Document ID: EPA-HQ-OPP-2005-0232-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-08-17T04:00Z

Page
1
of
32
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
June
13,
2005
MEMORANDUM
SUBJECT:
Procymidone:
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
Document
(
TRED).
PC
Code:
129044.
DP
Barcode:
D317735.
Regulatory
Action:
Reregistration
Preliminary
Risk
Assessment
Risk
Assessment
Type:
Single
Chemical
FROM:
Toiya
Jimerson,
Chemist
and
Risk
Assessor
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THROUGH:
Elizabeth
Mendez,
Ph.
D.,
Toxicologist
and
Whang
Phang,
Ph.
D.,
Branch
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

TO:
Demson
Fuller,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508C)

The
Human
Health
Risk
Assessment
for
the
Procymidone
Tolerance
Reassessment
Eligibility
Decision
Document
(
TRED)
is
attached.
The
HED
chapter
includes
the
Toxicology
and
Hazard
Assessment
from
Elizabeth
Mendez,
Reregistration
Branch
I
and
Dietary
Exposure
Analysis
from
Toiya
Jimerson,
Reregistration
Branch
1.
Information
was
also
drawn
from
the
Procymidone:
RfD/
Peer
Review
Report
from
George
Ghali,
HED,
Toxicology
Branch
and
the
Procymidone:
Revised
Quantitative
Risk
Assessment
(
Q
1*)
Report
from
Lori
Brunsman,
HED,
Science
Information
Management
Branch.

Executive
Summary
Page
2
of
32
A
human
health
risk
assessment
was
performed
for
the
procymidone
TRED.
Procymidone
is
a
systemic,
dicarboximide
fungicide
used
to
treat
wine
grapes
outside
of
the
United
States.
A
tolerance
of
5
ppm
for
wine
grapes
has
been
established,
with
no
U.
S.
registrations,
to
permit
the
import
of
wine
produced
from
procymidone
treated
grapes.
Currently,
procymidone
exposures
to
the
U.
S.
general
population
exist
only
through
the
drinking
imported
wine
made
from
procymidone
treated
grapes.

The
HED
RfD/
Peer
Review
Committee
has
selected
an
acute
reference
dose
(
RfD)
for
the
dietary
risk
assessment,
and
calculated
the
Population
Adjusted
Dose
(
PAD),
which
is
the
RfD
divided
by
the
FQPA
safety
factor.
The
endpoint
of
concern
is
a
decrease
in
anogenital
distance
in
male
fetuses
with
a
NOAEL
of
3.5
mg/
kg.
It
is
presumed
that,
given
the
rapidly
changing
environment
during
development,
the
treatment­
related
effects
seen
in
the
fetuses
may
result
from
a
single
exposure
event;
thus,
this
endpoint
is
appropriate
for
acute
dietary
risk
assessment.
The
same
NOAEL
was
used
for
chronic
dietary
risk
assessment
since
comparable
NOAELs
were
identified
after
chronic
dietary
exposure.
Furthermore,
the
endpoints
identified
in
the
chronic
studies
(
increased
testicular
weights,
hypospadia,
decreased
male
fertility,
etc.)
were
consistent
with
the
effect
noted
in
the
study
used
for
acute
dietary
risk
assessment
in
that
they
are
all
indicative
of
toxicity
to
the
male
reproductive
tract
presumably
related
to
procymidone's
antiandrogenic
properties.
The
procymidone
toxicological
database
is
adequate
for
hazard
characterization
and
sufficient
data
are
available
to
conduct
an
FQPA
assessment
(
assess
potential
increase
susceptibility
of
the
young).
HED
has
concluded
that
the
FQPA
Safety
Factor
(
SF)
may
be
reduced
to
1X.
Therefore,
the
PAD
is
equal
to
the
RfD.
The
acute
reference
dose
and
the
PAD
are
0.035
mg/
kg/
day.

The
Carcinogenicity
Peer
Review
Committee
classified
procymidone
as
a
probable
human
carcinogen
in
1990.
A
Q
1*
value
of
0.0235
(
mg/
kg/
day)­
1
has
been
established
for
procymidone
based
on
female
mouse
liver
combined
adenoma
and/
or
tumor
rates.

A
Tier
I
acute
dietary
exposure
assessment
for
food
only
was
performed
using
DEEM­
FCID
 
.
The
assumptions
of
this
dietary
exposure
assessment
were
tolerance
level
residues
and
100%
crop
treated.
The
dietary
exposure
analysis
for
procymidone
resulted
in
dietary
risk
estimates
for
food
that
are
below
the
Agency's
level
of
concern
for
acute
dietary
exposure.
Estimates
from
DEEMFCID
 
show
that
the
acute
exposure
is
1.7%
of
the
aPAD.

A
Tier
I
cancer
dietary
exposure
assessment
for
food
only
was
also
performed
using
DEEMFCID
 
.
The
assumptions
of
this
assessment
were
tolerance
level
residues
and
100%
crop
treated.
For
the
U.
S.
Population
subgroup,
the
cancer
risk
was
calculated
to
be
1.8
x
10­
6
(
based
on
a
Q
1*
value
of
0.0235
(
mg/
kg/
day)­
1)
with
an
exposure
value
of
0.000077
mg/
kg/
day.
The
cancer
risk
estimate
for
procymidone
slightly
exceeds
the
1.0
x
10­
6.
However,
given
the
conservative
assumptions
used
in
this
risk
assessment,
the
Agency
has
determined
that
actual
exposure
is
likely
to
be
substantially
lower
than
the
estimated
exposure
and
consequently
not
of
concern.
Page
3
of
32
3,5­
Dichloroaniline
(
3,5­
DCA)
is
a
common
metabolite
to
iprodione,
vinclozolin,
and
procymidone.
The
aggregate
carcinogenic
risk
estimate
for
consumption
of
food
and
wine
containing
residues
of
3,5­
DCA
as
a
result
of
use
of
iprodione,
vinclozolin,
and
procymidone
is
1.3
x
10­
6.
A
surrogate
Q
1*
was
used
to
obtain
the
carcinogenic
risk
estimate
for
3,5­
DCA.
Since
3,5­
DCA
is
not
a
registered
pesticide,
there
are
no
toxicology
data
for
this
compound.
Consequently,
the
established
Q
1*
for
p­
chloroaniline
(
PCA)
was
used
in
this
assessment
because
of
the
structural
similarities
between
3,5­
DCA
and
PCA.
HED
believes
that
the
use
of
the
PCA
Q
1*
represents
a
reasonable
risk
estimate.

Since
there
are
no
registered
uses
of
procymidone
in
the
U.
S.,
no
occupational,
residential,
or
drinking
water
exposures
are
expected.
Therefore,
aggregate
risks
are
identical
to
food
only
dietary
risks.

Currently,
there
are
no
data
gaps
for
the
chemical
procymidone.

In
conclusion,
human
health
risks
associated
with
procymidone
are
considered
to
be
minimal
in
the
United
States
due
to
its
low
acute
toxicity
and
its
low
dietary
exposure.
Although,
the
cancer
risk
for
procymidone
slightly
exceeds
the
1.0
x
10­
6,
the
estimated
exposure
is
not
of
concern
given
the
conservative
assumptions
used
in
this
risk
assessment.
There
are
no
occupational
or
residential
uses
for
procymidone
in
the
U.
S.

Introduction
This
risk
assessment
was
performed
to
support
the
tolerance
reassessment
eligibility
decision
for
procymidone
[
N­(
3,5­
dichlorophenyl)­
1,2­
dimethylcyclopropane­
1,2­
dicarboximide].
Procymidone
is
a
systemic,
dicarboximide
fungicide
used
to
treat
wine
grapes
outside
of
the
U.
S.
Systemic
chemicals
are
absorbed
by
the
plant
and
carried
by
translocation
through
the
cuticle
and
across
leaves
to
the
growing
points.
Most
systemic
fungicides
have
eradicant
properties
that
stop
the
progress
of
existing
infections.

A
tolerance
of
5
ppm
for
wine
grapes
has
been
established,
with
no
U.
S.
registrations,
to
permit
the
import
of
wine
produced
from
procymidone
treated
grapes.
Exposures
and
risks
from
drinking
water,
occupational,
and
residential
uses
of
procymidone
are
not
expected
in
the
U.
S.
and
were
not
assessed.
Known
exposures
to
procymidone
in
the
United
States
exist
only
through
the
drinking
of
treated,
imported
wine.

