UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES,
ANDTOXIC
SUBSTANCES
March
8,
2002
MEMORANDUM
SUBJECT:
Pronamide.
Tolerance
Reassessment
Eligibility
Decision
(TRED).
Chemical
ID
No.
101701.
DP
Barcode
No.
D275194.

FROM:
Gary
Bangs,
Risk
Assessor
Michelle
Centra,
Pharmacologist
Jose
Morales,
Chemist
Barry
O'Keefe,
Biologist
David
Soderberg,
Chemist
Reregistration
Branch
3
Health
Effects
Division
(7509C)

THRU:
Catherine
Eiden,
Branch
Senior
Scientist
Reregistration
Branch
3
Health
Effects
Division
(7509C)

TO:
Cecelia
Watson,
Chemical
Review
Manager
Michael
McDavit,
Acting
Branch
Chief
Reregistration
Branch
II
Special
Review
and
Reregistration
Division
(7508W)

This
memorandum
and
attachments
constitute
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
for
pronamide
and
updates
the
Health
Effects
Division
(HED)
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(RED)
for
pronamide
(August
24,
1993)
taking
into
consideration
requirements
of
the
1996
Food
Quality
Protection
Act
(FQPA).
The
Agency
RED
for
pronamide
was
issued
in
May
1994.
A
Tolerance
Reassessment
Eligibility
Decision
(TRED)
document
is
required
because
EPA
completed
the
RED
for
pronamide
before
passage
of
the
FQPA.
This
document
only
discusses
the
human
health
risk
assessment
required
for
reassessment
of
pesticide
residue
tolerances
and
does
not
revise
the
occupational
risk
assessment
conducted
in
the
1993
HED
human
health
risk
assessment
document.
Therefore,
data
submitted
for
assessment
of
occupational
exposure
have
been
used
only
for
non­
dietary
(i.
e.,
residential)
risk
assessment
under
FQPA.
Cumulative
risk
assessment
considering
risks
from
other
pesticides
which
have
a
common
mechanism
of
toxicity
is
also
not
addressed
in
this
document.

NOTE:
Only
the
Rohm
and
Haas
94.6%
technical
and
51%
wettable
powder
formulation
are
subject
to
the
tolerance
reassessment.
Rohm
and
Haas
sold
this
product
to
Dow
Agro
Sciences
(Letter
sent
to
J.
Tompkins
in
RD,
9/
21/
01).
In
addition,
Earth
Care,
Division
of
United
Industries
Corp.,
(previously
Pursell
Industries)
has
requested
voluntary
cancellation
of
the
product
GREEN
UP
KERB
50W,
EPA
Reg.
No.
8660­
85,
which
is
the
only
label
which
contains
a
residential
turf
use.
However,
as
of
the
time
of
this
TRED,
the
product
is
registered
and
a
postapplication
residential
exposure
and
risk
assessment
have
been
included
in
this
document.
Cancellation
of
the
GREEN
UP
label
(8660­
85)
would
eliminate
all
uses
that
result
in
potential
public
or
residential
exposure.

Attachments:
C
Hazard
Identification
Assessment
Review
Committee
(HIARC)
report
(M.
Centra,
December
10,
2001)
C
Report
of
the
FQPA
Safety
Factor
Committee
(C.
Christensen,
December
19,
2001)
C
Toxicology
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
(M.
Centra,
March
7,
2002)
C
Report
of
the
Mechanism
of
Toxicity
Assessment
Review
Committee
(MTARC)
(M.
Centra,
January
21,
2001)
C
Review
of
Pronamide
Incident
Reports
(
J.
Blondell
&
M..
Spann,
August
12,
2001)
C
Chronic
and
Cancer
Dietary
Exposure
Assessments
(D.
Soderberg,
et
al.,
February
7,
2002)
C
Pronamide
Residue
Chemistry
chapter
(J.
Morales,
February
28,
2002)
C
Residential
Risk
Assessment,
(B.
O'Keefe,
March
7,
2002)
C
Drinking
Water
Assessment
to
Support
TRED
for
Propyzamide
(Pronamide)
(L.
Shanaman,
May
16,
2001)
TABLE
OF
CONTENTS
1.0
EXECUTIVE
SUMMARY
.......................................................
1
2.0
PHYSICAL
CHEMICAL
PROPERTIES
CHARACTERIZATION
.....................
9
3.0
HAZARD
CHARACTERIZATION
................................................
9
3.1
Hazard
Profile
............................................................
9
3.2
FQPA
Considerations
.....................................................
19
3.3
Hazard
Endpoint
Selection
................................................
20
3.4
Endocrine
Disruption
.....................................................
24
4.
0
EXPOSURE
ASSESSMENT
..................................................
25
4.1
Summary
of
Registered
Uses
...............................................
25
4.2
Dietary
Exposure
and
Risk
Assessment
.......................................
26
4.2.1
Residues
in
Food
..................................................
26
4.3
Dietary
Exposure
from
Water
Sources
.......................................
29
4.3.1.
Environmental
Fate
..............................................
29
4.3.2
Drinking
Water
Exposure
Estimates
.................................
29
4.4
Residential
Exposure
......................................................
30
4.4.1
Residential/
Recreational
Postapplication
Exposure
and
Risk
............
30
4.4.2
Spray
Drift
.....................................................
35
5.0
AGGREGATE
RISK
ASSESSMENT
AND
RISK
CHARACTERIZATION
...........
35
5.1
Acute
Risk
...............................................................
36
5.2
Short­
Term
Risk
.........................................................
36
5.2.1
Aggregate
Short­
Term
Risk
Assessment
..............................
36
5.2.2
Short­
Term
DWLOC
Calculations
.................................
36
5.3
Intermediate­
Term
Risk
...................................................
37
5.4
Chronic
Risk
............................................................
37
5.5
Cancer
Risk
Estimates
.....................................................
39
5.5.1
Cancer
Aggregate
Risk
Assessment
.................................
39
5.5.2
Cancer
DWLOC
Calculations
.....................................
39
6.0
CUMULATIVE
EXPOSURE
TO
SUBSTANCES
WITH
A
COMMON
MECHANISM
OF
TOXICITY.................................................................
41
7.
0
INCIDENT
DATA...........................................................
42
8.0
TOLERANCE
REASSESSMENT
RECOMMENDATIONS
...........................
42
8.1
Tolerance
Reassessment
Recommendation
....................................
42
9.0
DATA
NEEDS
.................................................................
44
1
1.0
EXECUTIVE
SUMMARY
Purpose
A
Tolerance
Reassessment
Eligibility
Decision
(TRED)
document
is
required
for
pronamide
(propyzamide).
EPA
completed
the
1994
RED
for
pronamide
before
passage
of
the
1996
Food
Quality
Protection
Act
(FQPA).
Consequently,
pronamide
is
herein
reassessed
in
accordance
with
the
FQPA.
This
document
only
discusses
the
human
health
risk
assessment
required
for
reassessment
of
pesticide
residue
tolerances.
Potential
drinking
water
and
residential
exposure
is
also
considered
in
order
to
estimate
the
potential
aggregate
risk.
Cumulative
risk
assessment
considering
risks
from
other
pesticides
which
have
a
common
mechanism
of
toxicity
is
not
addressed
in
this
document.

Uses:
Pronamide
[3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide]
is
a
selective,
systemic,
preand
post­
emergence
herbicide
registered
for
the
control
of
grasses
and
broadleaf
weeds
in
several
food
and
feed
crops
as
well
as
woody
ornamentals,
Christmas
trees,
nursery
stocks,
turf,
and
fallow
land.
Pronamide
is
a
restricted
use
herbicide
applied
as
a
liquid
spray,
which
is
packaged
in
water
soluble
pouches
and
then
mixed
in
water
before
application.
It
is
a
soil
active
systemic
herbicide
with
uptake
by
susceptible
weeds
occurring
through
the
roots.
Application
rates
range
from
0.5
to
6
lbs
active
ingredient
(ai)
per
acre
per
application,
with
one
to
four
applications
per
year,
but
no
more
than
8
lbs
ai
per
acre
per
year.

Only
the
Rohm
and
Haas
94.6%
technical
and
51%
wettable
powder
formulation
are
subject
to
the
tolerance
reassessment.
Rohm
and
Haas
sold
this
product
to
Dow
Agro
Sciences
(Letter
sent
to
J.
Tompkins
in
RD,
9/
21/
01).
In
addition,
Earth
Care,
Division
of
United
Industries
Corp.,
(previously
Pursell
Industries)
has
requested
voluntary
cancellation
of
the
product
GREEN
UP
KERB
50W,
EPA
Reg.
No.
8660­
85
(letter
to
C.
Watkins,
B.
Metzger,
1/
14/
02),
which
is
the
only
label
containing
a
residential/
recreational
turf
use.
Cancellation
of
the
GREEN
UP
label
(8660­
85)
would
eliminate
all
uses
that
result
in
potential
public
or
residential
exposure.

Hazard
Assessment
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.

The
active
ingredient
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
multi­
generation
reproduction
studies),
mouse
(carcinogenicity
studies),
rabbit
(developmental
toxicity
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
multi­
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
multi­
generation
reproduction
studies).

There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
the
fetuses
or
the
2
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.
In
the
rat
developmental
toxicity
study,
the
highest
dose
of
pronamide
tested
exceeded
the
doses
tested
in
both
the
rabbit
developmental
toxicity
study
and
the
rat
multigeneration
reproduction
study
without
demonstrating
toxicities
in
either
maternal
animals
or
fetuses.
Since
this
study
failed
to
provide
evidence
concerning
the
potential
increased
susceptibility
to
infants
and
children
(a
LOAEL
was
not
be
established)
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996,
a
repeat
developmental
toxicity
study
in
the
rat
is
required
to
fulfill
the
OPPTS
harmonized
test
guideline
870.3700.

Results
of
the
battery
of
mutagenicity
studies
(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.
However,
the
Carcinogenicity
Peer
Review
Committee
(CPRC)
classified
Pronamide
as
a
group
B2
­
probable
human
carcinogen
(with
inadequate
evidence
in
humans)
based
on
the
finding
of
two
tumor
types
in
the
rat
(benign
testicular
interstitial
cell
tumors
and
uncommon
thyroid
follicular
cell
adenomas)
and
one
tumor
type
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
animals
to
humans
by
use
of
the
(mg/
kg
body
weight)
3/
4
interspecies
scaling
factor].

Pronamide
has
been
identified
by
the
Agency's
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC)
as
a
potential
endocrine
disruptor.
Evidence
of
endocrine
effects
from
several
guideline
toxicity
studies
as
well
as
two
special
studies
submitted
to
the
Agency
by
the
Registrant
include,
in
part,:
(i)
histopathology
of
the
thyroid
gland,
pituitary
gland,
adrenal
glands,
testes
and
ovaries,
(ii)
changes
in
hormone
levels;
decreased
T4
and
increased
TSH,
LH
and
FSH,
and
(iii)
the
induction
of
enzymes
such
as
cytochrome­
P450
and
­B5,
and
NADPH­
cytochrome­
c­
reductase
in
addition
to
those
enzymes
involved
in
the
oxidation
of
testosterone.

Mammalian
neurotoxicity
studies
for
pronamide
have
not
been
conducted.
However,
since
pronamide
does
not
belong
to
a
class
of
chemicals
known
to
exhibit
neurotoxicity,
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)
are
not
required.

Pronamide
is
rapidly
absorbed
and
completely
and
rapidly
eliminated
equally
in
the
urine
(40­
61%)
and
feces
(40­
60%)
within
7
days
post­
dosing.
No
bioaccumulation
was
apparent
and
very
little
unchanged
pronamide
was
recovered
in
the
urine.
All
of
the
fecal
metabolites
were
unidentified
and
comprised
less
than
1%
of
the
dose
whereas
two
major
urinary
metabolites
have
been
identified
and
quantified;
2­(
3,5­
dichlorophenyl)­
4,4­
dimethyl­
5­
carboxyoxazoline
(metabolite
SS47­
70,
3.0­
5.9%
of
the
administered
dose)
and
N­
carboxymethyl­
3,5­
dichlorobenzamide
(metabolite
10,
12.7­
18.9%
of
the
administered
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
3
purposes.

A
FQPA
safety
factor
is
required
for
all
population
subgroups
when
assessing
dietary
and
residential
exposure
scenarios
because
of
the
evidence
of
endocrine
effects
in
the
pronamide
data
base.
However,
the
FQPA
safety
factor
was
reduced
to
3x
because:
(i)
the
toxicological
database
is
adequate
for
FQPA
assessment
(ii)
there
is
no
indication
of
quantitative
or
qualitative
increased
susceptibility
of
rabbits
to
in
utero
exposure
or
to
rats
following
pre/
post­
natal
exposure.
Also,
in
the
available,
unacceptable
rat
study,
no
increased
susceptibility
was
seen
even
though
the
animals
could
have
tolerated
higher
doses
(iii)
a
developmental
neurotoxicity
study
is
not
required
and
(iv)
the
dietary
(food
and
drinking
water)
and
residential
exposure
assessments
will
not
underestimate
the
potential
exposures
for
infants
and
children.

Toxicological
endpoints
were
established
for
all
relevant
exposure
scenarios.
Acute
dietary
exposure
for
females
13­
50
years
of
age
or
for
the
general
population
is
not
assessed
since
there
was
no
appropriate
endpoint
attributable
to
a
single
dose
available
in
the
pronamide
data
base.
Two
toxicological
studies
determined
all
toxicological
endpoint
doses
used
in
the
risk
assessment:
a
prenatal
developmental
toxicity
study
in
the
rabbit
and
a
chronic
toxicity/
carcinogenicity
in
the
rat.
A
discussion
of
the
dose­
response
relationships
for
chronic
dietary
endpoints
as
well
as
residential
exposure
endpoints
follows
the
presentation
of
the
summary
of
toxicological
endpoint
selection
(See
Table
3,
Section
3.3
of
the
text).

A
chronic
reference
dose
(cRfD)
of
0.08
mg/
kg/
day
was
determined
on
the
basis
of
the
two­
year
chronic
toxicity/
carcinogenicity
study
in
rats
and
the
application
of
an
uncertainty
factor
of
100
(10x
for
interspecies
extrapolation
and
10x
for
intra­
species
variation).
The
NOAEL
in
this
study
was
8.46
mg/
kg/
day
and
the
LOAEL
was
42.59
mg/
kg/
day
based
upon
increased
relative
liver
weight
and
the
non­
neoplastic
histologic
changes
in
the
liver
(centrilobular
hypertrophy
and
hepatocellular
eosinophilic
alteration
in
males
and
females),
thyroid
(follicular
cell
hypertrophy
in
males
and
females)
and
ovaries
(sertoliform
tubular
hyperplasia
in
females).
The
3x
FQPA
safety
factor
was
applied
to
the
chronic
dietary
risk
assessment
because
there
is
evidence
of
endocrine
effects
(thyroid,
testes,
ovaries,
adrenal
glands,
pituitary
gland,
thymus)
identified
in
the
majority
of
subchronic/
chronic
studies
conducted
across
species.
The
cPAD
is
the
cRfD
adjusted
for
the
FQPA
safety
factor.
Therefore,
the
cPAD
is
0.027
mg/
kg/
day.
Dietary
risk
estimates
which
are
less
than
100%
of
the
cPAD
do
not
exceed
HED's
level
of
concern.

For
risk
assessments
based
on
short­
term
(1­
30
days)
incidental
oral,
dermal
and
inhalation
exposures,
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
the
clinical
signs
(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.
Although
selection
of
this
study
for
short­
term
exposure
scenarios
is
appropriate
for
the
route
(oral)
and
duration
(13
days),
the
NOAEL
of
5
mg/
kg/
day
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
doses
of
pronamide
selected
for
testing
in
these
studies.
The
Hazard
Identification
Assessment
Review
Committee
(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
3x
FQPA
safety
factor
was
also
applied
to
these
risk
assessments
because
of
the
evidence
of
endocrine
effects
in
the
pronamide
toxicity
data
base.
Due
to
the
lack
of
appropriate
dermal
or
inhalation
endpoints,
absorption
factors
of
4
100%
(default
value)
were
used
with
the
oral
endpoints.

Intermediate­
and
long­
term
toxicity
endpoints
were
also
selected,
however
only
short­
term
oral,
dermal
or
inhalation
exposures
to
pronamide
are
anticipated,
based
on
its'
use
pattern.

Exposure
and
Risk
Assessment
There
is
a
potential
for
dietary
(food
and
drinking
water)
exposure
from
commercial
applications
of
pronamide
in
agriculture
and
for
postapplication
dermal
and
incidental
oral
exposures
from
residential/
recreational
uses
(lawns
and
turf).
If
the
label
allowing
residential/
recreational
turf
uses
is
canceled,
the
nondietary
exposures
will
be
eliminated.
The
occupational
exposure
was
assessed
in
the
1993
HED
RED
chapter.
However,
because
this
is
a
tolerance
reassessment
document,
only
nonoccupational
dietary
and
residential
postapplication
exposures
to
pronamide
are
considered
in
this
document.
Short­
term,
chronic
and
cancer
exposures
were
assessed
for
pronamide
residues
in
food
and
water.

A
review
of
incident
data
sources
found
that
relatively
few
incidents
of
pronamide
poisonings
were
reported.
There
are
only
two
Poison
Center
reports,
no
incident
reports
in
OPP's
Incident
Data
System
and
only
two
reports
from
the
California
Pesticide
Illness
Surveillance
Program.

Dietary
The
dietary
risk
assessment
for
chronic
exposures
to
pronamide
shows
that
chronic
dietary
exposure
to
pronamide
is
not
a
significant
exposure
pathway.
As
stated
previously,
an
acute
toxicity
endpoint
was
not
selected,
therefore
an
acute
exposure
assessment
was
not
conducted.
Refined
tier
3
chronic
and
cancer
dietary
exposure
assessments
were
conducted
for
all
supported
food
uses
(i.
e.,
all
currently
registered
and
proposed
uses).
Pronamide
and
its
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety
are
the
residues
of
concern
and
are
included
in
the
assessment.
Although
tolerance
level
residues
were
used
for
four
registered
crops
(dried
peas,
endives,
radicchio,
and
cranberries),
the
assessment
was
based
primarily
upon
residue
monitoring
data
for
fruits
and
vegetables
and
upon
calculation
of
anticipated
residues
for
meat,
milk,
poultry
and
eggs,
and
is
the
most
refined
assessment
to
date
for
pronamide.
These
data
are
based
mostly
upon
non­
detectable
residues.
Estimates
of
percent
crop
treated
(%
CT)
generated
by
the
Biological
and
Economic
Analysis
Division
(BEAD)
were
used
to
further
refine
the
dietary
exposure
assessment.

