Document ID: EPA-HQ-OPP-2004-0147-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-06-18T04:00Z

1
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
April
1,
2004
Memorandum
SUBJECT:
Zinc
Pyrithione
(
Zinc
Omadine
®
)
:
Toxicology
Science
Chapter
For
the
Reregistration
Eligibility
Decision
Document,
PC
Code
088002,
Case
3030,
Barcode:
D301369
FROM:
Timothy
F.
McMahon,
Ph.
D.
Senior
Toxicologist
Antimicrobials
Division
(
AD)
(
7510C)

THRU:
Nader
Elkassabany,
Ph.
D.
Team
Leader
Team
II
Risk
Assessment
and
Science
Support
Branch
Antimicrobials
Division
(
AD)
(
7510C)

TO:
Deborah
Smegal,
Risk
Assessor
Risk
Assessment
and
Science
Support
Branch
Antimicrobials
Division
(
AD)
(
7510C)

Attached
please
find
the
Toxicology
science
chapter
for
Zinc
Pyrithione
(
Zinc
Omadine
®
)
in
support
of
the
Reregistration
Eligibility
Decision
document.
2
TABLE
OF
CONTENTS
1.0
Hazard
Characterization...................................................................................................
3
2.0
Toxicology
Data
Requirements........................................................................................
5
3.0
Data
Gaps.........................................................................................................................
5
4.0
Hazard
Assessment..........................................................................................................
6
4.1
Acute
Toxicity...................................................................................................
6
4.2
Subchronic
Toxicity...........................................................................................
6
4.3
Developmental/
Reproductive
Toxicity..............................................................
7
4.4
Chronic
Toxicity/
Carcinogenicity.....................................................................
10
4.5
Mutagenicity.....................................................................................................
11
4.6
Neurotoxicity....................................................................................................
11
4.7
Metabolism.......................................................................................................
12
5.0
Hazard
Endpoint
Selection...........................................................................................
13
5.1
Acute
Reference
Dose......................................................................................
14
5.2
Chronic
Reference
Dose...................................................................................
16
5.3
Occupational/
Residential
Exposure..................................................................
17
5.3.1
Dermal
Absorption................................................................................
17
5.3.2
Short­
Term
Dermal
(
1­
7
Days).............................................................
18
5.3.3
Intermediate­
Term
Dermal....................................................................
18
5.3.4
Long­
Term
Dermal................................................................................
19
5.3.5
Inhalation
Exposure...............................................................................
19
5.3.6
Margins
of
Exposure.............................................................................
20
5.4
Classification
of
Carcinogenic
Potential...........................................................
20
6.0
FQPA
Considerations....................................................................................................
20
6.1
Special
Sensitivity
to
Infants
and
Children.......................................................
20
6.2
Database
Uncertainty........................................................................................
22
7.0
References....................................................................................................................
24
3
1.0
Hazard
Characterization
The
toxicology
database
for
zinc
pyrithione
has
been
reviewed
by
the
Office
of
Pesticide
Program's
Health
Effects
Division
and
Antimicrobials
Division.
The
hazard
database
supporting
the
uses
to
be
reregistered
is
adequate
for
this
purpose.
A
database
uncertainty
factor
was
applied
to
non­
occupational
risk
assessments
for
lack
of
studies
characterizing
the
dose­
response
relationship
for
neurotoxicity
of
zinc
pyrithione
and
for
lack
of
chronic
studies
to
select
a
chronic
dietary
endpoint.
Acute
and
subchronic
neurotoxicity
studies
have
been
requested
for
zinc
pyrithione.

The
toxicology
database
for
zinc
pyrithione
indicates
that
by
the
oral
route,
zinc
pyrithione
is
moderately
toxic
(
LD50
is
267
mg/
kg;
Toxicity
Category
II)
but
that
acute
toxicity
by
the
dermal
route
is
not
as
significant
(
LD50
>
2000
mg/
kg;
Toxicity
Category
III).
Acute
toxicity
by
the
inhalation
route
is
also
relatively
low
(>
0.61
mg/
L;
Toxicity
Category
III).
Zinc
pyrithione
is
a
severe
eye
irritant
(
Toxicity
category
I)
but
does
not
appear
to
demonstrate
significant
dermal
irritation
(
Toxicity
category
IV).
Zinc
pyrithione
does
not
demonstrate
dermal
sensitization
potential.

Repeated
dose
(
13
weeks)
toxicity
studies
indicate
that
by
the
dermal
route,
zinc
pyrithione
is
relatively
non­
toxic
(
decreased
food
consumption,
decreased
body
weight
gain,
decreased
food
efficiency
at
the
limit
dose
of
1000
mg/
kg/
day),
but
by
the
oral
route,
toxicity
is
significantly
greater
(
increased
relative
organ
weights,
clinical
toxicity,
and
hindlimb
weakness
at
3.75
mg/
kg/
day).
In
both
oral
developmental
studies
in
rats
and
rabbits,
there
was
no
quantitative
evidence
of
increased
susceptibility
[
i.
e.,
maternal
and
developmental
no­
observed­
adverse
effect
levels
(
NOAELs)
were
the
same].
There
was
however,
qualitative
evidence
of
increased
susceptibility
(
i.
e.,
fetal
effects
were
considered
to
be
more
severe
in
the
presence
of
minimal
maternal
toxicity).
Neurotoxicity
in
maternal
animals
is
also
manifest
at
these
doses.
Data
on
neurotoxicity
in
developing
animals
are
lacking.
Reproductive
toxicity
testing
using
sodium
pyrithione
showed
no
apparent
increased
susceptibility
of
offspring
to
the
reproductive
toxicity
of
sodium
pyrithione.
However,
based
on
the
available
evidence,
the
HIARC
concluded
that
there
was
qualitative
evidence
of
increased
susceptibility
to
developing
fetuses/
pups.

