given;
Lot
No.
36346)
by
subcutaneous
injection
in
corn
oil
(1
ml/
kg)
at
doses
of
0,
5,
15,
or
30
mg/
kg/
day
on
gestation
days
(GD)
6­
15,
inclusive.
On
GD
19,
dams
were
sacrificed
and
the
fetuses
removed.
Approximately
one­
third
of
the
fetuses
from
each
litter
were
sectioned
and
examined
for
visceral
malformations/
variations.
The
remaining
two­
thirds
of
each
litter
were
"examined
externally"
and
processed
and
examined
for
skeletal
malformations/
variations.

Two
high­
dose
animals
died
prematurely.
Clinical
signs
of
toxicity,
including
tremors,
convulsions,
urine
stains,
excit
ability,
and
anorexia,
were
reported
for
one
high­
dose
animal.
However,
it
was
not
possible
to
correlate
clinical
signs
with
death
since
individual
animal
data
were
not
included.
No
other
clinical
signs
of
toxicity
were
reported.
Body
weight
gains
by
the
mid­
and
high­
dose
dams
were
76%
and
23%,
respectively,
of
the
control
levels
during
the
treatment
interval
with
both
groups
attaining
statistical
significance
(p

0.
05).
Overall
body
weight
gain
by
the
highdose
group
was
69%
(p

0.05)
of
the
controls.
Food
consumption
by
the
high­
dose
group
was
47%
of
the
control
level
during
GD
6­
11.
Body
weight
gains
by
the
low­
dose
group
and
food
consumption
for
the
low­
and
mid­
dose
groups
were
similar
to
the
controls
throughout
the
study.
Gross
necropsy
data,
other
than
uterine
data,
for
the
dams
were
not
provided.

Therefore,
the
maternal
toxicity
LOAEL
is
15
mg/
kg/
day
based
on
decreased
body
weight
gain.
The
maternal
toxicity
NOAEL
is
5
mg/
kg/
day.

No
treatment­
related
effects
were
observed
between
the
control
group
and
the
treated
groups
for
number
of
corpora
lutea,
number
of
implantation
sites,
live
fetuses/
dam,
pre­
and
postimplantation
losses,
fetal
body
weights,
or
fetal
crown­
rump
lengths.
No
treatment­
related
visceral
or
skeletal
malformations/
variations
were
observed
in
any
of
the
fetuses.
Results
of
external
examination
were
not
reported.

Therefore,
the
developmental
toxicity
NOAELis
>30
mg/
kg/
day
and
the
developmental
toxicity
LOAEL
was
not
identified.
Lindane/
September
2000
RED
Toxicology
Chapter
12
This
study
is
classified
as
Unacceptable/
nonguideline
and
does
not
satisfy
the
requirements
for
a
developmental
toxicity
study
(83­
3a)
in
rats.
Several
deficiencies
were
noted
in
the
conduct
of
this
study:
the
subcutaneous
route
is
not
the
preferred
method
of
administration,
percent
purity
of
the
test
article
was
not
given,
dosing
solutions
were
not
analyzed
for
concentration,
stability,
or
homogeneit
y,
less
than
20
litters/
group
were
available
for
evaluation,
and
much
of
the
individual
maternal
and
fetal
data
were
not
included.
However,
this
data
may
be
used
as
supplemental
information.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
42808002),
13
presumed
pregnant
NewZealand
white
rabbits
per
group
were
administered
lindane
(puritynot
given;
Batch
No.
6801/
403)
by
gavage
in
0.
5%
carboxymethyl­
cellulose
at
doses
of
0,
5,
10,
or
20
mg/
kg/
day
on
gestation
days
(GD)
6­
18,
inclusive.
On
GD
29,
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
examined
for
visceral
and
skeletal
malformations/
variations.
Data
from
external
examination
of
the
fetuses
was
not
included.

All
does
survived
to
scheduled
sacrifice.
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
Maternal
body
weight
and
food
consumption
were
similar
between
the
treated
and
control
groups.
Gross
necropsy
was
unremarkable.
Organ
weights
were
similar
between
the
treated
and
control
groups.

Therefore,
the
maternal
toxicity
NOAEL
is
>20
mg/
kg/
day
and
the
maternal
toxicity
LOAEL
was
not
identified.

No
treatment­
related
effects
were
observed
in
any
dose
group
for
number
of
corpora
lutea,
number
of
implantation
sites,
live
fetuses/
dam,
pre­
and
post­
implantation
losses,
fetal
body
weights,
or
fetal
sex
ratios.
No
treatment­
related
visceral
or
skeletal
malformations/
variations
were
observed
in
any
of
the
fetuses.

Therefore,
the
developmental
toxicity
NOAELis
>20
mg/
kg/
day
and
the
developmental
toxicity
LOAEL
was
not
identified.

This
study
is
classified
as
Unacceptable/
not
upgradable
and
does
not
satisfy
the
requirements
for
a
developmental
toxicity
study
(83­
3b)
in
rabbits.
Maternal
and
developmental
toxicity
LOAELs
were
not
identified
and
the
highest
dose
did
not
approach
the
limit
dose.
Therefore,
dose
selection
was
considered
inadequate.
Doses
were
based
on
the
results
of
a
subcutaneous
study
in
the
rabbit
(MRID
00062658)
which
is
not
a
valid
method
for
selecting
doses
for
an
oral
study.
Several
other
deficiencies
were
noted
in
the
conduct
of
this
study:
percent
purity
of
the
test
article
was
not
given,
dosing
solutions
were
not
analyzed
for
concentration,
stability,
or
homogeneity,
and
much
of
the
individual
animal
data
were
not
included.

EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
00062658),
15
presumed
pregnant
New
Zealand
white
rabbits
per
group
following
artificial
insemination
were
administered
lindane
(purity
and
Batch
No.
not
given)
by
subcutaneous
injection
in
corn
oil
Lindane/
September
2000
RED
Toxicology
Chapter
13
(0.
5
ml/
kg)
at
doses
of
0,
5,
15,
or
45
mg/
kg/
day
on
gestation
days
(GD)
6­
18,
inclusive.
Due
to
excessive
toxicity,
the
high
dose
was
reduced
to
30
mg/
kg/
day
after
GD
9.
On
GD
29,
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
examined
for
visceral
and
skeletal
malformations/
variations.
Data
from
external
examination
of
the
fetuses
was
not
included.

One
mid­
dose
damaborted
and
died
on
GD21
and
14/
15
high­
dose
animals
died
between
GD10
and
26.
The
high­
dose
group
was
then
discontinued
due
to
excessive
mortality.
Decreased
activity
and
immobilized
rear
quarters
were
observed
in
the
mid­
dose
group
(frequency
and
number
affected
not
reported).
No
clinical
signs
of
toxicity
were
observed
in
the
low­
dose
group.
During
GD
6­
20,
does
in
the
mid­
dose
group
had
a
body
weight
loss
of
126.7
g
as
compared
with
a
body
weight
gain
of
218.0
g
by
the
controls.
Body
weight
loss
was
accompanied
by
"markedly
lower"
food
consumption
by
the
mid­
dose
animals.
Body
weight
changes
and
food
consumption
for
the
low­
dose
group
were
similar
to
the
controls
throughout
the
study.

It
appeared
that
does
in
the
mid­
and
high­
dose
group
had
differences
in
the
texture
of
the
liver,
however,
data
from
gross
necropsy
were
difficult
to
interpret
due
to
poor
copy
quality
of
the
original
report.

Therefore,
the
maternal
toxicity
LOAEL
is
15
mg/
kg/
day
based
on
clinical
signs
of
toxicity,
death,
and
reduction
in
body
weight.
The
maternal
toxicity
NOAEL
is
5
mg/
kg/
day.

No
treatment­
related
effects
were
observed
between
the
control
group
and
the
treated
groups
for
number
of
corpora
lutea,
number
of
implantation
sites,
live
fetuses/
dam,
pre­
and
postimplantation
losses,
fetal
body
weights,
or
fetal
crown­
rump
distances.
No
treatment­
related
visceral
or
skeletal
malformations/
variations
were
observed
in
any
of
the
fetuses.
Abortion
by
one
mid­
dose
doe
was
assumed
to
be
due
to
excessive
maternal
toxicity
and
not
to
a
direct
effect
on
the
embryos
or
fetuses.

Therefore,
the
developmental
toxicity
NOAELis
>15
mg/
kg/
day
and
the
developmental
toxicity
LOAEL
was
not
identified.

This
study
is
classified
as
Unacceptable/
not
upgradable
and
does
not
satisfy
the
requirements
for
a
developmental
toxicity
study
(83­
3b)
in
rabbits.
Several
deficiencies
were
noted
in
the
conduct
of
this
study:
the
subcutaneous
route
is
not
the
preferred
method
of
administration,
excessive
toxicity
occurred
at
the
high­
dose,
percent
purity
of
the
test
article
wast
not
given,
dosing
solutions
were
not
analyzed
for
concentration,
stability,
or
homogeneity,
and
much
of
the
individual
maternal
and
fetal
data
were
not
included.
However,
these
study
results
may
be
used
in
conjunction
with
the
oral
developmental
toxicitystudyin
rabbits
(MRID42808002)
as
supplemental
information.

870.6300
Developmental
Neurotoxicity
Study
­
Rat
See
Section
4.
8
Neurotoxicity
for
Executive
Summary
4.4
Reproductive
Toxicity
Lindane/
September
2000
RED
Toxicology
Chapter
14
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Both
parental
and
offspring
LOAELs
are
13
mg/
kg;
however
there
is
a
qualitative
difference
in
the
severity
of
effects.
In
the
parental
animals,
toxicity
was
seen
in
the
form
of
reduction
in
body
weight
gain
during
gestation
while
offspring
toxicity
was
correlated
with
decreases
in
pup
viability
and
pup
body
weight
in
the
F1
and
F2
generations
as
well
as
delayed
maturation
in
the
F2
generation.
Evidence
for
quantitative
increase
in
susceptibility
could
not
be
ascertained
due
to
the
wide
spread
in
the
doses
tested.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
EXECUTIVE
SUMMARY:
In
a
multigeneration
reproductive
toxicity
study
(MRID
42246101),
lindane
(99.5%
a.
i.;
Batch
No.
DA433)
was
administered
to
groups
of
30
male
and
30
female
Charles
River
CD
rats
at
dietary
concentrations
of
0,
1,
20,
or
150
ppm
(0.
087,
1.71,
and
13.05
mg/
kg/
day,
respectively)
during
the
per
mating
period
for
two
generations.
One
litter
was
produced
in
each
generation.
F1
pups
chosen
as
parental
animals
were
weaned
onto
the
same
diet
as
their
parents.
Test
or
control
diets
were
administered
to
the
F0
and
F1
parental
animals
for
71
and
70
days,
respectively,
before
the
animals
were
mated
within
the
same
dose
group.
All
animals
were
continuously
exposed
to
test
material
either
in
the
diet
or
during
lactation
until
sacrifice.

Premature
sacrifices
or
intercurrent
deaths
of
two
F0
animals
and
five
F1
animals
were
considered
incidental
to
treatment;
all
other
F0
and
F1
males
and
females
survived
to
terminal
sacrifice.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
males
or
females
of
either
generation
at
any
time
during
the
study.
No
treatment­
related
effects
on
body
weights,
body
weight
gains,
food
consumption,
or
food
efficiency
were
observed
for
the
F0
and
F1
males
and
females
during
premating.
Gross
necropsy
and
histopathology
of
females
was
unremarkable.

