Document ID: EPA-HQ-OPP-2005-0497-0036
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-23T04:00Z

Page
1
of
112
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
June
28,
2006
SUBJECT:
Propiconazole:
Phase
4,
HED
Chapter
of
the
Re­
registration
Eligibility
Decision
Document
(
RED).
PC
Code:
122101.
Reregistration
Case
No.
3125.
DP
Barcode
D329668.

FROM:
Yan
Donovan,
Chemist
and
Risk
Assessor
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

And
Abdallah
Khasawinah,
Toxicologist
James
Miller,
Environmental
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C))

THROUGH:
Susan
Hummel
Branch
Senior
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

TO:
Christina
Scheltema
Reregistration
Branch
I
Special
Review
&
Reregistration
Division
(
7508W)

Attached
is
Health
Effect
Division's
Phase
IV
risk
assessment
for
Propiconazole
RED.
This
is
a
revised
risk
assessment
(
from
phase
2)
incorporating
registrant's
comments
from
phase
III
public
comment
period
(
dated
Feb
15,
2006
to
April
17,
2006).
Most
of
the
registrant's
comments
have
been
addressed
and
incorporated
into
this
document.
Comments
that
are
not
addressed
in
this
document
will
be
addressed
in
a
separate
memo.

Propiconazole
is
among
the
group
of
chemicals
which
generates
a
common
metabolite
called
1,2,4­
Triazole
and
conjugates.
A
separate
document
will
be
available
to
address
this
common
Page
2
of
112
metabolite
issue.
1,2,4­
Triazole
and
its
conjugates
will
not
be
further
discussed
in
this
document.
There
are
antimicrobial
uses
for
propiconazole
as
well,
and
some
of
the
antimicrobial
uses
may
result
in
dietary
exposure,
but
will
be
covered
by
exposures
from
agricultural
uses.
This
document
only
addresses
exposures
and
risks
from
the
agricultural/
commercial/
residential
uses,
antimicrobial
uses
will
be
addressed
by
Antimicrobial
Division
(
AD).
This
document,
however,
includes
the
aggregate
risk
from
antimicrobial
use
in
mushroom
houses
(
dietary),
aggregate
risk
from
the
antimicrobial
use
in
paints
(
residential),
and
aggregate
risk
from
the
antimicrobial
use
in
treated
wood
in
play
sets
and
residential
decks
(
residential
post­
application
exposure).

Syngenta
(
previously
Novartis)
recently
submitted
new
petitions
to
the
Registration
Division
(
RD)
for
propiconazole:
PP#
5E4437,
and
PP#
2F6371(
supersedes
PP#
4F3007,
4G3075,
5F4498,
PP#
9F3740,
5F4424,
and
5F4591).
The
data
package
for
the
new
uses
and
revisions
to
the
existing
uses
are
being
reviewed
concurrently,
and
are
not
included
in
this
assessment
of
the
existing
uses
for
Reregistration
Eligibility
Decision
(
RED),
due
to
the
fact
that
RD
is
scheduled
to
complete
its
assessment
after
the
RED
signature
date,
July
2006.

The
Team
Reviewers
who
contributed
to
the
disciplinary
chapters
and
the
Human
Health
Risk
Assessment
are
listed
below.

Hazard
Identification
Assessment;
Abdallah
Khasawinah
­
Section
4
and
Appendix
1­
4
Revised
Endpoints;
Abdallah
Khasawinah
(
D324651,
12/
29/
2005)
Revised
Residue
Chemistry
Assessment;
Yan
Donovan
(
D329394,
6/
15/
2006)
Product
Chemistry
Review;
Yan
Donovan
(
D318480,
08/
18/
05)
Revised
Occupational
and
Residential
Exposure
Assessment;
James
Miller,
Environmental
Scientist
(
D329393,
6/
15/
06)
Revised
Occupational
and
Residential
Exposure
Assessment
of
the
Antimicrobial
Uses;
Tim
Leighton
(
D324052,
02/
01/
06)
Amendment
to
the
Propiconazole
RED
for
Children's
Post­
application
Exposure
from
Treated
Structures;
Tim
Leighton
(
D330159,
06/
20/
06)
Revised
Dietary
Exposure
and
Risk
Assessment;
Yan
Donovan
(
D329667,
6/
15/
06)
Incident
Report;
Jerry
Blondell
(
D319239,
07/
26/
05)
Drinking
Water
Assessment;
James
Lin
from
EFED
(
D312353,
06/
29/
05)
Revised
Drinking
Water
Assessment;
James
Lin
from
EFED
(
D323440,
06/
07/
06)
Page
3
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112
TABLE
OF
CONTENTS
1.0
Executive
Summary............................................................................................
6
2.0
Ingredient
Profile
................................................................................................
8
2.1.
Summary
of
Registered/
Proposed
Uses
................................................................................................
9
2.2
Structure
and
Nomenclature
...............................................................................................................
24
2.3
Physical
and
Chemical
Properties.......................................................................................................
25
3.0
Metabolism
Assessment
..................................................................................
25
3.1
Comparative
Metabolic
Profile...........................................................................................................
25
3.2
Nature
of
the
Residue
in
Foods...........................................................................................................
26
3.2.1.
Description
of
Primary
Crop
Metabolism
..................................................................................
26
3.2.2
Description
of
Livestock
Metabolism..........................................................................................
26
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation.
.........................................................................................
27
3.3
Environmental
Degradation................................................................................................................
27
3.4
Tabular
Summary
of
Metabolites
and
Degradates
...............................................................................
27
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
........................................................................
32
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
................................................
32
3.6.1
Tabular
Summary
.......................................................................................................................
32
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates..............................................................
32
4.0
Hazard
Characterization/
Assessment.............................................................
33
4.1
Hazard
Characterization.....................................................................................................................
33
4.2
FQPA
Hazard
Considerations
.......................................................................................................................
43
4.2.1
Adequacy
of
the
Toxicity
Data
Base............................................................................................
43
4.2.2
Evidence
of
Neurotoxicity............................................................................................................
43
4.2.3
Developmental
Toxicity
Studies
..................................................................................................
44
4.2.4
Reproductive
Toxicity
Study.......................................................................................................
46
4.2.5
Additional
Information
from
Literature
Sources
.......................................................................
47
4.2.6
Pre­
and/
or
Postnatal
Toxicity.....................................................................................................
47
4.2.6.1
Determination
of
Susceptibility..........................................................................................
48
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility....................................................................................................................
48
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
...............................................................
48
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
...................................
48
4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study.............................
49
Page
4
of
112
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection........................................................................
49
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
.............................................................................
49
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population..........................................................
49
4.4.3
Chronic
Reference
Dose
(
cRfD).........................................................................................
50
4.4.4.1
Incidental
Oral
Exposure
(
Short
Term
1­
30
days)
............................................................
50
4.4.4.2
Incidental
Oral
Exposure
(
Intermediate
Term
1­
6
months)
.........................................................
50
4.4.5
Dermal
Absorption......................................................................................................................
51
4.4.6.1
Dermal
Exposure
(
Short
Term
1­
30
days
for
females
13­
50
years
old)
........................................
51
4.4.6.2
Dermal
Exposure
(
Short
Term
1­
30
days
for
general
population
including
infants
and
children)
.............................................................................................
Error!
Bookmark
not
defined.
4.4.6.3
Dermal
Exposure
(
Intermediate
1­
6
months
and
long
term
>
6
months
......................................
51
4.4.7.1
Inhalation
Exposure
(
Short
Term
1­
30
days)
....................................................................
51
4.4.7.2
Inhalation
Exposure
(
Intermediate
1­
6
months
and
long
term
>
6
months)
.....................
51
4.4.8
Margins
of
Exposure
...................................................................................................................
52
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
....................................................
52
4.4.10
Classification
of
Carcinogenic
Potential......................................................................................
52
4.5
Special
FQPA
Safety
Factor
...............................................................................................................
56
4.6
Endocrine
Disruption
.........................................................................................................................
56
5.0
PUBLIC
HEALTH
DATA....................................................................................
57
5.1
Incident
Reports.................................................................................................................................
57
6.0
Exposure
Characterization/
Assessment
............................................................
57
6.1
Dietary
Exposure/
Risk
Pathway
.........................................................................................................
57
6.1.1
Residue
Profile.............................................................................................................................
57
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk..........................................................................
59
6.2
Water
Exposure/
Risk
Pathway
...........................................................................................................
59
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
....................................................................
61
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization.............................
64
7.1
Acute
Aggregate
Risk
........................................................................................................................
65
7.2
Short­
Term
Aggregate
Risk................................................................................................................
65
7.3
Intermediate­
Term
Aggregate
Risk.....................................................................................................
67
7.4
Long­
Term
Aggregate
Risk................................................................................................................
68
7.5
Cancer
Risk
.......................................................................................................................................
69
8.0
Cumulative
Risk
Characterization/
Assessment
.............................................
69
9.0
Occupational
Exposure/
Risk
Pathway............................................................
69
Page
5
of
112
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk......................................................................................
69
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk...........................................................................
75
10.0
Data
Needs
and
Label
Requirements..............................................................
77
10.1
Residue
Chemistry
Data
Needs
..........................................................................................................
77
10.2
ORE
Data
Needs................................................................................................................................
78
10.3
Toxicology
Data
Needs
.....................................................................................................................
79
Page
6
of
112
1.0
EXECUTIVE
SUMMARY
A
Human
Health
Risk
Assessment
is
being
conducted
for
propiconazole
[
1­[[
2­(
2,4­
dichlorophenyl)­
4­
propyl­
1,3­
dioxolan­
2­
yl]
methyl]­
1H­
1,2,4­
triazole]
to
support
the
Propiconazole
RED.
This
document
addresses
exposures
and
risks
for
the
agricultural/
commercial/
residential
/
antimicrobial
uses.
Propiconazole
is
a
systemic
broadspectrum
fungicide
registered
for
treatment
of
disease
in
a
variety
of
agricultural
crops
and
residential
settings.
The
propiconazole
formulations
registered
for
food/
feed
and
residential
uses
include
emulsifiable
concentrate
(
EC),
flowable
concentrate
(
FlC)
formulations,
WP
wettable
powder,
GL
emulsifiable
gel
and
SE
suspoemulsion
formulations.
Except
for
pineapple
(
seed
piece
treatment)
and
sugarcane
(
seed
piece
treatment),
all
other
agricultural
uses
are
pre­
harvest
foliar
application,
ground
or
air.
Pineapple
and
sugarcane
uses
are
post­
harvest
uses.
The
application
rates
for
agricultural
uses
range
from
0.081
lbs
ai/
A/
season
(
such
as
on
wheat)
to
0.90
lbs
ai/
A/
season
(
grass
grown
for
seed),
and
for
residential
uses
the
highest
rate
is
7.2
lbs
ai/
A/
year
(
turf).