Structure
and
Nomenclature
Table
1
below
provides
the
structure
and
nomenclature
for
procymidone.
Page
4
of
32
Cl
Cl
N
O
O
CH
3
CH
3
Table
1.
Procymidone
­
Test
Compound
Nomenclature
Chemical
Structure
Empirical
Formula
C13H11Cl2NO2
Common
name
Procymidone
IUPAC
name
N­(
3,5­
dichlorophenyl)­
1,2­
dimethylcyclopropane­
1,2­
dicarboximide
CAS
name
3­(
3,5­
dichlorophenyl)­
1,5­
dimethyl­
3­
azabicyclo[
3.1.0]
hexane­
2,4­
dione
CAS
Registry
Number
32809­
16­
8
Chemical
Class
Fungicide,
dicarboximide
Hazard
Characterization/
Assessment
Studies
Available
and
Considered
The
toxicological
database
for
procymidone
contains
acceptable
guideline
developmental
toxicity
studies
in
rats
and
rabbits,
multigeneration
reproduction
toxicity
studies
in
rats,
and
a
special
developmental
toxicity
study
in
rats
that
included
a
post­
natal
evaluation
period.
In
addition,
special
mechanistic
studies
evaluating
a
variety
of
endpoints
including
reproductive
organ
weights
and
histopathology,
as
well
as
hormone
levels
(
leutenizing
Hormone,
testosterone,
and
17­
 
estradiol)
are
available.
These
studies
were
conducted
to
characterize
the
potential
endocrine
disrupting
capabilities
of
procymidone,
as
it
is
structurally
related
to
vinclozolin
and
iprodione,
compounds
that
exhibit
endocrine
disrupting
properties.
Critical
studies
employed
for
procymidone
toxicity
endpoint
selection
are
summarized
below.

Carcinogenicity
Study
­
MOUSE
OPPTS
870.4200
[
§
83­
2]

In
a
carcinogenicity
study
(
MRID
No.
41477705),
procymidone
technical
(
99.86%
a.
i.)
was
administered
to
B6C3F1
mice
(
50/
sex/
dose)
in
the
diet
at
concentrations
of
0,
30,
100,
300,
and
1000
ppm
(
0,
4.3,
14.3,
42.9,
and
142.9
mg/
kg/
day)
for
18
months
(
main
study).
Satellite
groups
of
40
animals/
sex/
dose
were
exposed
to
the
test
article
in
a
similar
manner
and
used
for
interim
sacrifices
on
weeks
26,
52
and
78
of
the
study.

No
effects
that
could
be
unequivocally
attributed
to
compound
exposure
were
noted
in
body
weight,
body
weight
gain,
food
and
water
consumption,
or
ophthalmoscopic
parameters.
While
a
Page
5
of
32
number
of
statistically
significant
changes
in
hematology
and
clinical
chemistry
parameters
were
noted
throughout
the
study,
none
of
these
changes
appeared
to
be
biologically
relevant.
Doserelated
increases
in
absolute
and
relative
liver
weights
(
liver/
brain)
were
noted
at
the
end
of
the
study
period
at
the
100
ppm
dose
level
and
higher.
Histopathology
examination
revealed
an
increased
incidence
of
liver
cytomegaly
in
males
at
the
300
ppm
and
1000
ppm
dose
levels
(
12%
and
88%,
respectively).
The
liver
cytomegaly
incidence
in
females
was
only
increased
at
the
highest
dose
tested
(
5/
50
at
1000
ppm
vs.
0/
50
control).
Other
findings
reported
included
increased
incidence
of
multifocal
fatty
changes
in
males
(
10%
and
22%
at
the
300
and
1000
ppm
dose
levels,
respectively)
and
diffuse
fatty
tissue
in
females
treated
at
the
highest
dose
(
16%).
Though
increased
incidence
of
focal
hyperplasia,
multifocal
hyperplasia
and
mononuclear
infiltration
of
the
epididymides
were
also
reported,
no
clear
dose­
response
relationship
could
be
established.

In
females,
an
apparent
dose­
related
increase
in
the
incidence
of
hepatocellular
adenomas
was
noted
at
the
300
and
1000
ppm
dose
levels
(
6%
and
14%,
respectively).
Although
these
increases
are
within
the
historical
control
range
of
0­
18%
from
the
National
Toxicology
Program,
they
are
outside
the
historical
control
range
seen
at
the
testing
facility.
The
incidences
of
hepatocellular
carcinoma
in
males
are
increased
by
18%
and
20%
(
100
ppm
and
1000
ppm
dose
levels,
respectively)
while
the
incidence
at
300
ppm
was
only
increased
by
8%
when
compared
to
the
concurrent
control.
In
addition,
an
increase
in
the
incidence
of
hepatoblastomas
was
also
reported
at
the
300
and
1000
ppm
dose
level
(
4%
and
10%
increase,
respectively).

The
doses
tested
in
this
study
are
considered
adequate
to
assess
procymidone's
potential
carcinogenic
activity
given
the
increased
incidences
of
liver
cytomegaly,
multifocal
fatty
changes,
and
diffuse
fatty
tissue
as
well
as
the
increases
in
the
absolute
and
relative
liver
weights
reported
at
the
highest
dose
tested.

Under
the
conditions
of
this
study,
the
NOAEL
is
established
at
30
ppm
(
14.3
mg/
kg/
day).
The
LOAEL
is
established
at
100
ppm
(
42.9
mg/
kg/
day)
based
on
increases
in
incidences
of
liver
cytomegaly,
multi­
focal
fatty
changes,
hepatocellular
adenomas,
and
hepatoblastomas.

Combined
Chronic/
Oncogenicity
Study
­
RAT
OPPTS
870.4300
[
§
83­
5]

In
a
combined
chronic/
oncogenicity
study
(
MRID
41477703),
procymidone
technical
(
99.8%
a.
i.)
was
administered
to
Osborn­
Mendel
rats
(
100/
sex/
dose)
in
the
diet
at
concentrations
of
0,
100,
300,
1000,
and
2000
ppm
(
0,
4.6,
14.0,
47.6,
and
96.9
mg/
kg/
day
for
males
and
0,
6,
17.9,
61,
and
121.6
mg/
kg/
day
for
females)
for
104
weeks.
Half
of
the
animals
in
the
study
(
50/
sex/
dose)
were
assigned
to
a
"
satellite
study"
and
used
for
clinical
pathology,
necropsy
and
organ
weight
evaluations
following
interim
sacrifices
at
weeks
26,
52,
78,
and
104
(
10
animals/
sex/
dose
sacrificed
at
each
interim
interval;
20
animals/
sex/
dose
sacrificed
on
week
104).
The
50
animals/
sex/
dose
in
the
"
main
study"
were
evaluated
for
several
parameters
indicative
of
toxicity
Page
6
of
32
or
carcinogenicity
including
but
not
limited
to
body
weight
changes,
food
consumption,
hematology
changes,
etc.

Mortality
rate
was
not
affected
by
treatment
with
the
test
compound.
However,
the
survival
rates
for
males
in
the
100
and
300
ppm
dose
groups
were
considerably
low
(<
25%)
at
the
end
of
the
study
period.
No
effects
that
could
be
unequivocally
attributed
to
compound
exposure
were
noted
in
food
and
water
consumption,
clinical
observations,
hematology,
clinical
chemistry,
gross
pathology
or
ophthalmoscopic
parameters.
A
consistent
and
statistically
significant
(
p

0.05)
decrease
in
body
weight
was
reported
for
animals
of
both
sexes
at
the
300
ppm
dose
level
and
above
throughout
the
majority
of
the
study
period.
Males
in
these
dose
groups
also
exhibited
an
increase
in
the
incidence
of
testicular
interstitial
cell
tumors
and
hyperplasia
while
females
showed
evidence
of
an
increase
in
the
incidence
of
ovarian
stromal
hyperplasia
at
the
2000
ppm
dose
level.
Hepatic
cytomegaly
was
noted
for
both
sexes
at
the
1000
ppm
and
2000
ppm
dose
level.
In
addition,
a
statistically
significant
increase
in
liver
weights
was
noted
for
females
at
the
1000
and
2000
ppm
dose
levels
and
for
males
at
the
2000
ppm
dose
levels.
A
statistically
significant
trend
for
the
increase
in
the
incidence
of
pituitary
adenomas
was
reported
for
females
in
the
300
ppm
dose
group
and
above.
These
pituitary
adenomas
also
appeared
earlier
in
the
study
at
the
300
ppm
dose
level
and
higher
than
it
did
at
the
100
ppm
and
control
levels.
(
362
vs.
659
days
into
the
study
at
300
ppm
and
0
ppm
dose
levels,
respectively).