During
gestation
days
10­
13,
mean
body
weight
gain
by
the
high­
dose
F0
females
was
significantly
reduced
(11%).
Mean
body
weight
gains
by
the
high­
dose
F0
females
were
also
significantly
lower
on
lactation
day
1
(interval
not
specified)
as
compared
to
the
controls,
but
recovery
was
apparent
by
weaning.
No
treatment­
related
changes
in
body
weights
or
body
weight
gains
were
observed
in
the
F1
females
during
gestation
or
lactation.

High­
dose
male
rats
of
both
generations
had
a
significantly
(p

0.01)
increased
incidence
of
pale
kidneys
(10/
29
F0
males
and
10/
30
F1
males)
as
compared
with
the
controls
(0/
30
and
0/
28,
respectively).
Areas
of
change
on
the
kidneys
(not
defined)
were
observed
in
7/
29
high­
dose
F0
males
compared
with
2/
30
controls
and
in
4/
30
mid­
dose
F1
males
and
5/
30
high­
dose
F1
males
compared
with
1/
28
controls.
Significantly
(p
<
0.01)
increased
incidence
of
hydronephrosis
was
observed
in
high
dose
F1
males
(7/
30)
as
compared
to
controls
(0/
28).
Absolute
and
relative
kidney
weights
of
the
mid­
and
high­
dose
F0
males
and
the
high­
dose
F1
males
were
significantly
(p

0.01)
increased
as
compared
with
the
controls.

F0
and
F1
males
in
the
mid­
and
high­
dose
groups
had
significantly
(p

0.01)
increased
incidences
of
chronic
interstitial
nephritis,
cortical
tubular
cell
regeneration,
hyaline
droplets
in
proximal
tubules,
tubular
necrosis
with
exfoliation
and
cellular
casts,
and
cortical
tubular
casts
(n.
s.).
These
changes
are
characteristic
of
alpha
2    
globulin
accumulation,
which
is
specific
to
male
rats.
Lindane/
September
2000
RED
Toxicology
Chapter
15
Increased
absolute
and
relative
liver
weights,
accompanied
by
hepatocellular
hypertrophy,
in
the
mid­
and
high­
dose
males
and
females
of
both
generations
were
considered
adaptive
and
of
no
biological
significance.

Therefore,
the
LOAEL
for
systemic
toxicity
is
150
ppm
(13.05
mg/
kg/
day)
based
on
decreased
body
weight
gains
by
the
F0
females
during
gestation.
The
systemic
toxicity
NOAEL
is
20
ppm.
In
addition,
the
LOAEL
for
male
rats
is
20
ppm
(1.
71
mg/
kg/
day)
based
on
increased
kidney
weights
and
histopathological
lesions
in
the
kidney
characteristic
of
alpha
2µ
globulin
accumulation;
the
NOAEL
for
males
is
1
ppm
(0.
087
mg/
kg/
day).

Mating,
fertility,
gestation
survival
(postimplantation
index),
and
liveborn
indices,
mean
precoital
interval,
and
mean
gestation
length
were
similar
between
the
treated
and
control
groups
of
both
generations.
The
sex
distribution
was
not
affected
by
the
test
material.
Mean
litter
sizes
of
the
treated
groups
were
not
different
from
the
controls
throughout
lactation
for
both
generations.
Viability
indices
for
the
high­
dose
F1
and
F2
pups
were
81%
and
85%,
respectively,
compared
with

96%
for
the
controls.
This
reduction
in
survival
on
lactation
day
4
was
due
to
the
death
or
sacrifice
(for
humane
reasons)
of
three
F1
litters
and
two
F2
litters.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
the
pups
of
either
generation
during
lactation.
Pup
necropsy
was
unremarkable.

Body
weights
of
the
low­
and
mid­
dose
F1
and
F2
pups
were
similar
to
the
controls
throughout
lactation.
Body
weights
of
the
high­
dose
pups
of
both
generations
were
significantly
(p

0.01)
less
than
the
controls
on
lactation
days
1
and
25.
In
high­
dose
F2
pups,
the
onset
and
completion
of
tooth
eruption
and
completion
of
hair
growth
were
significantly
(p

0.01)
delayed
10.5%,
11.6%,
and
24%,
respectively,
as
compared
with
the
controls.

Therefore,
the
LOAEL
for
reproductive
toxicity
is
150
ppm
(13.05
mg/
kg/
day)
based
on
reduced
pup
body
weights
and
decreased
viability
in
both
generations
and
delayed
maturation
of
the
F2
pups.
The
reproductive
toxicity
NOAEL
is
20
ppm
(1.71
mg/
kg/
day).

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
reproduction
study
(83­
4)
in
rats.
No
major
deficiencies
were
identified
in
the
conduct
of
this
study.
4.5
Chronic/
Carcinogenicity
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
liver
appears
to
be
the
major
target
organ.
The
incidence
of
periacinar
hepatocytic
hypertrophy
was
significantly
(p

0.01)
increased
in
the
100­
and
400­
ppm
(4.
81
and
6.00
mg/
kg/
day,
respectively)
males
and
the
400­
ppm
females
at
30
days
and
26
weeks.
In
addition,
increased
liver
and
spleen
weights,
and
decreased
platelets
were
also
noted.

Kidney
lesions
in
males
indicative
of
alpha
2µ
globulin
accumulation
were
observed
in
animals
treated
with

10
ppm,
but
are
not
considered
relevant
to
human
health
risk
assessment.
Lindane/
September
2000
RED
Toxicology
Chapter
16
870.4100a
(870.4300)
Chronic
Toxicity
B
Rat
EXECUTIVE
SUMMARY:
Results
from
interim
sacrifice
of
15
rats/
sex/
group,
at
30
days
and
26
weeks,
of
an
ongoing
chronic/
oncogenicity
study
are
presented
in
this
report
(MRID
41094101).
In
the
chronic
toxicity/
oncogenicity
study
(MRID41853701),
lindane
(99.75%
a.
i.,
Lot
no.
DA433)
was
administered
in
the
diet
to
groups
of
115
male
and
115
female
Wistar
rats
at
concentrations
of
0,
1,
10,
100,
or
400
ppmfor
2
years.
Corresponding
delivered
doses
were
0,
0.
05,
0.47,
4.81,
and
19.66
mg/
kg/
day,
respectively,
for
males
and
0,
0.
06,
0.59,
6.00,
and
24.34
mg/
kg/
day,
respectively,
for
females.

No
clinical
signs
of
toxicity
were
observed.
Mortalities
in
the
0,
1,
10,
100,
and
400
ppm
groups
included
1,
2,
2,
2,
and
0
males,
respectively,
and
2,
0,
1,
1,
and
8
females,
respectively.
Deaths
in
high­
dose
females
occurred
during
weeks
2­
4
and
the
cause
of
death
was
not
determined.
Body
weights
were
slightly
less
than
the
controls
for
the
high­
dose
males
(­
6%)
and
females
(­
8%)
during
weeks
1­
5
of
the
study,
but
gradually
increased
to
within
2%
of
the
control
level
by
week
26
for
males
and
week
9­
10
for
females.
Food
consumption
was
"marginally
lower"
in
high­
dose
males
and
females
and
water
consumption
was
"marginallyhigher"
in
high­
dose
males
(63
ml/
kg/
day
versus
50
ml/
kg/
day
for
controls).

High­
dose
females
had
significantly
(p

0.01)
decreased
hemoglobin
(­
4
to
­7%)
at
weeks
3,
12,
and
24,
decreased
RBC
counts
(­
6
to
­6.
3%)
at
weeks
3
and
24,
and
decreased
PCV
(­
4.
2
to
­9.
1%)
at
weeks
3
and
24.
These
red
cell
parameters
were
"marginally
lower"
for
high­
dose
males,
but
statistical
significance
was
not
reached.
Platelet
counts
were
increased
by
up
to
13­
14%
in
mid
not
defined)
and
high­
dose
males
(week
12)
and
females
(week
24).
White
cell
counts
were
significantly
(p

0.05)
increased
27.5%
in
mid­
dose
(not
defined)
and
23.5%
in
high­
dose
females
due
to
increases
in
neutrophils.

Statistically
significant
(p

0.05
or
0.01)
changes
in
clinical
chemistry
parameters
were
observed
in
high­
dose
males
and
females
during
the
first
24
weeks.
Inorganic
phosphorous
was
increased
by
7.3­
29%
and
calcium
was
increased
by
3.5­
10%.
Females
in
the
1,
10,
and
100
ppm
groups
also
had
significantly
(+
6
to
+8%;
p

0.01)
increased
calcium
levels
at
week
3
as
compared
with
the
controls.
Differences
in
urea
and
total
cholesterol
by
the
high­
dose
males
and
females
were
not
consistent
over
time
and
did
not
appear
to
be
dose­
related.

Urinalyses
were
conducted
by
routine
analysis,
after
water
deprivation,
and
after
water
loading.
Differences
in
urinalysis
parameters
between
treated
and
control
females
were
considered
random
and
not
treatment­
related.
No
clear
evidence
of
an
effect
on
kidney
function
was
observed
in
males.

Absolute
kidney
weights
were
significantly
(p

0.05
or
0.01)
increased
in
high­
dose
males
by
12.9%
and
39.3%,
and
relative
kidney
weights
were
increased
by
27.3%
and
43.0%
at
30
days
and
26
weeks,
respectively.
Absolute
and
relative
kidney
weights
from
the
100­
ppm
males
were
increased
by
16.
9%
and
23.
6%,
respectively,
at
30
days,
but
were
similar
to
the
controls
at
26
weeks.

Absolute
liver
weights
were
significantly
(p

0.01)
increased
by
40.8%
in
high­
dose
males
at
26
weeks
and
by
29.3%
and
32.3%
in
high­
dose
females
at
30
days
and
26
weeks,
respectively.
Lindane/
September
2000
RED
Toxicology
Chapter
17
Relative
liver
weights
of
the
high­
dose
males
and
females
were
significantly
(p

0.05
or
0.01)
were
greater
(14.0­
37.2%)
than
the
controls
at
both
sacrifice
times.

Increases
in
the
incidence
of
pale
kidneys
in
100­
and
400­
ppmmales
were
noted
at
necropsy.
At
both
30
days
and
26
weeks
hyaline
droplets
in
the
proximal
tubules
were
observed
in
the
kidneys
of
all
males
(10/
10;
p

0.01)
receiving
10,
100,
and
400
ppm
compared
with
none
of
the
controls.
Tubular
regeneration
(p

0.01)
was
observed
after
30
days
in
9­
10/
10
males
treated
with

10
ppm,
but
at
26
weeks
was
seen
in
only
8/
10
males
given
100
ppm
and
7/
10
given
400
ppm.
In
the
100
and
400
ppm
groups,
interstitial
chronic
nephritis
occurred
in
5­
6
males
at
30
days
and
26
weeks
and
cortical
tubular
necrosis
was
observed
in
9­
10
males
at
30
days.
At
26
weeks
cortical
tubular
necrosis
was
seen
in
only
2
100­
ppmmales
and
5
(p

0.05)
400­
ppmmales.
These
treatment­
related
kidney
lesions
were
not
observed
in
control
males
or
in
females
at
any
dose
level.

