Document ID: EPA-HQ-OPP-2002-0202-0010
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,
PESTICIDE
AND
TOXIC
SUBSTANCES
HED
DOC.
NO.
014595
DATE:
June
18,
2001
MEMORANDUM
SUBJECT:
Lindane
(PC
Code:
009001)­
A
Second
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Suhair
Shallal,
Toxicologist.
Reregistration
Branch
4
Health
Effects
Division
(7509C)

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

TO:
Mark
T.
Howard
Special
Review
and
Registration
Division
On
May
22,
2001,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
met
to
reconsider
the
endpoint
for
occupation
risk
assessment
for
the
inhalation
route
of
exposure.
Previouslythe
endpoint
was
based
on
kidneylesions
and
increased
kidney
weights
resulting
fromthe
accumulation
of
alpha
2    
globulin.
These
effects
have
been
deemed
not
relevant
for
human
risk
assessment.
The
Committee's
decision
is
presented
in
this
report
along
with
the
previously
conclusions
of
the
June
13,
2000
HIARC
meeting.
In
that
meeting
the
Reference
Dose
(RfD)
and
the
toxicological
endpoints
for
acute
and
chronic
dietary,
as
well
as,
occupational
exposure
risk
assessments
were
selected.
HIARC
re­
assessed
the
Reference
Dose
(RfD)
established
in
1994,
as
well
as
the
toxicological
endpoints
selected
for
acute
dietary
and
occupational/
residential
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
enhanced
sensitivity
of
infants
and
children
from
exposure
to
lindane
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
This
Report
has
been
revised
to
reflect
a
change
in
the
endpoint
selection
for
occupational
risk
assessment
through
the
inhalation
route
of
exposure.
2
1996.

Committee
Members
in
Attendance
Members
present
were:
Elizabeth
Doyle
David
Nixon
Jess
Rowland
Elizabeth
Mendez
William
Burnam
Pamela
Hurley
Yung
Yang
Brenda
Tarplee
Jonathan
Chen
Paula
Deschamp
Member(
s)
in
absentia:
Ayaad
Assaad
Data
was
presented
by
Suhair
Shallal
of
the
Reregistration
Branch
4.

Also
in
attendance
were:
Susan
Henley,
Whang
Phang,
Joseph
Nevola
Data
Presentation:
and
Suhair
Shallal,
Report
Presentation
Toxicologist
Report
Concurrence:
Brenda
Tarplee
Executive
Secretary
cc:
RD
Casewell
file
3
I.
INTRODUCTION
On
May
22,
2001,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
met
to
reconsider
the
endpoint
for
occupation
risk
assessment
for
the
inhalation
route
of
exposure.
Previously
the
endpoint
was
based
on
kidney
lesions
and
increased
kidney
weights
resulting
from
the
accumulation
of
alpha
2    
globulin.
These
effects
have
been
deemed
not
relevant
for
human
risk
assessment.
The
Committee's
decision
is
presented
in
this
report
along
with
the
previously
conclusions
of
the
June
13,
2000
HIARC
meeting.
In
that
meeting
the
Reference
Dose
(RfD)
and
the
toxicological
endpoints
for
acute
and
chronic
dietary,
as
well
as,
occupational
exposure
risk
assessments
were
selected.
HIARC
re­
assessed
the
Reference
Dose
(RfD)
established
in
1994,
as
well
as
the
toxicological
endpoints
selected
for
acute
dietary
and
occupational/
residential
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
enhanced
sensitivity
of
infants
and
children
from
exposure
to
lindane
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.

II.
HAZARD
IDENTIFICATION
A.
Acute
Reference
Dose
(RfD)*
General
population
Selected
Study:
Acute
Neurotoxicity
Study
Guideline
#:
OPPTS
870.6200
[§
81­
8]

MRID
No.:
44769201
Executive
Summary:
In
an
acute
oral
neurotoxicity
study,
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,
weeklyduring
the
study
period
and
on
FOBassessment
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
4
Acute
RfD
=
NOAEL
(mg/
kg)
=6=
0.
06mg/
kg
UF
100
ratios
in
the
treated
groups
were
not
changed
compared
to
control
groups.

At
the
first
FOB
assessment
on
Day
0
(3
hours
aft
er
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)
and
tremor/
twitching
(1)
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
(2).
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
changes
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
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.

Dose
and
Endpoint
for
Establishing
an
Acute
RfD:
The
NOAEL
is
6
mg/
kg
based
on
increased
forelimb
grip
strength
and
decreased
grooming
behavior
and
motor
activity
in
female
rats
Uncertainty
Factor(
s):
100
;
10X
intraspecies
variations
and
10X
interspecies
etrapolation
Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
5
Acute
Reference
Dose
(RfD)*
Females
(13­
50
years)

An
appropriate
endpoint
attributable
to
a
single
dose
could
not
be
ascertained
fromeither
the
developmental
toxicity
study
in
rats
and
in
rabbits
or
in
the
developmental
neurotoxicity
study.
Although,
there
was
evidence
of
increased
susceptibility
in
the
DNT,
the
offspring
effects
were
not
attributable
to
a
single
dose.
A
separate
endpoint
for
this
subpopulation
was
therefore
not
identified.