Under
the
conditions
of
this
study,
the
NOAEL
is
set
at
100
ppm
(
4.6
mg/
kg/
day).
The
LOAEL
is
established
at
300
ppm
based
on
statistically
significant
decreases
in
body
weight,
increased
incidence
of
testicular
interstitial
cell
tumor
and
hyperplasia,
and
increased
incidence
of
pituitary
adenomas.

Special
Study
­
Developmental
Toxicity
Study
with
Post­
Natal
Evaluation
­
RAT
In
a
special
developmental
study
(
MRID
No.
42383401,
42383402,
42482002),
5
groups
of
presumed
pregnant
Crl:
CD
®
VAF/
Plus
®
rats
(
45/
dose)
were
administered,
by
gavage,
procymidone
technical
(
98.5%
a.
i.)
in
corn
oil
at
dose
levels
of
0,
3.5,
12.5,
125,
and
500
mg/
kg/
day
from
days
6
through
19
of
gestation.
The
test
article
was
administered
at
a
volume
of
5
ml/
kg
body
weight.
The
animals
were
observed
daily
for
mortality
or
signs
of
toxicity.
The
results
show
that
41
­
44
females/
dose
were
pregnant.

I.
Prenatal
Developmental
Section
For
the
pre­
natal
developmental
segment
of
this
study,
25
dams/
dose
were
initially
assigned
for
sacrifice
and
cesarean
sections
on
GD
20.
No
mortality
was
reported
during
the
duration
of
the
study.
Signs
of
maternal
toxicity
included
a
statistically
significant
(
p

0.01)
increase
in
the
number
of
dams
exhibiting
ungroomed
fur
at
the
125
mg/
kg/
day
dose
level
and
higher;
and
statistically
significant
(
p

0.01)
decreases
in
body
weight
gain
and
food
consumption
at
the
125
Page
7
of
32
and
500
mg/
kg/
day
dose
levels
during
gestation.

Under
the
conditions
of
this
study,
the
maternal
LOAEL
is
established
at
125
mg/
kg/
day
based
on
statistically
significant
decreases
in
body
weight
gain
and
food
consumption
during
gestation.
The
maternal
NOAEL
is
set
at
12.5
mg/
kg/
day.

Developmental
Toxicity
­
While
reproductive
parameters
(
i.
e.
number
of
resorptions,
postimplantation
losses,
or
corpora
lutea)
in
the
test
groups
did
not
differ
from
the
concurrent
controls
in
a
consistent
dose­
dependent
manner,
male
fetuses
appeared
to
be
affected
by
treatment
with
the
test
article
as
indicated
by
a
statistically
significant
decrease
in
ano­
genital
distance
(
AGD)
at
the
12.5
mg/
kg/
day
dose
level
and
higher.
While
an
increase
in
the
incidence
of
arched
thoracic
vertebrae
is
reported
on
both
a
litter
and
pup
basis,
this
is
the
only
anomaly
reported
during
the
skeletal
examination.
The
toxicological
relevance
of
this
finding
is,
therefore,
unclear.

Under
the
conditions
of
this
study,
the
developmental
LOAEL
(
for
this
segment
of
the
study)
is
established
at
12.5
mg/
kg/
day
based
on
statistically
significant
reduction
in
ano­
genital
distance
in
males.
The
developmental
NOAEL
is
set
at
3.5
mg/
kg/
day.

II.
Postnatal
Evaluation
Section
For
the
postnatal
evaluation
section
of
the
study
19
­
22
pregnant
dams
were
allowed
to
deliver
at
the
end
of
gestation.
No
signs
of
maternal
toxicity
were
reported
at
any
dose
level
for
this
portion
of
the
study.
A
slight
increase
in
the
number
of
pups
dying
on
PND
2
­
4
was
noted
at
the
125
and
500
mg/
kg/
day
dose
levels
(
statistically
significant
{
p

0.01}
only
for
the
500
mg/
kg/
day
dose
group).
As
was
reported
during
the
pre­
natal
developmental
portion
of
this
study,
a
statistically
significant
decrease
in
AGD
was
observed
in
males
at
the
125
mg/
kg/
day
dose
level
and
higher.
Increases
in
the
incidence
of
undescended
testes,
hypospadias,
and
distended
preputial
glands
were
also
reported
at
the
125
mg/
kg/
day
dose
level
and
higher.
A
dose
dependent
increase
in
the
severity
of
hypospadia
was
reported
with
82
pups
(
16
litters)
exhibiting
slight
to
moderate
severity
at
the
125
mg/
kg/
day
dose
level
and
52
pups
(
16
litters)
showing
severe
hypospadia.
In
contrast,
at
the
500
mg/
kg/
day
dose
level
(
HDT)
all
of
the
incidences
of
hypospadia
were
classified
as
severe
(
112
pups,
18
litters).
Upon
termination
(
PND
45),
animals
treated
at
the
125
and
500
mg/
kg/
day
dose
levels
exhibited
statistically
significantly
lower
absolute
and
relative
testes
weight
(
testes/
brain
and/
or
testes/
body
weight
ratio),
body
weights,
and
brain
weights
when
compared
to
concurrent
controls.

No
compound­
related
signs
of
toxicity,
body
weight
changes,
or
organ
weight
changes
were
noted
for
females.
Although
a
statistically
significant
(
p

0.05)
decrease
in
AGD
was
noted
for
females
at
the
125
and
500
mg/
kg/
day
dose
level
(
during
the
evaluations
on
PND
21
and
PND1,
respectively),
these
decreases
were
not
dose
dependent
and
their
toxicological
relevance
is
equivocal.
Page
8
of
32
Under
the
conditions
of
this
study,
the
developmental
LOAEL
for
the
postnatal
section
of
this
study
is
established
at
125
mg/
kg/
day
based
on
statistically
significant
increases
in
and
the
incidence
of
hypospadia,
undescended
testes
and
distended
preputial
glands,
as
well
as
statistically
significant
decreases
in
AGD,
absolute
and
relative
testes
weight,
body
weights
and
brain
weights.
The
developmental
NOAEL
is
set
at
12.5
mg/
kg/
day.

Acute
Reference
Dose
(
aRfD)

In
1993,
the
Health
Effects
Division
RfD/
Peer
Review
Committee
determined
the
reference
dose
for
procymidone.
Based
on
a
developmental
toxicity
study
in
rats,
a
no
observed
adverse
effect
level
(
NOAEL)
of
3.5
mg/
kg/
day
was
determined
after
developmental
toxicity
effects
(
reduced
anogenital
distance
in
males)
were
observed
at
12.5
mg/
kg/
day.
An
uncertainty
factor
(
UF)
of
100
was
recommenced
to
account
for
interspecies
extrapolation
and
intraspecies
variability.
The
reference
dose
(
NOAEL
÷
UF)
was
calculated
to
be
0.035
mg/
kg/
day.

The
toxicological
database
for
procymidone
contains
acceptable
guideline
developmental
toxicity
studies
in
rats
and
rabbits,
multigeneration
reproduction
toxicity
studies
in
rats
as
well
as
a
special
developmental
toxicity
study
in
rats
that
includes
a
post­
natal
evaluation
period.
In
addition,
special
mechanistic
studies
evaluating
a
variety
of
endpoints
including
reproductive
organ
weights
and
histopathology
as
well
as
hormone
levels
(
leutenizing
hormone,
testosterone,
and
17­
 
estradiol)
are
available.
These
studies
were
conducted
to
characterize
the
potential
endocrine
disrupting
capabilities
of
procymidone
as
it
is
structurally
related
to
vinclozolin
and
iprodione,
compounds
that
exhibit
endocrine
disrupting
properties.
Though
several
effects
indicative
of
endocrine
disruption
as
well
as
changes
in
hormone
levels
were
evident
in
several
studies
in
the
database,
these
effects
have
been
adequately
characterized
and
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
following
exposure
to
procymidone.
Given
the
data
available,
the
procymidone
database
is
considered
adequate
for
the
assessment
of
potential
increased
susceptibility
of
the
young
to
procymidone
exposure.
Although
there
is
evidence
of
increased
susceptibility
in
the
Developmental
Toxicity
Study
in
Rats
(
Dev.
NOAEL
=
3.5
mg/
kg/
day
vs.
Maternal
NOAEL
of
12.5
mg/
kg/
day),
an
FQPA
SF
of
1X
is
recommended.
This
recommendation
is
based
on
the
fact
that
the
Developmental
NOAEL
of
3.5
mg/
kg/
day
based
on
the
most
sensitive
endpoint
identified
in
the
database
(
reduced
anogenital
distance)
is
currently
used
as
the
dose
for
the
risk
assessment,
clear
NOAELs
and
LOAELs
have
been
identified
for
the
critical
studies,
and
the
developmental
toxicity
profile
for
procymidone
has
been
adequately
characterized.

