Page
1
of
19
DATE:
April
1,
2004
MEMORANDUM
SUBJECT:
ZINC
PYRITHIONE
(
ZINC
OMADINE
®
)
­
REVISED
Toxicology
Endpoint
Selection
Report
 
Revised
to
address
Registrant
Error
comments
FROM:
Timothy
F.
McMahon,
Ph.
D.
Senior
Toxicologist
Antimicrobials
Division
(
7510C)

THROUGH:
John
Redden,
Roger
Gardner,
Ph.
D.,
Stephen
Dapson,
Ph.
D.,
Karen
Hamernik,
Ph.
D.,
Melba
Morrow,
D.
V.
M.,
Sanyvette
Williams­
Foy,
D.
V.
M,
Jonathan
Chen,
Ph.
D.;
Michelle
Centra;
Najm
Shamim,
Ph.
D.;
Timothy
Leighton.

PC
Code:
088002
On
February
4,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicology
data
base
of
zinc
pyrithione
(
zinc
omadine
®
)
,
established
acute
and
chronic
Reference
Doses
(
RfD)
and
selected
the
toxicological
endpoints
for
acute
dietary
as
well
as
occupational
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
increased
susceptibility
of
infants
and
children
from
exposure
to
zinc
pyrithione
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

On
September
3rd
and
September
30th,
2003,
the
Antimicrobials
Division's
Toxicology
Endpoint
Selection
Committee
(
ADTC)
met
to
discuss
scientific
issues
with
respect
to
the
endpoints
previously
selected
for
zinc
pyrithione.
Specifically,
discussions
were
held
to
determine
the
suitability
of
bridging
the
toxicology
data
for
sodium
pyrithione
to
be
applicable
to
zinc
pyrithione
risk
assessments,
the
determination
of
the
need
for
a
developmental
neurotoxicity
study
for
zinc
Page
2
of
19
pyrithione,
the
use
of
a
maternal
endpoint
for
selection
of
the
chronic
Reference
Dose
value
for
zinc
pyrithione,
and
the
magnitude
of
the
special
hazard­
based
FQPA
factor
and
database
uncertainty
factor
for
zinc
pyrithione
.
The
results
of
the
ADTC's
discussions
are
included
in
this
memorandum
and
this
memorandum
reflects
the
latest
conclusions
regarding
endpoint
selection
for
zinc
pyrithione,
thus
superceding
the
previous
HIARC
memo
(
HED
document
number
013318).

1999
HIARC
Committee
Members
in
Attendance
Members
present
were:
David
Anderson,
Bill
Burnam,
Virginia
Dobozy,
Pam
Hurley,
Mike
Ioannou,
Tina
Levine,
Sue
Makris,
Nicole
Paquette,
Kathleen
Raffaele,
Jess
Rowland,
PV
Shah,
and
Brenda
Tarplee
(
executive
secretary).
Data
was
presented
by
Tim
McMahon
of
the
Risk
Assessment
and
Science
Support
Branch,
Antimicrobials
Division.

2003
ADTC
Committee
Members
in
Attendance
John
Redden,
Roger
Gardner,
Ph.
D.,
Stephen
Dapson,
Ph.
D.,
Sanyvette
Williams­
Foy,
D.
V.
M,
Jonathan
Chen,
Ph.
D.,
Timothy
F.
McMahon,
Ph.
D;
Najm
Shamim,
Ph.
D.;
Timothy
Leighton.

Member(
s)
in
absentia:
Karen
Hamernik,
Melba
Morrow
(
provided
comments
via
email)
Michelle
Centra
(
provided
comments
via
email)

Other
Attendees:
Debbie
Smegal,
Bill
Burnam
Data
evaluation
prepared
by:
Timothy
F.
McMahon,
Ph.
D.
Page
3
of
19
COMMITTEE
MEMBERS
(
Signature
indicates
concurrence
unless
otherwise
stated)

Stephen
Dapson
Jonathan
Chen
Roger
Gardner
Karen
Hamernik
Tim
McMahon
(
chair)

Melba
Morrow
John
Redden
Sanyvette
Williams­
Foy
Tim
Leighton
_______________________

Michelle
Centra
_______________________

Najm
Shamim
______________________

OTHER
ATTENDEES:

William
Burnam
_________________

Deborah
Smegal
_____________________
Page
4
of
19
I.
INTRODUCTION
On
February
4,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicology
data
base
of
zinc
pyrithione,
established
a
Reference
Dose
(
RfD)
and
selected
the
toxicological
endpoints
for
acute
dietary
as
well
as
occupational
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
increased
susceptibility
of
infants
and
children
from
exposure
to
zinc
pyrithione
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
A
report
was
issued
by
the
HIARC
on
March
19,
1999
for
zinc
pyrithione.

In
the
1999
report,
the
following
recommendations
were
made
as
listed
below:

1)
The
committee
recommended
retaining
the
special
hazard­
based
FQPA
safety
factor
(
10x),
based
on
qualitative
evidence
of
increased
susceptibility
in
the
rat
and
rabbit
prenatal
developmental
toxicity
studies.

Since
that
time,
updated
guidance
on
interpretation
of
the
FQPA
safety
factor
(
http://
www.
epa.
gov/
oppfead1/
trac/
science/
determ.
pdf
)
has
been
published
which
necessitated
re­
consideration
of
this
safety
factor
for
zinc
pyrithione.

2)
The
1999
HIARC
report
recommended
the
conduct
of
a
developmental
neurotoxicity
study
for
zinc
pyrithione,
based
on
evidence
of
significant
nervous
system
deficits
following
either
acute
or
subchronic
oral
administration
of
zinc
pyrithione.
For
example,
intravenous
administration
of
5
mg/
kg
zinc
pyrithione
to
female
Yorkshire
pigs
produced
cholinergic
effects
lasting
for
30­
60
minutes
post­
dose
(
HED
document
003933).
Increased
salivation
was
reported
immediately
after
dosing
in
the
rat
developmental
toxicity
study
at
a
dose
of
3
mg/
kg/
day
(
MRID
#
42827904).
Subchronic
administration
of
zinc
pyrithione
at
3.75
mg/
kg/
day
has
been
shown
to
produce
hindlimb
weakness
(
HED
document
no.
003933).
Peripheral
neuropathy
in
the
form
of
axonal
degeneration
has
been
observed.