Estimates
were
generated
for
chronic
(long­
term)
and
cancer
dietary
exposure
using
the
most
recent
version
of
the
Dietary
Exposure
Evaluation
Model
(DEEM™,
Version
7.75).
This
assessment
showed
that
the
chronic
dietary
risk
estimates
are
below
the
Agency's
level
of
concern
(<
100%
of
the
cPAD)
for
the
U.
S.
population
and
for
all
population
subgroups.
The
chronic
dietary
exposure
estimates
for
the
two
most
highly
exposed
population
subgroups,
children
(1­
6)
and
seniors
(55+),
are
both
estimated
at
0.000005
mg/
kg/
day
(<
1%
cPAD).
The
cancer
dietary
risk
estimate
is
1.06
x
10
­7
for
the
U.
S.
population,
and
is
below
the
level
that
the
Agency
generally
considers
to
be
of
concern
(1.0
x
10
­6
or
one
in
one
million).

Residential
Postapplication
Exposure
Based
on
the
application
frequency
and
rate
of
residue
dissipation,
only
short­
term
residential
5
postapplication
exposures
to
pronamide
are
anticipated
after
lawn
and
turf
treatments.
A
margin
of
exposure
(MOE)
of
300
(10x
for
interspecies
extrapolation,
10x
for
interspecies
variation
and
a
3x
FQPA
safety
factor)
is
required
for
short­
term
incidental
oral,
dermal
and
inhalation
risk
assessments.
Therefore,
short­
term
residential
risk
estimates
with
a
MOE
>
300
do
not
exceed
the
level
of
concern.

The
risk
assessment
for
short­
term
residential
postapplication
exposure
indicates
that
dermal
exposures
to
pronamide
are
a
significant
pathway
of
exposure.
All
pronamide
end
use
products
are
labeled
as
restricted
use
pesticides.
Therefore,
consumers
are
restricted
from
handling
or
applying
pronamide
products.
Consequently,
only
residential/
recreational
postapplication
exposures
to
the
general
population
are
anticipated
and
are
evaluated
in
this
assessment.
Adults
and
children
are
potentially
exposed
to
pronamide
residues
via
the
dermal
route
after
application
of
pronamide
products
by
professional
lawn
care
operators
(LCOs)
in
residential/
recreational
settings.
Inhalation
exposure
to
pronamide
is
not
anticipated
after
application
due
to
the
low
vapor
pressure
of
the
active
ingredient
and
outdoor
air
dilution.
Incidental
oral
exposure
is
expected
to
occur
for
small
children
and
is
combined
with
their
dermal
exposures,
where
applicable
(i.
e.,
playing
on
turf).
Residential
exposures
were
estimated
based
on
label
application
frequency
and
the
persistence
of
pronamide.
Most
assumptions
for
risk
estimation
were
based
on
the
Agency's
Residential
SOPs.
Residents
are
assumed
to
play
or
work
on
treated
lawns
or
recreational
turf
within
the
first
24
hours
of
spraying.
Only
short­
term
risks
from
residential
postapplication
dermal
and
incidental
oral
exposures
are
anticipated
since
turf
residues
dissipate
below
the
limit
of
quantitation
by
day
14
following
application
(based
on
the
submitted
pronamide
turf
transferable
residue
(TTR)
study).

Risk
estimates
based
on
residue
data
from
the
TTR
study
for
short­
term
dermal
exposures
to
treated
turf
during
high
contact
lawn
activities
on
day
zero
following
application
(DAT
0)
exceed
HED's
level
of
concern,
i.
e.
result
in
MOEs
<
300
for
adults
(MOE
=
71)
and
children
(MOE
=
42).
After
the
turf
was
watered,
residues
declined
sufficiently
that
all
risk
estimates
were
below
the
level
of
concern
for
adults
(MOE
=
890)
and
children
(MOE
=
530).
However,
label
language
regarding
immediate
watering­
in
after
application
to
turf
is
neither
required
nor
enforceable
for
consumers.
Risk
estimates
for
short­
term
dermal
contact
with
residues
on
treated
turf
during
the
low
contact
activities
of
grass
mowing
or
golfing
on
the
day
of
treatment
do
not
exceed
the
level
of
concern
for
adults
(MOEs
2100
and
1000,
respectively).
Postapplication
cancer
risk
was
estimated
using
14­
day
average
residues
and
only
a
single
day's
activity,
based
on
a
single
dormant
season
application.
The
estimated
cancer
risk
from
one
day
per
year
of
high­
contact
(e.
g.,
playing
on
lawn)
postapplication
dermal
exposure
to
pronamide
treated
turf
was
8.4
x
10
­7
and
did
not
exceed
the
Agency's
level
of
concern
of
1
x
10
­6
.
Other,
lower
contact
activities
(e.
g.,
golfing)
could
be
conducted
for
several
days
without
exceeding
the
level
of
concern.

The
risk
estimates
for
small
children's
incidental
ingestion
of
pronamide
from
treated
turf
indicate
that
risks
do
not
exceed
the
level
of
concern
(i.
e.
MOEs
>
300)
for
hand­
to­
mouth
(MOE
=
380),
ingestion
of
soil
(MOE
=
113,000),
and
object
to
mouth
(MOE
=
1500)
scenarios.
The
small
children's
combined
oral
hand­
to­
mouth
incidental
ingestion
scenarios
(MOE
=
300)
also
do
not
exceed
the
level
of
concern.
When
risks
from
dermal
exposures
to
pronamide
by
small
children
are
combined
with
risks
from
incidental
oral
exposures,
the
combined
short­
term
risk
estimates
exceed
the
level
of
concern
(MOEs
<
300),
with
a
MOE
of
37.
There
is
significant
uncertainty
involved
in
predicting
co­
occurrence
of
exposures
by
different
routes
and
in
adding
these
scenarios,
as
well
as
the
degree
of
conservatism
generated
in
the
combined
risk
estimate.
6
Drinking
Water
Risk
assessment
for
short­
term
and
chronic
exposure
to
pronamide
indicates
that
drinking
water
is
not
a
significant
exposure
pathway,
but
may
be
of
some
potential
concern
for
cancer.
Risk
estimates
for
exposure
to
pronamide
in
drinking
water
are
assessed
by
comparing
drinking
water
levels
of
comparison
(DWLOCs)
to
the
estimated
environmental
concentrations
(EECs)
of
pronamide
in
surface
water
and
groundwater.
In
the
case
of
pronamide,
there
are
monitoring
data
available
for
surface
and
ground
water.
The
monitoring
database
used
in
the
risk
assessment
is
considered
to
be
of
good
quality
(US
Geological
Survey),
but
the
data
are
not
specific
to
pronamide
use
areas.
Therefore
they
are
cited
for
comparison,
rather
than
verification
of
modeling
estimates.

A
Tier
I
Drinking
Water
Assessment
for
pronamide
was
calculated
(L.
Shanaman,
May
16,
2001)
using
the
SCIGROW
model
to
provide
groundwater
EECs.
The
Tier
I
groundwater
concentration
estimates
were
predicted
from
application
of
pronamide
at
maximum
label
rate,
and
represent
upper­
bound
estimates
of
the
concentrations
that
might
be
found
in
shallow
groundwater
at
vulnerable
sites
due
to
the
use
of
pronamide/
propyzamine.
The
resulting
modeled
groundwater
screening
concentration
is
3.0
ppb,
which
does
not
exceed
the
DWLOC
for
short­
term
exposure
for
the
most
sensitive
populations
(females
>55
years
)
of
560
ppb.

The
Tier
II
PRZM­
EXAMS
model
(L.
Shanaman,
in
progress,
2002)
was
used
to
predict
EECs
for
pronamide
in
surface
water,
i.
e.,
90
th
percentile
average
annual
concentration
values
for
use
in
chronic
exposure
assessments,
and
36­
year
mean
concentration
values
for
use
in
"cancer"
exposure
assessments.
Maximum
label
application
rates
were
used
for
major
use
crops.
Chronic
exposure
values
ranged
from
1.5
to
6.4
ppb,
which
are
lower
than
the
chronic
DWLOC
of
300
ppb
for
the
most
sensitive
populations,
infants
and
children.
Conservative
inputs
were
used
for
the
environmental
(soil
and
water
metabolism)
assumptions,
i.
e.,
2­
3x
uncertainty
factors
were
applied
to
soil
and
water
half­
lives
used
in
the
PRZMEXAMS
assessment.

The
Tier
II
cancer
risk
assessment
for
exposure
to
pronamide
in
water
indicates
that
drinking
water
may
be
a
significant
exposure
pathway.
The
the
refined
Tier
II
modeling
result
is
greater
than
the
aggregate
cancer
DWLOC
estimate
of
<0.1
ppb
and
therefore
exceeds
the
cancer
level
of
concern
of
1
x
10
­6
.
The
estimated
DWLOC
for
cancer
based
on
dietary
exposures
only
(food
+
water)
is
1.2
ppb,
which
is
below
some
of
the
drinking
water
concentrations
estimated
by
EFED
and
above
others
(0.535
­
4.3
ppb
for
surface
water
and
3
ppb
for
groundwater)
and
therefore
is
of
concern
for
some
scenarios.
Surface
and
ground
water
monitoring
data
are
available
for
pronamide
from
routine
USGS
sampling,
and
are
being
analyzed
to
determine
if
they
provide
support
for
the
modeling
estimates.

Aggregate
Exposure
Aggregate
risk
assessments
were
conducted
for
short­
term
and
chronic
exposures,
and
for
cancer.
All
of
the
aggregate
risk
estimates
are
considered
high­
end,
or
conservative,
due
to
the
compounding
of
conservative
assumptions
in
individual
exposure
route
estimates.
Aggregate
risk
estimates
for
acute
exposures
were
not
conducted
as
no
acute
endpoint
was
selected
from
the
toxicity
database.
Because
there
are
no
intermediate­
term
or
chronic
non­
dietary
exposures
to
pronamide,
the
chronic
aggregate
risk
assessment
only
considers
exposures
from
dietary
(via
food
and
drinking
water)
consumption.
HED
has
no
concerns
for
aggregate
chronic
exposures
to
pronamide
residues
in
food
and
drinking
water.
7
Estimated
drinking
water
exposures
using
Tier
2
modeling
and
actual
sampling
data
for
surface
water
and
groundwater
result
in
equivocal
cancer
risk
estimates
of
approximately
1
to
3
x
10
­6
,
independent
of
dietary
and
residential
exposures
to
pronamide.
Therefore,
HED
has
some
concerns
for
the
potential
exposures
from
surface
and
groundwater
sources
under
the
cancer
asessment,
particulary
for
the
scenario
assessed
surface
water
for
alfalfa
in
California.
Aggregated
exposures
from
food,
water,
and
residential
uses
result
in
cancer
risk
estimates
that
further
exceed
HED's
level
of
concern
for
cancer.

The
short­
term
aggregate
risk
assessment
conducted
for
pronamide
considered
ingestion
of
food
and
drinking
water,
combined
with
postapplication
dermal
and
incidental
oral
exposures.
Because
the
risk
estimates
for
high­
contact
dermal
exposures
for
both
children
and
adults
alone
are
of
concern,
a
shortterm
aggregate
exposure
assessment
was
not
conducted
for
those
populations
and
scenarios,
as
they
would
only
further
exceed
the
HED's
level
of
concern.
Risk
estimates
are
in
excess
of
the
level
of
concern
(MOE
<
300)
for
short­
term
dermal
exposures
to
pronamide
residues
on
turf
for
adults
(MOE
=
71)
and
children
(MOE
=
42)
engaged
in
high­
contact
activities,
such
as
playing
on
treated
turf
immediately
after
pronamide
application.

However,
as
the
risk
estimate
for
short­
term
exposures
of
adults
golfing
does
not
exceed
HED's
level
of
concern,
HED
included
this
short­
term
residential
exposure
with
food
and
drinking
water
exposure
in
a
short­
term
aggregate
risk
assessment.
The
aggregate
risk
estimate
for
food
and
golfing
exposure
was
a
MOE
of
1050,
and
there
was
still
enough
room
to
add
the
estimated
drinking
water
exposure
without
exceeding
the
HED
DWLOC.
This
short­
term
aggregate
risk
estimate
including
adults
engaged
in
lowcontact
activities
on
turf
may
be
useful
in
risk
management
decisions.
HED
notes
that
all
of
the
residential
scenarios
with
risk
estimates
of
concern,
including
the
aggregate
cancer
risk
estimate
are
considered
high­
end
estimates
based
on
standard
HED
assumptions
and
a
100%
dermal
absorption
factor.

Data
Gaps
Most
pertinent
product
chemistry
data
requirements
are
satisfied
for
the
Rohm
and
Haas
94.6%
T/
TGAI,
and
51%
FI.
Some
additional
physical
chemistry
and
processing
information
are
required.
There
is
confidence
in
the
overall
scientific
quality
of
the
available
toxicity
data,
but
several
data
gaps
were
identified:
a
developmental
toxicity
study
in
rats,
a
21­
day
dermal
toxicity
study,
28­
day
inhalation
toxicity
study,
a
dermal
penetration
study
and
a
comparative
thyroid
rat
assay
in
adult
animals
and
offspring.
Some
label
amendments
and
data
submissions
are
required,
including
additional
residue
data
for
use
on
grasses,
dried
winter
peas
(outstanding),
the
vines
and
hay
of
winter
peas,
grass
forage,
and
hay.
The
registrant
is
required
to
improve
the
analytical
method
for
animal
residue
data;
and
to
submit
bridging
independent
laboratory
validation
data.
Additional
confirmatory
storage
stability
data
for
the
regulated
pronamide
metabolites
on
alfalfa,
apples,
grapes,
lettuce,
and
peaches
or
plums
are
required.
8
Cl
Cl
O
N
H
CH
3
CH
3
CH
2.0
PHYSICAL
CHEMICAL
PROPERTIES
CHARACTERIZATION
The
chemical
name
for
pronamide
is
[3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide].
The
chemical
structure
is
Empirical
Formula:
C12H11NOCl2
Molecular
Weight:
256.13
CAS
Registry
No.:
23950­
58­
5
PC
Code:
101701
Technical
pronamide
is
a
white
crystalline
solid
with
a
melting
point
of
155­
156
°C,
specific
gravity
of
0.48
g/
cc,
octanol/
water
partition
coefficient
(log
POW)
of
3.05­
3.27,
and
vapor
pressure
of
8.50
x
10
­5
torr
at
25
°C.
Because
of
its'
low
vapor
pressure,
pronamide
is
not
expected
to
present
an
inhalation
exposure
risk
when
used
outdoors.
There
are
no
toxicologically
significant
impurities
in
the
manufacturing
process.

3.0
HAZARD
CHARACTERIZATION
The
active
ingredient
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.
Other
target
organs
included
the
thyroid,
testes
and
pituitary
in
rats,
and
the
kidneys,
adrenal
glands,
thymus,
heart,
testes,
and
brain
in
dogs.

3.1
Hazard
Profile
Acute
Toxicity
The
acute
toxicity
data
base
for
pronamide
technical
is
considered
complete.
No
additional
studies
are
required
at
this
time.
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.
The
acute
toxicity
data
for
pronamide
is
summarized
below
in
Table
1.
9
Table
1.
Acute
Toxicity
of
Pronamide
(Propyzamide)

Guideline
Number
Study
Type
MRID
Number
Results
Toxicity
Category
870.1100
(§
81­
1)
Acute
Oral
­
Rat,
>
92.0%
a.
i.
00085505
LD50
(males
and
females)
is
greater
than
5000
mg/
kg
IV
870.1100
(§
81­
1)
Acute
Oral
(Limit
test)
Rat
95.7%
a.
i.
43583901
LD50
(males
and
females)
is
greater
than
5000
mg/
kg
IV
870.1200
(§
81­
2)
Acute
Dermal
(Limit
Test)
­
Rabbit,
95.7%
a.
i.
43583902
LD50
(males
and
females)
is
greater
than
2000
mg/
kg
III
870.1300
(§
81­
3)
Acute
Inhalation
­
Rat,
95.7%
a.
i.
44034201
LC50
is
greater
than
2.1
mg/
L
following
a
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
Subchronic
Toxicity
The
data
base
for
subchronic
toxicity
is
considered
incomplete.
The
HIARC
identified
two
subchronic
toxicity
study
data
gaps
and
recommended
the
following
studies
be
conducted
in
order
fulfill
the
requirements
cited
for
a
food/
feed
use
chemical
(40
CFR
158.340):

1)
a
21­
day
dermal
toxicity
study
(guideline
870.3200;
old
82­
2);
and
2)
a
28­
day
inhalation
toxicity
study
(non­
guideline)

However,
the
pronamide
subchronic
data
base
does
contain
two
acceptable
studies
conducted
in
the
rat
that
can
be
used
for
regulatory
purposes;
a
4­
week
oral
toxicity
study
(non­
guideline)
and
a
13­
week
oral
toxicity
study
(guideline).
In
the
non­
guideline,
4­
week
study,
systemic
toxicities
were
noted
in
males
treated
with
37.24
or
74.05
mg/
kg/
day
pronamide
and
in
females
treated
with
43.65
or
87.65
mg/
kg/
day
pronamide.
These
toxicities
were
limited
to
the
liver
and
included
increases
in
absolute
and
relative
(to
body)
liver
weights
(males:
both
doses;
females:
high­
dose)
and
a
positive
trend
in
the
increased
incidence
of
centrilobular
hypertrophy
(males).
When
pronamide
was
administered
in
the
diet
for
13
consecutive
weeks,
male
rats
treated
with
60.0
mg/
kg/
day
and
females
rats
treated
with
74.6
mg/
kg/
day
presented
with
the
following
systemic
toxicities
in
one
or
both
sexes:
decreased
body
weight,
body
weight
gain
and
food
consumption,
increased
blood
cholesterol
levels,
increased
relative
(to
body)
liver
weights
and
incidence
of
hepatic
centrilobular
hypertrophy.
At
the
highest
dose
tested
(254.0
mg/
kg/
day
for
males
and
289.2
mg/
kg/
day
in
females),
many
of
these
toxicities
were
observed
in
both
10
sexes
and
showed
an
increase
in
incidence
and/
or
severity.
The
following
additional
changes
were
also
observed
in
high­
dose
animals:
clinical
signs
(brown
and/
or
yellow
staining
of
the
anogenital
area
(males),
increased
enzyme
activity
(SGOT
and
alkaline
phosphatase)
in
males,
triglyceride
blood
levels
(females),
increased
absolute
liver
weights
(males
and
females),
and
increased
incidences
of
thyroid
follicular
cell
hypertrophy
(males
and
females)
sexes
and
anterior
pituitary
cellular
hypertrophy
(males).
After
4
weeks
of
recovery,
most
of
the
adverse
effects
observed
at
the
high­
dose
were
partially
or
completely
reversed
with
the
exception
of
the
increase
in
incidence
of
pituitary
cellular
hypertrophy
(males
only).

