Document ID: EPA-HQ-OPP-2002-0159-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-07-12T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR
NO.
0050364
MEMORANDUM
DATE:
December
10,
2001
SUBJECT:
Pronamide
(Propyzamide):
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(HIARC)
Meeting
for
the
Herbicide,
Pronamide.

FROM:
Michelle
M.
Centra,
Pharmacologist
Reregistration
Branch
III
Health
Effects
Division
(7509C)

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

TO:
Jose
Morales,
Chemist/
Risk
Assessor
Reregistration
Branch
III
Health
Effects
Division
(7509C)

PC
Code:
101701
On
November
6,
2001,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
PRONAMIDE
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PRONAMIDE
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Jess
Rowland,
Elizabeth
Doyle,
William
Burnam,
Pamela
Hurley,
David
Nixon,
Paula
Deschamp,
Susan
Makris,
John
Liccione,
and
Brenda
Tarplee.

Member(
s)
in
absentia:
Ayaad
Assaad,
Jonathan
Chen,
and
Elizabeth
Mendez.

Data
evaluation
prepared
by:
Michelle
M.
Centra,
Reregistration
Branch
III.

Also
in
attendance
were:
Jose
Morales
(HED),
Barry
O'Keefe
(HED),
Steve
Knizner
(HED),
Virginia
Fornillo
(HED),
Lucy
Shanaman
(EFED),
Kevin
Crofton
(NHEERL/
ORD),
Michael
McDavit
(SRRD),
and
Cecelia
Watson
(SRRD).

Data
Evaluation
/
Report
Presentation
_______________________
Michelle
M.
Centra
Pharmacologist
3
Cl
Cl
O
C
CH
3
N
H
CH
CH
3
1.
INTRODUCTION
Pronamide
[3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide],
trade
name
Kerb
®
,
is
a
selective,
systemic,
pre­
and
post­
emergence
herbicide
which
inhibits
root
and
shoot
growth
from
seedlings
and
is
used
to
control
a
wide
range
of
annual
and
perennial
grasses
as
well
as
certain
broadleaf
weeds.
Pronamide
is
produced
and
formulated
for
use
as
a
50­
W
wettable
powder
in
water
soluble
pouches
(Kerb
®
,
EPA
Reg.
No.
707­
159)
by
Rohm
and
Hass
Co.,
Springhouse,
Pennsylvania
and
may
be
applied
to
various
food/
feed
using
ground
spray
equipment,
by
soil
incorporation,
or
by
aircraft.
It
is
registered
for
use
in/
on
several
food
and
feed
crops
(alfalfa,
apples,
globe
artichokes,
birdsfoot
trefoil,
blackberries,
blueberries,
cherries,
clover,
crown
vetch,
endive,
grapes,
lettuce,
nectarines,
peaches,
pears,
plums,
prunes,
raspberries,
and
sainfoin).
Pronamide
is
also
registered
for
terrestrial
non­
domestic,
non­
food
use
on
woody
ornamentals
(azalea,
holly,
juniper,
pine,
rhododendron,
and
yew),
Christmas
trees,
nursery
stocks
(forsythia,
holly,
juniper,
pine,
rhododendron,
and
yew)
and
for
domestic
outdoor
uses
on
lawns,
turfs,
and
fallow
land
to
control
bermudagrass,
centipedegrass,
St.
Augustinegrass,
and
zoysiagrass.

Technical
pronamide
[also
known
as
propyzamide]
is
a
white
crystalline
solid
with
a
melting
point
of
155­
156
0
C
and
a
specific
gravity
of
0.48
g/
cc.
Pronamide
is
soluble
in
water
(15
ppm
at
25
0
C);
in
dimethyl
sulfoxide
and
dimethyl
formamide
at
33
ppm;
in
mesityl
oxide,
isophorone,
methyl
ethyl
ketone,
and
cyclohexanone
at
20
ppm;
in
methanol,
isopropanol,
and
chlorobenzene
at
12­
15
ppm;
in
butyl
cellosolve,
xylene,
acetonitrile,
and
kerosene
at
10
ppm;
and
in
nitrobenzene
and
ethylene
dichloride
at
5
ppm.
The
chemical
structure
of
pronamide
is
shown
below:

Empirical
Formula:
C12H11NOCl2
Molecular
Weight:
256.13
CAS
Registry
Number:
23950­
58­
5
On
November
6,
2001,
the
HIARC
met
to
evaluate
the
available
toxicology
data
base,
re­
assess
the
existing
chronic
RfD,
select
the
toxicological
endpoints
for
occupational
and
residential
exposure
risk
assessments,
and
assess
the
potential
susceptibility
of
infants
and
children
from
exposure
as
required
by
the
FQPA
for
the
pronamide
tolerance
reassessment
eligibility
decision
(TRED).
4
2
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(RfD)

No
appropriate
endpoint
was
available
to
quantitate
risk
to
the
general
population
from
a
single­
dose
administration
of
pronamide.
The
developmental
effect,
abortions,
were
not
considered
to
occur
after
a
single
dose
in
this
instance
because
they
were
observed
in
rabbits
during
the
postdosing
phase
of
the
study
(days
22­
24).
Therefore,
no
endpoint
was
chosen
to
quantitate
risk
to
females
13­
50
from
a
single­
dose
administration
of
pronamide.

2.2
Chronic
Reference
Dose
(RfD)

Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
In
a
chronic
oral
(dietary)
toxicity/
carcinogenicity
study
(MRID#
41714001
and
41714002),
Crl:
CD(
BR)
VAF/
Plus
Rats
(Supplier:
Charles
River
Laboratories,
Inc.,
Kingston,
NY)
received
either
0,
25,
100,
or
400
ppm
for
the
first
2
weeks
then
0,
35,
140,
or
560
ppm
for
the
next
3
weeks
and
then
0,
40,
200,
or
1000
ppm
thereafter
(equal
to
0,
1.73,
8.46,
and
42.59
mg/
kg/
day
for
males
and
0,
2.13,
10.69,
and
55.09
mg/
kg/
day
for
females,
respectively)
Kerb
®

Technical
(Purity:
96.4%;
Batch
No.
2­
5002)
in
the
diet.
Animals
were
observed
twice
daily
for
moribundity,
mortality
and
toxic
signs.
Body
weights
and
food
consumption
were
recorded
weekly
for
14
weeks
and
then
biweekly
thereafter,
food
efficiency
was
calculated
at
26
and
53
weeks.
Ophthalmological
examinations
were
conducted
on
all
animals
prior
to
study
initiation
and
in
the
control
and
high
dose
animals
at
sacrifice
at
6,
12,
and
24
months.
Blood
was
collected
from
10
animals/
sex/
dose
group
in
the
satellite
groups
at
6
and
12
months
and
from
10
animals/
sex/
dose
group
at
24
months
for
hematological
and
clinical
chemistry
studies.
Urine
was
collected
form
10
animals/
sex/
dose
group
at
5
months
and
due
to
the
small
amount
of
urine
collected,
it
was
repeated
at
6
months.
At
11
months
in
the
satellite
group
and
23
months
in
the
main
study,
urine
was
collected
from
10
animals/
sex/
dose
group
in
the
control
and
high
dose
groups
and
prior
to
sacrifice
at
24
months,
urine
was
collected
from
the
low
and
mid
dose
groups.
Animals
were
sacrificed
as
specified
at
6,
12,
and
24
months
and
received
a
complete
gross
examination,
organs
were
weighed
as
required
and
required
tissues
were
collected
and
fixed
for
histopathological
examination.

At
1000
ppm
(55.09
mg/
kg/
day),
mean
body
weights
and
body
weight
gains
were
decreased
in
female
rats.
Increased
incidences
of
non­
neoplastic
lesions
were
observed
in
the
liver,
thyroid,
and
ovaries
of
high­
dose
(1000
ppm)
rats.
In
the
liver,
centrilobular
hypertrophy
was
observed
in
males
and
females
at
12
months
(65%
in
males;
95%
in
females)
and
24
months
(20%
in
males;
48%
in
females).
Hypertrophy
was
accompanied
by
eosinophilic
cell
alteration
at
24months
(positive
trend
in
both
sexes;
pair­
wise
comparison
in
high­
dose/
controls
for
males
and
females).
The
histologic
liver
changes
were
accompanied
by
increases
in
relative
(to
body)
weight
in
the
high­
dose
groups
of
both
sexes.
In
the
thyroid,
follicular
cell
hypertrophy
was
observed
(positive
trend
in
males
and
in
females)
at
12
months
but
not
at
24
months.
The
increased
incidence
observed
at
1000
ppm
was
only
significant
(pair­
wise
comparison
in
high­
dose/
controls)
in
females.
At
24
months,
follicular
cell
hyperplasia
was
observed
in
females
(positive
trend)
but
the
increased
incidence
observed
at
5
1000
ppm
was
not
statistically
significant.
In
the
ovaries,
sertoliform
tubular
hyperplasia
(positive
trend)
was
observed
in
females
at
24
months
and
the
increase
in
incidence
observed
at
1000
ppm
was
significant
by
pair­
wise
comparison.
No
toxicologic
effects
were
observed
at
25
ppm
or
200
ppm
treated
male
and
female
rats.

