Document ID: EPA-HQ-OPP-2003-0268-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-08-05T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
WASHINGTON,
D.
C.
20460
This
revised
report
reflects
a
change
from
the
previous
HIARC
report
only
in
the
selection
of
long­
term
dermal
and
inhalation
end
points
and
identification
of
datagaps.
No
other
changes
were
made.

HED
DOC.
NO.
014466
DATE:
February
8,
2001
MEMORANDUM
SUBJECT:
DINOCAP
­
Report
#
2
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Paul
Chin,
Ph.
D.
Reregistration
Branch
I
Health
Effects
Division
(
7509C)

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

TO:
William
Hazel,
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
(
Report
dated
Feb.
23,
2000,
HED
Doc.
#
014006).

At
the
HIARC
meeting
(
Dec.
1,
1999),
it
was
reported
that
there
was
no
long­
term
dermal
or
inhalation
exposure
based
on
the
current
use
pattern.
However,
the
only
dinocap
use
still
registered
in
the
U.
S.
is
the
use
on
ornamentals
in
greenhouses.
Such
uses
often
result
in
long­
term
occupational
exposure.
Therefore,
on
December
19,
2000,
the
HIARC
revisited
dinocap
to
select
long­
term
dermal
and
long­
term
inhalation
endpoints
for
risk
assessment
purposes.
2
Committee
Members
in
Attendance
Members
present
were:
William
Burnam,
Elizabeth
Doyle,
Pamela
Hurley,
Elizabeth
Mendez,
Yung
Yang,
Jess
Rowland,
Ayaad
Assaad,
Jonathan
Chen
and
Brenda
Tarplee.

Member
in
an
absentia:
David
Nixon.

Data
evaluation
prepared
by:
Paul
Chin,
Reregistration
Branch
I.

Also,
in
attendance
were:
William
Hazel
and
Whang
Phang,
RRB1.

Data
Evaluation/
Report
Presentation
Paul
Chin
Toxicologist
3
1.
INTRODUCTION
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
(
Report
dated
Feb.
23,
2000,
TXR
#
014006).

At
the
HIARC
meeting
(
Dec.
1,
1999),
it
was
reported
that
there
was
no
long­
term
dermal
or
inhalation
exposure
based
on
the
current
use
pattern.
However,
the
only
dinocap
use
still
registered
in
the
U.
S.
is
the
use
on
ornamentals
in
greenhouses.
Such
uses
often
result
in
long­
term
occupational
exposure.
Therefore,
on
December
19,
2000,
the
HIARC
revisited
dinocap
to
select
long­
term
dermal
and
long­
term
inhalation
endpoints
for
risk
assessment
purposes.

The
Health
Effects
Division
(
HED)
FQPA
Safety
Factor
Committee
met
on
March
13,
2000
to
evaluate
the
hazard
and
exposure
data
for
dinocap
and
recommended
that
the
FQPA
safety
factor
(
as
required
by
the
Food
Quality
Protection
Act
of
August
3,
1996)
be
retained
at
10x
when
assessing
the
risks
posed
from
the
use
of
this
pesticide
(
HED
DOC.
#
014071).

2.
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(
RfD)

2.1.1
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
body
weight
and
body
weight
gains.
4
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
inter­
species
extrapolation
(
10
x)
and
intra­
species
variability
(
10
x).

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.
5
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.

ACUTE
RfD
(
females
13+)
:
4
mg/
kg
(
NOAEL)
=
0.04
mg/
kg
100
(
UF)

2.1.2
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.

2.2
Chronic
Reference
Dose
(
RfD)

The
following
RfD
was
established
in
1994.

Study
Selected:
Chronic
Feeding
Study
­
Dog
Guideline
#:
83­
1b
Accession
No.:
247957
Executive
Summary:

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
6
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
inter­
species
extrapolation
(
10X)
and
intra­
species
variability
(
10X).

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.).

Chronic
RfD
=
0.375
mg/
kg/
day
(
NOAEL)
=
0.00375
mg/
kg/
day
100
(
UF)
7
2.3
Occupational
/
Residential
Exposure
2.3.1
and
2.3.2
Short­
Term
(
1­
7
days)
and
Intermediate­
Term
(
7
Days
to
Several
Months)
Incidental
Oral
Exposure
No
endpoint
selection
is
required
for
this
exposure
period
since
this
chemical
is
not
registered
for
residential
use
and
incidental
oral
exposure
is
not
expected
to
occur.

2.3.3
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:
waterwash
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
(
waterwash
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.

Dermal
Absorption
Factor:
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.

2.3.4
Short­
Term
Dermal
(
1
­
7
days)
Exposure
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
the
developmental
effects
seen
at
lower
doses,
via
the
oral
route
in
two
studies
(
LOAEL
=
10
9
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.