See
Table
3
below
for
a
summary
of
toxicological
doses
and
endpoints
for
procymidone.

Cancer
Q
1*
Page
9
of
32
Procymidone
was
classified
as
a
probable
human
carcinogen
in
1990
by
the
Carcinogenicity
Peer
Review
Committee.
A
Q
1*
value
of
0.0235
(
mg/
kg/
day)­
1
has
been
established
based
on
a
female
mouse
carcinogenicity
study.
See
the
executive
summary
above
in
the
"
Studies
Available
and
Considered"
section.
The
dose
levels
used
from
the
105­
week
dietary
study
were
0,
30,
100,
300
and
1000
ppm
of
procymidone.
The
corresponding
censored
tumor
rates
for
the
female
mouse
liver
combined
tumors
were
2/
57,
2/
56,
2/
56,
6/
60
and
9/
60,
respectively.

The
original
Q
1*
value
for
procymidone
was
generated
using
the
mg/
kg
b.
w.
2/
3'
s/
day
cross
species
scaling
factor.
The
current
value
of
0.0235
(
mg/
kg/
day)­
1
reflects
the
incorporation
of
the
Agency
policy
change
from
use
of
the
2/
3
to
the
3/
4
scaling
factor
in
1994.
See
Table
2
below
for
a
summary
of
toxicological
doses
and
endpoints
for
procymidone.

Table
2.
Summary
of
Toxicological
Dose
and
Endpoints
for
Procymidone.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Female
13­
49
yrs
of
age)
NOAEL
=
3.5
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.035
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
(
0.035)
FQPA
SF
(
1)

=
0.035mg/
kg/
day
Developmental
toxicity
study
in
rats
LOAEL
=
12.5
mg/
kg/
day
based
on
statistically
significant
reduction
in
anogenital
distance
in
males.

Cancer
(
oral,
dermal,
inhalation)
Probable
human
carcinogen
Q1*
=
0.0235
(
mg/
kg/
day)­
1
UF
=
uncertainty
factor,
FQPA
SF
=
Special
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,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
Endocrine
Disruption
EPA
is
required
under
the
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
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
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
Page
10
of
32
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

Procymidone
and
certain
of
its
metabolites
are
known
to
interfere
with
the
endocrine
system
related
to
its
antiandrogenic
activity
ultimately
resulting
in
reproductive
effects.
Some
of
the
reproductive/
anti­
androgenic
effects
induced
by
procymidone
include
increased
incidences
of
hypospadia,
undescended
testes,
testicular
interstitial
cell
tumors,
and
distended
preputial
glands
as
well
as
decreases
in
anogenital
distance,
testes
weights,
and
male
fertility.
These
effects
were
observed
at
one
or
more
dose
levels
in
the
developmental,
multigeneration,
and
chronic
toxicity
studies
in
rats.
The
decreases
in
anogenital
distance
are
used
as
the
endpoint
for
this
risk
assessment.

When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
procymidone
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

No
additional
toxicological
data
are
required
at
this
time.

Exposure
Characterization/
Assessment
Residue
Profile
A
5
ppm
tolerance
on
wine
grapes
has
been
established
for
the
residues
of
procymidone
(
40
CFR180.455).

Adequate
grape
metabolism
data
has
been
submitted
for
procymidone.
Two
metabolism
studies
were
reviewed;
the
first
for
phenyl­
labeled
procymidone
and
the
second
for
carbonyl­
labeled
procymidone.
Both
studies
reported
that
procymidone
accounted
for
>
90%
of
the
total
radioactive
residues
(
TRR).
The
3,5­
DCA
metabolite
was
not
detected
in
grapes,
but
it
occurred
during
fermentation.
The
maximum
proportion
of
3,5­
DCA
was
20%
TRR
of
parent
levels.
Based
on
this
evidence,
the
Metabolism
Committee
determined
that
the
residue
of
concern
is
the
parent
only
for
tolerance
purposes,
however,
the
metabolite
3,5­
dichloroaniline
should
also
be
included
in
the
dietary
exposure
assessment.

Acute
and
cancer
dietary
assessments
were
performed
for
procymidone
only,
and
a
cancer
assessment
was
performed
for
3,5­
DCA
as
a
result
of
procymidone,
iprodione,
and
vinclozolin
uses.

Dietary
Exposure
Both
acute
and
cancer
dietary
risk
assessments
were
conducted
for
procymidone
using
the
Page
11
of
32
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
)
,
Version
2.0,
which
uses
food
consumption
data
from
the
United
States
Department
of
Agriculture's
(
USDA's)
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
HED
is
concerned
when
dietary
risk
dietary
risk
exceeds
100%
of
the
PAD
for
acute
exposures,
and
1
X
10­
6
for
cancer
exposures.
Both
analyses
were
performed
to
support
the
reregistration
eligibility
decision
for
procymidone.

A
chronic
dietary
assessment
was
not
performed
since
the
same
NOAEL
and
endpoint
(
developmental
effect,
NOAEL
=
3.5
mg/
kg/
day)
were
chosen
for
both
the
chronic
and
acute
assessments,
and
the
acute
dietary
exposure
will
always
exceed
the
chronic
dietary
exposure.
No
risk
concerns
were
identified
in
the
acute
assessment,
therefore
the
chronic
dietary
risk
is
also
of
no
concern.

Acute
Dietary
Exposure
Results
and
Characterization
A
Tier
I
acute
dietary
exposure
assessment
was
performed
for
procymidone
using
tolerance
level
residues
and
100%
crop
treated.
For
the
acute
analysis,
the
applicable
population
subgroup
was
females
13­
49
years
old
(
Table
3).
At
the
95th
Percentile,
the
acute
exposure
was
0.000607
mg/
kg/
day,
which
utilized
1.7%
of
the
aPAD.
The
acute
exposure
to
procymidone
does
not
exceed
the
Agency's
level
of
concern.

Table
3.
Acute
and
Cancer
Dietary
Exposure
and
Risk
Estimates
for
Procymidone
Using
DEEM­
FCID
Acute
Dietary
Estimate
Population
Subgroup
PAD,
mg/
kg/
day
Exposure,
mg/
kg/
day
%
PAD
Females
13­
49
yrs
0.035
0.000607
1.7
Cancer
Dietary
Estimate
Population
Subgroup
Q1*,
(
mg/
kg/
day)­
1
Exposure,
mg/
kg/
day
Lifetime
risk
U.
S.
Population
0.0235
0.000077
1.81
x
10­
6
Cancer
Dietary
Exposure
Results
and
Characterization
Like
the
acute
dietary
exposure
assessment,
a
Tier
I
cancer
dietary
exposure
assessment
was
performed
for
procymidone
employing
tolerance
level
residues
and
100%
crop
treated
values
(
Table
3).

For
the
U.
S.
Population
subgroup,
the
cancer
risk
was
calculated
to
be
1.8
x
10­
6
(
based
on
a
Q
1*
value
of
0.0235
(
mg/
kg/
day)­
1)
with
an
exposure
value
of
0.000077
mg/
kg/
day.
The
cancer
risk
for
procymidone
slightly
exceeds
the
1.0
x
10­
6
benchmark
value.
However,
it
is
not
of
concern
Page
12
of
32
since
conservative
exposure
assumptions
were
used
in
the
assessment
and
actual
risks
are
expected
to
be
significantly
lower.

Contributions
to
Dietary
Risk
from
3,5­
Dichloroaniline
(
3,5­
DCA)

3,5­
Dichloroaniline
is
a
common
metabolite
to
iprodione,
vinclozolin,
and
procymidone.
The
aggregate
carcinogenic
risk
estimate
for
consumption
of
food
and
wine
containing
residues
of
3,5­
DCA
as
a
result
of
use
of
iprodione,
vinclozolin,
and
procymidone
is
1.3
x
10­
6.
Metabolism
studies
for
iprodione
and
vinclozolin
were
used
to
estimate
the
amount
of
3,5­
DCA
present
in
various
commodities
by
using
total
radioactive
residues
to
convert
iprodione
or
vinclozolin
exposures
to
3,5­
DCA
exposures.