Propiconazole
is
a
member
of
the
class
of
the
ergosterol
biosynthesis
inhibiting
fungicides.
The
mode
of
antifungal
action
of
propiconazole
is
attributed
to
the
inhibition
of
CYP51
(
lanosterol­
14­
a­
demethylase).
Propiconazole
has
low
to
moderate
toxicity
in
experimental
animals
by
the
oral,
dermal
and
inhalation
routes,
is
moderately
irritating
to
the
eyes,
and
minimally
irritating
to
the
skin,
and
it
is
a
dermal
sensitizer.
The
primary
target
organ
for
propiconazole
toxicity
in
animals
is
the
liver.
HED's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
concluded
that
the
toxicology
database
for
propiconazole
is
complete
for
FQPA
assessment.
Endpoints
and
dose
response
have
been
selected
for
acute,
chronic
dietary,
short
and
intermediate­
term
dermal,
inhalation,
and
incidental
oral,
and
long
term
dermal
and
inhalation
exposures.

The
HIARC
also
concluded
that
the
database
was
adequate
to
characterize
any
potential
for
prenatal
or
postnatal
risk
for
infants
and
children.
There
is
low
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
propiconazole,
and
no
residual
uncertainties
were
identified.
The
Special
FQPA
factor
is
thus
1X.
The
HIARC
had
previously
determined
that
an
acute
neurotoxicity
(
ACN)
study
was
required
based
on
neurotoxic
signs
in
pregnant
rats
administered
high
propiconazole
doses
(
360
mg/
kg/
day)
during
gestation.
HIARC
had
determined
that
for
acute
(
female
age
13­
49)
and
short­
term
exposure
scenarios,
a
3X
database
uncertainty
factor
(
UFDB)
was
adequate
to
account
for
the
lack
of
the
ACN.
In
September,
2005,
the
ACN
was
submitted
to
the
Agency
and
was
reviewed.
The
study
confirms
that
neurotoxic
signs
are
observed
at
high
doses,
but
there
was
no
neuropathology
and
there
were
no
effects
on
neurobehavioral
parameters.
Accordingly,
the
propiconazole
risk
assessment
team
determined
that
a
developmental
neurotoxicity
study
was
not
necessary
and
the
3X
database
uncertainty
factor
for
acute
and
short­
term
scenarios
was
removed.

The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
classified
propiconazole
as
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization
the
reference
Dose
(
RfD)
approach
should
be
used
and
would
be
protective.
Page
7
of
112
Tolerances
are
established
for
residues
of
propiconazole
and
its
metabolites
determined
as
2,4­
dichlorobenzoic
acid,
all
expressed
as
parent
compound
in/
on
various
plant
and
animal
commodities
[
40
CFR
§
180.434].
The
reassessed
tolerances
will
be
expressed
as
propiconazole
per
se.
As
a
result,
in
some
cases
the
tolerance
levels
will
be
over
estimated,
due
to
the
fact
that
the
analytical
method
for
data
collection
is
a
moiety
method
that
detects
all
residues
convertible
to
2,4­
dichlorobenzoic
acid
(
DCBA),
and
the
field
data
were
reported
as
propiconazole
and
all
its
metabolites
containing
2,4­
DCBA,
as
a
result,
HED
is
unable
to
separate
out
the
parent
residue
from
the
metabolites
at
this
time.
HED
recommends
that
the
registrant
analyze
parent
and
metabolites
separately
in
all
future
field
trials,
so
that
more
realistic
tolerances
can
be
set
in
the
future.
With
the
exception
of
sunflower,
the
reregistration
requirements
for
magnitude
of
the
residue
in/
on
all
the
raw
agricultural
commodities,
based
on
the
currently
registered
use
patterns,
will
be
fulfilled
pending
label
revisions
and/
or
tolerance
adjustments
on
a
few
commodities.
A
pineapple
processing
study
is
required.

Except
for
the
rice
use,
the
estimated
drinking
water
concentrations
from
surface
water
sources
were
calculated
using
Tier
II
PRZM
(
Pesticide
Root
Zone
Model)
and
EXAMS
(
Exposure
Analysis
Modeling
System).
The
Policy
for
Estimating
Aqueous
Concentrations
from
Pesticides
Labeled
for
Use
on
Rice,
dated
October
29,
2002,
was
followed
in
estimating
drinking
water
concentrations
from
rice
use.
Since
propiconazole
degrades
quickly
in
the
rice
paddy
environment
with
a
half­
life
of
5
days,
which
is
equivalent
to
a
first
order
degradation
rate
of
0.
l39/
day,
this
degradation
rate
was
used
in
simulating
the
continuing
degradation
in
the
rice
paddy
environment.
Several
of
EFED's
standard
scenarios
were
simulated
for
this
drinking
water
assessment.
The
rice
use
predicts
the
highest
peak
(
acute)
drinking
water
concentration
(
86.49
ug/
L)
among
all
scenarios
assessed.
The
turf
use
predicts
the
highest
chronic
values
(
37.5
and
26.5
ug/
L,
respectively
for
Pennsylvania
and
Florida
turf
scenarios).
The
high
values
are
the
results
of
high
application
rate
(
up
to
7.2
lb
ai/
ac
per
year).
The
estimated
drinking
water
concentrations
from
ground
water
sources
were
calculated
using
the
Tier
I
SCIGROW
(
Screening
Concentration
In
Ground
Water)
model.
The
higher
estimated
drinking
water
concentrations
are
associated
with
the
higher
use
rate.
Turf
and
ornamentals
uses
have
the
highest
concentration
of
0.72
µ
g/
L
(
ppb)
(
both
acute
and
chronic).

Acute
and
chronic
dietary
analyses
for
propiconazole
were
conducted
using
tolerance
levels
and
100
%
CT
for
all
existing
and
proposed
uses.
The
results
of
the
analyses
indicate
that
acute
and
chronic
risk
from
the
dietary
exposure
(
food
and
water)
to
propiconazole
from
the
requested
uses
did
not
exceed
HED's
level
of
concern
for
the
United
States
population
or
any
population
subgroup.

Homeowners
can
be
exposed
to
propiconazole
through
dermal
and
inhalation
while
applying
home
use
products.
All
risk
calculations
were
conducted
using
the
maximum
turf
application
rate
(
1.8
lb
ai/
acre).
None
of
the
residential
handler
exposure
scenarios
exceeded
HED's
level
of
concern.
The
residential
use
patterns
result
in
post
application
dermal
exposures
to
adults,
and
dermal
and
oral
exposures
to
infants
and
children.
These
exposures
are
considered
short
term
only.
In
addition
to
using
HED's
SOP
for
residential
assessment,
the
turf
transferable
residue
(
TTR)
was
used
in
the
calculation.
The
dermal
and
incidental
oral
exposure
to
infants
and
children
were
combined,
and
all
MOEs
do
not
exceed
the
level
of
concern.
Risk
to
children
Page
8
of
112
playing
on
propiconazole­
treated
structures
(
from
antimicrobial
use)
was
also
assessed
using
a
screening
level
assessment.
This
risk
assessment,
based
on
high
end
screening­
level
assumptions,
indicates
no
risk
of
concern.
Confirmatory
data
for
the
surface
residues
are
needed
to
verify
this
screening­
level
assessment.

Aggregate
risk
assessments
were
conducted
for
acute,
chronic,
short
and
intermediate
term
exposure
duration.
The
risks
do
not
exceed
HED's
level
of
concern.
Acute
aggregate
risk
included
food
and
water
only;
chronic
aggregate
risk
also
included
food
and
water
because
no
chronic
exposure
from
residential
uses
is
expected.
Short
term
aggregate
included
food,
water,
and
residential/
antimicrobial
exposures.
Intermediate
term
aggregate
included
food,
water,
and
residential
exposure
to
Children
1­
2
years
old
from
treated
wood
used
in
deck
and
play
structures.

The
short­
and
intermediate­
term
occupational
handler
non­
cancer
risk
assessment
for
propiconazole
indicates
that
with
use
of
chemical­
resistant
gloves,
all
scenarios
fall
below
HED's
level
of
concern
(
i.
e.,
MOEs
>
100).
The
non­
cancer
residential
handler
risk
assessment
indicates
that
for
all
residential
handler
scenarios,
risks
do
not
exceed
HED's
level
of
concern
(
i.
e.,
MOEs
>
100)
assuming
baseline
level
of
protection.

For
occupational
post­
application
exposures
and
risks,
data
from
propiconazole­
specific
studies
were
used
along
with
crop­
specific
transfer
coefficients
[
from
Science
Advisory
Council
for
Exposure
(
ExpoSAC)
Policy
3.1
 
Agricultural
Transfer
Coefficients]
were
used.
Risk
from
turf
use
was
calculated
using
the
arithmetic
mean
of
data
generated
at
the
California,
Indiana
and
Pennsylvania
test
sites.
The
non­
cancer
occupational
post­
application
worker
risk
assessment
indicates
that
for
most
agricultural
post­
application
exposure
scenarios,
risks
do
not
exceed
HED's
level
of
concern
(
i.
e.,
MOEs
>
100)
on
the
day
of
the
treatment
(
day
after
treatment
(
DAT)
=
0).
All
short­
term
occupational
risks
are
below
HED's
level
of
concern.
The
postapplication
exposure
scenario
that
exceeded
HED's
level
of
concern
is
intermediate­
term
handharvesting
(
cut
flowers),
with
an
MOE
of
97
at
Day
0.
The
MOE
reaches
100
at
DAT=
1.