The
Systemic
Toxicity
NOAEL
was
200
ppm
(8.46
mg/
kg/
day
for
males;
10.69
mg/
kg/
day
for
females)
and
the
Systemic
Toxicity
LOAEL
was
1000
ppm
(42.59
mg/
kg/
day
for
males;
55.09
mg/
kg/
day
for
females)
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

At
1000
ppm,
in
the
24­
month
phase,
both
male
and
female
rats
had
increased
rates
of
thyroid
follicular
cell
adenomas,
and
male
rats
had
an
increased
incidence
of
benign
testicular
interstitial
cell
tumors.
Thyroid
tumors
were
not
observed
until
weeks
53
and
82
for
males
and
females,
respectively,
and
testicular
tumors
were
not
observed
until
week
67.
The
increase
in
thyroid
tumor
rate
was
statistically
significant
by
pair­
wise
comparison
(p
<
0.01)
only
in
males,
but
there
was
a
positive
trend
(p
<
0.01)
for
both
sexes.
Both
high
dose
male
and
female
tumor
rates
(21%
and
10%,
respectively)
exceeded
the
historical
control
range
which
was
0­
14.8%
(mean
5%)
for
males
and
0­
9.5%
(mean
2%)
for
females
(Hazleton
Laboratories,
Vienna,
VA:
historical
control
data
for
SD
rats
obtained
from
13
studies
conducted
between
1985
and
1990).
There
were
no
significant
differences
in
thyroid
follicular
cell
carcinoma
rates
between
groups.
There
was
increasing
trends
and/
or
rates
in
combined
thyroid
follicular
cell
adenomas
and
carcinomas
(trend
p
<
0.01
in
males,
p
<
0.05
in
females;
pair­
wise
comparison
of
high
dose
males/
controls,
p
<
0.05)
which
were
a
reflection
of
the
treatment­
related
changes
in
thyroid
follicular
cell
adenoma
rates.
The
increase
in
testicular
interstitial
cell
benign
tumor
rate
was
statistically
significant
by
pair­
wise
comparison
(p
<
0.05)
and
there
was
a
positive
trend
(p
<
0.01).
In
high
dose
males,
the
tumor
rate
(27%)
exceeded
the
historical
range
of
4.8­
18.2%
with
a
mean
value
of
5.6%
(Hazleton
Laboratories,
Vienna,
VA:
historical
control
data
for
SD
rats
obtained
from
11
studies
conducted
between
1985
and
1990).
In
the
12­
month
phase,
thyroid
follicular
cell
and
testicular
interstitial
cell
neoplasia
were
not
observed
in
any
group.

Benign
pituitary
adenomas
of
the
pars
distalis
were
observed
in
every
dose
group
during
both
the
12­
and
24­
month
phases,
but
the
tumor
rates
were
statistically
comparable
among
all
groups.
The
respective
tumor
rates
for
the
0,
40,
200,
and
1000
ppm
dose
groups
were
1/
19,
0/
19,
0/
20,
and
3/
20
in
males
and
0/
20,
2/
20,
1/
19,
and
3/
20
in
females
in
the
12­
month
phase
and
31/
60,
33/
60,
35/
60,
and
34/
60
in
males
and
49/
60,
49/
60,
49/
60,
and
54/
60
in
females
in
the
24­
month
phase.

Under
the
conditions
of
this
study,
the
dosing
was
considered
adequate
for
assessing
carcinogenic
potential
of
Pronamide,
based
on
body
weight
gain
depressions
(p
<
0.05)
of
$
10%
observed
at
1000
ppm
(weeks
0­
26
in
males;
weeks
0­
52
in
females),
increased
relative
liver
weight
in
both
sexes
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid
and
ovaries.
The
statistical
evaluation
of
mortality
indicates
no
significant
incremental
changes
with
increasing
doses
of
pronamide
in
either
male
or
female
rats.

CLASSIFICATION:
This
study
is
classified
as
Acceptable­
Guideline
and
satisfies
the
guideline
requirements
(OPPTS
870.4300;
§
85­
3)
for
a
chronic
oral
(dietary)
toxicity/
carcinogenicity
study
in
rodents.
6
Dose
and
Endpoint
for
Establishing
RfD:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Uncertainty
Factor(
s):
Uncertainty
factor
of
100
was
applied
to
account
for
intraspecies
extrapolation
(10x)
and
interspecies
variability
(10x).

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
current
RfD
(0.08
mg/
kg/
day)
for
pronamide
is
based
on
the
NOAEL
of
8.46
mg/
kg/
day
established
in
the
two­
year
chronic
toxicity/
carcinogenicity
study
in
rats
(MRID
41714001,
41714002)
and
an
uncertainty
factor
of
100
(10x
for
intraspecies
extrapolation
and
10x
for
interspecies
variation).
The
LOAEL
of
42.59
mg/
kg/
day
was
based
on
increased
relative
liver
weight
and
non­
neoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries.
Since
the
long­
term
feeding/
carcinogenicity
study
in
rats
is
appropriate
for
the
route
and
duration
of
exposure
and
the
dose/
endpoint
established
in
this
study
is
the
most
protective
dose
(NOAEL
=
8.46
mg/
kg/
day)
for
the
target
effects
of
concern
(organ
toxicities
in
the
liver,
thyroid,
and
ovaries)
in
the
available
pronamide
toxicity
data
base,
it
will
remain
as
the
study
selected
for
the
chronic
RfD.

2.3
Occupational/
Residential
Exposure
2.3.1
Short­
Term
(1­
30
Days)
Incidental
Oral
Exposure
Study
Selected:
Developmental
Toxicity
in
Rabbits
Guideline
#:
870.3700
MRID
No.:
00148065,
00148064
Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(MRID#
00148065,
00148064),
pregnant
six
month
old
New
Zealand
white
rabbits
received
Pronamide
as
an
aqueous
suspension
in
0.5%
methyl
cellulose
by
gavage
from
gestation
days
7
through
19,
inclusive,
at
dose
levels
of
0,
5,
20,
or
80
mg/
kg/
day.
Each
animal
was
examined
once
daily
for
signs
of
toxicity
and
mortality.
Body
weights
were
recorded
on
gestation
days
0,
4,
7,
11,
15,
20,
25,
and
29.
All
surviving
rabbits
were
weighed
and
sacrificed
on
gestation
day
29,
the
numbers
or
corpora
lutea,
implantation
sites,
live
and
dead
fetuses
and
embyronic
deaths
were
recorded,
in
addition
the
maternal
livers,
gall
bladders
and
kidneys
(with
ureters)
were
removed
and
process
for
microscopic
examination.
All
live
fetuses
were
weighed
and
examined
for
external
abnormalities.
The
fetuses
were
then
sacrificed,
internally
sexed
and
the
viscera
was
examined
for
anomalies.
The
brain
was
examined
by
mid­
coronal
incision
and
the
heart
by
a
modified
Staples
technique.
The
fetuses
were
then
fixed
and
cleared
and
stained
in
Alizarin
red
S
for
skeletal
examinations.
Maternal
toxicity
was
noted
at
the
mid
dose
as
soiled
anal
area,
anorexia,
and
punctate
vacuolation
of
hepatocytes.
The
high
dose
group
was
also
associated
with
abortions,
late
resorptions,
and
1
death
as
well
as
additional
histopathology
in
the
liver
(hepatocellular
necrosis
eosinophilia,
swelling
of
hepatocytes,
pigmentation
of
Kupffer
cells,
etc).
The
Maternal
Toxicity
NOAEL
is
5
mg/
kg/
day
and
Chronic
RfD
=
8.46
mg/
kg/
day
(NOAEL)
=
0.08
mg/
kg/
day
100
(UF)
7
the
Maternal
Toxicity
LOAEL
is
20
mg/
kg/
day
based
on
clinical
signs
of
toxicity
and
liver
effects.

Developmental
Toxicity
was
seen
at
the
high
dose
as
abortions.
The
Developmental
Toxicity
NOAEL
is
20
mg/
kg/
day
and
the
Developmental
Toxicity
LOAEL
is
80
mg/
kg/
day
based
on
abortions.

CLASSIFICATION:
This
study
is
classified
as
Acceptable­
Guideline
and
satisfies
the
guideline
requirements
for
a
prenatal
developmental
toxicity
study
in
rabbits
(OPPTS
870.3700;
OPP
§83­
3b).

Dose
and
Endpoint
for
Risk
Assessment:
An
adjusted
dose
of
8.46
mg/
kg/
day
was
established
for
use
in
this
risk
assessment.
The
dose
selection
is
based
on
a
maternal
toxicity
NOAEL
of
5
mg/
kg/
day
and
clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes)
observed
at
the
LOAEL
of
20
mg/
kg/
day
in
the
developmental
toxicity
study
conducted
in
rabbits.

Comments
about
Study/
Endpoint:
Although
the
developmental
toxicity
study
in
rabbits
selected
for
short­
term
incidental
exposure
is
of
the
appropriate
route
(oral)
and
duration
(13
days),
the
NOAEL
(5
mg/
kg/
day)
in
this
study
is
lower
than
the
NOAEL
(8.46
mg/
kg/
day)
established
in
the
chronic
toxicity/
carcinogenicity
study
in
the
rat.
The
apparent
disparity
between
these
NOAELs
is
driven
by
the
the
doses
of
pronamide
selected
for
testing
in
these
studies.
The
HIARC
concluded
that
using
a
more
realistic
NOAEL
of
8.46
mg/
kg/
day
rather
than
5
mg/
kg/
day
would
provide
a
sufficiently
protective
dose
for
risk
assessment.

The
NOAEL
of
3
mg/
kg/
day
established
in
the
special
thyroid
study
conducted
in
male
rats
was
also
considered.
However
this
dose
was
not
selected
because
the
wide
gap
between
the
NOAEL
(3
mg/
kg/
day)
and
the
LOAEL
(67
mg/
kg/
day)
in
this
study
resulted
in
the
3
mg/
kg/
day
dose
(NOAEL)
being
artificially
low.
In
addition,
the
LOAEL
of
67
mg/
kg/
day
is
comparable
to
the
LOAEL
(56
mg/
kg/
day)
established
in
the
chronic
toxicity
/carcinogenicity
study
conducted
in
rats.

