HED
Doc.
No.
014006
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
WASHINGTON,
D.
C.
20460
DATE:
February
23,
2000
MEMORANDUM
SUBJECT:
DINOCAP
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Paul
Chin
Reregistration
Branch
I
Health
Effects
Division
(
7509C)

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

TO:
Catherine
Joseph,
Risk
Assessor
Reregistration
Branch
I
Health
Effects
Division
(
7509C)

PC
Code:
036001
On
December
1,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicology
database
of
dinocap
and
selected
the
toxicological
endpoints
for
acute
and
chronic
dietary,
occupational,
and
residential
(
dermal
and
inhalation)
exposure
risk
assessments.
During
this
meeting,
one
issue,
which
required
further
evaluation
of
the
available
data,
was
unresolved.
The
issue
was
to
confirm
whether
an
increase
in
the
duration
of
gestation
in
treated
CD
 
1
mice
at
all
dose
levels
in
a
developmental
toxicity
in
mice
was
toxicologically
significant.
David
Anderson
was
requested
to
verify
the
results
of
this
developmental
toxicity.
After
reviewing
the
historical
control
data,
the
re­
evaluation
of
the
statistical
analyses
and
the
manner
in
which
the
gestational
length
(
days)
were
recorded,
the
increase
in
gestational
time
was
not
considered
to
be
toxicological
significance
in
the
mice
developmental
toxicity
in
study
(
MRID#
41313001;
HED
Document#
008299).
This
reviewer
agrees
with
the
conclusions
derived
by
the
study
reviewer,
Joint
Meeting
on
pesticide
Residues
(
JMPR),
and
the
registrant
that
the
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
2
palate
and
eyelids­
open
relative
to
the
controls.
The
NOAEL
for
maternal
toxicity
is
10
mg/
kg/
day;
the
LOAEL
is
25
mg/
kg/
day
based
on
the
slight
decrease
in
body
weight
and
body
weight
gains.
The
Committee's
conclusions
are
presented
in
this
report.

Committee
Members
in
Attendance
December
1,
1999
Members
present
were
David
Anderson,
Bill
Burnam,
Virginia
Dobozy,
Pamela
Hurley,
Mike
Ioannou,
Tina
Levine,
Sue
Makris,
Nancy
McCarroll,
Nicole
Paquette,
Kathleen
Raffaele,
Jess
Rowland,
PV
Shah,
Pauline
Wagner,
and
Brenda
Tarplee
(
Executive
Secretary).
Members
in
an
absentia
was
Karen
Hamernik.
Data
were
presented
by
Paul
Chin
of
Reregistration
Branch
I.
Also,
in
attendance
were
Whang
Phang,
Catherine
Joseph,
Elizabeth
Mendez,
Vicki
Dellarco,
and
Karl
Baetcke.

Data
Presentation:
and
Report
Presentation
Paul
Chin
Toxicologist
3
I.
INTRODUCTION
There
are
no
current
food
uses
in
the
U.
S.
It
is
registered
only
for
greenhouse
ornamentals.
The
registrant
wants
to
maintain
the
tolerances
on
grapes
and
apples.
Since
the
registrant
wants
to
maintain
the
import
tolerances,
dinocap
will
be
treated
as
a
food
use
chemical.

Chemically,
technical
dinocap
is
a
mixture
of
dinitro­
octylphenylcrotonate
isomers
and
dinitrooctylphenols
Toxicological
database
shows
that
there
are
two
purities
(
76­
88%
a.
i.
and
92­
96%
a.
i.)
for
the
technical
dinocap.
The
older
studies
were
conducted
mainly
with
76­
88%
a.
i.
and
the
newer
studies
were
conducted
with
92­
96%
a.
i..
The
amount
of
dinitro­
octylphenols
in
76­
88%
and
92­
96%
dinocap
constitutes
6%
and
0.5%
of
the
a.
i.,
respectively.
2,4­
Dinitrophenol
is
well
known
developmental
toxicant.
There
is
evidence
to
suggest
that
technical
dinocap
is
a
developmental
toxicant
in
rabbits
and
mice.

The
HED
RfD/
Peer
Review
Committee
(
HED
Doc.
No.
011076
dated
June
24,
1994)
considered
that
the
carcinogenicity
phase
of
the
rat
study
(
MRID
No.
41065401;
ACCESSION
No.
00247959)
and
the
carcinogenicity
study
in
mice
(
MRID
Nos.
418639801,
42079102)
were
considered
to
be
adequate.
The
high
dose
levels
tested
in
both
rats
and
mice
carcinogenicity
studies
were
considered
to
be
adequate
for
carcinogenicity
testing.
The
dinocap
treatment
did
not
alter
the
spontaneous
tumor
profile
in
either
animal
species.
The
chemical
was
classified
as
a
"
Group
E".

II.
HAZARD
IDENTIFICATION
A.
Acute
Reference
Dose
(
RfD)
Subpopulation
(
Females
13+)

Study
Selected:
Developmental
Toxicity
Study
in
Mice
Guideline
#:
83­
3(
a)

MRID
No.:
41313001
Executive
Summary:

In
a
developmental
toxicity
study
(
MRID
No.
41313001),
Dinocap
(
94.4%
a.
i.)
suspension
in
an
aqueous
1%
Tragacanth
Gum
was
administered
by
gavage
to
CD­
1
(
ICR)
BR
mice
(
24/
dose)
at
0,
4,
10
or
25
mg/
kg/
day
from
gestation
days
6
through
15.
One
group
of
12
presumed
pregnant
females
underwent
caesarean
section
while
the
other
12
pregnant
females
were
allowed
to
deliver
naturally.

There
were
no
maternal
deaths.
No
clinical
signs
or
post
mortem
observations
were
attributed
to
test
article
administration.
Although
not
statistically
significant,
the
body
weight
in
the
high­
dose
animals
(
25
mg/
kg/
day)
was
5%
lower
than
the
controls
on
day
18
of
gestation.
In
this
group,
the
body
weight
gains
were
7
and
11%
lower
than
the
controls
from
gestation
days
6­
15
and
0­
18,
respectively.
The
NOAEL
for
maternal
toxicity
is
10
mg/
kg/
day;
the
LOAEL
is
25
mg/
kg/
day
based
on
the
slight
decrease
in
4
body
weight
and
body
weight
gains.

Although
not
statistically
significant,
dinocap
at
25
mg/
kg/
day
caused
the
following:
reduction
in
numbers
of
corpora
lutea,
implantation
size,
litter
size,
and
the
percent
of
dams
with
any
resoprtions.
The
number
of
total
resorption
and
dead
or
resorbed
conceptuses/
litter
in
the
high­
dose
animals
were
increased
(
p<
0.05)
when
compared
to
the
controls.
In
addition,
dinocap
at
25
mg/
kg/
day
caused
the
following
when
compared
to
the
controls:
reduction
in
live
fetal
body
weights
(
29%
less
than
the
controls,
p<
0.01);
increased
incidence
of
cleft
palate
(
p<
0.01),
"
eye
lids
open"
(
p<
0.01),
and
head
tilt;
and
an
effect
on
swimming
performance
(
p<
0.01)
(
as
measured
by
mice
which
sank
and
required
rescue
or
swam
on
their
side).

In
the
10
mg/
kg/
day
group,
the
number
of
total
resorption
was
increased
(
p<
0.05)
and
live
fetal
body
weights
were
decreased
(
7%
lower
than
the
controls,
p<
0.05).
However,
these
differences
from
control
groups
are
considered
to
be
of
little
or
no
toxicological
significance.
In
the
10
mg/
kg/
day
group,
in
addition,
a
slight
(
non­
significant)
increased
incidences
in
cleft
palate
and
eyelids­
open
occurred
relative
to
the
control
group.
Due
to
the
absence
of
any
occurrence
in
either
concurrent
or
historical
controls,
the
NOAEL
is
set
conservatively
at
4
mg/
kg/
day.