2.0
INGREDIENT
PROFILE
Propiconazole
is
a
systemic
broad­
spectrum
fungicide
registered
for
treatment
of
disease
in
a
variety
of
crops.
It
is
a
member
of
the
class
of
the
ergosterol
biosynthesis
inhibiting
fungicides.
The
mode
of
antifungal
action
of
conazoles
is
attributed
to
the
inhibition
of
CYP51
(
lanosterol­
14­
a­
demethylase).
Propiconazole
end­
use
products
are
marketed
in
the
United
States
under
the
trade
names
Tilt
®
,
Alamo
®
,
Banner
®
,
Orbit
®
,
and
Quilt
TM.
The
amount
of
active
ingredients
in
the
various
formulations
range
from
11.4%
to
45%.
Recently,
propiconazole
is
also
registered
for
use
on
a
variety
of
crops
under
the
trade
names
of
Stratego
 
Twin­
Pak
 
and
Stratego
 
,
which
are
end­
use
products
containing
a
mixture
of
trifloxystrobin
and
propiconazole.
The
propiconazole
formulations
registered
for
food/
feed
uses
include
emulsifiable
concentrate
(
EC)
and
flowable
concentrate
(
FlC)
formulations.
Except
for
pineapple
and
sugarcane
(
seed
pieces),
all
uses
are
pre­
harvest
foliar
application,
ground
or
air.
Pineapple
and
sugarcane
uses
are
postharvest
uses.
The
application
rates
range
from
0.081
lbs
ai/
A/
season
(
such
as
wheat)
to
0.90
Page
9
of
112
lbs
ai/
A/
season
(
grass
grown
for
seed),
and
for
residential
uses
the
highest
rate
is
7.2
lbs
ai/
A/
year.
Occupational
application
methods
include
aerial,
groundboom,
chemigation,
airblast,
seed
piece
dip,
tree
injection,
and
handheld
equipment
(
i.
e.,
low­
pressure
handwand,
handgun
sprayer,
backpack
sprayer).
Residential
applications
are
done
using
handheld
equipment.

2.1.
Summary
of
Registered/
Proposed
Uses
Table
2.1A
summarized
the
agricultural
uses.
Table
2.1B
and
Table
2.1C
summarized
the
nonagricultural
(
residential
and
antimicrobial)
uses.
Propiconazole
can
be
mixed
with
other
fungicides.
Formulations
which
contain
both
propiconazole
and
trifloxystrobin
(
e.
g.
Stratego
 
Twin­
Pak
 
and
Stratego
 
Fungicide,
EPA
Reg.
Nos.
264­
779
)
have
been
registered
for
uses
on
corn,
peanuts,
pecans,
rice,
and
wheat.
These
uses
were
registered
based
on
reviews
of
trifloxystrobin.
Residue
data
for
trifloxystrobin
were
reviewed
in
PP#
9F5070
(
DP
Barcodes
D254213,
D254217,
D254218,
and
D254221,
4/
6/
00,
L.
Cheng).
After
comparing
the
use
rates
of
Stratego
 
Twin­
Pak
 
/
Stratego
 
on
corn,
peanuts,
pecans
and
rice
to
the
use
rates
which
current
propiconazole
tolerances
of
corn,
peanuts,
pecans
and
rice
are
based
on,
HED
concluded
that
the
Stratego
 
use
rates
on
these
crops
are
below
the
use
rates
which
tolerances
are
based
on,
except
for
wheat.
Residue
data
for
propiconazole
on
wheat
have
been
recently
reviewed
by
Y.
Donovan
(
HED
memo
of
02/
02/
05,
Y.
Donovan,
D271790).
Since
there
are
adequate
field
trial
data
to
support
Section
3
registration
of
propiconazole
uses
on
wheat
at
the
rate
of
0.08
­
0.11
lbs
ai/
A/
application,
maximum
2
applications,
and
35
day
PHI
(
HED
memo
of
02/
02/
05,
Y.
Donovan,
D271790),
HED
can
support
the
label
use
direction
changes
provided
that
the
existing
tolerances
on
wheat
RAC
are
raised.
These
new
reassessed
tolerances
will
cover
all
existing
24C
uses
on
wheat
as
well.
HED
recommends
canceling
all
24C
uses
while
revising
the
Section
3
label
to
include
these
24C
uses.
Page
10
of
112
Table
2.1A
Summary
of
Directions
for
Agricultural
Use
of
Propiconazole
Site
Application
Type
Application
Equipment
Formulati
on
1
[
EPA
Reg.

No.]
Maximum
Single
Application
Rate
(
lb
ai/
A)
Maximum
Number
of
Applications
Per
Season
Maximum
Seasonal
Rate
(
lb
ai/
A)
Preharvest
Interval
(
days)
Use
Directions
and
Limitations
2
Bananas
and
Plantains
Preharvest
foliar
Ground
41.8%
EC
[
PR40005]
0.086
8
NS
NS
Apply
before
disease
symptoms
appear
at
the
onset
of
the
rainy
season.
Apply
3
fl.
oz.

per
acre.
Apply
no
more
than
2
consecutive
applications
on
a
21­
25
day.
Apply
up
to
8
applications.
Applications
should
be
made
using
an
orchard
oil
and
an
emulsifier.

Applications
within
100
yards
of
nonbagged
bananas
or
directly
to
non­
bagged
bananas
are
prohibited.

celery
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.1125
4
0.45
14
Apply
multiple
treatments
on
a
7­
day
schedule.
May
be
tank­
mixed
with
a
spreader­
sticker.
Applications
should
be
made
using
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Foliar
Quilt
[
100­
1178]
0.1138
NS
0.45
7
Aerial,
ground,
and
sprinkler
irrigation
Cereals
(
Including
Wheat,
Barley,
Triticale,
and
Rye)
Page
11
of
112
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.1125
NS
0.167
NS
Highest
yields
when
applied
to
the
emerging
flag
leaf;
do
not
apply
after
the
ligule
of
the
flag
leaf
emerges
(
Feekes
growth
stage
9)
on
barley
,
rye,
oats
and
triticale.
For
wheat
only,
Tilt
can
be
applied
until
full
head
emergence
(
Feekes
growth
stage
10.5).
Grazing
or
feeding
livestock
treated
forage
or
cutting
the
green
crop
for
hay
or
silage
is
prohibited;

following
harvest,
straw
may
be
used
for
bedding
or
feed.
Applications
should
be
made
in
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal.
of
water/
A.

Corn
(
Including
Field
Corn,
Field
Corn
Grown
for
Seed,
Sweet
Corn,
and
Popcorn)

Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.1125
NS
0.45
14
(
sweet
corn)
Treatment
should
be
started
when
disease
appears
and
repeated
on
a
7­
to
14­
day
schedule.
Application
to
field
corn
and
field
corn
grown
for
seed
after
silking
is
prohibited.
Harvest
of
forage
from
field
corn,
field
corn
grown
for
seed,
and
popcorn
within
30
days
of
application
and
of
sweet
corn
forage
within
14
days
of
application
is
prohibited.
Applications
should
be
made
in
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Preharvest
foliar
Ground
or
aerial
(
post
silk)
41.8%
EC
(
3.6
lb
ai/
gal)

[
LA990002]

[
KS030002]

[
MN990014]

[
NE990006]

[
IL040004]
0.1125
NS
0.45
14
(
sweet
corn)

30
(
seed,

field,
and
popcorn)
Treatment
should
be
started
when
disease
appears
and
repeated
on
a
7­
to
14­
day
schedule.
Feeding
livestock
treated
forage
or
fodder
and
harvest
of
sweet
corn
forage
within
14
days
of
application
are
prohibited.
Applications
should
be
made
in
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal
of
water/
A.
Page
12
of
112
Between
V4
to
after
silking
Stratego
R
[
264­
779]
0.1125
NS
0.29
30(
forage
)
before
silking
Corn
Grown
for
Seed
(
See
Also
"
Corn")

Preharvest
foliar
Ground
or
aerial,
and
sprinkler
irrigation
41.8%
EC
(
3.6
lb
ai/
gal)

[
IN990003]
0.1125
NS
0.45
30
Treatment
should
be
started
when
disease
appears
and
repeated
on
a
7­
to
14­
day
schedule.
Making
more
than
two
applications
after
50%
silk
and
feeding
livestock
treated
forage
or
fodder
are
prohibited.
Applications
should
be
made
in
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Preharvest
foliar?
Tilt
0.1125
NS
0.45
7
When
disease
first
appears.
Aerial,
ground,

and
sprinkler
irrigation.

Grasses
Grown
for
Seed
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.225
(
0.1125­
bluegrass)
NS
0.9
20
Use
is
limited
to
ID,
MN,
NE,
OR,
and
WA.
Apply
multiple
treatments
on
a
14­
to
21­
day
schedule.
The
feeding
of
treated
hay
is
prohibited
within
20
days
of
the
last
application,
and
the
grazing
of
treated
areas
is
prohibited
within
140
days.
Applications
should
be
made
in
a
minimum
of
20
(
ground)
or
10
(
aerial)
gal
of
water/
A.
Page
13
of
112
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
ID950012]

[
OR050012]

[
WA950033]

[
IN990003]

[
NV010004]

[
MT030004]
0.225
2
0.45
20
Apply
just
prior
to
anthesis.
Make
second
application
7­
10
days
later.
Should
be
tank
mixed
with
an
appropriate
surfactant.
The
feeding
of
treated
hay
is
prohibited
within
20
days
of
the
last
application,
and
the
grazing
of
treated
areas
is
prohibited
within
140
days.
Applications
should
be
made
in
a
minimum
of
20
(
ground)
or
10
(
aerial)
gal
of
water/
A.