Additionally,
a
surrogate
Q
1*
is
being
used
for
the
3,5­
DCA
carcinogenic
risk
estimate.
Since
3,5­
DCA
is
not
a
registered
pesticide,
there
are
no
toxicology
data
for
this
compound.
In
the
past,
HED
has
used
the
Q
1
*
for
p­
chloroaniline
(
PCA)
to
assess
the
carcinogenic
risk
for
other
structurally
related
chloroanilines.
The
HED
policy
on
chloroanilines
specifies
that
chloroaniline
metabolites
should
be
considered
to
be
toxicologically
equivalent
to
PCA
unless
there
is
sufficient
evidence
that
the
metabolite
is
not
carcinogenic.
A
Q
1
*
of
6.38
X
10­
2
(
mg/
kg/
day)­
1
in
human
equivalents
has
been
calculated
for
p­
chloroaniline.
This
Q
1*
is
based
on
the
spleen
sarcoma
rate
in
male
rats
from
an
NTP
bioasssay,
linearized
low
dose
multistage
model,
and
the
3/
4
interspecies
scaling
factor.
Due
to
the
structural
similarities
of
3,5­
DCA
and
PCA,
HED
believes
that
for
3,5­
DCA,
the
use
of
the
PCA
Q
1*
represents
a
reasonable
risk
estimate.
These
are
the
best
risk
estimates
that
can
be
supplied
by
HED.

Cumulative
Risk
Characterization/
Assessment
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
formally
made
a
common
mechanism
of
toxicity
finding
as
to
procymidone
and
any
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
procymidone
has
a
common
mechanism
of
toxicity
with
other
substances.
However,
it
is
noted
that
procymidone
is
structurally
related
to
vinclozolin
and
iprodione,
and
the
metabolite
3,5­
dichloroaniline
is
produced
by
each
of
these
chemicals.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

Occupational
and
Residential
Exposure
Page
13
of
32
There
are
no
occupational
or
residential
exposure
risks
associated
with
procymidone
in
the
United
States.

Data
Needs
and
Label
Requirements
Currently,
there
are
no
data
gaps
for
the
chemical
procymidone.

References
Abbotts,
John.
DP
Barcode
D236691.
July
1,
1997.
3,5­
Dichloroaniline
Residues:
Iprodione,
Procymidone,
and
Vinclozolin.

Author
unknown.
February
14,
1994.
Risk
Assessment
for
"
Chloroanilines",
and
Other
Carcinogenic
Metabolites.

Brunsman,
Lori
L.
TXR
No.
0053372.
May
17,
2005.
Procymidone:
Revised
Quantitative
Risk
Assessment
(
Q
1
*)
Based
On
B6C3F1
Mouse
Dietary
Study
With
3/
4'
s
Interspecies
Scaling
Factor.

Fisher,
Bernice.
TXR
No.
014156.
November
20,
1990.
Procymidone:
TB100
Sumisclex
­
Quantitative
Risk
Assessment,
B6C3F1
Mouse
&
Osbourne­
Mendel
Rat
Study.

Fisher,
Bernice.
November
28,
1994.
P­
Chloroaniline
(
Dimilin
metabolite)
Quantitative
Risk,
Q
1*
(
Updated)
from
NTP
Rat
Oncogenicity
Study.

Ghali,
George
Z..
November
18,
1993.
Procymidone:
RfD/
Peer
Review
Report.

Hazel,
William
J.
DP
Barcode
D265863.
May
12,
2000.
Vinclozolin:
Revised
Human
Health
Risk
Assessment
Sheltema,
Christina.
DP
Barcode
D233218.
July
31,
1998.
The
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED)
for
Iprodione.

Willett,
Stephanie
H.
DP
Barcode
D170254.
MRID
Nos.
42042000,
42042001,
42042002.
April
7,
1992.
Procymidone
on
Imported
Wine
Grapes.
CBTS
Review
of
Grape
Metabolism
Studies.

List
of
Attachments
Page
14
of
32
Attachment
1:
Toxicology
Profile.
Attachment
2:
DEEM­
FCID
 
Acute
Food
Input
File.
Attachment
3:
DEEM­
FCID
 
Acute
Food
Results
File.
Attachment
4:
DEEM­
FCID
 
Chronic­
Cancer
Food
Input
File.
Attachment
5:
DEEM­
FCID
 
Chronic­
Cancer
Food
Results
File.
Attachment
6:
Procymidone:
RfD/
Peer
Review
Report.
Attachment
7:
Procymidone:
Revised
Quantitative
Risk
Assessment
(
Q
1*).

RDI:
WPhang
6/
13/
05
7509C:
TJimerson:
RRB1:
CM2:
Rm
722H:
703­
308­
0070:
6/
13/
05
Attachment
1:
Toxicology
Profile.
Page
15
of
32
Study
type
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)
Endpoints
Combined
Chronic
Toxicity/
Carcinogenicity
RATS
(
870.4300)
MRID
41477708
0,
100,
300,
1000,
and
2000
ppm
(
0,
4.6,
14.0,
47.6,
and
96.9
mg/
kg/
day
for
males
and
0,
6,
17.9,
61,
and
121.6
mg/
kg/
day
for
females)
4.6
14

body
weight,

incidences
of
testicular
interstitial
cell
tumor,
hyperplasia
and
pituitary
adenomas
Chronic
Toxicity
Study
­
DOGS
(
870.4100)
MRID
42575001
0,
20,
100,
and
500
mg/
kg/
day
500
Not
identified
Multi­
generation
Reproductive
Toxicity
­
RATS
(
870.3800)
MRID
41477708
0,
50,
250,
and
750
ppm
(
0,
2.5,
12.5,
and
37.5
mg/
kg/
day)
Parental:
2.5
Reproductive:
12.5
Offspring:
12.5
Parental:
12.5
Reproductive:
37.5
Offspring:
37.5
Parental:

abs.
And
rel.
liver
&
testes
weights
Reproductive:


incidence
hypospadia,

anogenital
distance,

male
fertility
Offspring:

pup
weight
at
birth
Developmental
Toxicity
­
RATS
(
870.3700)
MRID
41477706
0,
30,
100,
or
300
mg/
kg/
day
Maternal:
300
Developmental:
300
Not
identified
Special
Study:
Developmental
Toxicity
Study
with
post­
natal
evaluation
MRID
42383401,
42383402,
42482002
0,
3.5,
12.5,
125,
and
500
mg/
kg/
day
Acceptable/
non­
guideline
Maternal:
12.5
Developmental:
3.5
Offspring:
12.5
Maternal:
125
Developmental:
12.5
Offspring:
125
Maternal:

body
weight
and
food
consumption
during
lactation
Developmental:

anogenictal
distance
in

Offspring:

incidence
of
hypospadia,
undescended
testes,
distended
preputial
glands,
and

anogencital
distance,
absolute
and
relative
testes
weights,
body
weights,
and
brain
Study
type
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)
Endpoints
Page
16
of
32
weights
Developmental
Toxicity
­
RABBITS
(
870.3700)
MRID
41477707
0,
30,
150,
750,
and
1000
mg/
kg/
day
0,
30,
100,
300,
and
1000
ppm
(
0,
4.3,
14.3,
42.9,
and
142.9
mg/
kg/
day)
Maternal:
1000
Developmental:
1000
Not
identified
Carcinogenicity
Study
­
MICE
(
870.4200)
MRID
41477705
0,
30,
100,
300,
and
1000
ppm
(
0,
4.3,
14.3,
42.9,
and
142.9
mg/
kg/
day)
14.3
42.9

incidences
of
liver
cytomegaly,
multifocal
fatty
changes,
hepatocellula
r
adenomas,
and
hepatoblastomas
Subchronic
Oral
Toxicity
Study
­
RATS
(
6
months)
(
870.3100)
MRID
41484905
0,
150,
500,
and
1500
ppm
(
0,
7.5,
25,
and
75
mg/
kg/
day)
Unacceptable/
non­
guideline
7.5
25

body
weight,

relative
spleen,
adrenal,
and
liver
weights
Subchronic
Oral
Toxicity
Study
­
DOGS
(
870.3150)
MRID
41484904
0,
20,
100,
and
500
mg/
kg/
day
Acceptable/
guideline
100
500

incidence
emesis
and
diarrhea,

alkaline
phosphatase
&
blood
urea
nitrogen
Subchronic
Oral
Toxicity
Study
­
MICE
(
870.3100)
MRID
41484902
0,
100,
500,
2500,
and
10000
ppm
(
0,
14.3,
71.4,
357.1,
and
1428.6
mg/
kg/
day)
Acceptable/
non­
guideline
14.3
71.4

levels
of
BUN
and
creatinine
and

incidence
of
coagulative
liver
necrosis,
hepatocyte
nuclear
enlargement,
hepatocyte
cytoplasmic
swelling,
and
multinucleated
hepatocytes
Special
Study:
In
vitro
Binding
to
Androgen
Receptor
MRID
41477704
This
study
suggests
that
procymidone
may
interact
with
the
androgen
receptor
in
a
manner
similar
to
flutamide
­
a
non­
Study
type
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)
Endpoints
Page
17
of
32
Unacceptable/
non­
guideline
steroidal
androgen.