2.2
Chronic
Reference
Dose
(RfD)

Selected
Study:
Combined
chronic
toxicity/
oncogenicity
feeding
–
Rat
Guideline
#:
OPPTS
870.4300
[§
83­
5]

MRID
No.:
41094101,
41853701
and
42891201
Executive
Summary:
Results
from
interim
sacrifice
of
15
rats/
sex/
group
at
30
days
and
26
weeks,
as
well
as,
15
rats/
sex/
group
at
52
weeks
and
final
results
of
an
ongoing
chronic/
oncogenicity
study
are
presented
in
this
report
(MRID
41094101,
41853701
and
42891201).

In
this
chronic
toxicity/
oncogenicity
study,
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
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.

No
clinical
signs
of
toxicity
were
observed
during
the
first
26
weeks;
however
by
52
weeks
convulsions
in
11
high­
dose
females
were
observed.
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
ppmgroups,
respectively.
Survival
of
highdose
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
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.
Because
final
body
weights
of
the
100
ppm
males
were
similar
to
the
controls,
the
init
ial
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
t
he
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
6
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
ppmand
40/
50
males
and
43/
50
females
affected
at
400
ppm.
No
treatment­
related
histopathological
lesions
were
observed
in
the
spleen
or
bone
marrow.

Kidney
lesions
in
males
indicative
of
alpha
2    
globulin
accumulation
were
observed
in
animals
treated
with
10
ppm.

Therefore,
the
systemic
toxicity
LOAEL
for
male
and
female
rats
is
100
ppm
(4.
81
and
6.0
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
for
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
7
Chronic
RfD
=
NOAEL
(mg/
kg/
day)
=0.
47=
0.0047
mg/
kg/
day
UF
100
100
ppm
group.

Therefore,
no
evidence
of
dose­
related
and
statistically
significant
increase
in
adrenal
tumors
was
observed
in
this
study.
The
study
was
conducted
at
adequate
dose
levels.

Dose
and
Endpoint
for
Establishing
a
Chronic
RfD:
The
NOAEL
is
0.47
mg/
kg/
day
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver
and
spleen
weights,
and
decreased
platelets
in
male
rats
Uncertainty
Factor(
s):
100;
10X
intraspecies
variations
and
10X
interspecies
extrapolation
Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
HIARC
concurred
with
the
TES
committee's
decision
(1994,
DOC
013460)
that
the
toxicological
endpoint
of
concern
was
the
periacinar
hepatocyte
hypertrophy
and
not
kidney
lesions
associated
with
alpha
2    
globulin
which
is
thought
to
be
inappropriate
for
human
risk
assessment.

2.3
Occupational/
Residential
Exposure
2.3.1
Dermal
Absorption
Selected
Study:
Dermal
absorption
study
Guideline
#:
OPPTS
870.7600
[§
85­
3]

MRID
No.:
40056107,
40056108
Executive
Summary:
In
a
dermal
absorption
study,
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
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
8
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].

Percent
Dermal
Absorption
by
Rats
Based
on
Exposure
and
Duration
Applied
dose/
rat
(mg/
kg)
Exposure
Duration
4
hr
10
hr
24
hours
0.1
mg
(.
25
mg/
kg)
10.1
18.1
27.7%

1.0
mg
(2.5
mg/
kg)
5.3
8.
3
20.9%

10.0
mg
(25
mg/
kg)
2.0
2.
8
5.0%

Executive
Summary:
In
a
dermal
absorption
study,
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
from
urine,
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].

At
10
hours,
18%
of
the
applied
material
is
absorbed.
IPCS
(1991)
sites
even
higher
percentages
at
24
hours,
ranging
from
28%
for
rat
and
17
to
56%
for
rabbit.

Percentage
(%)
Dermal
Absorption:
9
The
absorption
has
been
determined
to
be
10%.

Comments
about
Dermal
Absorption:

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).

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).

2.
3.
2
Short­
term
Dermal
(1
­
7
days)
Exposure
Selected
Study:
Developmental
Neurotoxicity
Study
Guideline
#:
OPPTS
870.6200
[§
83­
6]

MRID
No.:
45073501
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
from
gestation
day
(GD)
6
through
lactation
day
10.
These
concentrations
resulted
in
F0
maternal
doses
of
0.
8­
0.
9,
4.
2­
4.
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
neurotoxicity
of
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
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
10
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
high­
dose
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
highdose
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
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).
11
The
developmental
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
developmental
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.

Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
is
1.2
mg/
kg
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
A
90­
day
dermal
toxicity
study
in
rabbits
was
available;
the
NOAEL
was
10
mg/
kg/
day
and
the
LOAEL
was
60
mg/
kg/
day
based
on
hepatic
toxicity.
The
HIARC
did
not
consider
this
study
to
be
appropriate
for
risk
assessment
and
instead
selected
an
oral
endpoint
due
to:

1)
the
concern
for
developmental
effects
as
seen
in
pups
in
the
developmental
neurotoxicity
study
2)
developmental
effects
are
not
evaluated
in
the
dermal
toxicity
study
3)
the
dermal
toxicity
study
was
conducted
in
the
rabbit,
while
the
increased
susceptibility
was
seen
in
rat
pups
via
an
oral
route
4)
this
endpoint
will
be
protective
of
dermally
exposed
workers
Since
an
oral
endpoint
was
selected,
a
10%
dermal
absorption
factor
should
be
used
for
route
to
route
extrapolation.
Although
this
study
is
classified
as
unacceptable/
guideline,
it
is
adequate
for
endpoint
selection
because
the
deficiencies
are
related
to
submission
of
additional
data
and
not
the
quality
of
the
study.

2.3.3
Intermediate­
term
Dermal
(1­
Week
to
Several
Months)

Selected
Study:
Developmental
Neurotoxicity
Study
in
rats
Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
is
1.2
mg/
kg
based
on
reduced
pup
survival,
decreased
body
weights
and
bodyweight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.

Comments
about
Study/
Endpoint:
See
Short­
term
Dermal
Section
2.
3.
2
12
2.3.4
Long­
term
Dermal
(Several
Months
to
Lifetime)

Selected
Study:
Chronic
toxicity
and
Oncogenicity
Study
in
rats
MRID
No.:
41094101,
41853701
and
42891201
Dose
and
Endpoint:
The
NOAEL
is
0.47
mg/
kg/
day
based
on
periacinar
hepatocyte
hypertrophy,
increased
liver
and
spleen
weights,
and
decreased
platelets
in
male
rats
Comments
about
Study/
Endpoint:
This
dose
and
endpoint
was
used
to
derive
the
chronic
RfD.
Since
an
oral
NOAEL
was
selected,
a
10%
dermal
absorption
factor
should
be
used.

2.
4
Inhalation
Exposure
(All
Durations)

Short­
term
(1­
7
days):

Selected
Study:
Subchronic
Inhalation
Toxicity
Study
Guideline
#:
OPPTS
870.3465
[§
82­
4]

Accession
No.:
255003
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,
beginning
at
14
days
after
exposure
and
continuing
for
20
days.
No
exposure­
related
effects
were
noted
for
body
weight
gain,
food
consumption,
water
consumption,
or
urinalysis
parameters.
Although
hematologyparameters
did
appear
to
be
affected
bytreatment,
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
13
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%),
stem
cells
(+
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.
9­
8.
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.
These
effects
are
consistent
with
the
accumulation
of
alpha
2    
globulin
and
is
not
relevant
for
human
risk
assessment.

Therefore,
the
systemic
toxicity
LOAEL
is
5.0
mg/
m
3
based
on
increased
kidney
weights
of
female
rats
and
bone
marrow
effects.
The
systemic
toxicity
NOAEL
is
0.5
mg/
m
3
.

This
study
is
considered
Acceptable/
guideline
and
satisfies
the
requirement
for
a
subchronic
inhalation
toxicity
study
in
rats
[82­
4].
It
should
be
noted
that
several
translation
errors
were
found
and
corrected
by
referring
to
the
original
text.
Individual
animal
data
were
not
available
for
statistical
analysis
of
blood
elements
or
clinical
chemistry
data.

Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
is
0.5
mg/
m
3
(0.
13
mg/
kg)
based
on
clinical
signs
(diarrhea
and
piloerection)
seen
at
day
14
after
exposure
and
continuing
for
20
days.
14
Comments
about
Study/
Endpoint:
The
HIARC
established
a
NOAEL
of
0.5
mg/
m
3
for
this
risk
assessment
based
on
clinical
signs
seen
at
the
highest
concentration
tested
(5
mg/
m
3
).
This
NOAEL
is
applicable
and
appropriate
only
for
short­
termexposure
risk
assessment
because
the
effects
were
seen
during
this
period
of
exposure.
The
Committee
further
noted
that
this
dose
would
be
protective
against
developmental
effects.

Intermediate
term
(7
days
to
several
months):

Selected
Study:
Subchronic
Inhalation
Toxicity
Study
Accession
No.:
255003
Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
is
0.5
mg/
m
3
(0.
13
mg/
kg)
based
on
increased
kidney
weights
in
females
and
bone
marrow
effects
(increased
reticulocytes,
increased
myelocytes,
decreased
lymphocytes)
at
5
mg/
m
3
.

Comments
about
Study/
Endpoint:
The
NOAEL
of
0.1
mg/
m
3
based
on
kidney
lesions
and
increased
kidney
weights
in
male
rats
at
0.5
mg/
m
3
,
selected
previously
on
June
13
th
,
2001
HIARC
meeting,
has
been
changed.
The
change
in
endpoint
selection
was
necessary
because
the
kidney
effects
are
due
to
the
accumulation
of
alpha
2    
globulin,
a
low
molecular
weight
protein
in
the
male
rat
kidney,
and
this
accumulation
initiates
a
sequences
of
events
that
may
lead
to
tumor
formation.
This
phenomenon
does
not
occur
in
female
rats.
The
Agency
has
determined
that
in
this
special
situation,
the
male
rat
is
not
a
good
model
for
assessing
human
risk
(USEPA,
1991).