The
issue
of
the
requirement
for
a
developmental
neurotoxicity
study
was
re­
considered
by
the
ADTC.

In
addition
to
the
above,
two
other
issues
were
raised
from
the
Risk
Assessment
Oversight
Review
committee's
(
RAOC)
review
of
the
draft
risk
assessment
for
zinc
pyrithione
as
listed
below:

1)
Selection
of
the
chronic
dietary
endpoint
for
zinc
pyrithione.
It
was
stated
in
the
RAOC
memo
that
a
maternal
effect
should
not
be
used
for
chronic
risk
2)
Whether
the
toxicology
database
for
sodium
pyrithione
can
be
used
in
risk
assessments
for
zinc
pyrithione.
The
toxicology
database
for
zinc
pyrithione
is
missing
a
two­
generation
reproduction
toxicity
study,
which
is
required
for
the
food
contact
uses
of
zinc
pyrithione.
However,
a
reproduction
study
exists
for
sodium
pyrithione.
Page
5
of
19
The
ADTC's
discussion
of
these
issues
and
the
conclusions
reached
are
summarized
below
as
part
of
the
updated
toxicology
endpoint
selection
document.

II.
HAZARD
IDENTIFICATION
A.
ACUTE
DIETARY
(
Acute
Reference
Dose)

A.
1.
Acute
RfD
Subpopulation:
Females
13+

Study
Selected:
Developmental
Toxicity
­
Rabbit
§
83­
3a
MRID
No.:
42827905
Executive
Summary:
In
a
developmental
toxicity
study
in
rabbits
(
MRID
#
42827905),
inseminated
New
Zealand
White
rabbits,
randomly
assigned
to
one
control
and
three
treatment
groups
of
20
animals
each,
were
administered
zinc
pyrithione
48%
Aqueous
Dispersion
by
oral
gavage
at
doses
of
0,
0.5,
1.5,
or
3.0
mg/
kg/
day
on
gestation
days
(
GD)
6
­
18.
Cesarean
section
examinations
were
performed
on
all
surviving
does
on
GD
29,
followed
by
an
examination
of
all
fetuses.
One
mid­
dose
doe
died
on
GD
16,
probably
due
to
a
gavage
error.
A
decrease
in
body
weight
gain
(
p
0.01)
during
the
dosing
period
for
the
mid
and
high­
dose
groups
(
41%
and
99%,
respectively)
cannot
be
considered
biologically
significant
since
the
absolute
body
weight
changes
were
only
­
4%
and
­
6%,
respectively.
There
was
no
dose­
related
effect
on
food
consumption.
The
does'
body
weights
rebounded
after
the
dosing
interval.
There
were
no
compound­
related
gross
lesions.
One
high­
dose
doe
aborted
on
GD
27,
and
five
others
had
total
resorptions.
One
mid­
dose
doe
had
total
litter
resorption.
Dose­
related
early
resorptions
were
seen
in
the
mid
and
high­
dose
does.
These
findings
corresponded
with
a
dose­
related
increase
in
postimplantation
loss(
early
resorption)
and
a
decrease
in
viable
fetuses.
It
is
not
clear
whether
the
resorptions
were
due
to
maternal
or
developmental
toxicity.
No
statistically
significant
differences
were
seen
in
the
incidence
of
external,
visceral,
or
skeletal
anomalies
in
the
treated
groups
as
compared
to
controls.
Three
fetuses
from
two
high­
dose
litters
contained
multiple
cephalic
and
limb
malformations.
The
Maternal/
Developmental
NOAEL
is
0.5
mg/
kg/
day.
The
LOAEL
is
1.5
mg/
kg/
day,
based
on
increased
postimplantation
loss
and
decreased
number
of
viable
fetuses
(
it
is
not
clear
whether
the
resorptions
were
due
to
maternal
or
developmental
toxicity).

Dose
Selected
for
Risk
Assessment:
NOAEL=
0.5
mg/
kg/
day
based
on
increased
postimplantation
loss
and
decreased
viable
fetuses
at
1.5
mg/
kg/
day
(
LOAEL).

Uncertainty
Factors:
300
(
10
x
for
inter­
species
variation
and
10x
for
intra­
species
extrapolation;
3x
database
UF
for
lack
of
neurotoxicity
studies)

Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
endpoint
of
concern
(
increased
post­
implantation
loss
and
decreased
viable
fetuses)
is
an
in
utero
effect,
and
therefore
is
applicable
only
to
this
subpopulation
(
Females
13+).
Also,
these
developmental
effects
are
Page
6
of
19
presumed
to
occur
after
a
single
exposure
(
dose),
thus
are
applicable
for
this
exposure
period
of
concern.
The
additional
database
UF
of
3x
was
applied
based
on
lack
of
acute
and
subchronic
neurotoxicity
studies
determined
to
be
necessary
by
the
ADTC
for
proper
dose­
response
characterization
for
neurotoxic
effects
of
zinc
pyrithione.

Acute
RfD
(
aPAD)
(
Females
13+)
=
0.5
mg/
kg/
day
(
NOAEL)
=
0.0016
mg/
kg
300
(
UF)

This
risk
assessment
is
required.

A.
2.
Acute
RfD
Subpopulation:
General
Population
including
Infants
and
children
Study
Selected
:
Developmental
Toxicity
­
Rat
Guideline
#:
§
83­
3
MRID
No.:
42827905
Executive
Summary:
In
a
developmental
study
(
MRID
42827904),
thirty
pregnant
Sprague­
Dawley
rats
per
group
were
administered
Zinc
Pyrithione
by
oral
gavage
on
days
6­
15
of
gestation
at
doses
of
0,
0.75,
3,
or
15
mg/
kg/
day.
One
dam
in
the
15
mg/
kg/
day
dose
group
died
on
gestation
day
16
of
unspecified
causes.
No
maternal
or
developmental
toxicity
was
observed
at
0.75
mg/
kg/
day.
The
most
sensitive
indicator
of
maternal
toxicity
was
increased
salivation
immediately
after
dosing
which
was
observed
in
the
3
and
15
mg/
kg/
day
groups
(
27%
and
97%
of
dams,
respectively).
Other
dose­
related
signs
seen
at
15
mg/
kg/
day
included
biologically
significant
decreases
in
body
weight
gains
(
67%;
p
0.01;
absolutes
of
4­
12%)
and
food
consumption
(
24%
during
dosing,
16%
throughout
gestation;
p
0.01),
and
dilated
pupils
(
57%).
The
maternal
toxicity
NOEL
is
0.75
mg/
kg/
day,
and
the
maternal
toxicity
LOAEL
is
3.0
mg/
kg/
day,
based
upon
excessive
salivation
during
the
dosing
period.