Special
Subchronic
Oral
Toxicity
Study
­
RATS
MRID
41477704
100
­
6000
ppm
(
5­
300
mg/
kg/
day)
Unacceptable/
non­
guideline
Inconsistent

testosterone
and
leutenizing
hormone,

body
weights
Special
Subchronic
Oral
Toxicity
Study
­
RATS
&
MICE
MRID
41477704
Rats:
0,700,
2000,
and
6000
ppm
(
0,
62,
174,
and
519
mg/
kg/
day)
Mice:
0,
1000,
5000,
and
10000
ppm
(
0,
150,
743,
and
6154
mg/
kg/
day)
Unacceptable/
non­
guideline
Rats:
62
Mice:
not
identified
Rats:
174
Mice:
not
identified
Rats:
Transient,
nondose
related
changes
in
testicular
testosterone,
serum
testosterone,
serum
leutenizing
hormone
(
LH),
pituitary
LH
levels.

body
weight
at

174
mg/
kg/
day,
transient

testicular
weights
at
62
and
174
mg/
kg/
day
but
persistent
at
519
mg/
kg/
day,
transient

seminal
vesicles
weight
at

174
mg/
kg/
day.
In
vitro
testosterone
production

after
stimulation
with
human
chorionic
gonadrotopin
hormone
(
hCG)
at

174
mg/
kg/
day
Mice:
Transient,
non­
dose
related
changes
in
testicular
testosterone,
serum
testosterone,
serum
leutenizing
hormone
(
LH),
pituitary
LH
levels
Mteabolism
&
Pharmacokinetic
Study
­
RATS
&
MICE
MRID
41477710
Procymidone
appears
to
be
readily
absorbed
from
the
gastrointestinal
tract
and
is
extensively
metabolized
by
both
rats
and
mice.
The
two
major
metabolites
are
procymidone­
Study
type
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)
Endpoints
Page
18
of
32
100
mg/
kg
NH'­(
COOH)
2
and
procymidone­
COOH.
Procymidone­
NH'­(
COOH)
2
accounts
for
46.5
and
37.4%
of
the
administered
dose
in
rats
and
mice,
respectively;
while
procymidone­
COOH
accounts
for
21.5
and
19.5%
of
the
dose
administered
to
rats
and
mice,
respectively
Based
on
the
tissue
accumulation
profile,
procymidone
and/
or
its
metabolites
appear
to
be
lipid
soluble.
Of
all
the
tissues
examined,
fat
appears
to
accumulate
the
highest
concentration
of
procymidone
(
4.95
and
2.08
µ
g
procymidone
equivalent/
g
wet
tissue
for
rats
and
mice
,
respectively)
72
hours
after
treatment
with
the
test
article.
Accumulation
of
radioactivity
was
also
reported
in
mesenteric
lymph
nodes,
seminal
vesicles,
adrenal
glands,
liver,
prostate,
kidneys,
and
skin.
In
rats,
24
hours
after
administration,

59%
of
the
radiolabel
was
recovered
in
the
excreta
(
urine
and
feces).
Urinary
excretion
comprised

54%
of
the
dose
while
fecal
output
totaled

5%.
Within
48
hours,
93%
of
the
administered
dose
was
excreted
(
81%
in
urine
and
12%
in
feces).
Seventy­
two
hours
after
administration
>
95%
of
the
administered
radiolabel
was
excreted
(
83%
urine,
13%
feces).
The
pattern
of
radiolabel
excretion
in
mice
appears
to
be
faster
than
in
rats
with
92%
of
the
administered
dose
being
excreted
(
74%
in
urine
and
18%
in
feces)
24
hours
after
treatment
with
the
test
compound;
by
the
48
hour
evaluation,
all
of
the
administered
radiolabel
appeared
to
have
been
excreted.
Page
19
of
32
Attachment
2:
DEEM­
FCID
 
Acute
Food
Input
File.

U.
S.
Environmental
Protection
Agency
Ver.
2.02
DEEM­
FCID
Acute
analysis
for
PROCYMIDONE
Residue
file
name:
C:\$
MyFiles\
Procymidone.
R98
Analysis
Date
06­
13­
2005
Residue
file
dated:
06­
13­
2005/
09:
10:
55/
8
Reference
dose
(
aRfD)
=
0.035
mg/
kg
bw/
day
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
EPA
Crop
Def
Res
Adj.
Factors
Code
Grp
Food
Name
(
ppm)
#
1
#
2
­­­­­­­­
­­­­
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
­­­­­­­­­­
­­­­­­
­­­­­­
95001790
O
Grape,
wine
and
sherry
5.000000
1.000
1.000
Page
20
of
32
Attachment
3:
DEEM­
FCID
 
Acute
Food
Results
File.

U.
S.
Environmental
Protection
Agency
Ver.
2.02
DEEM­
FCID
ACUTE
Analysis
for
PROCYMIDONE
(
1994­
98
data)
Residue
file:
Procymidone.
R98
Adjustment
factor
#
2
NOT
used.
Analysis
Date:
06­
13­
2005/
09:
13:
24
Residue
file
dated:
06­
13­
2005/
09:
10:
55/
8
Daily
totals
for
food
and
foodform
consumption
used.
Run
Comment:
""
===============================================================================

Summary
calculations
(
per
capita):

95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
%
aRfD
Exposure
%
aRfD
Exposure
%
aRfD
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
Females
13­
49
yrs:
0.000607
1.73
0.027816
79.48
0.055496
158.56
Page
21
of
32
Attachment
4:
DEEM­
FCID
 
Chronic­
Cancer
Food
Input
File.

U.
S.
Environmental
Protection
Agency
Ver.
2.00
DEEM­
FCID
Chronic
analysis
for
PROCYMIDONE
1994­
98
data
Residue
file:
C:\
DEEMFCID\
procymidone.
R98
Adjust.
#
2
NOT
used
Analysis
Date
04­
25­
2005
Residue
file
dated:
04­
18­
2005/
10:
48:
26/
8
Q1*
=
0.0235
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Food
Crop
Residue
Adj.
Factors
Comment
EPA
Code
Grp
Food
Name
(
ppm)
#
1
#
2
­­­­­­­­
­­­­
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
­­­­­­­­­­
­­­­­­
­­­­­­
­­­­­­­
95001790
O
Grape,
wine
and
sherry
5.000000
1.000
1.000
Page
22
of
32
Attachment
5:
DEEM­
FCID
 
Chronic­
Cancer
Food
Results
File.

U.
S.
Environmental
Protection
Agency
Ver.
2.00
DEEM­
FCID
Chronic
analysis
for
PROCYMIDONE
(
1994­
98
data)
Residue
file
name:
C:\
DEEMFCID\
procymidone.
R98
Adjustment
factor
#
2
used.
Analysis
Date
04­
11­
2005/
07:
43:
48
Residue
file
dated:
04­
08­
2005/
10:
23:
50/
8
Q1*
=
0.0235
COMMENT
1:
Q1*
for
wine
grapes
using
import
factor
of
0.12
===============================================================================
Total
exposure
by
population
subgroup
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­

Total
Exposure
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
Population
mg/
kg
Lifetime
risk
Subgroup
body
wt/
day
(
Q1*=
.0235)
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
­­­­­­­­­­­­­
­­­­­­­­­­­­­
U.
S.
Population
(
total)
0.000077
1.81E­
06
Page
23
of
32
Attachment
6:
Procymidone:
RfD/
Peer
Review
Report.

TXR
No.
0014158
Dated:
11/
18/
93
MEMORANDUM
SUBJECT:
Procymidone:
RfD/
Peer
Review
Report
CASRN:
32809­
16­
8
EPA
Chem.
Code:
129044
Caswell
No.
704J
FROM:
George
Z.
Ghali,
PhD
Manager,
RfD/
Quality
Assurance
Peer
Review
Committee
Health
Effects
Division
(
H7509C)

TO:
Susan
Lewis,
PM
21
Insecticide­
Rodenticide
Branch
Registration
Division
(
H7505C)

The
Health
Effects
Division
RfD/
Peer
Review
Committee
met
on
August
12,
1993
to
discuss
and
evaluate
the
toxicology
data
submitted
in
support
of
Procymidone
registration
and
to
assess
the
Reference
Dose
for
this
chemical.