Reproductive
&
Developmental
Toxicity
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.
Fetal/
offspring
effects
in
both
of
these
species
were
observed
at
either
the
same
or
higher
dose
levels
which
produced
maternal/
parental
toxicity.
In
the
developmental
toxicity
study
in
rabbits,
abortions
were
observed
at
a
higher
dose
level
(80
mg/
kg/
day)
compared
to
the
dose
(20
mg/
kg/
day)
at
which
maternal
toxicity
(soiled
anal
area,
anorexia
and
punctate
vacuolation
of
hepatocytes)
was
observed.
Also,
no
evidence
of
increased
susceptibility
was
demonstrated
in
the
two­
generation
reproduction
study
in
rats.
Offspring
toxicity
(decreased
combined
male/
female
pup
weight/
litter)
was
observed
at
the
same
dose
that
caused
parental
toxicity
(decreased
body
weight
and
food
consumption
in
both
sexes,
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).
Parental
and
offspring
toxicities
were
observed
at
the
same
LOAEL
of
1500
ppm
(130.1
mg/
kg/
day
for
males
and
120.7
mg/
kg/
day
for
females).

Evidence
for
susceptibility
could
not
be
ascertained
in
the
developmental
toxicity
study
conducted
in
rats.
No
toxicities
were
observed
in
either
maternal
animals
or
fetuses
at
any
dose
tested
(5­
160
mg/
kg/
day);
a
LOAEL
could
not
be
established
in
the
rat
developmental
toxicity
study.
Since
this
study
failed
to
provide
evidence
concerning
the
potential
increased
susceptibility
to
infants
and
children
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996,
a
repeat
developmental
toxicity
study
in
the
rat
is
required
to
fulfill
the
OPPTS
harmonized
test
guideline
870.3700.

Chronic
Toxicity:
Following
chronic
exposure
(mid­
dose
and/
or
high­
dose
groups;
33.1
mg/
kg/
day
and/
or
67.7
mg/
kg/
day)
in
dogs,
systemic
toxicities
presented
as
decreased
body
weights,
body
weight
gains,
food
consumption,
serum
albumin,
platelet
counts,
increased
enzyme
activity
(alkaline
phosphatase,
alanine
aminotransferase,
and
gamma
glutamyltransferase),
increased
absolute
and/
or
relative
weights
of
the
thyroid,
liver,
heart,
testes,
adrenal
glands,
kidneys
and
thymus,
and
histopathology
of
the
liver
(hepatocytic
hypertrophy,
hyperplasia
and
granular
brown
pigmentation/
mononuclear
infiltration
of
Kupffer
cells)
and
kidneys
(granular
brown
pigment
in
the
epithelial
cells
of
the
proximal
convoluted
tubules).
In
rats,
the
toxicities
observed
included
decreased
body
weight/
body
weight
gain,
increased
liver
weight
and
histopathology
of
the
liver
(hypertrophy
accompanied
by
eosinophilic
cell
alteration),
thyroid
(follicular
cell
hypertrophy
and
hyperplasia),
and
ovaries
(sertoliform
tubular
hyperplasia)
at
42.59
mg/
kg/
day
(LOAEL).
In
the
carcinogenicity
study
conducted
in
mice,
systemic
toxicities
observed
at
the
LOAEL
of
75
mg/
kg/
day
were
limited
to
decreased
body
weight/
body
weight
gain,
increased
liver
weight
and
histopathology
of
the
liver
(hypertrophy,
nodules/
masses,
parenchymal
necrosis,
and
cholestasis).
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
11
pronamide
based
on
liver
effects
(non­
neoplastic
lesions
and
increased
weight).

Mutagenicity:
With
the
exception
of
one
gene
mutation
assay,
the
remaining
five
mutagenicity
studies
were
determined
to
be
acceptable
for
regulatory
purposes
(The
acceptable
studies
satisfy
the
1991
mutagenicity
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.

Carcinogenicity:
The
Carcinogenicity
Peer
Review
Committee
(CPRC)
classified
Pronamide
as
a
group
B2
­
probable
human
carcinogen
with
inadequate
evidence
in
humans
(Memorandum:
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
and
the
tumor
incidence
data
used
in
this
calculation
is
derived
from
the
1982
mouse
carcinogenicity
study
(MRID
00114114,
00151822).
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).

Neurotoxicity:
Mammalian
neurotoxicity
studies
for
pronamide
have
not
been
conducted.
However,
since
pronamide
does
not
belong
to
a
class
of
chemicals
known
to
exhibit
neurotoxicity,
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.

Metabolism:
Pronamide
is
rapidly
absorbed
from
the
gastrointestinal
tract
and
extensively
and
rapidly
metabolized;
93­
103%
the
radioactivity
administered
was
recovered
.
It
is
excreted
(7
days
post­
dosing)
equally
in
both
the
urine
(40­
61%)
and
the
feces
(40­
60%).
No
bioaccumulation
was
apparent;
radioactivity
recovered
in
all
tissues
were
consistently
highest
at
the
first
sampling
time
(8
hours
postdose
then
gradually
declined
to
insignificant
levels
7
days
after
dosing.
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
hrs
(females)]
and
that
of
the
high
dose
rats
was
monophasic
[t½
=
24.1
hrs
(males)
and
24.8
hrs
(females)].
Tissues
with
the
highest
radioactivity
contents
were,
in
decreasing
order,
the
fat,
adrenals,
bone
marrow,
thyroids,
liver,
kidney,
and
plasma.
Very
little
unchanged
pronamide
was
recovered
in
the
urine
and
no
significant
difference
in
the
urinary
metabolite
profile
was
observed
between
the
doses
or
the
sexes.
Approximately
27
unidentified
metabolites
were
found
in
the
urine
and
none
exceeded
3.3%
of
the
dose
whereas
all
of
the
fecal
metabolites
were
unidentified
and
comprised
less
than
1%
of
the
dose.
Two
major
urinary
metabolites
have
been
identified
and
quantified;
2­(
3,5­
dichlorophenyl)­
4,4­
dimethyl­
5­
carboxyoxazoline
(metabolite
SS47­
70,
3.0­
5.9%
of
the
administered
dose)
and
N­
carboxymethyl­
3,5­
dichlorobenzamide
(metabolite
10,
12.7­
18.9%
of
the
administered
dose).

Dermal
Absorption/
Toxicity:
No
dermal
penetration
study
conducted
with
pronamide
technical
is
available
in
the
toxicity
data
base.
A
dermal
penetration
study
conducted
with
the
Kerb
50W
and
3.3F
12
pronamide
formulations
was
submitted,
however,
this
study
was
classified
as
unacceptable­
guideline
(the
actual
doses
applied
to
the
skin
were
not
determined
and
there
were
discrepancies
in
the
percent
radioactive
recovery).
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.
A
repeat
dermal
penetration
study
in
the
rat
is
required
to
fulfill
the
OPPTS
harmonized
test
guideline
870.7600.

Endocrine
Effects:

Pronamide
is
an
organochlorine
herbicide
which
has
been
identified
by
the
Agency's
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC)
as
a
potential
endocrine
disruptor.
Evidence
of
endocrine
effects
from
several
guideline
toxicity
studies
as
well
as
two
special
studies
submitted
to
the
Agency
by
the
Registrant
include,
in
part:
(i)
histopathology
of
the
thyroid
gland,
pituitary
gland,
adrenal
glands,
testes
and
ovaries,
(ii)
changes
in
hormone
levels;
decreased
T4
and
increased
TSH,
LH
and
FSH,
and
(iii)
the
induction
of
enzymes
such
as
cytochrome­
P450
and
­B5,
and
NADPH­
cytochrome­
c­
reductase
in
addition
to
those
enzymes
involved
in
the
oxidation
of
testosterone.

Two
special
studies
were
conducted
by
the
Registrant
to
evaluate
pronamide's
effect
on
hormonal
balance
in
support
of
a
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms.
Although
the
results
of
these
special
endocrine
studies
are
suggestive
of
a
pronamide­
induced
thyroid
and
testicular
neoplastic
effect
via
disruption
of
the
pituitary­
thyroid
and
pituitary­
testis
hormonal
balance,
these
data
are
far
from
conclusive.
Based
on
the
absence
of
any
additional
information
as
well
as
the
Mechanism
of
Toxicity
Assessment
Review
Committee's
(MTARC)
evaluation
of
the
existing
pronamide
toxicology
data
base
(Memorandum:
M.
Centra,
January
21,
2001)
and
the
Agency's
previous
hazard
characterization
of
this
active
ingredient
(Memorandum:
N.
Thoa,
May
26,
1993),
it
was
determined
that
the
postulated
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
is
not
supported
by
the
available
data.
Therefore,
HED
has
recommended
that
additional
studies
be
conducted
with
pronamide
to
determine
its
mechanism
of
endocrine
toxicity.
One
such
study,
a
comparative
assay
in
the
rat
that
is
designed
to
assess
thyroid
function
in
adult
animals
and
their
offspring
as
well
as
potential
central
nervous
system
effects
in
the
young,
is
required
because
of
the
endocrine
toxicities
observed
in
various
organ
systems
(thyroid
gland,
testes,
ovaries,
adrenal
glands,
pituitary
gland)
of
rats
and/
or
dogs.

The
toxicity
study
profile
is
summarized
in
Table
2.

TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
870.3100
(§
82­
1a)
4­
Week
Oral
Toxicity
Rat
MRID
42669402
(6/
18/
87)/
Acceptable­
Nonguideline
ppm
=
0,
500,
or
1000
mg/
kg/
day
(males)
=
0,
37.24,
or
74.05
mg/
kg/
day
(females)
=
0,
43.65,
or
87.65
NOAEL
=
less
than
500
ppm
(37.24
mg/
kg/
day
for
males;
43.65
mg/
kg/
day
for
females)
LOAEL
=
less
than
or
equal
to
1000
ppm
(74.05
mg/
kg/
day
for
males;
87.65
mg/
kg/
day
for
females)
based
upon
increased
absolute
and
relative
(to
body)
liver
weights
in
males
and
females
and
a
positive
trend
in
increased
incidence
of
liver
centrilobular
hypertrophy
in
males.
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
13
870.3100
(§
82­
1a)
90­
Day
Oral
Toxicity
Rat
MRID
42669403
(11/
2/
67)/
Acceptable­
Guideline
ppm
=
0,
40,
200,
1000,
or
4000
mg/
kg/
day
(males)
=
0,
2.5,
12.3,
60.0,
or
254.0
mg/
kg/
day
(females)
=
0,
3.1,
15.0,
74.6,
or
289.2
NOAEL
(males
and
females)
=
200
ppm
(12.3
mg/
kg/
day
in
males;
15.0
mg/
kg/
day
in
females)
LOAEL
=
1000
ppm
(60.0
mg/
kg/
day
in
males;
74.6
mg/
kg/
day
in
females)
based
upon
increased
relative
liver
weights
and
increased
incidence
of
centrilobular
hypertrophy
of
the
liver
in
both
sexes,
decreased
body
weight,
body
weight
gain
and
food
consumption
in
females
and
increased
blood
cholesterol
levels
in
males.

870.3700
(§
83­
3a)
Developmental
Toxicity
­
Rat
MRID
40334501
(7/
10/
87)/
Unacceptable­
Guideline
(not
upgradeable)
mg/
kg/
day
=
0,
5,
20,
80,
or
160
Maternal
Toxicity
NOAEL
=
greater
than
or
equal
to
160
mg/
kg/
day
LOAEL
=
greater
than
160
mg/
kg/
day
(highest
dose
tested;
LOAEL
not
established)

Developmental
Toxicity
NOAEL
=
greater
than
or
equal
to
160
mg/
kg/
day
LOAEL
=
greater
than
160
mg/
kg/
day
(highest
dose
tested;
LOAEL
not
established)

870.3700
(§
83­
3b)
Developmental
Toxicity
­
Rabbit
MRID
00148065,
00148064
(6/
4/
85
)/
Acceptable­
Guideline
mg/
kg/
day
=
0,
5,
20,
or
80
Maternal
Toxicity
NOAEL
=
5
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day
based
upon
clinical
signs
of
toxicity
(soiled
anal
area,
anorexia
and
punctate
vacuolation
of
hepatocytes)
and
liver
effects
(hepatocellular
necrosis,
eosinophilia,
swelling
of
hepatocytes,
pigmentation
of
Kupffer
cells).

Developmental
Toxicity
NOAEL
=
20
mg/
kg/
day
LOAEL
=
80
mg/
kg/
day
based
upon
abortions.

870.3800
(§
83­
4)
Multigeneration
Reproductive
Toxicity
­
Rat
MRID
41540301
(1968)/
Acceptable­
guideline
ppm
=
0,
40,
200,
or
1500
mg/
kg/
day
(males)
=
0,
3.1,
16.0,
or
120.7
mg/
kg/
day
(females)
=
0,
3.6,
18.0,
or
130.1
Parental/
Systemic
Toxicity
NOAEL
=
200
ppm
(16.0
mg/
kg/
day
for
females
and
18.0
mg/
kg/
day
for
males)
LOAEL
=
1500
ppm
(120.7
mg/
kg/
day
for
females
and
130.1
mg/
kg/
day
for
males)
based
upon
decreases
in
body
weight
and
feed
consumption
in
both
sexes
and
increased
incidences
of
histology
of
the
liver
(centrilobular
hepatocyte
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.

Reproductive
Toxicity
NOAEL
=
greater
than
or
equal
to
1500
ppm
LOAEL
=
greater
than
1500
ppm;
not
established
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
14
870.4100
(§
83­
1b)
Chronic
Toxicity
­
Dog
MRID
41807601,41807602,
4213030
(8/
5/
68)/
Acceptable­
Guideline
ppm
=
0,
300,
875,
or
1750
mg/
kg/
day
(males)
=
0,
11.9,
33.1,
or
67.7
mg/
kg/
day
(females)
=
0,
11.9,
36.1,
or
69.0
NOAEL
(males,
females)
=
300
ppm
(11.9
mg/
kg/
day)
LOAEL
=
875
ppm
(33.1
mg/
kg/
day
in
males;
36.1
mg/
kg/
day
in
females)
based
upon
increased
serum
alkaline
phosphatase
(males),
increased
thyroid
and
liver
weights
(females),
and
increased
incidence
in
liver
histopathology
(males
and
females;
increased
incidence
of
hepatocyte
hypertrophy,
granular
pigmentation,
mononuclear
infiltration,
and
granular
brown
pigmentation
in
Kupffer
cells).

870.4300
(§
83­
1/
2a/
5)
Combined
Chronic
Toxicity/
Carcinogenicity
­Rat
MRID
41714001,
41714002
(10/
1/
90)/
Acceptable­
Guideline
ppm
=
0,
40,
200,
or
1000
mg/
kg/
day
(males)
=
0,
1.73,
8.46,
or
42.59
mg/
kg/
day
(females)
=
0,
2.13,
10.69,
or
55.09
NOAEL
(males
and
females)
=
200
ppm
(8.46
mg/
kg/
day
in
males;
1069
mg/
kg/
day
in
females)
LOAEL
=
1000
ppm
(42.59
mg/
kg/
day
in
males;
55.09
mg/
kg/
day
in
females)
based
upon
increased
relative
liver
weight
and
the
non­
neoplastic
histologic
changes
in
the
liver
(centrilobular
hypertrophy
and
hepatocellular
eosinophilic
alteration
in
males
and
females),
thyroid
(follicular
cell
hypertrophy
in
males
and
females)
and
ovaries
(sertoliform
tubular
hyperplasia
in
females).

Rats
fed
diets
containing
1000
ppm
pronamide
showed
an
increased
incidence
of
thyroid
follicular
cell
adenomas
in
male
and
female
rats
and
benign
testicular
interstitial
cell
tumors
in
male
rats.
There
was
no
progression
of
tumors
to
carcinomas.

Under
the
conditions
of
this
study,
the
dosing
was
considered
to
be
adequate
based
upon
decreased
body
weight
gain
and
the
non­
neoplastic
histologic
changes
in
the
liver.
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
15
870.4200
(§
83­
2b)
Carcinogenicity
­Mouse
MRID
00107968
(1974)/
Although
this
study
would
not
normally
meet
the
guideline
requirement
for
a
carcinogenicity
study
(870.4300)
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
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
00114114)
that
confirm
the
tumor
findings.
If
reviewed
in
conjunction
with
the
1982
study,
the
present
study
is
adequate
to
assess
the
carcinogenic
potential
of
pronamide
in
mice
and
it
can
be
used
for
regulatory
and
risk
assessment
purposes.
ppm
=
0,
1000,
or
2000
mg/
kg/
day
=
0,
150,
or
300
NOAEL
(males,
females)
=
not
established
LOAEL
=
1000
ppm
(150
mg/
kg/
day)
based
upon
decreases
in
body
weight
gain
in
high­
dose
females
and
increases
in
relative
(to
body)
weight
of
the
liver
in
both
sexes.

Male
and
female
B6C3F1
mice
fed
diets
containing
pronamide
for
18
months
showed
a
dose
related
increase
in
the
incidence
of
hepatocellular
carcinomas
in
male
mice.
Pronamide
did
not
induce
hepatocellular
carcinomas
in
female
mice.

Under
the
conditions
of
this
study,
the
dosing
was
considered
to
be
adequate
based
upon
decreases
in
body
weight
gain
in
high­
dose
females
and
increases
in
relative
(to
body)
weight
of
the
liver
in
both
sexes
at
doses
greater
than
or
equal
to
1000
ppm.

870.4300
(§
83­
1/
2a/
5)
Carcinogenicity
­Mouse
(Males
)
MRID
00114114,
00151822
(1982)/
This
special
carcinogenicity
study
in
the
male
mouse
is
classified
as
AcceptableNonguideline
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.
ppm
=
0,
20,
100,
500,
or
2500
mg/
kg/
day
=
0,
3,
15,
75,
or
375
NOAEL
(males)
=
100
ppm
(15
mg/
kg/
day)
LOAEL
=
500
ppm
(75
mg/
kg/
day)
based
upon
gross
findings
(increased
incidences
of
hepatic
nodules/
masses
and
hepatic
enlargement)
observed
after
24
months
of
treatment.