2.3.2
Intermediate­
Term
(1­
6
Months)
Incidental
Oral
Exposure
Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
NOAEL
of
12.3
mg/
kg/
day
established
in
the
90­
day
subchronic
toxicity
study
in
rats
was
considered
for
risk
assessment.
However,
the
severity
of
the
toxicities
(increased
absolute
and
relative
liver
weights
and
hepatocellular
hypertrophy)
observed
in
this
study
were
determined
to
be
minimal.
Since
this
NOAEL
(12.3
mg/
kg/
day)
is
numerically
close
to
the
NOAEL
of
8.46
mg/
kg/
day
established
in
the
8
long­
term
toxicity
study
conducted
in
rats
and
the
organ
toxicities
(liver,
thyroid,
and
ovaries)
observed
in
the
24
month
study
occurred
as
early
as
6
months
and
continued
to
study
termination,
the
HIARC
determined
that
the
chronic
feeding/
carcinogenicity
study
in
rats
is
an
appropriate
study
for
the
(1­
6
months)
intermediate­
term
exposure
duration.
Therefore,
the
selection
of
a
NOAEL
of
8.46
mg/
kg/
day
for
the
intermediate­
term
incidental
oral
exposure
scenario
is
adequately
protective
of
the
population
of
concern
(infants
and
children).

2.3.3
Dermal
Absorption
Percentage
(%)
Dermal
Absorption:
100%
dermal
absorption
(default
value).

Comments
about
Dermal
Absorption:
A
dermal
absorption
study
submitted
to
the
Agency
was
classified
as
unacceptable
because
1)
the
actual
dose
applied
to
the
skin
was
not
determined
and
2)
there
were
discrepancies
in
recovery
for
the
50W
formulation
doses
(78%
and
122%
of
nominal
doses).
In
addition,
there
were
no
dermal
toxicity
studies
submitted
which
could
be
used
for
comparison
to
oral
toxicity
studies.
A
100%
dermal
absorption
default
value
was
determined
for
risk
assessment
purposes
due
to
the
limitations
of
the
available
pronamide
toxicity
data
base
(absence
of
dermal
toxicity
studies
as
well
as
an
unacceptable
dermal
absorption
study).

2.3.4
Short­
Term
(1
­
30
Days)
Dermal
Exposure
Study
Selected:
Developmental
Toxicity
in
Rabbits
Guideline#:
870.3700
MRID
No.:
00148065,
00148064
Executive
Summary:
See
Short­
Term
(1­
30
days)
Incidental
Oral
Exposure,
Section
2.3.1
Dose
and
Endpoint
for
Risk
Assessment:
An
adjusted
dose
of
8.46
mg/
kg/
day
was
established
for
use
in
this
risk
assessment.
The
dose
selection
is
based
on
a
maternal
toxicity
NOAEL
of
5
mg/
kg/
day
and
clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes)
observed
at
the
LOAEL
of
20
mg/
kg/
day
in
the
developmental
toxicity
study
conducted
in
rabbits.

Comments
about
Study/
Endpoint:
See
Short­
Term
(1­
30
days)
Incidental
Oral
Exposure,
Section
2.3.1.
Since
there
were
no
dermal
toxicity
studies
submitted,
it
is
appropriate
to
select
an
endpoint
from
an
oral
study
of
the
appropriate
duration
of
exposure.
A
dermal
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.

2.3.5
Intermediate­
Term
(1­
6
Months)
Dermal
Exposure
Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
9
Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Comments
about
Study/
Endpoint:
See
Intermediate­
Term
(1­
6
months)
Incidental
Oral
Exposure,
Section
2.3.2.
Since
no
dermal
toxicity
studies
were
submitted,
it
is
appropriate
to
select
an
oral
endpoint
from
a
study
of
the
appropriate
duration
of
exposure.
A
dermal
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.

2.3.6
Long­
Term
(>
6
Months)
Dermal
Exposure
Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Comments
about
Study/
Endpoint:
Since
no
dermal
toxicity
studies
were
submitted,
the
selected
endpoint
is
from
an
oral
study
of
the
appropriate
duration
of
exposure.
A
dermal
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.

2.3.7
Short­
Term
(1
­
30
Days)
Inhalation
Exposure
Study
Selected:
Developmental
Toxicity
in
Rabbits
Guideline
#:
870.3700
MRID
No.:
00148065,
00148064
Executive
Summary:
See
Short­
Term
(1­
30
days)
Incidental
Oral
Exposure,
Section
2.3.1
Dose
and
Endpoint
for
Risk
Assessment:
An
adjusted
dose
of
8.46
mg/
kg/
day
was
established
for
use
in
this
risk
assessment.
The
dose
selection
is
based
on
a
maternal
toxicity
NOAEL
of
5
mg/
kg/
day
and
clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes)
observed
at
the
LOAEL
of
20
mg/
kg/
day
in
the
developmental
toxicity
study
conducted
in
rabbits.

Comments
about
Study/
Endpoint:
See
Short­
Term
(1­
30
days)
Incidental
Oral
Exposure,
Section
2.3.1.
With
the
exception
of
an
acute
oral
inhalation
toxicity
study
conducted
with
the
50W
Kerb
formulation,
no
other
inhalation
toxicity
studies
were
submitted.
Therefore,
an
oral
end
point
was
selected
from
a
study
of
the
appropriate
duration
of
exposure.
An
inhalation
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.
10
2.3.8
Intermediate­
Term
(1­
6
Months)
Inhalation
Exposure
Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Comments
about
Study/
Endpoint:
See
Intermediate­
term
(1­
6
months)
Incidental
Oral
Exposure,
Section
2.3.2.
With
the
exception
of
an
acute
oral
inhalation
toxicity
study
conducted
with
the
50W
Kerb
formulation,
no
other
inhalation
toxicity
studies
were
submitted.
Therefore,
an
oral
end
point
was
selected
from
a
oral
study
of
the
appropriate
duration
of
exposure.
An
inhalation
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.

2.3.9
Long­
Term
(>
6
Months)
Inhalation
Exposure
Study
Selected:
Chronic
Toxicity/
Carcinogenicity
in
Rats
Guideline
#:
870.4300
MRID
No.:
41714001,
41714002
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
8.46
mg/
kg/
day
based
on
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.

Comments
about
Study/
Endpoint:
With
the
exception
of
an
acute
oral
inhalation
toxicity
study
conducted
with
the
50W
Kerb
formulation,
no
other
inhalation
toxicity
studies
were
submitted.
Therefore,
an
oral
end
point
was
selected
from
a
oral
study
of
the
appropriate
duration
of
exposure.
An
inhalation
absorption
factor
of
100%
should
be
applied
for
this
risk
assessment.

2.3.10
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
A
MOE
of
100
is
required
for
short­,
intermediate­,
and
long­
term
occupational
risk
assessments
for
both
dermal
and
inhalation
routes
of
exposure.
This
includes
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variation.

The
acceptable
MOEs
for
residential
exposure
will
be
determined
by
the
FQPA
SF
committee.
11
2.4
Recommendation
for
Aggregate
Exposure
Risk
Assessments
For
short­
term
exposure,
incidental
oral,
dermal,
and
inhalation
routes
can
be
aggregated
because
of
the
use
of
oral
equivalents
and
a
common
endpoint
(clinical
signs
of
toxicity
and
liver
effects).
For
intermediate­
term
and
long­
term
exposure,
incidental
oral,
dermal
and
inhalation
routes
can
be
aggregated
because
of
oral
equivalents
and
a
common
endpoint
(increased
relative
liver
weight
and
non­
neoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries).

3
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
00417140,
00417141
Executive
Summary:
See
Chronic
Reference
Dose
(RfD),
Section
2.2
Discussion
of
Tumor
Data:
Statistical
analysis
of
tumor
rates
was
based
on
the
Cochran­
Armitage
Trend
Test
and
Fisher's
Exact
Test
for
pair­
wise
comparison
of
controls
and
each
treated
group
since
there
was
no
significant
statistical
evidence
of
differential
mortality
with
increasing
doses
of
Pronamide.

At
1000
ppm,
in
the
24­
month
phase,
both
male
and
female
rats
had
increased
rates
of
thyroid
follicular
cell
adenomas,
and
male
rats
had
an
increased
incidence
of
benign
testicular
interstitial
cell
tumors.
Thyroid
tumors
were
not
observed
until
weeks
53
and
82
for
males
and
females,
respectively,
and
testicular
tumors
were
not
observed
until
week
67.
The
increase
in
thyroid
tumor
rate
was
statistically
significant
by
pair­
wise
comparison
(p
<
0.01)
only
in
males,
but
there
was
a
positive
trend
(p
<
0.01)
for
both
sexes.
Both
high
dose
male
and
female
tumor
rates
(21%
and
10%,
respectively)
exceeded
the
historical
control
range
which
was
0­
14.8%
(mean
5%)
for
males
and
0­
9.5%
(mean
2%)
for
females
(Hazleton
Laboratories,
Vienna,
VA:
historical
control
data
for
SD
rats
obtained
from
13
studies
conducted
between
1985
and
1990).
There
were
no
significant
differences
in
thyroid
follicular
cell
carcinoma
rates
between
groups.
There
were
increasing
trends
and/
or
rates
in
combined
thyroid
follicular
cell
adenomas
and
carcinomas
(trend
p
<
0.01
in
males,
p
<
0.05
in
females;
pair­
wise
comparison
of
high
dose
males/
controls,
p
<
0.05)
which
were
a
reflection
of
the
treatment­
related
changes
in
thyroid
follicular
cell
adenoma
rates.
The
increase
in
testicular
interstitial
cell
benign
tumor
rate
was
statistically
significant
by
pair­
wise
comparison
(p
<
0.05)
and
there
was
a
positive
trend
(p
<
0.01).
In
high
dose
males,
the
tumor
rate
(27%)
exceeded
the
historical
range
of
4.8­
18.2%
with
a
mean
value
of
5.6%
(Hazleton
Laboratories,
Vienna,
VA:
historical
control
data
for
SD
rats
obtained
from
11
studies
conducted
between
1985
and
1990).
In
the
12­
month
phase,
thyroid
follicular
cell
and
testicular
interstitial
cell
neoplasia
were
not
observed
in
any
group.