Developmental
toxicity
was
characterized
by
a
dose
related
increase
in
post­
implantation
loss
at
the
mid
and
high
doses
with
the
15
mg/
kg/
day
group
being
significantly
different
than
controls
(
p
<
0.01).
This
correlated
with
an
increase
in
early
resorptions
(
3.6%/
dam)
with
whole
litter
resorption
occurring
in
3
high
dose
dams.
There
was
also
a
significant
reduction
(
p
<
0.05)
in
the
number
of
live
fetuses
per
litter
(
12.5/
litter
compared
to
14.5/
litter
in
the
controls),
mean
fetal
weights
(
16%),
and
gravid
uterine
weights
(
16%;
p
0.01)
in
the
15
mg/
kg/
day
group
as
compared
to
controls.
A
significantly
greater
number
of
litters
in
the
15
mg/
kg/
day
group
contained
fetuses
with
external,
visceral,
or
skeletal
malformations/
variations.
The
most
common
were
digit
anomalies
(
5
of
24
treated
litters
vs.
0
of
27
control
litters;
p
0.05),
dilated
renal
pelvis
(
7
of
24
treated
litters
vs.
1
of
27
control
litters;
p
0.05)
which
is
considered
indicative
of
hydronephrosis,
and
a
vertebral/
rib
anomaly
(
24
of
24
treated
litters
vs.
0
of
27
control
litters;
p
<
0.01).
Others
included
sternal,
rib,
and
limb
(
radius
or
ulna
absent)
malformations.
Dose­
related
fused
ribs
were
observed
in
the
mid
and
high­
dose
groups
(
3
fetuses/
2
litters,
and
5
fetuses/
4
litters,
respectively).
Although
pairwise
comparisons,
on
the
basis
of
litters,
were
not
statistically
significant
(
p=
0.226
and
p=
0.060
for
the
mid
and
high­
dose
groups,
respectively),
a
statistically
significant
linear
trend
was
evident
(
Cochran­
Armitage
test;
p=
0.009),
and
historical
control
values
were
exceeded.
The
developmental
toxicity
NOEL
is
Page
7
of
19
0.75mg/
kg/
day,
and
the
developmental
toxicity
LOAEL
is
3.0
mg/
kg/
day,
based
upon
increased
incidences
of
fused
ribs.

Dose
Selected
for
Risk
Assessment:
NOAEL=
0.75
mg/
kg/
day
based
on
salivation
in
dams
at
3.0
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor:
300
(
10
x
for
inter­
species
variation
and
10x
for
intra­
species
extrapolation;
3x
for
database
uncertainty)

Acute
RfD
(
aPAD
gen.
pop.)
=
0.75
mg/
kg/
day
(
NOAEL)
=
0.0025
mg/
kg
300
(
UF)

Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
endpoint
(
salivation)
was
seen
in
maternal
animals
during
the
dosing
period,
and
is
thus
relevant
for
this
subpopulation
and
exposure
period
of
concern.
In
addition,
the
ADTC
expressed
concern
that,
although
the
chemical
may
have
been
irritating,
that
it
may
also
be
reflective
of
a
neurotoxic
effect.

B.
CHRONIC
DIETARY
(
Chronic
Reference
Dose)

Type
of
Study:
Developmental
Toxicity
­
Rabbits
Guideline
#:
§
83­
3
MRID
No.:
42827905
Executive
Summary:
See
Acute
Dietary
Females
13+.

Uncertainty
Factor:
300
(
10
x
for
inter­
species
variation,
10x
for
intra­
species
extrapolation
and
3x
for
database
uncertainty).

Chronic
RfD
=
0.5
mg/
kg/
day
(
NOAEL)
=
0.0016
mg/
kg/
day
300
(
UF)

Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
ADTC
concluded
that
a
chronic
toxicity
study
is
not
required
for
the
indirect
food
use
of
zinc
pyrithione,
based
upon
the
Tier
I
data
requirements
for
indirect
food
uses
for
antimicrobial
pesticides
that
do
not
require
such
studies.
Therefore,
use
of
the
rabbit
developmental
toxicity
study
is
conservative
by
nature
since,
of
the
data
available
for
zinc
pyrithione,
this
study
showed
the
lowest
NOAEL
value.
As
support,
the
committee
also
noted
the
available
chronic
toxicity
study
for
for
sodium
pyrithione
(
MRID
42100901)
with
a
NOAEL
of
0.5
mg/
kg/
day.
Page
8
of
19
C.
OCCUPATIONAL
/
RESIDENTIAL
EXPOSURE
1.
DERMAL
ABSORPTION
Study
Selected:
Dermal
Absorption
­
Domestic
Swine
Guideline
#:
§
85­
2
MRID
No.:
HED
document
no.
003933
Executive
Summary:
Twenty­
six
mature
Yorkshire
pigs
were
used
in
this
study.
Radiolabeled
zinc
pyrithione
was
applied
for
8
hours
either
as
a
single
dose
(
50,100,
and
400
mg/
kg)
or
as
a
5
day
repeated
dose
(
100
mg/
kg).
Serial
samples
of
blood,
urine,
and
feces
were
taken
after
dosing.
Radioassay
of
necropsy
material,
urine,
blood,
and
feces
showed
recovery
of
86.8­
98.2%
of
applied
radioactivity.
Greater
than
90%
of
recovery
was
obtained
from
washings
of
the
application
site.
Urinary
excretion
was
3%
in
animals
with
intact
skin.
Levels
of
radioactivity
in
blood,
urine,
and
feces
returned
to
background
by
48
hours
post­
application.