The
incidence
of
periacinar
hepatocytic
hypertrophy
was
significantly
(p

0.01)
increased
in
the
100­
and
400­
ppm
males
and
the
400­
ppm
females
at
30
days
and
26
weeks.
At
30
days
the
incidences
were
7/
10
and
10/
10
for
males,
respectively,
and
9/
9
for
females.
After
26
weeks
of
treatment,
the
incidences
were
8/
10
and
10/
10
for
males,
respectively,
and
9/
9
for
females.
This
lesion
was
not
seen
in
control
animals
of
either
sex.
No
treatment­
related
histopathological
lesions
were
observed
in
the
spleen,
adrenals,
brain,
or
thymus.
Bone
marrow
data
presentation
was
inadequate
for
assessment.

Therefore,
the
systemic
toxicity
LOAEL
is
10
ppm
(0.
59
mg/
kg/
day)
based
on
microscopic
lesions
in
the
kidney
of
male
rats.
The
systemic
toxicity
NOAEL
is
1
ppm
(0.06
mg/
kg/
day).
This
study
is
considered
Acceptable/
nonguideline
as
an
interim
report
for
a
combined
chronic
toxicity/
oncogenicity
study
in
rats
[83­
5].
It
is
sufficient
for
the
purpose
for
which
it
was
intended
as
an
interim
report.

EXECUTIVE
SUMMARY:
In
a
chronic
toxicity/
oncogenicity
study
(MRID
41853701),
lindane
(99.
75%
a.
i.,
Lot
no.
DA433)
was
administered
in
the
diet
to
groups
of
50
male
and
50
female
Wistar
rats
at
concentrations
of
0,
1,
10,
100,
or
400
ppm
for
2
years.
Corresponding
delivered
doses
were
0,
0.
05,
0.47,
4.81,
and
19.66
mg/
kg/
day,
respectively,
for
males
and
0,
0.
06,
0.59,
6.00,
and
24.34
mg/
kg/
day,
respectively,
for
females.
An
additional
15
rats/
sex/
group
were
designated
for
interimsacrifices
at
30
days
and
26
weeks
(the
results
fromthese
interimsacrifices
are
presented
separately
(MRID
41094101);
more
sacrifices
were
performed
at
52
and
78
weeks.

Clinical
signs
of
toxicity
consisted
of
convulsions
in
11
high­
dose
females.
No
other
clinical
signs
were
observed.
Survival
at
the
end
of
the
study
was
36,
36,
31,
20,
and
16%
for
males
and
49,
38,
44,
35,
and
18%
for
females
in
the
0,
1,
10,
100,
and
400
ppm
groups,
respectively.
Survival
of
high­
dose
males
was
similar
to
the
controls
through
week
93.
For
females,
however,
survival
was
significantly
decreased
in
the
high­
dose
group
with
50%
survival
reached
at
week
89
compared
to
week
104
for
the
control
group.

Body
weight
gains
were
significantly
(p

0.01)
decreased
for
the
100­
and
400­
ppm
males
during
the
first
few
weeks
of
the
study
as
compared
to
the
controls.
Because
final
body
weights
of
Lindane/
September
2000
RED
Toxicology
Chapter
18
t
he
100
ppm
males
were
similar
to
the
controls,
the
initial
reduction
in
weight
gain
was
not
considered
biologically
significant.
Final
body
weights
of
the
high­
dose
males
were
significantly
14
p

0.
05)
less
than
the
controls.
Body
weights
and
body
weight
gains
for
the
treated
females
were
similar
to
the
controls
throughout
the
study.
Food
consumption
by
the
high­
dose
groups
was
decreased
15%
in
males
and
19%
in
females
during
the
first
week
of
the
study,
however,
total
food
consumption
for
the
entire
study
was
similar
to
the
control
levels.

Platelet
counts
were
significantly
(p

0.05
or
0.01)
increased
(20%
or
less
)
in
the
100­
and
400­
ppm
males
at
week
12
and
in
100­
and
400­
ppm
males
and
females
at
week
24,
but
not
at
later
time
points.
High­
dose
males
and
females
had
significant
(p

0.05
or
0.01)
decreases
in
red
blood
cell
parameters
at
week
104
as
compared
with
the
controls:
hemoglobin
was
­15.6%
and
­17.6%,
respectively,
erythrocyte
counts
were
­14.1%
and
­21%,
respectively,
and
PCV
was
­15.9%
and
18.2
respectively.

Significant
(p

0.05
or
0.01)
changes
in
clinical
chemistry
parameters
were
observed
in
highdose
males
and
females
during
the
first
year
of
the
study.
Inorganic
phosphorous
was
increased
by
7.3­
38.5%
and
calcium
was
increased
by
3.4­
10%
in
males
and
females;
cholesterol
was
increased
by
45­
110%
and
urea
was
increased
by
20­
54%
in
females;
and
the
albumin/
globulin
ratio
was
decreased
by
8.
3­
18.
2%
in
females.
All
parameters
were
similar
to
the
control
levels
by
week
104.

High­
dose
males
and
females
had
increased
absolute
and
relative
liver
weights
at
all
interim
sacrifices,
although
statistical
significance
was
not
always
reached.
At
study
termination,
absolute
and
relative
liver
weights
were
significantly
(p

0.01)
increased
by
21.2%
and
38.5%,
respectively,
in
high­
dose
males
and
by
31.6%
and
33.5%,
respectively,
in
high­
dose
females.
At
100
ppm,
absolute
liver
weights
were
increased
by
8.6­
11.2%
(n.
s.)
and
relative
liver
weights
were
increased
by
14.4­
17.6%
(p

0.05
or
0.01)
for
both
sexes
at
week
104.
Significant
(p

0.05
or
0.01)
increases
in
absolute
and
relative
spleen
weights
at
week
52
and
in
relative
spleen
weights
at
week
104
were
also
noted,
but
the
sex
was
not
identified.
The
incidence
rate
of
periacinar
hepatocytic
hypertrophy
was
significantly
increased
in
the
100­
and
400­
ppmgroups
with
25/
50
males
and
19/
50
females
affected
at
100
ppm
and
40/
50
males
and
43/
50
females
affected
at
400
ppm.
No
treatmentrelated
histopathological
lesions
were
observed
in
the
spleen
or
bone
marrow.

Kidney
lesions
in
males
indicative
of
alpha
2µ
globulinaccumulation
were
observed
in
animals
treated
with

10
ppm,
but
are
not
considered
relevant
to
human
health
risk
assessment.

Therefore,
the
systemic
toxicity
LOAEL
for
male
and
female
rats
is
100
ppm
(4.
81
and
6.00
mg/
kg/
day,
respectively)
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver
and
spleen
weights,
and
decreased
platelets.
The
systemic
toxicity
NOAEL
is
10
ppm.

Among
high­
dose
males,
there
was
an
apparent
increase
in
adrenal
pheochromocytomas.
The
percentage
of
animals
with
tumors
(benign
and
malignant)
was
14,
12,
19,
14,
and
26%
in
the
0,
1,
10,
100,
and
400
ppm
groups,
respectively.
Statistical
significance
can
be
shown
depending
on
the
test
used.
Based
on
the
data
presented
in
this
study,
an
assessment
of
the
carcinogenic
potential
of
lindane
cannot
be
made.
Additional
histopathological
examination
of
the
adrenals
from
animals
in
Lindane/
September
2000
RED
Toxicology
Chapter
19
the
1,
10,
and
100
ppm
groups,
as
well
as
historical
control
data
for
this
tumor
type,
are
required.
These
data
were
submitted
as
a
separate
study
(MRID
42891401).

This
chronic
toxicity/
oncogenicity
study
in
the
rat
is
Unacceptable/
upgradable
and
does
not
satisfy
the
guideline
requirement
for
a
combined
chronic
toxicity/
oncogenicity
study
in
rats
[83­
5].
Additional
data
on
adrenal
pheochromocytomas
is
necessary
to
complete
the
assessment.

EXECUTIVE
SUMMARY:
The
current
study
(MRID
42891201)
was
submitted
as
supplemental
information
to
the
combined
chronic
toxicity/
oncogenicity
study.
Data
fromadditional
microscopic
examination
of
the
adrenal
gland
from
males
in
the
low­
and
two
mid­
dose
groups
and
historical
control
data
are
included.
In
a
chronic
toxicity/
oncogenicity
study
(MRID
41853701),
lindane
(99.75%
a.
i.,
Lot
no.
DA433)
was
administered
in
the
diet
to
groups
of
50
male
and
50
female
Wistar
rats
at
concentrations
of
0,
1,
10,
100,
or
400
ppm
for
2
years.
Corresponding
delivered
doses
were
0,
0.
05,
0.47,
4.81,
and
19.66
mg/
kg/
day,
respectively,
for
males
and
0,
0.
06,
0.59,
6.00,
and
24.34
mg/
kg/
day,
respectively,
for
females.
An
additional
15
rats/
sex/
group
were
designated
for
interimsacrifices
at
30
days
and
26
weeks;
the
results
fromthese
interimsacrifices
are
presented
separately
(MRID
41094101).

Clinical
signs
of
toxicity
consisted
of
convulsions
in
11
high­
dose
females.
No
other
clinical
signs
were
observed.
Survival
at
the
end
of
the
study
was
36,
36,
31,
20,
and
16%
for
males
and
49,
38,
44,
35,
and
18%
for
females
in
the
0,
1,
10,
100,
and
400
ppm
groups,
respectively.
Survival
of
high­
dose
males
was
similar
to
the
controls
through
week
93.
For
females,
however,
survival
was
significantly
decreased
in
the
high­
dose
group
with
50%
survival
reached
at
week
89
compared
to
week
104
for
the
control
group.

Body
weight
gains
were
significantly
(p

0.01)
decreased
for
the
100­
and
400­
ppm
males
during
the
first
few
weeks
of
the
study
as
compared
to
the
controls.
Because
final
body
weights
of
the
100
ppm
males
were
similar
to
the
controls,
the
initial
reduction
in
weight
gain
was
not
considered
biologically
significant.
Final
body
weights
of
the
high­
dose
males
were
significantly
14
p

0.
05)
less
than
the
controls.
Body
weights
and
body
weight
gains
for
the
treated
females
were
similar
to
the
controls
throughout
the
study.
Food
consumption
by
the
high­
dose
groups
was
decreased
15%
in
males
and
19%
in
females
during
the
first
week
of
the
study,
however,
total
food
consumption
for
the
entire
study
was
similar
to
the
control
levels.

Platelet
counts
were
significantly
(p

0.05
or
0.01)
increased
(20%
or
less)
in
the
100­
and
400­
ppm
males
at
week
12
and
in
100­
and
400­
ppm
males
and
females
at
week
24,
but
not
at
later
time
points.
High­
dose
males
and
females
had
significant
(p

0.05
or
0.01)
decreases
in
red
blood
cell
parameters
at
week
104
as
compared
with
the
controls:
hemoglobin
was
­15.6%
and
­17.6%,
respectively,
erythrocyte
counts
were
­14.1%
and
­21%,
respectively,
and
PCV
was
­15.9%
and
18.2
respectively.

Significant
(p

0.05
or
0.01)
changes
in
clinical
chemistry
parameters
were
observed
in
highdose
males
and
females
during
the
first
year
of
the
study.
Inorganic
phosphorous
was
increased
by
Lindane/
September
2000
RED
Toxicology
Chapter
20
7.3­
38.5%
and
calcium
was
increased
by
3.4­
10%
in
males
and
females;
cholesterol
was
increased
by
45­
110%
and
urea
was
increased
by
20­
54%
in
females;
and
the
albumin/
globulin
ratio
was
decreased
by
8.
3­
18.
2%
in
females.
All
parameters
were
similar
to
the
control
levels
by
week
104.