Benign
pituitary
adenomas
of
the
pars
distalis
were
observed
in
every
dose
group
during
both
the
12­
and
24­
month
phases,
but
the
tumor
rates
were
statistically
comparable
among
all
groups.
The
respective
tumor
rates
for
the
0,
40,
200,
and
1000
ppm
dose
groups
were
1/
19,
0/
19,
0/
20,
and
3/
20
in
males
and
0/
20,
2/
20,
1/
19,
and
3/
20
in
females
in
the
12­
month
phase
and
31/
60,
33/
60,
35/
60,
and
34/
60
in
males
and
49/
60,
49/
60,
49/
60,
and
54/
60
in
females
in
the
24­
month
phase.
12
Adequacy
of
the
Dose
Levels
Tested:
The
dosing
was
considered
to
be
adequate
for
assessing
carcinogenic
potential
of
Pronamide,
based
on
body
weight
gain
depressions
(p
<
0.05)
of
$
10%
observed
at
1000
ppm
(weeks
0­
26
in
males;
weeks
0­
52
in
females).
Feed
consumption
was
also
depressed
(p
<
0.05)
at
1000
ppm
in
males
during
weeks
1­
13
(7%),
1­
26
(7%),
and
1­
52
(5%).
Survival
rate
was
comparable
between
groups.
The
statistical
evaluation
of
mortality
indicates
no
significant
incremental
changes
with
increasing
doses
of
Pronamide
in
either
male
or
female
rats.

3.2
Carcinogenicity
Studies
in
Mice
Carcinogenicity
Study
in
Male
and
Female
Mice,
1974
MRID
No.:
00107968,
00066794
Executive
Summary:
In
a
carcinogenicity
study
(MRID#
00107968),
pronamide
(97
%
a.
i.)
was
administered
to
male
and
female
B6C3F1
mice
(125/
sex/
dose)
in
the
diet
at
dose
levels
of
0
(control)
1000,
or
2000
ppm
for
18
months.
This
corresponds
approximately
to
0,
150,
and
300
mg/
kg/
day.
Mice
(25/
sex/
dose)
were
sacrificed
at
the
end
of
a
30­
week
treatment
period
(interim
sacrifice);
the
remaining
mice
were
sacrificed
at
the
end
of
the
18­
month
treatment
period.
The
study
design
also
included,
for
comparison,
mice
treated
with
known
hepatocarcinogens,
including
4­
6
mg/
kg/
day
diethylnitrosamine
(DEN)
and
2­
acetamidofluorene
(AAF).

There
were
no
apparent
treatment­
related
effects
on
survival.
At
the
end
of
the
18­
month
study,
survival
rates
were
comparable
between
groups
with
no
gender
differences
(rates
greater
than
90%).
Significant
decreases
in
mean
body
weights
were
observed
in
females
treated
with
2000
ppm
(the
high
dose)
during
the
study.
Mean
body
weight
gains
were
reduced
in
the
low­
dose
(1000
ppm)
females
(50­
78
weeks),
the
high­
dose
females
(0­
30
weeks;
50­
78
weeks)
and
the
high­
dose
males
(
50­
78
weeks).
At
interim
sacrifice,
absolute
and
relative
liver
weights
were
significantly
increased
in
the
low­
dose
and
high­
dose
females,
and
in
the
high­
dose
males.
At
terminal
sacrifice,
relative
liver
weights
were
significantly
increased
in
the
low­
and
high­
dose
males
and
females.

A
dose­
related
increase
in
the
incidence
of
hepatocellular
carcinomas
(respective
rates
at
0,
1000,
and
2000
ppm
were
7/
100,
18/
99,
and
24/
99)
was
observed
in
male
mice
sacrificed
at
18
months.
The
hepatocellular
carcinomas
were
characterized
as
non­
metastisizing.
Pronamide
did
not
significantly
induce
hepatocellular
carcinomas
in
female
mice
compared
to
controls
(respective
rates
at
0,
1000,
and
2000
ppm
were
0/
100,
1/
100,
and
2/
100)
at
18
months.
Some
of
the
high­
dose
males
exhibited
cholestasis
in
hepatocytes
and/
or
Kupffer's
cells.

The
LOAEL
is
1000
ppm
(150
mg/
kg/
day)
based
on
decreased
body
weight
gain
in
treated
females
and
increased
relative
(to
body
weight)
liver
weights
in
both
sexes.
A
NOAEL
was
not
established.

Under
the
conditions
of
this
study,
there
was
evidence
of
a
treatment­
related
increase
in
tumor
incidence
in
the
livers
of
male
mice
when
compared
to
controls.
Dosing
is
considered
adequate
to
assess
the
carcinogenic
potential
of
pronamide
based
on
body
weight
gain
depressions
in
treated
females
and
increases
in
relative
(to
body)
weight
of
the
liver
at
$
1000
ppm
in
both
sexes.

Although
this
study
would
not
normally
meet
the
guideline
requirement
for
a
carcinogenicity
study
(83­
2b)
in
this
species
(i.
e.,
study
deficiencies
included
lack
of
dietary
analyses
and
food
consumption
to
ensure
homogeneity,
stability,
and
concentration
of
test
material
in
the
diet,
and
to
13
assess
potential
palatability
problems
with
the
diet),
confidence
in
the
reported
tumor
data
is
enhanced
by
the
findings
of
a
subsequent
1982
special
carcinogenicity
study
in
male
mice
(MRID#
001114114)
that
confirm
the
tumor
findings.
Moreover,
if
reviewed
in
conjunction
with
the
1982
special
carcinogenicity
study
in
male
mice,
the
present
study
is
adequate
to
assess
the
carcinogenic
potential
of
pronamide
in
mice,
and
can
be
used
for
regulatory
and
risk
assessment
purposes.

Discussion
of
Tumor
Data:
A
dose­
related
increase
in
the
incidence
of
hepatocellular
carcinomas
was
observed
in
male
mice
sacrificed
at
termination
(18
months).
The
increases
in
tumor
rates
observed
at
1000
and
2000
ppm
were
both
statistically
significant
by
pair­
wise
comparison
with
controls
(p
<
0.01).
Pronamide
did
not
induce
hepatocellular
carcinomas
in
female
mice
(rates
at
termination
were
0/
100
in
controls;
1/
100
at
1000
ppm;
2/
100
at
2000
ppm).
Survival
rates
of
all
groups
were
comparable
(
$
90%).

Adequacy
of
the
Dose
Levels
Tested:
The
dosing
was
considered
to
be
adequate
for
assessing
the
carcinogenic
potential
of
Pronamide,
based
on
body
weight
gain
depressions
in
high
dose
females
(16.5%
decrease,
weeks
2­
78,
p
<
0.05),
and
increasers
in
relative
body
weight
of
the
liver
at
$
1000
ppm
in
both
sexes
[23%
at
1000
ppm
and
41%
at
2000
ppm,
p
<
0.05
(males);
14%
at
1000
ppm
and
36%
at
2000
ppm,
p
<
0.05
(females)].

Carcinogenicity
Study
in
Male
Mice,
1982
MRID
No.:
00114114,
00151822
Executive
Summary:
In
a
special
carcinogenicity
study
(MRID#
0011411),
pronamide
(93.8­
99%
a.
i.)
was
administered
to
male
B6C3F1
mice
(63/
group)
in
the
diet
at
dose
levels
of
0
(control
group1
and
control
group
2),
20,
100,
500,
or
2500
ppm
for
24
months.
This
corresponds
to
0,
3,
15,
75,
and
375
mg/
kg/
day.
The
two
matched
control
groups
received
untreated
diet.
Additional
groups
were
assigned
to
interim
sacrifices
at
6
months
(42
mice
at
0
ppm;
42
mice
at
2500
ppm)
and
at
15
and
18
months
(42/
group
including
control
groups
1
and
2,
and
20,
100,
500,
and
2500
ppm
groups).
Survival
rats
were
greater
than
93%
for
all
groups.
Both
the
500
ppm
and
2500
ppm
males
exhibited
gross
findings
of
increased
incidences
of
liver
nodules/
masses
and
enlarged
livers
at
the
24­
month
interval.
Non­
neoplastic
hepatic
effects
observed
in
males
treated
with
the
high
dose
(2500
ppm)
for
24
months,
included
increased
incidences
of
liver
enlargement,
liver
nodules/
masses,
hypertrophy,
parenchymal
necrosis,
and
cholestasis.
Administration
of
pronamide
also
resulted
in
decreased
body
weights.