Natural
delivery
data
showed
that
viability
index,
number
of
live
precull
on
day
4
divided
by
number
of
live
on
day
1,
was
decreased
(
p<
0.01)
at
25
mg/
kg/
day
(
87%
versus
97­
100%)
in
the
control
and
two
lower
dose
groups.
Lactation
index
was
reduced
(
p<
0.01)
in
the
4
mg/
kg/
day
group
only.
However,
this
was
primarily
due
to
8
pups
from
one
litter
dying
by
day
7
of
weaning.

The
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

This
study
is
classified
as
ACCEPTABLE/
NONGUIDELINE
and
does
not
satisfy
the
guideline
data
requirement
for
a
developmental
study
(
83­
3a)
in
mice.
The
study
was
designed
to
answer
specific
question
(
the
inner
ear
formation).
The
Agency
requested
that
the
registrant
perform
a
"
modified"
developmental
toxicity
study
in
mice
in
order
to
elucidate
developmental
toxicity
potential
of
purified
dinocap
(
Q.
Bui
of
the
Agency
to
D.
Edwards,
dated
10/
19/
88,
Tox.
Doc.
No.
007457).

Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

Uncertainty
Factor(
s):
An
uncertainty
factor
of
100
was
applied
to
account
for
interspecies
extrapolation
(
10
x)
and
intra­
species
variability
(
10
x).
5
ACUTE
RfD
(
females
13+)
:
4
mg/
kg
(
NOAEL)
=
0.04
mg/
kg
100
(
UF)

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
This
endpoint
is
appropriate
for
females
13+
subpopulation
only
since
the
end
point
is
an
in
utero
affect.

There
is
evidence
to
suggest
that
purified
dinocap
(
94.4%
a.
i.)
is
a
developmental
toxicant
in
mice
at
doses
which
were
not
maternally
toxic
(
see
executive
summary
described
above).
However,
technical
dinocap
(
84%
a.
i.)
is
also
a
developmental
toxicant
in
mice
at
doses
which
were
maternally
toxic
(
Rogers
J.
M.
et
al.
1986,
EPA's
Developmental
Biology
Division/
HERL.
The
doses
used
in
this
study
were
5,
10,
20,
40,
80,
and
120
mg/
kg/
day.
There
were
no
live
fetuses
at
the
120
mg/
kg
dose
level.
Dose­
related
decreases
in
gravis
uterus
weight
and
fetal
weight
were
significant
at
all
remaining
doses
of
dinocap.
Cleft
palate
was
found
in
fetuses
at
5
(
0.4%),
20
(
23.6%),
40
(
75.7%),
and
80
(
74.1%)
mg/
kg/
day.
There
was
also
a
dose­
related
increase
in
supernumerary
ribs,
but
a
low
frequency
of
exencephaly
and
umbilical
hernia
at
high
doses.
The
developmental
toxicity
potential
of
dinocap
was
thus
demonstrated
at
doses
well
below
those
causing
maternal
toxicity
(
LOAEL
=
80
mg/
kg
as
characterized
by
significant
decrease
in
weight
gain)
(
HED
Doc.
007456,
Nov
25,
1987).
The
LOAEL
for
developmental
toxicity
is
<
5
mg/
kg/
day
(
LDT).

Since
the
new
formulation
is
the
technical
product
with
92.2%
a.
i.,
the
HIARC
selected
the
study
conducted
with
the
new
formulation.

This
Risk
Assessment
is
Required.

For
General
Population
Dose
and
Endpoint
for
Risk
Assessment:
No
appropriate
endpoint
was
identified
for
this
population
group
because
there
were
no
effects
attributable
to
a
single
dose
was
identified
in
oral
toxicology
studies
including
developmental
toxicity
studies
in
mice
and
rabbits.

B.
Chronic
dietary
[
Reference
Dose
(
RfD)]

The
following
RfD
was
established
in
1994.

Study
Selected:
Chronic
Feeding
Study
­
Dog
Guideline
#:
83­
1b
Accession
No.:
247957
Executive
Summary:
6
In
a
chronic
toxicity
study
(
Accession
No.
247957),
technical
dinocap
(
78%
a.
i.)
was
administered
to
Beagle
dogs
(
4/
sex/
dose)
in
the
diet
at
levels
of
0,
15,
60
or
varying
levels
of
120­
240
ppm
(
0,
0.375,
1.5
or
3­
6
mg/
kg/
day
based
on
a
conversion
factor
of
1
ppm
=
0.025
mg/
kg/
day)
for
2
years.
[
The
test
compound
in
the
high
dose
group
was
fed
at
240
ppm
for
1
week,
removed
completely
from
the
diet
and
restarted
at
120
ppm
for
4­
30
weeks,
increased
again
to
240
ppm
for
11
days,
removed
completely,
and
then
restarted
at
180
ppm
for
33­
61
weeks.]

Treatment
of
dogs
with
varying
levels
of
120­
240
ppm
of
dinocap
was
lethal.
Four
dogs
(
2
males
and
2
females)
died
during
the
first
43
weeks.
One
died
from
unexplained
causes
and
the
other
3
deaths
were
related
to
dinocap
treatment.
The
remaining
4
dogs
had
significant
reduction
in
body
weights
and
food
consumption
and
they
were
sacrificed
during
week
62
because
of
weight
loss
and
poor
condition.
Other
compound
related
effects
included
occasional
ataxia
and
clonic
convulsions,
salivation,
decreased
activity,
and
rapid
and
labored
respiration.

Ocular
examination
revealed
changes
in
the
tapetum,
retina
and
ocular
disc
of
all
4
high
level
dogs
examined
(
4
died
before
examination)
and
6/
8
of
these
dogs
had
histologic
retinal
atrophy.

The
only
treatment
related
effects
noted
in
dogs
fed
60
ppm
of
dinocap
were
ophthalmoscopic
changes
in
7/
8
dogs
and
histologic
retinal
atrophy
in
3/
8
dogs.

Levels
of
15
and
60
ppm
of
dinocap
did
not
have
an
effect
on
oxidative
phosphorylation
in
liver
mitochondria;
mitochondria
from
dogs
in
the
high
level
were
not
tested.

Under
the
conditions
of
this
study,
dinocap
did
not
significantly
affect
hematology,
clinical
chemistry
parameters,
and
cholinesterase
activity
of
plasma,
RBC
or
brain
at
15
and
60
ppm.
Due
to
poor
conditions
of
the
high
dose
animals
the
certain
clinical
chemistry
parameters
such
as
albumin
and
globulin
levels
were
affected.

The
NOAEL
for
systemic
toxicity
is
15
ppm
(
0.375
mg/
kg/
day);
the
LOAEL
is
60
ppm
(
1.5
mg/
kg/
day)
based
on
ophthalmoscopic
changes
and
histologic
retinal
atrophy.

This
chronic
feeding
study
in
dogs
is
classified
as
Acceptable/
guideline
and
satisfies
the
guideline
data
requirement
for
a
chronic
toxicity
study
(
83­
1b)
in
dogs.

Dose
and
Endpoints
for
Risk
Assessment:
The
Systemic
Toxicity
NOAEL
=
0.375
mg/
kg/
day
and
LOAEL
=
1.5
mg/
kg/
day
in
male
dogs,
based
on
ophthalmoscopic
changes
and
histologic
retinal
atrophy.