870.5100
(§
84­
2)
Gene
Mutation/
In
vitro
mammalian
cell
assay
in
Chinese
hamster
ovary
[CHO]
cells
MRID
40090601
(2/
10/
87)/
Unacceptable­
Guideline
Fg/
plate
=
1,
10,
100
and
500
Negative.
Pronamide
did
not
induce
a
mutagenic
or
genotoxic
effect
in
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
at
concentrations
of
1,
10,
100
and
500
Fg/
plate
±
S9
activation.
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
16
870.5100
(§
84­
2)
Gene
Mutation
in
Salmonella
typhimurium,
Bacillus
subtilis
and
Escherichia
coli
MRID
40090602
(8/
10/
78)/
Acceptable­
Guideline
Escherichia.
coli
Fg/
plate
=
10
­
5000
Bacillus
subtilis
Fg/
disk
=
20
­
2000
Negative.
Pronamide
did
not
induce
a
mutagenic
or
genotoxic
effect
in
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
or
WP2
hcr
of
Escherichia
coli
at
concentrations
of
10­
5000
Fg/
plate
±
S9
activation.
Pronamide
did
not
induce
DNA
damage
in
Bacillus
subtilis
at
concentrations
of
20­
2000
Fg/
disk.

870.5300
(§
84­
2)
Gene
Mutation/
In
vitro
mammalian
cell
assay
in
Chinese
hamster
V79
cells
MRID
40211106
(10/
29/
84)/
Acceptable­
Guideline
Fg/
ml
=
2.5,
5,
10,
20
and
40
Negative.
Pronamide
did
not
induce
a
mutagenic
effect
in
Chinese
hamster
V79
cells
at
[noncytotoxic]
concentrations
of
2.5,
5,
10,
20
and
40
Fg/
ml
±
S9
activation
following
a
48,
96
or
168
hour
incubation
period.

870.5300
(§
84­
2)
Gene
Mutation/
In
vitro
mammalian
cell
assay
in
Chinese
hamster
ovary
[CHO]
cells
MRID
40211108
(2/
10/
87)/
Acceptable­
Guideline
Fg/
ml
=
25,
50,
75,
100
and
150
Negative.
Pronamide
did
not
induce
a
mutagenic
effect
in
Chinese
hamster
ovary
cells
at
[noncytotoxic]
concentrations
of
25,
50,
75,
100
and
150
Fg/
ml
±
S9
activation.

870.5385
(§
84­
2)
Cytogenetics/
In
vivo
cytogenetics
bone
marrow
assay
in
mice
MRID
40211105
(10/
31/
84)/
Acceptable­
Guideline
g/
kg
=
0,
0.48,
1.94
or
4.94
Negative.
Pronamide
did
not
induce
any
structural
chromosomal
aberrations
in
bone
marrow
cells
of
male
mice
given
doses
of
0,
0.48,
1.94
or
4.94
g/
kg
in
either
acute
or
subacute
dosing
regimens.

870.5900
(§
84­
2)
Other
Mutagenic
Mechanisms/
In
vitro
Unscheduled
DNA
Synthesis
in
primary
rat
hepatocytes
MRID
40211107
(2/
11/
87)/
Acceptable­
Guideline
g/
ml
=
1,
5,
10,
25
or
50
Negative.
There
was
no
evidence
that
Pronamide
caused
unscheduled
DNA
synthesis
in
primary
rat
hepatocytes
at
concentrations
of
1,
5,
10,
25
or
50
g/
ml.
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
17
870.7485
(§
85­
1)
Metabolism
and
Phamacokinetics­
Rat
MRID
41801801,
41929901
(2/
21/
91,
6/
25/
91)/
AcceptableGuideline
single
oral
dose
(2
or
100
mg/
kg)
or
multiple
low
doses
(20
ppm
a.
i.
in
the
diet
for
14
days)
followed
by
a
low
dose
(2
mg/
kg)
14
Cpronamide
Pronamide
is
rapidly
absorbed
and
completely
and
rapidly
eliminated.
Over
a
7
day
period,
most
of
the
radioactivity
administered
was
recovered
(93­
103%)
in
the
urine
(40­
61%)
and
feces
(40­
60%).
Only
0.08­
0.21
and
0.83­
2.43
percent
of
the
administered
dose
were
recovered
in
tissues
and
carcasses,
respectively.
No
bioaccumulation
was
apparent;
radioactivity
recovered
in
all
tissues
were
consistently
highest
at
the
first
sampling
time
(8
hours
post­
dose)
then
gradually
declined
to
insignificant
levels
7
days
after
dosing.
Tissues
with
the
highest
radioactivity
contents
were,
in
decreasing
order,
the
fat,
adrenals,
bone
marrow,
thyroids,
liver,
kidney,
and
plasma.
Very
little
unchanged
pronamide
was
recovered
in
urine.
Of
the
twenty
metabolites
found,
only
thirteen
(constituting
 
51.1%
of
the
total
radioactivity
in
urine)
were
clearly
identified.
The
feces
was
not
examined
for
metabolites.
However,
when
these
data
(MRID
41801801,
41929901)
are
reviewed
in
conjunction
with
the
characterization
of
the
urinary
and
fecal
metabolites
of
pronamide
(MRID
42858001),
the
guideline
requirement
for
a
metabolism
and
pharmacokinetics
study
[OPPTS
870.7485
(§
85­
1)]
is
satisfied.

870.7485
(§
85­
1)
Metabolism
and
Pharmacokinetics
­
Rat
MRID
42858001
(7/
15/
93)/
Acceptable­
Guideline
single
oral
dose
(2
or
100
mg/
kg)
or
multiple
low
doses
(20
ppm
a.
i.
in
the
diet
for
14
days)
followed
by
a
low
dose
(2
mg/
kg)
14
Cpronamide
Urinary
and
fecal
metabolites
of
pronamide
were
identified
in
male
and
female
rats.
No
significant
difference
in
urinary
metabolite
profile
was
observed
between
sex
or
dose.
The
major
urinary
metabolites
were:
2­(
3,5­
dichlorophenyl)­
4,4­
dimethyl­
5­
carboxyoxazoline
(metabolite
SS47­
70,
3.0­
5.9%
of
the
administered
dose)
and
N­
carboxymethyl­
3,5­
dichlorobenzamide
(metabolite
10,
12.7­
18.9%
of
the
administered
dose).
In
the
urine,
approximately
27
unidentified
metabolites
were
found
and
none
exceeded
3.3%
of
the
dose.
In
contrast,
significant
differences
in
the
fecal
metabolite
profile
was
observed
between
doses.
Fecal
excretion
of
parent
ranged
from
9.2­
10.9%
of
the
dose
for
the
low
dose
and
low
repeated
dose
groups
and
37.4­
40.9%
for
the
high
dose
group.
In
the
feces,
almost
all
of
the
unidentified
metabolites
are
under
1%
of
the
dose.
The
metabolic
pathway(
s)
of
the
test
compound
have
been
postulated
in
rats.
This
study
adequately
describes
the
characterization
of
urinary
and
fecal
metabolites
of
pronamide
in
rats
following
lowand
high­
dose
oral
and
repeated
oral
exposure.
When
these
data
(MRID
42858001)
are
reviewed
in
conjunction
with
previous
metabolism
studies
(MRID
41801801,
41929901),
the
guideline
requirement
for
a
metabolism
and
pharmacokinetics
study
[OPPTS
870.7485
(§
85­
1)]
is
satisfied.
TABLE
2.
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Pronamide
(Propyzamide
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification/
Doses
Results
18
870.7600
(§
85­
3)
Dermal
Penetration
Rats
Kerb
50W
and
3.3F
­
formulations
only
MRID
40256701,
41117201
(4/
14/
87,
1/
27/
89)
UnacceptableGuideline
(not
upgradeable)
0.08
and
4.4
mg/
cm
2
The
dermal
absorption
rates
per
6
hours
were
19%
and
17%
for
50W
and
15.1%
and
5.4%
for
3.3F.
However,
these
data
are
based
on
a
normalization
of
numerical
values
rather
than
the
actual
results
obtained
from
the
study.

The
actual
doses
applied
to
the
skin
were
not
determined
and
there
were
discrepancies
in
recovery
for
the
50W
doses
(78%
and
122%
of
nominal
doses).
A
default
dermal
absorption
factor
of
100%
is
used
in
this
risk
assessment.

Non
­Guideline
Thyroid
Function
and
Hepatic
Clearance
of
Thyroxine
in
Male
Rats.
This
non­
guideline
study
was
submitted
to
the
Agency
as
an
addendum
to
the
chronic
toxicity/
carcinogenicity
study
in
rats
(MRID
41714001,
41714002)
MRID
42093401
(10/
9/
91)/
Acceptable­
Nonguideline
ppm
=
0,
40,
1000,
or
4000
mg/
kg/
day
=
0,
3,
67
or
279
Systemic
and
Thyroid
Toxicity
NOAEL
=
40
ppm
(3
mg/
kg/
day)
LOAEL
=
1000
ppm
(67
mg/
kg/
day)
based
upon
decreases
in
body
weight
and
food
consumption,
increases
in
absolute
and/
or
relative
weight
of
the
liver
and
thyroid,
an
increase
in
serum
TSH
(at
4
weeks
but
not
at
13
weeks),
a
decrease
in
serum
T4,
and
an
increase
in
incidences
of
thyroid
and
pituitary
hypertrophy/
hyperplasia.

Non­
Guideline
Effects
of
Endocrine
Regulation
of
the
Testis
in
Rats
Pilot
Study
MRID
42139601
(12/
6/
91)/
Acceptable­
Nonguideline
ppm
=
0,
40,
1000,
or
4000
In
the
13
week
study,
Pronamide
treatment
(4000
ppm)
resulted
in
decreased
body
weight
(weeks
1­
13)
and
food
consumption
(weeks
1­
8),
increased
serum
LH
and
FSH
(respective
increases
at
4
and
13
weeks
were
60%
and
58%
for
FSH,
and
100%
and
77%
for
LH),
increased
absolute
and
relative
(to
body)
liver
weight,
increased
microsomal
protein
content,
increased
oxidation
of
testosterone,
increased
activity
of
cytochrome­
P450
and
­B5,
and
NADPH­
cyochrome­
creductase
increased
gross
pathology
of
the
liver
(enlarged/
dark),
increased
relative
(to
body)
testicular
weight,
and
increased
testicular
interstitial
cell
hyperplasia.

In
the
4­
week
study,
alterations
in
clinical
chemistry
parameters
were
noted
only
at
4000
ppm
as
increases
in
sreum
LH
and
FSH.
These
effects
were
comparable
with
increases
observed
after
13
weeks.

3.2
FQPA
Considerations
On
December
3,
2001,
the
FQPA
Safety
Factor
Committee
evaluated
the
hazard
(See
Section
5.0,
Hazard
Characterization
and
Dose
Response
Assessment
Summary),
endocrine
(See
Section
9.0,
Endocrine
Disruption)
and
exposure
data
for
pronamide
and
made
the
recommendation
for
the
FQPA
safety
factor
to
be
used
in
human
health
risk
assessments
as
required
by
Food
Quality
Protection
Act
of
August
3,
1996.
(Memorandum:
C.
Christensen,
December
19,
2001).
19
Based
on
these
available
data,
the
FQPA
SF
Committee
determined
that
the
safety
factor
is
necessary
when
assessing
the
risk
posed
by
pronamide
because:

1.
There
is
evidence
of
endocrine
effects
(thyroid,
testes,
ovaries,
adrenal
glands,
pituitary
gland,
thymus)
identified
in
the
majority
of
studies
conducted
across
species.
A
special
study
designed
to
assess
thyroid
function
in
adult
animals
and
their
offspring
will
be
required.

However,
the
Committee
concluded
that
the
FQPA
safety
factor
could
be
reduced
to
3x
in
assessing
the
risk
posed
by
exposure
to
pronamide
because:

1.
The
toxicological
database
is
adequate
for
FQPA
assessment;
and,
2.
There
is
no
indication
of
quantitative
or
qualitative
increased
susceptibility
of
rabbits
to
in
utero
exposure
or
to
rats
following
pre/
post­
natal
exposure.
Also,
in
the
available,
unacceptable
rat
study,
no
increased
susceptibility
was
seen
even
though
the
animals
could
have
tolerated
higher
doses.
3.
A
developmental
neurotoxicity
study
is
not
required;
and,
4.
The
dietary
(food
and
drinking
water)
and
residential
exposure
assessments
will
not
underestimate
the
potential
exposures
for
infants
and
children.

The
3x
FQPA
safety
factor
for
pronamide
is
applicable
to
all
population
subgroups
when
assessing
dietary
and
residential
exposure
scenarios
because
of
evidence
of
endocrine
effects.
The
FQPA
safety
factor
was
not
applied
to
the
acute
dietary
endpoint
because
no
appropriate
endpoint
was
available
to
quantitate
risk
to
either
the
general
population
or
to
females13­
50
years
of
age
from
a
single­
dose
administration
of
pronamide.

A
MOE
of
300
(10x
for
interspecies
extrapolation,
10x
for
interspecies
variation
and
a
3x
FQPA
safety
factor)
is
required
for
short­
term,
intermediate­
and
long­
term
incidental
oral,
dermal,
and
inhalation
risk
assessments.
Therefore,
short­
term,
intermediate
to
long­
term
risk
estimates
with
a
MOE
$
300
do
not
exceed
the
HED
level
of
concern.

3.3
Hazard
Endpoint
Selection
The
strengths
and
weaknesses
of
the
pronamide
toxicology
database
were
considered
during
the
process
of
toxicity
endpoint
and
dose
selection.
20
Table
3.
Summary
of
Toxicological
Dose
and
Endpoints
for
Pronamide
for
Use
in
Human
Risk
Assessment
1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
and
the
general
population
including
infants
and
children
No
appropriate
acute
dietary
endpoints
were
available
to
quantify
risk
to
females
13­
50
years
of
age
or
to
the
general
population
from
a
single­
dose
administration
of
pronamide.
The
adverse
effect
observed
in
the
rabbit
developmental
toxicity
study,
abortions,
were
not
considered
to
occur
after
a
single
dose
because
they
were
observed
in
rabbits
during
the
postdosing
phase
of
the
study
(days
22­
24).
Therefore,
no
acute
dietary
endpoints
were
selected
which
represented
toxicities
from
a
single­
dose
exposure.

Chronic
Dietary
all
populations
NOAEL
=
8.46
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.08
mg/
kg/
day
FQPA
SF
=
3
cPAD
=
chronic
RfD
FQPA
SF
=
0.027
mg/
kg/
day
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

Short­
Term
Oral
(1­
30
days)

(Residential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Developmental
Toxicity
Study
­
Rabbit
LOAEL
=
20
mg/
kg/
day
based
on
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes).

Intermediate­
Term
Oral
(1
­
6
months)

(Residential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

Short­
Term
Dermal
(1­
30
days)

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
dermal
absorption
rate
$

=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Developmental
Toxicity
Study
­
Rabbit
LOAEL
=
20
mg/
kg/
day
based
on
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes).

IntermediateTerm
Dermal
(1­
6
months)

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
dermal
absorption
rate
$
=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

Long­
Term
Dermal
(6
months
lifetime

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
dermal
absorption
rate
$
=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.
Table
3.
Summary
of
Toxicological
Dose
and
Endpoints
for
Pronamide
for
Use
in
Human
Risk
Assessment
1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
21
Short­
Term
Inhalation
(1­
30
days)

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
inhalation
absorption
rate
$
=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Developmental
Toxicity
Study
­
Rabbit
LOAEL
=
20
mg/
kg/
day
based
on
Clinical
signs
of
toxicity
(soiled
anal
area
and
anorexia)
and
liver
effects
(punctate
vacuolation
of
hepatocytes).

IntermediateTerm
Inhalation
(1­
6
months)

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
inhalation
absorption
rate
$
=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

Long­
Term
Inhalation
(6
months
­
lifetime)

(Occupational/
Resi
dential)
oral
study
NOAEL
=
8.46
mg/
kg/
day
inhalation
absorption
rate
$
=
100%
LOC
for
MOE
=
300
(Residential,
includes
the
FQPA
SF)
Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
LOAEL
=
42.59
mg/
kg/
day
based
on
increased
relative
(to
body)
liver
weight
and
nonneoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries.

Cancer
(oral,
dermal,
inhalation)
Group
B2
­
"Probable
human
carcinogen"
Q1*
=
2.59
x
10
­
2
(mg/
kg/
day)
­1
Cancer
classification
based
on
thyroid
follicular
cell
adenomas
(males
and
females)
and
benign
interstitial
cell
tumors
(males)
in
rats
and
hepatocellular
carcinomas
in
mice
(males).
1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(a
=
acute,
c
=
chronic),
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure,
Q1*
=
the
low­
dose
linear
extrapolation
value
used
to
express
the
risk
to
the
human
population
for
development
of
cancer
following
exposure
to
pesticide
residues.
"
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.
$
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.

Acute
Dietary
Risk
Assessment:
No
appropriate
acute
dietary
endpoints
were
available
to
quantify
risk
to
females
13­
50
years
of
age
or
to
the
general
population
from
a
single­
dose
administration
of
pronamide.
The
adverse
effect
observed
in
the
rabbit
developmental
toxicity
study,
abortions,
were
not
considered
to
occur
after
a
single
dose
because
they
were
observed
in
rabbits
during
the
postdosing
phase
of
the
study
(days
22­
24).
Therefore,
no
acute
dietary
endpoints
were
selected
which
represented
toxicities
from
a
single­
dose
exposure.

Chronic
Dietary
Risk
Assessment:
A
chronic
reference
dose
(cRfD)
of
0.08
mg/
kg/
day
was
determined
on
the
basis
of
the
two­
year
chronic
toxicity/
carcinogenicity
study
in
rats
and
the
application
of
an
uncertainty
factor
of
100
(10x
for
inter­
species
extrapolation
and
10x
for
intra­
species
variation).
The
22
NOAEL
in
this
study
was
8.46
mg/
kg/
day
and
the
LOAEL
was
42.59
mg/
kg/
day
based
upon
increased
relative
liver
weight
and
the
non­
neoplastic
histologic
changes
in
the
liver
(centrilobular
hypertrophy
and
hepatocellular
eosinophilic
alteration
in
males
and
females),
thyroid
(follicular
cell
hypertrophy
in
males
and
females)
and
ovaries
(sertoliform
tubular
hyperplasia
in
females).
The
3x
FQPA
safety
factor
was
applied
for
chronic
dietary
risk
assessment
because
there
is
evidence
of
endocrine
effects
(thyroid,
testes,
ovaries,
adrenal
glands,
pituitary
gland,
thymus)
identified
in
the
majority
of
subchronic/
chronic
studies
conducted
across
species.
The
chronic
population
adjusted
dose
is
the
cRfD
adjusted
for
the
FQPA
safety
factor.
Therefore,
the
chronic
population
adjusted
dose
(cPAD)
is
0.027
mg/
kg/
day.