Zinc
Pyrithione
has
not
been
classified
as
to
carcinogenicity
due
to
the
absence
of
carcinogenicity
studies
for
this
chemical.
A
dermal
carcinogenicity
study
in
mice
and
an
oral
carcinogenicity
study
in
rats
exist
for
sodium
pyrithione
which
have
been
reviewed
by
the
Office
of
Pesticide
Programs.
There
was
no
evidence
for
carcinogenicity
in
the
rat
study
or
the
mouse
study,
but
the
mouse
study
was
considered
inadequate
for
risk
assessment
purposes.
Therefore,
sodium
pyrithione
could
not
be
classified
as
to
carcinogenic
potential
without
an
adequate
study
in
the
mouse.

The
available
evidence
for
gene
mutations
using
the
Ames
Salmonella
test
system
suggests
that
zinc
pyrithione
is
negative
for
mutations
in
this
system.
In
a
Chinese
hamster
ovary
forward
gene
mutation
assay,
zinc
pyrithione
failed
to
induce
a
mutagenic
response
at
doses
which
included
4
cytotoxicity.
In
an
in
vivo
micronucleus
assay
in
mice,
there
was
no
evidence
of
a
positive
effect.
Therefore,
the
data
indicate
that
zinc
pyrithione
is
negative
for
mutagenic
effects.
Sodium
pyrithione
has
also
been
shown
to
be
negative
for
mutagenic
effects
in
the
same
assays.

Disposition
and
metabolism
of
zinc
pyrithione
has
been
examined
in
older
studies
which
provide
incomplete
data.
Studies
from
the
published
literature
were
summarized,
but
not
reviewed
by
the
Agency.
In
Yorkshire
pigs
administered
an
intravenous
5
mg/
kg
dose
of
zinc
pyrithione,
plasma
elimination
was
described
as
biphasic,
with
a
t
½
alpha
of
2.0­
2.9
hr,
and
a
t
½
beta
of
26.6­
36.3
hr.
There
were
apparent
differences
in
urinary
elimination
of
14C
derived
radioactivity
from
administration
of
sodium
pyrithione
(
95%)
vs.
Zinc
pyrithione
(
45­
65%).
In
rabbits
administered
a
40
mg/
kg
oral
dose
of
zinc
pyrithione,
75%
of
the
administered
radioactivity
(
14C)
was
eliminated
in
urine
by
6
hours
post­
dose,
but
only
0.05%
of
zinc
was
eliminated
in
urine.
Pharmacokinetic
studies
in
rats
showed
74­
84%
of
administered
oral
doses
of
0.5,
1.25,
and
12.5
mg/
kg
eliminated
in
urine
by
96
hours
post­
dose.
There
were
apparent
sex
differences
in
pharmacokinetics.
Klaasan
(
1976)
utilized
14C­
zinc
pyrithione
and
isotopic65­
zinc
pyrithione
to
study
zinc
pyrithione.
The
author's
conclusion
indicate
that
zinc
and
pyrithione
go
to
different
locations
in
the
body
and
are
eliminated
at
different
rates
and
different
routes.
The
data
do
suggest
less
in
vivo
dissociation
of
zinc
pyrithione
vs.
sodium
pyrithione
and
greater
retention
of
zinc
in
tissues
vs.
the
pyrithione
moiety.

In
making
its
determination
of
safety
for
human
health
risks,
AD
considered
potential
dietary
exposure
to
zinc
pyrithione
residues
in
food
and
water
through
the
indirect
food
contact
uses
of
this
chemical.
In
addition,
several
residential
exposure
scenarios
were
included
in
the
safety
assessment.
Thus,
for
purposes
of
this
reregistration
eligibility
decision,
aggregate
exposure
and
risk
assessments
were
conducted
for
dietary
and
short­
term,
intermediate­
term,
and
long­
term
occupational/
residential
risk
for
zinc
pyrithione.

Uncertainties
There
is
concern
for
the
neurotoxic
effects
of
zinc
pyrithione
that
have
not
been
completely
characterized
in
the
available
toxicology
data.
This
uncertainty
was
addressed
through
the
use
of
a
database
uncertainty
factor
applied
to
non­
occupational
risk
assessments
for
zinc
pyrithione
until
adequate
data
are
obtained.
5
2.0
Toxicology
Data
TOXICOLOGY
DATA
FOR
ZINC
Pyrithione
TABLE
1
TOXICOLOGY
DATA
SUMMARY
Guideline
Number
Data
Requirement
MRID
Number
870.1100
Acute
Oral
Toxicity
42827901
870.1200
Acute
Dermal
Toxicity
42146701
870.1300
Acute
Inhalation
Toxicity
42146703
870.2400
Primary
Eye
Irritation
42146702
870.2500
Primary
Dermal
Irritation
42146704
870.2600
Dermal
Sensitization
43950201
870.3250
Subchronic
Dermal
Toxicity
42827902
870.3465
Subchronic
Inhalation
Toxicity
42827903
870.4100
Chronic
Toxicity
(
sodium
pyrithione)
41178101
870.4200
Carcinogenicity
in
Mice
(
sodium
pyrithione)
42100801
870.4300
Combined
Chronic
Toxicity
/
Carcinogenicity
in
Rats
(
sodium
pyrithione)
42100901
870.3700
Developmental
Toxicity
in
Rats
42827904
870.3700
Developmental
Toxicity
in
Rabbits
42827905
870.3800
2­
Generation
Reproduction
Toxicity
in
Rats
(
sodium
pyrithione)
41097201
870.5575
Salmonella
Plate
Incorporation
Assay
41906502
870.5265
CHO/
HGPRT
Assay
41906503
870.5395
Mouse
Micronucleus
Assay
41906501
870.6200
Neurotoxicity
screening
battery
no
study
available
1
Y
=
Yes;
N
=
No;
N/
A
=
Not
Applicable.
2required
if
a
carcinogenicity
risk
assessment
is
needed.
3
studies
conducted
according
to
the
OPPTS
guideline
were
not
available
for
these
endpoints.
The
available
literature
data
indicate
the
need
for
conduct
of
a
Neurotoxicity
Screening
Battery.