Uncertainty
Factor(
s):
An
uncertainty
factor
of
100
is
proposed
to
account
for
interspecies
extrapolation
(
10X)
and
intra­
species
variability
(
10X).

Chronic
RfD:
0.375
mg/
kg/
day
(
NOAEL)
=
0.00375
g/
kg/
day
7
100
(
UF)
Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
endpoint
was
selected
from
the
chronic
dog
study
because
dogs
appear
to
be
more
sensitive
species
than
rats
or
mice.
Although
this
dog
chronic
study
was
conducted
with
dinocap
with
78%
a.
i.,
the
endpoint
was
selected
from
this
because
no
dog
chronic
study
is
available
with
new
formulation
(
92%
a.
i.).

C.
Occupational
/
Residential
Exposure
1.
Dermal
Absorption
Study
Selected:
Dermal
Penetration
Study
in
Monkey
Guideline
#:
85­
2
Accession
No.:
260614
Executive
Summary:

In
a
dermal
penetration
study
(
Accession
No.
260614),
14C­
ring­
labeled
dinocap
(
94%
a.
i.)
was
dermally
applied
to
female
Rhesus
monkeys
(
4/
dose)
at
the
rate
of
40
(
group
2a:
water­
wash),
40
(
group
2b:
ethanol­
wash)
and
2500
(
group
3:
ethanol­
wash)
ug/
cm2
for
6
hours.
The
application
area
was
40,
40
and
0.64
cm2
for
groups
2a,
2b
and
3,
respectively.
Six
hours
after
dermal
exposure,
the
application
site
was
washed
with
water
saturated
cotton
balls
(
group
2a)
or
ethanol
laden
cotton
balls
followed
by
water
laden
cotton
balls
(
groups
2b
and
3).

The
recovery
of
radioactivity
in
4
days
following
6
hours
exposure
to
40
(
water­
wash),
40
(
ethanol­
wash),
and
2500
(
group
3:
ethanol­
wash)
ug/
cm2
was
10.3,
5.1,
and
2.6%
of
the
applied
dose
in
urine
and
3.9,
7.3,
and
1.6%
of
the
dose
in
feces,
respectively.

The
recovery
of
radioactivity
in
dermal
wash
samples
after
6
hours
exposure
to
40
(
water­
wash),
40
(
ethanol­
wash),
and
2500
(
group
3:
ethanol­
wash)
ug/
cm2
was
17.5,
40.7,
and
75.2%
of
the
applied
dose,
respectively.
The
recovery
data
indicated
that
the
use
of
ethanol
as
washing
solution
(
groups
2b
and
3)
apparently
was
more
effective
in
removing
the
test
chemical
from
the
application
site
than
water.

Total
recovery
of
radioactivity
in
dermal
wash
samples
and
excreta
(
urine
and
feces)
in
4
days
following
6
hours
exposure
to
40
(
water­
wash),
40
(
ethanol­
wash),
and
2500
(
group
3:
ethanol­
wash)
ug/
cm2
was
49.28,
71.72,
and
84.94%
of
the
applied
dose,
respectively.
[
Note:
Some
radiolabel
may
still
be
retained
at
the
original
application
site.
However,
amounts
of
dose
remained
on
the
skin
were
not
measured.]

An
additional
excretion
study
of
dinocap
in
four
monkeys
was
conducted
after
a
single
intravenous
administration
of
14C­
ring­
labeled
dinocap
at
0.2
mg/
kg.
The
recovery
of
radioactivity
in
the
urine
and
feces
were
49.2
and
35.3%
of
the
injected
dose
in
4
days,
respectively.
8
Dermal
absorption
of
dinocap
in
4
days
following
6
hours
exposure
to
40
(
water­
wash
group),
40
(
ethanol­
wash
group)
and
2500
ug/
cm2
(
ethanol­
wash
group)
was
42.4,
20.9,
and
10.6%
of
the
applied
dose,
respectively,
using
the
following
equation:

Dermal
absorption
=
14C
urinary
excretion
(
dermal)
x
100
14C
urinary
excretion
(
i.
v.)

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
data
requirement
for
a
dermal
penetration
study
(
85­
2)
in
monkeys.

Percentage
(%)
Dermal
Absorption:
42.4%
in
4
days
following
6
hours
exposure.
Washing
skin
with
water
is
normally
done.
Ethanol
washing
may
not
be
appropriate
in
the
field
situation.
Therefore,
water
wash
group
is
preferred
over
ethanol
wash
groups.

Comments
about
Dermal
Absorption:

From
the
above
monkey
dermal
absorption
study,
HIARC
selected
4
day
excretion
data
instead
of
one
day
excretion
data
because
the
experimental
approach
utilized
to
determine
dermal
absorption
preclude
estimation
of
dermal
absorption
after
one
day.
Estimation
of
dermal
absorption
using
4
day
excretion
data
reflect
proper
correction
for
urinary
excretion
of
dinocap
following
i.
v.
dosing.

There
is
a
dermal
penetration
study
(
Accession
No.
259639)
in
rabbits.
This
study
showed
that
dermal
absorption
of
dinocap
(
expressed
as
%
of
applied
dose)
in
4
days
following
6
hours
exposure
to
14C­
dinocap
at
25,
100,
and
220
mg/
kg
varied
from
3.8%
(
applied
neat
at
25
mg/
kg)
to
9.2%
(
wettable
dust
formulation
at
25
mg/
kg).
This
study
would
be
useful
when
considering
the
possible
exposure
to
the
wettable
dust
formulation.

Because
the
permeability
characteristics
of
monkey
skin
are
closer
to
human
than
the
rabbit,
the
monkey
dermal
absorption
data
is
preferred
over
rabbit
data.

2.
Short­
Term
Dermal
(
1
­
7
days)

Study
Selected:
Developmental
Toxicity
Study
in
Mice
Guideline
#:
83­
3(
a)

MRID
No.:
41313001
Executive
Summary:
See
Acute
Dietary.

Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

Comments
about
Study/
Endpoint:
Although
a
dermal
developmental
toxicity
study
in
mice
is
available,
the
HIARC
selected
the
oral
study
in
mice
because
of
the
concern
for
9
the
developmental
effects
seen
at
lower
doses,
via
the
oral
route
in
two
studies
(
LOAEL
=
10
mg/
kg/
day;
<
5
mg/
kg/
day)
compared
to
the
dermal
study
(
LOAEL
=
100
mg/
kg/
day).

In
addition,
the
endpoint
was
selected
from
the
mouse
developmental
toxicity
study
because
mice
appear
to
be
more
sensitive
species
than
rats
or
rabbits.

Also,
the
endpoint
selection
from
mouse
developmental
toxicity
is
supported
by
a
dermal
developmental
study
in
rabbits
(
ACCESSION
Nos.
256934
and
259645).
In
this
study,
dinocap
(
87.8%
a.
i.)
was
dermally
applied
at
concentrations
of
0,
25,
50,
or
100
mg/
kg/
day
to
presumed
pregnant
New
Zealand
white
rabbits
(
18/
dose)
on
gestation
days
(
GDs)
7
through
19.
Does
were
sacrificed
on
GD
29.
The
NOAEL
for
maternal
toxicity
is
50
mg/
kg/
day;
the
LOAEL
is
100
mg/
kg/
day
based
on
decreased
body
weights
and
food
consumption.
The
NOAEL
for
developmental
toxicity
is
50
mg/
kg/
day;
the
LOAEL
is
100
mg/
kg/
day
based
on
increased
litter
and
fetal
incidences
of
skull
bone
islands
and
accessory
skull
bones
and
decreased
fetal
weight.

This
Risk
Assessment
for
Short­
Term
is
Required.

