HED
DOC.
NO.
014272
August
2,
2000
MEMORANDUM
SUBJECT:
LINDANE
­
Report
of
the
FQPA
Safety
Factor
Committee
FROM:
Brenda
Tarplee,
Executive
Secretary
FQPA
Safety
Factor
Committee
Health
Effects
Division
(7509C)

THROUGH:
Ed
Zager,
Chairman
FQPA
Safety
Factor
Committee
Health
Effects
Division
(7509C)

TO:
Sue
Shallal,
Risk
Assessor
Reregistration
Branch
4
Health
Effects
Division
(7509C)

PC
Code:
009001
The
FQPA
Safety
Factor
Committee
met
on
July
24,
2000
to
evaluate
the
hazard
and
exposure
data
bases
for
lindane
and
concluded
that
the
FQPA
Safety
Factor
(as
required
by
Food
Quality
Protection
Act
of
August
3,
1996)
for
use
in
human
health
risk
assessment
be
reduced
to
3x.
2
I.
HAZARD
ASSESSMENT
(Memorandum:
S.
Shallal
to
M.
T.
Howard
dated
July
27,
2000)

A.
Adequacy
of
the
Toxicology
Database
There
are
two
developmental
studies
conducted
in
rats
and
rabbits
in
which
Lindane
is
administered
via
the
oral
and
subcutaneous
(4
studies
in
all).
Although
the
rabbit
studies
were
classified
as
unacceptable,
the
HIARC
concluded
that
a
new
developmental
toxicity
study
in
rabbits
is
not
required
(see
Section
I.
B.
below
or
refer
to
the
HIARC
document
for
details).
An
acceptable
2­
generation
reproductive
study
is
also
available,
as
well
as,
acute,
subchronic
and
developmental
neurotoxicity
studies.

B.
Determination
of
Susceptibility
The
data
provided
no
indication
of
quantitative
or
qualitative
increased
susceptibility/
sensitivity
in
rats
following
in
utero
exposure
to
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
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.

Although
the
developmental
toxicity
study
in
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
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.

There
was,
however,
evidence
of
qualitative
increased
susceptibility
in
the
rat
multigeneration
reproduction
study:
Both
parental
and
offspring
LOAELS
are
13
mg/
kg;
however
there
is
a
qualitative
difference
in
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
3
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
hazards
to
the
nervous
system
were
noted.

C.
Studies
from
the
Literature
The
open
literature
does
contain
citations
which
suggest
an
increase
in
susceptibility
of
fetuses
and
young
animals
exposed
to
lindane.
The
transfer
of
lindane
via
mother's
milk
also
seems
to
be
efficient,
as
well
as,
its
metabolism
into
pentachlorobenzene
(refer
to
the
HIARC
document
for
details).

II.
EXPOSURE
ASSESSMENTS
A.
Dietary
(Food)
Exposure
Considerations
(Correspondence:
T.
Morton
to
B.
Tarplee
dated
July
15,
2000)

The
registrant
is
supporting
the
use
of
lindane
on
barley,
broccoli,
brussels
sprouts,
cabbage,
cauliflower,
corn,
lettuce,
oats,
radish,
rye,
sorghum,
spinach,
and
wheat.
Only
seed
treatment
uses
remain
on
the
label.
Seed
treatment
application
rates
range
from
0.
33
to
3.57
oz.
a.
i./
cwt
of
seed.
For
comparison,
the
3.57
oz.
a.
i./
cwt
application
rate
is
equivalent
to
0.04
lb.
a.
i./
acre.
Since
the
only
supported
use
is
seed
treatment,
application
is
made
only
once
per
season.

Tolerances
are
currently
established
for
residues
of
the
insecticide
lindane
(gamma
isomer
of
benzene
hexachloride)
in
or
on
many
raw
agricultural
commodities
at
levels
ranging
from
0.01ppm
(pecans)
to
7ppm
(meat
fat).
Codex
MRLs
range
from
0.
01
ppm
in
milk
to
3
ppm
in
cranberry
and
strawberry.
Codex
MRLs
for
supported
crops
in
the
US
are
0.
5
ppm
for
brussels
sprouts,
cabbage,
cauliflower,
and
cereal
grains;
0.
1
ppm
for
eggs;
2
ppm
for
head
lettuce,
meat
of
cattle,
pigs,
and
sheep,
and
spinach;
and
1
ppm
for
radish.

The
MARC
has
determined
that
until
adequate
seed
treatment
metabolism
studies
are
submitted,
the
total
radioactive
residues
will
be
used
for
risk
assessment
purposes.
In
a
4
confined
rotational
crop
study,
radioactive
lindane
was
found
in
barley
forage
but
not
barley
grain.
It
was
also
found
in
carrot
tops
and
to
a
lesser
extent
in
mature
lettuce.

No
monitoring
data
is
available
which
would
definitively
include
lindane
only
from
seed
treatment
uses.
However,
it
may
be
possible
to
use
available
monitoring
data
for
foliar
uses
on
imported
commodities.
Field
trials
were
conducted
on
wheat,
feeding
studies
on
ruminant
and
poultry,
but
will
not
be
used
since
the
MARC
has
concluded
that
the
total
radioactive
residues
must
be
used
for
risk
assessment
purposes.

In
1998,
BEAD
provided
percent
crop
treated
data
for
small
grains
(7
%
crop
treated),
field
corn
(6
%
crop
treated),
and
sorghum
(10
%
crop
treated).
HED
has
asked
BEAD
to
supply
current
%
crop
treated
data
for
the
above
crops
and
any
other
of
the
supported
crops.