3.0
Data
Gaps
The
toxicological
data
base
for
Zinc
Pyrithione
is
adequate
to
support
reregistration
of
this
chemical.
However,
the
need
for
acute
and
subchronic
neurotoxicity
studies
to
properly
characterize
the
dose­
response
relationship
for
this
effect
have
been
previously
noted.
6
4.0
Hazard
Assessment
4.1
Acute
Toxicity
The
following
table
summarizes
the
acute
toxicity
of
Zinc
Pyrithione.

Guideline
No.
Study
Type
MRID
#
Results
Toxicity
Category
§
81­
1
(
OPPTS
870.1100)
Acute
Oral
Toxicity
42827901
LD50
=
267
mg/
kg
II
§
81­
2
(
OPPTS
870.1200
Acute
Dermal
Toxicity
42146701
LD50
>
2000
mg/
kg
III
§
81­
3
Acute
Inhalation
Toxicity
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)
Neurotoxicity
screening
battery
non­
guideline
study
available 
progressive
hindlimb
weakness
and
muscle
atrophy
at
12.5
mg/
kg/
day
4.2
Subchronic
Toxicity
Acceptable
studies
are
available
to
satisfy
subchronic
testing
requirements
for
this
chemical.

870.3250
90­
Day
Dermal
Toxicity
in
Rats
In
a
subchronic
dermal
toxicity
study
(
MRID
#
42827902),
male
and
female
CrlCD
BR
rats
were
treated
with
Zinc
pyrithione
(
Zinc
Omadine
®
)
FPS
by
dermal
occlusion
at
doses
of
0,
20,
100,
7
and
1000
mg/
kg/
day
for
6
hours/
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
1000
mg/
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
.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
(
§
82­
3)
for
a
subchronic
dermal
toxicity
study
in
rats.

870.3465
Subchronic
Inhalation
Toxicity
in
Rats
In
a
subchronic
inhalation
toxicity
study
(
MRID
#
42827903),
groups
of
15
male
and
15
female
Sprague­
Dawley
rats
were
dynamically
exposed
in
whole­
body
exposure
chambers
to
zinc
pyrithione
(
52.2%
aqueous
suspension)
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
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.
Based
on
the
results
of
this
study,
the
systemic
NOAEL
=
0.0005
mg/
L/
day,
and
the
systemic
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)

This
study
is
classified
acceptable
and
satisfies
the
guideline
requirement
(
§
82­
4;
OPPTS
870.3465)
for
a
subchronic
inhalation
toxicity
study
in
rats.

4.3
Developmental
Toxicity
Available
developmental
toxicity
studies
are
adequate
to
satisfy
guideline
requirements.

870.3700
Developmental
Toxicity
in
Rats
8
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
postimplantation
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
0.75
mg/
kg/
day,
and
the
developmental
toxicity
LOAEL
is
3.0
mg/
kg/
day,
based
upon
increased
incidences
of
fused
ribs.

This
study
is
classified
Acceptable
and
satisfies
the
guideline
requirement
for
a
developmental
study
(
§
83­
3;
OPPTS
870.3700)
in
rats.

870.3700
Developmental
Toxicity
in
Rabbits
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,
9
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).

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
(
§
83­
3;
OPPTS
870.3700)
for
a
developmental
toxicity
study
in
rabbits.

870.3800
Reproductive
Toxicity
Data
are
available
for
sodium
pyrithione
that
will
satisfy
the
data
requirement
for
zinc
pyrithione.

In
a
two
generation
reproduction
study
(
MRID
#
41097201)
conducted
with
40%
sodium
pyrithione,
Crl:
CD(
SD)
BR
rats
received
the
test
chemical
in
distilled
water
by
gavage
at
dose
levels
of
0,
0.5,
1.5,
or
3.5
mg/
kg/
day
at
a
dose
volume
of
10ml/
kg.
The
high
dose
of
3.5
mg/
kg/
day
was
originally
4.5
mg/
kg/
day,
but
was
scaled
back
to
3.5
mg/
kg/
day
based
on
excessive
toxicity
at
the
4.5
mg/
kg/
day
dose.
At
3.5
mg/
kg/
day,
one
female
parental
rat
in
the
F0
generation
was
sacrificed
on
day
87
after
demonstrating
hunched
posture,
impaired
hindlimb
mobility,
rapid
breathing,
and
peri­
orbital,
peri­
nasal,
and
abdominal
staining.
In
the
F1
generation,
two
females
at
the
3.5
mg/
kg/
day
dose
were
also
sacrificed
in
days
225
and
235,
based
on
similar
clinical
signs
of
toxicity
as
those
observed
in
the
F0
female.
Excessive
salivation
was
also
observed
in
all
male
and
female
rats
at
the
1.5
and
3.5
mg/
kg/
day
dose
levels.
Decreased
body
weight
was
observed
in
both
parental
generations
of
females
and
the
F0
generation
of
males
at
the
3.5
mg/
kg/
day
dose.
Decreases
were
in
the
range
of
88­
96%
of
control
values.
There
was
no
reported
effect
on
food
consumption
of
either
sex
or
generation
of
parental
rats.
Wasting
of
hindlimb
muscles
was
observed
in
those
females
at
3.5
mg/
kg/
day
sacrificed
during
the
study.
Skeletal
muscle
atrophy
was
observed
histologically
in
both
sexes
and
generations
of
parental
rats
10
at
the
1.5
and
3.5
mg/
kg/
day
dose
levels.
This
was
characterized
as
reduction
and
variation
in
the
diameter
of
muscle
fibers,
increase
in
number
of
sarcolemmal
nuclei,
and
fatty
replacement
of
muscle
fibers.