3.
Intermediate­
Term
Dermal
(
1­
Week
to
Several
Months)

Mouse
developmental
toxicity
study
Guideline
#:
83­
3
(
a)

MRID
No.
41313001
Executive
Summary:
Short
term.

Dose
and
Endpoint
for
Risk
Assessment:
The
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

Comments
about
Study/
Endpoint:
See
short
term.

This
Risk
Assessment
is
Required.

4.
Long­
Term
Dermal
(
Several
Months
to
Lifetime)

The
current
use
pattern
does
not
indicate
a
concern
for
Long­
Term
exposure
or
risk.
This
risk
assessment
is
NOT
required.

5.
Occupational/
residential
Exposure
 
Inhalation
(
Any­
Time
Period)

Except
for
an
acute
inhalation
toxicity
study,
the
results
of
which
place
DINOCAP
in
Toxicity
Category
III
(
LC50
=
0.9
mg/
L),
no
other
studies
are
available
via
this
route.
Therefore,
the
HIARC
selected
the
oral
NOAELs
of
4
mg/
kg/
day
from
developmental
toxicity
study
in
mice
for
10
Short­
Term
and
Intermediate­
Term
inhalation
risk
assessments.
Since
an
oral
value
is
selected,
route­
to­
route
extrapolation
should
be
as
follows:

Step
I.
The
inhalation
exposure
component
(
i.
e.,
:
g
a.
i/
day)
using
a
100%
absorption
rate
(
default
value)
and
an
application
rate
should
be
converted
to
an
equivalent
oral
dose
(
mg/
kg/
day)

Step
II.
The
dermal
exposure
component
(
i.
e.,
mg/
kg/
day)
using
a
42%
dermal
absorption
value
and
an
application
rate
should
be
converted
to
an
equivalent
oral
dose.
This
dose
should
then
be
combined
with
the
converted
oral
dose
in
Step
I.

Step
III.
To
calculate
MOE's,
the
combined
dose
from
Step
II
should
then
be
compared
to
the
oral
NOAEL
of
4
mg/
kg/
day
for
both
Short­
Term
and
Intermediate­
Term
exposures.

This
risk
assessment
is
required
for
short
and
intermediate
term
inhalation
exposure.

Based
on
the
use
pattern,
Long­
Term
inhalation
exposure
risk
assessment
is
not
required.

D.
Recommendation
for
Aggregate
Exposure
risk
Assessments
For
acute
aggregate
exposure
risk
assessment,
combine
the
high
end
exposure
values
from
food
+
water
and
compare
it
to
the
acute
RfD.

For
short­
and
intermediate­
term
aggregate
exposure
risk
assessment,
combine
the
average
values
from
food
+
water
together
with
short
or
intermediate
dermal
(
corrected
for
%
DA)
+
short
or
intermediate
inhalation
(
corrected
for
%
IA)
exposure
and
compared
to
the
oral
NOAEL.

Based
on
the
use
pattern,
chronic
aggregate
exposure
risk
assessment
is
not
required.

E.
Margins
of
Exposures
for
Occupational/
Residential
Exposure
Risk
Assessments
A
MOE
of
100
is
adequate
for
occupational
exposure
and
the
MOEs
for
residential
(
dermal
and
inhalation)
exposure
will
be
determined
during
risk
characterization
by
the
FQPA
Safety
Factor
Committee.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
The
HED
RfD/
Peer
Review
Committee
(
HED
Doc.
No.
011076
dated
June
24,
1994)
considered
that
the
carcinogenicity
phase
of
the
rat
study
(
MRID
No.
41065401
and
ACCESSION
No.
00247959)
and
the
carcinogenicity
study
in
mice
(
MRID
Nos.
418639801,
42079102)
were
considered
to
be
adequate.
The
high
dose
levels
tested
in
both
rats
and
mice
11
were
considered
to
be
adequate
for
carcinogenicity
testing.
The
treatment
did
not
alter
the
spontaneous
tumor
profile
in
either
animal
species.
The
chemical
was
classified
as
a
"
Group
E".

IV.
MUTAGENICITY
Dinocap
was
negative
for
inducing
mutations
in
all
acceptable
guideline
studies
of
the
standard
battery
of
mutagenicity
tests
except
for
Ames
studies.
In
Ames
studies,
dinocap
was
weakly
positive
at
best
and
limited
to
high
doses.
These
studies
satisfy
mutagenicity
testing
requirements.

V.
FQPA
CONSIDERATIONS
1.
Neurotoxicity:

There
are
no
neurotoxicity
studies
available
for
dinocap.
However,
neurotoxicity
in
the
form
of
clinical
signs
[
such
as
swimming
behavior
abnormalities
characterized
by
torticollis
condition
consistent
with
malformation
of
the
inner
ear
(
absence
of
otoliths)]
was
observed
in
treated
offspring
at
3
weeks
of
age
in
the
12
and
25
mg/
kg/
day
groups
in
the
developmental
toxicity
study
in
mice
(
Grey,
L.
E.
et
al.
1988:
Tox.
Applied
Pharmacol.
Vol.
92,
pp.
266­
273).
In
addition,
ophthalmoscopic
changes
and
histologic
retinal
atrophy
was
observed
in
the
chronic
study
in
dogs
(
see
chronic
study
in
dogs
described
above;
Accession
No.
247957).
Because
of
the
neuropathological
concerns
of
dinocap
as
shown
in
mice
and
dogs,
the
HIARC
recommended
an
acute
and
subchronic
neurotoxicity
studies
be
conducted.
In
addition,
in
order
to
further
define
the
neurotoxic
potential
in
the
developing
fetus
the
HIARC
recommended
a
developmental
neurotoxicity
study
be
performed.

2.
Developmental
Toxicity:

A.
Mouse
Developmental
Toxicity
Study
Executive
Summary:

In
a
developmental
toxicity
study
(
MRID
No.
41313001),
Dinocap
(
94.4%
a.
i.)
suspension
in
an
aqueous
1%
Tragacanth
Gum
was
administered
by
gavage
to
CD­
1
(
ICR)
BR
mice
(
24/
dose)
at
0,
4,
10
or
25
mg/
kg/
day
from
gestation
days
6
through
15.
One
group
of
12
presumed
pregnant
females
underwent
caesarean
section
while
the
other
12
pregnant
females
were
allowed
to
deliver
naturally.

There
were
no
maternal
deaths.
No
clinical
signs
or
post
mortem
observations
were
attributed
to
test
article
administration.
Although
not
statistically
significant,
the
body
weight
in
the
high­
dose
animals
(
25
mg/
kg/
day)
was
5%
lower
than
the
controls
on
day
18
of
gestation.
In
this
group,
the
body
weight
gains
were
7
and
11%
lower
than
the
12
controls
from
gestation
days
6­
15
and
0­
18,
respectively.
The
NOAEL
for
maternal
toxicity
is
10
mg/
kg/
day.
The
LOAEL
for
maternal
toxicity
is
25
mg/
kg/
day
based
on
the
slight
decrease
in
body
weight
and
body
weight
gains.

Although
not
statistically
significant,
dinocap
at
25
mg/
kg/
day
caused
the
following:
reduction
in
numbers
of
corpora
lutea,
implantation
size,
litter
size
and
the
percent
of
dams
with
any
resoprtions.
The
number
of
total
resorption
and
dead
or
resorbed
conceptuses/
litter
in
the
high­
dose
animals
were
increased
(
p<
0.05)
when
compared
to
the
controls.
In
addition,
dinocap
at
25
mg/
kg/
day
caused
the
following
when
compared
to
the
controls:
reduction
in
live
fetal
body
weights
(
29%
less
than
the
controls,
p<
0.01);
increased
incidence
of
cleft
palate
(
p<
0.01),
"
eye
lids
open"
(
p<
0.01),
and
head
tilt;
and
an
effect
on
swimming
performance
(
p<
0.01)
[
as
measured
by
mice
which
sank
and
required
rescue
or
swam
on
their
side).