The
route
and
duration
of
exposure
in
this
study
is
appropriate
for
this
exposure
scenario.

Long
Term
Inhalation:

Based
on
the
use
pattern
(maximum
of
60
days),
no
long­
term
inhalation
exposure
is
expected.
If
there
is
a
change
in
the
use
pattern
and
a
long­
term
exposure
becomes
likely,
then
the
inhalation
NOAEL
of
0.
5
mg/
m
3
(0.
13
mg/
kg)
should
be
used
for
risk
assessment.

Recommendation
for
Aggregate
Exposure
Risk
Assessments
There
are
no
registered
residential
uses
at
this
present
time;
therefore,
non­
occupational
aggregate
exposure
risk
assessment
will
be
limited
to
food
and
water.

For
occupational
risks,
separate
assessments
should
be
conducted
for
dermal
and
inhalation
exposures
because
the
effects
selected
for
assessment
of
dermal
risk
do
not
share
a
common
toxicity
with
the
effects
selected
for
inhalation
risk.
15
Margins
of
Exposures
for
Occupational/
Residential
Exposure
Risk
Assessments
An
MOE
of
100
is
adequate
for
both
dermal
and
inhalation
occupational
exposure
at
all
time
durations.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
41094101,
41853701
and
42891201
Executive
Summary:
See
Chronic
RfD
section
Discussion
of
Tumor
Data:
No
tumors
were
noted
in
this
study.
The
findings
included
a
significant
increase
in
the
incidence
rate
of
periacinar
hepatocytic
hypertrophy
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.
For
further
details,
please
refer
to
the
chronic
RfD
section­
2.2.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
are
adequate
to
assess
the
carcinogenic
potential
of
Lindane.

3.2
Carcinogenicity
Study
in
Mice
NO
ACCEPTABLE
STUDY
IS
AVAILABLE
Comments
and
Discussion:
A
new
mouse
carcinogenicity
study
is
expected
in
December
2000
3.3
Classification
of
Carcinogenic
Potential
A
new
Cancer
Assessment
Review
Committee
(CARC)
meeting
will
review
the
recently
submitted
mouse
carcinogenicity
study
and
establish
a
new
classification
for
lindane,
if
applicable.
According
to
the
TES
committee
report
(1994,
Doc
013460),
Lindane
has
not
been
classified
by
the
HED
Cancer
Peer
Review
Committee.
It
was
determined
by
the
RfD/
Peer
Review
Committee
(8/
25/
93)
that:
"The
mouse
carcinogenicity
data
were
considered
insufficient
because
of
major
deficiencies
associated
with
all
studies
available."
Lindane
however
had
been
previously
classified
by
the
Cancer
Assessment
Group
of
the
Office
of
Research
and
Development
(memorandum
dated
7/
23/
85
from
R.
E.
McGaughy
to
Anne
Barton)
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
memorandum
as
Q1*
=
1.1
(mg/
kg/
day)
­1
.
16
IV.
MUTAGENICITY
Executive
Summary:
In
a
mammalian
cell
gene
mutation
assay
(MRID
00144500)
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
µ
g/
ml.
No
mutagenic
activity
of
lindane
was
observed
in
V79
cells
under
any
combination
of
conditions
up
to
cytotoxic
doses.
No
statistical
analysis
was
performed;
solvent
control
values
were
somewhat
variable;
the
positive
control
values
were
appropriate
for
the
experiments
under
aerobic
conditions,
but
the
positive
control
employed
for
anaerobic
conditions
did
not
exhibit
an
increase
in
anaerobic
mutation
frequency
compared
to
aerobic
mutation
frequency.

Moreover,
there
was
no
experimental
verification
that
anaerobic
conditions
were
either
established
before
exposure
to
lindane
or
maintained
throughout
the
exposure
period.
Since
the
anaerobic
positive
control
did
not
produce
more
mutations
under
anaerobic
than
under
aerobic
conditions,
anaerobic
metabolic
pathways
may
not
have
been
induced
in
the
cells.

This
study
is
classified
as
Unacceptable/
Guideline
and
does
not
satisfy
guideline
requirements
for
a
mammalian
cell
culture
gene
mutation
assay
in
V79
cells
(84­
2)
because
of
the
deficiencies
described
above.
This
classification
could
not
be
upgraded
without
repeating
the
experiments.

Executive
Summary:
In
a
mammalian
in
vivo
sister
chromatid
exchange
(SCE)
assay
(MRID
00024504),
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.
These
doses
were
reported
to
be
1/
75,
1/
15
and
1/
3
of
the
LD50
.
The
vehicle
control
group
received
arachis
oil
and
the
positive
control
group
received
10
mg/
kg
of
cyclophosphamide
in
saline.
Colcemid
was
administered
22
hours
later
to
arrest
cells
in
mitosis,
and
after
another
2
hours
the
animals
were
sacrificed.
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.
Slight
but
significant
increases
in
SCEs
over
the
vehicle
controls
were
observed
in
female
but
not
in
male
animals
at
all
dose
levels
tested
but
were
not
dose­
related
(1.29
[sic],
1.82,
and
2.
12
SCE/
cell).
Vehicle
control
17
values
for
female
animals
were
also
found
to
be
significantly
lower
than
those
for
males
(1.
56
±
0.089
SCE/
cell
compared
to
1.
86
±
0.207
SCE/
cell).
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.