Short­
Term
Incidental
Oral,
Dermal
and
Inhalation
Exposure
Risk
Assessments:
An
adjusted
dose
of
8.46
mg/
kg/
day
was
established
for
use
in
this
risk
assessment.
This
dose
selection
is
based
on
a
maternal
toxicity
NOAEL
of
5
mg/
kg/
day
and
the
clinical
signs
(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.
Although
selection
of
this
study
for
short­
term
exposure
scenarios
is
appropriate
for
the
route
(oral)
and
duration
(13
days),
the
NOAEL
of
5
mg/
kg/
day
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
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
3x
FQPA
safety
factor
was
also
applied
to
these
risk
assessments
because
of
the
evidence
of
endocrine
effects
in
the
pronamide
toxicity
data
base.

Intermediate­
Term
Incidental
Oral,
Dermal
and
Inhalation
Exposure
Risk
Assessments:
A
NOAEL
of
8.46
mg/
kg/
day
was
selected
from
the
combined
chronic
toxicity/
carcinogenicity
study
conducted
in
the
rat.
This
NOAEL
is
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
which
were
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.
The
HIARC
determined
that
this
study
is
appropriate
for
the
(1­
6
months)
intermediate­
term
exposure
duration
because
(i)
the
organ
toxicities
(liver,
thyroid,
and
ovaries)
observed
in
the
24
month
study
occurred
as
early
as
6
months
and
continued
to
study
termination
and
(2)
this
NOAEL
(8.46
mg/
kg/
day)
is
numerically
close
to
the
NOAEL
of
12.3
mg/
kg/
day
established
in
the
90­
day
subchronic
toxicity
study
conducted
in
the
rat.
Although
the
90­
day
subchronic
study
in
rats
demonstrated
liver
toxicities
(increased
absolute
and
relative
liver
weights
and
hepatocellular
hypertrophy)
at
a
LOAEL
of
60
mg/
kg/
day,
these
effects
were
considered
minimal.
Therefore
the
developmental
NOAEL
12.3
mg/
kg/
day
is
not
recommended
for
this
exposure
scenario.
The
3x
FQPA
safety
factor
is
applicable
because
of
the
evidence
of
endocrine
effects
in
the
pronamide
toxicity
data
base.

Long­
Term
Dermal
and
Inhalation
Exposure
Risk
Assessments:
The
NOAEL
of
8.46
mg/
kg/
day
was
also
selected
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats
and
is
considered
appropriate
for
these
exposure
scenarios.
This
NOAEL
is
based
on
increased
relative
liver
weight
and
the
non­
neoplastic
histological
changes
in
the
liver,
thyroid,
and
ovaries
which
were
observed
at
the
LOAEL
of
42.59
mg/
kg/
day.
The
3x
FQPA
safety
factor
is
applicable
because
of
the
evidence
of
endocrine
effects
in
the
pronamide
toxicity
data
base.

Dermal
and
Inhalation
Absorption:
Since
no
dermal
or
inhalation
toxicity
studies
were
submitted,
the
selected
endpoint
is
from
an
oral
study
of
the
appropriate
duration
of
exposure
and
a
100%
(default)
absorption
factor
was
applied
to
dermal
and
inhalation
exposure
routes.
23
Aggregating
doses:
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).

3.4
Endocrine
Disruption
Many
chemicals
belonging
to
the
class
of
organochlorine
chemicals
are
known
to
produce
disruption
of
the
endocrine
system.
Pronamide
is
an
organochlorine
herbicide
which
has
been
identified
by
the
Agency's
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC)
as
a
potential
endocrine
disruptor.
Evidence
of
endocrine
effects
from
several
guideline
toxicity
studies
as
well
as
two
special
studies
submitted
to
the
Agency
by
the
Registrant
include,
in
part:
(i)
histopathology
of
the
thyroid
gland,
pituitary
gland,
adrenal
glands,
testes
and
ovaries,
(ii)
changes
in
hormone
levels;
decreased
T4
and
increased
TSH,
LH
and
FSH,
and
(iii)
the
induction
of
enzymes
such
as
cytochromeP450
and
­B5,
and
NADPH­
cytochrome­
c­
reductase
in
addition
to
those
enzymes
involved
in
the
oxidation
of
testosterone.

On
October
23,
2001,
the
Mechanism
of
Toxicity
Assessment
Review
Committee
(MTARC)
reviewed
the
available
toxicology
data
submitted
in
support
of
a
proposed
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
resulting
from
exposure
to
pronamide.
Although
the
results
of
these
special
endocrine
studies
conducted
by
the
Registrant
are
suggestive
of
a
pronamide­
induced
thyroid
and
testicular
neoplastic
effect
via
disruption
of
the
pituitary­
thyroid
and
pituitary­
testis
hormonal
balance,
these
data
are
far
from
conclusive.
Based
on
the
Committee's
(MTARC)
evaluation
of
the
existing
pronamide
toxicology
data
base
(Memorandum:
M.
Centra,
January
21,
2001)
and
in
the
absence
of
any
additional
information,
it
was
determined
that
the
postulated
threshold
mechanism
for
the
induction
of
thyroid
and
testicular
neoplasms
is
not
supported
by
the
available
data.
Therefore,
HED
has
recommended
that
additional
studies
be
conducted
with
pronamide
to
determine
its
mechanism
of
endocrine
toxicity.
One
such
study,
a
comparative
assay
in
the
rat
that
is
designed
to
assess
thyroid
function
in
adult
animals
and
their
offspring
as
well
as
potential
central
nervous
system
effects
in
the
young,
is
required
by
the
Agency
because
of
the
endocrine
toxicities
observed
in
various
organ
systems
(thyroid
gland,
testes,
ovaries,
adrenal
glands,
pituitary
gland)
of
rats
and/
or
dogs.

The
Agency
is
required
under
the
Federal
Food,
Drug
and
Cosmetic
Act
(FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(including
all
pesticide
active
and
other
ingredients)
"may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(EDSP).
24
When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
pronamide
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

4.0
EXPOSURE
ASSESSMENT
4.1
Summary
of
Registered
Uses
Pronamide
[3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide],
or
propyzamide,
is
a
selective,
systemic,
pre­
and
post­
emergence
herbicide
registered
for
use
in
agricultural,
ornamental,
and
residential
settings.
There
are
two
manufacturers
of
pronamide
end­
use
products
with
only
two
active
section
3
registrations.
There
are
also
nine
active
Section
24C
registrations.
Approximately
225,000
lb
of
active
ingredient
are
used
domestically
each
year.

Major
food/
feed
crops
include:
stone
fruits
(apricot,
cherry,
nectarine,
peach,
plum,
prune),
pome
fruits
(apple,
pear),
grapes,
artichokes,
berries
(blackberry,
blueberry,
boysenberry,
red
raspberry,
black
raspberry),
leafy
greens
(lettuce,
endive,
radicchio),
winter
peas,
chicory,
rhubarb,
sugarbeets,
and
forages
(alfalfa,
clover,
birdsfoot
trefoil,
crown
vetch,
sainfoin).
Non­
agricultural
uses
include
woody
ornamentals,
ornamental
warm
season
grasses
grown
for
turf
(i.
e.
bermudagrass,
zoysiagrass,
St.
Augustine,
and
centipedegrass)
or
seed
(bermudagrass),
residential/
recreational
turf
(bermudagrass
lawns,
playing
fields,
and
golf
courses),
Christmas
trees,
grasses
grown
for
seed,
rangeland,
and
fallow
land.

In
terms
of
pounds
a.
i.,
total
usage
is
allocated
mainly
to
head
lettuce
(29%),
other
lettuce
(19%),
seed
crops
(13%),
fallowland
(11%),
hay
other
than
alfalfa
(8%),
horticulture
(3%)
and
alfalfa
(3%).
Rates
per
application
and
rates
per
year
are
each
generally
less
than
2
pounds
a.
i.
per
acre
for
agricultural
sites
(based
on
the
economic
analysis
by
A.
Holverson,
September
26,
2001).
Pronamide
label
rates
range
from
2
to
8
lbs
ai
per
acre
per
year
at
0.5
to
6
lbs
ai
per
acre
per
application,
with
from
one
to
four
applications
per
year.
Pronamide
is
formulated
as
a
wettable
powder
and
may
be
applied
by
ground
or
aerial
spray,
depending
on
the
crop.
States
with
significant
usage
in
terms
of
pounds
a.
i.
include
Arizona,
California,
Oregon
and
Washington.
Pre­
harvest
intervals,
where
specified,
are
generally
long,
ranging
from
25
to
180
days.

There
are
several
active
Section
24C
state
labels.
For
risk
assessment
purposes
the
use
sites
and
use
patterns
on
these
24C
labels
are
covered
by
EPA
Reg.
No.
707­
159.

4.2
Dietary
Exposure
and
Risk
Assessment
4.2.1
Residues
in
Food
Background
Pronamide/
propyzamide
[3,
5
dichloro­
n­(
1,1­
dimethyl­
2­
propynyl)
benzamide]
tolerances
are
established
under
40
CFR
§180.317(
a),
(b),
and
(c).
The
tolerance
expression,
listed
in
(a)
and
(c),
is
in
terms
of
"the
combined
residues
of
the
herbicide
propyzamide
and
its
metabolites
(containing
the
3,5­
dichlorobenzoyl
moiety
and
calculated
as
3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide)."
The
25
tolerance
expression,
listed
in
(b),
is
in
terms
of
the
parent
only.
Pronamide
tolerances
listed
in
40
CFR
§180.317(
a)
range
from
0.02
ppm
(for
certain
animal
commodities)
to
10.0
ppm
(for
a
non­
grass
animal
feeds
group).
The
time­
limited
tolerances
listed
in
40
CFR
§180.317(
b),
with
an
expiration
date
of
12/
31/
01,
are
for
Section
18
emergency
exemptions
for
pronamide
uses
on
cranberries
(0.05
ppm)
and
grasses
(forage
1.0
ppm
and
hay
0.5
ppm).
The
tolerances
listed
in
40
CFR
§180.317(
c)
are
for
regional
registrations
of
pronamide
on
dried
(winter)
peas
(0.05
ppm)
and
rhubarb
(0.1
ppm).

Residue
Profile
The
qualitative
nature
of
the
residue
in
plants
is
adequately
understood.
The
4/
16/
93
Residue
Chapter
reported
that
studies
with
alfalfa
and
lettuce
indicate
that
pronamide
is
readily
absorbed
by
plants
through
the
root
system,
translocated
upward,
and
distributed
into
the
entire
plant.
The
degree
of
translocation
from
leaf
absorption
is
not
appreciable.
Metabolism
primarily
occurs
via
conjugation
to
(malonyl)
glucose.
No
evidence
of
fragmentation
or
loss
of
the
chloro
substituent
of
the
aromatic
ring
was
observed.
The
terminal
residues
of
concern
are
pronamide
and
its
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety.
For
purposes
of
reregistration,
no
additional
plant
metabolism
studies
are
required;
however,
because
the
available
metabolism
studies
were
only
conducted
on
alfalfa
and
lettuce,
the
Agency
may
require
additional
metabolism
studies
in
the
future
should
the
registrants
seek
for
additional
uses
on
other
crop
groups.

The
qualitative
nature
of
the
residue
in
animals
is
adequately
understood.
The
4/
16/
93
Residue
Chapter
reported
studies
involving
lactating
goats
and
laying
hens
indicate
that
the
primary
route
of
elimination
is
by
excretion
(urine
and
feces).
Minimal
residues
were
distributed
to
goat
and
poultry
muscle.
The
major
metabolites
in
the
eggs,
liver,
and
fat
of
poultry
are
pronamide
and
3,5­
dichlorobenzoic
acid.
The
major
metabolites
in
the
milk,
fat,
muscle,
and
liver
of
goats
are
pronamide,
3,5­
dichlorobenzoic
acid,
and
compounds
containing
the
3,5­
dichlorobenzoyl
moiety.
The
metabolic
pathway
involves
modification
of
the
aliphatic
portion
of
pronamide.
The
terminal
residues
of
concern
are
pronamide
and
its
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety.

An
adequate
residue
analytical
method
is
available
for
plant
and
animal
tolerance
enforcement,
a
GLC/
ECD
method
listed
in
the
Pesticide
Analytical
Manual
(PAM)
Volume
II.
Designated
as
Method
I,
it
converts
residues
of
pronamide
and
its
metabolites
to
methyl
3,5­
dichlorobenzoate.
The
data­
collection
method
used
in
the
analysis
of
samples,
collected
from
a
recently
reviewed
field
rotational
crop
study,
was
a
GLC/
ECD
method
entitled
"An
Improved
Analytical
Method
for
the
Determination
of
Kerb
Residues
in
Crops
and
Soil."
The
method
was
adequately
validated
by
the
registrant
and
is
deemed
adequate
for
data­
gathering
purposes.
This
method
should
be
validated
by
EPA
in
order
to
support
the
established
and
proposed
tolerances
for
pronamide.

Since
the
1993
dietary
chapter
was
published,
the
registrant
has
submitted
independent
laboratory
validation
for
a
revised
animal
method
(TR
34­
91­
68).
However,
prior
to
Agency
validation
of
Method
TR
34­
91­
68,
the
registrant
is
required
to
further
optimize/
improve
the
method
to
yield
acceptable
recoveries
at
higher
fortification
levels.
Then,
following
method
improvement,
the
registrant
is
required
to
submit
bridging
ILV
data.

Multiresidue
method
testing
data
for
pronamide
and
a
metabolite
containing
the
3,5­
dichlorobenzoyl
moiety
are
also
available
(MRID434932­
03);
these
data
have
been
forwarded
to
FDA.
26
Plant
product
residue
storage
stability
data
were
submitted
but
provided
only
indirect
evidence
that
the
precursors
to
the
3,5
dichlorobenzoyl
moiety,
are
most
likely
stable.
Additional
confirmatory
storage
stability
data
for
the
regulated
pronamide
metabolites
on
alfalfa,
apples,
grapes,
lettuce,
and
peaches
or
plums
are
required.
Likewise,
animal
product
storage
stability
data
were
submitted,
but
an
analysis
of
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety
was
not
included
in
the
study.
Additional
confirmatory
storage
stability
data
for
the
regulated
pronamide
metabolites
on
milk
are
required.

4.2.2
Acute
Dietary
Risk
from
Food
Sources
As
there
was
no
toxicological
endpoint
selected
for
acute
exposure,
an
acute
dietary
risk
assessment
was
not
performed.

4.2.3
Chronic
and
Cancer
Dietary
Risk
from
Food
Sources
A
refined
tier
3,
chronic
and
cancer
dietary
exposure
assessment
has
been
performed
for
pronamide.
The
analysis
is
based
primarily
upon
residue
monitoring
data
for
fruits
and
vegetables
from
the
U.
S.
Department
of
Agriculture
(USDA),
Agricultural
Marketing
Service's
Pesticide
Data
Program
(PDP)
and
FDA
data.
Tolerance
level
residues
were
used
for
four
registered
crops
(dried
peas,
endives,
radicchio,
and
cranberries),
and
anticipated
residues
were
calculated
for
meat,
milk,
poultry
and
eggs.
The
percent
crop
treated
(%
CT)
data
from
OPP's
Biological
and
Economic
Assessment
Division
(BEAD)
(September
26,
2001)
were
used
to
further
refine
the
dietary
exposure
assessment.

Pronamide
and
its
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety
are
the
residues
of
concern
and
should
be
included
in
the
assessment.
The
residues
measured
in
field
trials
include
the
other
metabolites
by
incorporation
of
a
hydrolysis
step.
However,
the
PDP
analyses
measured
only
the
parent
compound;
therefore,
the
method
limit
of
detection
(LOD)
was
used
instead
of
1/
2
the
LOD
to
account
for
metabolites
of
concern
for
the
treated
portion
of
those
crops.

No
processing
information
was
used
in
this
assessment.
DEEM™
default
processing
factors
were
used
wherever
they
existed
for
processed
food
derived
from
the
relevant
crops.
However,
because
residue
data
were
available
in
the
PDP
database
for
grape
juice,
pear
juice
and
apple
juice,
these
PDP
data
were
used
directly,
i.
e.
without
DEEM
default
processing
factors,
for
grape
juice
and
grape
wine,
and
for
pear
juice
and
apple
juice.
Factors
for
the
juice
concentrates
were
estimated
from
the
ratio
of
the
DEEM
default
factors
for
juice/
juice
concentrate.

The
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
software
Version
7.75,
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
The
1989­
92
data
are
based
on
the
reported
consumption
of
more
than
10,000
individuals
over
three
consecutive
days,
and
therefore
represent
more
than
30,000
unique
"person
days"
of
data.
Foods
"as
consumed"
(e.
g.,
apple
pie)
are
linked
to
raw
agricultural
commodities
and
their
food
forms
(e.
g.,
apples­
cooked/
canned
or
wheat­
flour)
by
recipe
translation
files
internal
to
the
DEEM
software.

HED
notes
that
there
is
a
degree
of
uncertainty
in
extrapolating
exposures
for
certain
population
subgroups
from
the
general
U.
S.
population
which
may
not
be
sufficiently
represented
in
the
consumption
surveys,
(e.
g.,
nursing
and
non­
nursing
infants
or
Hispanic
females).
Therefore,
risks
estimated
for
these
population
subgroups
are
not
reported
explicitly
but
are
included
within
larger
27
representative
populations
having
sufficient
numbers
of
survey
respondents
(e.
g.,
all
infants
or
females,
13­
50
years).

For
chronic
and
cancer
exposure
and
risk
assessment,
an
estimate
of
the
residue
level
in
each
food
or
food­
form
(e.
g.,
orange
or
orange­
juice)
on
the
commodity
residue
list
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form.
The
resulting
residue
consumption
estimate
for
each
food/
food
form
is
summed
with
the
residue
consumption
estimates
for
all
other
food/
food
forms
on
the
commodity
residue
list
to
arrive
at
the
total
estimated
exposure.
Exposure
estimates
are
expressed
in
mg/
kg
body
weight/
day
and
as
a
percent
of
the
cPAD.
This
procedure
is
performed
for
each
population
subgroup.

A
summary
of
the
pronamide
chronic
dietary
risk
estimates
are
shown
in
Table
4.
The
dietary
cancer
risk
estimates
are
shown
in
Table
5.