Reproductive
toxicity
was
observed
at
the
3.5
mg/
kg/
day
dose
level
in
the
F0
parents
and
the
F1
offspring.
Mating
index
in
males
was
reduced
significantly
as
was
fertility
index.
The
number
of
estrous
cycles
per
mating
was
increased
in
F0
females
at
3.5
mg/
kg/
day.
There
were
no
effects
on
total
live
pups,
mean
number
of
live
pups
per
litter,
live
birth
index,
viability
index,
or
lactation
index
in
F1
pups.
Mean
pup
body
weight
was
decreased
slightly
on
post­
natal
day
1
but
this
decrease
was
not
significant.
Developmental
landmarks
(
percentage
of
pups
with
ears
open
on
lactation
day
3
and
percentage
of
pups
with
eyes
open
on
lactation
day
15)
was
decreased
by
19%
and
7%
respectively,
but
was
not
statistically
significant.
Mean
percentage
of
pups
with
startle
response
on
lactation
day
15
was
decreased
significantly
by
10%.
In
the
F1
parents
and
the
F2
offspring,
mating
and
fertility
indices
were
reduced
at
all
dose
levels
relative
to
control,
but
it
is
likely
that
atrophy
of
hindlimb
muscles
in
males
could
impact
mating
success
and
therefore
would
explain
the
decrease
in
mating
and
fertility
indices.
Mean
percentage
of
pups
with
startle
response
on
lactation
day
15
and
mean
percentage
of
pups
with
eyes
open
on
lactation
day
15
was
decreased
by
13%
and
14%
respectively,
but
this
was
not
statistically
significant.

Based
on
the
results
of
this
study,
the
Systemic
NOAEL
is
determined
to
be
0.5
mg/
kg/
day,
and
the
Systemic
LOAEL
is
determined
to
be
1.5
mg/
kg/
day,
based
on
increased
incidence
of
histological
alterations
of
the
hindlimb
skeletal
muscle
in
F0
males
and
F1
males
and
females.
The
Reproductive
toxicity
NOAEL
is
determined
to
be
1.5
mg/
kg/
day,
and
the
Reproductive
toxicity
LOAEL
is
determined
to
be
3.5
mg/
kg/
day,
based
on
slightly
decreased
number
of
pups
per
litter
in
both
generations,
delayed
development
in
pups
from
both
generations,
and
decreased
pup
body
weight
in
both
generations.
This
study
is
classified
as
acceptable
(
guideline)
and
satisfies
the
data
requirement
for
a
reproductive
toxicity
study
in
rats.

4.4
Chronic
Toxicity
and
Carcinogenicity
There
were
no
submitted
chronic
toxicity
or
carcinogenicity
studies
on
zinc
pyrithione.
A
dermal
carcinogenicity
study
in
mice
and
an
oral
carcinogenicity
study
in
rats
exist
for
sodium
pyrithione
which
have
been
reviewed
by
the
Office
of
Pesticide
Programs.
There
was
no
evidence
for
carcinogenicity
in
the
rat
study
or
the
mouse
study,
but
the
mouse
study
was
considered
inadequate
for
risk
assessment
purposes.
Therefore,
sodium
pyrithione
could
not
be
classified
as
to
carcinogenic
potential
without
an
adequate
study
in
the
mouse.

4.5
Mutagenicity
Mutagenicity
data
are
available
for
zinc
pyrithione
which
satisfy
the
data
requirements
for
this
11
chemical.

Gene
Mutation
Salmonella
typhimurium
Assay
In
a
mutagenicity
study
(
MRID
#
41906502),
doses
of
zinc
pyrithione
(
48%
aqueous
dispersion)
ranging
from
0.03­
5.0

g/
plate
under
non­
activated
condition
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.

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.

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..