Dermal
Absorption
Factor:
3%

Comments
about
Dermal
Absorption
Factor:
A
dermal
absorption
factor
is
not
required
since
a
dermal
NOAEL
was
selected
for
dermal
risk
assessments.
However,
it
is
noted
that
the
3%
dermal
absorption
factor
demonstrated
in
the
swine
study
is
supported
by
a
literature
study
in
mice
(
1975;
HED
Doc.
No.
003933)
which
also
showed
a
dermal
absorption
of
3%.
Additionally,
low
dermal
absorption
is
indicated
by
the
lack
of
systemic
toxicity
in
male
rats
following
repeated
dermal
applications
at
the
Limit
Dose
(
1000
mg/
kg/
day)
for
90­
days
in
a
dermal
toxicity
study.

2.
SHORT­
TERM
DERMAL
(
1
­
7
days)

Study
Selected:
90­
Day
Dermal
Toxicity
­
Rats
Guideline#:
§
82­
3
MRID
No.:
42827902
Executive
Summary:
In
a
subchronic
dermal
toxicity
study
(
MRID
#
42827902),
male
and
female
CrlCD
BR
rats
were
treated
with
Zinc
pyrithione
FPS
by
dermal
occlusion
at
doses
of
0,
20,
100,
and
1000
mg/
kg/
day
for
6hours/
day,
5
days/
week
for
13
weeks.
Treatment­
related
effects
included
decreased
food
consumption
(
91.6%
of
control),
decreased
body
weight
gain
(
48.9%
of
control),
and
decreased
food
efficiency
(
53.8%
of
control)
over
the
entire
treatment
period
for
females
in
the
1000mg/
kg/
day
dose
group.
Group
mean
body
weights
for
females
(
1000
mg/
kg/
day)
were
decreased
13%
to
21%
relative
to
controls
for
weeks
2­
13.
The
systemic
NOAEL
=
100
mg/
kg/
day
in
females,
and
1000
mg/
kg/
day
in
males.
The
systemic
LOAEL
=
1000
mg/
kg/
day
in
females
(
decreased
body
weight
gain,
food
consumption,
and
food
efficiency),
and
>
1000
mg/
kg/
day
in
males
.
Page
9
of
19
Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
route
(
dermal)
and
exposure
period
(
1­
7
days)
of
concerns
since
the
route
o
treatment
(
dermal)
in
animals
simulates
real
life
occupational
exposure
(
dermal)
scenarios.

This
risk
assessment
is
required.

3.
INTERMEDIATE­
TERM
DERMAL
(
1­
Week
to
Several
Months)

Study
Selected:
90­
Day
Dermal
Toxicity
­
Rats
Guideline#:
§
82­
3
MRID
No.:
42827902
Executive
Summary:
See
Short­
Term
Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
route
(
dermal)
and
exposure
period
(
7­
90
days)
of
concerns
since
the
route
o
treatment
(
dermal)
in
animals
simulates
real
life
occupational
exposure
(
dermal)
scenarios.

This
risk
assessment
is
required.

4.
LONG­
TERM
DERMAL
(
Several
Months
to
Lifetime)

Study
Selected:
90­
Day
Dermal
Toxicity
­
Rats
Guideline#:
§
82­
3
MRID
No.:
42827902
Executive
Summary:
See
Short­
Term
Comments
about
Study/
Endpoint:
The
90­
day
dermal
study
was
deemed
to
be
appropriate
since
following
repeated
dermal
dosing,
there
was
no
systemic
toxicity
in
males
at
the
Limit­
Dose
and
in
females
toxicity
at
this
dose
was
limited
decreased
body
weight
gain
and
food
consumption.

5.
INHALATION
(
ANY­
TIME
PERIOD).

Study
Selected:
Subchronic
Inhalation
­
Rats
Guideline
#:
§
82­
4
MRID
No.:
42827903
Executive
Summary:
Groups
of
15
male
and
15
female
Sprague­
Dawley
rats
were
dynamically
exposed
in
whole­
body
exposure
chambers
to
zinc
pyrithione
aerosols
at
concentrations
of
0.0005,
0.0025,
or
0.01
mg/
L/
day
for
6
hours/
day,
5
days/
week
for
13
weeks.
One
male
and
1
female
exposed
to
0.0025
mg/
L/
day
and
3
males
and
4
females
exposed
to
0.01
mg/
L/
day
died
over
the
course
of
the
study.
Treatment­
related
clinical
signs
of
toxicity
included
rales,
labored
breathing,
and
gasping
in
animals
that
died
on
study.
At
0.01
mg/
L/
day,
body
weights
of
females
were
depressed
as
much
as
23%,
compared
to
controls,
total
food
consumption
Page
10
of
19
was
decreased
10%,
and
food
efficiency
was
decreased
53%.
Hematologic,
clinical
chemistry,
or
urinalysis
effects
were
not
considered
biologically
significant
for
any
of
the
exposure
groups,
and
ophthalmologic
examinations
and
gross
necropsy
findings
were
negative.
Biologically
significant
increases
in
absolute
and
(
relative)
lung
weights
of
+
20%
(+
34%)
and
+
22%
(+
38%)
in
males,
and
+
13%
(+
18%)
and
+
25%
(+
68%)
in
females
were
seen
at
concentrations
of
0.0025
and
0.01
mg/
L/
day,
respectively.
The
increased
lung
weights
corresponded
to
histopathologic
findings
of
trace
to
mild
subacute
inflammation
of
the
interstitial
tissue
of
the
lung
and
medial
hypertrophy
of
pulmonary
arteries
which
were
biologically
significant
at
0.01
mg/
L/
day.
NOAEL
=
0.0005
mg/
L/
day.
LOAEL
=
0.0025
mg/
L/
day
(
labored
breathing,
rales,
increased
salivation,
decreased
activity,
dry
red­
brown
material
around
the
nose,
increased
absolute
and
relative
lung
weights,
and
death
of
undetermined
cause).

Comments
about
Study/
Endpoint:
The
selected
endpoint
will
be
used
for
short,
intermediate
and
long­
term
exposure
risk
assessments.

D.
Recommendation
of
Margins
of
Exposure
A
MOE
of
100
is
adequate
for
occupational
exposure
risk
assessments.
A
MOE
of
300
is
considered
adequate
for
residential
exposures
to
zinc
pyrithione.

