Document ID: EPA-HQ-OPP-2002-0159-0016
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
Number:
0050338
MEMORANDUM
DATE:
January
21,
2002
SUBJECT:
Pronamide
(Propyzamide):
Report
of
the
Mechanism
of
Toxicity
Assessment
Review
Committee
(MTARC)
Evaluation
of
the
Available
Mechanistic
Information
for
the
Active
Ingredient,
Pronamide.
PC
Code:
101701.
DP
Barcode:
D279550.
Submission
Number:
S597844.

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

THRU:
Pauline
Wagner,
Co­
Chair
Karl
Baetcke,
Co­
Chair
Mechanism
of
Toxicity
Science
Assessment
Review
Committee
(MTARC)
Health
Effects
Division
(7509C)

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

cc:
Anna
Lowit
MTARC
Secretary
Health
Effects
Division
(7509C)
and
Catherine
Eiden,
Branch
Senior
Scientist
Jose
Morales,
Risk
Assessor
Reregistration
Branch
III
Health
Effects
Division
(7509C)

On
October
23,
2001,
the
Mechanism
of
Toxicity
Assessment
Review
Committee
(MTARC)
met
to
prescreen
the
available
Pronamide
toxicology
data
submitted
in
support
of
a
proposed
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
and
to
determine
whether
a
full
MTARC
review
is
required.
The
Committee's
data
evaluation
and
conclusions
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Karl
Baetke,
Karen
Hammernik,
Anna
Lowit
Member(
s)
in
absentia:
Pauline
Wagner
Data
evaluation
prepared
by:
Michelle
M.
Centra,
Reregistration
Branch
III
(RRB
III)

Also
in
attendance
were:
Steve
Knizner
(RRBIII),
Jose
Morales
(RRBIII)

Data
Evaluation
/
Report
Presentation
Michelle
M.
Centra
Pharmacologist
3
Cl
Cl
O
C
CH
3
N
H
CH
CH
3
I.
MTARC
DECISION
Based
on
the
absence
of
any
additional
information
as
well
as
the
MTARC's
evaluation
of
the
existing
pronamide
toxicology
data
base
and
the
Agency's
previous
hazard
characterization
of
this
active
ingredient
(Memorandum:
N.
Thoa,
May
26,
1993),
the
Committee
determined
that
the
postulated
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
remains
incomplete
and
is
not
supported
by
the
available
data.
Therefore,
a
full
Committee
review
for
pronamide
is
not
required.

II.
BACKGROUND
INFORMATION
A.
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.
It
is
produced
and
formulated
for
use
as
a
50­
W
wettable
powder
in
water
soluble
pouches
(EPA
Reg.
No.
707­
159)
by
Rohm
and
Hass
Co.,
Springhouse,
Pennsylvania.
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.

B.
Chemical
Identification
Chemical
Structure:

Empirical
Formula:
C12H11NOCl2
Common
Synonyms:
propyzamide;
3,5­
dichloro
­N­
(1,1­
dimethyl­
2­
propynyl)
benzamide,
Kerb
®

9CI
Name:
23950­
58­
5
Physical
Properties:
Technical
pronamide
is
a
white
crystalline
solid.
Molecular
Weight:
256.13
Melting
point:
155­
156
0
C
Specific
gravity:
0.
48
g/
cc
Water
Solubility:
The
solubility
of
pronamide
in
water
at
25
0
C
is
15
ppm.
4
Pronamide
is
soluble
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.
CAS
No.:
23950­
58­
5
PC
Code:
101701
C.
Toxicity
Summary
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
1
.
Pronamide
belongs
to
this
class
of
chemicals.

The
Carcinogenicity
Peer
Review
Committee
(CPRC)
classified
Pronamide
as
a
group
B2
­
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
*)
was
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).