In
the
10
mg/
kg/
day
group,
the
number
of
total
resorption
was
increased
(
p<
0.05)
and
live
fetal
body
weights
were
decreased
(
7%
lower
than
the
controls,
p<
0.05).
However,
these
differences
from
control
groups
are
considered
to
be
of
little
or
no
toxicological
significance.
In
the
10
mg/
kg/
day
group,
in
addition,
a
slight
(
non­
significant)
increased
incidences
in
cleft
palate
and
eyelids­
open
occurred
relative
to
the
control
group.
Due
to
the
absence
of
any
occurrence
in
either
concurrent
or
historical
controls,
the
NOAEL
is
set
conservatively
at
4
mg/
kg/
day.

Natural
delivery
data
showed
that
viability
index,
number
of
live
precull
on
day
4
divided
by
number
of
live
on
day
1,
was
decreased
(
p<
0.01)
at
25
mg/
kg/
day
(
87%
versus
97­
100%)
in
the
control
and
two
lower
dose
groups.
Lactation
index
was
reduced
(
p<
0.01)
in
the
4
mg/
kg/
day
group
only.
However,
this
was
primarily
due
to
8
pups
from
one
litter
dying
by
day
7
of
weaning.

The
NOAEL
for
developmental
toxicity
is
4
mg/
kg/
day;
the
LOAEL
for
developmental
toxicity
is
10
mg/
kg/
day
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

This
study
is
classified
as
ACCEPTABLE/
NONGUIDELINE
and
does
not
satisfy
the
guideline
data
requirement
for
a
developmental
study
(
83­
3a)
in
mice.
The
study
was
designed
to
answer
specific
question
(
the
inner
ear
formation).
The
Agency
requested
that
the
registrant
perform
a
"
modified"
developmental
toxicity
study
in
mice
in
order
to
elucidate
developmental
toxicity
potential
of
purified
dinocap
(
Q.
Bui
of
the
Agency
to
D.
Edwards,
dated
10/
19/
88,
Tox.
Doc.
No.
007457).

B.
Rabbit
Developmental
Toxicity
Study
In
one
developmental
toxicity
study
(
ACCESSION
Nos.
251713,
255892,
Report
No.
83R­
022),
dinocap
(
84%
a.
i.)
in
aqueous
1%
(
w/
v)
tragacanth
gum
was
administered
to
pregnant
New
Zealand
white
rabbits
(
18/
dose)
by
gavage
at
doses
of
0,
3,
12,
48,
or
64
mg/
kg/
day
on
gestation
days
(
GDs)
7
through
19.
In
a
second
developmental
toxicity
13
study
(
ACCESSION
Nos.
252443,
255892;
Report
No.
83R­
113),
dinocap
(
87%
a.
i.)
was
administered
by
gavage
to
pregnant
rabbits
(
24­
48/
dose)
at
concentrations
of
0,
0.1,
0.5,
or
48
mg/
kg/
day.
These
two
studies
were
considered
jointly
to
satisfy
regulatory
requirements.
All
does
were
sacrificed
on
GD
29.

Part
1
(
Study
Report
No.
83R­
022)

Maternal
toxicity
­
Two
controls
died
as
a
result
of
a
dosing
error.
All
other
animals
survived
to
scheduled
sacrifice.
Decreased
(
p<
0.1)
body
weights
were
noted
during
GDs
25­
29
at
12
mg/
kg
and
body
weight
gains
were
also
reduced
(
945%,
not
statistically
significant
[
NS])
during
GDs
7­
20.
Decreased
fecal
output
was
noted
at
dose
levels
of
$
12
mg/
kg.

Five
abortions
occurred,
two
at
48
mg/
kg
and
three
at
64
mg/
kg.
When
compared
to
concurrent
controls,
observations
in
the
48
and
64
mg/
kg
animals
were
as
follows:
decreased
(
p<
0.05)
body
weights
from
GDs
7­
29;
absolute
weight
loss
during
GDs
7­
20;
reduced
body
weight
gains
(
48
mg/
kg,
9289%;
64
mg/
kg,
9267%)
during
GDs
7­
20;
and
reduced
(
noted
as
significant;
no
p­
value
provided)
body
weight
gains
on
GDs
11,
15,
20,
25,
and
29.

No
treatment­
related
changes
were
noted
in
maternal
necropsy
observations.

Developmental
toxicity
­
Litter
size
was
reduced
(
p<
0.05
at
12
mg/
kg)
in
all
treated
groups
when
compared
to
concurrent
controls.
The
mean
number
of
resorptions/
litter
for
the
0,
3,
12,
48,
and
64
mg/
kg
groups
was
0.44,
0.93,
1.33,
1.29,
and
1.57,
respectively;
the
historical
control
data
reported
a
mean
of
1.02.
The
number
of
litters
with
2
or
more
resorptions
was
increased
in
the
48
and
64
mg/
kg
groups.
Decreased
(
p<
0.05)
fetal
weights
were
observed
at
48
and
64
mg/
kg.

During
visceral
examination,
hydrocephaly
was
observed
only
in
the
treated
animals;
in
addition,
statistical
analysis
revealed
a
significant
dose­
response
relationship,
but
no
dose­
related
increase
in
severity
was
noted.

Upon
skeletal
examination,
neural
tube
or
skull
malformations
were
observed
at
all
dose
levels
as
follows
(
fetuses/
litter):
3
mg/
kg
(
9/
5),
12
mg/
kg
(
4/
3),
48
mg/
kg
(
17/
9),
and
64
mg/
kg
(
10/
5).
When
malformations
of
the
neural
tube,
spine,
and
skull
were
analyzed
together,
a
dose­
dependent
increase
was
found
with
statistical
significance
noted
at
3,
48,
and
64
mg/
kg
levels;
malformations
included
in
this
analysis
were
hydrocephaly,
scoliosis,
28
presacral
vertebrae,
short
tail,
fused
centra,
spina
bifida,
small
pinnae,
and
fused
skull
bones.
A
dose­
dependent
increase
in
the
incidence
of
bent
hyoid
arch(
es)
was
noted
as
follows
(
fetuses/
litter):
3
mg/
kg
(
2/
2),
12
mg/
kg
(
3/
2),
48
mg/
kg
(
7/
5),
and
64
mg/
kg
(
10/
6,
statistically
significant)
vs
1
control
fetus.
The
total
number
of
fetuses
with
reduced
ossification
(
hyoid,
sternebrae
5
and/
or
6,
talus,
pubis,
and
skull
bones)
was
increased
(
statistically
significant)
at
48
mg/
kg
(
27/
108
fetuses
and
9/
14
litters)
and
64
mg/
kg
(
19/
88
fetuses
and
7/
14
litters).
Scoliosis
was
observed
in
a
single
48
mg/
kg
fetus
and
5
fetuses
of
3
litters
at
64
mg/
kg
vs
0
controls.
14
Part
2
(
Study
Report
No.
83R­
113)

Maternal
toxicity
­
At
study
initiation,
assignment
to
test
groups
was
as
follows:
40,
48,
48,
and
24
females
to
the
0,
0.1,
0.5,
and
48
mg/
kg/
day
dose
levels,
respectively.
Five
deaths
occurred
during
the
study,
2
in
the
control
group,
1
in
the
0.1
mg/
kg
group,
and
2
in
the
48
mg/
kg
group.