E.
Aggregate
Exposure
Risk
Assessments
(
Food+
water+
Residential
exposures)

For
acute
aggregate
exposure
risk
assessment,
combine
the
high
end
exposure
values
from
food
+
water
and
compare
it
to
the
acute
RfD
for
Females
13+
and
the
acute
RfD
for
the
General
Population
including
Infants
and
Children.

For
Short,
intermediate
and
long­
term
aggregate
exposure
risk
assessment,
the
oral,
dermal
and
inhalation
MOEs
cannot
be
combined
due
to
different
toxicological
endpoints
for
oral
(
developmental),
dermal
(
decreased
body
weight
gain
and
food
consumption)
and
inhalation
(
clinical
signs)
routes.

IV.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
No
chronic
toxicity
or
carcinogenicity
studies
are
available
to
assess
the
carcinogenic
potential
of
zinc
pyrithione.
Two
studies
are
available
for
sodium
pyrithione.
The
first
study
(
MRID
42100901)
showed
no
evidence
of
carcinogenicity
when
administered
to
Sprague­
Dawley
rats
by
oral
gavage
for
2
years
at
doses
of
0,
0.5,
1.5,
and
5.0
mg/
kg/
day.
The
second
study
(
MRID
42100801)
showed
no
evidence
of
carcinogenicity
when
sodium
pyrithione
was
administered
dermally
to
CD­
1
mice
at
doses
of
0,
5,
15,
and
40
mg/
kg/
day
for
18
months.
As
noted
in
the
sodium
pyrithione
RED,
sodium
pyrithione
is
classified
as
Group
"
D"
(
insufficient
evidence
to
Page
11
of
19
classify).
Page
12
of
19
V.
MUTAGENICITY
I.
Salmonella
typhimurium
Assay
In
a
mutagenicity
study
(
MRID
#
41906502),
doses
of
zinc
omadine
(
48%
aqueous
dispersion)
ranging
from
0.03­
5.0
g/
plate
under
non­
activated
conditions
and
10­
333
g/
plate
under
S­
9
activated
conditions
were
evaluated
for
the
potential
to
induce
reverse
gene
mutations
in
five
tester
strains
of
Salmonella
typhimurium
(
TA98,
TA100,
TA1535,
TA1537,
TA1538).
Cytotoxicity
was
observed
in
this
assay
at
3.3
g/
plate
and
above
under
non­
activated
conditions,
and
at
333
g./
plate
and
above
under
activated
conditions.
There
was
no
reproducible
evidence
of
a
mutagenic
effect
in
either
the
absence
or
presence
of
metabolic
activation
in
this
study.

ii.
Gene
Mutation
in
Cultured
Chinese
Hamster
Ovary
Cells
In
a
mutagenicity
study
using
Chinese
Hamster
Ovary
(
CHO)
cells
(
MRID
#
41906503)
assays
were
conducted
in
the
absence
of
metabolic
activation
(
doses
of
0.25­
2.0
g/
ml)
and
the
presence
of
metabolic
activation
(
2.5­
30
g/
ml).
In
this
study,
zinc
pyrithione
failed
to
induce
a
mutagenic
response.

iii.
In
vivo
Micronucleus
Assay
in
Mice
In
this
study
(
MRID
#
41906501),
intraperitoneal
injection
of
single
doses
of
11,
22,
or
44
mg/
kg
zinc
pyrithione
(
48%
aqueous
dispersion)
to
ICR
mice
did
not
cause
a
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
(
MPEs)
in
bone
marrow
cells
harvested
24,
48,
or
72
hours
post­
dose.
High
dose
mice
exhibited
signs
of
toxicity
(
including
mortality,
lethargy,
piloerection,
and
diarrhea)
but
there
was
no
evidence
of
a
cytotoxic
effect
on
the
target
organ.
Therefore,
zinc
pyrithione
is
concluded
to
be
negative
for
mutagenicity
in
this
test
system.

VI.
FQPA
CONSIDERATIONS
1.
Adequacy
of
the
Data
Base
The
toxicology
data
base
is
not
complete
with
respect
to
assessing
adequate
to
assess
the
increased
susceptibility
to
infants
and
children
as
required
by
FQPA.
Acceptable
developmental
toxicity
studies
in
the
rat
and
rabbit
are
available
as
well
as
reproduction
toxicity
data
in
the
rat
for
sodium
pyrithione,
however,
a
datagap
exists
for
acute
and
subchronic
neurotoxicity
of
zinc
pyrithione.

2.
Neurotoxicity
Data
There
are
currently
no
guideline
neurotoxicity
studies
for
zinc
pyrithione.
The
existing
database,
however,
shows
significant
nervous
system
deficits
following
either
acute
or
Page
13
of
19
subchronic
oral
administration
of
zinc
pyrithione.
For
example,
intravenous
administration
of
5
mg/
kg
zinc
pyrithione
to
female
Yorkshire
pigs
produced
cholinergic
effects
lasting
for
30­
60
minutes
post­
dose
(
HED
document
003933).
Increased
salivation
was
reported
immediately
after
dosing
in
the
rat
developmental
toxicity
study
at
a
dose
of
3
mg/
kg/
day
(
MRID
#
42827904).
Subchronic
administration
of
zinc
pyrithione
at
3.75
mg/
kg/
day
has
been
shown
to
produce
hindlimb
weakness
(
HED
document
no.
003933).
Peripheral
neuropathy
in
the
form
of
axonal
degeneration
has
been
observed.

3.
Developmental
&
Reproductive
Toxicity
(
I)
Developmental
Toxicity:

Executive
summaries
for
the
prenatal
developmental
studies
are
provided
under
acute
RfD
(
Rat)
and
chronic
RfD
(
rabbit).
These
studies
showed
no
quantitative
evidence
of
increased
susceptibility
(
i.
e.,
maternal
and
developmental
NOAELs/
LOAELs
were
the
same).
There
was,
however,
qualitative
evidence
of
increased
susceptibility
(
i.
e.,
fetal
effects
were
considered
to
be
severe
in
the
presence
of
minimal
maternal
toxicity).

(
ii)
Reproductive
Toxicity:

A
two­
generation
reproduction
study
in
rats
is
available
for
sodium
pyrithione
to
assess
the
reproductive
toxic
potential
of
zinc
pyrithione.