In
addition
to
the
required
guideline
toxicity
studies,
two
special
studies
were
conducted
to
evaluate
pronamide's
effect
on
hormonal
balance
in
support
of
a
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms.
The
CPRC
also
considered
this
data
in
its
weight­
of­
evidence
deliberations
and
concluded
the
following:

°
The
data
provided
on
thyroid
mechanism
were
suggestive
of
a
thyroid­
pituitary
hormonal
control
mechanism
but
were
not
conclusive,
based
on
the
Agency's
six
criteria
for
a
threshold
model
of
thyroid
neoplasia
(See
Appendix,
Carcinogenicity
Peer
Review
of
Pronamide
3
rd
).
For
example,
there
were
no
dose­
related
and/
or
sustained
increases
in
TSH
levels,
no
dose­
related
increases
in
incidence
of
thyroid
hypertrophy/
hyperplasia,
and
no
information
on
thyroid
hormone
synthesis.
5
°
The
Agency
has
no
policy
which
implements
a
threshold
model
for
testicular
neoplasia.
Endocrine
function
of
the
testis
may
or
may
not
be
regulated
through
a
feedback
mechanism
similar
to
that
controlling
thyroid
function,
e.
g.
through
an
involvement
of
the
anterior
pituitary.
Even
if
a
testis­
pituitary
hormonal
control
mechanism
existed,
the
evidence
supporting
pronamide­
induced
testicular
tumors
in
the
rat
via
a
disruption
in
the
testis­
pituitary
balance
is
very
limited.
There
was
no
clear
increase
in
interstitial
cell
hypertrophy/
hyperplasia,
no
alteration
in
testosterone
level,
no
information
on
testicular
hormone
synthesis
and
no
reversibility
of
testicular
lesions.

Although
several
endocrine
effects
have
been
observed
in
pronamide
toxicity
studies,
the
data
provided
in
special
studies
conducted
to
explore
potential
mechanisms
of
endocrine
toxicity,
are
incomplete.
Based
on
the
CPRC's
weight­
of­
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
incidence
of
liver
tumors
in
mice).
Therefore,
a
mechanistic
approach
to
risk
assessment
for
the
active
ingredient
pronamide
is
not
plausible.

1
Hileman,
B.,
March
19,
1993.
Concerns
broaden
over
chlorine
and
chlorinated
hydrocarbons­
calls
for
gradual
phaseout
of
classes
of
chlorinated
organics
are
being
made
in
response
to
evidence
of
adverse
health
effects
on
humans
and
wild
life.
C
&
E
News,
volume
71,
No.
16,
pp
11­
20.
6
III.
Data
Presentation
A.
Listing
and
Presentation
of
Available
Data
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
Chronic
Toxicity/
Car
cinogenicity
Study
­
Rats
(MRID
41714001,
41714002)
Pronamide
was
administered
to
Crl:
CD(
BR)
VAF/
Plus
Rats
in
the
diet
at
either
0,
25,
100,
or
400
ppm
for
the
first
2
weeks,
followed
by
0,
35,
140,
or
560
ppm
for
the
next
3
weeks
and
thereafter,
0,
40,
200,
or
1000
ppm
(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).
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).

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
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.
Bailey,
D.
E.
(1990):
Kerb
®
Herbicide
(Technical,
no
clay):
24
Month
Dietary
Chronic
Toxicity/
Oncogenicity
Study
in
Rats;
Hazleton
Laboratories
America,
Inc.
for
Rohm
&
Haas
Co.;
HLA
417­
426S,
HLA
417­
426M;
November
2,
1990
(Unpublished
Study)