The
results
of
the
special
study
confirmed
that
long­
term
exposure
of
male
mice
to
pronamide
was
associated
with
an
increased
incidence
of
hepatocellular
carcinomas
(respective
rates
at
0,
0,
20,
100,
500,
or
2500
ppm
at
the
24­
month
sacrifice
were
5/
63,
5/
63,
9/
63,
12/
63,
18/
63,
and
14/
61).
Additionally,
hepatocellular
adenomas
were
observed
(respective
rates
at
0,
0,
20,
100,
500,
or
2500
ppm
at
the
24­
month
sacrifice
were
4/
63,
6/
63,
6/
63,
7/
63,
8/
63,
and
28/
61).
The
incidence
of
adenoma
and
carcinoma
was
significantly
increased
in
the
500
ppm
and
2500
ppm
males
when
compared
to
controls.
There
was
an
apparent
progression
from
benign
to
malignant
tumors.
This
special
study
confirmed
the
carcinogenic
effect
of
pronamide
in
male
mice.

The
LOAEL
is
500
ppm
(75
mg/
kg/
day)
based
on
gross
findings
(increased
incidences
of
hepatic
nodules/
masses
and
hepatic
enlargement)
observed
after
24
months
of
treatment.
The
NOAEL
is
100
ppm
(15
mg/
kg/
day).
14
Under
the
conditions
of
this
study,
there
was
evidence
of
a
treatment­
related
increase
in
tumor
incidence
in
the
liver
of
male
mice
when
compared
to
controls.
Dosing
is
considered
adequate
to
assess
the
carcinogenic
potential
of
pronamide
based
on
liver
effects
(non­
neoplastic
lesions
and
increased
weight).

This
special
carcinogenicity
study
in
the
male
mice
is
classified
as
Acceptable­
Nonguideline.
The
data
confirmed
the
results
of
a
previously
conducted
carcinogenicity
study
in
mice
(1974,
MRID#
00107968).
When
reviewed
in
conjunction
with
the
1974
carcinogenicity
study,
these
two
studies
fulfill
the
guideline
requirement
for
a
carcinogenicity
study
[870.4200
(§
83­
2b)]
in
mice
and
can
be
used
for
regulatory
and
risk
assessment
purposes.

Discussion
of
Tumor
Data:
This
study
confirmed
the
results
of
the
MCV
1974
study;
long
term
(24
months)
exposure
of
male
mice
to
Pronamide
was
associated
with
an
increased
incidence
of
hepatocellular
carcinomas.
A
positive
trend
(p
<
0.05)
in
incidences
of
hepatocellular
carcinomas
was
observed
in
mice
sacrificed
at
24
months,
and
the
increased
tumor
rates
observed
at
$
100
ppm
were
statistically
significant
(p
<
0.05
at
100
ppm;
p
<
0.01
at
500
and
2500
ppm).
Hepatocellular
adenomas
were
not
observed
in
pair­
wise
differences
at
2500
ppm
(p
<
0.01)
in
mice
sacrificed
at
24
months
in
this
study.
There
also
appeared
to
be
a
progression
from
benign
to
malignant
tumors.
Survival
rates
were
excellent
for
all
groups
(
$
93%).

Adequacy
of
the
Dose
Levels
Tested:
The
dosing
was
considered
to
be
adequate
for
assessing
the
carcinogenic
potential
of
Pronamide,
based
on
decreased
body
weight
(30%,
months
6­
24)
and
increased
liver
weight
(30­
40%
absolute
weight
increase;
100%
relative
body
weight
increase)
in
the
high
dose
group.

3.3
Classification
of
Carcinogenic
Potential
In
accordance
with
the
Agency's
Proposed
Guideline
for
Carcinogen
Risk
Assessment
(April,
1996),
the
HED
Carcinogenicity
Peer
Review
Committee
(CPRC)
classified
Pronamide
as
a
Group
B2
chemical,
probable
human
carcinogen
with
inadequate
evidence
in
humans
(Memorandum:
N.
B.
Thoa
and
E.
Rinde,
May
26,
1993).
This
decision
was
based
on
the
finding
of
two
types
of
tumors
in
the
rat
(benign
testicular
interstitial
cell
tumors
and
uncommon
thyroid
follicular
cell
adenomas),
and
one
type
of
tumor
in
the
mouse
(hepatocellular
carcinomas).
A
linear,
low
dose
approach
(Q1*)
is
used
for
human
risk
characterization.
The
most
potent
unit
risk
Q1*,
based
on
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates,
is
2.59
x
10
­2
(mg/
kg/
day)
­1
in
human
equivalents
[converted
from
animal
to
humans
by
use
of
the
(mg/
kg
body
weight)
3/
4
interspecies
scaling
factor]
(Memorandum:
L.
Brunsman,
October
26,
2001,
TXR#
0050181).

4
MUTAGENICITY
With
the
exception
of
one
gene
mutation
toxicology
study,
the
remaining
five
mutagenicity
studies
were
reviewed
and
found
to
be
acceptable
for
regulatory
purposes
(The
acceptable
studies
statisfy
the
1991
mutagencity
guideline
requirements).
The
results
from
these
studies
indicate
that
pronamide
was
not
mutagenic
in
Salmonella
typhimurium,
Escherichia
coli
or
in
cultured
Chinese
hamster
lung
cells
and
did
not
produce
a
genotoxic
response
in
Bacillus
subtiltis
or
in
cultured
primary
rat
hepatocytes.
There
was
also
no
evidence
of
clastogenicity
in
cultured
Chinese
hamster
ovary
cells
and
pronamide
administration
did
not
result
in
the
induction
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
of
mice.
Overall,
the
data
suggest
that
pronamide
is
negative
for
mutagenicity
in
vitro
and
in
vivo.
15
Gene
Mutation
in
Salmonella
typhimurium/
mammalian
microsome
mutagenicity
assay;
OPPTS
870.5100
[§
84­
2].
In
a
microbial
reverse
gene
mutation
assay
(MRID
No.
40090601)
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
were
exposed
to
four
doses
of
propyzamide
as
RH­
315
(purity
not
specified)
ranging
from
1­
500
:
g/
plate
in
both
the
presence
and
the
absence
of
S9
activation.
The
S9
fractions
were
derived
from
Aroclor
1254­
induced
C57BL/
6
x
C3H/
Anf
male
and
female
mouse
livers
and
the
test
material
was
delivered
to
the
test
system
in
an
unspecified
solvent.
Cytotoxicity
was
reported
at
levels
>500
µg/
plate
with
or
without
the
two
S9
fractions
(male
and
female
S9
fractions
were
processed
separately)
but
no
data
were
presented.
Strains
TA1535,
TA1538,
TA98
and
TA100
responded
in
the
expected
manner
to
the
solvent
and
the
appropriate
positive
controls.
However,
the
spontaneous
revertant
colony
counts
of
strain
TA1537
+/­
S9
were
outside
of
the
expected
range
and
this
strain
failed
to
respond
to
the
positive
control,
activated
by
either
the
S9
fraction
derived
from
male
or
female
mouse
livers.
There
was
no
evidence
that
RH­
315
induced
a
mutagenic
effect
in
any
strain
at
any
dose
without
or
without
the
S9
homogenates.
However,
the
study
is
not
valid
because
neither
the
test
material
purity
nor
the
solvent
were
reported,
the
claim
of
cytotoxicity
was
not
supported,
the
number
of
replicates
at
each
experimental
concentration
was
not
listed
and
strain
TA1537
performed
poorly.
This
study
is
classified
as
Unacceptable
and
does
not
satisfy
the
guideline
requirements
for
a
bacterial
gene
mutation
assay
(84­
2).

Gene
Mutation
in
Salmonella
typhimurium
and
Escherichia
coli/
mammalian
microsome
mutagenicity
assay/
Bacillus
subtiltis
DNA
damage/
repair
assay;
OPPTS
870.5100/
5500
[§
84­
2].
In
a
series
of
microbial
assays
(MRID
No.
40090602),
propyzamide
as
KERB®
(93.7%
a.
i.)
in
dimethyl
sulfoxide
(DMSO)
was
tested
for
the
ability
to
induce
reverse
gene
mutations
in
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
and
in
Escherichia
coli
WP2
hcr
at
10
to
5000
:
g/
plate
in
both
the
presence
and
the
absence
of
S9
activation.
DNA
damage/
repair
was
assessed
in
Bacillus
subtilis
H17
(rec
+
)
and
M45
(rec
­
)
at
20
to
2000
:
g/
disc
with
and
without
S9
activation.
The
S9
fractions
were
derived
from
Aroclor
1254­
induced
Sprague
Dawley
rat
livers.
No
cytotoxicity
was
seen
up
to
the
limit
dose
(5000
µg/
plate)
with
or
without
S9
activation
in
either
the
S.
typhimurium
or
the
E.
coli
strains
or
up
to
a
dose
approaching
the
limit
of
solubility
in
the
B.
subtilis
strains.
All
strains
responded
in
the
expected
manner
to
the
solvent
and
the
appropriate
positive
controls.
There
was
also
no
evidence
that
KERB®
induced
a
genotoxic
effect
in
any
strain
at
any
dose
without
or
without
the
S9
homogenate.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirements
for
a
bacterial
gene
mutation
assay
and
a
bacterial
DNA
damage/
repair
assay
(84­
2).