High­
dose
males
and
females
had
increased
absolute
and
relative
liver
weights
at
all
interim
sacrifices,
although
statistical
significance
was
not
always
reached.
At
study
termination,
absolute
and
relative
liver
weights
were
significantly
(p

0.01)
increased
by
21.2%
and
38.5%,
respectively,
in
high­
dose
males
and
by
31.6%
and
33.5%,
respectively,
in
high­
dose
females.
At
100
ppm,
absolute
liver
weights
were
increased
by
8.6­
11.2%
(n.
s.)
and
relative
liver
weights
were
increased
by
14.4­
17.6%
(p

0.05
or
0.01)
for
both
sexes
at
week
104.
Significant
(p

0.05
or
0.
01)
increases
in
absolute
and
relative
spleen
weights
at
week
52
and
in
relative
spleen
weights
at
week
104
were
also
noted,
but
the
sex
was
not
identified.

The
incidence
rate
of
periacinar
hepatocytic
hypertrophy
was
significantly
increased
in
the
100­
and
400­
ppm
groups
with
25/
50
males
and
19/
50
females
affected
at
100
ppm
and
40/
50
males
and
43/
50
females
affected
at
400
ppm.
No
treatment­
related
histopathological
lesions
were
observed
in
the
spleen
or
bone
marrow.

Kidneylesions
in
males
indicative
of
alpha
2µ
globulin
accumulation
were
observed
in
animals
treated
with

10
ppm,
but
are
not
considered
relevant
to
human
health
risk
assessment.

Therefore,
the
systemic
toxicity
LOAEL
for
male
and
female
rats
is
100
ppm
(4.
81
and
6.00
mg/
kg/
day,
respectively)
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver
and
spleen
weights,
and
decreased
platelets.
The
systemic
toxicity
NOAEL
is
10
ppm
(0.
47
and
0.59
mg/
kg/
day,
males
and
females,
respectively).

Eight
additional
males
were
identified
as
having
adrenal
pheochromocytomas.
The
revised
percentages
of
animals
with
adrenal
tumors
in
the
0,
1,
10,
100,
and
400
ppm
groups
are
14,
16,
16,
6,
and
24%
for
benign
tumors,
respectively,
and
0,
0,
6,
8,
and
2%
for
malignant
tumors,
respectively.
Statistical
significance
was
not
reached
by
relevant
tests.
For
comparison,
historical
control
data
fromCharles
River
and
publications
in
the
open
literature
were
submitted.
The
10
and
100
ppm
groups
had
malignant
tumor
incidence
rates
greater
than
the
historical
control
rate
(0­
2%).
The
high­
dose
group
also
had
a
slight
excess
of
benign
and
combined
tumor
rates
as
compared
with
the
historical
control
rates
(8­
22%
benign,
combined
could
not
be
calculated),
but
this
same
net
tumor
incidence
was
the
same
as
the
control
group
of
a
published
study.
In
the
current
study,
pheochromocytomas
were
not
considered
the
cause
of
death
for
any
animal
with
the
exception
of
a
single
animal
in
the
100
ppm
group.

Therefore,
no
evidence
dose­
related
and
statisticallysignificant
increase
inadrenal
tumors
was
observed
in
this
study.
The
study
was
conducted
at
adequate
dose
levels.

This
chronic
toxicity/
oncogenicity
st
udy
in
the
rat
is
Acceptable/
guideline
(revised)
and
satisfies
the
guideline
requirement
for
a
combined
chronic
toxicity/
oncogenicity
study
in
rats
[83­
5].
Lindane/
September
2000
RED
Toxicology
Chapter
21
870.4100b
Chronic
Toxicity
­
Dog
Chronic
studies
in
two
species,
rat
and
rabbit,
are
available.
See
chronic
oral
section
for
executive
summaries.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
incomplete.
According
to
the
TES
committee
report
(1994),
lindane
has
not
been
classified
by
the
HED
Cancer
Peer
Review
Committee.
It
was
determined
by
the
RfD/
Peer
Review
Committee
(1993)
that:
"The
mouse
carcinogenicity
data
were
considered
insufficient
because
of
major
deficiencies
associated
with
all
studies
available."
Lindane
however
had
been
previously
(1985)
classified
by
the
Cancer
Assessment
Group
of
the
Office
of
Research
and
Development
as
a
group
B2/
C
carcinogen
based
on
increased
incidence
of
mouse
liver
tumors.
The
upper­
bound
slope
of
the
dose­
response
was
given
in
that
memorandumas
Q1*
=
1.1
(mg/
kg/
day)
­1
.
Amouse
carcinogenicity
study
is
expected
to
be
submitted
in
December
2000.

870.4200a
Carcinogenicity
Study
­
rat
See
the
chronic
toxicity
section
for
executive
summaries
870.4200b
Carcinogenicity
(feeding)
­
Mouse
A
new
study
is
expected
in
December
2000.

EXECUTIVE
SUMMARY:
In
a
special
study,
(MRID
none)
three
strains
of
female
mice,
agouti,
pseudoagouti,
and
black,
were
administered
lindane
at
dietary
concentrations
of
0
or
160
ppm.
The
doses
were
selected
based
on
a
preliminary
st
udy
where
no
deaths
occurred
after
one
month.
Groups
of
36­
96
animals
per
strain
were
continuously
fed
treated
or
control
diets
for
up
to
24
months.
Additional
groups
of
48­
96
agouti
and
black
mice
were
fed
treated
or
control
diets
for
6
months
then
fed
control
diet
for
6
or
18
months
(recovery).

No
clinical
signs
of
toxicity
and
no
survival
information
were
reported.
No
apparent
effects
on
body
weights
or
food
consumption
were
observed,
but
only
limited
data
were
presented.
When
compared
with
untreated
controls
at
6
and
12
months,
benzo(
a)
pyrene
monooxygenase
activity
in
the
liver
was
increased
1.61­
1.84x
in
the
agouti,
2.71­
2.78x
in
the
pseudoagouti,
and
2.07­
2.09x
in
the
black
strains.

Liver
weights
were
increased
14.7­
31.2%
in
the
agouti,
13.5­
22.0%
in
the
pseudoagouti,
and
12.2­
16.4%
in
the
black
strains
at
interval
sacrifices
up
to
24
months.
Following
the
recovery
period,
liver
weights
of
the
treated
mice
were
similar
to
the
controls.

No
evidence
for
increased
incidence
or
decreased
latency
of
liver
tumors
was
observed
for
the
black
strain
at
any
time
during
the
study
(24
months)
or
for
the
pseudoagouti
strain
through
the
18
month
sacrifice.
At
18
months,
0/
34
control
and
12/
36
(33%)
of
the
treated
agouti
mice
Lindane/
September
2000
RED
Toxicology
Chapter
22
developed
hepatocellular
adenomas;
one
carcinoma
each
in
the
treated
and
control
groups
was
noted.
Both
the
treated
agouti
and
pseudoagouti
strains
had
clear
increases
in
adenomas
and
slight
increases
in
carcinomas
at
24
months.
The
incidence
rates
for
the
control
and
treated
agouti
groups
were
9%
and
35%,
respectively,
for
adenomas
and
13%
and
17%,
respectively,
for
carcinomas.
The
incidence
rates
for
the
control
and
treated
pseudoagouti
groups
were
5%
and
12%,
respectively,
for
adenomas
and
2%
and
5%,
respectively,
for
carcinomas.

Increases
in
Clara
cell
hyperplasia
were
noted
in
the
lung
at
all
sacrifice
intervals
for
each
strain
and
the
incidence
of
lung
tumors
was
increased
in
later
months
for
the
agouti
and
pseudoagouti
strains.
The
percentage
of
mice
with
Clara
cell
hyperplasia
in
the
control
and
treated
groups
was
631
and
72­
92%,
respectively,
for
the
agouti;
6­
17%
and
50­
79%,
respectively,
for
the
pseudoagouti;
and
0­
14%
and
56­
90%,
respectively,
for
the
black.
Lung
tumors
for
the
agouti
strain
occurred
in
0%
of
the
control
and
17%
of
the
treated
animals
at
18
months
and
4%
of
the
control
and
19%
of
the
treated
animals
at
24
months.
Lung
tumors
in
the
pseudoagouti
strain
occurred
in
6%
of
the
controls
and
14%
of
the
treated
animals
at
24
months.
After
recovery,
the
incidences
of
Clara
cell
hyperplasia
(agouti
and
black)
and
lung
tumors
(agouti)
remained
slightly
elevat
ed
as
compared
with
the
controls.

In
conclusion,
dietary
administration
of
lindane
resulted
in
the
induction
of
liver
and
lung
tumors
in
the
agouti
and
pseudoagouti
mouse
strains
and
caused
increased
liver
weights,
increased
enzyme
activity,
and
irreversible
Clara
cell
hyperplasia
in
the
lung
of
all
three
mouse
strains
tested.

This
study
is
considered
Acceptable/
nonguideline
as
a
special
study
in
mice.
The
study
deficiencies
include:
only
females
tested,
only
one
dose
level
tested,
histopathology
data
provided
for
lung
and
liver
only,
lack
of
analytical
chemistry
data,
and
no
individual
animal
data.
These
study
results
can
be
used
as
supplementary
information
to
the
chronic/
oncogenicity
study
in
rats.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
submitted
studies
and
reports
in
the
open
literature.
Lindane
does
not
appear
to
be
mutagenic.
In
a
mammalian
cell
gene
mutation
assay
and
an
in
vivo
sister
chromatid
exchange
assay,
no
mutagenic
response
was
detected.
The
open
literature
suggests,
however,
that
technical
grade
HCH
(hexachlorohexane;
6.
5%
­
HCH)
may
induce
some
mutagenic
activity
as
evidenced
in
a
dominant
lethal
mutation
assay
and
sister
chromatid
exchanges.
Overall,
based
on
the
results
of
acceptable
studies
on
lindane,
it
does
not
appear
to
have
mutagenic
potential.

Gene
Mutation
Lindane/
September
2000
RED
Toxicology
Chapter
23
cell
gene
mutation
assay
MRID
00144500
Unacceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
conducted
in
Chinese
hamster
V79
cells,
lindane
was
tested
in
the
absence
of
metabolic
activation
at
dose
levels
of
2.5,
5,
10,
25,
50,
70,
100,
and
150
µg/
ml
and
in
the
presence
of
metabolic
activation
at
dose
levels
of
5,
10,
25,
50,
100
250
and
500
µg/
ml.
The
S9
fraction
used
for
metabolic
activation
was
obtained
from
Aroclor
1254­
induced
mouse
liver.
Tests
with
and
without
activation
were
conducted
under
aerobic
and
anaerobic
conditions.

Under
anaerobic
conditions,
lindane
without
S9
was
cytotoxic
to
the
V79
cells
at
dose
levels
above
10
µg/
ml
and
with
S9
at
dose
levels
above
150
mg/
ml.
No
mutagenic
activity
of
lindane
was
observed
in
V79
cells
under
any
combination
of
conditions
up
to
cytotoxic
doses.

Cytogenetics
sister
chromatid
exchange
MRID
00024504
Acceptable/
Guideline
In
a
mammalian
in
vivo
sister
chromatid
exchange
(SCE)
assay,
50µg
tablets
of
bromodeoxy­
uridine
were
implanted
into
male
and
female
CF­
1
mice.
Two
hours
after
implantation,
lindane
was
administered
ip
in
arachis
oil
at
dose
levels
of
1.3,
6.4
and
32.1
mg/
kg.
For
each
dose
level
and
control
group,
30
bone
marrow
cells
from
each
of
5
animals
of
each
sex
were
examined
for
SCEs.