Acceptable­
Guideline
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
7
Non
Guideline
Endocrine
Study
­
Male
Rats
(MRID
42093401)
Pronamide
was
administered
to
male
Crl:
CD
®
BR
Rats
in
the
diet
at
concentrations
of
0,
40,
1000
or
4000
ppm
Pronamide
for
either
4
or
15
weeks.
Parameters
of
thyroid
function,
T4
hepatic
metabolism,
and
exogenous
125
I
biliary
clearance
were
investigated,
in
support
of
Pronamide's
thyroid
tumorigenic
mechanism
of
action
involving
disruption
of
the
thyroid­
pituitary
hormonal
balance.
At
1000
ppm,
pronamide
treatment
resulted
in
decreased
body
weights
and
food
consumption,
increased
absolute
and/
or
relative
weights
of
the
liver
and
thyroid
(absolute
after
4
weeks;
absolute
and
relative
after
15
weeks),
increased
serum
TSH
(at
4
weeks
but
not
at
13
weeks),
decreased
serum
T4,
and
an
increased
incidence
of
thyroid
and
pituitary
hypertrophy/
hyperplasia.
The
highest
dose
tested
(4000
ppm)
produced
more
profound
effects
on
the
body
weights,
liver
weights
and
serum
T4
than
was
seen
in
the
mid
dose
(1000
ppm).
Pronamide
exposure
resulted
in
increased
thyroid
(relative)
weight
and
increased
incidences
of
thyroid
and
pituitary
hypertrophy/
hyperplasia
which
were
comparable
to
the
mid­
dose,
but
did
not
statistically
change
serum
TSH
levels.
Specific
parameters
were
investigated
only
at
the
high
dose:
T4
hepatic
metabolism
and
125
I
biliary
clearance
were
both
increased
and
all
of
the
thyroid­
and
liver­
related
changes
occurring
after
4
weeks
of
dosing,
were
either
reduced
in
severity
or
absent
11
weeks
following
discontinuation
of
the
dosing.

Based
on
the
six
Agency
criteria
for
thyroid
effects,
there
is
suggestive
evidence
that
the
thyroid
tumors
in
the
rat
associated
with
pronamide
administration
may
result
from
disruption
of
the
thyroid­
pituitary
hormonal
balance.
This
evidence
is
weakened
by
the
lack
of
a
dose­
related
and
sustained
increase
in
serum
TSH,
and
the
lack
of
a
dose­
related
increase
in
the
incidence
of
thyroid
follicular
cell
hypertrophy/
hyperplasia.
There
was
also
no
investigation
of
T4
hepatic
metabolism
and
biliary
clearance
at
the
high
dose
level
(1000
ppm)
which
was
also
a
test
dose
used
in
the
rat
chronic
toxicity/
carcinogenicity
study
that
demonstrated
thyroid
adenomas.
Hazelton,
G.
A.,
Didonato,
L.
J.,
Donofrio,
K.
F,
Kulwich,
B.
A.
(1991):
Pronamide
(Kerb
®
Herbicide):
Thyroid
Function
and
Hepatic
Clearance
of
Thyroxine
inMale
Rats;
Rohm
&
Haas
Co.,
Toxicology
Department
for
Rohm
&
Haas
Co.;
90R­
178;
October
9,
1991
(Unpublished
Study)

Acceptable­
Nonguideline
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
8
Non
Guideline,
Pilot
Endocrine
Study
­
Male
Rats
(MRID
42139601)
Pronamide
was
administered
to
male
Crl:
CD
®
BR
Rats
in
the
diet
at
concentrations
of
either
0,
or
4000
ppm
for
13
weeks.
Clinical
chemistry
and
histopathological
parameters
of
testicular
function,
as
well
as
hepatic
metabolism
of
testosterone
were
investigated,
to
lend
support
to
Pronamide's
testicular
tumorigenic
mechanism
of
action
involving
disruption
of
the
pituitary­
testis
hormonal
balance.
Clinical
chemistry
parameters
were
also
measured
in
male
rats
treated
with
0,
40,
1000,
or
4000
ppm
pronamide
for
4
weeks.
In
the
13
week
study,
pronamide
(4000
ppm)
produced
decreased
body
weight
(weeks
1­
13)
and
food
consumption
(weeks
1­
8),
increased
serum
LH
and
FSH
levels
(respective
increases
at
4
and
13
weeks
were
60%
and
58%
for
FSH,
and
100%
and
77%
for
LH),
increased
liver
weight
(absolute
and
relative
to
body
and
brain
weight),
microsomal
protein
content,
oxidation
of
testosterone,
activity
of
cytochrome
P450
,
cytochrome­
B5,
NADPH
cytochrome­
C­
reductase,
and
gross
pathology
of
the
liver
(enlarged/
dark),
and
increased
testicular
relative
(to
body)
weight
,
and
testicular
interstitial
cell
hyperplasia.