Mint
Preharvest
foliar
Ground
41.8%
EC
(
3.6
lb
ai/
gal)

[
OR050011]
0.1125
NS
0.225
90
Apply
when
plants
are
2­
4"
high.
Make
second
application
10­
14
days
later.

Applications
should
be
made
in
a
minimum
of
20
gal
of
water/
A.

Nectarines
(
See
"
Stone
fruits")

Oats
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]
0.1125
NS
0.1125
40
Highest
yields
when
applied
to
the
emerging
flag
leaf;
do
not
apply
after
the
ligule
of
the
flag
leaf
emerges
(
Feekes
growth
stage
8).
Applications
should
be
made
in
a
minimum
of
10
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Peaches
(
See
"
Stone
fruits")

Peanuts
Page
14
of
112
Preharvest
foliar
Chemigation
or
directed
ground
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

45%
WP
[
100­
780]
0.225
2
0.45
21
Apply
to
crown
and
pegging
zones.
Begin
applications
45
or
60
days
after
planting
or
at
the
first
appearance
of
disease;
make
second
application
14
days
or
3­
4
weeks
later.
Grazing
livestock
or
feeding
hay
or
threshings
to
livestock
are
prohibited.

Applications
should
be
made
in
a
minimum
of
20
(
ground)
gal
of
water/
A.

Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.1125
NS
0.45
14
Begin
applications
35­
40
days
after
planting
and
repeat
on
a
10­
to
14­
day
schedule.
Grazing
of
livestock
or
feeding
green
vines
to
livestock
is
prohibited.

Applications
should
be
made
in
a
minimum
of
10­
20
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Preharvest
foliar
Ground
or
aerial
Stratego
R
[
264­
779]
0.1134
6
0.68
14
Pecans
Preharvest
foliar
Ground
or
aerial
Stratego
R
[
264­
779]

Tilt
[
100­
617]

Quilt
[
100­

1192]
0.081
NS
0.24
30
Apply
on
a
14­
day
schedule
during
bud
break,
prepollination
sprays,
or
during
nut
formation
and
cover
sprays.
Use
higher
rates
when
disease
pressure
is
heavier.
Do
not
apply
after
shuck
split.
Grazing
of
livestock
in
treated
areas
or
cutting
treated
cover
crops
for
feed
is
prohibited.

Application
should
be
made
using
a
minimum
of
20
gal.
of
water/
A.

Pineapple
Page
15
of
112
Postharvest
Cold
or
hot
water
dip
(
Seed
treatment)
45%
WP
[
100­
780]
0.1125
lb
ai/
500
gal
water
N/
A
N/
A
N/
A
Use
is
limited
to
HI;
immerse
or
soak
crowns
for
control
of
disease.
Feeding
livestock
treated
crowns
or
grazing
livestock
on
growing
plants
or
tops
before
fruit
is
harvested
is
prohibited.

Plantains
(
See
"
Bananas
and
Plantains")

Plums
(
See
"
Stone
fruits")

Rice
Preharvest
foliar
Aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]
0.2813
2@
0.1688
lb
ai/
A
or
1@
0.2813
lb
ai/
A
NS
NS
If
 
5%
of
tillers
are
infected,
two
applications
should
be
made,
the
first
application
at
first
internode
elongation
(
up
to
2­
inch
panicle)
and
the
second
at
swollen
boot
(
10­
14
days
following
the
first
but
before
the
boot
splits
and
head
emerges).
If
greater
than
10%
of
the
tillers
are
infected,

the
higher
single
application
rate
should
be
made
at
first
internode
elongation.
Use
is
prohibited
in
CA
and
areas
of
the
following
AR
counties:
Mississippi,
Poinsett,
Cross,

St.
Francis,
and
Lee.
The
following
are
prohibited:
use
in
rice
fields
where
commercial
farming
of
crayfish
is
practiced;
draining
water
from
treated
rice
fields
into
ponds
used
for
commercial
catfish
farming;
application
to
stubble
or
ratoon
crop
rice;
and
use
of
water
drained
from
treated
fields
to
irrigate
other
crops.

Applications
should
be
made
in
a
minimum
of
5
gal
of
water/
A.

Stratego
R
[
264­
779]
0.16
NS
0.31
35
Page
16
of
112
Rye
(
See
"
Cereals")

Stone
Fruits
(
Sweet
or
tart
Cherry,
Apricots,
Nectarines,
Peaches,
and
Plums
or
Prune)

Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
702]

45%
WP
[
100­
781]
0.1125
2
Not
Specified
(
NS)
0
Use
is
restricted
to
West
of
the
Rocky
Mountains
for
EPA
reg#
100­
781.
Two
applications
may
be
made
during
the
period
beginning
10­
14
days
before
harvest
through
the
day
of
harvest;
or
the
first
application
may
be
made
at
early
bloom
stage.
A
second
application
may
be
made
as
needed
through
petal
fall.
Applications
should
be
made
using
a
minimum
of
50
(
ground)
or
20
(
aerial)
gal
of
water/
A.

Sugarcane
Postharvest
Cold
or
hot
water
dip
45%
WP
[
100­
780]
0.1125
lb
ai/
500
gal
water
N/
A
N/
A
N/
A
Use
of
the
federal
label
is
limited
to
HI.

Immerse
or
soak
cut
seed
pieces
for
control
of
disease.
Use
of
treated
seed
pieces
for
food
or
feed
is
prohibited.

Sunflower
(
Breeder's
seed)

Foliar
spray
Tilt
[
IL050002]

[
TX000006]
0.1125
0.45
N/
A
N/
A
Foliar
spray,
When
disease
first
appears.

7­
day
retreatment
interval.

Wheat
(
See
also
"
Cereals")
Page
17
of
112
Preharvest
foliar
Ground
or
aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
AR990002]

[
GA980003]

[
ID980004]

[
IN980003]

[
MI980001]

[
MN980003]

[
MS980004]

[
VA980003]

[
WA980018]

Tilt
[
100­
617]

[
AR030008]

[
MO980003]

[
KS030001]

[
OK010002]

[
TN030002]

[
OH040002]

[
DE030003]

[
KY050002]
0.1125
NS
0.1125
40
Highest
yields
when
applied
to
the
emerging
flag
leaf;
do
not
apply
after
full
head
emergence
(
Feekes
growth
stage
10.5).
Grazing
or
feeding
livestock
treated
forage
or
cutting
the
green
crop
for
hay
or
silage
is
prohibited;
following
harvest,

straw
may
be
used
for
bedding
or
feed.

Applications
should
be
made
in
a
minimum
of
15
(
ground)
or
5
(
aerial)
gal
of
water/
A.
Page
18
of
112
Wheat
(
cont'd.)

Preharvest
foliar
Ground
or
aerial
Quilt
[
100­

1178]

[
AR050001]

[
WA040026]

[
MS040011]

[
AL040002]

[
OK040001]

[
GA040003]

[
TN040004]

[
MO040006]

[
TX040022]

[
ID050007]
0.1125
NS
0.1125
40
Highest
yields
when
applied
to
the
emerging
flag
leaf;
do
not
apply
after
late
boot,
sheath
split
stage
(
Feekes
growth
stage
10.0).
Grazing
or
feeding
livestock
treated
forage
or
cutting
the
green
crop
for
hay
or
silage
is
prohibited;
following
harvest,
straw
may
be
used
for
bedding
or
feed.
Applications
should
be
made
in
a
minimum
of
15
(
ground)
or
5
(
aerial)
gal
of
water/
A.

Trifloxystrobin
registration
(
coactive
ingredient
with
propiconazole)
Stratego
R
[
264­
779]
0.081
2
0.162
35
(
grain)

30
(
forage)

45
(
hay)

35
(
straw)
Page
19
of
112
Preharvest
foliar
Ground
or
aerial
(
Section
24C)
Stratego
[
3125­
562)

ND­
010009
MN­
010007
OH­
02001
WA­
030015
KS­
010002
VA­
100002
TX010009
AR­
010005
GA­
010002
IN­
020001
AL­
000003
0.081
1
0.081
35
(
grain)

30
(
forage)

45
(
hay)

35
(
straw)

Wild
Rice
Preharvest
foliar
Aerial
41.8%
EC
(
3.6
lb
ai/
gal)

[
100­
617]

[
100­
737]

45%
WP
[
100­
780]
0.225
2@
0.1688
lb
ai/
A
or
1@
0.225
lb
ai/
A
NS
NS
Use
is
limited
to
MN.
Applications
should
be
made
at
booting
and
heading,
or
a
single
application
may
be
made
at
the
higher
rate
at
booting.
Use
of
water
drained
from
treated
rice
fields
to
irrigate
other
crops
is
prohibited.
Applications
should
be
made
in
a
minimum
of
5
gal
of
water/
A.

Note:

1
The
41.8%
EC
formulations
have
been
determined
to
contain
3.6
lb
ai/
gal
of
propiconazole
based
on
historical
data.

2
Product
labels
specify
a
re­
entry
interval
(
REI)
of
24
hours,
except
for
the
45%
WP
(
EPA
Reg.
Nos.
100­
780
and
100­
781)
formulations
which
specify
an
REI
of
12
hours.
Propiconazole
may
be
tank
mixed
with
other
fungicides;
however
labels
for
EPA
Reg.
Nos.
100­
702
and
100­
781
state
that
tank
mixing
with
Cyprex
®
may
cause
crop
injury.

