Page
1
of
13
HED
DOC./
NO.
013318
DATE:
March
19,
1999
MEMORANDUM
SUBJECT:
ZINC
OMADINE
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Timothy
F.
McMahon,
Ph.
D.
Senior
Toxicologist,
RASSB
Antimicrobials
Division
(
7510C)

THROUGH:
Jess
Rowland,
Co­
Chair,
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)
and
Pauline
Wagner,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Marshall
Swindell
PM
Team
33
/
RMB
I
Antimicrobials
Division
(
7510C)

PC
Code:
088002
On
February
4,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicology
data
base
of
zinc
omadine,
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
omadine
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
Committee's
conclusions
are
presented
in
this
report.
Page
2
of
13
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.

Data
Presentation:
and
Report
Presentation
_____________________

Tim
McMahon
Toxicologist
Report
Concurrence:
_____________________

Brenda
Tarplee
Executive
Secretary
Page
3
of
13
I.
INTRODUCTION
On
February
4,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicology
data
base
of
zinc
omadine,
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
omadine
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

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
omadine
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
post­
implantation
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).
Page
4
of
13
Uncertainty
Factor:
100
(
10
x
for
inter­
species
variation
and
10x
for
intra­
species
extrapolation)

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)
=
0.005
mg/
kg
100
(
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
Omadine
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
Page
5
of
13
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:
100
(
10
x
for
inter­
species
variation
and
10x
for
intra­
species
extrapolation)

Acute
RfD
=
0.75
mg/
kg/
day
(
NOAEL)
=
0.0075
mg/
kg
100
(
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.

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:
1000
which
includes
10
x
for
inter­
species
variation,
10x
for
intraspecies
extrapolation
and
10
for
lack
of
long­
term
feeding
studies
(
data
gap).

Chronic
RfD
=
0.5
mg/
kg/
day
(
NOAEL)
=
0.0005
mg/
kg/
day
1000
(
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
and
an
additional
uncertainty
factor
for
datagaps
was
used
to
derive
the
chronic
RfD.
Page
6
of
13
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
omadine
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
omadine
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
7
of
13
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
omadine
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
8
of
13
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
dose
will
be
used
for
short,
intermediate
and
long­
term
exposure
risk
assessments.

This
risk
assessment
is
required.

D.
Recommendation
of
Margins
of
Exposure
An
MOE
of
100
is
adequate
for
occupational
exposure
risk
assessments.
MOEs
for
residential
exposure
risk
assessments
will
be
determined
by
the
FQPA
Safety
Factor
Committee
E.
Aggregate
Exposure
Risk
Assessments
(
Food+
water+
Residential
exposures)

For
acute
aggregate
exposure
risk
assessment,
combined
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
can
not
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
omadine
Page
9
of
13
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
omadine
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
omadine
(
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
omadine
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
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,
however,
datagap
exists
for
neuro­,
reproductive­,
and
chronic
toxicity
of
zinc
omadine
2.
Neurotoxicity
Data
There
are
currently
no
guideline
neurotoxicity
studies
for
zinc
omadine.
The
existing
database,
however,
shows
significant
nervous
system
deficits
following
either
acute
or
subchronic
oral
administration
of
zinc
omadine.
For
example,
intravenous
administration
Page
10
of
13
of
5
mg/
kg
zinc
omadine
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
omadine
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:

The
two­
generation
reproduction
study
in
rats
is
NOT
available
to
assess
the
reproductive
toxic
potential
of
zinc
omadine.

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
determined
that,
based
on
the
observed
effects
of
zinc
omadine
to
the
nervous
system
from
available
reviewed
data,
that
a
developmental
neurotoxicity
study
will
be
required
for
zinc
omadine.

(
I)
Evidence
supporting
a
developmental
neurotoxicity
study
The
existing
database,
however,
shows
significant
nervous
system
deficits
following
either
acute
or
subchronic
oral
administration
of
zinc
omadine.
For
example,
intravenous
administration
of
5
mg/
kg
zinc
omadine
to
female
Yorkshire
Page
11
of
13
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
omadine
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.

(
ii)
Evidence
that
does
not
support
a
developmental
neurotoxicity
study
There
is
no
evidence
to
support
a
conclusion
of
not
requiring
a
developmental
neurotoxicity
study.