Maternal
body
weight
gains
were
reduced
(
p<
0.05)
at
48
mg/
kg
from
GDs
7­
20.

Twelve
abortions
occurred,
two
at
0.1
mg/
kg,
one
at
0.5
mg/
kg,
and
nine
at
48
mg/
kg.
In
addition,
only
50%
of
the
48
mg/
kg
females
(
12/
24)
were
pregnant
at
GD
29.
At
48
mg/
kg,
an
increased
mean
number
of
corpora
lutea
(
817%,
NS)
was
observed.
Implantation
efficiency
(#
implantation
sites/#
corpora
lutea)
and
viability
index
(#
live
fetuses/#
implantation
sites)
were
decreased
(
p<
0.05)
at
48
mg/
kg.

Developmental
toxicity
­
The
mean
number
of
resorptions/
litter
was
0.54,
0.67,
0.54,
and
1.33
for
the
0,
0.1,
0.5,
and
48
mg/
kg
(
high­
dose,
8146%
vs
controls)
levels,
respectively.
The
number
of
viable
fetuses/
litter
was
reduced
(
913%,
NS)
at
48
mg/
kg.
There
were
no
treatment­
related
external,
visceral,
or
skeletal
malformations
or
variations
at
any
dose
level.
At
48
mg/
kg,
the
number
of
litters
and
fetuses
(
12
litters
and
80
fetuses)
was
small
and
may
have
concealed
a
teratogenic
effect
at
this
dose
level.

The
NOAEL
for
maternal
toxicity
is
3
mg/
kg/
day;
the
LOAEL
is
12
mg/
kg/
day
based
on
decreased
body
weights.

The
NOAEL
for
developmental
toxicity
is
0.5
mg/
kg/
day;
the
LOAEL
is
3
mg/
kg/
day
based
on
increased
incidences
of
hydrocephaly
and
malformations
of
neural
tube,
spine
and
skull.

When
evaluated
separately,
each
of
these
two
studies
were
classified
as
supplementary
data;
however,
when
considered
jointly,
these
studies
are
classified
acceptable/
guideline
and
do
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rabbit
(
§
83­
3[
b]).

C.
Rabbit
Dermal
Developmental
Toxicity
Study
Executive
Summary:

In
a
dermal
developmental
study
(
ACCESSION
Nos.
256934
and
259645),
neat
dinocap
(
87.8%
a.
i.)
was
dermally
applied
at
concentrations
of
0,
25,
50,
or
100
mg/
kg/
day
to
presumed
pregnant
New
Zealand
white
rabbits
(
18/
dose)
on
gestation
days
(
GDs)
7
through
19.
Does
were
sacrificed
on
GD
29.
All
dermal
applications
were
made
to
a
clipped
area
on
the
back
of
the
rabbits
and
the
animals
were
collared
to
prevent
preening
of
the
treated
skin.
Data
from
the
range
finding
study
indicated
that
the
test
substance
could
not
be
applied
repeatedly
to
the
same
skin
site
without
resulting
in
severe
dermal
15
irritation;
therefore,
the
test
material
was
applied
to
7
sections,
each
5
x
8
cm,
for
a
total
of
40
cm2.
The
test
substance
was
removed
after
a
6­
hour
exposure
by
wiping
the
treatment
site
with
ethanol.

Maternal
toxicity
­
At
all
dose
levels,
dermal
irritation
was
observed
and
the
severity
of
the
injury
was
proportional
to
the
dose
level.
From
GDs
8­
20,
dose­
dependent
increases
(
statistically
significant)
in
erythema
and
edema
scores
were
observed
in
the
treated
groups
(
low­
dose,
0.3­
2.0;
mid­
dose,
0.4­
2.1;
high­
dose,
0.5­
3.1;
maximum
score=
4)
and
the
severity
of
the
injury
was
proportional
to
the
concentration
applied.
Signs
of
recovery
were
noted
in
all
dose
groups
on
GD
29.
One
25
mg/
kg
doe
aborted
and
died
on
GD
26
and
one
50
mg/
kg
doe
aborted
on
GD
23
and
was
subsequently
sacrificed.
At
100
mg/
kg,
clinical
signs,
such
as,
soiled
anal
area
(
6/
18
treated
vs
3/
18
controls)
and
irregular
feces
(
18/
18
treated
vs
10/
18
controls)
were
noted;
additionally,
systemic
toxicity,
characterized
by
decreases
(
p<
0.05)
in
food
consumption
(
921%,
GDs
6­
20,
g/
day)
and
body
weight
gains
(
9153%,
GDs
7­
20;
9122%,
GDs
0­
29;
9290%,
GDs
0­
20
minus
fetal
weight)
was
observed.
Dermal
administration
of
the
test
substance
did
not
affect
maternal
survival,
reproductive
status,
fetal
weight,
or
percent
males.

Developmental
toxicity
­
Upon
skeletal
examination,
treatment­
related
effects
were
observed
regarding
skull
bone
islands
at
100
mg/
kg.
Bone
islands
in
the
skull
were
observed
in
one
fetus
each
of
the
control
(
fetal
incidence,
0.8%;
litter
incidence,
5.8%)
and
low­
dose
group
(
fetal,
0.9%;
litter,
6.3%)
and
in
3
fetuses
of
3
litters
(
fetal,
2.6%;
litter,
21.4%)
of
the
high­
dose
group;
this
finding
was
not
reported
in
the
historical
control
data.
Above
the
historical
control
mean,
accessory
skull
bones
was
observed
in
all
treated
groups
at
fetal
and
litter
incidences,
respectively,
as
follows:
low­
dose,
1.8
(
12.5);
mid­
dose,
5.2
(
30.0);
and
high­
dose
0.9
(
7.1)
vs
concurrent
controls
at
0
(
0)
and
historical
controls
at
0.66
(
4.3).
The
litter
incidence
of
accessory
skull
bones
and
skull
bone
islands
combined
was
9/
40
(
22.5%)
as
compared
to
concurrent
controls
at
1/
17
(
5.9%)
and
historical
controls
at
6/
138
(
4.3%);
these
findings
are
suggestive
of
fetal
toxicity
at
all
dose
levels
tested.

Neural
tube
or
skull
malformations
were
reported
in
all
treated
groups
with
litter
incidences
of
11.8,
18.7,
20.0,
and
21.4%
in
the
control,
25,
50,
and
100
mg/
kg
groups,
respectively.
Although
these
increased
incidences
were
not
statistically
significant,
the
slight
increase
noted
in
the
treated
groups
may
suggest
that
a
definitive
teratogenic
response
may
be
observed
at
a
higher
dose
level.
Scoliosis
with
or
without
rib
anomalies
was
noted
only
in
the
treated
groups
at
a
low
incidence
(
single
litter
at
each
dose
level)
and
was
beyond
the
historical
control
mean
(
3/
40=
7.5%
vs
0%
of
concurrent
controls
and
3/
155=
1.9%
historical
controls);
this
finding
was
also
observed
in
a
dose­
dependent
manner
in
a
previous
oral
teratology
study,
and
therefore,
the
toxicological
significance
of
scoliosis
relative
to
dinocap
exposure
is
unknown.

This
study
has
undergone
peer
review
(
Accession
No.
004905).

Based
on
local
effects,
the
NOAEL
for
maternal
toxicity
is
not
established.
The
LOAEL
for
maternal
toxicity
is
25
mg/
kg/
day
based
on
dermal
irritation
at
the
16
application
site
at
the
lowest
dose
tested.

Based
on
systemic
effects,
the
NOAEL
for
maternal
toxicity
is
50
mg/
kg/
day;
the
LOAEL
is
100
mg/
kg/
day
based
on
decreased
body
weights
and
food
consumption.