³
The
41.8%
EC
(
EPA
Reg.
Nos.
100­
617
and
100­
737)
and
the
45%
WP
(
EPA
Reg.
No.
100­
780)
are
the
only
products
currently
registered
for
use
on
rotatable
crops.
The
labels
for
these
formulations
state
that
soybeans
may
be
planted
as
a
double
crop
following
a
cereal
crop
which
has
been
treated
with
the
product,
but
soybean
hay,
forage,
and
fodder
may
not
be
used
as
any
component
of
animal
feed
or
bedding.
The
labels
specify
that
any
food/
feed
crops
not
listed
on
the
label
should
not
be
planted
within
105
days
of
treatment.
Page
20
of
112
Table
2.1B:
Maximum
Rates
and
Applications
for
the
Non
­
Agricultural
Uses
of
Propiconazole
Crop
Maximum
Application
Rate
(
Reg.
#)
Maximum
#
Applications/
Crop
Cycle
Maximum
amount
of
ai
applied
(
lb
ai/
A/
year)
Timing
Minimum
Retreatment
Interval
Application
Methods
Section
3
Uses
Non­
bearing
Apple
0.08
lb
ai/
A
(
100­
741)
2
(
100­
617)
NS
(
7.2
lb/
yr
for
Banner,

Tilt,
and
Banner
Maxx)
NS
7.2
lb
ai/
A/
year
for
Tilt
Foliar
As
needed
Hose­
end
and
pump­
up
sprayer
Non­
bearing
Nectarine,
Peach
Plum,
Cherry
0.04
lb
ai/
100
gal
(
100­
741)

(
100­
617)
NS
(
7.2
lb/
yr
for
Banner,

Tilt
and
Banner
Maxx)
NS
7.2
lb
ai/
A/
year
for
Tilt
Foliar
14
days
Hose­
end
and
pump­
up
sprayer
Non­
bearing
Pecan
0.12
lb
ai/
100
gal
(
100­
741)

(
100­
617)
3
NS
7.2
lb
ai/
A/
yr
for
Tilt
Non­
bearing
14
days
Aerial,
ground,

hose­
end
and
pump­
up
sprayer
Non­
bearing
Citrus
0.225
lb
ai/
A
(
100­
702)
NS
(
7.2
lb/
yr
for
Banner,

Tilt
and
Banner
Maxx)
NS
June
July
August
NS
Aerial,
ground,

hose­
end
and
pump­
up
sprayer
Non­
bearing
Walnut
0.08
lb
ai/
100
gal.
(
100­
617)
NS
7.2
lb
ai/
A/
yr
Foliar
14
days
Spray
Turf
and
Ornamentals­
Ground
Cover
0.7524
lb
ai/
A
(
100­
736)
NS
37
packets
Foliar
14
days
Hose­
end
and
pump­
up
sprayer
Turf
and
Ornamentals­
Lawns
and
Turf
&
Golf
Courses
1.79
lb
ai/
A
(
100­
741)
NS
(
7.2
max
per
year)

(
100­
617)
7.2
Foliar
14
days
Hose­
end
and
pump­
up
sprayer
Ground
boom
sprayer
Turf
and
Ornamentals­

Industrial
/
Commercial
Lawns
and
Turf
0.02
lb/
1K
sq.

ft.

(
100­
1192)
2
NS
When
needed
14
days
Ground
spray
Page
21
of
112
Table
2.1B:
Maximum
Rates
and
Applications
for
the
Non
­
Agricultural
Uses
of
Propiconazole
Crop
Maximum
Application
Rate
(
Reg.
#)
Maximum
#
Applications/
Crop
Cycle
Maximum
amount
of
ai
applied
(
lb
ai/
A/
year)
Timing
Minimum
Retreatment
Interval
Application
Methods
Turf
and
Ornamentals­
Shade
Trees
(
injection)
0.0069
lb
ai/

DBH
(
100­
741)
1
NS
Injection
NS
Injection
Turf
and
Ornamentals­
Shade
Trees
(
outdoor
spray),

Herbaceous
Plants,

Ornamental
Woody
Shrubs
and
Vines
0.24
lb
ai/
100
gal
(
100­
741)
NS
(
7.2
max
per
year)

(
100­
617)
NS
NS
NS
Hose­
end
and
pump­
up
sprayer
Turf
and
Ornamentals
Sod
Farm
(
Turf)
1.79
lb
ai/
A(
100­
741)
NS
(
7.2
max
per
year)

(
100­
617)
7.2
NS
NS
Ground
bloom
Sprayer
Non­
bearing
Blueberries
0.169
lb
ai/
A
(
FL940005)
5
(
4
week
interval
from
June
through
October)
Non­
bearing
28
days
Spray
Non­
bearing
Hazelnuts
0.225
lb
ai/
A
(
OR­
040003)
NS
(
no
more
than
32
oz
of
Orbit/
A/
season)
0.90
At
emergence
14
days
Aerial
and
ground
Note:

¹
Updated
use
information
was
provided
by
Syngenta
Crop
Protection,
Inc.,
in
an
e­
mail
correspondence
on
4/
13/
2005,
to
supplement
the
1999
use
information
in
the
LUIS
report.

2
Product
PPZ
1.55%
HG
(
100­
773)
and
PPZ
1.55%
Multi­
purpose
fungicide
(
100­
952)
are
also
used
in
residential
consumer
market.
These
labels
have
lower
application
rates
than
Banner
MAXX
(
100­
741).
Table
2.1C:
Maximum
Rates
and
Applications
for
the
Antimicrobial
Uses
of
Propiconazole
Crop
Maximum
Application
Rate
(
Reg.
#)
Maximum
#
Applications
Timing
Minimum
Retreatment
Interval
Application
Method
from
Labels
Antimicrobial
Uses
Adhesives
12000
W
(
43813­
37)
NS
NS
NS
Dissolved
in
solvent
or
premixed
wetting
agent
Industrial
Coatings,
Industrial
Specialty
Industrial
Products
12125
W
(
43813­
37)

Wood
in
Commercial/
Industrial
Water
Cooling
Systems
0.46
lb/
1000
sq.

ft.

(
43813­
16)
NS
When
Needed
NS
Spray
and
painted
on
Leather
Processing
Liquors
4500
V
180
W
(
70227­
6)

(
71406­
1)
NS
NS
NS
Added
to
pickling
solution
or
tanning
liquor
and
added
to
finish,
paste,
or
fatliquor
Metal
working
Cutting
Fluids
700
ppb
(
43813­
18)

(
43813­
37)
NS
NS
NS
Added
to
metalworking
fluid
Mushroom
Houses­
Empty
Premises/

Equipment
0.31
lb/
25
gal
0.06
lb/
1000
sq.

ft.

(
43813­
16)
NS
(
13
week
application
interval)
NS
NS
Spray
and
dip
tank
Textiles/
Textile
Fibers/
Cordage
2800
U
2000
W
(
5383­
114)

(
43813­
37)
NS
NS
NS
Wood
Protection
Treatment
to
Buildings
(
Indoor)
30
l
cu.
m
(
L)
NS
(
typically
1)
NS
NS
Conventional
or
electrostatic
spray
and
dip
tank
Wood
Protection
Treatment
to
Buildings
(
Outdoor)
.3532
lb
ai/
iK
sq.

ft.
NS
(
typically
1)
NS
NS
Conventional
or
electrostatic
spray
and
dip
tank
Page
23
of
112
Table
2.1C:
Maximum
Rates
and
Applications
for
the
Antimicrobial
Uses
of
Propiconazole
Crop
Maximum
Application
Rate
(
Reg.
#)
Maximum
#
Applications
Timing
Minimum
Retreatment
Interval
Application
Method
from
Labels
Wood
Protection
Treatment
to
Forest
Products
(
Seasoned)
6.8
lb/
90
gal
NS
(
typically
1)
NS
NS
Pressure
treatment
(
double
vacuum,

full­
cell
or
modified
full­
cell)

and
brush
applied
Wood
Protection
Treatment
to
Forest
Products
(
Unseasoned)
41.7
lb/
90
gal
NS
(
typically
1)
NS
NS
Note:

¹
Information
was
provided
by
Syngenta
Crop
Protection,
Inc.
in
a
November
9,
2001
letter
to
the
Agency,
subject:
Correction
to
Propiconazole
Use
Patters.

²
Updated
use
information
was
provided
by
Syngenta
Crop
Protection,
Inc.,
in
an
e­
mail
correspondence
on
4/
13/
2005,
to
supplement
the
1999
use
information
in
the
LUIS
report.
Page
24
of
112
2.2
Structure
and
Nomenclature
All
pertinent
product
chemistry
data
requirements
have
been
satisfied
for
the
Novartis
95%
T/
TGAI,
except
that
additional
data
are
required
concerning
stability
and
UV/
visible
absorption
(
OPPTS
830.6313
and
7050).
Product
chemistry
refers
to
HED
memo
of
Yan
Donovan,
08/
17/
05,
D318480.

TABLE
2.2.
Test
Compound
Nomenclature
Chemical
Structure
Cl
Cl
O
O
N
N
N
CH
3
Empirical
Formula
C15H17Cl2N3O2
Common
name
Propiconazole
Company
experimental
name
CGA­
64250
IUPAC
name
1­((
2­(
2,4­
Dichlorophenyl)­
4­
propyl­
1,3­
dioxolan­
2­
yl)
methyl)­
1H­
1,2,4­
triazole
CAS
name
1H­
1,2,4­
Triazole,
1­((
2­(
2,4­
dichlorophenyl)­
4­
propyl­
1,3­
dioxolan­
2­
yl)
methyl)­

CAS
Registry
Number
60207­
90­
1
End­
use
product/
EP
Tilt
®
,
Alamo
®
,
Banner
®
,
and
Orbit
®
,
Quilt
,
Stratego
 
Twin­
Pak
 
and
Stratego
 
.