The
study
authors
concluded
that
no
chromosome
damage
was
observed
in
this
test.

This
study
was
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
sister
chromatid
exchange
study
in
mice
(in
vivo
SCE)
(84­
2).

Executive
Summary:
In
a
mammalian
dominant
lethal
assay
(MRID
00062657),
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.
Immediately
following
treatment,
each
male
was
housed
with
two
virgin
females.
After
one
week,
the
females
were
replaced
with
two
more
virgin
females.
No
positive
control
group
was
included
in
the
study.
Females
were
sacrificed
14
days
after
evidence
of
mating
or,
lacking
evidence,
14
days
after
removal
from
males.
Uteri
were
examined
for
live
and
dead
implants
and
abnormalities.
Males
were
also
sacrificed
and
gross
pathological
analysis
performed.

Very
slight
but
not
statistically
significant
weight
loss
was
observed
in
the
male
animals
at
the
two
higher
doses.
No
mortality
or
treatment­
related
clinical
signs
of
toxicity
were
noted.
No
treatment
related
effect
on
pregnancy
rate
was
observed,
although
pregnancy
rates
in
all
groups
were
low
during
the
first
week.
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
in
this
study.

This
study
is
classified
as
Unacceptable/
Guideline
and
does
not
satisfy
the
guideline
requirements
for
a
dominant
lethal
test
in
the
rodent
(84­
2)
because
no
positive
control
was
done,
the
criteria
for
toxicity
were
inadequate,
animal
age
was
not
given,
and
insufficient
numbers
of
pregnant
dams
were
produced
for
meaningful
evaluation.
Moreover,
no
rationale
was
provided
for
the
dose
selection,
unusual
route
of
administration
or
dosing
regime.
This
classification
could
not
be
upgraded
without
repeating
the
study.

IPCS
has
also
determined
that
Lindane
does
not
appear
to
have
mutagenic
potential.
18
V.
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
­­
Acute
delayed
neurotoxicity
study
in
hen
(if
applicable)
­X­
Acute
and
subchronic
neurotoxicity
studies
(if
applicable)
­X­
Developmental
toxicity
studies
in
Rat
&
Rabbits
­X­
Two­
Generation
Reproduction
Study
­X­
Developmental
neurotoxicity
study
(if
applicable)

THESE
STUDIES
ARE
AVAILABLE
AND
THE
DATA
BASE
IS
ADEQUATE
FOR
FQPA
EVALUATION
OF
FQPA.

5.
2
Neurotoxicity
Data
1­
Acute
Neurotoxicity
­§
81­
7:
See
Acute
RfD
section
2­
Subchronic
Neurotoxicity­
§82­
5
MRID:
44781101
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
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
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
ppm
were
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
19
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<
0.05
or
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
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
the
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
LOAEL
levels
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
20
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.

5.3
Developmental
Toxicity
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
42808001),
20
presumed
pregnant
CFY
(derived
from
Charles
River
CD)
rats
per
group
were
administered
technical
Lindane
(purity
not
given;
Batch
No.
6801/
403)
by
gavage
in
0.5%
carboxymethylcellulose
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
by
the
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
highdose
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
LOAEL
is
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
within
the
upper
limit
of
historical
control
data,
they
were
considered
treatment­
related
due
to
the
dose­
related
manner
of
increase.
21
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.

This
study
is
classified
as
Acceptable/
nonguideline
and
does
satisfy
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
was
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.
This
study
was
conducted
prior
to
implementation
of
current
guidelines.

Executive
Summary:
In
a
developmental
toxicity
study
(MRID
00062658),
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,
excitability,
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
high­
dose
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,
preand
post­
implantation
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.
22
Therefore,
the
developmental
toxicity
NOAEL
is
>30
mg/
kg/
day
and
the
developmental
toxicity
LOAEL
was
not
identified.

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
homogeneity,
less
than
20
litters/
group
were
available
for
evaluation,
and
much
of
the
individual
maternal
and
fetal
data
were
not
included.
However,
this
study
may
be
used
as
supplemental
information.

This
study
was
classified
unacceptable;
however,
a
new
developmental
toxicity
study
in
rabbits
is
not
required
and
thought
to
not
be
beneficial
for
the
following
reasons:
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
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)
A
developmental
neurotoxicity
study
has
already
been
submitted.

Executive
Summary:
In
a
developmental
toxicity
study
(MRID
42808002),
13
presumed
pregnant
New
Zealand
white
rabbits
per
group
were
administered
Lindane
(purity
not
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.
23
Therefore,
the
developmental
toxicity
NOAEL
is
>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
(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
dam
aborted
and
died
on
GD
21
and
14/
15
high­
dose
animals
died
between
GD
10
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
24
and
post­
implantation
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
NOAEL
is
>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
toxicity
study
in
rabbits
(MRID
42808002)
as
supplemental
information.