4.
Determination
of
Susceptibility
Qualitative
evidence
of
increased
susceptibility
was
demonstrated
both
in
the
rat
and
rabbit
prenatal
developmental
toxicity
studies.
In
rats,
fetal
effects
were
manifested
as
increased
incidence
of
fused
ribs
at
the
same
dose
that
caused
only
minimal
maternal
toxicity
characterized
as
salivation.
In
the
rabbit
study,
fetal
effects
were
manifested
as
increased
post­
implantation
loss
and
decreased
viable
fetuses
at
the
same
dose
that
caused
only
minimal
maternal
toxicity
characterized
as
resorptions.
A
two­
generation
reproduction
study
is
not
available
in
the
database.
Although
no
fetal
abnormalities
were
seen
in
the
prenatal
studies,
available
data
indicated
neurotoxic
effects
in
adult
animals
at
doses
of
approximately
3
mg/
kg/
day
and
higher.

5.
Determination
of
the
Need
for
Developmental
Neurotoxicity
Study
The
HIARC
in
1999
initially
determined
that,
based
on
the
observed
effects
of
zinc
pyrithione
to
the
nervous
system
from
available
reviewed
data,
that
a
developmental
neurotoxicity
study
will
be
required
for
zinc
pyrithione.
However,
the
ADTC,
in
revisiting
this
issue
in
2003,
concluded
that
the
requirement
for
the
developmental
neurotoxicity
study
should
be
held
in
reserve
pending
submission
of
acute
and
subchronic
neurotoxicity
studies
for
zinc
pyrithione.
Page
14
of
19
6.
Special
FQPA
Safety
Factor:

The
HIARC
in
1999
recommended
retention
of
the
10x
safety
factor
for
the
protection
of
infants
and
children
based
on
qualitative
evidence
of
increased
susceptibility
in
the
rat
and
rabbit
prenatal
developmental
toxicity
studies.
Since
that
time,
updated
guidance
on
interpretation
of
the
FQPA
safety
factor
(
http://
www.
epa.
gov/
oppfead1/
trac/
science/
determ.
pdf
)
has
been
published.
Based
on
this
updated
guidance
and
the
determination
of
the
Antimicrobials
Division's
Toxicology
Endpoint
Selection
Committee,
the
special
hazard­
based
FQPA
safety
factor
for
zinc
pyrithione
was
reduced
to
1x.
This
reduction
was
based
on
the
following:
For
zinc
pyrithione,
the
developmental
toxicity
database
shows
effects
in
offspring
at
similar
dose
levels
as
effects
in
adults,
while
the
reproductive
toxicity
database
for
sodium
pyrithione
(
a
structurally
related
chemical)
shows
effects
in
offspring
at
doses
above
those
occurring
in
parental
animals.
Effects
observed
in
offspring
from
developmental
toxicity
studies
have
been
selected
for
use
in
dietary
risk
assessments,
thus
being
protective
of
infants
and
children.
Therefore
the
hazard
based
FQPA
safety
factor
can
be
reduced
to
1x
since
the
degree
of
concern
is
low
(
i.
e.
a
complete
developmental
and
reproductive
database
is
available
with
clear
NOAELs/
LOAELs
for
parental
and
offspring
toxicity)
and
there
are
no
residual
uncertainties
for
prenatal
toxicity.

7.
Database
Uncertainty
Factor
Based
on
the
need
for
additional
neurotoxicity
testing
and
evidence
of
neurotoxicity
in
the
open
scientific
literature
(
Ross
and
Lawhorn,
Neurotoxicol.
Teratol
12(
2):
153­
159,
1990;
Snyder
et
al.,
Food
Cosmet.
Toxicol.
17(
6),
651­
660,
1979;
Grant,
W.
M.
Toxicology
of
the
Eye.
3rd
ed.
Springfield,
IL.
Charles
C.
Thomas,
Pub.)
,
a
database
uncertainty
factor
of
3x
is
applied
to
nonoccupational
risk
assessments
for
zinc
pyrithione,
due
to
the
lack
of
characterization
of
neurotoxic
dose­
response
relationships
for
zinc
pyrithione.
A
3x
factor
for
lack
of
neurotoxicity
data
(
as
opposed
to
a
higher
factor
of
10x)
is
adequate
because
neurotoxicity
observed
in
the
available
data
occurs
at
similar
effect
levels
as
other
adverse
responses,
the
doses
and
endpoints
selected
for
dietary
and
non­
dietary
assessments
encompass
the
doses
at
which
neurotoxicity
is
observed,
there
is
no
quantitative
evidence
of
susceptibility
to
the
toxic
effects
of
zinc
pyrithione,
and
traditional
uncertainty
factors
afford
a
degree
of
protection
that
is
considered
conservative.

VII.
Bridging
of
Toxicology
Data
for
Sodium
Pyrithione
Zinc
pyrithione
is
structurally
related
to
sodium
pyrithione,
the
primary
differences
being
the
presence
of
zinc
vs.
sodium
and
the
presence
of
two
pyrithione
moieties
for
zinc
vs.
one
moiety
for
sodium.
It
is
useful
to
compare
the
results
of
toxicity
testing
of
zinc
and
sodium
pyrithione
when
considering
the
bridging
issue.
The
tables
below
provide
a
comparison
of
results
from
both
chemicals:
Page
15
of
19
Study
Type2
ZINC
Pyrithione
Doses
(
mg/
kg/
day)
ZINC
Pyrithione
NOAEL/
LOAEL
SODIUM
Pyrithione
Doses
(
mg/
kg/
day)
SODIUM
Pyrithione
NOAEL/
LOAEL
81­
1
Acute
Oral
MRID
#
42827901
(
Zn)
MRID
#
40247801
(
Na)
260,
329,
417,
529,
668
mg/
kg
LD50
=
267
mg/
kg
(
M+
F)
LD50
=
1500
mg/
kg
(
M+
F)

81­
2
Acute
Dermal
MRID
#
42146701
(
Zn)
MRID
#
40247802
(
Na)
2000
mg/
kg
(
limit
dose)
LD50
>
2000
mg/
kg
LD50
=
1800
mg/
kg
(
M+
F)