The
Dietary
Exposure
Evaluation
Model
(DEEM)
is
used
to
estimate
the
dietary
risk
resulting
from
the
residues
of
lindane
on
foods.
The
DEEM
analyses
are
refined
using
the
available
%CT
data.

B.
Dietary
(Drinking
Water)
Exposure
Considerations
(Correspondence:
D.
Young
to
B.
Tarplee,
dated
July
10,
2000.)

The
environmental
fate
database
for
lindane
is
adequate
to
characterize
the
potential
for
contamination
of
drinking
water
sources.
These
data
indicate
that
parent
lindane
is
persistent
and
moderately
mobile.
It
is
transported
through
the
environment
by
both
hydrologic
and
atmospheric
means.
It
is
resistant
to
photolysis
and
hydrolysis
(except
at
high
pH),
and
degrades
very
slowly
by
microbial
actions
(980
day
soil
half
life).

Degradates
are
predominantly
benzene
hexachloride,
pentachlorocyclohexane,
1,2,4,trichlorobenzene
and
1,
2,
3­
trichlorobenzene.
In
submitted
studies,
degradates
were
observed
at
much
less
than
10%
of
applied.

Currently,
U.
S.
agricultural
uses
of
lindane
are
restricted
to
seed
treatments,
and
application
rates
are
quite
low.
Even
under
these
restriction,
however,
lindane
may
reach
water
resources
at
levels
above
the
Maximum
Concentration
Level
(MCL
=
0.
2
µg/
L).
Monitoring
data
are
available
which
demonstrate
the
presence
of
lindane
in
the
environment:

In
the
U.
S.
EPA
STORET
data
base,
720
detections
(after
culling
of
data
to
eliminate
dubious
data,
e.
g.
K
and
U
codes)
in
ground
water
were
reported
between
the
years
1968
and
1995,
in
nearly
all
regions
of
the
country,
with
especially
high
numbers
of
detections
in
the
South
and
West.
For
these
720
detections,
the
median
and
mean
concentrations
were
0.01
and
11
µg/
L,
respectively.
For
surface
waters,
8775
detections
were
reported
with
median
and
mean
concentrations
of
0.
005
and
0.
18
µg/
L.
STORET
Detections
were
reported
in
nearly
all
regions
of
the
conterminous
U.
S.

In
the
USGS
NAWQA
study,
lindane
was
detected
in
2.
58%
of
surface
water
samples
5
(0.
67%
at
levels
greater
than
0.
05
mg/
L,
maximum
concentration
reported
was
0.
13
mg/
L).
For
groundwater,
USGS
NAWQA
reported
a
detection
frequency
of
0.
1
%
(0.
07%
at
levels
greater
than
0.
01
mg/
L,
maximum
concentration
reported
was
0.
032
mg/
L).

Since
all
monitoring
data
represent
detections
resulting
from
all
previous
uses
of
lindane
(including
foliar
uses
which
are
currently
not
supported
by
the
registrant),
models
were
used
to
calculate
the
estimated
environmental
concentrations
(EECs):
GENEEC
model
for
surface
water;
and
SCI­
GROWfor
ground
water.

Due
to
the
persistence
of
lindane,
its
past
wide­
spread
use,
and
its
mobility
by
both
atmospheric
at
hydrologic
means,
the
extent
of
population
exposed
could
be
high
in
comparison
to
other
chemicals.

C.
Residential
Exposure
Considerations
(Telephone
communication:
D.
Jaquith
on
July
19,
2000)

Only
seed
treatment
uses
remain
on
the
label
for
lindane.
There
are
no
registered
residential
uses
and
therefore,
residential
exposure
to
lindane
is
not
expected.

III.
SAFETY
FACTOR
RECOMMENDATION,
RATIONALE,
AND
APPLICATION
A.
Recommendation
of
the
Factor
The
Committee
recommended
that
the
FQPA
safety
factor
for
protection
of
infants
and
children
(as
required
by
FQPA)
should
be
reduced
to
3x
for
lindane.

B.
Rationale
for
the
Selection
of
the
FQPA
Safety
Factor
The
FQPA
SFC
concluded
that
a
safety
factor
is
required
for
lindane
since
there
is
evidence
of
increased
susceptibility
of
the
young
demonstrated
in
both
the
developmental
neurotoxicity
study
(quantitative)
and
the
2­
generation
reproduction
study
in
rats
(qualitative).

The
Committee
recommended
that
the
FQPA
safety
factor
be
reduced
to
3x
because:
1)
the
toxicology
data
base
is
complete;
2)
the
available
data
provide
no
indication
of
quantitative
or
qualitative
increased
susceptibility
in
rats
from
in
utero
exposure
to
lindane
in
the
prenatal
developmental
study;
3)
although
the
developmental
toxicity
study
in
rabbits
was
classified
unacceptable,
the
HIARC
concluded
that
a
new
study
is
not
required
(See
Section
I.
B.);
4)
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
hazards
to
the
nervous
system
were
noted);
and
5)
adequate
actual
data,
surrogate
data,
and/
or
modeling
outputs
are
available
to
satisfactorily
assess
food
exposure
and
to
provide
a
screening
level
drinking
water
exposure
assessment;
and
6
6)
there
are
currently
no
residential
uses.

C.
Application
of
the
Safety
Factor
­
Population
Subgroups/
Risk
Assessment
Scenarios
The
FQPA
safety
factor
for
lindane
is
applicable
to
All
Population
Subgroups
for
Acute
and
Chronic
Dietary
Risk
Assessments
(there
are
currently
no
residential
scenarios),
since
there
is
concern
for
increased
susceptibility
of
the
young
demonstrated
in
the
developmental
neurotoxicity
study
and
in
the
2­
generation
reproduction
study.