No
toxicity
was
reported
in
any
treatment
group.
When
results
for
male
and
female
animals
were
pooled,
only
the
highest
dose
produced
a
significant
increase
in
SCEs
over
the
controls.
Positive
control
values
were
appropriate.

,dominant
lethal
assay
MRID
00062657
Unacceptable/
Guideline
In
a
mammalian
dominant
lethal
assay,
10
male
Sprague­
Dawley
rats
of
unspecified
age
per
group
were
exposed
to
lindane
administered
by
subcutaneous
injection
in
corn
oil
at
doses
of
0,
1,
3,
and
10
mg/
kg
five
time
per
week
for
10
weeks.
Uteri
were
examined
for
live
and
dead
implants
and
abnormalities.
Males
were
also
sacrificed
and
gross
pathological
analysis
performed.

The
incidence
of
dead
implants
was
significantly
increased
at
the
lowest
dose
but
not
at
the
two
higher
doses
in
the
first
week
of
mating
but
this
increase
was
not
observed
during
the
second
week.
The
authors
conclude
that
lindane
did
not
cause
an
increase
in
the
incidence
of
dominant
lethals
inthis
study.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
Neurotoxicity
studies
(acute,
subacute
and
developmental)
have
been
submitted.
Lindane
is
a
neurotoxicant.
In
acute,
subchronic
and
developmental
neurotoxicity
studies,
it
was
found
to
cause
neurotoxic
effects
including
tremors,
convulsions,
decreased
motor
activity,
increased
forelimb
grip
strength,
hypersensit
ivity
to
touch,
hunched
posture
and
decreased
motor
activity
habituation.
There
also
appears
to
be
a
greater
susceptibility
to
exposure
by
offspring
compared
to
parental
animals.
The
LOAEL
for
offspring
toxicity
is
50
ppm
(5.
6
mg/
kg/
day)
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation
compared
to
a
LOAEL
of
120
ppm
(13.7
mg/
kg/
day)
based
on
decreased
body
weight
gains,
Lindane/
September
2000
RED
Toxicology
Chapter
24
decreased
food
consumption,
and
increased
reactivity
to
handling
for
maternal
toxicity.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Not
required
870.6200
Acute
Neurotoxicity
Screening
Battery
EXECUTIVE
SUMMARY:
In
an
acute
oral
neurotoxicity
study
(MRID44769201),
groups
of
10
Crl:
CD®
BR
rats/
sex/
dose
were
administered
single
dose
of
lindane
(Batch
No.
HLS96/
1,
Purity
99.78%)
by
gavage
at
concentrations
of
0
(control),
6,
20,
or
60
mg/
kg.
Functional
observational
battery
(FOB)
and
motor
activity
(MA)
testing
were
performed
prior
to
administration
and
within
3
hours
(time
of
peak
effect)
of
dosing
(day
0),
and
on
days
7
and
14
post­
dose.
Body
weights
were
recorded
pre­
test,
weekly
during
the
study
period
and
on
FOB
assessment
days.
Clinical
signs
were
recorded
at
least
once
daily.
At
study
termination
all
animals
were
sacrificed
and
fixed
by
whole
body
perfusion,
designated
tissues
of
the
nervous
system
were
processed
for
microscopic
neuropathological
evaluation.

All
animals
survived
to
scheduled
termination.
One
male
in
the
60
mg/
kg
group
was
observed
to
convulse
on
the
day
of
treatment
within
2.
75
hours
after
dosing.
Clinical
signs
were
also
observed
in
females
treated
at
60
mg/
kg
within
24
hours
of
dosing
and
included:
staining
of
the
fur,
stained
urogenital
region,
hunched
posture,
and
piloerection.
These
effects
in
females
persisted
for
four
days.
Significant
treatment­
related
decreases
in
body
weight
gains
were
observed
for
males
in
the
60
mg/
kg
group
compared
to
the
control
group
for
the
first
week
of
the
study.
Females
administered
this
concentration
also
had
slightly
lower
body
weight
gains
throughout
the
study.
Food
consumption
for
males
and
females
administered
60
mg/
kg
was
significantly
decreased
compared
to
controls
for
Week
1
of
the
study.
Food
conversion
ratios
in
the
treated
groups
were
not
changed
compared
to
control
groups.

At
the
first
FOB
assessment
on
Day
0
(3
hours
after
dosing)
males
and
females
in
the
60
mg/
kg
group
exhibited
piloerection
(1

,2

),
decreased
rectal
temperature
(1

,1

),
increased
hindlimb
foot
splay
and
hunched
posture
(4

,7

).
Among
males
dosed
at
60
mg/
kg,
increased
respiration
(3

,1

)
and
one
observation
of
tremor/
twitching
were
observed.
Females
administered
60
mg/
kg
were
observed
to
have
increased
incidences
of
walking
on
tip
toes
(10),
licking
behavior
(3),
decreased
foot
splay
(3)
and
an
absence
of
grooming
(8)
behavior.
Females
in
the
20
mg/
kg
also
had
decreased
grooming
(3)
behavior
and
increased
forelimb
grip
strength.
Motor
activity
was
significantly
decreased
for
males
and
females
treated
with
60
mg/
kg
as
well
as
among
females
treated
with
20
mg/
kg
three
hours
post­
treatment.
The
6
mg/
kg
group
remained
comparable
to
controls
in
FOB
assessment
parameters
and
MA.

No
neuropathological
endpoints
were
observed
during
the
histological
examinations
of
the
peripheral
or
central
nervous
systems
of
these
animals
at
any
exposure
concentration.

The
NOAEL
for
systemic
toxicity
is
20
mg/
kg
for
males
and
6
mg/
kg
for
females.
Based
on
the
substance­
related
effects
on
body
weight,
body
weight
gain,
food
consumption,
and
clinical
signs
of
toxicity
the
LOAEL
for
systemic
toxicity
in
males
is
60
mg/
kg.
The
LOAEL
for
females
is
20
mg/
kg
based
on
a
lower
incidence
of
grooming
behavior
and
decreased
Lindane/
September
2000
RED
Toxicology
Chapter
25
locomotor
activity
immediately
after
dosing,
in
addition
to
the
parameters
mentioned
above.

The
NOAEL
for
neurotoxic
effects
is
6
mg/
kg
for
females
and
the
LOAEL
is
20
mg/
kg
based
on
increased
forelimb
grip
strength
and
decreased
grooming
behavior
and
motor
activity
(MA).
The
NOAEL
for
neurotoxicity
in
males
is
20
mg/
kg
and
the
LOAEL
for
males
is
60
mg/
kg
based
on
tremors,
convulsions,
decreased
MA,
and
increased
forelimb
grip
strength.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
Subdivision
F
guideline
requirement
for
an
acute
oral
neurotoxicity
study
(§
81­
8)
in
rats.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
EXECUTIVE
SUMMARY:
In
a
subchronic
oral
neurotoxicity
study
(MRID
44781101),
groups
of
10
Crl:
CD®
BR
rats/
sex/
group
were
administered
lindane
(Batch
No.
HLS96/
1,
Purity
99.78%)
in
the
diet
for
13
weeks
at
concentrations
of
0
(control),
20,
100,
or
500
ppm.
Due
to
severe
toxic
reactions
to
treatment
at
500
ppm,
the
dose
was
reduced
to
400
ppm
on
day
11
of
treatment
thereafter.
These
doses
resulted
in
average
daily
intake
values
of
0,
1.4,
7.1,
and
28.1
mg/
kg/
day
for
males
and
0,
1.6,
7.9,
and
30.2
mg/
kg/
day
in
females
for
0,
20,
100,
and
500/
400
ppm,
respectively.
Functional
observational
battery
(FOB)
and
motor
activity
(MA)
tests
were
performed
prior
to
administration
and
after
4,
8,
and
13
weeks
of
treatment.
Body
weights
were
recorded
pretest
weekly
during
the
study
period
and
on
FOB
assessment
days.
Clinical
signs
were
recorded
at
least
once
daily.
At
study
termination
all
animals
were
sacrificed
and
fixed
by
whole
body
perfusion
and
designated
tissues
of
the
nervous
system
were
processed
for
microscopic
neuropathological
evaluation.

Three
females
in
the
500/
400
group
died
prior
to
scheduled
termination.
These
deaths
were
attributed
to
treatment
with
lindane.
One
death
was
recorded
on
Day
11
of
the
study,
one
during
week
10
and
one
during
week
13.
Clinical
signs
prior
to
death
included
weight
loss,
swollen
muzzle
with
scabbing,
hunched
posture,
piloerection,
and
staining
of
the
anogenital
region.
Observations
in
surviving
females
treated
at
500/
400
ppmwere
hypersensitivity
to
touch,
staining
of
the
urogenital
region,
and
scabbing
of
the
toes.

Significant
treatment­
related
decreases
(p<
0.05
or
p<
0.01)
in
body
weight
were
observed
among
males
and
females
treated
with
500/
400
ppm
of
14%
and
23%,
respectively.
Decreases
in
body
weight
gains
(70%

and
180%

,
p<
0.01),
food
consumption
(35%

and
50%

,p<
0.
05or
p<
0.01,
respectively),
and
food
conversion
ratios
were
observed
for
males
and
females
in
the
500
ppm
groups
compared
to
the
control
group
for
the
first
week
of
the
study.
Male
rats
tended
to
recover
from
these
effects
after
the
dose
was
lowered.
Females,
however,
did
not
exhibit
this
same
level
of
recovery
as
their
food
consumption
remained
slightly
depressed
throughout
the
remainder
of
the
study.

Females
in
the
100
ppm
group
had
significantly
decreased
body
weight
gains
(40%,
p<
0.05)
compared
to
the
control
group
during
the
first
week
of
the
study
and
this
effect
continued,
although
not
at
a
level
of
significance
throughout
the
remainder
of
the
study.
Females
in
the
100
ppm
group
had
significantly
decreased
food
consumption
(16%,
p<
0.01)
for
the
first
week
of
the
study
and
this
Lindane/
September
2000
RED
Toxicology
Chapter
26
trend
continued
throughout
the
study.
Liver
weights
were
also
found
to
be
increased
at
500/
400
ppm
for
both
sexes;
no
additional
information
was
given.

During
the
FOB
assessment
(table
A
is
attached
at
t
he
end
of
this
document),
males
and
females
treated
at
the
highest
dose
(500/
400
ppm)
were
perceived
as
difficult
to
handle.
They
also
were
observed
to
have
piloerection
and
hunched
posture.
Females
in
the
highest
dose
group
had
missing
claws
(3),
tended
to
urinate
more
often
than
controls,
had
a
higher
incidence
of
grooming
behavior,
rearing,
motor
activity,
and
one
female
was
observed
to
convulse.
Females
across
the
dose
groups
were
observed
walking
on
tiptoes
(5­
7)
and
these
incidences
were
significantly
increased
compared
to
the
control
(1)
for
the
highest
dose
group.
Females
(5)
in
the
100
ppm
group
also
had
increased
incidences
of
grooming
behavior
at
the
Week
4
evaluation
and
one
animal
in
this
group
was
extremely
difficult
to
handle.