Gene
Mutation/
in
vitro
mammalian
cell
assay
in
Chinese
hamster
lung
(CHL)
cells;
OPPTS
870.5300
[§
84­
2].
In
independently
performed
in
vitro
mammalian
cell
gene
mutation
assays
(MRID
No.
40211106),
cultures
of
Chinese
hamster
lung
(CHL)
fibroblasts
were
exposed
for
3
hours
to
concentrations
of
of
2.5
to
40
:
g/
mL
propyzamide
as
KERB®
Technical
(96.3%)
in
the
presence
and
absence
of
S9
activation.
Treated
cell
cultures
were
allowed
three
expression
times
(48,
96
and
168
hours)
with
or
without
S9
activation.
The
S9
homogenate
was
derived
from
rat
livers
induced
with
phenobarbitone
and
$
naphthoflavone
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide
(DMSO).
KERB®
Technical
was
slightly
cytotoxic
at
40
:
g/
mL+/­
S9;
higher
levels
were
insoluble.
Cells
responded
as
expected
to
the
solvent
and
positive
controls.
There
was,
however,
no
evidence
that
KERB®
Technical
was
mutagenic
at
any
dose
under
any
assay
condition.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
gene
mutation
in
cultured
mammalian
cell
assay
(§
84­
2).

Cytogenetics/
in
vitro
mammalian
cell
assay
in
Chinese
hamster
ovary
(CHO)
cells;
OPPTS
870.5375
[§
84­
2].
In
a
mammalian
cell
cytogenetic
assay
(MRID
No.
40211108),
cultured
Chinese
hamster
ovary
(CHO)
cells
were
exposed
continuously
to
propyzamide
as
KERB
technical
(94.2%)
at
seven
doses
ranging
from
16
25­
400
:
g/
mL
in
the
absence
of
metabolic
activation
for
14
and
24
hours.
Cells
were
also
exposed
to
S9­
activated
doses
of
25­
400
:
g/
mL
for
2
hours
and
harvested
following
a
12­
and
22­
hour
recovery
period.
The
S9
homogenate
was
derived
from
Aroclor
1254­
induced
Sprague
Dawley
rat
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.
Doses
$
250
:
g/
mL
were
insoluble;
cytotoxicity
was
not
seen
at
any
concentration.
The
positive
controls
induced
the
expected
clastogenic
responses
with
or
without
S9
activation.
There
was,
however,
no
evidence
that
KERB
technical
induced
a
clastogenic
response
either
in
the
presence
or
the
absence
of
S9
activation.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
mammalian
cell
cytogenetic
assay
(§
84­
2).

Cytogenetics/
in
vivo
mammalian
bone
marrow
chromosomal
aberration
test
in
mice;
OPPTS
870.5385
[§
84­
2].
In
an
in
vivo
cytogenetic
assay
(MRID
No.
40211105),
groups
of
10
male
B6C3F1
mice
received
single
doses
of
480,
1940
or
4940
mg/
kg
propyzamide
as
KERB®
technical
(96.8%)
once
daily
for
1
day
or
for
5
consecutive
days
and
were
sacrificed
6,
12
or
24
hours
postdosing
(acute
exposure)
or
6
hours
postdosing
(subacute
exposure).
The
highest
assayed
dose
was
determined
based
on
the
estimated
oral
LD50
>5
g/
kg
in
male
B6C3F1
mice.
The
test
material
was
delivered
to
the
animals
in
0.5%
methyl
cellulose.
At
the
appropriate
sacrifice
intervals
(6,
24
and
48
hrs
postdosing
with
4940
mg/
kg
­acute
exposure
or
6
hrs
after
the
5­
day
administration
of
1940
mg/
kg/
day),
bone
marrow
cells
were
harvested
and
were
examined
for
the
incidence
of
structural
chromosome
aberrations.
Unscheduled
deaths
occurred
as
follows:
7%
in
the
acute
high
dose
group,
10%
in
the
subacute
intermediate
dose
group
and
60%
in
the
subacute
high
dose
group
(Days
2
or
3).
Other
signs
of
compound
toxicity
observed
in
the
surviving
animals
included
signs
of
central
nervous
system
depression
[i.
e.,
lethergy
and
ataxia
­­
Day
1
(high
and
mid
dose
–acute
regimen);
lethergy,
ataxia,
reduced
spontaneous
motor
activity,
loss
of
righting
reflex,
catalepsy
and
abdominal
breathing
[Day
1
and/
or
Day
2
(high
and
mid
dose
–subacute
regimen)].
The
positive
control
induced
the
expected
significant
increase
in
the
frequency
of
cells
with
aberrant
chromosomes.
There
was,
however,
no
evidence
that
KERB®
technical
induced
a
clastogenic
effect
at
the
selected
dose
or
sacrifice
times.
The
study
is
classified
as
Acceptable
and
satisfies
the
requirements
for
FIFRA
Test
Guideline
84­
2
for
in
vivo
cytogenetic
mutagenicity
data.

Other
Mutagenic
Mechanisms/
in
vitro
unscheduled
DNA
synthesis
in
mammalian
cells
in
culture;
OPPTS
870.5550
[§
84­
2].
In
an
in
vitro
unscheduled
DNA
synthesis
(UDS)
assay
(MRID
No.
40211107),
primary
rat
hepatocytes
were
exposed
to
propyzamide
as
KERB®
technical
(94.2%)
at
9
doses
ranging
from
0.1­
500
µg/
mL.
Hepatocytes,
harvested
19
hours
after
treatment
with
1,
5,
10,
25
or
50
µg/
mL
were
scored
for
net
nuclear
grains/
nucleus.
The
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.
Cytotoxicity
(<
50%
cell
survival)
was
seen
at
$
100
µg/
mL
and
cells
treated
with
these
doses
were
not
scored.
The
positive
control
induced
the
expected
marked
increases
in
UDS.
There
was,
however,
no
evidence
that
KERB®
technical
induced
a
genotoxic
response.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
UDS
assay
(84­
2).

5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
following
pronamide
toxicity
studies
are
available
and
adequate
for
evaluation
of
FQPA:

­­
Developmental
Toxicity
Study
in
Rabbits
­­
Two­
Generation
Reproduction
Study
There
is
a
data
gap
for
a
developmental
toxicity
study
in
rats.
A
definitive
NOAEL
as
well
as
a
LOAEL
were
not
established
in
this
study;
no
toxicities
were
observed
in
the
maternal
animals
and
17
their
fetuses.
Therefore,
the
rat
developmental
toxicity
study
is
classified
as
unacceptable­
guideline
(not
upgradeable)
and
can
not
be
used
for
endpoint
selection.

5.2
Neurotoxicity
Data
Mammalian
neurotoxicity
studies
for
Pronamide
have
not
been
conducted.
However,
since
this
chemical
is
not
an
organophosphate
and
there
is
no
evidence
of
neurotoxicity
seen
in
any
of
the
existing
studies,
neurotoxicity
studies
(e.
g.,
an
acute
delayed
neurotoxicity
study
in
the
hen,
a
neurotoxicity
screening
battery
or
a
developmental
neurotoxicity
study)
were
not
required.

5.3
Developmental
Toxicity
Developmental
Rat
In
a
prenatal
developmental
toxicity
study
(MRID#
40334501),
pregnant
Crl:
CD
®
BR
rats
(Charles
River
Breeding
Laboratories,
Montreal
Quebec)
received
KERB
®
Herbicide
(94.2%
a.
i.;
Lot
4859)
as
an
aqueous
suspension
in
0.5%
methyl
cellulose
by
gavage
from
gestation
days
6
through
15
inclusive
at
dose
levels
of
0,
5,
20,
80
or
160
mg/
kg/
day.
Each
animal
was
examined
once
daily
for
signs
of
toxicity
and
mortality.
Body
weights
were
recorded
on
gestation
days
0,
6,
8,
10,
13,
16,
and
20.
All
surviving
rats
were
sacrificed
on
gestation
day
20,
the
thoracic
and
abdominal
cavities
were
examined
for
gross
pathologic
changes.
The
gravid
uterus
was
weighed
and
the
the
numbers
of
corpora
lutea,
implantation
sites,
and
resorptions
were
recorded.
The
number
of
fetuses
were
counted
and
their
locations
in
the
uterus
were
recorded.
All
fetuses
were
weighed
and
examined
for
external
abnormalities.
Half
of
the
fetuses
were
then
fixed
and
cleared
and
stained
in
Alizarin
red
S
for
skeletal
examinations
and
the
other
half
were
examined
for
visceral
anomalies.

No
Maternal
Toxicity
was
noted
at
the
dose
levels
tested.
The
Maternal
Toxicity
NOAEL
is
equal
to
or
greater
than
160
mg/
kg/
day
and
the
Maternal
Toxicity
LOAEL
is
greater
than
160
mg/
kg/
day.

No
Developmental
Toxicity
was
noted
at
the
dose
levels
tested.
The
Developmental
Toxicity
NOAEL
is
equal
to
or
greater
than
160
mg/
kg/
day
and
the
Developmental
Toxicity
LOAEL
is
greater
than
160
mg/
kg/
day.

CLASSIFICATION:
This
study
is
classified
as
Unacceptable­
Guideline
(not
upgradeable).
It
does
not
satisfy
the
guideline
requirements
for
a
prenatal
developmental
toxicity
study
in
rats
(OPPTS
870.3700;
OPP
§83­
3a)
because
there
were
no
maternal
or
fetal
toxicities
observed
at
any
dose
tested
(a
LOAEL
was
not
established).
In
addition,
the
highest
dose
tested
may
not
be
the
definitive
NOAEL.