In
the
4­
week
study,
alterations
in
clinical
chemistry
parameters
(increases
in
serum
LH
and
FSH)
were
noted
only
at
4000
ppm
and
were
comparable
to
the
increases
observed
after
13
weeks
of
dosing.

The
most
positive
supporting
evidence
for
the
involvement
of
the
pituitary
in
testicular
neoplasia
is
the
increase
in
serum
LH
and
FSH
levels
after
4
and
15
weeks
of
treatment.
There
was,
however,
no
concomitant
decrease
in
serum
testosterone.
Futhermore,
studies
were
not
conducted
which
may
have
demonstrated
that
this
lack
of
effect
was
produced
by
some
additional
effect
of
pronamide
(e.
g.,
an
increase
in
testosterone
clearance
accompanying
the
moderate
stimulatory
effect
[54%
increase/
g
liver]
on
testosterone
metabolism).
There
also
was
no
evidence
of
testicular
lesion
progression
and/
or
lesion
reversibility.
The
CPRC
concluded
that
this
data
is,
at
best,
incomplete
and
additional
studies
should
be
conducted
in
order
to
support
the
Registrant's
theory
of
a
pronamide­
induced
testicular
neoplastic
effect
via
disruption
of
the
pituitary­
testis
hormonal
balance.
Hazelton,
G.
A.,
Didonato,
L.
J.,
Donofrio,
K.
F.,
Kulwich,
B.
A.
(1991):
Pronamide
(Kerb
®
Herbicide):
Effects
on
Endocrine
Regulation
of
the
testis
in
Rats
­
Pilot
Study;
Rohm
&
Haas
Co.,
Toxicology
Department
for
Rohm
&
Haas
Co.;
90R­
179;
December
6,
1991
(Unpublished
Study)

Acceptable­
Nonguideline
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
9
Two
Generation
Reproduction
Study
­
Rats
(MRID
41540301)
Pronamide
was
administered
to
Crl:
CD
®
BR
Rats
in
the
diet
at
concentrations
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).
Parental
systemic
effects
were
observed
in
rats
treated
with
1500
ppm
pronamide:
decreased
body
weight
and
feed
consumption
in
both
sexes
and
increased
incidences
of
histopathology
of
the
liver
(centrilobular
hepatocytes
hypertrophy;
both
sexes),
adrenal
glands
(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.
Solomon,
H.
M.,
Brown,
W.
R.
(1990):
Pronamide:
Two­
Generation
Reproduction
Study
in
Rats;
Rohm
andHaas
Company,
Toxicology
Department
for
Rohm
and
Haas
Company;
Study
Number:
88P­
309;
Report
No.
88R­
257;
June
14,
1990
(Unpublished)

Acceptable­
Guideline
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
10
Subchronic
Toxicity
Study
­
Rats
(MRID
42669403)
Pronamide
was
administed
to
Crl:
CD
®
BR
Rats
in
the
diet
at
concentrations
of
0,
40,
200,
1000,
or
4000
ppm
(equal
to
0,
2.5,
12.3,
60.0,
and
254.0
mg/
kg/
day
for
males
and
0,
3.1,
15.0,74.6,
and
289.2
mg/
kg/
day
for
females,
respectively)
for
3
months
At
1000
ppm,
pronamide
treatment
resulted
in
increases
in
liver
relative
(to
body)
weight,
and
incidence
of
liver
centrilobular
hypertrophy
in
both
sexes,
decreases
in
body
weight/
weight
gain
and
feed
consumption
in
females,
and
increases
in
blood
cholesterol
levels
in
males.

Additional
toxicities
observed
at
4000
ppm
included
an
increase
in
clinical
signs
(brown
and/
or
yellow
staining
of
the
anogenital
area)
in
males,
decreases
in
body
weight/
weight
gain
and
feed
consumption
in
males
and
further
exacerbation
of
the
later
in
females.
In
addition,
more
pronounced
effects
were
observed
in
the
liver,
thyroid
and
pituitary
at
the
highest
dose
tested:
increases
in
cholesterol
(both
sexes),
SGOT
and
alkaline
phosphatase
(males),
triglycerides
(females),
liver
absolute/
relative
weights
(both
sexes),
incidence/
severity
of
liver
centrilobular
hypertrophy
(both
sexes),
incidence
of
thyroid
follicular
hypertrophy
(both
sexes)
and
anterior
pituitary
cellular
hypertrophy
(males).
The
liver,
thyroid
and
pituitary
appear
to
be
target
organs.