The
NOAEL
for
developmental
toxicity
is
50
mg/
kg/
day;
the
LOAEL
for
is
100
mg/
kg/
day
based
on
increased
litter
and
fetal
incidences
of
skull
bone
islands
and
accessory
skull
bones
and
decreased
fetal
weight.

This
study
is
classified
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
dermal
developmental
study
in
rabbits
(
§
83­
3[
b]).

3.
Reproductive
Toxicity:

Executive
Summary
In
a
2­
generation
reproduction
study
(
MRID
No.
41542501),
Dinocap
(
96%
a.
i.)
was
administered
to
Crl:
CD
BR(
VAF/
Plus)
rats
(
26/
sex/
dose)
in
the
diet
at
levels
of
0,
40,
200
or
1000/
400
ppm
(
0,
2.6­
3.7,
12.9­
18.0
or
65.1­
77.3/
32.4­
38.7
mg/
kg/
day).
Because
of
increased
pup
mortality
during
the
first
7
days
post­
lactation,
the
1000
ppm
was
reduced
to
400
ppm
in
the
F1
pups
at
weaning
(
week
19
of
the
study).

The
body
weights
of
F0
high­
dose
males
were
4­
8%
lower
than
controls
(
p<
0.01)
throughout
the
study.
In
this
group,
the
body
weight
gains
were
12,
12
and
10%
(
p<
0.01)
lower
than
the
controls
at
the
0­
6,
0­
10,
and
0­
19
week
periods,
respectively
and
food
consumption
were
statistically
significantly
lower
than
controls
at
the
0­
1,
1­
2,
2­
3,
3­
4
and
6­
7
week
periods.
During
the
premating
period,
the
body
weights
of
F0
high­
dose
females
were
6­
7%
lower
than
controls
(
p<
0.05
or
0.01)
from
weeks
6
through
10.
In
this
group,
the
body
weight
gains
were
26
and
20%
lower
(
p<
0.01)
than
controls
at
the
0­
6
and
0­
10
week
periods,
respectively
and
food
consumption
were
statistically
significantly
lower
than
controls
at
0­
1
and
3­
10
week
periods.

During
gestation
in
F0
high­
dose
females,
the
body
weights
were
6­
7%
lower
than
controls
(
p<
0.05
or
0.01)
at
days
0,
6,
10
and
15,
and
food
consumption
was
statistically
significantly
lower
than
controls
at
0­
6,
6­
10
and
10­
15
day
periods.
During
lactation
in
F0
high­
dose
females,
the
body
weights
were
6­
9%
lower
than
controls
(
p<
0.05
or
0.01)
at
0,
4,
7
and
14
days.

The
body
weights
of
F1
high­
dose
males
were
44,
41,
15,
9,
9,
7
and
7%
lower
than
controls
(
p<
0.05
or
0.01)
at
0,
1,
6,
10,
16,
22
and
28
week
periods,
respectively.
Food
consumption
was
statistically
significantly
lower
than
controls
at
weeks
1­
8
and
14­
16.
The
body
weights
of
F1
high­
dose
females
were
37­
41%
lower
than
controls
(
p<
0.01)
at
weeks
0
and
1.

During
gestation
in
F1
high­
dose
females,
the
body
weights
were
8­
9%
lower
(
p<
0.05
or
0.01)
than
respective
control
values
at
all
measuring
intervals,
and
food
consumption
17
was
statistically
significantly
lower
than
controls
at
days
0­
6.
During
lactation
in
F1
high­
dose
females,
the
body
weights
were
5­
9%
lower
than
respective
control
values
(
p<
0.05
or
0.01)
at
all
measuring
intervals.

The
test
chemical
did
not
significantly
affect
any
of
the
reproductive
parameters.

The
NOAEL
for
reproductive
toxicity
is
equal
to
or
greater
than
1000/
400
ppm
(
65.1­
77.3/
32.4­
38.7
mg/
kg/
day,
HDT)
and
the
LOAEL
is
not
established.

In
F1
offspring
in
1000
ppm
group,
pup
weights
were
24,
28
and
32%
less
than
control
values
at
days
7,
14
and
21,
respectively.
In
F2
offspring
in
400
ppm
group
(
highest
concentration),
liveborn
pups
delivered,
live
pups
on
day
0
(
birth)
of
lactation,
and
live
pups
on
day
4
(
precull)
were
15,
17
and
7%
lower
than
controls,
respectively.

In
high­
dose
group,
relative
liver
weights
were
6­
8%
higher
(
p<
0.05)
than
respective
control
values
in
F0
males,
F0
females
and
F1
females.
In
addition,
in
F0
high­
dose
males,
relative
testes
weights
were
8%
higher
(
p<
0.05)
than
respective
control
values.

The
NOAEL
for
parental
toxicity
is
200
ppm
(
12.9­
18.0
mg/
kg/
day)
and
the
LOAEL
is
1000/
400
ppm
(
65.1­
77.3
/
32.4­
38.7
mg/
kg/
day)
based
on
decreased
body
weight
gain.

The
NOAEL
for
offspring
toxicity
is
200
ppm
(
12.9­
18.0
mg/
kg/
day)
and
the
LOAEL
is
1000/
400
ppm
(
65.1­
77.3
/
32.4­
38.7
mg/
kg/
day)
based
on
increased
pup
mortality
during
the
first
7
days
post­
lactation
(
F1
offspring,
1000
ppm),
decreased
pup
weight/
litter,
and
reduced
number
of
pups/
litter.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
data
requirement
for
a
multi­
generation
reproduction
study
(
83­
4)
in
rats.

4.
Additional
information
from
the
literature
There
are
no
additional
neurotoxicity
studies
or
developmental
neurotoxicity
studies
via
inhalation
or
any
other
routes
from
the
published
literature.

5.
Determination
of
Susceptibility
The
data
provided
indication
of
increased
susceptibility
in
mice
and
rabbits
to
in
utero
exposure
to
dinocap.
In
the
prenatal
developmental
toxicity
study
in
mice,
while
the
LOAEL
for
maternal
toxicity
was
25
mg/
kg/
day,
the
LOAEL
for
developmental
toxicity
was
10
mg/
kg/
day.
The
NOAELs
were
10
mg/
kg/
day
and
4
mg/
kg/
day,
respectively.
Developmental
toxicity
was
based
on
the
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.

In
the
prenatal
developmental
toxicity
study
in
rabbits,
while
the
LOAEL
for
maternal
toxicity
18
was
12
mg/
kg/
day,
the
LOAEL
for
developmental
toxicity
was
3
mg/
kg/
day.
The
NOAELs
were
3
mg/
kg/
day
and
0.5
mg/
kg/
day,
respectively.
Developmental
toxicity
was
based
on
increased
incidences
of
hydrocephaly
and
malformations
of
neural
tube,
spine,
and
skull.

In
the
two­
generation
reproduction
study
in
rats,
effects
in
the
offspring
were
observed
only
at
or
above
treatment
levels
which
resulted
in
evidence
of
parental
toxicity.

6.
Recommendation
for
a
Developmental
Neurotoxicity
Study
Based
on
the
available
data,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
recommended.

i.
Evidence
that
suggest
requiring
a
developmental
neurotoxicity
study
include
treatmentrelated
anomalies
in
the
development
of
the
fetal
nervous
system
were
observed
in
the
prenatal
developmental
toxicity
study
in
mice
at
10
mg/
kg/
day
was
seen
in
the
presence
of
maternal
toxicity
at
25
mg/
kg/
day
as
indicated
by
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
relative
to
the
controls.
In
addition,
in
the
prenatal
developmental
toxicity
study
in
rabbits,
evidence
of
developmental
toxicity
at
3
mg/
kg/
day
was
seen
in
the
presence
of
maternal
toxicity
at
12
mg/
kg/
day
as
indicated
by
increased
incidences
of
hydrocephaly
and
malformations
of
neural
tube,
spine
and
skull.