6.
Determination
of
the
FQPA
Factor:

Based
on
hazard
alone,
the
HIARC
recommended
that
the
10x
safety
factor
for
the
protection
of
infants
and
children
(
as
required
by
FQPA)
should
be
retained.
This
recommendation
is
based
on
the
qualitative
evidence
of
increased
susceptibility
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.
In
addition,
a
datagap
exists
for
the
two­
generation
reproduction
study.
Additionally,
publications
in
the
open
literature
indicate
neurotoxicity
in
adult
animals
at
doses
of
approximately
3
mg/
kg/
day
and
higher.

VII.
HAZARD
CHARACTERIZATION
Zinc
Omadine
demonstrates
frank
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
omadine
also
demonstrates
significant
neurotoxic
effects
in
a
variety
of
studies
as
shown
by
hindlimb
weakness
and
distal
axonopathy.
The
data
supporting
this
conclusion
are
considered
adequate,
but
further
neurotoxicity
testing
is
necessary
to
define
a
NOAEL
for
the
neurotoxic
effects
of
zinc
omadine.
Reproductive
toxicity
data
for
zinc
omadine
are
not
available.
Data
are
available
for
sodium
omadine,
but
the
Agency
has
not
yet
formally
reviewed
a
request
submitted
which
attempts
to
draw
bioequivalence
between
the
two
omadine
salts.
In
addition,
developmental
neurotoxicity
data
as
well
will
be
required
for
zinc
omadine.
As
related
to
human
health,
the
nervous
system
toxicity
and
developmental
toxicity
are
of
concern.
These
areas
will
require
further
study.
Of
interest
are
the
data
for
sodium
omadine
which
show
similar
toxic
effects
at
similar
or
slightly
higher
doses.
It
is
hypothesized
that
the
NOAELs
for
zinc
omadine
may
be
lower
based
upon
differences
in
disposition
between
the
two
omadine
salts,
i.
e.
the
zinc
complex
being
retained
longer
than
the
sodium
salt,
thus
resulting
in
effects
at
lower
doses.
Page
12
of
13
VIII.
DATA
GAPS
Data
gaps
exist
for
the
standard
Subdivision
F
Guideline
requirements
for
the
proposed
uses
of
zinc
omadine.
Specifically,
chronic
toxicity,
carcinogenicity,
developmental
neurotoxicity,
and
reproductive
toxicity
data
are
not
available.
It
is
possible
that
the
data
for
sodium
omadine
will
be
used
as
bridging
data
to
support
these
endpoints.
However,
in
the
absence
of
a
compelling
argument,
these
data
will
be
required
unless
the
bridging
issue
is
resolved
favorably.

IX.
ACUTE
TOXICITY
ENDPOINTS:

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

§
81­
1
(
OPPTS870.1100)
Acute
Oral
42827901
LD50
=
630
mg/
kg
(
M);
LD50
=
460
mg/
kg
(
F)
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)
Neurotoxicity
screening
battery
study
not
available
X
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
Page
13
of
13
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
Females
13+
Developmental
NOAEL=
0.5
Increased
post
implantation
loss
and
decreased
viable
fetuses
Developmental­
Rabbit
UF
=
100
Acute
RfD
=
0.005
mg/
kg
Acute
Dietary
General
Population/
Infants
and
Children
Maternal
NOAEL=
0.75
Maternal
toxicity
characterized
as
increased
salivation.
Developmental­
Rat
UF
=
100
Acute
RfD
=
0.0075
mg/
kg
Chronic
Dietary
Developmental
NOAEL=
0.5
Increased
post
implantation
loss
and
decreased
viable
fetuses.
Additional10x
required
for
lack
of
long­
term
feeding
studies
(
data
gap).
Developmental­
Rabbit
UF=
1000
Chronic
RfD
=
0.005
mg/
kg/
day
Short­,
Intermediate
and
Long­
Term
(
Dermal)
Dermal
NOAEL=
100
Decreased
body
weight
gain
and
food
consumption/
food
efficiency
90­
Day
Dermal­
Rat
Inhalation
(
Any
Time
Period)
Inhalation
NOAEL=
0.0005
mg/
L
Clinical
signs
of
toxicity,
decreased
activity,
and
increased
lung
weights..
90­
Day
Inhalation
­
Rat