After
4
weeks
of
recovery,
most
of
the
adverse
effects
observed
at
the
high
dose
were
partially
or
totally
reversed
but
the
increase
in
the
incidence
of
pituitary
cellular
hypertrophy
in
males
was
not
diminished.
Anderson,
D.
M.,
Kulwich,
B.
A.,
Hazelton,
G.
A.
(1989):
Pronamide
Technical
(no
clay):
Three­
Month
Dietary
Toxicity
Study
in
Rats;
Rohm
&
Haas
Co.
Tox
Dept
for
Rohm
&
Haas
Co.;
Report
No.
88R
053;
September
15,
1989
(Unpublished
Study)

Acceptable­
Guideline
Table
1.
Endocrine/
Other
Effects
Observed
in
Pronamide
Toxicity
Studies
Study
Type
(MRID
Number)
Dose
and
Exposure
Duration
Endocrine
and
Other
Effects
Study
Citation
and
Study
Classification
11
Chronic
Toxicity
Study
­
Dogs
(MRID
41807601,
41807602)
Pronamide
was
administered
to
Beagle
Dogs
in
the
diet
at
concentrations
of
0,
300,
875,
or
1750
ppm
(equal
to
0,
11.9,
33.1,
67.7
mg/
kg/
day
for
males
and
0,
11.9,
36.1,
69.0
mg/
kg/
day
for
females,
respectively)
for
52
weeks.
At
875
ppm,
pronamide
treatment
produced
toxicity
in
several
organs.

In
the
liver,
systemic
toxicity
included
increases
in
serum
alkaline
phosphatase
activity
(males),
increases
in
absolute
and
relative
(to
body)
liver
weight
(males
and
females),
increases
in
the
incidence
of
hepatocytic
hypertrophy/
hyperplasia
and
granular
brown
pigmentation
and
mononuclear
infiltration
of
Kupffer
cells
(males
and
females).

At
1750
ppm,
further
increases
in
serum
alkaline
phosphatase
activity
were
observed
in
both
sexes,
along
with
increases
in
serum
gamma
glutamyl
transferase
(males
and
females)
and
alanine
amino
transferase
activities
(females).
The
incidence/
severity
of
the
histopathologic
alterations
in
the
liver
were
also
exacerbated.

Other
organs
affected
at
1750
ppm
dose
included
the
kidneys
(increase
in
relative
weight
in
females
and
occurrence
of
brown
pigmentation
in
proximal
tubules
in
both
sexes),
thyroid
gland
(increase
in
relative
weight
in
females),
adrenal
glands
(increase
in
relative
weight
in
males
and
absolute/
relative
weights
in
females),
thymus
(increase
in
relative
weight
in
females),
and
heart
and
testes
(increases
in
relative
weights
in
males).
Briffaux,
J.
P.
(1991):
Pronamide
(Kerb
®

Technical
Herbicide):
52
week
oral
(dietary)
toxicity
study
in
the
Beagle
Dog;
Hazleton
France
(HF)
for
Rohm
&
Haas
Co.;
HF
Project
ID
No.
616/
503,
Report
No.
HF
505069,
Rohm
&
Haas
Report
No.:
89RC
110;
February
20,
1991
(Unpublished
Study)

Acceptable­
Guideline
12
B.
Data
Evaluation
The
following
data
is
excerpted
from
the
CPRC
document
(Memorandum:
N.
Thoa,
May
26,
1993):

Study
Citation
Bailey,
D.
E.
(1990):
Kerb
®
Herbicide
(Technical,
no
clay):
24­
Month
Dietary
Chronic
Toxicity/
Oncogenicity
Study
in
Rats;
Hazleton
Laboratories
America,
Inc.
for
Rohm
&
Haas
Co.;
HLA
417­
426S,
HLA
417­
426M;
November
2,
1990
(Unpublished
Study);
MRID
Number
41714001
and
41714002.