4.6
Neurotoxicity
No
recent
guideline
studies
have
been
submitted
to
the
Agency
with
respect
to
the
neurotoxicity
of
zinc
pyrithione.
In
a
non­
guideline
toxicity
study,
CD
male
rats,
150­
250g,
were
divided
into
63
pairs.
Technical
grade
zinc
pyrithione
(
97.0%)
was
administered
to
one
rat
of
each
pair
at
a
dose
of
250
ppm
for
either
9
or
14
days.
Gastrocnemius
and
soleus
muscles
were
examined
in
five
treated
and
five
pair­
fed
controls.
Eighteen
treated
and
18
pair­
fed
controls
were
used
for
ultrastructural
evaluation
of
nervous
tissue.
Nerve
conduction
velocity
of
the
sural
nerve
was
determined
in
a
total
of
74
treated
and
pair­
fed
controls.
In
vitro
recording
of
nerve
conduction
velocity
was
also
made
using
the
sciatic
nerve.
Histologic
morphology
of
all
examined
muscles
was
normal.
Sciatic,
sural,
and
spinal
nerve
roots
were
not
altered
after
14
days
of
treatment.
Myelinated
sural
nerve
axons
in
rats
recovered
for
2
weeks
showed
accumulation
of
dense
12
granular
axoplasmic
deposits.
The
most
prominent
changes
were
observed
in
intramuscular
lumbrical
fibers,
where
axons
were
enlarged
and
contained
abundant
mitochondria
and
electron
dense
granules.
Sensory
nerve
conduction
velocities
measured
in
vivo
showed
no
significant
difference
between
treated
and
control
rats.
However,
peak­
to­
peak
sensory
potential
amplitudes
were
significantly
different
between
treated
and
control
rats.
At
2
and
4
weeks
after
treatment,
clinical
signs
were
absent
in
treated
rats,
but
sensory
nerve
evoked
potential
amplitudes
remained
significantly
different
after
2
weeks
recovery.
The
results
of
this
study
suggest
a
primary
toxic
effect
of
zinc
pyrithione
on
muscle
fibers,
and
a
toxic
effect
on
nerve
fibers
consistent
with
random
axonal
loss
by
Wallerian
degeneration
or
inactivation.
i.
e.
approximately
5
mg/
kg
and
above.

Several
studies
published
in
the
open
scientific
literature
have
also
noted
neurotoxic
effects
from
exposure
to
zinc
pyrithione.
Ross
and
Lawhorn
(
Neurotoxicol.
Teratol
12(
2):
153­
159,
1990)
observed
reduction
in
forelimb
and
hindlimb
grip
strength
and
electrophysiological
changes
after
administration
of
zinc
pyrithione
in
the
diet
at
50
ppm
(
2.5
mg/
kg/
day)
indicative
of
neurotoxicity
at
the
neuromuscular
junction.
Snyder
et
al.
(
Food
Cosmet.
Toxicol.
17(
6),
651­
660,
1979)
observed
progressive
hind­
limb
weakness,
motor
incoordination,
and
reduced
sensory
and
mixed
sensory/
motor
nerve­
evoked
potential
amplitude
(
but
no
reduction
in
conduction
velocity)
in
male
rats
administered
250
ppm
(
12.5
mg/
kg/
day)
zinc
pyrithione
in
the
diet
for
9
or
14
days
with
a
4
week
recovery
period.
Although
clinical
signs
abated
during
the
recovery
period,
decreases
in
nerve­
evoked
potential
amplitude
remained
decreased.
Administration
of
zinc
pyrithione
to
dogs
has
produced
blindness
and
retinal
detachment
(
Grant,
W.
M.
Toxicology
of
the
Eye.
3rd
ed.
Springfield,
IL.
Charles
C.
Thomas,
Pub.)

4.7
Metabolism
Metabolism
data
for
zinc
pyrithione
are
incomplete.
Available
data
consist
Agency
summaries
of
submitted
data,
performed
in
1978,
and
a
single
report
from
the
scientific
literature,
also
dated
1978.

An
Agency
summary
of
a
report
published
in
Toxicology
and
Applied
Pharmacology
36:
523­
531,
1976,
was
obtained.
In
this
study,
a
single
dose
of
zinc
pyrithione
at
5
mg/
kg
(
labeled
in
the
2,6
positions)
was
administered
intravenously
through
the
jugular
vein
to
2
female
Yorkshire
pigs.
Plasma
half­
life,
urinary
excretion
rate,
and
metabolism
was
investigated.
Cholinergic
effects
(
parasympathetic
and
somatomotor)
were
observed
after
test
article
administration,
although
the
time
of
onset
after
test
article
administration
was
not
observed.
The
duration
of
symptoms
was
stated
as
30­
60
minutes.
Plasma
decline
was
described
as
biphasic.
Specific
values
for
zinc
pyrithione
were
not
stated,
as
the
sodium
salt
and
magnesium
adduct
were
also
examined
in
this
study.
The
alpha
phase
was
stated
as
2.0­
2.9
hours,
and
the
beta
phase
from
26.6­
36.3
hours.
Urine
appears
to
have
been
the
major
route
of
excretion
for
the
administered
radioactivity.
While
95%
of
the
administered
radioactivity
from
administration
of
sodium
pyrithione
was
recovered
in
urine,
the
summary
stated
that
only
between
45­
65%
of
zinc
pyrithione
radioactivity
was
recovered
in
urine.
This
observed
difference
could
reflect
the
fact
that
zinc
pyrithione
would
dissociate
less
in
vivo
than
sodium
pyrithione.
This
observation
is
also
consistent
with
the
finding
13
that
a
higher
percentage
of
radioactivity
was
found
in
tissues
(
liver,
kidney,
and
pancreas)
from
zinc
pyrithione
treated
pigs
vs.
other
treated
groups,
although
specific
values
were
not
stated.
TLC
analysis
of
urine
indicated
the
presence
of
the
metabolite
2­(
pyridyl­
N­
oxide)
sulfonic
acid
after
zinc
pyrithione
administration,
while
sodium
pyrithione
metabolites
in
urine
consisted
of
pyrithione
disulfide.