Table
4.
Results
of
Chronic
Dietary
Exposure
Analysis
Population
Subgroup
cPAD
1
(mg/
kg/
day)
Exposure
(mg/
kg/
day)
%
cPAD
U.
S.
Population
(total)
0.
03
mg/
kg/
day
0.
000004
<1%

All
Infants
(<
1
year)
0.
03
mg/
kg/
day
0.
000002
<1%

Children
1­
6
years
0.
03
mg/
kg/
day
0.
000005
<1%

Children
7­
12
years
0.
03
mg/
kg/
day
0.
000004
<1%

Females
13­
50
0.03
mg/
kg/
day
0.
000004
<1%

Males
13­
19
0.03
mg/
kg/
day
0.
000003
<1%

Males
20+
years
0.
03
mg/
kg/
day
0.
000004
<1%

Seniors
55+
0.03
mg/
kg/
day
0.
000005
<1%
cPAD
1
=
Chronic
PAD
=
Chronic
Population
Adjusted
Dose
=
0.03
mg/
kg/
day
Table
5.
Results
of
Dietary
Cancer
1
Exposure
Analysis
Population
Subgroup
Exposure
(mg/
kg/
day)
Cancer
Risk
Estimate
U.
S.
Population
(total)
0.
000004
1.06
X
10
­7
1
Q1
*
=
0.0259
mg/
kg/
day
­1
Because
the
estimated
exposure
is
well
below
the
chronic
and
cancer
levels
of
concern,
and
conservative
assumptions
were
used,
any
uncertainties
are
unlikely
to
cause
the
exposure
to
exceed
a
level
of
concern.
However,
there
are
some
conservative
assumptions
that
may
have
introduced
some
uncertainties
into
this
assessment.
Tolerance
level
residues
and
100
%
CT
was
used
for
endives,
dried
peas,
cranberries
and
radicchio.
The
LOD
was
used
instead
of
½LOD
for
the
non­
detects
in
the
PDP
data.
For
the
animals
ARs
the
maximum
percent
crop
treated
was
assumed
instead
of
the
average
percent
crop
treated.
Default
DEEM
processing
factors
were
used
for
many
processed
foods.
28
4.3
Dietary
Exposure
from
Water
Sources
4.3.1.
Environmental
Fate
According
to
the
May
1994
Reregistration
Eligibility
Decision
for
pronamide,
results
from
environmental
fate
studies
indicate
that
pronamide
is
very
persistent
in
soil
and
water
with
half­
lifes
of
many
months.
Pronamide
is
very
stable
in
water
and
photolytically
persistent
in
water
and
on
soil.
It
is
very
persistent
in
soil
under
aerobic
conditions,
with
an
estimated
half­
life
of
13
months,
and
even
more
persistent
under
anaerobic
conditions.
Pronamide
is
persistent
but
relatively
mobile
in
soil.
Additionally,
rotational
crop
studies
show
accumulation
in
several
crop
types
at
one,
six
and
twelve
months
after
application.
For
these
reasons,
residues
of
pronamide,
per
se,
are
the
residues
of
concern
in
assessing
drinking
water
exposures.

4.3.2
Drinking
Water
Exposure
Estimates
Although
there
is
no
legal
requirement
under
the
Safe
Drinking
Water
Act
to
monitor
for
pronamide,
it
has
been
detected
in
surface
and
groundwater
in
various
locations
in
the
U.
S.
The
maximum
level
detected
was
0.365
ppb
(surface
water)
at
Zollner
Creek
near
Mt.
Abgel,
OR
on
Nov.
16,
1998
and
the
range
was
0.0037
to
0.365
(surface
water)
ppb
or
ug/
liter
(USGS
­
NAWQA
Data
Retrieval).
The
maximum
ground
water
detection
at
Benton
Ozark,
AK
was
0.82
ppb
on
April
13,
1994,
and
ranging
from
0.005
­
0.82
ppb
(ground
water).

A
Tier
I
Drinking
Water
Assessment
for
pronamide
was
calculated
(L.
Shanaman,
2001)
using
the
SCIGROW
model
for
groundwater
concentration
estimates.
The
Tier
I
groundwater
estimates
were
predicted
from
application
of
pronamide
at
maximum
label
rate
(2
lbs
active
ingredient
per
acre
four
times
per
year)
for
ornamental
herbaceous
plants,
and
represent
upper­
bound
estimates
of
the
concentrations
that
might
be
found
in
groundwater
due
to
the
use
of
pronamide/
propyzamine.
The
resulting
modeled
groundwater
screening
concentration
is
3.0
ppb.
The
Tier
II
PRZM­
EXAMS
model
(L.
Shanaman,
2002)
was
used
to
predict
EECs
for
pronamide
in
surface
water,
i.
e.,
90
th
percentile
average
annual
concentration
values
for
use
in
chronic
exposure
assessments,
and
36­
year
mean
concentration
values
for
use
in
"cancer"
exposure
assessments.
Maximum
label
application
rates
were
used
for
major
use
crops.
Chronic
exposure
values
ranged
from
1.5
to
6.4
ppb,
and
cancer
average
exposure
values
ranged
from
0.535
to
4.3
ppb.
Conservative
inputs
were
used
for
the
environmental
(soil
and
water
metabolism)
assumptions,
i.
e.,
2­
3x
uncertainty
factors
were
applied
to
soil
and
water
half­
lives
used
in
the
PRZM­
EXAMS
assessment.

4.4
Residential
Exposure
4.4.1
Residential/
Recreational
Postapplication
Exposure
and
Risk
Pronamide
is
a
restricted­
use
herbicide,
so
the
public/
consumers
are
prohibited
from
handling
this
chemical.
Therefore
only
postapplication
exposures
were
assessed.

Earth
Care,
Division
of
United
Industries
Corp.,
(previously
Pursell
Industries)
has
requested
voluntary
cancellation
of
the
product
GREEN
UP
KERB
50W,
EPA
Reg.
No.
8660­
85,
which
is
the
only
end
use
product
label
that
allows
professional
application
in
a
residential/
recreational
setting.
Pending
29
cancellation
of
this
use,
a
residential/
recreational
exposure
assessment
was
conducted.
The
agricultural
label
(EPA
Reg.
No.
707­
159)
allows
one
application
per
year
to
grasses
grown
for
turf
for
sod
or
seed.
Based
on
the
application
rate,
timing,
and
residue
dissipation
data,
there
are
no
concerns
for
residential/
recreational
exposure
to
the
treated
turf
from
a
sod
farm.

This
label
No.
8660­
85
indicates
a
maximum
application
rate
of
1.5
lb
ai/
acre
for
pre­
emergence
applications
by
lawn
care
operators
(LCOs)
to
lawns,
playing
fields,
and
golf
courses
as
a
single
application.
The
maximum
application
rate
for
post­
emergence
applications
is
1.0
lb
ai/
acre.
This
residential
label
does
not
specify
or
restrict
the
number
of
applications
allowed
per
year
to
turf.
Applications
to
turf
are
only
made
in
the
late
Fall
or
late
Winter.
For
residential
turf,
HED
assumed
one
application
per
year
to
estimate
short­
term
exposures.

The
scenarios
assessed
for
the
purpose
of
determining
screening­
level
risk
estimates
included
adults
and
children
(toddlers)
performing
high­
contact
play
or
work
activities
on
treated
lawns,
and
adults
mowing
lawns
or
golfing
(see
Tables
6a,
6b,
and
6c)
.
Small
children
(toddlers)
were
also
assessed
for
incidental
oral
exposure
from
ingestion
of
soil,
object­
to­
mouth
activity
(turfgrass
mouthing),
and
hand­
to­
mouth
activity
while
playing
on
treated
lawns.
Some
of
these
exposures
were
combined,
where
it
was
deemed
reasonably
likely
that
activities
would
co­
occur.
Residential
risk
estimates
utilized
data
from
a
submitted
turf
transferable
residue
(TTR)
study,
as
well
as
the
EPA's
original
and
revised
Draft
SOPs
for
Residential
Exposure
Assessment.
3,
5
For
pronamide
short­
term
non­
occupational
risks,
HED
has
established
a
level
of
concern
for
MOEs
<
300.

Results
from
a
recent
turf
transferable
residue
study
on
turf
using
pronamide
(i.
e.
MRID
44952501)
indicate
that
the
half­
life
of
turf
transferrable
(TTR)
residues
was
slightly
less
than
two
days.
The
residential
label
(EPA
Reg.
No.
8660­
85)
instructs
applicators
to
lightly
irrigate
within
a
day
of
application
if
no
rain
occurs.
Such
irrigation
occurred
at
24
hours
after
application
in
the
TTR
study.
Since
the
compound
is
soluble
in
water,
and
therefore
mobile,
it
is
likely
the
irrigation
dissolves
the
compound
and
transports
it
from
the
turf
into
the
soil.
Study
data
showed
that
residues
dissipate
to
below
the
level
of
quantification
by
day
14
following
application.
Therefore,
only
short­
term
(i.
e.,
one
day
to
one
month)
exposures
would
be
anticipated,
since
most
of
the
pesticide
should
move
into
the
soil,
and
any
remaining
foliar
residues
should
dissipate
within
a
month.
While
residues
in
soil
could
persist
for
greater
than
30
days,
it
is
unlikely
that
children
will
play
on
or
contact
soil
for
greater
than
30
consecutive
days
during
the
winter
months.

Risk
estimates
based
on
residue
data
from
the
TTR
study
for
short­
term
dermal
contact
with
treated
turf
during
high
contact
lawn
activities
on
day
zero
following
application
(DAT
0)
exceed
HED's
level
of
concern,
i.
e.
result
in
MOEs
<
300
for
adults
(MOE
=
71)
and
children
(MOE
=
42).
However,
using
DAT
2
residue
data
from
the
TTR
study
yielded
MOEs
that
do
not
exceed
the
level
of
concern
(MOEs
$
300)
for
adults
(MOE
=
890)
and
children
(MOE
=
530)
during
high
contact
lawn
activities.
Note
that
the
test
plots
were
irrigated
immediately
after
the
DAT
1
samples
were
taken,
i.
e.
24
hours
after
application
of
pronamide,
as
specified
on
the
label.
Using
DAT
2
residue
data
from
the
TTR
study
yielded
MOEs
that
do
not
exceed
the
level
of
concern
(MOEs
$
300)
for
adults
(MOE
=
890)
and
children
(MOE
=
530)
during
high
contact
lawn
activities.
The
data
show
that
thorough
watering­
in
the
pronamide
product
clearly
alleviates
the
risk
concerns
for
dermal
exposure.
Risk
estimates
for
shortterm
dermal
contact
with
residues
on
treated
turf
during
the
low
contact
activities
of
grass
mowing
or
golfing
on
the
day
of
treatment
do
not
exceed
the
level
of
concern
(MOEs
$
300)
for
adults
(MOEs
2050
and
1025,
respectively).
30
Based
on
the
pesticide
label,
a
typical
residential/
recreational
lawn
application
rate
of
1.0
lb/
acre,
with
an
application
frequency
of
once
per
year,
was
assumed
for
the
residential
cancer
risk
assessment.
Pronamide
is
applied
in
the
dormant
season,
which
reduces
the
number
of
contact
days
expected.
A
single
exposure
is
deemed
more
likely,
but
up
to
14
days
exposure
could
occur
based
on
the
residue
dissipation
pattern.
The
14­
day
average
turf
residues
from
the
TTR
study
(MRID
44952501)
were
used
(i.
e.
0.07913
µg/
cm
2
,
when
adjusted
to
a
typical
application
rate
of
1.0
lb
ai/
acre);
since
residues
in
the
TTR
study
dissipated
to
the
level
of
quantitation
by
14
days
after
application.
The
average
residue,
and
an
exposure
frequency
of
one
day
per
year,
or
50
days
in
a
lifetime,
was
assumed
for
high
contact
activities
(e.
g.
playing
and
working
on
lawns
and
turf)
and
low
contact
activities
(e.
g.
mowing
or
golfing).
An
adult
mowing
a
treated
lawn
one
day
each
year
has
a
cancer
risk
of
5.7
x
10
­8
.
The
average
golfer
plays
18
times
per
year,
so
one
day's
exposure
is
possible
if
pronamide
is
applied
once
per
year
on
average.
The
adult
golfer
cancer
risk
is
estimated
at
1.2
x
10
­7
.
An
adult
performing
dermal
high
contact
activities
on
turf
during
the
2
week
period
of
residue
dissipation
has
a
cancer
risk
of
8.4
x
10
­7
.
The
HED
endeavors
to
reduce
estimated
cancer
risks
for
the
general
population
to
less
than
one
in
one
million
(10
­6
).
In
order
to
exceed
the
cancer
risk
(1.0
x
10
­6
),
exposure
frequencies
of
17.5,
8.7
and
1.2
days
per
year
would
be
needed
for
the
activities
of
mowing,
golfing
and
high
contact
work,
respectively.

Both
the
short­
term
exposure
estimates
and
the
cancer
risk
estimate
relied
on
a
100%
dermal
absorption
factor,
which
results
in
a
high­
end
dose
estimate.
The
short­
term
dose
selection
from
a
developmental
study
is
based
on
a
weight­
of­
evidence
evaluation
of
the
entire
pronamide
database,
but
is
considered
protective
of
all
populations.
31
Table
6a:
Pronamide
Residential
Postapplication
Activities
on
Treated
Turf:
Dermal
Exposure
and
Non­
Cancer
Risk
Estimates
Short­
term
Risk
Estimates
at
DAT
0
using
TTR
Data
from
Turf
Study
Short­
term
Risk
Estimates
at
DAT
2
using
TTR
Data
from
Turf
Study
Activity
Transfer
Coefficient
(cm
2
/hr)
(a)
TTR
µg/
cm
2
DAT
0
(b)
Dermal
Dose
(mg/
kg/
day)
(c)
MOE
(d)
TTR
µg/
cm
2
DAT
2
(b)
Dermal
Dose
(mg/
kg/
day)
(c)
MOE
(d)

high
contact
lawn
activities:
adults
14,500
0.2886
0.1196
71
0.023
0.00953
890
high
contact
lawn
activities:
toddler
5,200
0.2886
0.2001
42
0.023
0.0159
530
mowing
turf:
adults
500
0.2886
0.00413
2100
0.023
0.000329
26,000
golf
course
reentry:
adult
500
0.2886
0.00825
1000
0.023
0.000657
13,000
a
Transfer
coefficients
from
the
Residential
SOP's
(02/
01).

b
TTR
Source:
MRID
#
44952501
turf
transferable
residue
study
­
see
study
review
for
raw
data
and
regression
statistics.
Mean
observed
residue
values
from
DAT
0
through
DAT
0.5
were
used
for
the
DAT
0
short­
term
assessments.
Mean
observed
residue
values
from
DAT
2
were
used
for
the
DAT
2
short­
term
assessments.

c
Dermal
Dose
=
TTR
(µg/
cm
2
)
x
TC
(cm
2
/hr)
x
conversion
factor
(1
mg/
1,000
µg)
x
exposure
time
(2
hrs/
day
playing
&
mowing;
4
hrs
golfing)
x
Dermal
Absorption
Factor
(100%/
100)/
body
weight
(70
kg
adult
or
15
kg
child
1­
6
yrs).
Short­
term
MOEs
were
calculated
using
DAT
0
or
DAT
2
values.

d
MOE
=
NOAEL
(8.
46
mg/
kg/
day;
based
on
an
oral
study)
/
dermal
dose;
Note:
Target
MOE
is
300
or
greater;
numbers
are
rounded
to
two
significant
figures.

Note:
TTR
=
turf
transferable
residue
DAT
=
days
after
treatment
MOEs
in
bold
exceed
HEDs
level
of
concern
(i.
e.
MOEs
<
300).
32
Table
6b:
Pronamide
Postapplication
Dermal
Cancer
Risk
Estimates
for
Activities
on
Treated
Turf
Activity
Typical
Application
Rate
(lb
ai/
acre)
(a)
Days
of
Exposure
per
Year
(b)
14­
day
avg
TTR,

adjusted
for
"typical"

rate
(µg/
cm
2
)
(c)
Transfer
Coefficient
(cm2/
hr)
(d)
Absorbed
Dermal
Daily
Dose
(mg/
kg/
day)
(e)
LADD
(mg/
kg/
day)
(f)
Cancer
Risk
(g)
Days
of
Exposure
per
Year
to
Exceed
1.0E­
06
High­
contact
activities
1.
0
1
0.
07913
7300
1.65E­
02
3.
23E­
05
8.
36E­
07
1.
2
Mowing
1.0
1
0.07913
500
1.13E­
03
2.
21E­
06
5.
73E­
08
17.5
Golfing
1.
0
1
0.
07913
500
2.26E­
03
4.
42E­
06
1.
15E­
07
8.
7
a
Typical
(not
maximum)
application
rates
were
used
to
adjust
TTR
study
residue
data;
rate
confirmed
per
label
and
registrants'
comments.

b
Average
or
typical
days
per
year
for
cancer
risk
estimates,
based
upon
a
single
annual
application
and
a
fairly
rapid
foliar
dissipation
rate
(half
life
of
1.8
days,

from
TTR
study,
i.
e.
MRID
#
44952501).

c
TTR
source:
MRID
#
44952501
turf
transferable
residue
study
­
see
residential
exposure
assessment
for
raw
data
and
regression
statistics.
Mean
observed
residue
values
for
DAT
0
through
DAT
14
were
used
for
the
assessment.
The
study
was
conducted
in
NC
using
a
maximum
application
rate
of
1.5
lb
ai/
acre.

When
assessing
activities
involving
a
different
application
rate
than
what
was
used
in
the
study,
the
TTR
values
are
adjusted
proportionately
to
reflect
the
different
application
rate.
For
example,
for
the
"typical"
application
rate
of
1.0
lb
ai/
acre
:
normalized
(adjusted)
TTR
=
Turf
study
TTR
x
1.0
lb
ai/
A
assessed
rate
/
1.5
lb
ai/
A
study
rate;
0.1187
µg/
cm
2
x
1.0
lb
ai/
A
assessed
rate
/
1.5
lb
ai/
A
study
rate
=
0.07913
µg/
cm
2
.

d
Transfer
coefficient
from
the
updated
Residential
SOP's
(02/
01).

e
Absorbed
daily
dose
=
Average
day
0­
14
TTR
(µg/
cm
2
)
x
intermediate­
term
transfer
coefficient
(cm
2
/hr)
x
mg/
1,000
µg
x
exposure
duration
(2
hrs/
day
for
playing/
gardening/
mowing;
4
hrs/
day
to
play
golf)
x
dermal
absorption
factor
(100%)
/
body
weight
(70
kg
adult).

f
LADD
=
absorbed
daily
dose
(mg/
kg/
day)
x
days
of
exposure/
year
x
50
years
of
expected
exposure/
(365
days/
year
x
70
year
lifetime);

g
Cancer
Risk
=
LADD
x
Q
1
*
,
where
Q
1
*
=
2.59
x
10
­2
(mg/
kg/
day)
­1
TTR
used
for
cancer
risk
estimate
=
0­
14
DAT
average
residue
normalized
for
typical
application
rate.