Increased
incidences
of
non­
neoplastic
lesions
were
observed
in
the
liver,
thyroid,
and
ovaries
of
highdose
rats.

In
the
liver,
a
positive
trend
(p
<
0.01)
in
the
incidence
of
centrilobular
hypertrophy
was
observed
in
males
and
females
in
both
phases
(12­
and
24­
month);
the
increases
observed
at
1000
ppm
were
significant
by
pair­
wise
comparison
(p
<
0.01,
both
sexes)
and
appeared
more
pronounced
in
the
12­
month
phase
(rate
=
65%
in
males
and
95%
in
females)
than
in
the
24­
month
phase
(rate
=
20%
in
males
and
48%
in
females).
Hypertrophy
was
accompanied
by
eosinophilic
cell
alteration
in
the
24month
phase(
p<
0.
01forpositivetrendin
both
sexes;
pair­
wisecomparison
in
high­
dose/
controls,
p
<
0.
05
in
males
and
p
<
0.
01
in
females).

In
the
thyroid,
a
positive
trend
(p
<
0.
05
in
males
and
p
<
0.
01
in
females)
in
the
incidence
of
follicular
hypertrophy
was
observed
in
the
12­
month
phase
but
not
the
24­
month
phase.
The
increased
incidence
observed
at
1000
ppm
was
only
significant
(p
<
0.01,
high­
dose/
controls)
in
females,
but
the
increased
incidence
observed
at
1000
ppm
was
not
statistically
significant.

In
the
ovaries,
a
positive
trend
(p
<
0.01)
in
the
incidence
of
sertoliform
tubular
hyperplasia
was
observed
in
females
in
the
24­
month
phase,
and
the
increase
in
incidence
observed
at
1000
ppm
was
significant
(p
<
0.01)
by
pair­
wise
comparison.

Discussion
of
Tumor
Data
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%
(a
mean
value
of
5%
for
males)
and
0­
9.
5%
(a
mean
value
of
2%
for
females).
Historical
control
data
for
SD
rats
was
obtained
from
13
studies
conducted
between
1985
and
1990
at
Hazleton
Laboratories,
Vienna,
VA.
There
were
no
significant
differences
in
thyroid
follicular
cell
carcinoma
rates
between
groups.
There
were
increasing
trends
and/
or
rates
in
combined
incidences
of
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
13
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
for
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
for
the
24­
month
phase.

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
(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.

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.

Study
Citation
Hazelton,
G.
A.,
Didonato,
L.
J.,
Donofrio,
K.
F.,
Kulwich,
B.
A.
(1991):
Pronamide
(Kerb
®
Herbicide):
Thyroid
Function
and
Hepatic
Clearance
of
Thyroxine
in
Male
Rats;
Rohm
&
Haas
Co.,
Toxicology
Department
for
Rohm
&
Haas
Co.;
90R­
178;
October
9,
1991
(Unpublished
Study);
MRID
Number
42093401.

Histopathology
of
the
Thyroid
Treatment
with
1000
and
4000
ppm
pronamide
for
4
or
15
weeks
was
associated
with
similar
increases
(p
<
0.
05)
in
incidence
of
diffuse
hypertrophy/
hyperplasia
of
the
thyroid
follicular
cells.
There
was
a
positive
trend
after
both
4
and
15
weeks.
The
lesions
were
observed
throughout
the
thyroid
and
were
characterized
by
follicular
cells
with
increased
height,
and
by
follicles
reduced
in
size
and
in
colloid
content.
The
increase
in
incidences
observed
after
4
weeks
of
treatment
with
the
highdose
(10/
10)
was
reduced
(5/
9)
after
the
recovery
period.
The
severity
of
the
lesions
was
greater
at
4000
ppm
than
at
1000
ppm.