Developmental
Rabbit
See
Short­
Term
Incidental
Oral
Exposure
(Section
2.3.1)
for
executive
summary.
18
5.4
Reproductive
Toxicity
Reproduction
Rat
In
a
2
generation
reproduction
study
(MRID#
41540301),
Pronamide
(93.1%
a.
i.;
Lot
Number
WHC1742
was
administered
to
Crl:
CD®
BR
Rats
(Charles
River
Labs,
Kingston,
N.
Y.)
in
the
diet
at
dose
levels
of
0,
40,
200
or
1500
ppm
(equal
to
3.1,
16.0
and
120.7
mg/
kg/
day
for
females
and
3.6,
18.0
and
130.1
mg/
kg/
day
for
males
for
the
40,
200
and
1500
ppm
dose
groups,
respectively)
through
2
generations
(one
mating
period
per
generation).
All
animals
were
observed
daily
for
clinical
signs
of
toxicity
and
twice
daily
for
mortality/
moribundity.
Individual
body
weights
and
food
consumption
were
recorded
weekly
during
the
premating
period
and
females
body
weights
were
recorded
on
gestation
days
0,
7,
14,
and
21
and
on
lactation
days
0,
7,
14,
and
21.
Reproductive
parameters
were
recorded
including
number
of
females
paired,
mated,
pregnant,
duration
of
gestation,
number
of
females
with
live
litters,
and
sex
ratio/
litter.
The
litter
observations
included
number
of
pups
born
alive
or
dead,
sex,
gross
abnormalities
and
the
pus
were
examined
twice
daily
for
mortality/
moribundity
and
were
weighed
and
examined
for
behavior
and
appearance
on
lactation
days
0,
4,
7,
14,
and
21.
All
animals
found
dead,
sacrificed
early
and
at
termination
were
subject
to
a
complete
necropsy,
this
included
all
pups
found
dead
before
weaning,
those
not
selected
for
breeding
and
all
F2
weanling
at
study
termination.

No
treatment­
related
mortalities
and/
or
clinical
signs
were
observed
in
either
parental
(Pl
and
P2)
generations.
There
were
parental
systemic
effects
at
the
high
dose
based
on
decreases
in
body
weight
and
feed
consumption
in
both
sexes
and
increased
incidences
of
histopathology
of
the
liver
(centrilobular
hepatocytes
hypertrophy;
both
sexes),
adrenal
gland
(zona
glomerulosa
cellular
hypertrophy;
both
sexes),
thyroid
gland
(follicular
cell
hypertrophy;
females),
and
anterior
pituitary
gland
(cellular
hypertrophy;
males)
in
both
P1
and
P2
generations,
and
increased
incidences
of
uterine
gross
pathology
(black
foci/
serosal
surface)
in
P2
females.
The
Parental
Systemic
Toxicity
NOAEL
was
200
ppm
(16.0
mg/
kg/
day
for
females
and
18.0
mg/
kg/
day
for
males)
and
the
Parental
Systemic
LOAEL
was
1500
ppm
(120.7
mg/
kg/
day
for
females
and
130.1
mg/
kg/
day
for
males),
based
on
decreases
in
body
weight
and
feed
consumption
in
both
sexes
and
increased
incidences
of
histopathology
of
the
liver,
adrenal
gland,
thyroid
gland,
and
anterior
pituitary
gland
in
both
P1
and
P2
generations,
and
increased
incidences
of
uterine
gross
pathology
in
P2
females.

There
were
no
reproductive
effects
in
either
the
P1
or
P2
generations,
including
the
females'
mating,
fertility,
and
gestation
indexes,
the
number
of
pups
born
dead
or
alive/
litter
and
sex
ratio
per
litter.
The
Reproductive
Toxicity
NOAEL
is
equal
to
or
greater
than
1500
ppm
and
the
Reproductive
Toxicity
LOAEL
is
greater
than
1500
ppm.

There
were
no
effects
on
F1/
F2
litter
parameters
including
the
number
of
live
pups/
litter
on
lactation
days
0,
4,
7,
14,
or
21
and
the
viability
and
lactation
indexes.
Combined
(male
+
female)
F1/
F2
pups
body
weight/
litter
at
birth
and/
or
during
the
lactation
period
were
unaffected
by
the
low­
or
mid­
dose,
but
was
significantly
reduced
by
the
high
dose
(F1
at
birth
and
during
the
entire
lactation
period;
F2
during
lactation
days
14
and
21).
There
were
no
treatment­
related
filial
abnormal
necropsy
findings.
The
Developmental/
Offspring
Toxicity
NOAEL
was
200
ppm
and
the
Developmental/
Offspring
Toxicity
LOAEL
was
1500
ppm,
based
on
decreases
in
combined
male/
female
pup
weight/
litter.
19
Classification:
This
study
is
classified
as
Acceptable­
Guideline
and
satisfies
the
guideline
requirements
for
a
2­
generation
reproductive
toxicity
study
in
rats
(OPPTS
870.3800;
OPP
§83­
4).

5.5
Additional
Information
from
Literature
Sources
(if
available)

There
is
no
additional
toxicity
information
from
literature
sources
for
the
herbicide,
pronamide.

5.6
Determination
of
Susceptibility
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
the
fetuses
or
the
offspring
of
rats
or
rabbits
following
pre­
and/
or
postnatal
exposure
to
pronamide.
In
the
prenatal
developmental
toxicity
study
in
rabbits
and
the
multigeneration
reproduction
study
in
rats,
any
observed
toxicity
to
the
fetuses
or
offspring
occurred
at
equivalent
or
higher
doses
than
did
toxicity
to
parental
animals.

Evidence
for
susceptibility
could
not
be
ascertained
in
the
developmental
toxicity
study
conducted
in
rats
because
there
were
no
maternal
or
fetal
toxicities
observed
at
any
dose
tested
(a
LOAEL
was
not
established).
In
addition,
the
highest
dose
tested
may
not
be
the
definitive
NOAEL.
The
HIARC
determined
that
this
study
is
a
data
gap.

Although
this
study
failed
to
demonstrate
maternal
and/
or
developmental
toxicities,
it
can
be
used
in
the
weight­
of­
evidence
evaluation
for
determining
the
FQPA
safety
factor
since
the
highest
dose
tested
in
this
rat
developmental
toxicity
study
exceeded
the
highest
doses
tested
in
both
the
rabbit
developmental
toxicity
study
(80
mg/
kg/
day)
and
the
rat
multigeneration
reproduction
study
(120.7
mg/
kg/
day
in
males;
130.1
mg/
kg/
day
in
females).

5.7
Determination
of
the
Need
for
Developmental
Neurotoxicity
Study
5.7.1
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

­­
The
results
of
several
toxicity
studies
conducted
in
both
the
rat
and
dog
demonstrated
evidence
of
endocrine
organ
toxicity
(thyroid,
testes,
ovaries,
adrenal
glands,
pituitary
gland,
thymus)
following
exposure
to
pronamide.

­­
Pronamide
is
listed
as
a
potential
endocrine
disruptor
on
EPA's
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC)
list.

5.7.2
Evidence
that
do
not
support
the
need
for
a
Developmental
Neurotoxicity
study
–
There
was
no
evidence
of
increased
susceptibility
to
rabbit
fetuses
in
the
developmental
toxicity
study
or
to
rat
offspring
in
the
multigeneration
reproduction
study
following
pronamide
exposure.

–
There
was
no
evidence
of
neurotoxicity
in
any
of
the
available
mammalian
toxicity
studies
conducted
with
pronamide.

The
HIARC
recommended
that
a
developmental
neurotoxicity
study
in
the
rat
not
be
required.
A
comparative
study
designed
to
assess
thyroid
function
in
adult
animals
and
their
offspring
as
well
as
potential
central
nervous
system
effects
in
the
young
will
be
required
due
to
endocrine
toxicities
20
observed
in
several
organ
systems
(thyroid,
testes,
ovaries,
adrenal
glands,
pituitary
gland
and
thymus)
of
the
rat
and/
or
dog.
Since
the
data
obtained
from
these
toxicity
studies
(a
special
endocrine/
thyroid
study
in
addition
to
the
required
guideline
studies)
are
suggestive
of
a
potential
hormonal
mechanism
for
thyroid
toxicity
and
considering
that
it
is
thyroid
hormone
which
is
essential
for
growth,
brain
development
and
nervous
system
maturation,
a
comparative
thyroid
assay
rather
than
a
developmental
neurotoxicity
study,
would
provide
a
more
complete
characterization
of
endocrine
disruption
(precursor
effects
in
the
thyroid)
associated
with
exposure
to
pronamide.
The
Registrant
is
advised
to
consult
the
Agency
with
regard
to
the
submission
of
a
thyroid
assay
protocol
prior
to
the
initiation
of
this
special
study.

6
HAZARD
CHARACTERIZATION
Pronamide
technical
has
a
low
order
of
acute
toxicity
via
the
oral,
dermal,
and
inhalation
routes
of
exposure
(Toxicity
Category
III
or
IV),
produces
mild
irritation
to
the
eyes
and
skin
(Toxicity
Category
IV),
and
is
not
a
dermal
sensitizer.

Pronamide
appears
to
be
a
liver
toxicant.
Adverse
liver­
related
effects
(increases
in
liver
weight
and/
or
liver­
related
serum
enzymes
and/
or
histopathology)
were
consistently
observed
in
every
animal
species
studied,
including
the
rat
(subchronic,
chronic,
and
2­
generation
reproduction
studies),
mouse
(carcinogenicity
studies),
rabbit
(developmental
study),
and
dog
(subchronic
and
chronic
studies).
Other
target
organs
included
the
thyroid
in
rats
(increase
in
weight
and/
or
histopathology
observed
in
the
chronic
toxicity/
carcinogenicity
and
the
2­
generation
reproduction
studies
as
well
as
a
subchronic,
special
13­
week
thyroid
function
study),
the
testes
in
rats
(histopathology
in
the
chronic
toxicity/
carcinogenicity
study)
and
the
kidneys,
adrenal
glands
thymus,
heart,
testes,
and
brain
in
dogs
(increase
in
organ
weights
in
the
chronic
toxicity
study),
and
the
pituitary
in
rats
(histopathology
observed
in
the
subchronic
and
2­
generation
reproduction
studies).
Many
chemicals
belonging
to
the
class
of
organochlorine
chemicals
are
known
to
produce
disruption
of
the
endocrine
system.
Pronamide
belongs
to
this
class
of
chemicals.