The
assessments
of
forelimb
and
hindlimb
grip
strength
as
well
as
hindlimb
splay
revealed
no
differences
for
any
of
the
treated
groups
compared
to
the
control
groups.
Colburn
motor
activity
was
also
similar
among
treated
groups
compared
to
the
control
groups.

No
neuropathological
endpoints
attributable
to
lindane
administration
were
observed
during
the
histological
examinations
of
the
peripheral
or
central
nervous
systems
of
these
animals
at
any
exposure
concentration.

The
NOAEL
for
systemic
toxicity
is
100
ppm
for
males
(7.
1
mg/
kg)
and
20
ppm
for
females
(1.6
mg/
kg).
Based
on
the
substance­
related
effects
on
body
weight,
body
weight
gain,
food
consumption,
and
clinical
signs
of
toxicity
the
LOAELlevels
for
systemic
toxicity
in
males
is
500/
400
ppm
(28.1
mg/
kg)
and
100
ppm
for
females
(7.
9
mg/
kg).

The
NOAEL
for
neurotoxic
effects
is
100
ppm
for
males
(7.
1
mg/
kg)
and
females
(7.
9
mg/
kg).
The
neurotoxicity
LOAEL
is
500/
400
ppm
based
on
hypersensitivity
to
touch
and
hunched
posture.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
Subdivision
F
guideline
requirement
for
an
acute
oral
neurotoxicity
study
(§
81­
8)
in
rats.

870.6300
Developmental
Neurotoxicity
Study
EXECUTIVE
SUMMARY:
In
a
developmental
neurotoxicity
study
(MRID
45073501),
lindane
(Batch
No.
HLS
96/
1;
99.78%
a.
i.)
was
administered
to
presumed
pregnant
Hsd
Brl
Han:
Wist
(Han
Wistar)
rats
in
the
diet
at
concentrations
of
0,
10,
50,
or
120
ppm
fromgestation
day
(GD)
6
through
lactation
day
10.
These
concentrations
resulted
in
F0
maternal
doses
of
0.
8­
0.
9,
4.
24.6
and
8.
0­
10.5
mg/
kg/
day,
respectively,
during
gestation
and
1.
2­
1.
7,
5.
6­
8.
3,
and
13.7­
19.1
mg/
kg/
day,
respectively,
during
lactation.
The
developmental
neurotoxicityof
lindane
was
evaluated
in
the
F1
offspring.
F1
animals
(10/
sex)
were
evaluated
for
FOB,
motor
activity,
auditory
startle
response,
and
learning
and
memory
as
well
as
developmental
landmarks
such
as
vaginal
perforation
and
balanopreputial
separation,
and
brain
weights
and
histopathology
on
days
11
and
65,
including
Lindane/
September
2000
RED
Toxicology
Chapter
27
morphometrics.

Small
differences
in
absolute
maternal
body
weights
(7­
8%)
were
observed
between
the
high
dose
and
control
groups
during
gestation
and
early
lactation
(through
day
11).
Body
weight
gains
by
the
high­
dose
dams
from
GD
6
through
GD
20
were
64­
79%
(p

0.
01)
of
the
control
level.
Body
weight
changes
during
lactation
were
similar
between
the
treated
and
control
groups.
During
gestation,
food
consumption
by
the
high­
dose
group
was
significantly(
p

0.01;
74­
92%
of
controls)
less
than
the
control
group
for
the
intervals
of
GD
10­
13,
14­
17,
and
18­
19.
Food
consumption
by
the
low­
and
mid­
dose
groups
during
gestation
and
by
all
treated
groups
during
lactation
was
similar
to
the
controls.

Absolute
body
weights
of
the
treated
male
and
female
pups
in
mid
and
high
dose
groups
during
lactation
were
12­
18%
and
16­
20%
less
than
controls,
respectively
on
days
4­
11
of
lactation
with
recovery
to
less
than
10%
by
day
21.
Body
weight
gains
(p

0.05
or
0.01)
on
lactation
days
1­
4
and
1­
11
were
76%
and
84%,
respectively,
of
the
control
levels
for
mid­
dose
males,
79%
and
79%,
respectively,
for
mid­
dose
females,
60%
and
73%,
respectively
for
highdose
males,
and
63
and
75%,
respectively,
for
high­
dose
females.
Body
weight
gains
by
all
treated
groups
were
similar
to
the
controls
during
lactation
days
11­
21.
Except
for
mid
and
high
dose
females,
postweaning,
body
weight
gains
were
similar
between
the
treated
and
control
groups.
Body
weight
differences
for
high
dose
dams
were
10%
less
at
the
beginning
of
lactation
and
recovered
to
6%
less
by
the
end
of
the
study.

The
high­
dose
group
had
a
greater
number
of
stillborn
pups
as
indicated
by
a
live
birth
index
of
77%
compared
with
99%
for
the
control
group.
In
addition,
nine
high­
dose
litters
either
died
or
were
sacrificed
moribund
on
lactation
days
1­
4.
This
resulted
in
a
viability
index
for
the
high­
dose
group
of
71%
compared
with
89%
for
the
controls.
Pup
mortality
in
the
mid
and
high­
dose
groups
in
litters
surviving
to
weaning
was
greater
before
day
4
than
in
controls
[
3
pups
in
2/
20
controls;
18
pups
in
8/
22
litters,
mid
dose;
14
pups
in
4/
15
litters,
high
dose].
Survival
was
not
affected
at
any
time
in
the
low
dose
group
as
compared
with
the
control
group.
No
dose­
or
treatment­
related
differences
were
observed
between
treated
and
control
groups
for
duration
of
gestation,
number
of
pups/
litter
on
day
1,
or
per
cent
male
offspring.

At
necropsy,
no
treatment­
related
gross
abnormalities
were
observed
in
the
dams
or
offspring.
Absolute
and
relative
liver
and
kidney
weights
of
the
offspring
were
not
affected
by
treatment.

A
few
clinical
signs
were
observed
in
high
dose
dams
and
pups;
increased
reactivity
to
handling
in
dams
on
weeks
2
and
3
of
dosing,
and
slower
surface
righting
in
pups
on
day
4.
There
were
no
effects
on
measures
of
physical
or
sexual
development.

There
was
an
increase
in
motor
activity
at
the
mid
and
high
dose
during
lactation
in
both
sexes.
Some
decrease
in
habituation
of
motor
activity
in
females
on
day
22
was
also
seen.
While
there
was
no
effect
on
auditory
startle
reflex
amplitudes,
there
was
a
clear
reduction
in
auditory
startle
response
habituation
in
both
sexes
at
the
high
dose
on
day
28
and
on
day
60.
Slight
decreases
in
absolute,
but
not
relative,
brain
weights
in
mid
and
high
dose
female
pups
were
observed
on
postnatal
day
11
(9­
10%)
but
narrowed
to
3­
5%
less
by
day
65.
Brain
lengths
and
widths
were
Lindane/
September
2000
RED
Toxicology
Chapter
28
similar
between
the
treated
and
control
pups.
Morphometric
brain
measurements
did
not
show
any
significant
differences
in
the
sizes
of
the
neocortex,
hippocampus,
corpus
callosum,
or
cerebellum
on
days
11
or
65.
There
were
no
effects
on
histopathology
of
the
nervous
system.

The
maternal
toxicity
LOAEL
is
120
ppm
(13.7
mg/
kg/
day)
based
on
decreased
body
weight
gains,
decreased
food
consumption,
and
increased
reactivity
to
handling.

The
maternal
toxicity
NOAEL
is
50
ppm
(5.
6
mg/
kg/
day).

The
offspring
toxicity
LOAEL
is
50
ppm
(5.6
mg/
kg/
day)
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.

The
offspring
toxicity
NOAEL
is
10
ppm
(1.2
mg/
kg/
day).

This
study
is
classified
as
Unacceptable/
Guideline
[870.6300
(§
83­
6)]
since
laboratory
validation
studies
of
the
neurobehavioral
tests
were
not
included,
but
it
may
be
upgraded
and
found
acceptable
if
this
information
is
obtained.
The
number
of
animals
tested
at
the
highest
dose
is
only
6
compared
to
the
required
number
of
10
animals
per
dose.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
formetabolismis
considered
tobe
complete.
No
additional
studies
are
required
at
this
time.
Lindane
is
distributed
to
all
organs
at
measurable
concentrations
within
a
few
hours
after
oral
administration.
The
highest
concentrations
are
found
in
adipose
tissue.
The
metabolism
of
lindane
is
initiated
through
one
of
pathways:
Dehydrogenation
leading
to
­
HCH,
Dehydrochlorination
leading
to
formation
of
­
PCCH,
Dechlorination
leading
to
formation
of
­
tetrachlorohexene,
or
Hydroxylation
leading
to
formation
of
hexachlorocyclohexanol.
Further
metabolismleads
to
a
large
number
of
metabolites.
Volatilizalion
appears
to
be
an
important
route
of
its
dissipation
under
the
high­
temperature
conditions
of
tropical
regions.
Lindane
is
converted
by
enzymatic
reactions,
mainly
in
the
liver.
In
mammals,
including
humans,
lindane
is
excreted
very
rapidly
in
urine
and
faeces
after
metabolic
degradation;
only
small
amounts
are
eliminated
unchanged.
The
half­
life
of
lindane
administered
to
rats
is
2­
4
days
depending
on
the
frequency
of
exposures,
single
or
repeated.

870.7600
Dermal
Absorption
­
Rat
EXECUTIVE
SUMMARY:
In
a
dermal
absorption
study,
(MRID
40056107)
24
male
Crl:
CD
®
(SD)
BRrats
per
group
received
dermal
applications
of
lindane
20%
emulsifiable
concentrate
([
14
C]­
Lindane
and
unlabeled
Lindane)
at
doses
of
0.
1,
1.
0,
or
10
mg/
rat.
Four
animals/
group
were
bled
and
sacrificed
at
intervals
of
0.
5,
1,
2,
4,
10,
or
24
hours
after
application
of
the
test
article.

Quantities
absorbed
increased
with
dose
and
duration
of
exposure
while
percent
absorbed
Lindane/
September
2000
RED
Toxicology
Chapter
29
increased
with
time
and
decreased
with
dose.
Percents
of
the
low­,
mid­,
and
high­
doses
absorbed
were
0.6,
0.96,
and
0.
66%
after
0.
5
hours;
18.07,
8.31,
and
2.
81%
after
10
hours;
and
then,
increased
to
27.72,
20.86,
and
5.
05%
after
24
hours.
The
total
amount
of
test
article
absorbed
after
24
hours,
as
calculated
from
urine,
feces,
and
carcass,
was
0.
028,
0.21,
and
0.
51
mg
for
the
low­,
mid­,
and
high­
dose
groups,
respectively.
The
process
appears
to
be
approaching
saturation
at
the
high
dose.
Recovered
radioactivity
(absorbed,
skin,
skin
rinse,
filter
paper
and
spreader)
was
74.19,
70.19
and
58.35%
of
the
applied
dose
after
24
hours
of
exposure
in
the
low­,
mid­,
and
high­
dose,
respectively.

This
study
is
considered
Acceptable/
guideline
and
satisfies
the
requirements
for
a
dermal
absorption
study
in
rats
[85­
2].

EXECUTIVE
SUMMARY:
In
a
dermal
absorption
study,
(MRID
40056108)
24
male
Hra:(
NZW)
SPF
rabbits
per
group
received
dermal
applications
of
lindane
20%
emulsifiable
concentrate
([
14
C]­
Lindane
and
unlabeled
Lindane)
at
doses
of
0.
5,
5.
0,
or
50
mg/
rabbit.
Four
animals/
group
were
bled
and
sacrificed
at
intervals
of
0.
5,
1,
2,
4,
10,
or
24
hours
after
application
of
the
test
article.