Study:
Developmental
Neurotoxicity
Study
Executive
Summary:
See
Short­
Term
Dermal
(1­
7
days);
Section
2.
3.
2
5.4
Reproductive
Toxicity
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
hist
opathology
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
25
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
highdose
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.

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
LOAELfor
systemic
toxicity
is
150
ppmbased
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
based
on
increased
kidney
weights
and
histopathological
lesions
in
the
kidney
characteristic
of
alpha
2u
globulin
accumulation;
the
NOAEL
for
males
is
1
ppm.

Mating,
fert
ility,
gestation
survival
(postimplantation
index),
and
liveborn
indices,
mean
precoital
interval,
and
mean
gestation
lengt
h
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
fromthe
controls
throughout
lactation
for
both
generations.
Viability
indices
for
t
he
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
26
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
LOAELfor
reproductive
toxicity
is
150
ppm
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.

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.

5.5
Additional
Information
from
Literature
Sources
Karmaus,
W.
et
al,
Reduced
Birthweight
and
Length
in
the
Offspring
of
Females
Exposed
to
PCDFs,
PCP,
and
Lindane.
Environmental
Health
Perspectives;
103(
12).
1995.
1120­
1125.

The
objective
of
this
study
was
to
investigate
a
broad
range
of
adverse
health
outcomes
and
their
potential
association
to
wood
preservative
used
in
daycare
centers.
This
article
focuses
on
reproductive
effects.
A
sample
of
221
exposed
teachers
was
provided
by
the
employer's
liability
insurers.
A
comparison
group
(n
=
189)
insured
by
the
same
two
organizations
was
recruited
from
nonexposed
daycare
centers.
In
a
face­
to­
face
interview,
job
history
and
reproductive
history
of
398
female
teachers
were
ascertained.
Data
on
exposure
were
provided,
including
measurements
on
concentration
of
pentachlorophenol
(PCP)
and
lindane
in
wood
panels,
and
of
PCP,
lindane,
polychlorinated
dibenzo­
p­
dioxins
and
dibenzofurans
in
indoor
air.
An
exposure
matrix
based
on
individual
job
history,
independent
exposure
information
from
each
center,
and
reproductive
history
was
set
up
with
regard
to
the
vulnerable
time
windows
for
each
pregnancy.
Using
this
approach,
49
exposed
and
507
nonexposed
pregnancies
were
identified,
including
32
exposed
and
386
nonexposed
live
births.
For
subgroup
analyses
the
observations
were
restricted
to
independent
pregnancies,
excluding
multiple
and
consecutive
births.
The
data
were
analyzed
with
linear
regression
techniques,
taking
confounders
into
account.
The
crude
median
difference
between
exposed
and
nonexposed
was
175
g
in
birthweight
and
2
cm
in
length.
Controlling
for
confounders,
the
results
showa
significantly
reduced
but
weight
(p
=
0.04)
and
length
(p
=
0.02)
in
exposed
pregnancies,
even
after
restricting
the
data
to
independent
pregnancies
and
pregnancies
for
which
data
could
be
validated
from
the
mother's
health
cards.
These
differences
were
not
explained
by
differences
in
gestational
age
indicating
that
a
toxic
effect,
which
could
cause
small­
for
date
newborns,
might
have
affected
the
fetus.

Rivera,
S.
et
al,
Behavioral
Changes
Induced
in
Developing
Rats
by
an
Early
Postnatal
Exposure
to
Lindane.
Neurotoxicity
and
Teratology,
12(
6).
1990.
591­
595
The
purpose
of
this
studywas
to
determine
whether
the
behavioral
developmental
pattern
was
altered
by
an
early
postnatal
exposure
to
lindane.
Male
and
female
offspring
of
Wist
ar
rat
s
27
were
daily
orally
administered
with
a
nonconvulsant
dose
of
lindane
(10
mg/
kg)
during
7
days
either
the
1st
or
the
2nd
postnatal
week
days.
Effects
on
pups
were
evaluated
with
a
reduced
developmental
neurotoxicological
test
battery.
Body
weight
evolution,
neuromotor
reflexes
(surface
righting,
cliff
avoidance
and
tail
hang
reflex)
and
spontaneous
motor
activity
were
analyzed
from
day
1
after
birth
up
to
day
28.
The
body
weight
pattern
was
unaffected
by
treatment
with
lindane
and
no
signs
of
overt
toxicity
were
observed.
Lindane­
treated
pups
showed
an
increased
positive
response
of
the
neuromotor
reflexes.
Furthermore,
lindane
produced
hyperactivity,
especially
manifested
between
days
12
and
16.
Apeak
of
activity
was
reached
at
day
16
in
lindane­
treated
group,
while
control
animals
had
a
maximum
between
days
20
and
24.
These
results
suggest
that
low
nonconvulsant
doses
of
lindane
may
induce
behavioral
changes
in
developing
rats.