There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
the
fetuses
or
the
offspring
of
rats
or
rabbits
following
pre­
and/
or
postnatal
exposure
to
pronamide.
In
the
prenatal
developmental
toxicity
study
in
rabbits
and
the
multigeneration
reproduction
study
in
rats,
any
observed
toxicity
to
the
fetuses
or
offspring
occurred
at
equivalent
or
higher
doses
than
did
toxicity
to
parental
animals.
Although
the
highest
dose
of
pronamide
tested
in
the
rat
developmental
toxicity
study
exceeded
the
highest
doses
tested
in
both
the
rabbit
developmental
toxicity
study
and
the
rat
multigeneration
reproduction
study
without
demonstrating
toxicities,
it
failed
to
assess
the
potential
increased
susceptability
to
infants
and
children
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.

The
Carcinogenicity
Peer
Review
Committee
(CPRC)
classified
Pronamide
as
a
group
B2
­
probable
human
carcinogen
with
inadequate
evidence
in
humans.
This
decision
was
based
on
the
finding
of
two
types
of
tumors
in
the
rat
(benign
testicular
interstitial
cell
tumors
and
uncommon
thyroid
follicular
cell
adenomas),
and
one
type
of
tumor
in
the
mouse
(hepatocellular
carcinomas).
A
linear,
low
dose
approach
(Q1*)
is
used
for
human
risk
characterization.
The
most
potent
unit
risk
Q1*,
based
on
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates,
is
2.59
x
10
­2
(mg/
kg/
day)
­1
in
human
equivalents
[converted
from
animal
to
humans
by
use
of
the
(mg/
kg
body
weight)
3/
4
interspecies
scaling
factor].

Although
endocrine
effects
have
been
observed
in
several
toxicity
studies,
the
data
provided
in
two
special
studies
conducted
to
explore
pronamide's
effect
on
hormonal
balance
in
support
of
a
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms,
are
incomplete.
Based
on
the
CPRC's
weight
of
the
evidence
evaluation
of
this
data
base,
it
was
determined
that
even
if
a
hormonal
mechanism
could
be
demonstrated
for
tumors
in
the
rat,
the
mouse
liver
tumors
can
not
be
discounted
(the
Q1*
is
based
on
the
21
incidence
of
liver
tumors
in
mice).
Therefore,
a
mechanistic
approach
to
risk
assessment
for
the
active
ingredient
pronamide
is
not
plausible.

Results
of
mutagenicity
studies
with
an
acceptable
classification
(forward
and
reverse
gene
mutation,
in
vivo
and
in
vitro
cytogenetic/
structural
chromosome
aberration
and
unscheduled
DNA
synthesis
assays)
indicate
that
pronamide
is
not
a
mutagenic
agent.

Mammalian
neurotoxicity
studies
for
Pronamide
have
not
been
conducted.
However,
since
this
chemical
is
not
an
organophosphate
and
there
is
no
evidence
of
neurotoxicity
seen
in
any
of
the
existing
studies,
neurotoxicity
studies
(e.
g.,
an
acute
delayed
neurotoxicity
study
in
the
hen,
a
neurotoxicity
screening
battery
or
a
developmental
neurotoxicity
study)
were
not
required.

Pronamide
is
rapidly
absorbed
and
completely
and
rapidly
eliminated;
the
radioactivity
administered
was
recovered
(93­
103%)
in
the
urine
(40­
61%),
feces
(40­
60%)
and
tissues
and
carcass
(0.08­
2.43%).
No
bioaccumulation
was
apparent
and
tissues
with
the
highest
radioactivity
content
were,
in
decreasing
order,
the
fat,
adrenals,
bone
marrow,
thyroids,
liver
kidney,
and
plasma.
The
elimination
of
radioactivity
from
the
plasma
of
low
dose
rats
was
biphasic
[rapid
phase
=
12.6
hrs
(males)
and
12.7
hrs
(females);
slow
phase
=
36.6
hrs
(males)
and
45.3
(females)]
and
that
of
the
high
dose
rats
was
monophasic
[t½
=
24.1
hrs
(males)
and
24.8
hrs
(females)].
Very
little
unchanged
pronamide
was
recovered
in
the
urine
and
no
significant
difference
in
urinary
metabolite
profile
was
observed
between
the
doses
or
the
sexes.
The
two
major
urinary
metabolites
were
SS47­
70
(3.0­
5.9%)
of
the
dose
and
metabolite
10
(12.7­
18.9%).
In
the
urine,
27
metabolites
were
found
and
none
exceeded
3.3%
of
the
dose,
whereas,
almost
all
of
the
unknowns
were
less
than
1%
of
the
dose.

There
is
no
acceptable
dermal
absorption
study
in
the
pronamide
data
base.
In
addition,
there
were
no
dermal
toxicity
studies
submitted
which
could
be
used
for
comparison
to
oral
toxicity
studies.
Therefore,
a
100%
(default
value)
dermal
absorption
factor
was
determined
for
risk
assessment
purposes.

7
DATA
GAPS
Developmental
Toxicity
Study
in
Rats
21­
Day
Dermal
Toxicity
Study
28­
Day
Inhalation
Toxicity
Study
Dermal
Penetration
Study
A
Comparative
Thyroid
Rat
Assay
in
Adult
Animals
and
Offspring
22
8
ACUTE
TOXICITY
Acute
Toxicity
of
Pronamide
(Propyzamide)

Guideline
Number
Study
Type
MRID#
Results
Toxicity
Category
870.1100
(§
81­
1)
Acute
Oral
­
Rat,
>
92.0%
a.
i.
00085505
LD50
(males
and
females)
>
5000
mg/
kg
IV
870.1100
(§
81­
1)
Acute
Oral
(Limit
test)
Rat
95.7%
a.
i.
43583901
LD50
(males
and
females)
>
5000
mg/
kg
IV
870.1200
(§
81­
2)
Acute
Dermal
(Limit
Test)
­
Rabbit,
95.7%
a.
i.
43583902
LD50
(males
and
females)
>
2000
mg/
kg
III
870.1300
(§
81­
3)
Acute
Inhalation
­
Rat,
95.7%
a.
i.
44034201
LC50
>
2.1
mg/
L
(4
hour
exposure)
III
870.2400
(§
81­
4)
Primary
Eye
Irritation
Rabbit
95.7%
a.
i.
43583904
Mild
occular
irritant
IV
870.2500
(§
81­
5)
Primary
Dermal
Irritation
­
Rabbit,
95.7%
a.
i.
43583903
Slight
dermal
irritant
IV
870.2600
(§
81­
6)
Dermal
Sensitization
Guinea
pig,
>
92.0%
a.
i.
00062605
Not
a
sensitizer
N/
A
23
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
females
(13­
50)
and
general
population
including
infants
and
children
No
appropriate
endpoint
was
available
to
quantitate
risk
to
the
general
population
from
a
single­
dose
administration
of
pronamide.
The
developmental
effect,
abortions,
were
not
considered
to
occur
after
a
single
dose
in
this
instance
because
they
were
observed
in
rabbits
during
the
post­
dosing
phase
of
the
study
(days
22­
24).
Therefore,
no
endpoint
was
chosen
to
quantitate
risk
to
females
13­
50
from
a
single­
dose
administration
of
pronamide.

Chronic
Dietary
(all
populations)
NOAEL
=
8.46
Increased
relative
(to
body)
liver
weight
and
nonneoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
UF
=
100
Chronic
RfD
=
0.08
mg/
kg/
day
Cancer
Q1*
=
2.59
x
10
­
2
(mg/
kg/
day)
­1
Group
B2
chemical
­
"Probable
human
carcinogen"
based
on
thyroid
follicular
cell
adenomas
(males
and
females)
and
benign
interstitial
cell
tumors
(males)
in
rats
and
hepatocellular
carcinomas
in
male
mice.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
Incidental
Oral,
Short­
Term
NOAEL
=
8.46*
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes).
Developmental
Toxicity
Study
­
Rabbit
Incidental
Oral,
Intermediate­
Term
NOAEL
=
8.46
Increased
relative
(to
body)
liver
weight
and
nonneoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
Dermal,
Short­
Term
a
NOAEL
=
8.46*
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes).
Developmental
Toxicity
Study
­
Rabbit
Dermal,
Intermediateand
long­
Term
a
NOAEL
=
8.46
Increased
relative
(to
body)
liver
weight
and
nonneoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
Inhalation,
Short­
Term
a
NOAEL
=
8.46*
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
hepatocytes).
Developmental
Toxicity
Study
­
Rabbit
Inhalation,
Intermediateand
Long­
Term
a
NOAEL
=
8.46
Increased
relative
(to
body)
liver
weight
and
nonneoplastic
histologic
changes
in
the
liver,
thyroid,
and
ovaries.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
a
Since
an
oral
endpoint
was
selected,
a
dermal
absorption
factor
of
100%
(default
value)
and
an
inhalation
absorption
factor
of
100%
(default
value)
should
be
used
in
route­
to­
route
extrapolation.
*
An
adjusted
dose
of
8.46
mg/
kg/
day
was
established
for
use
in
this
risk
assessment
based
on
a
maternal
toxicity
NOAEL
of
5
mg/
kg/
day
and
clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes)
observed
at
the
LOAEL
of
20
mg/
kg/
day
in
the
developmental
toxicity
study
conducted
in
rabbits.