2.3.5
Intermediate­
Term
Dermal
(
1­
Week
to
Several
Months)
Exposure
Study
Selected:
Mouse
developmental
toxicity
study
Guideline
#:
83­
3
(
a)

MRID
No.:
41313001
Executive
Summary:
See
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.

2.3.6
Long­
Term
Dermal
(
Several
Months
to
Lifetime)
Exposure
Study
Selected:
Chronic
Feeding
Study
­
Dog
Guideline
#:
83­
1b
Accession
No.:
247957
Executive
Summary:
see
Chronic
Dietary
Dose
and
Endpoint
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.

Comments
about
Study/
Endpoint:

This
dose/
endpoint
was
also
used
to
derive
the
chronic
RfD.
10
2.3.7
Inhalation
Exposure
(
All
Duration)

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
Short­
Term
and
Intermediate­
Term
inhalation
risk
assessments.
For
Long­
term
risk
assessment,
the
HIARC
selected
the
oral
NOAEL
of
0.375
mg/
kg/
day
from
the
chronic
feeding
study
in
dogs.
Since
an
oral
value
is
selected,
route­
to­
route
extrapolation
should
be
as
follows.

When
route­
to­
route
extrapolations
is
recommended:
1)
convert
the
inhalation
exposure
(:
g/
lb
a.
i)
and
the
dermal
exposure
(
mg/
lb
a.
i)
to
oral
equivalent
doses
(
mg/
kg);
2)
combine
the
converted
oral
equivalent
doses
to
get
a
combined
dose
for
total
(
dermal
+
inhalation)
exposure;
and
3)
this
combined
dose
should
then
be
compared
with
the
oral
NOAEL
to
calculate
the
Margins
of
Exposure.

2.3.8
Margins
of
Exposures
for
Occupational/
Residential
Risk
Assessments
A
MOE
of
100
is
adequate
for
occupational
exposure
and
the
MOEs
for
residential
(
dermal
and
inhalation)
exposure
are
1000
as
determined
during
risk
characterization
by
the
FQPA
Safety
Factor
Committee.

2.4
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,
intermediate­,
and
long­
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
(
oral
equivalent
doses
were
selected
for
dermal
and
inhalation
exposures).

3.
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
were
considered
to
be
adequate
for
carcinogenicity
testing.
The
treatment
did
not
alter
the
spontaneous
tumor
profile
in
either
animal
species.
In
accordance
with
the
1986
Cancer
Risk
Assessment
Guideline,
dinocap
is
placed
in
"
Group
E";
non­
carcinogenic
to
humans.
11
4.
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.

5.
FQPA
CONSIDERATIONS
The
Health
Effects
Division
(
HED)
FQPA
Safety
Factor
Committee
met
on
March
13,
2000
to
evaluate
the
hazard
and
exposure
data
for
dinocap
and
recommended
that
the
FQPA
safety
factor
(
as
required
by
the
Food
Quality
Protection
Act
of
August
3,
1996)
be
retained
at
10x
when
assessing
the
risks
posed
from
the
use
of
this
pesticide
(
HED
DOC.
NO.
014071).

6.
HAZARD
CHARACTERIZATION
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)
12
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).

7.
DATA
GAPS
Acute
and
subchronic
neurotoxicity
studies
in
rats
and
a
developmental
neurotoxicity
study
in
rats
have
been
recommended
by
the
HIARC.
In
addition,
due
to
the
potential
of
long­
term
inhalation
exposure
the
HIARC
recommended
a
90­
day
inhalation
toxicity
study
in
rats
to
address
the
concerns
for
assessing
risks
posed
to
workers
(
greenhouse
use)
by
this
route.
13
8
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
14
9
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
UF=
100
Acute
RfD
=
0.04
mg/
kg/
day
Acute
Dietary
(
General
population)
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified.

Chronic
Dietary
NOAEL=
0.375
ophthalmoscopic
changes
and
histologic
retinal
atrophy
Chronic
feeding
 
dog
UF=
100
Chronic
=
0.00375
mg/
kg/
day
Incidental
Oral,
Short­
and
Intermediate­
Term
No
endpoint
selection
is
required
for
this
exposure
period
since
this
chemical
is
not
registered
for
residential
use
and
incidental
oral
exposure
is
not
expected
to
occur.

Short­
Term
(
a)

(
Dermal)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
Intermediate­
Term
(
Dermal)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
Long­
Term
(
Dermal)
oral
NOAEL=
0.375
ophthalmoscopic
changes
and
histologic
retinal
atrophy
Chronic
feeding
 
dog
Inhalation
(
short
&
intermediate)
(
b)
oral
NOAEL=
4
slight
(
non­
significant)
increase
in
incidences
of
cleft
palate
and
eyelids­
open
Developmental
 
mouse
Inhalation
(
long)
oral
NOAEL=
0.375
ophthalmoscopic
changes
and
histologic
retinal
atrophy
Chronic
feeding
 
dog
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:\
1­
new­
file\
dinocap\
hazid.
final.
pc036001
2/
7/
2001