In
addition,
neurotoxicity
in
the
form
of
clinical
signs
[
such
as
swimming
behavior
abnormalities
characterized
by
torticollis
condition
consistent
with
malformation
of
the
inner
ear
(
absence
of
otoliths)]
was
observed
in
treated
offspring
at
3
weeks
of
age
in
the
12
and
25
mg/
kg/
day
groups
in
the
developmental
toxicity
study
in
mice
(
Grey,
L.
E.
et
al.
1988:
Tox.
Applied
Pharmacol.
Vol.
92,
pp.
266­
273).
Also,
ophthalmoscopic
changes
and
histologic
retinal
atrophy
was
observed
in
the
chronic
study
in
dogs
(
see
chronic
study
in
dogs
described
above;
Accession
No.
247957).

In
order
to
further
define
the
neurotoxic
potential
in
the
developing
fetus
the
HIARC
recommended
a
developmental
neurotoxicity
study
be
conducted.

7.
Determination
of
the
FQPA
Safety
Factor:

The
HIARC,
based
on
hazard
assessment
alone,
recommends
that
the
additional
10
x
factor
be
retained
because
of
the
following:

Developmental
toxicity
study
showed
increased
sensitivity
in
fetuses
as
compared
to
maternal
animals
following
in
utero
exposures
in
mice
and
rabbits
and
the
need
for
a
developmental
neurotoxicity
study
in
rabbits.

The
final
recommendation
on
the
FQPA
Safety
Factor
will
be
made
by
the
FQPA
Safety
Committee.

VI.
HAZARD
CHARACTERIZATION
19
The
toxicity
data
indicate
that
dinocap
has
low
acute
oral,
dermal
and
inhalation
toxicity.
It
is
a
skin
sensitizer.
It
causes
moderate
eye
and
skin
irritation.
The
chronic
feeding
toxicity
study
in
rats
demonstrated
that
dinocap
induced
liver
toxicity
(
increased
relative
liver
weights
and
slight
to
moderate
panlobular
hepatocellular
hypertrophy)
and
thyroid
toxicity
(
increased
incidences
of
thyroid
follicular
cell
hypertrophy
and
altered
colloid).
The
chronic
feeding
toxicity
study
in
dogs
demonstrated
that
dinocap
induced
ophthalmoscopic
changes
and
histologic
retinal
atrophy.
The
carcinogenicity
data
showed
that
carcinogenic
potential
was
not
exhibited
by
dinocap
in
rats
and
mice.

Dinocap
produced
developmental
toxicity
in
mice
and
rabbits
and
it
did
not
affect
reproductive
parameters
in
rats.
Dinocap
was
negative
for
inducing
mutations
in
all
acceptable
guideline
studies
of
the
standard
battery
of
mutagenicity
tests
except
for
Ames
studies.
In
Ames
studies,
dinocap
was
weakly
positive
at
best
and
limited
to
high
doses.

Dermal
absorption
studies
showed
that
dermal
absorption
of
dinocap
(
expressed
as
%
of
applied
dose)
in
4
days
following
6
hours
exposure
to
14C­
dinocap
was
42.4%
and
9.2%
in
monkeys
and
rabbits,
respectively.

There
is
high
confidence
in
the
chronic
RfD
of
0.00375
mg/
kg/
day.
This
was
based
on
the
NOAEL
of
0.375
mg/
kg/
day
from
the
chronic
study
in
dog
and
uncertainty
factor
of
100.
The
LOAEL
for
1.5
mg/
kg/
day
in
male
dogs
was
based
on
ophthalmoscopic
changes
and
histologic
retinal
atrophy.

The
database
is
adequate
to
evaluate
FQPA
assessment
and
consists
of
developmental
studies
in
the
mice
and
rabbits,
and
a
two
generation
reproduction
study
in
the
rats.
Based
on
the
findings
in
the
developmental
toxicity
study
in
mice
and
rabbits,
there
appears
to
be
an
increased
severity
of
effects
noted
in
the
offspring
at
maternally
toxic
doses.
In
addition,
neurotoxicity
in
the
form
of
clinical
signs
[
such
as
swimming
behavior
abnormalities
characterized
by
torticollis
condition
consistent
with
malformation
of
the
inner
ear
(
absence
of
otoliths)]
was
observed
in
the
developmental
toxicity
study
in
rats.
Also,
ophthalmoscopic
changes
and
histologic
retinal
atrophy
was
observed
in
the
chronic
study
in
dogs.
In
addition,
a
30­
month
chronic/
carcinogenicity
study
in
rat
(
1980
study)
showed
an
increased
incidence
of
degeneration/
atrophy
of
the
calf
muscle
in
the
mid
and
high
dose
(
10
and
100
mg/
kg/
day)
females
and
degeneration/
atrophy
of
the
sciatic
nerve
in
the
high
dose
(
100
mg/
kg/
day)
males
and
females
(
MRID
No.
41065401;
Accession
No.
247959).

VII.
DATA
GAPS
Acute
and
subchronic
neurotoxicity
studies
in
rats
and
a
developmental
neurotoxicity
study
in
rabbit
have
been
recommended
by
the
HIARC.
20
VIII.
ACUTE
TOXICITY
Acute
Toxicity
of
Dinocap
Guideline
No.
Study
Type
MRID
No.
RESULTS
TOXICITY
CATEGORY
870.1100
Acute
Oral
­
Rat
42124301
LD
50
=
>
500
and
5,000
mg/
kg
(
both
sexes)
III
870.1200
Acute
Dermal
­
Rabbit
42124302
LD50
=>
5,000
mg/
kg
IV
870.1300
Acute
Inhalation
­
Rat
42124303
LC50=
0.9
mg/
L
III
870.2400
Eye
Irritation­
Rabbit
42124304
moderate
irritation;
Corneal
and
conjunctival
effects
at
24
hours;
corneal
effects
cleared
by
day
2
and
conjunctival
effects
cleared
by
day
7.
III
870.2500
Dermal
Irritation­
Rabbit
42124305
moderate
irritation
at
day
3
and
cleared
by
day
14.
III
870.2600
Dermal
sensitization
­
Guinea
pig
42124306
a
sensitizer
N/
A
21
IX.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
(
Female
13+)
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
MRID
No.
41313001
UF=
100
Acute
RfD
=
0.04
mg/
kg/
day
Acute
Dietary
(
General
population)
No
endpoint
established
Chronic
Dietary
NOAEL=
0.375
ophthalmoscopic
changes
and
histologic
retinal
atrophy
Chronic
feeding
 
dog
ACCESSION
No.
247957
UF=
100
Chronic
=
0.00375
mg/
kg/
day
Short­
Term
(
a)

(
Dermal)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
MRID
No.
41313001
Intermediate­
Term
(
Dermal)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
MRID
No.
41313001
Long­
Term
(
Dermal)
Not
required
under
the
registered
use
patterns
Inhalation
(
short
&
intermediate)
(
b)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
MRID
No.
41313001
Inhalation
(
long)
None
Not
required
under
the
registered
use
patterns
a
=
Since
an
oral
NOAEL
was
selected,
a
dermal
absorption
factor
of
42%
should
be
used
in
route­
to­
route
extrapolation.
b
=
Since
an
oral
NOAEL
was
selected,
an
inhalation
absorption
factor
of
100%
(
default
value)
should
be
used
in
route­
to­
route
extrapolation.
C:\
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new­
file\
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23/
2000