TTR
=
turf
transferable
residue
DAT
=
days
after
treatment
33
HED
also
assessed
short­
term
risks
to
small
children
from
incidental
oral
ingestion
of
pronamide
residues
following
application
to
residential
lawns.
The
risk
calculations
for
small
children's
nondietary
ingestion
of
pronamide
on
treated
turf
indicate
that
risks
do
not
exceed
the
level
of
concern
(i.
e.
MOEs
$
300)
for
hand­
to­
mouth
(MOE
=
380),
incidental
ingestion
of
soil
(MOE
=
11,000),
and
incidental
object
to
mouth
(MOE
=
1500).
The
small
children's
combined
oral
hand­
to­
mouth
scenarios
(MOE
=
300)
also
do
not
exceed
the
level
of
concern.
When
risks
from
dermal
exposures
from
pronamide
to
small
children
are
combined
with
risks
from
incidental
oral
exposures,
the
combined
short­
term
risk
estimates
exceed
the
level
of
concern
(MOEs
<
300),
with
an
MOE
at
37.
Note
that
the
high­
contact
dermal
exposure
is
driving
the
overall
risk.
Also,
the
likelihood
of
all
of
the
assessed
incidental
oral
exposures
co­
occuring
with
dermal
exposures
is
low.

Table
6c.
Residential
Oral
Nondietary
Short­
term
Postapplication
Risks
to
Children
from
"Hand­
to­
Mouth"
and
Ingestion
Exposure
When
Reentering
Lawns
Treated
with
Pronamide
Type
of
Exposure
Short­
term
Oral
Dose
a
(mg/
kg/
day)
Short­
term
MOE
b
(1)
Hand
to
Mouth
Activity
0.0224
380
(2)
Incidental
Object
to
Mouth
(Turfgrass
Mouthing)
0.0056
1500
(3)
Incidental
Ingestion
of
Soil
7.51E­
5
113,000
Combined
Oral
Nondietary
c
0.028
300
Combined
Oral
and
Dermal
d
­­­
37
a
Application
rate
for
the
short­
term
estimates
represents
maximum
label
rate
from
current
EPA
registered
label:
EPA
Reg.
No.
8660­
85
wettable
powder
product
formulation,
max
rate
is
1.5
lb
ai/
acre.
Incidental
oral
doses
were
calculated
using
formulas
presented
in
the
Residential
SOPs
(updated
1999­
2000).
Short­­
term
doses
were
calculated
using
the
following
formulas:
(1)
Hand­
to­
mouth
oral
dose
to
children
on
the
day
of
treatment
(mg/
kg/
day)
=
[application
rate
(lb
ai/
acre)
x
fraction
of
residue
dislodgeable
from
potentially
wet
hands
(5%)
x
11.2
(conversion
factor
to
convert
lb
ai/
acre
to
µg/
cm
2
)]
x
median
surface
area
for
1­
3
fingers
(20
cm
2
/event)
x
hand­
to­
mouth
rate
(20
events/
hour)
x
exposure
time
(2
hr/
day)
x
0.001
mg/
:
g]
x
50%
extraction
by
saliva
/
bw
(15
kg
child
1­
6
yrs).
This
formula
is
based
on
proposed
changes
to
the
December
1999
Residential
SOPs.
(2)
Turf
mouthing
oral
dose
to
child
on
the
day
of
treatment
(mg/
kg/
day)
=
[application
rate
(lb
ai/
acre)
x
fraction
of
residue
dislodgeable
for
transfer
to
mouth
(20%)
x
11.2
(conversion
factor
to
convert
lb
ai/
acre
to
µg/
cm
2
)
x
ingestion
rate
of
grass
(25
cm
2
/day)
x
0.001
mg/
:
g]
/
bw
(15
kg
child
1­
6
yrs).
(3)
Soil
ingestion
oral
dose
to
child
on
the
day
of
treatment
(mg/
kg/
day)
=
[(
application
rate
(lb
ai/
acre)
x
fraction
of
residue
retained
on
uppermost
1
cm
of
soil
(100%
or
1.0/
cm)
x
4.54e+
08
µg/
lb
conversion
factor
x
2.47e­
08
acre/
cm
2
conversion
factor
x
0.67
cm
3
/g
soil
conversion
factor)
x
100
mg/
day
ingestion
rate
x
1.0e­
06
g/
µg
conversion
factor]
/
bw
(15
kg;
child
1­
6
yrs).
Short
term
dose
based
residue
on
the
soil
on
day
of
application.
b
Short­
term
MOE
=
NOAEL
(8.46
mg/
kg/
day)
/
Oral
Dose
(mg/
kg/
day).
NOAEL
from
a
non­
developmental
toxicity
study
in
rabbits;
target
MOE
of
100.
Numbers
are
rounded
to
two
significant
figures.
c
Combined
MOEs
=
NOAEL
/
[sum
of
incidental
oral
doses],
with
a
target
MOE
of
100.
d
Combined
Dermal
+
Incidental
Oral
MOEs
=
1/
[1/
MOEdermal
+
1/
MOEoral
];
see
Table
6a
for
dermal
MOE
for
high­
contact
short­
term
activity
for
toddlers
on
turf
(MOE
=
42).
MOEs
in
bold
exceed
HEDs
level
of
concern
(i.
e.
MOEs
<
300).

The
exposure
estimates
generated
for
the
residential/
recreational
turf
uses
used
the
HED
SOPs
that
are
based
on
some
upper­
percentile
assumptions
(i.
e.,
duration
of
exposure
and
maximum
application
rate
for
short­
term
assessments)
and
are
considered
to
be
representative
of
high
end
exposures.
The
34
uncertainties
associated
with
this
assessment
stem
from
the
use
of
assumptions
regarding
the
transfer
of
pronamide
residues.
The
exposure
estimates
are
believed
to
be
reasonably
high­
end
estimates,
since
the
maximum
application
rate
is
used,
a
100%
dermal
absorption
factor
is
assumed,
and
exposures
are
assumed
to
occur
on
the
day
of
treatment.

4.4.2
Spray
Drift
Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
groundboom
application
methods.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
The
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
and
risks
associated
with
aerial
as
well
as
other
application
types
where
appropriate.

5.0
AGGREGATE
RISK
ASSESSMENT
AND
RISK
CHARACTERIZATION
FQPA
requires
an
aggregate
risk
assessment
to
be
conducted
considering
all
non­
occupational
sources,
including
exposure
from
water,
food,
and
residential
use.
Because
there
are
potential
exposures
to
treated
turf,
the
aggregate
exposure
assessment
for
pronamide
includes
exposure
estimates
from
residential
sources
as
well
as
food
and
drinking
water.

HED
has
calculated
drinking
water
levels
of
comparison
(DWLOCs)
for
chronic
exposure
to
pronamide
in
surface
and
groundwater
which
are
presented
in
Tables
7a,
7b
and
7c.
DWLOCs
were
calculated
using
default
body
weights
and
drinking
water
consumption
figures.
Assumptions
used
in
calculating
the
DWLOCs
include
70
kg
body
weight
for
the
U.
S.
population,
60
kg
body
weight
for
adult
females,
10
kg
body
weight
for
children,
two
liters
of
water
consumption
per
day
for
adults,
and
one
liter
consumption
for
children.

Generally,
risks
from
drinking
water
are
assessed
by
comparing
the
DWLOCs
to
the
estimated
environmental
concentrations
(EECs)
in
surface
water
and
groundwater.
In
the
case
of
pronamide,
there
are
monitoring
data
available
for
surface
and
ground
water.
The
monitoring
database
used
in
the
risk
assessment
is
considered
to
be
of
good
quality
(USGS),
but
the
data
are
not
from
sampling
specifically
targeted
for
pronamide
use
areas.
These
data
have
been
compared
to
the
model
results
to
characterize
the
Tier
I
and
Tier
II
estimates
for
the
groundwater
and
surface
water,
respectively.
As
can
be
seen
from
that
comparison,
the
monitoring
data
are
typically
at
least
10­
fold
lower
than
the
model
estimates.
The
USGS
monitoring
data
are
also
lower
than
the
short­
term
and
chronic
DWLOC.

However,
the
model
estimates
for
Northwest
pears
and
apples,
and
alfalfa
grown
in
CA
indicate
that
an
extreme
case
using
highest
label
rates
might
present
a
concern
for
cancer.
Typical
rates
for
the
fruit
are
one­
half
,
and
alfalfa
is
one­
quarter
the
rates
used
in
the
model,
according
to
the
latest
QUA
report.
The
model
estimates
would
therefore
be
decreased
proportionately
for
those
crops
if
pronamide
were
applied
35
at
the
lower
or
more
typical
use
rate.
See
Tables
7a,
7b,
7c.

5.1
Acute
Risk
Acute
aggregate
risk
was
not
estimated
as
no
acute
toxicological
endpoints
were
identified
for
pronamide.

5.2
Short­
Term
Risk
5.2.1
Aggregate
Short­
Term
Risk
Assessment
Because
the
short­
term
dermal
postapplication
exposure
estimates
for
children
exceeded
the
level
of
concern,
an
aggregate
exposure
estimate
combining
dermal
exposure
with
food
and
drinking
water
intake
was
not
conducted
for
that
population.
Adults
engaged
in
high­
contact
activities
on
newly
treated
turf
also
had
dermal
exposures
which
exceeded
the
level
of
concern.
However,
an
aggregate
short­
term
exposure
assessment
was
conducted
for
the
low­
contact
adult
golfing
exposure
scenario.
This
shortterm
risk
estimate
may
be
useful
in
risk
management
decisions.
The
short­
term
aggregate
exposure
estimate
which
included
the
golfer
dermal
exposure
did
not
exceed
the
level
of
concern
(golfer
MOE
=
1000)
.

5.2.2
Short­
Term
DWLOC
Calculations
Since
the
drinking
water
calculations
were
based
on
modeling
estimates,
Drinking
Water
Levels
of
Comparison
(DWLOCs)
were
calculated
for
short­
term
exposure.
The
DWLOC
is
the
concentration
of
a
chemical
in
drinking
water
that
would
be
acceptable
as
an
upper
limit
in
light
of
total
aggregate
exposure
to
that
chemical
from
food,
water,
and
(for
short­
term
estimate)
non­
occupational
(residential)
sources.
Comparisons
are
made
between
DWLOCs
and
the
estimated
concentrations
of
pronamide
in
surface
water
and
ground
water
generated
via
PRZM/
EXAMS
and
SCI­
GROW,
respectively.
If
the
model
estimate
is
less
than
the
DWLOC,
there
is
generally
no
drinking
water
concern.

Monitoring
data
for
pronamide
in
surface
water
had
a
maximum
value
from
all
samples
and
all
years
of
0.365
ppb,
and
0.82
ppb
for
groundwater.
Monitoring
data
ranged
from
0.0037
to
0.365
ppb
in
surface
water,
and
from
0.82
­
0.005
ppb
in
ground
water.
Results
showed
that
for
low­
contact
adult
activities,
such
as,
mowing
and
golfing,
modeled
and
measured
concentrations
of
pronamide
are
considerably
less
than
the
DWLOCs
(range
560
­700
ppb)
for
all
populations.
Consequently,
for
these
adult,
low­
contact
activities,
there
is
no
short­
term
concern
for
drinking
water
from
surface
or
groundwater
sources.
However,
as
noted
above,
short­
term
postapplication
dermal/
incidental
oral
exposures
of
children
to
pronamide
on
lawns
after
application
result
in
risk
estimates
that
exceed
HED's
levels
of
concern.
Aggregating
children's
exposures
through
food,
water,
and
residential
uses
results
in
risk
estimates
that
further
exceed
levels
of
concern.
36
Table
7a.
Short­
Term
Aggregate
Risk
and
DWLOC
Calculations
for
Adult
Low­
Contact
Activities
only
Population
Short­
Term
Scenario
NOAEL
mg/
kg/
day
Target
MOE
1
Max
Exposure
2
mg/
kg/
day
Average
Food
Exposure
mg/
kg/
day
Residential
Exposure
3
mg/
kg/
day
Aggregate
MOE
(food
and
residential)
4
Max
Water
Exposure
5
mg/
kg/
day
Ground
Water
EEC
6
(µg/
L)
Surface
Water
EEC
6
(µg/
L)
Short­
Term
DWLOC
7
(µg/
L)

Adult
Male
8
8.46
300
0.0282
4
e­
06
0.00825
1000
0.020
3
1.
6­
6.5
700
Adult
Female
4
e­
06
0.0096
880
0.0186
560
Child
5
e­
06
0.20
9
NA
9
0
0
Highest
Exposed
Adult
Subpop
10
5
e­
06
0.0096
880
0.0186
560
1
Based
on
10x
uncertainty
for
interspecies
and
10x
for
intraspecies
variation
and
3x
for
FQPA
for
endocrine
effects;
body
weights
used
are
70kg
male,
60
kg
female,
10
kg
child)

2
Maximum
Exposure
(mg/
kg/
day)
=
NOAEL/
Target
MOE
3
Residential
Exposure
=
[Oral
exposure
+
Dermal
exposure
+
Inhalation
Exposure]

4
Aggregate
MOE
=
[NOAEL
÷
(Avg
Food
Exposure
+
Residential
Exposure)]

5
Maximum
Water
Exposure
(mg/
kg/
day)
=
Target
Maxium
Exposure
­
(Food
Exposure
+
Residential
Exposure)

6
The
crop
producing
the
highest
level
was
used.

7
DWLOC(
µg/
L)
=
[maximum
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
;
where
male
bw
=
70
kg;
female
bw=
60
kg;
child
1­
7
bw
=
10
kg;

[water
consumption
(L)
x
10
­3
mg/
µg]
water
consumption
2
L/
day
(adults);
1
L/
day
(
infants
and
children)

8
While
the
high­
contact
dermal
exposure
estimate
alone
exceeds
the
level
of
concern,
the
lower­
contact
exposure
from
golfing
does
not
and
was
aggregated
to
illustrate
the
total
risk
for
this
non­
residential,
recreational
use
scenario
9
NA
=
doses
not
aggregated,
as
the
small
child
estimated
hand­
mouth
incidental
oral
exposure
alone
exceeds
the
level
of
concern
10
Exposure
refers
to
the
highest
dietary
exposure,
in
this
case
for
female
seniors.

5.3
Intermediate­
Term
Risk
Based
on
the
label
use
pattern,
including
seasonal
applications,
and
residue
dissipation
on
turf
in
14
days,
no
intermediate
or
long­
term
residential
non­
dietary
exposures
to
pronamide
are
anticipated.
An
intermediate­
term
risk
assessment
was
not
conducted
as
there
were
no
exposures
of
applicable
(30
days
to
six
months)
duration.

5.4
Chronic
Risk
37
5.4.1
Chronic
Aggregate
Risk
Assessment
Due
to
the
short­
term,
intermittent
nature
of
residential
or
recreational
exposure
to
pronamide,
only
dietary
and
water
intake
were
included
in
the
chronic
aggregate
exposure
estimate.
The
DWLOC
chronic
is
the
concentration
in
drinking
water
as
a
part
of
the
aggregate
chronic
exposure
that
occupies
no
more
than
100%
of
the
chronic
PAD
when
considered
together
with
other
sources
of
exposure.
To
calculate
the
DWLOC
for
chronic
exposure
relative
to
a
chronic
toxicity
endpoint,
the
chronic
dietary
food
exposure
(from
DEEM™)
was
subtracted
from
the
chronic
PAD
to
obtain
the
acceptable
chronic
exposure
to
pronamide
in
drinking
water.
The
DWLOC
was
calculated
and
compared
to
the
EECs.

The
EECs
for
average
concentrations
of
pronamide
were
based
on
PRZM­
EXAMS
for
surface
water
and
SCI­
GROW
for
groundwater.
The
chronic
DWLOCs
(300
­
1050
ug/
L)
were
greater
than
the
EECs
for
modeled
surface
water
(1.6­
6.5
ug/
L),
and
modeled
groundwater
(3
ug/
L).
In
addition,
non­
targeted
USGS
monitoring
data
ranged
from
0.0037
to
0.365
ppb
in
surface
water,
and
from
0.005
­
0.82
ppb
in
ground
water.
HED
concludes
the
chronic
aggregate
risk
estimates
do
not
exceed
the
level
of
concern.

5.4.2
Chronic
DWLOC
Calculations
Table
7b.
Pronamide
­
Summary
of
Chronic
DWLOC
Calculations
Population
Subgroup
cPAD
(mg/
kg/
day)
Food
Exposure
(mg/
kg/
day)
Available
Water
Exposure
(mg/
kg/
day)
Chronic
DWLOC
(µg/
L)
EFED
Generated
EECs
1
USGS
SW
/
GW
Monitoring
6
(µg/
L)

Ground
Water
SCI

GROW)
(µg/
L)
PRZM­
EXAMS
Chronic
(µg/
L)

U.
S.
Population
a
0.03
4
e­
06
0.03
1050
3
1.6
­
6.5
SW:
0.0037
­
0.365
GW:
0.005
­
0.82
Females
13­
50
yrs
b
4
e­
06
900
Children
1­
6
yrs
25
e­
06
300
All
Infants
2
e­
06
300
Chronic
aggregate
exposures
represent
only
dietary
and
water
consumption;
no
chronic
non­
dietary
exposures
anticipated
1
EEC
=
Estimated
Environmental
Concentrations
2
Pronamide
surface
water
EECs
are
from
FIRST
modeling
.

DWLOC
=
water
exposure
X
body
weight
(where
water
exposure
=
cPAD
­
food
exposure)

Liters
of
water
X
10
­3
Body
weight
=
70
kg
for
U.
S.
Population,
60
kg
for
females,
10
kg
for
infants
and
children
Consumption
=
2L/
day
for
Adults
and
1L/
day
for
infants
and
children
5
USGS
­
NAWQA
Data
Retrieval;
Maximum
ground
water
detection
at
Benton
Ozark,
AK
at
0.82
ppb
on
April
13,
1994,
data
ranging
form
0.82
­
0.005
ppb
(ground
38
water).

5.5
Cancer
Risk
Estimates
5.5.1
Cancer
Aggregate
Risk
Assessment
The
estimated
cancer
risk
from
one
day
per
year
of
postapplication
(high
or
low
contact)
exposure
to
average
pronamide
residues
on
treated
turf
did
not
exceed
the
Agency's
level
of
concern
of
1.0
x
10
­6
(one
in
a
million).
High
contact
activities
for
more
than
one
day
would
exceed
the
level
of
concern.
Based
on
the
seasonal
use
pattern,
only
one
to
several
days
postapplication
exposure
are
considered
likely,
and
it
is
unlikely
that
a
single
person
would
have
have
daily
high
contact
exposure
during
the
14­
day
dissipation
period.
The
use
of
a
100
%
dermal
absorption
factor
adds
to
the
conservatism
of
the
cancer
risk
estimate.
For
average
dietary
consumption,
the
dose
did
not
result
in
a
cancer
risk
estimate
of
concern.
Therefore
the
cancer
estimates
from
each
route
can
be
aggregated.