Sircar,
S.
et
al,
Lindane
(gamma­
HCH)
Causes
Reproductive
Failure
and
Fetotoxicity
in
Mice.
Toxicology
59(
2).
1989.
171­
177.

Lindane
(gamma­
Hexachlorocyclohexane)
was
orally
given
to
pregnant
Swiss
female
mice
at
various
stages
of
pregnancy.
During
early
pregnancy
(1­
4
days
of
gestation),
the
insecticide
caused
total
absence
of
any
implantation
site,
while
given
during
mid
pregnancy
(6­
12
days
of
gestation),
lindane
caused
total
resorption
of
fetuses.
Lindane
administration
during
late
pregnancy
(14­
19
days
of
gestation)
resulted
in
death
of
all
pups
either
within
12
h
(high­
dosed
group)
or
5
days
(low­
dosed
group)
of
parturition.
Body
weight
of
such
pups
were
also
highly
reduced.
When
estrogen
was
given
together
with
lindane
at
early
pregnancy,
implantation
was
normal,
although
subsequent
fetal
development
was
adversely
affected.
Progesterone,
unlike
estrogen,
could
not
correct
lindane­
induced
failure
in
implantation.
On
the
other
hand,
when
estrogen
and
progesterone
were
simultaneously
given
to
lindane­
fed
mice
during
early
pregnancy,
both
implantation
and
subsequent
fetal
development
became
comparable
to
normal
mice.
The
insecticide
besides
being
fetotoxic,
thus
appears
to
cause
steroid
hormone
deficiency
resulting
in
reproductive
and
developmental
failure.

Pompa,
G.
et
al,
Transfer
of
Lindane
and
Pentachlorobenzene
From
Mother
to
Newborn
Rabbits,
Pharmacology
and
Toxicology;
74(
1).
1994.
28­
34.

After
administration
of
gamma­
hexachlorocyclohexane
(lindane)
(30
mg/
kg)
to
sixteen
pregnant
rabbits,
the
transfer
and
distribution
of
this
insecticide
and
its
metabolite
pentachlorobenzene,
in
foetuses
and
newborns
at
the
5th,
10th
and
20th
days
after
birth,
were
investigated.
Over
one
lactation
the
mothers
excreted
via
the
milk
about
30%
of
the
lindane
present
in
tissues
at
the
28
th
day
of
pregnancy.
The
total
amount
of
lindane
transferred
via
milk
to
5
day­
old
newborns
was
higher
than
that
transferred
across
the
placenta
during
pregnancy.
Lindane
concentrations
in
newborns
decreased
in
spite
of
the
efficient
transfer
to
off­
spring
by
lactating
mothers.
This
cannot
be
explained
by
growth
alone
and
indicates
that
newborns
are
able
to
actively
metabolize
the
insecticide.
The
pentachlorobenzene
metabolite
produced
after
lindane
administration
to
the
mothers
crossed
the
placental
barrier
with
difficulty
during
pregnancy,
but
was
readily
transferred
to
off­
spring
via
milk.
Pentachlorobenzene
levels
in
28
neonates
increased
during
lactation
by
transfer
and
also
as
a
consequence
of
endogenous
production.
At
the
20th
day
of
lactation
the
pentachlorobenzene
concentration
in
maternal
and
foetal
tissues
was
higher
than
that
of
lindane.

5.6
Determination
of
Susceptibility
No
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
to
in
utero
exposure
in
developmental
toxicitystudies.
Inthe
two
generation
reproductive
study,
there
was
qualitative
evidence
of
an
increased
susceptibility
to
exposure
to
lindane
by
pups.
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.

In
the
DNT
study,
there
is
supporting
evidence
of
a
qualitative
and
quantitative
increase
in
susceptibility.
At
the
high
dose
(13.
7
mg/
kg/
day)
,
animals
in
t
he
F0
generation
have
a
reduced
body
weight
and
body
weight
gain
while
at
the
mid­
dose
(5.6
mg/
kg/
day)
F1
and
F2
animals
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
open
literature
also
contains
citations
which
suggest
an
increase
in
susceptibility
of
fetuses
and
young
animals
to
exposure
to
lindane
(see
Section
5.
5).

6
HAZARD
CHARACTERIZATION
Lindane
is
a
moderately
toxic
compound
in
EPA
toxicity
class
II.
It
is
neither
an
eye
nor
dermal
sensitizer.
Labels
for
products
containing
it
must
bear
the
Signal
Word
WARNING.
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;
in
both
acute,
subchronic,
and
developmental
neurotoxicity
studies
and
chronic
toxicity/
oncogenicity
study,
Lindane
appears
to
cause
neurotoxic
effects
including
tremors,
convulsions
and
hypersensitivity
to
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,
2­
generation
reproduction
and
chronic
toxicity
studies
in
the
rat.

In
developmental
toxicity
studies,
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
maternal
toxicity
(10
29
mg/
kg/
day).
In
the
reproductive
toxicity
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
susceptibility
to
exposure.
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)
,
animals
in
the
F0
generation
have
a
reduced
body
weight
and
body
weight
gain
while
at
the
mid­
dose
(5.6
mg/
kg/
day)
F1
and
F2
animals
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.