Thyroid
Hormone
and
TSH
(4
and
15
week
observations
at
1000
and
4000
ppm
in
male
rats)

Treatment
with
40­
4000
ppm
pronamide
for
4
or
15
weeks
was
not
associated
with
any
reduction
in
T3
or
rT3
.T4
was
moderately
reduced
(decreased
at
1000
ppm:
61%
after
4
weeks
and
48%
after
15
weeks;
decreased
at
4000
ppm:
87%
after
4
weeks
and
84%
after
15
weeks).
Except
for
a
moderate
increase
(72%)
observed
after
4
weeks
of
treatment
with
1000
ppm
pronamide,
TSH
remained
unaffected.
The
decrease
in
T4
which
observed
after
4
weeks
of
treatment
with
4000
ppm
pronamide
was
absent
after
11
weeks
of
recovery.
14
T4
­Hepatic
Uridine
Diphosphate
Glucuronosyl
Transferase
(UDPGT)
Activity
Treatment
with
4000
ppm
pronamide
for
4
or
15
weeks
was
associated
with
a
2­
2.
5
fold
increase
in
UDP­
GT
activity
(enzyme
activity
was
expressed
as
nmol
T4
­glucuronide
formed/
min/
mg
liver
microsomal
protein).
The
increased
activity
observed
after
4
weeks
of
treatment
with
4000
ppm
pronamide
was
absent
after
11
weeks
of
recovery.

Bile
flow
and
Biliary
Clearance
of
125
I­
T4
Treatment
with
4000
ppm
pronamide
for
4
or
15
weeks
was
associated
with
significant
(p
<
0.05)
increases
in
bile
flow
(

65%),
biliary
clearance
of
125
I­
T4
(7­
10
fold)
and
125
I­
T4
glucuronide
(1
­2
fold),
and
125
I
bile/
plasma
ratio
after
4
weeks
of
treatment.
The
alterations
in
bile
flow
and
biliary
clearance
were
completely
reversed
after
11
weeks
of
recovery.

Adequacy
of
Dosing
for
Assessment
of
Thyroid
Effects
The
dosing
was
considered
to
be
adequate
for
assessing
the
thyroid
effects
of
pronamide,
based
on
significant
(p
<
0.05)
depressions
of
body
weight
(2­
5%
at
1000
ppm,
weeks
1­
4;
17­
24%
at
4000
ppm,
weeks
1­
15)
and
feed
consumption
(4­
10%
at
1000
ppm,
weeks
1­
4;
11­
38%
at
4000
ppm,
weeks
1­
15).
Absolute
(abs)
and/
or
relative
(rel)
liver
weight
was
significantly
increased
(p
<
0.
05)
at

1000
ppm,
in
a
dose­
related
manner
(4
week
increases:
29%
abs
and
36%
rel
at
1000
ppm,
50%
abs
and
91%
rel
at
4000
ppm;
15
week
increases:
32%
rel
at
1000
ppm;
42%
abs
and
86%
rel
at
4000
ppm).
Thyroid
weight
was
significantly
increased
(p
<
0.
05)
at

1000
ppm
in
a
non
dose­
related
manner
(4
week
increases:
29%
abs
and
36%
rel
at
1000
ppm,
32%
rel
at
4000
ppm.
15
week
increases:
21%
rel
at
1000
ppm,
33%
rel
at
4000
ppm).

Study
Citation
Hazelton,
G.
A.,
Didonato,
L.
J.,
Donofrio,
K.
F.,
Kulwich,
B.
A.
(1991):
Pronamide
(Kerb
®
Herbicide):
Effects
on
Endocrine
Regulation
of
the
testis
in
Rats
­
Pilot
Study;
Rohm
&
Haas
Co.,
Toxicology
Department
for
Rohm
&
Haas
Co.;
90R­
179;
December
6,
1991
(Unpublished
Study).
MRID
42139601.