In
a
second
study
published
in
Toxicology
and
Applied
Pharmacology
(
35:
581­
587,
Klaassen,
1976),
rabbits
(
three
per
group)
were
given
either
a
1
mg/
kg
intravenous
dose
via
the
ear
vein
or
a
40
mg/
kg
oral
dose
by
gavage
of
zinc
pyrithione
labeled
either
with
14­
C
(
position
of
label
not
stated)
or
65­
Zn.
A
dual
label
was
not
administered
in
this
experiment.
Rabbits
were
sacrificed
at
6
hours
post­
dose.
Urinary
excretion
and
plasma
clearance
were
measured
at
timed
intervals
prior
to
sacrifice.
Tissue
levels
were
examined
at
sacrifice.
After
intravenous
administration,
75%
of
administered
14­
C
was
stated
to
be
in
urine,
while
the
blood
level
of
65­
Zn
was
stated
to
be
relatively
constant,
with
only
0.05%
excreted
in
urine.
Tissue
concentrations
of
radiolabeled
zinc
at
6
hours
post­
dose
were
stated
to
be
approximately
10
times
that
of
the
radiolabeled
pyridinethione.
(
i.
e.
5%
14­
C
vs.
55%
65­
Zn
per
gram
liver
tissue).
The
author's
conclusion
indicate
that
zinc
and
pyrithione
go
to
different
locations
in
the
body
and
are
eliminated
at
different
rates
and
different
routes.
It
appears
that,
based
on
the
starting
material,
zinc
pyrithione
does
not
dissociate
to
the
extent
that
sodium
pyrithione
does.

In
a
third
published
report
(
J.
H.
Wedig,
et
al.,
Fd.
Cosmet.
Toxicol.
16:
553­
561),
the
pharmacokinetics
of
2,6
[
C­
14]
labeled
zinc
pyrithione
were
examined
in
male
and
female
Sprague­
Dawley
rats.
Concentration
of
radioactivity
was
determined
in
blood,
urine,
and
feces
as
a
function
of
time
following
oral
doses
of
0.5,
1.25,
and
12.5
mg/
kg.
Urine
appeared
as
the
major
route
of
excretion
at
all
dose
levels
(
74­
84%
of
administered
radioactivity),
with
fecal
excretion
between
13­
21%
of
the
administered
radioactivity.
Sex
differences
were
apparent
with
respect
to
plasma
elimination,
renal
clearance,
time
required
to
maximum
blood
concentration,
and
rate
of
absorption.
Male
rats
were
observed
with
significantly
lower
blood
concentrations
of
[
C­
14],
and
were
also
observed
with
a
higher
rate
for
metabolism
of
zinc
pyrithione.

5.0
Hazard
Endpoint
Selection
Toxicity
end
point
selection
is
summarized
below.

5.1
Acute
Reference
Dose
(
RfD)

Subpopulation:
Females
13+

Study
Selected:
Developmental
Toxicity
­
Rabbit
MRID
No.:
42827905
Executive
Summary:
In
a
developmental
toxicity
study
in
rabbits
(
MRID
#
42827905),
14
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
post­
implantation
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
Factor:
300
(
10
x
for
inter­
species
variation,
10x
for
intra­
species
extrapolation,
3x
database
uncertainty)

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
presumed
to
occur
after
a
single
exposure
(
dose),
thus
are
applicable
for
this
exposure
period
of
concern.

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

Acute
RfD
Subpopulation:
General
Population
including
Infants
and
children
Study
Selected
:
Developmental
Toxicity
­
Rat
15
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
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,
10x
for
intra­
species
extrapolation,
3x
database
uncertainty)

Acute
RfD
=
0.75
mg/
kg/
day
(
NOAEL)
=
0.0025
mg/
kg
16
300
(
UF)

Comments
about
Study/
Endpoint
Uncertainty
Factor:
The
endpoint
(
salivation)
was
seen
in
maternal
animals
during
the
dosing
period,
and
thus
are
relevant
for
this
subpopulation
and
exposure
period
of
concern.

5.2
Chronic
Reference
Dose
Study
Selected:
Developmental
Toxicity
­
rat
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
LOEL
is
3.0
mg/
kg/
day,
based
upon
excessive
salivation
during
the
dosing
period.

Developmental
toxicity
was
characterized
by
a
dose
related
increase
in
postimplantation
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
17
developmental
toxicity
NOEL
is
0.75
mg/
kg/
day,
and
the
developmental
toxicity
LOEL
is
3.0
mg/
kg/
day,
based
upon
increased
incidences
of
fused
ribs.

Dose
and
endpoint:
NOAEL
of
0.5
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
decreased
viable
fetuses
at
1.5
mg/
kg/
day.

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

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

Comments
about
Study/
Endpoint
Uncertainty
Factor:
Since
no
long­
term
feeding
studies
are
available,
a
developmental
toxicity
study
in
rats
with
the
lowest
NOAEL
in
the
toxicology
database
was
selected.

5.3
Occupational
/
Residential
Exposure
5.3.1
Dermal
Absorption
Study
Selected:
Dermal
Absorption
­
Domestic
Swine
MRID
No.:
HED
document
no.
003933
Executive
Summary:
Twenty­
six
mature
Yorkshire
pigs
were
used
in
this
study.
Radiolabelled
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.
18
5.3.2
Short­
Term
Dermal
(
1
day­
1
month)

Study
Selected:
90­
Day
Dermal
Toxicity
­
rats
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
6
hours/
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
1000
mg/
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
.

Dose
and
Endpoint
:
NOAEL
of
100
mg/
kg/
day,
based
on
body
weight
decrements
in
female
rats
at
the
limit
dose
of
1000
mg/
kg/
day.
An
uncertainty
factor
of
100
was
recommended
for
this
risk
assessment.

Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
route
(
dermal)
and
exposure
period
(
1­
7
days)
of
concerns
since
the
route
of
treatment
(
dermal)
in
animals
simulates
real
life
occupational
exposure
(
dermal)
scenarios.