81­
3
Acute
Inhalation
MRID
#
42146703
(
Zn)
MRID
#
40339001
(
Na)
0.24,
0.61
mg/
L
LC50
>
0.61
mg/
L
LC50
=
1.08
mg/
L
81­
4
Primary
Eye
MRID
#
42154601;
42146702
(
Zn)
0.1ml
of
a
48%
solution
severe
eye
irritant
data
gap
81­
5
Primary
Dermal
MRID
#
42146704
(
Zn)
MRID
#
40247803
(
Na)
0.5g
as
an
aqueous
paste
slight
erythema
and
edema,
reversible
by
48
hr.
slight
erythema
and
edema
81­
6
Dermal
Sensitization
MRID
#
43950201
(
Zn)
MRID
#
40247804
(
Na)
Buehler
method
using
0.4ml
undiluted
48%
solution
non­
sensitizer
non­
sensitizer
82­
1a
90­
day
feeding­
rat
Doc
no.
003933
(
Zn)
MRID
#
40756901
(
Na)
0.75,
3.75,
9.4,
18.75,
37.5,
46.9,
and
93.75
mg/
kg
NOAEL
=
0.75
mg/
kg
LOAEL
=
3.75
mg/
kg
(
increased
liver,
kidney,
testes
weight;
decreased
survival,
hindlimb
weakness
0,
0.5,
2.0,
8.0
mg/
kg/
day
NOAEL
=
0.5
mg/
kg/
day
LOAEL
=
2.0
mg/
kg/
day
(
evidence
of
neurotoxicity)
Page
16
of
19
83­
3a
Developmental
tox­
rat
MRID
#
42827904
(
Zn)
0,
0.75,
3,
and
15
mg/
kg/
day
Mat.
NOAEL
=
0.75
mg/
kg/
day;
Mat.
LOAEL
=
3.0
mg/
kg/
day
(
excessive
salivation).
Devel.
NOAEL
=
0.75
mg/
kg/
day;
Devel.
LOAEL
=
3.0
mg/
kg/
day
(
increased
incidence
of
fused
ribs)
no
data
83­
3b
Developmental
tox
­
rabbit
MRID
#
42827905
(
Zn)
MRID
#
40487201
(
Na)
0,
0.5,
1.5,
3.0
mg/
kg/
day
Mat./
Devel.
NOAEL
=
0.5
mg/
kg/
day;
Mat./
Devel.
LOAEL
=
1.5
mg/
kg/
day
(
incr.
Post­
impl.
loss
and
decr.
Viable
fetuses).
0,
1,
2.5,
and
5
mg/
kg/
d
NOAEL
=
5
mg/
kg/
d
LOAEL
=
7.5
mg/
kg/
d
(
based
on
toxicity
observed
in
range­
finding
study)

82­
3
90
Day
dermal
MRID
#
42827902
(
Zn)
MRID
#
40936201
(
Na)
0,
20,
100,
1000
mg/
kg/
day
NOAEL
=
100
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day
(
decr.
B.
w.,
food
cons.,
food
eff.)
0,
5,
15,
and
50
mg/
kg
NOAEL
=
15
mg/
kg/
d
(
M);
5
mg/
kg/
d
(
F)
LOAEL
=
50
mg/
kg/
d
(
M);
15
mg/
kg/
d
(
F)
[
atrophy
of
hindlimb
muscles
and
panniculus
muscles]
82­
4
90
Day
inhalation
MRID
#
42827903
(
Zn)
MRID
#
41178201
(
Na)
0.0005,
0.0025,
0.01
mg/
L
NOAEL
=
0.0005
mg/
kg/
day
LOAEL
=
0.0025
mg/
kg/
day
(
clinical
toxicity,
incr.
Abs.
And
rel.
Lung
weights)
0,
0.00046,
0.0011,
and
0.0038
mg/
L
(
0.0038
mg/
L
changed
to
0.0081
mg/
L
after
6
weeks)
NOAEL
=
0.0081
mg/
L
(
M);
0.0011
mg/
L
(
F)
LOAEL
=
0.0081
mg/
L
(
F,
based
on
hindlimb
dysfunction)
83­
4
Reproduction
MRID
#
41097201
(
Na)
no
data
0,
0.5,
1.5,
3.5
mg/
kg/
day
Systemic
NOAEL
=
0.5
mg/
kg/
d
Systemic
LOAEL
=
1.5
mg/
kg/
d
(
F);
3.5
mg/
kg/
d
(
M)
[
histologic
atrophy
of
hindlimb
skeletal
muscles]
Repro
NOAEL
=
1.5
mg/
kg/
d;
Repro
LOAEL
=
3
5
mg/
kg/
d
(
decr.
no.
of
pups/
litter,
decr.
pup
b.
w.
and
wt.
gain)
Page
17
of
19
83­
2
Carcinogenicity
MRID
#
42100901
(
Na)
no
data
0,
0.5,
1.5,
5.0/
3.5
g/
day
NOAEL
=
0.5
mg/
kg/
day
LOAEL
=
1.5
mg/
kg/
day
(
degeneration
of
skeletal
muscle
in
both
sexes)

84­
2
Mutagenicity
MRID
#
40411501
(
Na)
MRID
#
41906502
(
Zn)
non­
mutagenic
to
Salmonella
in
the
presence
and
absence
of
metabolic
activation
negative
for
forward
gene
mutations
in
CHO
cells
up
to
0.08

g/
ml
84­
2
Mutagenicity
MRID
#
40343701
(
Na)
MRID
#
41906503
(
Zn)
negative
for
gene
mutation
at
the
HGPRT
locus
in
CHO
cells
up
to
cytotoxic
concentrations
negative
for
micronucleus
induction
in
CD­
1
mice
up
to
toxic
doses
(
238
mg/
kg)

84­
2
Mutagenicity
MRID
#
40387501
(
Na)
MRID
#
41906501
(
Zn)
not
clastogenic
in
mouse
bone
marrow
cells
no
induction
of
UDS
in
rat
hepatocytes
up
to
cytotoxic
concentrations
85­
1
Metabolism
MRID
#
41269001
(
Na)
rapidly
absorbed
and
excreted;
Sglucuronide
the
major
metabolite.