Quantities
absorbed
increased
with
dose
and
duration
of
exposure
while
percent
absorbed
increased
with
time
and
decreased
with
dose.
Percentages
of
the
low­,
mid­,
and
high­
doses
absorbed
were
5.97,
6.68,
and
1.
99%
after
0.
5
hours
;
51.68,
23.76
and
10.96%
after
10
hours;
and
then
increased
to
55.68,
39.99,
and
16.56%
after
24
hours.
The
total
amount
of
test
article
absorbed
after
24
hours,
as
calculated
fromurine,
feces,
and
carcass,
was
0.
28,
2.00,
and
8.
46
mg
for
the
low­,
mid­,
and
high­
dose
groups,
respectively.
The
original
DER
states
that
no
evidence
of
saturation
of
the
absorption
process
was
observed;
however
upon
further
examination
it
appears
that
there
is
evidence
of
saturation
at
the
highest
dose
(50
mg/
rabbit)
tested.
Recovered
radioactivity
(absorbed,
skin,
skin
rinse,
filter
paper
and
spreader)
was
82.01,
78.27
and
66.34%
of
the
applied
dose
after
24
hours
of
exposure
in
the
low­,
mid­,
and
high­
dose,
respectively.

This
study
is
considered
Acceptable/
guideline
and
satisfies
the
requirements
for
a
dermal
absorption
study
in
rabbits
[85­
2].
However,
it
should
be
noted
that
the
rabbit
is
not
the
preferred
species
for
dermal
absorption
studies
as
it
grossly
overestimates
absorption
compared
to
man.

5.
0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.
2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
10
%

The
HIARC
concurred
with
the
TES
committee
decision
(HED
Doc.
#
013460)
that
the
dermal
absorption
factor
is
10%
based
on
a
published
report
by
Feldman
and
Maibach
(Toxicology
and
Applied
Pharmacology
28,
126­
132,
1974).
Lindane/
September
2000
RED
Toxicology
Chapter
30
The
Maibach
study
tested
12
pesticides
and
herbicides,
including
lindane,
on
human
subjects
(6
per
chemical)
to
quantitate
their
dermal
penetration.
C
14
­labeled
chemicals
were
applied
topically
(4    
g/
cm
2
)
to
the
forearm
or
via
the
intravenous
route
(1    
Ci).
Excretion
of
the
chemicals
was
then
monitored
by
collecting
and
analyzing
urine
samples
during
the
5
day
testing
period.
All
results
were
calculated
as
percent
of
the
injected
or
applied
dose.
Data
obtained
after
IV
dosing
was
used
to
correct
the
skin
penetration
data
for
incomplete
urinary
recovery.
Lindane
was
shown
to
have
a
penetration
factor
of
9.3%
±
3.
7
(SD).

The
dermal
absorption
factor
is
required
for
dermal
exposure
for
all
durations
of
exposure
risk
assessment
since
oral
doses
were
selected
for
these
exposure
periods.

5.3
Classification
of
Carcinogenic
Potential
The
classification
of
carcinogenic
potential
will
be
re­
evaluated
upon
receipt
of
a
new
mouse
carcinogenicity
study,
expected
in
December
2000.
Currently,
according
to
the
TES
committee
report
(1994,
Doc
013460),
lindane
has
not
been
classified
by
the
HED
Cancer
Peer
Review
Committee.
The
RfD/
Peer
Review
Committee
in
1993
concluded
that:
"The
mouse
carcinogenicity
data
were
considered
insufficient
because
of
major
deficiencies
associated
with
all
studies
available."
Lindane
however
had
been
previously
(1985)
classified
by
the
Cancer
Assessment
Group
of
the
Office
of
Research
and
Development
as
a
group
B2/
C
carcinogen
based
on
increased
incidence
of
mouse
liver
tumors.
Although
the
animal
data
was
limited,
the
presence
of
a
carcinogenic
metabolite,
2,4,6­
trichlorophenol,
in
meaningful
quantities
in
the
urine
of
humans
exposed
to
lindane
and
the
structural
similarity
with
a
rodent
carcinogen,
alpha­
hexachlorocyclohexane,
elevated
the
classification
above
a
"C"
to
"B2".
The
upper­
bound
slope
of
the
dose­
response
was
Q1*
=
1.
1
(mg/
kg/
day)
­1
.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
Although
the
developmental
study
in
rats
provided
no
indication
of
a
quantitative
increased
susceptibility/
sensitivity
following
in
utero
exposure
to
lindane,
evidence
of
a
qualitative
increase
in
susceptibility
was
noted
in
the
developmental
neurotoxicity
study
and
the
2­
generation
reproductive
study
in
rats.
Therefore,
the
FQPAcommittee
decided
to
reduce
the
safety
factor
to
3X
for
lindane.

In
the
prenatal
developmental
toxicity
studies
in
rats,
developmental
effects
were
observed
only
at
or
above
doses
causing
maternal
toxicity.
The
prenatal
developmental
study
in
rabbits
is
classified
as
Unacceptable
(not
upgradable)
since
maternal
and
developmental
toxicityLOAELs
were
not
identified
and
the
highest
dose
did
not
approach
the
limit
dose.
Therefore,
dose
selection
was
considered
inadequate.
Doses
were
based
on
the
results
of
a
subcutaneous
studyin
the
rabbit
(MRID
00062658)
which
is
not
a
valid
method
for
selecting
doses
for
an
oral
study.
Several
other
deficiencies
were
noted
in
the
conduct
of
this
study,
included:
percent
purity
of
the
test
article
was
Lindane/
September
2000
RED
Toxicology
Chapter
31
not
given,
dosing
solutions
were
not
analyzed
for
concentration,
stability,
or
homogeneity,
and
much
of
the
individual
animal
data
were
not
included.

Although
the
developmental
toxicitystudyin
rabbits
was
classified
unacceptable,
the
HIARC
concluded
that
a
new
study
is
not
required
because:
1)
The
developmental
toxicity
study
in
rabbits
and
rats
using
a
subcutaneous
route
of
administration
shows
no
developmental
effects
at
the
maternally
toxic
dose;
2)
The
incidences
of
skeletal
effects
observed
in
the
developmental
toxicity
study
in
rats,
with
gavage
as
the
route
of
administration,
are
within
historical
controls;
3)
More
severe
maternal
effects
are
seen
in
the
rabbit
study
with
subcutaneous
administration;
4)
The
rat
appears
to
be
the
more
sensitive
species
for
developmental
effects;
5)
Adevelopmental
neurotoxicity
study
has
already
been
submitted.

There
was,
however,
evidence
of
qualitative
increased
susceptibility
in
the
rat
multi­
generation
reproduction
study:
Both
parental
and
offspring
LOAELS
are
13
mg/
kg;
however
there
is
a
qualitative
difference
in
the
severity
of
effects.
In
the
parental
animals,
toxicity
was
seen
in
the
form
of
reduction
in
body
weight
gain
during
gestation
while
offspring
toxicity
was
correlated
with
decreases
in
pup
viability
and
pup
body
weight
in
the
F1
and
F2
generations
as
well
as
delayed
maturation
in
the
F2
generation.
Evidence
for
quantitative
increase
in
susceptibility
could
not
be
ascertained
due
to
the
wide
spread
in
the
doses
tested.

There
is
also
quantitative
increased
susceptibility
demonstrated
in
the
rat
developmental
neurotoxicity
study:
Maternal
toxicity
observed
at
120
ppm
(13.7
mg/
kg/
day,
LOAEL)
is
based
on
decreased
body
weight
gains,
decreased
food
consumption,
and
increased
reactivity
to
handling
(maternal
NOAEL
is
50
ppm;
5.
6
mg/
kg/
day).
Offspring
toxicity
was
observed
at
50
ppm
(5.
6
mg/
kg/
day,
LOAEL)
and
is
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation
(NOAEL
is
10
ppm;
1.
2
mg/
kg/
day).

The
offspring
effects
seen
in
the
developmental
neurotoxicity
study
were
the
same
as
those
seen
in
the
the
two­
generation
reproduction
study
­
no
additional
functional
or
morphological
changes
in
the
nervous
system
were
noted.
In
the
open
literature,
lindane
is
found
in
mother's
milk
and
metabolites
of
lindane
have
been
shown
to
cross
the
placental
barrier.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
has
already
been
conducted.
Lindane/
September
2000
RED
Toxicology
Chapter
32
7.
0
REFERENCES
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00062656.
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1976.
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00062657.
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Medford,
?.?.
(1976)
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benzene
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S.
P.).
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Laboratories
America,
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405­
107.
November
12,
1976.
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00062658.
Reno,
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E.
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(gamma
benzene
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2000
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hexachloride,
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103.
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Unpublished.

00144500.
Glatt
H.
R.
(1985).
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cell
(V79)
mutagenicity
test
on
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using
anaerobic
exposure
conditions.
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of
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University
of
Mainz,
Obere
Zahlbacher
Strasse
67,
D­
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540­
VT21­
b.
October
18,
1985.

255003.
Anonymous.
1983.
90­
day
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in
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with
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Institut
fur
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und
Aerosolforschung,
D­
5948
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Germany.
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104264.
February
28,
1983.
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from
German)

40056107.
Bosch,
A.
L.
1987.
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lindane
in
male
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6188­
103.
January
13,
1987.
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40056108.
Bosch,
A.
L.
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Dermal
absorption
of
14
C­
lindane
in
male
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America.
HLA
Study
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6188­
104.
January
7,
1987.
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40873501.
Klonne,
D.
R.
and
Kintigh,
W.
J.
1988.
Lindane
technical
fourteen­
week
dust
aerosol
inhalation
study
on
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Run
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BRCC
#51­
524;
Metpath
#14014.
October
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41094101.
Aymes,
S.
J.
1989.
Lindane:
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oncogenicity
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toxicity
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to
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­
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816.
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41427601.
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Lindane:
13
week
dermal
toxicity
study
(with
interim
kill
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recovery
period)
in
the
rabbit.
Hazleton,
Inc.,
North
Yorkshire,
England.
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6164­
580/
6.
February
22,
1990.
Unpublished.

41853701.
Aymes,
S.
J.
1989.
Combined
oncogenicity
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toxicity
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by
dietary
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for
104
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CIL002/
0839.
November
7,
1989.
Unpublished.

42246101.
King,
V.
C..
(1991)
Lindane:
Reproductive
performance
study
in
rats
treated
continuously
through
two
successive
generations.
Life
Sciences
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Ltd.,
Suffolk,
England.
Study
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91/
CIL004/
0948.
September
12,
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42808001.
Palmer,
A.
K.
and
Lovell,
M.
R.
(1971)
Effect
of
lindane
on
pregnancy
of
the
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Huntingdon
Research
Centre,
England.
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No.
4307/
71/
463.
December
3,
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September
2000
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1971.
Unpublished.

42808002.
Palmer,
A.
K.
and
Neuff,
A.
M.
(1971)
Effect
of
lindane
on
pregnancy
of
the
New
Zealand
white
rabbit.
Huntingdon
Research
Centre,
England.
Study
No.
4308/
71/
464.
December
2,
1971.
Unpublished.