5.3.3
Intermediate­
Term
Dermal
(
1­
6
months
)

Study
Selected:
90­
Day
Dermal
Toxicity
­
rats
MRID
No.:
42827902
Executive
Summary:
See
executive
summary
above
for
short­
term
dermal.

Dose
and
Endpoint
Proposed
for
Consideration:
NOAEL
of
100
mg/
kg/
day,
based
on
body
weight
decrements
in
female
rats
at
the
limit
dose
of
1000
mg/
kg/
day.
An
uncertainty
factor
of
100
was
recommended
for
this
risk
assessment.

Comments
about
Study/
Endpoint:
none
19
5.3.4
Long­
Term
Dermal
(>
6
months)

Study
Selected:
90­
Day
Dermal
Toxicity
­
rats
MRID
No.:
42827902
Executive
Summary:
see
above
for
short­
term
dermal
Dose
and
Endpoint
:
see
above
for
short­
term
dermal.

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.

5.3.5
Inhalation
Exposure
Study
Selected:
90­
day
Inhalation
Toxicity
Study
in
Rats
MRID
No.:
42827903
Executive
Summary:
Groups
of
15
male
and
15
female
Sprague­
Dawley
rats
were
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
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)
20
Dose
and
Endpoint:
NOAEL
of
0.0005
mg/
L/
day,
based
on
clinical
signs,
increased
lung
weights,
and
mortality
at
0.0025
mg/
L/
day.

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

5.3.6
Margin
of
Exposure
for
Occupational/
Residential
Exposures:

An
MOE
of
100
is
adequate
for
occupational
dermal
exposure
risk
assessments.
For
residential
incidental
oral,
dermal,
and
inhalation
risk
assessments,
an
MOE
of
300
is
adequate.

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.

5.4
Classification
of
Carcinogenic
Potential
No
chronic
toxicity
or
carcinogenicity
studies
are
available
to
assess
the
carcinogenic
potential
of
zinc
pyrithione
.
Data
on
sodium
pyrithione
suggest
no
carcinogenic
potential
but
data
are
inadequate
to
make
a
final
determination.

6.0
FQPA
Considerations
The
following
evaluation
of
zinc
pyrithione
is
provided
to
address
FQPA
considerations
on
the
sensitivity
of
infants
and
children.

6.1
Special
sensitivity
for
infants
and
children:

Under
the
Food
Quality
Protection
Act
(
FQPA),
P.
L.
104­
170,
which
was
promulgated
in
1996
as
an
amendment
to
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
and
the
Federal
Food,
Drug
and
Cosmetic
Act
(
FFDCA),
the
Agency
was
directed
to
"
ensure
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children"
from
aggregate
exposure
to
a
pesticide
chemical
residue.
The
law
further
states
that
in
the
case
of
threshold
effects,
for
purposes
of
providing
this
reasonable
certainty
of
no
harm,
"
an
additional
tenfold
margin
of
safety
for
the
pesticide
chemical
residue
and
other
sources
of
exposure
shall
be
applied
for
infants
and
children
to
take
into
account
potential
pre­
and
post­
natal
toxicity
and
completeness
of
the
data
21
with
respect
to
exposure
and
toxicity
to
infants
and
children.
Notwithstanding
such
requirement
for
an
additional
margin
of
safety,
the
Administrator
may
use
a
different
margin
of
safety
for
the
pesticide
residue
only
if,
on
the
basis
of
reliable
data,
such
margin
will
be
safe
for
infants
and
children."

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,
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.

The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.
22
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
Rat
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..

6.2
Database
Uncertainty
Based
on
the
need
for
acute
and
subchronic
neurotoxicity
testing,
a
database
uncertainty
factor
of
3x
is
applied
to
non­
occupational
risk
assessments
for
zinc
pyrithione,
due
to
the
lack
of
23
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.
24
REFERENCES
1)
Moreno
O.
M.,
Cerven
D.
R.,
Altenbach,
E,
J.
(
1986):
Single
Dose
Oral
Toxicity
in
Rats/
LD
50
in
Rats.
Study
performed
by
M
B
Research
Laboratories,
Inc,
Spinnerstown,
Pennsylvania
for
Olin
Corporation.
MRID
#
42827901.
Unpublished.

2)
Cerven,
D.
R.
(
1991):
Acute
Dermal
Toxicity
in
Rabbits/
LD50
in
Rabbits.
Study
performed
by
M
B
Research
Laboratories,
Inc,
Spinnerstown,
Pennsylvania
for
Olin
Corporation.
MRID
#
42146701.
Unpublished.

3)
Ulrich,
C.
E.
(
1991):
Acute
Inhalation
Toxicity
Evaluation
on
Zinc
Omadine
in
Rats.
Study
performed
by
International
Research
and
Development
Corporation
for
Olin
Corporation.
MRID
#
42146703.
Unpublished.

4)
Cerven,
D.
R.
(
1991):
Primary
Eye
Irritation/
Corrosion
in
Rabbits.
Study
performed
by
M
B
Research
Laboratories,
Inc,
Spinnerstown,
Pennsylvania
for
Olin
Corporation.
MRID
#
42146702.
Unpublished.

5)
Cerven,
D.
R.
(
1991):
Primary
Dermal
Irritation
in
Albino
Rabbits.
Study
performed
by
M
B
Research
Laboratories,
Inc,
Spinnerstown,
Pennsylvania
for
Olin
Corporation.
MRID
#
42146704.
Unpublished.

6)
Newconb,
T
(
1996):
Delayed
Contact
Dermal
Sensitization
Test
(
Buehler
Method).
Study
performed
by
M
B
Research
Laboratories,
Inc,
Spinnerstown,
Pennsylvania
for
Olin
Corporation.
MRID
#
43950201.
Unpublished.