5.5.2
Cancer
DWLOC
Calculations
The
estimated
DWLOC
for
cancer
from
food,
drinking
water,
and
residential
exposure
is
<0.1
ppb.
The
Tier
2
PRZM/
EXAMS
37
year
mean
concentration
estimates
range
from
less
than
1
ppb
to
4.3
ppb.
The
available
USGS
surface
and
groundwater
monitoring
data
ranged
from
0.0037
to
0.365
ppb
in
surface
water,
and
from
0.82
­
0.005
ppb
in
ground
water.
Further
refinement
of
the
drinking
water
modeling
estimates
and/
or
detailed
analysis
of
water
monitoring
data
might
be
useful
for
risk
assessment
and
risk
management
decisions,
once
the
final
disposition
of
residential/
recreational
uses
is
known..
39
Table
7c.
Cancer
DWLOC
Calculations
USGS
SW
/

GW
Monitoring
6
(µg/
L)

Population
Target
Max
Exposure
2
mg/
kg/
day
Chronic
Food
Exposure
mg/
kg/
day
Residential
Exposure
(LADD)
mg/
kg/
day
Aggregate
cancer
risk
(food
and
residential)
Max
Water
Exposure
3
mg/
kg/
day
Cancer
DWLOC
5
(µg/
L)
Ground
Water
EEC
4
(µg/
L)
PRZM
EXAMS
Cancer
(µg/
L)

U.
S.
Pop
3.
86
e­
05
4
e­
06
3.2
e­
05
9.3
e­
07
2.6
e­
06
<0.1
3
0.
535
­
4.35
SW:
0.0037
­
0.365
GW:
0.005


0.82
1
EPA's
goal
is
to
mitigate
cancer
risk
to
1
x
10
­6
.

2
Target
Maximum
Exposure
(mg/
kg/
day)
=
[negligible
risk/
Q*]
;
negligible
risk
=
1.0
e­
06;
Q
1
*
=
0.0259
3
Maximum
Water
Exposure
(mg/
kg/
day)
=
[Target
Maximum
Exposure
­
(Chronic
Food
Exposure
+
Residential
Exposure
(Lifetime
Average
Daily
Dose))]

4
The
crop
producing
the
highest
level
was
used.

5
Cancer
DWLOC(
µg/
L)
=
[maximum
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]

[water
consumption
(L)
x
10
­3
mg/
µg]
2
Body
weight
=
70
kg
for
U.
S.
Population
Consumption
=
2L/
day
for
Adults
and
1L/
day
for
infants
and
children
6
USGS
­
NAWQA
Data
Retrieval;
Maximum
ground
water
detection
at
Benton
Ozark,
AK
at
0.82
ppb
on
April
13,
1994,
data
ranging
form
0.82
­
0.005
ppb
(ground
water).

The
estimated
cancer
risk
from
one
day
per
year
of
postapplication
(high
or
low
contact)
exposure
to
pronamide
treated
turf
did
not
exceed
the
Agency's
level
of
concern
of
1.0
x
10
­6
(one
in
a
million).
However,
more
than
one
day's
exposure
to
treated
turf
while
golfing
could
result
in
a
cancer
risk
estimate
greater
than
1.0
x
10
­6
.
For
average
dietary
consumption,
the
dose
did
not
result
in
a
cancer
risk
estimate
of
concern.
However,
when
the
golfing
exposure
is
added
to
the
chronic
food
exposure,
the
estimated
DWLOC
for
cancer
is
<0.1
ppb,
which
is
below
most
of
the
screening
level
drinking
water
concentrations
estimated
by
EFED,
and
therefore
exceeds
the
level
of
concern.
Some
of
the
surface
and
groundwater
monitoring
data
are
greater
than
the
DWLOC,
which
generates
a
concern
for
cancer.

Therefore,
HED
has
some
concerns
for
exposures
to
pronamide
in
drinking
water
for
cancer
risk.
The
model
estimates
for
Northwest
pears
and
apples,
and
alfalfa
grown
in
CA
indicate
that
an
extreme
case
using
highest
label
rates
might
present
a
concern
for
cancer.
Typical
rates
for
the
fruit
are
one­
half
,
and
alfalfa
is
one­
quarter
the
rates
used
in
the
model,
according
to
the
latest
QUA
report.
The
model
estimates
40
would
therefore
be
decreased
proportionately
for
those
crops
if
pronamide
were
applied
at
the
lower
or
more
typical
use
rate.

The
registrant
for
pronamide
has
requested
cancellation
of
the
turf
use
in
a
letter
dated
January
14,
2002.
If
the
turf
use
is
canceled,
there
will
be
no
residential
or
recreational
non­
dietary
exposures,
and
the
only
remaining
risk
of
concern
will
be
the
aggregate
food
and
drinking
water
cancer
estimate.
Without
residential/
recreational
exposure,
the
cancer
DWLOC
will
be
1.2
ppb.
Additional
monitoring
data,
targeted
at
water
sources
near
pronamide
high
use
sites,
such
as
lettuce
fields
in
Monterey
County,
CA,
could
help
refine
the
cancer
risk
assessment.

Uncertainties
Aggregate
risk
estimates
as
conducted
in
this
document
are
considered
to
be
high­
end
or
conservative
estimates,
and
can
generally
be
refined,
if
necessary,
with
chemical­
specific
data.
The
postapplication
dermal
risk
estimates
were
based
on
the
Office
of
Pesticide's
Residential
SOPs
(1997,
2001),
which
utilize
both
central
tendency
and
upper­
percentile
assumptions
(i.
e.,
duration
of
exposure
and
maximum
application
rate
for
short­
term
assessments)
and
are
considered
to
be
representative
of
high
end
exposures.
The
adult
and
children's
transfer
coefficients
are
based
on
the
Jazzercise
protocol
and
an
upper
percentile
exposure
duration
value.
Where
study
data
were
used
with
the
SOP
formulae,
these
risk
estimates
were
better
refined,
and
hence,
less
conservative.
Therefore,
the
exposure
estimates
related
to
turf
skin
contact
(which
were
based
on
study
data)
are
more
refined
than
the
estimates
of
incidental
ingestion
In
addition,
dermal
doses
assumed
a
100%
dermal
absorption
factor,
and
exposures
are
assumed
to
occur
on
the
day
of
treatment
(highest
residue).

6.0
CUMULATIVE
EXPOSURE
TO
SUBSTANCES
WITH
A
COMMON
MECHANISM
OF
TOXICITY
The
Food
Quality
Protection
Act
(1996)
stipulates
that
when
determining
the
safety
of
a
pesticide
chemical,
EPA
shall
base
its
assessment
of
the
risk
posed
by
the
chemical
on,
among
other
things,
available
information
concerning
the
cumulative
effects
to
human
health
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
other
substances
that
have
a
common
mechanism
of
toxicity.
The
reason
for
consideration
of
other
substances
is
due
to
the
possibility
that
low­
level
exposures
to
multiple
chemical
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
could
lead
to
the
same
adverse
health
effect
as
would
a
higher
level
of
exposure
to
any
of
the
other
substances
individually.
A
person
exposed
to
a
pesticide
at
a
level
that
is
considered
safe
may
in
fact
experience
harm
if
that
person
is
also
exposed
to
other
substances
that
cause
a
common
toxic
effect
by
a
mechanism
common
with
that
of
the
subject
pesticide,
even
if
the
individual
exposure
levels
to
the
other
substances
are
also
considered
safe.

HED
did
not
perform
a
cumulative
risk
assessment
as
part
of
this
risk
assessment
for
pronamide
because
HED
has
not
yet
initiated
a
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
pronamide.
For
purposes
of
this
tolerance
reassessment
review,
EPA
has
assumed
that
pronamide
does
not
have
a
common
mechanism
of
toxicity
with
other
substances.
41
7.0
INCIDENT
DATA
A
review
of
incident
data
sources
found
that
relatively
few
incidents
of
pronamide
poisonings
were
reported
(J.
Blondell,
M.
Spann,
August
10,
2001).
There
are
only
two
Poison
Center
reports,
no
incident
reports
in
OPPs
Incident
Data
System
and
only
two
reports
from
the
California
Pesticide
Illness
Surveillance
Program.
On
the
list
of
the
top
200
chemicals
for
which
National
Pesticide
Telecommunications
Network
(NPTN)
received
calls
from
1984­
1991
inclusively,
pronamide
was
not
reported
to
be
involved
in
human
incidents.

8.0
TOLERANCE
REASSESSMENT
RECOMMENDATIONS
8.1
Tolerance
Reassessment
Recommendation
Pronamide
tolerances
are
established
under
40
CFR
§180.317(
a),
(b),
and
(c).
The
tolerance
expression,
listed
in
(a)
and
(c),
is
in
terms
of
the
combined
residues
of
the
herbicide
propyzamide
and
its
metabolites
(containing
the
3,5­
dichlorobenzoyl
moiety
and
calculated
as
3,5­
dichloro­
N­(
1,1­
dimethyl2
propynyl)
benzamide).
The
tolerance
expression,
listed
in
(b),
is
in
terms
of
the
parent
only.
HED
recommends
that
the
tolerance
expression
under
(b)
be
modified
to
include
the
metabolites
(containing
the
3,5­
dichlorobenzoyl
moiety
and
calculated
as
3,5­
dichloro­
N­(
1,1­
dimethyl­
2­
propynyl)
benzamide).

A
summary
of
pronamide
tolerance
reassessments
is
presented
in
Table
8.
For
a
full
discussion
of
tolerances
see
the
HED
Residue
Chemistry
Chapter
(J.
Morales,
February
28).

Tolerances
for
inadvertent
residues
of
pronamide
and
its
metabolites
containing
the
3,5­
dichlorobenzoyl
moiety
should
be
proposed
for:
(1)
the
forage
of
cereal
grains
crop
at
0.6
ppm;
(2)
the
straw
of
cereal
grains
crop
at
0.3
ppm;
and
(3)
the
hay
of
cereal
grains
crop
at
0.2
ppm.
The
required
tolerance
proposal
is
concomitant
with
a
recommendation
for
a
label
revision
to
establish
a
180­
day
plantback
interval
for
Crop
Group
16.
.
Table
8.
Tolerance
Reassessment
Summary
for
Pronamide
Commodity
Established
Tolerance
(ppm)
Reassessed
Tolerance
(ppm)
Comment
Correct
Commodity
Definition
Tolerances
Listed
Under
40
CFR
§180.317(
a)

Apples
0.1
0.
1
Apple
Artichokes
0.
1
0.051
Artichoke
Blackberries
0.05
0.05
Blackberry
Blueberries
0.05
0.05
Blueberry
Boysenberries
0.05
0.05
Boysenberry
Cattle,
fat
0.
02
0.
20
Cattle,
kidney
0.
4
0.4
Cattle,
liver
0.4
0.
4
Cattle,
mbyp
(except
kidney,
liver)
0.02
0.02
Cattle,
meat
0.02
0.02
Eggs
0.02
0.02
Table
8.
Tolerance
Reassessment
Summary
for
Pronamide
Commodity
Established
Tolerance
(ppm)
Reassessed
Tolerance
(ppm)
Comment
Correct
Commodity
Definition
42
Endive
(escarole)
1.0
1.
0
Goats,
fat
0.
02
0.
20
Goats,
kidney
0.
4
0.4
Goats,
liver
0.4
0.
4
Goats,
mbyp
(except
kidney,
liver)
0.02
0.02
Goats,
meat
0.02
0.02
Grapes
0.1
0.
1
Grape
Hogs,
fat
0.
02
0.
20
Hogs,
kidney
0.
4
0.4
Hogs,
liver
0.4
0.
4
Hogs,
mbyp
(except
kidney,
liver)
0.02
0.02
Hogs,
meat
0.02
0.02
Horses,
fat
0.
02
0.
20
Horses,
kidney
0.
4
0.4
Horses,
liver
0.4
0.
4
Horses,
mbyp
(except
kidney,
liver)
0.02
0.02
Horses,
meat
0.02
0.02
Lettuce
1.0
1.
0
Lettuce,
head
Only
head
lettuce
is
supported
by
acceptable
data;
leaf
lettuce
uses
must
be
removed
from
the
label.
Alternatively,
the
label
may
be
revised
to
specify
a
practical
PHI
(35­
day)
for
leaf
lettuce
and
supporting
data
be
submitted.

Milk
0.02
0.02
Nongrass
animal
feeds
10.0
10.0
Nongrass
animal
feeds
(forage,
fodder,
straw,
and
hay)
group
Pears
0.
1
0.1
Pear
Poultry,
fat
0.
02
0.
02
Poultry,
kidney
0.
2
Revoke
Tolerances
are
typically
not
established
for
poultry
kidneys.

Poultry,
liver
0.2
0.
2
Poultry,
mbyp
(except
kidney,
liver)
0.02
0.02
Poultry,
mbyp
(except
liver)

Poultry,
meat
0.02
0.02
Radicchio,
greens
(tops)
2.
0
2.0
Raspberries
0.05
0.05
Raspberry
Sheep,
fat
0.
02
0.
20
Sheep,
kidney
0.
4
0.4
Sheep,
liver
0.4
0.
4
Table
8.
Tolerance
Reassessment
Summary
for
Pronamide
Commodity
Established
Tolerance
(ppm)
Reassessed
Tolerance
(ppm)
Comment
Correct
Commodity
Definition
43
Sheep,
mbyp
(except
kidney,
liver)
0.02
0.02
Sheep,
meat
0.02
0.02
Stone
fruits
0.1
0.
1
Stone
fruits
group
Tolerances
To
Be
Proposed
Under
40
CFR
§180.317(
a)

Alfalfa,
seed
­­
10.0
Tolerance
recommendation
is
contingent
upon
required
label
revision
to
specify
a
50­
day
PHI
and
a
maximum
seasonal
rate
of
2.0
lb
ai/
A.

Tolerances
Listed
Under
40
CFR
§180.317(
b)

Cranberries
0.05
[with
12/
31/
01
expiration
date]
0.05
Cranberry
Grass,
forage
1.0
[with
12/
31/
01
expiration
date]
1.0
Additional
data
are
required
for
the
establishment
of
permanent
tolerances
on
grass
forage
and
hay.
Grass,
hay
0.5
[with
12/
31/
01
expiration
date]
0.5
Tolerances
Listed
Under
40
CFR
§180.317(
c)

Peas,
dried
(winter)
0.05
TBD
Pea,
field,
seed
Rhubarb
0.1
0.
1
Tolerances
To
Be
Proposed
Under
40
CFR
§180.317(
c)

Pea,
field,
hay
­­
TBD
Pea,
field,
vines
–
TBD
CODEX
HARMONIZATION
No
Codex
MRLs
have
been
established
or
proposed
for
residues
of
pronamide.
Therefore,
issues
of
compatibility
with
respect
to
U.
S.
tolerances
and
Codex
MRLs
do
not
exist.

9.0
DATA
NEEDS
Product
Chemistry
Most
pertinent
product
chemistry
data
requirements
are
satisfied
for
the
Rohm
and
Haas
94.6%
T/
TGAI,
except
additional
data
are
required
concerning
the
materials
used
to
produce
the
product
and
UV/
Visible
absorption
(OPPTS
830.1600
and
7050).
Additional
data
are
also
required
for
the
Rohm
and
Haas
51%
FI
concerning
oxidation/
reduction,
explodability,
storage
stability,
and
corrosion
characteristics
(OPPTS
830.6314,
6316,
6317,
and
6320).
Provided
that
the
registrant
submits
the
data
required
in
the
attached
data
summary
tables
for
the
pronamide
T/
TGAI
and
FI,
and
either
certifies
that
the
suppliers
of
beginning
materials
and
the
manufacturing
processes
have
not
changed
since
the
last
comprehensive
product
chemistry
reviews
or
submits
complete
updated
product
chemistry
data
packages,
HED
has
no
44
objections
to
the
reregistration
of
pronamide
with
respect
to
product
chemistry
data
requirements.

Toxicology
Although
there
is
confidence
in
the
overall
scientific
quality
of
the
available
toxicity
data,
several
data
gaps
were
identified:
a
developmental
toxicity
study
in
rats,
a
21­
day
dermal
toxicity
study,
28­
day
inhalation
toxicity
study,
a
dermal
penetration
study
and
a
comparative
thyroid
rat
assay
in
adult
animals
and
offspring.

Residue
Chemistry
A
review
of
the
product
labels
and
the
supporting
residue
data
indicate
the
following
label
amendments
and
data
submissions
are
required:

C
additional
residue
data
are
required
for:
use
on
grasses,
dried
winter
peas
(outstanding),
the
vines
and
hay
of
winter
peas,
grass
forage,
and
hay.
C
label
amendments
are
required
for
alfalfa
grown
for
seed,
lettuce,
and
peas
(winter);
see
chemistry
chapter
for
details;
C
label
revisions
should
be
made
for
rotational
crops
as
listed:
1.
30­
day
plantback
interval
for
leafy
vegetables
(except
Brassica
vegetables)
(Crop
Group
4);
2.
90­
day
plantback
interval
for
root
and
tuber
vegetables
(Crop
Group
1);
3.
360­
day
plantback
interval
for
cereal
grains
(Crop
Group
15)
and
the
forage,
fodder,
and
straw
of
cereal
grains
(Crop
Group
16).

For
purposes
of
reregistration,
no
additional
plant
metabolism
studies
are
required;
however,
because
the
available
metabolism
studies
were
only
conducted
on
alfalfa
and
lettuce,
the
Agency
may
require
additional
metabolism
studies
in
the
future
should
the
registrants
seek
for
additional
uses
on
other
crop
groups.

The
registrant
is
required
to
further
optimize/
improve
the
revised
animal
enforcement
method
(TR
34­
91­
68)
to
yield
acceptable
recoveries
at
a
fortification
level
equal
to
established
animal
tolerances.
Following
method
improvement,
the
registrant
is
required
to
submit
bridging
independent
laboratory
validation
data;
the
required
ILV
data
should
include
two
control
samples
fortified
at
0.4
ppm,
the
reassessed
tolerance
level
for
the
kidney
and
liver
of
ruminants.

Additional
confirmatory
storage
stability
data
for
the
regulated
pronamide
metabolites
on
alfalfa,
apples,
grapes,
lettuce,
and
peaches
or
plums
are
required.