42891201.
Aymes,
S.
J.
1993.
Lindane:
Combined
oncogenicity
and
toxicity
study
by
dietary
administration
to
Wistar
rats
for
104
weeks.
Addendum
to
final
report
(Adrenal
histopathology
­
additional
investigations).
Life
Sciences
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England.
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90/
CIL002/
0839.
June
2,
1993.
Unpublished.

44769201
Hughes,
E.
W.,
1999.
Neurotoxicity
study
by
a
single
oral
gavage
administration
to
CD
rats
followed
by
a
14­
day
observation
period.
Huntingdon
Life
Sciences
Ltd.,
P.
O.
Box
2,
Huntingdon,
Cambridgeshire,
PE186ES,
England.
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011
February
25,
1999,
Unpublished.

44781101
Hughes,
E.
W.,
1999.
13­
week
neurotoxicity
study
in
rats
by
dietary
administration.
Huntingdon
Life
Sciences
Ltd.,
P.
O.
Box
2,
Huntingdon,
Cambridgeshire,
PE18
6ES,
England.
Project
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CIL/
012,
March
5,
1999,
Unpublished.

45073501.
Myers,
D.
P.
(1999)
Lindane:
Developmental
neurotoxicity
study
in
the
Han
Wistar
rat
by
dietary
administration.
Huntingdon
Life
Sciences
Ltd.
Eye,
Suffolk,
IP23
7PX,
England.
Laboratory
Project
No.
CIL/
022,
September
21,
1999.
Unpublished.

TOX
DOCUMENT
#

013460
Copley,
Marion,
Toxicology
Endpoint
Selection
Document,
November
4,
1994
014263
Shallal,
Suhair,
Lindane­
Report
of
the
Hazard
Identification
Assessment
Review
Committee,
July
27,
2000.

014272
Tarplee,
Brenda,
Lindane­
Report
of
the
FQPA
Safety
Factor
Committee,
August
2,
2000
014275
Lindane­
Revision
of
dermal
absorption
factor,
August
1,
2000.

International
Programme
on
Chemical
Safety
(IPCS),
Environmental
Health
Criteria
124,
Lindane,
WHO,
Geneva,
1991
Feldmann,
RJ
and
HI
Maibach,
Percutaneous
penetration
of
some
pesticides
and
herbicides
in
man,
Toxicology
and
Applied
Pharmacology,
28:
126­
132
(1974).
Lindane/
September
2000
RED
Toxicology
Chapter
35
Wolff,
G.
L.,
Roberts,
D.
W.,
Morrissey,
R.
L.,
Greenman,
D.
L.,
Allen,
R.
R.,
Campbell,
W.
L.,
Bergman,
H.,
Nesnow,
S.,
and
Firth,
C.
H.
Tumorigenic
responses
to
lindane
in
mice:
potentiation
by
a
dominant
mutation.
National
Center
for
Toxicological
Research,
Jefferson,
AK.
MRID
none.
As
published
in
Carcinogenesis
8:
1889­
1897
(1987).
Lindane/
September
2000
RED
Toxicology
Chapter
36
8.
0
APPENDICES
Tables
for
Use
in
Risk
Assessment
Lindane/
September
2000
RED
Toxicology
Chapter
37
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Table
­
See
Section
4.
1
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Table
1
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3250
90­
Day
dermal
toxicity
41427601
acceptable/
guideline
1990
NOAEL
=
60
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day
based
on
lesion
in
the
liver
in
males
and
females
and
adrenal
gland
weight
increases
in
males
870.3465
90­
Day
inhalation
toxicity
00255003
acceptable/
guideline
1983
NOAEL
=
0.
025
mg/
kg/
day
LOAEL
=
0.
13
mg/
kg/
day
based
on
transient
microscopic
lesions
in
the
kidney
and
increased
kidney
weights
in
the
males.

40873501
acceptable/
guideline
1988
NOAEL
=
0.
08
mg/
kg/
day
LOAEL
=
0.
25
mg/
kg/
day
based
on
death
of
one
male
and
one
female
870.3700a
Prenatal
developmental
in
rat
00062656
(Subcutaneous)
unacceptable/
nonguideline
1976
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
15
mg/
kg/
day
based
on
reduced
body
weight
Developmental
NOAEL
=
>30
mg/
kg/
day
LOAEL
=
not
identified
42808001
acceptable/
guideline
1971
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day
based
on
reduced
body
weight
and
food
consumption
Developmental
NOAEL
=
10
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day
based
on
skeletal
variation.

870.3700b
Prenatal
developmental
in
rabbit
00062658
(Subcutaneous)
unacceptable/
nonguideline
1976
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
15
mg/
kg/
day
based
on
clinical
signs,
mortality,
reduced
body
weight
Developmental
NOAEL

15
mg/
kg/
day
LOAEL
=
not
identified
42808002
unacceptable/
nonguideline
1971
Maternal
NOAEL

20
mg/
kg/
day
LOAEL
=
not
identified
Developmental
NOAEL

20
mg/
kg/
day
LOAEL
=
not
identified
Lindane/
September
2000
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
38
870.3800
Reproduction
and
fertility
effects
42246101
acceptable/
guideline
1991
NOAEL
=
1.
7
mg/
kg/
day

;
0.
09mg/
kg/
day

LOAEL
=
13
mg/
kg/
day
based
on
reduced
body
weight

;
1.
7
mg/
kg/
day
based
on
increased
kidney
weight
and
alpha­
2
globulin
accumulation

870.4100a
Chronic
toxicity
rodents
870.4200
Carcinogenicity
rats
41094101
41853701
42891201
acceptable/
guideline
1993
NOAEL
=0.
6
mg/
kg/
day
LOAEL
=
4.
8
mg/
kg/
day

;
6
mg/
kg/
day

based
on
periacinar
hepatocyte
hypertrophy,
increased
liver
and
spleen
weights,
and
decreased
platelets
no
evidence
of
carcinogenicity
870.4300
Carcinogenicity
mice
special
study
1987
NOAEL
=
not
identified
LOAEL
=
23
mg/
kg/
day
based
on
induction
of
tumors,
increased
liver
weights,
increased
enzyme
activity,
and
irreversible
Clara
cell
hyperplasia
in
lung
evidence
of
carcinogenicity­
liver
and
lung
tumors
870.5300
Gene
Mutation
Mammalian
Cell
00144500
unacceptable/
guideline
1985
negative
870.5915
In
Vivo
Sister
Chromatid
Exchange
00024504
unacceptable
guideline
1984
negative
870.5450
dominant
lethal
assay
00062657
unacceptable
guideline
negative
870.6200a
Acute
neurotoxicity
screening
battery
44769201
acceptable/
guideline
1999
NOAEL
=
6
mg/
kg/
day

;
20
mg/
kg/
day

LOAEL
=
20
mg/
kg/
day
based
on
icreased
grip
strength
and
motor
activity.
60
mg/
kg/
day
based
on
tremors,
convulsions,
decreased
motor
activity
and
increased
grip
strngth.

870.6200b
Subchronic
neurotoxicity
screening
battery
44781101
acceptable/
guideline
1999
NOAEL
=
7.
9
mg/
kg/
day

;
7.
1
mg/
kg/
day

LOAEL
=
30.
2
mg/
kg/
day
and
28.
1
mg/
kg/
day
based
on
hypersensitivity
to
touch
and
hunched
posture
Lindane/
September
2000
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
39
870.6300
Developmental
neurotoxicity
45073501
unacceptable/
guideline
1999
Maternal
NOAEL
=
5.
6
mg/
kg/
day
LOAEL
=
13.
7
mg/
kg/
day
based
on
decreased
body
weight
gains,
decreased
food
consumption,
and
increased
reactivity
to
handling.
Offspring
NOAEL
=
1.
2
mg/
kg/
day
LOAEL
=
5.
6
mg/
kg/
day
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.

870.7600
Dermal
penetration
40056107­
rat
40056108­
rabbit
acceptable/
guideline
1987
18
%
absorption
at
10
hours
Lindane/
September
2000
RED
Toxicology
Chapter
40
Table
2
Summary
of
Toxicological
Dose
and
Endpoints
for
LINDANE
for
Use
in
Human
Risk
Assessment
1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
not
applicable;
no
relevant
single
exposure
endpoint
was
identified
Acute
Dietary
general
population
including
infants
and
children
NOAEL=
6
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.06
mg/
kg/
day
FQPA
SF
=
3
aPAD
=
acute
RfD
FQPA
SF
=
0.
02
mg/
kg/
day
Acute
Neurotoxicity
in
Rats/
MRID
44769201
LOAEL
is
20
mg/
kg
based
on
increased
grip
strength,
increased
Motor
Activity
Chronic
Dietary
all
populations
NOAEL=
0.47
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.
0047
mg/
kg/
day
FQPA
SF
=
3
cPAD
=chrRfD
FQPA
SF
=
0.
0016
mg/
kg/
day
Chronic
Feeding
and
Carcinogenicity
in
Rats
MRID
41094101,
41853701,
42891201
LOAEL
is
4.
81
mg/
kg/
day
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver/
spleen
weigt,
increased
platelets
Short­
Term
Dermal
(1­
7
days)

(Occupational/
Residential)
oral
study
NOAEL=
1.
2
mg/
kg/
day
(dermal
absorption
rate
=
10%
)
LOC
for
MOE
=
100
(Occupational)

no
residential
exposure
expected
Developmental
Neurotoxicity
Study
in
Rats
(MRID
45073501)

LOAEL
is
5.
6
mg/
kg/
day
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation
Lindane/
September
2000
RED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
41
Intermediate
Term
Dermal
(1
week
­
several
months)

(Occupational)
oral
study
NOAEL=
1.
2
mg/
kg/
day
(dermal
absorption
rate
=
10%
)
LOC
for
MOE
=
100
(Occupational)
Developmental
Neurotoxicity
Study
in
Rats
(MRID
45073501)

LOAEL
is
5.
6
mg/
kg/
day
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.

Long­
Term
Dermal
(several
months

lifetime)

(Occupational)
oral
study
NOAEL=
0.47
mg/
kg/
day
(dermal
absorption
rate
=
10%
)
LOC
for
MOE
=
100
(Occupational)
Chronic
Feeding
and
Carcinogenicity
in
Rats
MRID
41094101,
41853701,
42891201
LOAEL
is
4.
81
mg/
kg/
day
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver/
spleen
weigt,
increased
platelets
Short­
Term
Inhalation
(1­
7
days)

(Occupational)
inhalation
study
LOAEL=
0.13
mg/
kg/
day
LOC
for
MOE
=
100
(Occupational)
90­
Day
Inhalation
Toxicity
MRID
00255003
based
on
clinical
signs
(diarrhea,
piloerection)
seen
at
day
14
and
continuing
for
20
days.

Intermediate
Term
Inhalation
(1
week

several
months)

(Occupational)
inhalation
study
NOAEL=
0.025
mg/
kg/
day
LOC
for
MOE
=
100
(Occupational)
90­
Day
Inhalation
Toxicity
MRID
00255003
LOAEL
is
0.
13
mg/
kg/
day
based
on
micro
lesions
in
kidney,
increased
kidney
weight
Cancer
(oral)
group
B2/
C
carcinogen
Q1*
=
1.1
(mg/
kg/
day)
­1
based
on
increased
incidence
of
mouse
liver
tumors
1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
Lindane/
September
2000
RED
Toxicology
Chapter
42
SignOff
Date:
9/
28/
00
DP
Barcode:
D269338
HED
DOC
Number:
014351
Toxicology
Branch:
RRB4