Chemical
Class
Triazole
Known
Impurities
of
Concern
none
Page
25
of
112
2.3
Physical
and
Chemical
Properties
TABLE
2.3.
Physicochemical
Properties
Parameter
Value
Reference
Molecular
Weight
342.23
MRID
No.:
40583701
Boiling
point/
range
>
250
°
C
at
101.325
kPa,
120
°
C
at
1.9
Pa
MRID
No.:
43698701
pH
4.9
@
25
°
C
(
1%
aqueous
dispersion)
MRID
No.:
43698701
Density
1.289
g/
cm3
typical
@
20
°
C
MRID
No.:
43698701
Water
solubility
(
20
°
C)
0.10
g/
L
at
20
°
C
MRID
No.:
41720301
Solvent
solubility
(
temperature
not
specified)
Completely
miscible
in
ethanol,

acetone,
toluene
and
n­
octanol.

n­
hexane
=
47
g/
L
MRID
No.:
42030201
Vapor
pressure
(
25
°
C)
4.2
x
10­
7
mmHg
@
25
°
C
MRID
No.:
41720301
Dissociation
constant,
pKa
pKa
1.09
MRID
No.:
43698701
Octanol/
water
partition
coefficient,
Log(
KOW)
(
25
°
C)
3.72
@
pH
6.6
MRID
No.:
43698701
UV/
visible
absorption
spectrum
(
8max,
nm)
Not
available
MRID
No.:
40583703
3.0
METABOLISM
ASSESSMENT
3.1
Rat
Metabolic
Profile
The
Rat
metabolism
study
labeled
with
14C
at
the
triazole­[
3,5]
position
indicated
that
parent
compound
was
extensively
metabolized;
a
group
of
metabolites
(
peak
U8,
11%)
appearing
in
the
urine.
Another
study
labeled
with
(
U­
14C)­
Phenyl
found
several
metabolites,
including
CGA
118245
(
61.8%
in
males,
2.4%
in
females),
CGA
217495
(
8.9%
in
males,
58.3%
in
females),
CGA
91304
(
2.3%
in
males
only),
and
CGA
118244
(
3.6%
in
females
only)
after
intravenous
dosing.
These
metabolites
were
also
detected
to
varying
degrees
in
the
urine
of
the
orally
dosed
groups.
In
the
feces,
no
parent
material
was
detected
in
the
iv
group,
but
detected
in
the
other
groups
(
6.8­
17.6%
of
the
fecal
radioactivity
in
males
and
females).
Radiolabeled
materials
cochromatographing
with
standards
CGA
91305,
CGA
118245
and
CGA
177291
were
reported
ranging
from
0.5%
­
10.9%
of
the
fecal
radioactivity
in
males
and
females
or
in
one
sex
alone.
Most
of
the
fecal
radioactivity
was
not
characterized.
Metabolites
CGA
217495
and
CGA
177291
are
not
found
in
plant
or
livestock
metabolism
(
see
Appendix
for
structures).
In
two
other
(
U­
14C)­
phenyl
and
14C­
triazole
ring
labeled
propiconazole
studies,
the
percentages
of
fecal
metabolites
extracted
and
distributed
at
various
pH's
were
not
substantially
different
between
the
triazole
and
phenyl
labeled
samples,
which
suggest
that
the
bridge
between
the
Page
26
of
112
phenyl
ring
and
the
triazole
ring
remained
intact.
The
proposed
metabolic
pathway
appears
to
involve
the
cleavage
of
the
dioxolane
ring
through
the
oxidation
of
the
propyl
side
chain,
with
subsequent
dechlorination
and
conjugation.
In
a
(
U­
14C)­
phenyl
labeled
propiconazole
metabolism
study
in
mice,
it
was
concluded
that
the
major
metabolic
pathway
in
mice
proceeds
via
elimination
of
the
dioxolane
ring
leading
to
ketone
formation
(
CGA
91304)
and
reduction
to
yield
the
corresponding
alcohol
(
CGA
91305).
Both
CGA
91304
and
CGA
91305
are
found
in
plants
and
livestock.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
Available
plant
metabolism
data
(
primary
and
rotated
crops)
show
that
plants
absorb,
metabolize
and
translocate
propiconazole
throughout
the
plant.
A
major
metabolic
pathway
in
plants
appears
to
be
hydroxylation
(
primarily
of
the
beta­
carbon)
of
the
n­
propyl
group
on
the
dioxolane
ring
of
the
cis/
trans
isomers
of
propiconazole.
These
metabolites
appear
to
readily
form
sugar
conjugates.
The
majority
of
TRR
was
found
in
the
stalks,
such
as
peanut
stalk,
wheat
forage
and
straw,
grape
leaves,
and
celery
stalks
(
See
Table
3.4
for
TRRs).
A
possible
alternative
pathway
involves
reductive
deketalization
of
the
dioxolane
ring
and
sugar
conjugation
of
the
resulting
metabolite.
The
alkyl
bridge
between
the
phenyl
and
triazole
rings
is
metabolized
and
free
triazole,
as
1H­
1,2,4­
triazole,
is
released.
The
free
triazole
is
readily
conjugated
with
the
amino
acid,
serine/
alanine,
forming
triazole
aniline
which
is
further
metabolized
to
triazole
acetic
acid
possibly
through
the
intermediate
formation
of
triazole
lactic
acid.
As
mentioned
earlier,
the
triazole
issue
will
be
addressed
separately.

3.2.2
Description
of
Livestock
Metabolism
For
one
ruminant
study,
three
lactating
goats
received
[
phenyl­
14C]
propiconazole
at
67­
92
ppm
for
four
consecutive
days
in
feed.
The
parent
(
1.7­
13.9%
TRR),
and
metabolites
CGA­
118244
(
9.4­
34%
TRR),
and
CGA­
91305
(
15.9­
31.3%
TRR)
were
identified
in
the
organic
extract
of
tissues;
metabolites
CGA­
118244
(
23%
TRR)
and
CGA­
91305
(
24%
TRR)
were
also
identified
in
milk.
In
addition,
an
unknown
was
quantitated
(
6.2­
31.1%
TRR)
in
goat
tissues.
In
a
second
ruminant
study,
a
single
goat
was
fed
[
triazole­
14C]
propiconazole
at
4.53
ppm
(
0.2x)
for
10
days.
The
TRR
in
tissues
and
milk
ranged
from
0.01
ppm
in
muscle
to
0.96
ppm
in
liver;
TRR
in
milk
were
0.015
ppm.
On
further
analysis
of
subsamples
of
milk
and
liver,
sulfate
and
glucuronide
conjugates
were
found
in
milk,
and
conjugation
with
amino
acids
was
suggested
in
liver;
propiconazole
per
se
was
not
identified
in
milk
or
liver.

For
the
poultry
study,
four
laying
hens
received
[
phenyl­
14C]
propiconazole
at
67
ppm
for
eight
consecutive
days
in
feed.
The
dosing
level
corresponds
to
560x
the
maximum
theoretical
dietary
burden
to
poultry.
The
parent
(
1.4­
39.0%
TRR),
and
metabolites
CGA­
118244
(
1.5­
50.0%
TRR),
and
CGA­
91305
(
17.7­
78.6%
TRR)
were
identified
in
the
organic
extracts
of
tissues
and
eggs.
Page
27
of
112
3.2.
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation.

The
nature
of
the
residue
in
confined
rotational
crops
is
understood,
and
no
additional
confined
rotational
crop
data
are
required
for
the
purpose
of
reregistration.
Based
on
acceptable
studies
reviewed
by
EFED,
the
metabolism
of
propiconazole
in
rotational
crops
is
similar
to
that
in
primary
crops.
In
a
rotational
crop
study,
metabolites
in
peanut
kernels
were
identified
as
triazole
acetic
acid
(
3.8%
TRR)
and
triazole
alanine
(
67.9%
TRR).
Metabolites
identified
in
the
rotational
crop
samples
included
triazole
acetic
acid
(
2.4%­
68.7%
TRR),
triazole
alanine
(
6.7%­
79.4%
TRR),
triazole
lactic
acid
(
4.9%­
35.8%
TRR)
and
polar
metabolites
E,
F,
G,
H
(
1.0%­
7.0%
TRR).

3.3
Environmental
Degradation
Acceptable
and
supplemental
environmental
fate
data
indicate
that
propiconazole
is
persistent
in
most
soil
and
aqueous
environments.
Propiconazole
is
stable
to
hydrolysis
and
photodegradation
in
water.
It
has
an
aerobic
soil
metabolism
half­
life
of
69
days
and
is
persistent
in
aquatic
environments
(
t
½
=
426
days).
Aqueous
photolysis
may
occur
in
the
presence
of
sensitizers
(
t
½
=
<
1
day).
Its
principal
route
of
dissipation
in
terrestrial
environments
appears
to
be
adsorption
to
soil;
adsorption
increases
with
soil
organic
matter
content
(
Kd
values=
1.2
on
sand
to
9.34
on
silty
clay
loam
soils).
Terrestrial
field
dissipation
half­
lives
of
about
100
days
were
reported
in
four
soils.
In
supplemental
aquatic
dissipation
studies
in
rice
fields,
propiconazole
dissipated
rapidly
(
t
½
=
<
5
days)
although
the
route
of
dissipation
was
not
apparent.

Propiconazole
is
moderately
mobile
to
relatively
immobile
in
most
soil
and
aqueous
environments.
Propiconazole
is
not
volatile
(
vapor
pressure
is
1.3
x
10­
6
Torr
at
200
C).
Propiconazole
adsorbs
to
soil
with
adsorption
increasing
with
soil
organic
matter
content
(
Kd
values
=
1.2
on
sand
to
9.34
on
silty
clay
loam
soils).

Propiconazole
is
broken
down
through
hydroxylation
of
the
propyl
side
chain
and
the
dioxolane
ring
to
give
1,2,4­
triazole
and
other
products,
including
particle­
bound
material
and
carbon
dioxide.

CGA­
136735,
CGA­
118245
and
CGA­
71019
were
identified
as
major
degradates
(>
10%
of
applied)
in
environmental
fate
studies.

Minor
degradates
include
CGA­
91304
and
CGA­
91305.