The
RfD/
Peer
Review
Committee
recommended
that
an
RfD
be
established
based
upon
a
NOAEL
of
3.5
mg/
kg/
day
for
developmental
toxicity
effects
observed
at
12.5
mg/
kg/
day
in
a
developmental
toxicity
study
in
rats.
The
Committee
considered
the
chronic
toxicity
study
in
rats
with
a
NOAEL
of
4.8
mg/
kg/
day
and
the
two­
generation
reproduction
study
in
rats
with
a
NOAEL
of
5.0
mg/
kg/
day
to
be
supportive
studies.
An
uncertainty
factor
(
UF)
of
100
was
recommended
to
account
for
the
inter­
species
extrapolation
and
intra­
species
variability.
On
this
basis
the
RfD
was
calculated
to
be
0.035
mg/
kg/
day.
It
should
be
noted
that
a
regulatory
value
of
0.1
mg/
kg/
day
was
established
for
this
chemical
by
the
World
Health
Organization
(
WHO)
in
1989.

Since
the
carcinogenicity
and
developmental
toxicity
issues
for
this
chemical
have
already
been
addressed
by
other
HED­
Committees,
these
issues
were
not,
Page
24
of
32
therefore,
examined
any
further
by
the
RfD/
Peer
Review
Committee.
However,
the
Committee
indicated
that,
because
of
the
relatively
low
NOAEL
for
developmental
toxicity
(
3.5
mg/
kg/
day)
demonstrated
in
the
rat
study,
an
acute
dietary
risk
assessment
will
be
necessary.

The
Committee
considered
the
chronic
toxicity
phase
of
the
rat
chronic
toxicity/
carcinogenicity
study
(
83­
1a)
and
the
chronic
toxicity
study
in
dogs
(
83­
1b)
to
be
acceptable
and
the
data
evaluation
records
to
be
adequate.

A.
Individual
in
Attendance
1.
Peer
Review
Committee
Members
and
Associates
(
Signature
indicates
concurrence
with
the
peer
review
unless
otherwise
stated).

William
Burnam*
_________________________

Reto
Engler
_________________________

Marcia
Van
Gemert*
_________________________

Karl
Baetcke
_________________________

Henry
Spencer*
_________________________

William
Sette*
_________________________

Esther
Rinde*
_________________________

Roger
Gardner*
_________________________

James
Rowe
_________________________

John
Tice
_________________________

George
Ghali
_________________________

Rick
Whiting
_________________________

Wang
Phang
_________________________

2.
Scientific
Reviewer(
s)
(
Committee
or
non­
committee
members
responsible
for
data
presentation;
signatures
indicate
technical
accuracy
of
panel
report).
Page
25
of
32
Clark
Swentzel
__________________________

3.
Others:

Myron
Ottley
and
Stephanie
Willett
of
the
Health
Effects
Division
as
observers
CC:
Penny
Fenner­
Crisp
Richard
Schmitt
Kerry
Dearfield
Marcia
Van
Gemert
Clark
Swentzel
Rick
Whiting/
RfD
Fiels
James
Kariya
*
Permanent
or
rotational
members
unable
to
attend.

B.
Material
Reviewed
Material
available
for
review
included
a
chronic
toxicity/
carcinogenicity
study
in
rats
(
83­
5
or
83­
1a
and
­
2a),
a
long­
term
toxicity
study
in
dogs
(
83­
1b),
a
carcinogenicity
study
in
mice
(
83­
2b),
developmental
toxicity
studies
in
rats
and
rabbits
(
83­
3a
and
­
3b),
a
reproductive
toxicity
study
in
rats
(
83­
4)
and
the
tox
one­
liner.

Since
the
carcinogenicity
and
developmental
toxicity
issues
for
this
chemical
have
already
been
addressed
by
other
HED­
Committees,
these
issues
were
not,
therefore,
examined
any
further
by
the
RfD/
Peer
Review
Committee.
However,
the
Committee
indicated
that,
because
of
the
relatively
low
NOAEL
for
developmental
toxicity
(
3.5
mg/
kg/
day)
demonstrated
in
the
rat
study,
an
acute
dietary
risk
assessment
will
be
necessary.

The
Committee
considered
the
chronic
toxicity
phase
of
the
rat
chronic
toxicity/
carcinogenicity
study
(
83­
1a)
and
the
chronic
toxicity
study
in
dogs
(
83­
1b)
to
be
acceptable
and
the
data
evaluation
records
to
be
adequate.
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
Attachment
7:
Procymidone:
Revised
Quantitative
Risk
Assessment
(
1*).

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No.
0053372
MEMORANDUM
DATE:
May
17,
2005
SUBJECT:
Procymidone:
REVISED
Quantitative
Risk
Assessment
(
Q
1
*)
Based
On
B6C3F1
Mouse
Dietary
Study
With
3/
4'
s
Interspecies
Scaling
Factor
P.
C.
Code:
129044
TO:
Elizabeth
Mendez,
Biologist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

FROM:
Lori
L.
Brunsman,
Statistician
Science
Information
Management
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Jess
Rowland,
Branch
Chief
Science
Information
Management
Branch
Health
Effects
Division
(
7509C)

Summary
The
revised
unit
risk,
Q
1
*
(
mg/
kg/
day)­
1,
of
Procymidone
based
upon
female
mouse
liver
combined
adenoma
and/
or
carcinoma
tumor
rates
is
1.339
x
10­
2
in
human
equivalents.
The
dose
levels
used
from
the
105­
week
dietary
study
were
0,
30,
100,
300
and
1000
ppm
of
Procymidone.
The
corresponding
censored
tumor
rates
for
the
female
mouse
liver
combined
tumors
were
2/
57,
2/
56,
2/
56,
6/
60
and
9/
60,
respectively.

Background
1See
memo
­
Deriving
Q
1
*
s
Using
the
Unified
Interspecies
Scaling
Factor,
P.
A.
Fenner­
Crisp,
Director,
HED,
7/
1/
94.

Page
27
of
32
On
October
10,
1990,
the
Carcinogenicity
Peer
Review
Committee
classified
Procymidone
as
a
Group
B2
carcinogen
(
probable
human
carcinogen)
and
recommended
that
a
low
dose
extrapolation
model
be
applied
to
the
experimental
animal
tumor
data
and
that
quantifications
of
risk
be
estimated
for
female
mouse
liver
and
male
rat
testes
interstitial
cell
tumors.
The
most
potent
unit
risk
will
be
used
for
the
purpose
of
lifetime
cancer
risk
assessment
by
the
Agency.
In
this
case,
the
most
potent
unit
risk,
Q
1
*,
is
that
for
female
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates.
A
Q
1
*
of
2.4
x
10­
2
(
mg/
kg/
day)­
1
based
upon
female
mouse
liver
(
carcinoma
and/
or
adenoma)
tumor
rates
was
generated
using
the
mg/
kg
b.
w.^
2/
3'
s/
day
cross
species
scaling
factor
(
Procymidone
(
TB100
Sumisclex)
­
Quantitative
Risk
Assessment,
B6C3F1
Mouse
&
Osbourne­
Mendel
Rat
Study,
B.
Fisher,
11/
20/
1990).
This
current
memo
has
been
generated
to
reflect
the
Agency
policy
change
from
use
of
the
2/
3'
s
to
the
3/
4'
s
scaling
factor
in
19941.

For
the
conversion
to
human
equivalents,
weights
of
0.35
kg
for
the
rat,
0.03
kg
for
the
mouse,
70
kg
for
humans,
molecular
weight
of
284.14,
and
life­
span
defaults
of
105
weeks
for
the
female
mice
and
106
weeks
for
the
male
rats
were
used.
The
unit
risks,
Q
1
*,
for
female
mice
and
male
rats
were
obtained
by
the
application
of
the
Multi­
Stage
quantal
model,
which
uses
censored
tumor
rates.
All
unit
risks
have
been
converted
from
animals
to
humans
by
use
of
the
3/
4'
s
scaling
factor
(
Tox_
Risk
program,
Version
5.31,
K.
Crump,
2001).

It
is
to
be
noted
that
the
Q
1
*
(
mg/
kg/
day)­
1
is
an
estimate
of
the
upper
bound
on
risk
and
that,
as
stated
in
the
EPA
Risk
Assessment
Guidelines,
"
the
true
value
of
the
risk
is
unknown,
and
may
be
as
low
as
zero."

Mouse
Dose­
Response
Analysis
A
2­
year
dietary
study
in
B6C3F1
mice
was
conducted
by
Hazleton
Laboratories
America,
Vienna,
Virginia,
for
Sumitomo
Chemical
Company,
Osaka,
Japan,
and
issued
June
3,
1990
(
Study
Nos.
BT­
81­
0126
and
BT­
81­
0127;
HLA
No.
22254;
MRID
No.
41477705).