Histopathology
of
the
Testes
Treatment
with
4000
ppm
pronamide
for
13
weeks
was
associated
with
an
increase
in
the
number
of
testicular
interstitial
cells.
The
incidences
were
1/
20
for
the
control
group
and
7/
20
for
the
treated
group.
Interstitial
cells
are
located
between
the
seminiferous
tubules,
normally
in
2­
3
cell
focal
clusters
instead
of
layers.
In
this
study,
the
observed
increase
was
determined
to
be
equivocal
because
of
"the
small
degree
of
change
being
evaluated
and
the
possibility
of
producing
this
appearance
through
fortuitous
tangential
sectioning
of
seminiferous
tubules."
The
CPRC
determined
that
this
type
of
sectioning
could
be
seen
in
all
dose
groups.

Clinical
Chemistry
Changes
Treatment
with
4000
ppm
pronamide
for
4
or
13
weeks
was
associated
with
increases
in
serum
LH
and
FSH.
The
increases
were
moderate
and
were
slightly
higher
at
4
weeks
than
at
13
weeks
(respective
increases
at
4
and
13
weeks
were
60%
and
58%
for
FSH,
and
100%
and
77%
for
LH).
Serum
LH
and
FSH
levels
were
not
affected
by
the
mid­
level
dose
(1000
ppm).
Serum
testosterone
levels
were
not
affected
by
treatment
with
pronamide.
15
Liver
Microsomal
Enzymes
Activity
Treatment
with
4000
ppm
pronamide
for
13
weeks
increased
the
activity
of
the
liver
microsomal
enzymes
(cytochrome­
P450,
cytochrome­
B5,
and
NADPH­
cytochrome­
C­
reductase)
and
the
rate
of
oxidation
of
testosterone,
expressed
as

mol
product/
whole
liver.
Concomitant
increases
in
liver
weight
(50%)
and
liver
microsomal
protein
content
(34%)
were
observed,
which
suggests
that
oral
administration
of
relatively
high
doses
of
pronamide
(4000
ppm)
for
a
certain
period
of
time
(13
weeks)
may
result
in
induction
of
the
liver
enzymes
responsible
for
its
metabolism.

Adequacy
of
Dosing
for
Assessment
of
Testicular
Effects
The
dosing
(4000
ppm)
was
considered
to
be
adequate
for
assessing
the
testicular
effects
of
pronamide,
based
on
significant
(p
<
0.05)
depressions
of
body
weight
(14­
17%,
weeks
1­
13)
and
feed
consumption
(37%,
week
1;
9­
12%,
weeks
2­
8).
Testicular
relative
(to
body)
weights
were
slightly
increased
(26%;
p
<
0.
05)
and
liver
absolute
and
relative
(to
body)
weights
were
moderately
increased
(59%
absolute;
92%
relative;
p
<
0.
05).
The
liver­
related
enzymes,
SGPT
and
SGOT,
were
not
affected
by
treatment
with
pronamide.

IV.
Conclusions
Based
on
an
evaluation
of
the
pronamide
toxicology
data
presented
in
this
report
,
the
MTARC
reaffirmed
the
following
conclusions
of
the
CPRC
(Memorandum:
N.
Thoa,
May
26,
1993):

°
The
postulated
mechanism
of
action
is
at
best
incomplete;
the
Registrant's
postulated
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
is
not
supported
by
the
available
data.

°
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
incidence
of
liver
tumors
in
mice)
Therefore,
a
mechanistic
approach
to
risk
assessment
for
the
active
ingredient
pronamide
is
not
plausible.

°
Additional
studies
should
be
conducted
to
evaluate
the
potential
for
a
pronamideinduced
thyroid
and
testicular
neoplastic
effect
via
disruption
of
the
pituitary­
thyroid
and
pituitary­
testis
hormonal
balance,
respectively.

In
the
absence
of
any
additional
data,
the
MTARC
prescreening
committee
determined
that
a
full
MTARC
review
of
the
toxicology
data
base
for
the
active
ingredient
pronamide
is
not
required.

V.
Attachment
(not
available
electronically)

Carcinogenicity
Peer
Review
of
Pronamide
(3rd;
Memorandum:
N.
Thoa,
May
26,
1993)
16
ATTACHMENT
Carcinogenicity
Peer
Review
of
Pronamide
(3rd;
Memorandum:
N.
Thoa,
May
26,
1993)

An
electronic
version
of
this
document
is
not
available.
See
the
hard
copy
file.