3.4
Tabular
Summary
of
Metabolites
and
Degradates
(
The
highest
%
TRR
are
chosen
when
both
[
14C]
triazole­
labeled
propiconazole
or
[
14C]
phenyllabeled
studies
were
conducted).
Page
28
of
112
Table
3.4.
Tabular
Summary
of
Metabolites
and
Degradates
Percent
TRR
(
PPM)
1
Chemical
Name
(
other
names
in
parenthesis)
Commodity
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)
Structure
Wheat
grain
(
0.1
lbs
ai/
A)
0.4
Wheat
forage
(
0.1
lbs
ai/
A)
7.3
Wheat
straw
(
0.1
lbs
ai/
A)
3.9
Wheat
grain
(
0.5
lbs
ai/
A)
0.8
Wheat
forage
(
0.5
lbs
ai/
A
17.2
Wheat
straw
(
0.5
lbs
ai/
A)
9.0
Celery,
stalk
85.3
Grape,
fruit
14.6
Grape,
juice
2.0
Peanut,
kernel
(
field)
­­

Peanut,
stalk
(
field)
54
Peanut,
shell
(
field)
­­

Peanut,
kernel
(
green
house)
N/
A
Peanut,
stalk
(
green
house)
89
Peanut,
shell
(
green
house)
N/
A
Rotational
Crops
Peanut,
stalk
5
Peanut,
shell
­­

Peanut,
kernel
­­

Wheat,
grain
­­

Wheat,
mature
stalk
­­

Wheat,
immature
stalk
0.7
Parent
Lettuce,
head
­­
Cl
Cl
O
O
N
N
N
CH
3
Page
29
of
112
Table
3.4.
Tabular
Summary
of
Metabolites
and
Degradates
Percent
TRR
(
PPM)
1
Chemical
Name
(
other
names
in
parenthesis)
Commodity
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)
Structure
Carrot
­­

Corn,
kernel
­­

Corn,
cob
­­

Corn,
immature
stalk
­­

corn,
mature
stalk
­­

Ruminant
1.7­
13.9
Poultry
1.4­
39
Rat
­­

Water
­­

Wheat
grain
(
0.1
lbs
ai/
A)
0.1
Wheat
forage
(
0.1
lbs
ai/
A)
0.3
Wheat
straw
(
0.1
lbs
ai/
A)
1.2
Wheat
grain
(
0.5
lbs
ai/
A)
0.3
Wheat
forage
(
0.5
lbs
ai/
A
0.3
Wheat
straw
(
0.5
lbs
ai/
A)
1.5
Celery,
stalk
1.1
Grape,
fruit
32.6
Grape,
juice
31.4
Rotational
Crops
­­

Ruminant
­­

Poultry
­­

Rat
2
­
3.6
CGA­
91304
Water
<
10%
Cl
Cl
O
N
N
N
Wheat
grain
(
0.1
lbs
ai/
A)
0.1
Wheat
forage
(
0.1
lbs
ai/
A)
0.3
CGA­
91305
Wheat
straw
(
0.1
lbs
ai/
A)
0.1
Page
30
of
112
Table
3.4.
Tabular
Summary
of
Metabolites
and
Degradates
Percent
TRR
(
PPM)
1
Chemical
Name
(
other
names
in
parenthesis)
Commodity
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)
Structure
Wheat
grain
(
0.5
lbs
ai/
A)
0.1
Wheat
forage
(
0.5
lbs
ai/
A
0.3
Wheat
straw
(
0.5
lbs
ai/
A)
0.1
Celery,
stalk
1.9
Grape,
fruit
4.9
Grape,
juice
2.9
Peanut,
kernel
(
field)
­­

Peanut,
stalk
(
field)
3
Peanut,
shell
(
field)
­­

Peanut,
kernel
(
green
house)
8
Peanut,
stalk
(
green
house)
­­

Peanut,
shell
(
green
house)
­­

Rotational
Crops
Peanut,
stalk
2
Peanut,
shell
­­

Peanut,
kernel
­­

Wheat,
grain
­­

Wheat,
mature
stalk
­­

Wheat,
immature
stalk
2.1
Lettuce,
head
­­

Carrot
­­

Ruminant
15.9­
31.3
­­

Poultry
17.7­
78.6
­­

Rat
­­
CGA­
91305
Water
<
10%
Cl
Cl
OH
N
N
N
Page
31
of
112
Table
3.4.
Tabular
Summary
of
Metabolites
and
Degradates
Percent
TRR
(
PPM)
1
Chemical
Name
(
other
names
in
parenthesis)
Commodity
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)
Structure
Wheat
grain
(
0.1
lbs
ai/
A)
0.4
Wheat
forage
(
0.1
lbs
ai/
A)
0.4
Wheat
straw
(
0.1
lbs
ai/
A)
1.0
Wheat
grain
(
0.5
lbs
ai/
A)
0.2
Wheat
forage
(
0.5
lbs
ai/
A
0.4
Wheat
straw
(
0.5
lbs
ai/
A)
1.1
Celery,
stalk
1.4
Rotational
Crops
­­

Ruminant
9.4­
34
­­

Poultry
2­
50
­­

Rat
3.6
CGA­
118244
Water
­­
Cl
Cl
O
O
N
N
N
CH
3
OH
Wheat
grain
(
0.1
lbs
ai/
A)
0.4
Wheat
forage
(
0.1
lbs
ai/
A)
0.2
Wheat
straw
(
0.1
lbs
ai/
A)
0.4
Wheat
grain
(
0.5
lbs
ai/
A)
0.1
Wheat
forage
(
0.5
lbs
ai/
A
0.1
Wheat
straw
(
0.5
lbs
ai/
A)
0.3
Celery,
stalk
­­
CGA­
118245
Rat
61.8
Cl
Cl
O
O
N
N
N
OH
Page
32
of
112
Wheat
grain
(
0.1
lbs
ai/
A)
­­

Wheat
forage
(
0.1
lbs
ai/
A)
ND
Wheat
straw
(
0.1
lbs
ai/
A)
0.1
Wheat
grain
(
0.5
lbs
ai/
A)
ND
Wheat
forage
(
0.5
lbs
ai/
0.1
Wheat
straw
(
0.5
lbs
ai/
A)
0.8
Celery,
stalk
­­
CGA­
136735
Rat
­­
Cl
Cl
O
O
N
N
N
CH
3
O
H
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
See
Section
3.6.2
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Table
3.6.
HED
MARC
Meeting
Summary
Chart
:
Propiconazole
Date:
18­
Dec­
2001,
and
08­
Jan­
2002
Residues
of
Concern
Matrix
For
Risk
Assessment
i
For
Tolerance
Expression
Plants
Parent
plus
all
metabolites
convertible
to
2,4­
DCBA
Parent
only
Rotational
crop
Parent
plus
all
metabolites
convertible
to
2,4­
DCBA
Parent
only
Livestock:
Parent
plus
all
metabolites
convertible
to
2,4­
DCBA
Parent
only
Water
Parent
only
N/
A
i
Triazole
is
also
a
residue
of
concern,
but
it
will
be
addressed
separately.

3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
Page
33
of
112
Plant:
The
analytical
method
is
a
single
moiety
method
which
detects
all
residues
convertible
to
2,4­
dichlorobenzoic
acid
(
DCBA),
therefore,
MARC
concluded
that
for
risk
assessment,
parent
and
all
metabolites
convertible
to
2,4­
DCBA
are
residue
of
concern.
The
metabolites
that
have
the
basic
structure
of
propiconazole
(
e.
g.
alkanol,
beta­
hydroxy
and
conjugates)
would
likely
exhibit
some
of
the
same
toxicity
as
the
parent
compound,
but
would
not
likely
be
more
toxic
than
the
parent
compound.
For
the
purposes
of
risk
assessment
HED
would
assume
these
metabolites
would
have
equal
toxicity
as
the
parent
compound.
(
The
conjugates
are
included
because
of
the
possibility
they
could
be
hydrolyzed
in
the
stomach
to
the
unconjugated
form).
For
tolerance
expression,
MARC
recommended
parent
only
for
the
following
reasons:
1)
To
harmonize
with
the
Codex
MRL
which
is
parent
only;
2)
There
are
a
number
of
pesticides
that
have
2,4­
DCBA
as
common
metabolite;
and
3)
FDA
multiresidue
method
detects
parent
only,
and
that
FDA
monitoring
pattern
only
detects
parent.

Rotational
crop:
As
with
primary
crops,
parent
and
all
metabolites
convertible
to
2,4­
DCBA
are
residue
of
concern
for
risk
assessment
since
the
analytical
method
is
a
single
moiety
method
which
detects
all
residues
convertible
to
2,4­
dichlorobenzoic
acid
(
DCBA).
Although
these
metabolites
are
detected
at
very
low
levels,
they
are
of
toxicological
concern
and
can
not
be
excluded
from
risk
assessment.
For
tolerance
expression,
MARC
recommended
that
parent
only.
The
most
blatent
misuse
of
propiconazole
would
be
application
to
unlabeled
crops.
If
rotational
crop
tolerances
are
expressed
in
terms
of
parent,
then
any
residues
of
propiconazole
on
rotated
crops
would
likely
be
due
to
direct
application
to
these
crops.
While
triazole
acetic
acid
is
the
major
metabolite
in
rotational
crop
study,
triazole
is
a
common
metabolite
from
a
number
of
other
pesticides
and
it
will
be
dealt
with
by
triazole
work
group.

Animals:
MARC
recommended
that
parent
and
all
metabolites
convertible
to
2,4­
DCBA
are
residue
of
concern
for
risk
assessment
since
the
analytical
method
detects
all
residues
convertible
to
2,4­
dichlorobenzoic
acid
(
DCBA).
Tolerance
expression
will
be
parent
only.
If
only
propiconazole
per
se
is
regulated,
there
will
not
likely
be
a
need
for
meat
and
milk
tolerances;
only
meat
by­
products
would
likely
require
a
tolerance.
Should
there
be
detectable
residues
of
the
parent
compound
in
meat
and
milk,
it
would
most
certainly
be
as
a
result
of
a
misuse.