The
statistical
evaluation
of
mortality
indicated
no
statistically
significant
incremental
changes
in
mortality
with
increasing
doses
of
Procymidone
in
female
mice
(
Procymidone
­
Qualitative
Risk
Assessment,
B6C3F1
Mouse
Study,
B.
Fisher,
8/
28/
1990).

Female
mice
had
a
significant
increasing
trend
at
p
<
0.01,
and
a
significant
difference
in
the
pair­
wise
comparison
of
the
1000
ppm
dose
group
with
the
controls
at
p
<
0.05,
for
liver
adenomas
and/
or
carcinomas
combined.

Additional
Q
1
*
Calculations
Page
28
of
32
The
revised
unit
risk,
Q
1
*
(
mg/
kg/
day)­
1,
of
Procymidone
based
upon
male
rat
testes
interstitial
cell
tumor
rates
is
1.294
x
10­
2
in
human
equivalents.
The
dose
levels
used
from
the
106­
week
dietary
study
were
0,
100,
300,
1000
and
2000
ppm
of
Procymidone.
The
censored
tumor
rates
were
1/
76,
1/
72,
2/
76,
10/
75
and
24/
75,
respectively.

Rat
Dose­
Response
Analysis
A
2­
year
dietary
study
in
Osborne­
Mendel
rats
was
conducted
by
Litton
Bionetics,
Inc.,
Rockville,
Maryland,
for
Sumitomo
Chemical
Company,
Osaka,
Japan,
and
dated
July
1,
1985
(
LBI
Project
No.
22048­
03/
13;
MRID
No.
41477703).

The
statistical
evaluation
of
mortality
indicated
no
statistically
significant
incremental
changes
in
mortality
with
increasing
doses
of
Procymidone
in
male
rats
(
Procymidone
(
TB100
Sumisclex)
Qualitative
Risk
Assessment,
Osborne­
Mendel
Rat
Study,
B.
Fisher,
10/
4/
1990).

Male
rats
had
a
significant
increasing
trend,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
1000
and
2000
ppm
dose
groups
with
the
controls,
for
testes
interstitial
cell
tumors,
all
at
p
<
0.01.
Page
29
of
32
Generating
Model
Fit
Table
­­­
TITLE:
Procymidone
Female
Mouse
Liver
Adenomas
and/
or
Carcinomas
Combined
Model:
Multistage
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonefmlivcom.
txd
Functional
form:
1
­
EXP(
­
Q0
­
Q1
*
D
­
Q2
*
D^
2
...
­
Qk
*
D^
k
)
Chi­
square:
0.82
P­
value:
0.84
Maximum
Log­
Likelihood
=
­
7.118324e+
001
Parameter
Estimates
:
k
=
4
Q
0
=
3.461222E­
002
Q
1
=
1.427955E­
004
Q
2
=
0.000000E+
000
Q
3
=
0.000000E+
000
Q
4
=
0.000000E+
000
Experimental
Expected
90.0%
Doses
#
responses/
number
of
Binomial
Limits
(
ppm)
#
subjects
responders
Lower
Upper
0
2
/
57
1.94
0.356
6.078
30
2
/
56
2.14
0.372
6.070
100
2
/
56
2.67
0.372
6.070
300
6
/
60
4.47
2.553
11.262
1000
9
/
60
9.75
4.793
14.828
Generating
Statistics
Table
­­­
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonefmlivcom.
txd
TITLE:
Procymidone
Female
Mouse
Liver
Adenomas
and/
or
Carcinomas
Combined
Trend
Test
Results
Mantel­
Haenszel
(
Z):
2.93
P­
value:
0.0017
Pearson's
r:
0.172
Comparisons
against
control
using
Fisher's
Exact
Test
Dose
(
ppm)
#
responses/#
subjects
P­
value
0
2
/
57
control
30
2
/
56
0.68
100
2
/
56
0.68
300
6
/
60
0.15
1000
9
/
60
0.03
Generating
Protocol
and
q1*
Table
­­­
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonefmlivcom.
txd
TITLE:
Procymidone
Female
Mouse
Liver
Adenomas
and/
or
Carcinomas
Combined
Doses
#
responses/
(
ppm)
#
subjects
0
2/
57
30
2/
56
100
2/
56
300
6/
60
1000
9/
60
Body
Weight
0.03
kg
70
kg
LifeSpan
105
weeks
70
years
Breathing
Rate
0.0347
l/
min
0.833
m^
3/
hr
Food
Consumption
3.9
g/
day
1400
g/
day
Drinking
Rate
6
ml/
day
2
l/
day
Route
FOOD
(
ppm)
N/
A
Dosing:
Hrs/
Day
24
N/
A
Days/
Week
7
N/
A
Weeks
105
N/
A
Weeks
of
Study
105
N/
A
Averaging
Factor
1
1
Model:
Multistage
Risk
Type:
Extra
Risk
Molecular
Wt.:
284.140
Confidence
limit:
95.000%
Adjustment
for
Experiment
Length:
1.000
(
EPA
METHOD)
Animal
to
human
conversion
method:
MG/
KG
BODY
WEIGHT(
3/
4)/
DAY
Unit
Potency
[
per
mg/
kg/
day
]
(
computed
for
Risk
of
1.0E­
6)
Page
30
of
32
Lower
Bound
=
Not
Reqstd
MLE
=
7.6342E­
003
Upper
Bound
=
1.3393E­
002
Page
31
of
32
Generating
Model
Fit
Table
­­­
TITLE:
Procymidone
Male
Rat
Interstitial
Cell
Tumors
Model:
Multistage
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonemrtesintcelltumor.
txd
Functional
form:
1
­
EXP(
­
Q0
­
Q1
*
D
­
Q2
*
D^
2
...
­
Qk
*
D^
k
)
Chi­
square:
0.22
P­
value:
0.90
Maximum
Log­
Likelihood
=
­
9.641615e+
001
Parameter
Estimates
:
k
=
4
Q
0
=
1.106539E­
002
Q
1
=
4.453640E­
005
Q
2
=
7.390388E­
008
Q
3
=
0.000000E+
000
Q
4
=
0.000000E+
000
Experimental
Expected
90.0%
Doses
#
responses/
number
of
Binomial
Limits
(
ppm)
#
subjects
responders
Lower
Upper
0
1
/
76
0.84
0.030
4.629
100
1
/
72
1.16
0.028
4.625
300
2
/
76
2.33
0.356
6.116
1000
10
/
75
9.11
5.529
16.196
2000
24
/
75
24.51
17.408
31.462
Generating
Statistics
Table
­­­
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonemrtesintcelltumor.
txd
TITLE:
Procymidone
Male
Rat
Interstitial
Cell
Tumors
Trend
Test
Results
Mantel­
Haenszel
(
Z):
7.50
P­
value:
less
than
1E­
06
Pearson's
r:
0.388
Comparisons
against
control
using
Fisher's
Exact
Test
Dose
(
ppm)
#
responses/#
subjects
P­
value
0
1
/
76
control
100
1
/
72
0.74
300
2
/
76
0.50
1000
10
/
75
0.0042
2000
24
/
75
less
than
1E­
06
Generating
Protocol
and
q1*
Table
­­­
Dataset:
C:\
Program
Files\
TOX_
RISK\
procymidonemrtesintcelltumor.
txd
TITLE:
Procymidone
Male
Rat
Interstitial
Cell
Tumors
Doses
#
responses/
(
ppm)
#
subjects
0
1/
76
100
1/
72
300
2/
76
1000
10/
75
2000
24/
75
Body
Weight
0.35
kg
70
kg
LifeSpan
106
weeks
70
years
Breathing
Rate
0.1805
l/
min
0.833
m^
3/
hr
Food
Consumption
17.5
g/
day
1400
g/
day
Drinking
Rate
35
ml/
day
2
l/
day
Route
FOOD
(
ppm)
N/
A
Dosing:
Hrs/
Day
24
N/
A
Days/
Week
7
N/
A
Weeks
106
N/
A
Weeks
of
Study
106
N/
A
Averaging
Factor
1
1
Model:
Multistage
Risk
Type:
Extra
Risk
Molecular
Wt.:
284.140
Confidence
limit:
95.000%
Adjustment
for
Experiment
Length:
1.000
(
EPA
METHOD)
Animal
to
human
conversion
method:
MG/
KG
BODY
WEIGHT(
3/
4)/
DAY
Unit
Potency
[
per
mg/
kg/
day
]
(
computed
for
Risk
of
1.0E­
6)
Page
32
of
32
Lower
Bound
=
Not
Reqstd
MLE
=
3.3498E­
003
Upper
Bound
=
1.2936E­
002