7)
Ulrich,
C.
E.
(
1993):
90­
Day
Subchronic
Dermal
Toxicity
Study
on
Zinc
Omadine
in
Rats.
Study
performed
by
International
Research
and
Development
Corporation
for
Olin
Corporation.
MRID
#
42827902.
Unpublished.

8)
Schardein,
J.
L.
(
1993):
Developmental
Toxicity
Study
in
Rats
with
Zinc
Omadine.
Study
performed
by
International
Research
and
Development
Corporation
for
Olin
Corporation.
MRID
#
42827904.
Unpublished.

9)
Schardein,
J.
L.
(
1993):
Developmental
Toxicity
Study
in
New
Zealand
White
Rabbits
with
Zinc
Omadine.
Study
performed
by
International
Research
and
Development
Corporation
for
Olin
Corporation.
MRID
#
42827905
and
42827906.
Unpublished.

10)
Ridgway,
P.
and
Wood,
C.
M.
(
1989):
Sodium
Omadine
Rat
Two­
Generation
Reproduction
Toxicity
Study.
Study
performed
by
Toxicol
Laboratories
for
Olin
Corporation.
MRID
#
41097201.
Unpublished.

11)
Ulrich,
C.
E.
(
1993):
Thirteen
Week
Subchronic
Inhalation
Toxicity
Study
on
Zinc
Omadine
in
Rats.
Study
performed
by
International
Research
and
Development
Corporation
for
Olin
Corporation.
MRID
#
42827903
and
42827907.
Unpublished.

12)
San,
R.
H.
C.
and
Shelton,
J.
B.
(
1990):
Salmonella/
Mammalian
­
Microsome
Plate
Incorporation
Mutagenicity
Assay
(
Ames
Test)
with
a
Confirmatory
Assay.
Study
performed
by
Microbiological
Associates,
Inc.,
Rockville,
MD
for
Olin
Corporation.
MRID
#
41906502.
Unpublished.

13)
Jacobson­
Kram,
D.
and
Sigler,
C.
I.
(
1990):
CHO/
HGPRT
Mutation
Assay
with
Confirmation.
Study
performed
by
Microbiological
Associates,
Inc.,
Rockville,
MD
for
Olin
Corporation.
MRID
#
41906503.
Unpublished.

14)
Putman,
D.
L.
and
Morris,
M.
J.
(
1990):
Micronucleus
Cytogenetic
Assay
in
Mice.
Study
performed
by
Microbiological
Associates,
Inc.,
Rockville,
MD
for
Olin
Corporation.
MRID
#
41906501.
Unpublished.
25
15)
Preliminary
Neurological
Evaluation
of
Generalized
Weakness
in
Zinc­
Pyrithione
treated
rats.
Study
performed
by
Olin
Corporation
(
no
date
given).
Unpublished.
HED
document
number
003933.

16)
Klaassen,
C
(
1976):
Absorption,
Distribution,
and
Excretion
of
Zinc
Pyridinethione
in
Rabbits.
Toxicol.
Appl.
Pharmacol.
35:
581­
587.

17)
Wedig,
J.
H.,
et
al.
(
1978):
Disposition
of
Zinc
Pyrithione
in
the
Rat.
Fd.
Cosmet.
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16:
553­
561.

18)
Adams,
M.,
Jordan,
R.,
and
Borzelleca,
J.
(
no
date):
Acute
Toxicity
and
Disposition
of
Sodium
Omadine,
Zinc
Omadine,
and
Omadine­
MDS
following
Intravenous
Administration
to
Swine.
Study
performed
by
the
Medical
College
of
Virginia.

19)
Husband,
R.
F.,
Newman,
A.
J.,
Lee,
P.
N.
(
1991):
104­
Week
Oral
(
Gavage)
Combined
Carcinogenicity
and
Toxicity
Study
in
the
Rat.
Study
conducted
by
Toxicol
Laboratories
Ltd.,
Ledbury,
England
and
submitted
to
the
EPA
under
MRID
42100901.
Unpublished.

20)
Husband,
R.
F.,
Newman,
A.
J.,
Lee,
P.
N.
(
1991):
80­
Week
Dermal
Carcinogenicity
Study
in
the
Mouse.
Study
conducted
by
Toxicol
Laboratories
Ltd.,
Ledbury,
England
and
submitted
to
the
EPA
under
MRID
42100801.
Unpublished.

21)
Johnson
D.
E.
(
1989):
One
Year
Oral
Toxicity
Study
in
Cynomolgus
Monkeys.
Study
conducted
by
International
Research
and
Development
Corporation,
Mattawan,
MI
and
submitted
to
the
EPA
under
MRID
41178101.
Unpublished.

22)
Ross,
J.
F.
and
Lawhorn,
G.
T.
(
1990):
ZPT­
related
Distal
Axonopathy:
behavioral
and
electrophysiologic
correlates
in
rats.
Neurotoxicol.
Teratol
12(
2):
153­
159,
1990
23)
Snyder,
D.
R.,
deJesus,
C.
P.
V.,
Towfighi,
J.,
Jacoby,
R.
O.,
Wedig,
J.
H.
(
1979):
Neurological,
Microscopic,
and
Enzyme­
Histochemical
Assessment
of
Zinc
Pyrithione
Toxicity.
Food
Cosmet.
Toxicol.
17(
6),
651­
660,
1979.

24)
Grant,
W.
M.
Toxicology
of
the
Eye,
3rd
edition.
Charles
C.
Thomas,
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1993)