The
tables
above
show
that
in
large
part,
both
zinc
and
sodium
pyrithione
produce
similar
toxic
responses
at
similar
dose
levels.
Some
differences
are
noted
with
respect
to
the
dermal
NOAELs
for
the
two
chemicals
(
NOAEL
of
15
mg/
kg/
day
for
sodium
pyrithione;
NOAEL
of
100
mg/
kg/
day
for
zinc
pyrithione)
and
the
observation
that
sodium
pyrithione
resulted
in
apparent
neurotoxic
effects
by
the
dermal
route
vs.
zinc
pyrithione.
The
dermal
absorption
values
also
differ
between
zinc
(
3.0%)
and
sodium
(
0.1%)
pyrithione,
although
the
value
for
sodium
pyrithione
was
estimated
and
not
measured
directly.
Outside
of
these
issues,
however,
the
oral
toxicity
data
do
show
a
similarity
in
toxic
response
at
similar
dose
levels,
so
in
the
case
of
bridging,
as
it
involves
oral
exposure,
it
is
possible
to
use
the
reproduction
study
for
sodium
pyrithione
as
a
substitute
for
zinc
pyrithione.
Since
a
90­
day
dermal
toxicity
study
is
available
for
both
zinc
and
sodium
pyrithione,
bridging
of
dermal
toxicity
data
is
not
necessary,
as
a
chemical
specific
endpoint
can
be
selected
in
this
case
as
needed.
Page
18
of
19
VII.
HAZARD
CHARACTERIZATION
Zinc
Pyrithione
demonstrates
developmental
toxicity
as
well
as
neurotoxicity.
In
the
developmental
toxicity
studies
in
the
rat
and
rabbit,
severity
of
effects
in
offspring
were
significant
in
comparison
to
maternal
effects,
even
though
the
doses
at
which
developmental
and
maternal
effects
occurred
were
the
same.
Zinc
pyrithione
also
demonstrates
significant
neurotoxic
effects
in
a
variety
of
studies
as
shown
by
hindlimb
weakness
and
distal
axonopathy.
Acute
and
subchronic
neurotoxicity
testing
is
necessary
to
define
the
dose­
response
relationships
for
the
neurotoxic
effects
of
zinc
pyrithione.
Reproductive
toxicity
data
for
zinc
pyrithione
are
not
available.
Data
are
available
for
sodium
pyrithione
and
can
be
used
as
bridging
data
for
this
aspect
of
zinc
pyrithione
hazard
as
concluded
by
the
ADTC
in
2003.

VIII.
DATA
GAPS
Data
gaps
exist
for
the
standard
Subdivision
F
Guideline
requirements
for
the
proposed
uses
of
zinc
pyrithione.
Acute
and
subchronic
neurotoxicity
studies
will
be
required
for
zinc
pyrithione.

IX.
ACUTE
TOXICITY
ENDPOINTS:

Guideline
No.
Study
Type
MRID
#
Results
Tox.
Cat.

§
81­
1
(
OPPTS870.1100)
Acute
Oral
42827901
LD50
=
267
mg/
kg
II
§
81­
2
(
OPPTS
870.1200
Acute
Dermal
42146701
LD50
>
2000
mg/
kg
III
§
81­
3
Acute
Inhalation
42146703
LC50
>
0.61
mg/
L
III
§
81­
4
(
OPPTS
870.2400)
Primary
Eye
Irritation
42146702
severe
irritant
I
§
81­
5
(
OPPTS
870.2500)
Primary
Dermal
Irritation
42146704
slight
erythema
and
edema
IV
§
81­
6
(
OPPTS
870.2600
Dermal
Sensitization
43950201
no
sensitization
observed
using
Buehler
method
N/
A
§
81­
8
(
OPPTS
870.6200)
Acute
and
Subchronic
Neurotoxicity
study
not
available
Page
19
of
19
X
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
for
zinc
pyrithione
are
summarized
below.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
LOC
for
Risk
Assessment
Study
and
Toxicological
Endpoints
Acute
Dietary
(
Females
13
­
50)
NOAEL
=
0.5
mg/
kg/
day
UF
=
300
Acute
RfD
=
0.0016
mg/
kg/
day
FQPA
SF
=
1x
aPAD
=
acute
RfD
FQPA
SF
aPADa
(
females
13+)
=
0.0016
mg/
kg/
day
Developmental
Toxicity
Study
in
Rabbits
LOAEL
=
1.5
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
decreased
viable
fetuses
Acute
Dietary
(
General
population,
including
infants/
children)
NOAEL
=
0.75
mg/
kg/
day
UF
=
300
Acute
RfD
=
0.0025
mg/
kg/
day
FQPA
SF
=
1x
aPAD
=
acute
RfD
FQPA
SF
aPAD
=
0.0025
mg/
kg/
day
Developmental
Toxicity
Study
in
Rats
LOAEL
=
3.0
mg/
kg/
day
based
on
increased
salivation
in
maternal
rats.

Chronic
Dietary
(
all
populations)
NOAEL
=
0.5
mg/
kg/
day
UF
=
300
Chronic
RfD
=
0.0016
mg/
kg/
day
FQPA
SF
=
1x
cPAD
=
acute
RfD
FQPA
SF
cPAD
=
0.0016
mg/
kg/
day
Developmental
Toxicity
Study
in
Rabbits
LOAEL
=
1.5
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
decreased
viable
fetuses
Incidental
Oral,
Short­
and
Intermediate­
Term
Maternal
NOAEL=
0.75
mg/
kg/
day
MOE
=
300
(
residential)
Developmental
Toxicity
Study
in
Rats
LOAEL
=
3.0
mg/
kg/
day,
Based
on
increased
salivation
in
maternal
rats.

Short­,
Intermediate­,
and
Long­
Term
Dermal
Dermal
NOAEL
=
100
mg/
kg/
day
MOE
=
300
(
residential)
MOE
=
100
(
occupational)
Subchronic
Dermal
Toxicity
in
Rats
LOAEL
=
1000
mg/
kg/
day,
based
on
decreased
body
weight
gain,
food
consumption,
and
food
efficiency
in
female
rats.

Short­,
Intermediate­,
and
Long­
Term
Inhalation
Inhalation
NOAEL
=
0.0005
mg/
L
MOE
=
300
(
residential)
MOE
=
100
(
occupational)
Subchronic
Inhalation
Toxicity
Study
in
Rats
LOAEL
=
0.0025
mg/
L
Based
on
clinical
signs
of
toxicity,
decreased
activity,
and
increased
lung
weights..