According
to
the
TES
committee
report
(1994,
Doc
013460),
Lindane
has
not
been
classified
by
the
HED
Cancer
Peer
Review
Committee.
It
was
determined
by
the
RfD/
Peer
Review
Committee
(8/
25/
93)
that:
"The
mouse
carcinogenicity
data
were
considered
insufficient
because
of
major
deficiencies
associated
with
all
studies
available."
Lindane
however
had
been
previously
classified
by
the
Cancer
Assessment
Group
of
the
Office
of
Research
and
Development
(memorandum
dated
7/
23/
85
from
R.
E.
McGaughy
to
Anne
Barton)
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
.
Anew
mouse
oncogenicitystudyis
expected
in
December
2000.

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
also
states
that
Lindane
does
not
appear
to
have
mutagenic
potential.

7
DATA
GAPS
none
30
8
ACUTE
TOXICITY
STUDY
TYPE
MRID
CATEGORY
RESULT
81­
1
Acute
oral
00049330
II
LD50
88
mg/
kg
­
males
91
mg/
kg
­
females
81­
2
Acute
dermal
00109141
II
LD50
1000
mg/
kg
­
males
900
mg/
kg
­
females
81­
3
Acute
inhalation
Acc.
263946
III
LC50
1.56
mg/
L
both
sexes
81­
4
Eye
irritation
Acc.
263946
III
PIS
=
0.6
no
corneal
involvement
irritation
cleared
after
24
hours
81­
5
Dermal
irritation
Acc.
263946
IV
PIS
=
0
not
an
irritant
81­
6
Dermal
sensitization
Acc.
263946
NA
not
a
sensitizer
31
9
TOXICOLOGIC
PROFILE
EXPOSURE
SCENARIO
DOSE
(mg/
kg/
day)
ENDPOINT
STUDY
TYPE/
MRID
Acute
Dietary­
general
population
NOAEL=
6
mg/
kg
UF
=
100
LOAELis20
mg/
kgbased
on
increasedgrip
strength,
increased
Motor
Activity
Acute
Neurotoxicity
in
Rats/
44769201
Acute
Dietary­
females
13­
50
NOAEL=
N/
A
UF
=
N/
A
No
relevant
single
exposure
endpoint
was
identified.
N/
A
Acute
RfD
(Gen.
Pop.)
=
0.
06
mg/
kg/
day
Acute
RfD
(Females
13­
50)
=
N/
A
Chronic
Dietary
NOAEL=
10
ppm
(0.
47
mg/
kg/
day)

UF
=
100
LOAEL
is
100
ppm
(4.
81
mg/
kg/
day)
periacinar
hepatocyte
hypertrophy,
increased
liver/
spleen
weigt,
increased
platelets
Chronic
Feeding
and
Carcinogenicity
in
Rats
41094101
41853701
42891201
Chronic
RfD
=
0.
047
mg/
kg/
day
Cancer
Risk
3
Q1*=
1.1
(mg/
kg/
day)
­1
Short­
Term
1
(Dermal)
NOAEL=
10
ppm
(1.
2
mg/
kg/
day)
LOAEL
is
50
ppm
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.
Developmental
Neurotoxicity
Study
in
Rats
45073501
Intermediate­
Term
1
(Dermal)
NOAEL=
10
ppm
(1.
2
mg/
kg/
day)
LOAEL
is
50
ppm
based
on
reduced
pup
survival,
decreased
body
weights
and
body
weight
gains
during
lactation,
increased
motor
activity,
and
decreased
motor
activity
habituation.
Developmental
Neurotoxicity
Study
in
Rats
45073501
Long­
Term
1
(Dermal)
NOAEL=
10
ppm
(0.
47
mg/
kg/
day)
LOAEL
is
100
ppm
(4.
81
mg/
kg/
day)
periacinar
hepatocyte
hypertrophy,
increased
liver/
spleen
weigt,
increased
platelets
Chronic
Feeding
and
Carcinogenicityin
Rats
41094101
41853701
42891201
Dermal
Absorption
Factor
=
10%

Short
Term
1
(Inhalation)
0.5
mg/
m
3
(0.
13
mg/
kg/
day)
based
on
clinical
signs
(diarrhea,
piloerection)
seen
at
day
14
and
continuing
for
20
days
90­
Day
Inhalation
Toxicity
00255003
Intermediate
Term
1
(Inhalation)
0.5
mg/
m
3
(0.
13
mg/
kg/
day)
increased
kidney
weights
in
females
and
bone
marrow
effects
(incr.
reticul,
incr
myelo,
decr.
lympho.)
90­
Day
Inhalation
Toxicity
00255003
Long
Term
2
(Inhalation)
N/
A
N/
A
N/
A
1
An
MOE
of
100
was
selected
2
Exposure
thru
this
route
for
this
duration
is
not
expected
3
The
Cancer
Risk
will
be
re­
evaluated
upon
review
of
the
Mouse
Carcinogenicity
Study
submitted
in
December
2000
32