Water:
MARC
recommended
that
parent
only
is
needed
to
be
included
in
the
risk
assessment
since
the
parent
is
persistent
and
immobile.
There
are
several
minor
degradates
(<
10%
TRR)
but
none
of
them
are
of
any
significantly
more
toxic
than
the
parent.
Triazole
is
not
a
major
degradates
in
water
and
therefore
was
not
included
in
the
water
modeling;
the
potential
for
exposure
to
triazole
in
drinking
water
will
be
addressed
in
a
separate
document.

4.0
HAZARD
CHARACTERIZATION/
ASSESSMENT
4.1
Hazard
Characterization
Propiconazole
is
a
N­
substituted
triazole
(
cis­
trans­
1­[
2­(
2,4­
dichlorophenyl)
4­
propyl­
1,3­
dioxolan­
2­
ylmethyl]­
1H­
1,2,4­
triazole).
It
is
a
member
of
the
class
of
the
ergosterol
Page
34
of
112
biosynthesis
inhibiting
fungicides.
It
is
used
as
a
fungicide
on
fruits,
grains,
seeds,
hardwoods
and
conifers.
The
mode
of
antifungal
action
of
conazoles
is
attributed
to
the
inhibition
of
CYP51
(
lanosterol­
14­
a­
demethylase)
(
Zarn
et
al,
2003:
cited
in
Sun
et
al,
2005:
Toxicology
Letters
155:
277 
287.).
However,
in
mammalian
systems
several
N­
substituted
azoles
are
able
to
induce
mammalian
hepatic
cytochrome
P450s
in
the
rat
(
various
authors
as
cited
by
Sun
et
al,
2005).
Recent
work
have
demonstrated
that
propiconazole
induces
CYP1A2
in
rat
liver
and
CYP2B
and
CYP3A
families
of
isoforms
in
rat
and
mouse
liver
(
Sun
et
al,
2005).

Propiconazole
is
rapidly
absorbed
from
the
gut
and
is
eliminated
in
the
urine
and
feces.
It
is
extensively
metabolized
through
hydroxylation,
oxidation,
cleavage,
dechlorination
and
conjugation.

Propiconazole
has
low
to
moderate
toxicity
in
experimental
animals
by
the
oral
(
Category
III),
dermal
(
Category
III)
and
inhalation
routes
(
Category
IV),
is
moderately
irritating
to
the
eyes
(
Category
III),
and
minimally
irritating
to
the
skin
(
Category
IV).
It
is
a
dermal
sensitizer.
Propiconazole
is
readily
absorbed
by
the
rat
skin
with
a
40%
absorption
within
10
hours
of
dermal
application.

The
primary
target
organ
for
propiconazole
toxicity
in
animals
is
the
liver.
Increased
liver
weights
were
seen
in
mice
after
subchronic
or
chronic
oral
exposures
to
propiconazole
at
doses
>
50
mg/
kg/
day.
Liver
lesions
such
as
vacuolation
of
hepatocytes,
ballooned
liver
cells,
foci
of
enlarged
hepatocytes,
hypertrophy
and
necrosis
are
characteristic
of
propiconazole
toxicity
in
rats
and
mice.
Mice
appear
to
be
more
susceptible
to
its
toxicity
than
rats.
Decreased
body
weight
gain
in
experimental
animals
was
seen
in
subchronic,
chronic,
developmental
and
reproductive
studies.
Dogs
appeared
to
be
more
sensitive
to
the
localized
toxicity
of
propiconazole
as
manifested
by
stomach
irritations
at
6
mg/
kg/
day
and
above.

In
rabbits,
developmental
toxicity
occurred
at
a
higher
dose
than
the
maternal
toxic
dose,
while
in
rats,
developmental
toxicity
occurred
at
lower
doses
than
maternal
toxic
doses.
Increased
incidences
of
rudimentary
ribs
occurred
in
rat
and
rabbit
fetuses.
Increased
cleft
palate
malformations
were
noted
in
two
studies
in
rats.
In
one
published
study
in
rats
developmental
effects
(
incomplete
ossification
of
the
skull,
caudal
vertebrae
and
digits,
extra
rib
(
14th
rib)
and
missing
sternbrae,
malformations
of
the
lung
and
kidneys)
were
reported
at
doses
that
were
not
maternally
toxic.
In
the
two
generation
reproduction
study
in
rats,
offspring
toxicity
occurred
at
a
higher
dose
than
the
parental
toxic
dose
suggesting
lower
susceptibility
of
the
offspring
to
the
toxic
doses
of
propiconazole.

Propiconazole
was
negative
for
mutagenicity
in
the
in
vitro
BALB/
3T3
cell
transformation
assay,
bacterial
reverse
mutation
assay,
Chinese
hamster
bone
marrow
chromosomal
aberration
assay,
unscheduled
DNA
synthesis
studies
in
human
fibroblasts
and
primary
rat
hepatocytes,
mitotic
gene
conversion
assay
and
the
dominant
lethal
assay
in
mice.
It
caused
proliferative
changes
in
the
rat
liver
with
or
without
pretreatment
with
an
initiator,
like
phenobarbital,
a
known
liver
tumor
promoter.
Liver
enzyme
induction
studies
with
propiconazole
in
mice
demonstrated
that
propiconazole
is
a
strong
phenobarbital
type
inducer
of
xenobiotic
Page
35
of
112
metabolizing
enzymes.
Hepatocellular
proliferation
studies
in
mice
suggest
that
propiconazole
induces
cell
proliferation
followed
by
treatment­
related
hypertrophy
in
a
manner
similar
to
the
known
hypertrophic
agent
phenobarbital.

Propiconazole
was
carcinogenic
to
CD­
1
male
mice.
Propiconazole
was
not
carcinogenic
to
rats
nor
to
female
mice.
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
classified
propiconazole
as
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization
the
reference
Dose
(
RfD)
approach
be
used
for
quantification
of
human
risk
(
HED
Doc.
No.
009771,
April
15,
1992
meeting).

Table
4.1a
:
Acute
Toxicity
Profile
­
Propiconazole
Guideline
No.
Study
Type
MRID
#
Results
Toxicity
Category
870.1100
Acute
Oral
­
rat
00058591
LD50
=
1517
mg/
kg
III
870.1200
Acute
Dermal­
rabbit
00058596
LD50
=
>
4000
mg/
kg
III
870.1300
Acute
Inhalation
­
rat
41594801
LC50
=
>
5.84
mg/
L
IV
870.2400
Primary
Eye
Irritation
00058597
Corneal
opacity
reversed
in
72
hours
III
870.2500
Primary
Skin
Irritation
00058598
No
irritation
IV
870.2600
Dermal
Sensitization
44949501
Sensitizer
­

Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
Feeding
Study
in
Rat
00058606
(
1997)
Acceptable/
Guideline
0,
240,
1200
or
6000
ppm
(
M:
0,
15.9,
76.1,
461.7,
F:
0,
16.8,
77.6,
400.9
mg/
kg/
day
)
LOAEL
=
6000
ppm
in
males
(
462
mg/
kg
bw
/
day)
and
1200
ppm
in
females
(
77.59
mg/
kg
bw/
day)
based
on
reduced
body
weight
gain.
NOAEL
=
1200
ppm
in
males
(
76
mg/
kg
bw/
day)
and
240
ppm
in
females
(
16.82
mg/
kg
bw/
day).
Page
36
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
3­
month
oral
toxicity
study
­
mice
42050501,(
1991)
Acceptable/
Guideline
0,
20
500
or
2500
ppm
(
M:
0,
2.7,
65,
or
352,
F:
0,
3.4,
85,
434
mg/
kg/
day)
Two
additional
male
groups
at
850,
1450
ppm
(
112,
194
mg/
kg/
day)
LOAEL
=
500
ppm
(
65
mg/
kg/
day)
in
males
and
2500
ppm
(
434
mg/
kg/
day)
in
females
based
on
increase
in
absolute
and
relative
liver
weights
and
histopathological
changes
(
hypertrophy,
necrosis).
NOAEL
is
20
ppm
in
males
(
2.7
mg/
kg/
day)
and
500
ppm
in
females
(
85
mg/
kg/
day).

870.3100
3­
month
oral
­
male
mice
42050502
(
1991)
Acceptable/
Guideline
0,
20,
500,
850,
1450
,2500
ppm
(
0,
2.7,
65,
112,
194,
352
mg/
kg/
day
LOAEL
=
500
ppm
(
65
mg/
kg/
day),
based
on
increase
in
absolute
and
relative
liver
weights
and
histopathological
liver
lesions
(
hypertrophy,
necrosis,
vacuolation)
seen
at
4,
8
and
13
weeks
sacrifices.
The
NOAEL
is
20
ppm
(
2.7
mg/
kg/
day)

870.3100
3­
month
oral
­
male
mice.
45215801
(
1997)
Supplement
to
MRID
42050502:
Reexamination
of
liver
Confirms
findings
in
MRID
42050502.
No
change
to
NOAEL
or
LOAEL
870.3150
3­
month
dog
(
dietary)
00058607(
1979)
Acceptable/
Guideline
0,
50,
250
or
1250
ppm
(
0,
1.25,
6.25,
31.25
mg/
kg/
day)
LOAEL
is
250
ppm
(
59
mg/
kg/
day)
based
on
the
finding
of
lymphoid
follicles
in
the
mucous
membrane
of
the
pyloric
part
of
the
stomach.
NOAEL
is
50
ppm
(
13mg/
kg/
day)

870.3200
21
­
Day
dermal
toxicity
­
rabbits
00116591
(
1982)
Acceptable/
Guideline
0,
3,
30
or
300
mg/
kg/
day
LOAEL:
3
mg/
kg/
day
based
on
mild
dermal
irritation
(
Hyperkeratosis,
acanthosis,
mild
dilation
of
blood
vessels
and
mononuclear
cells
and/
or
heterophils
in
the
proximal
dermis).
No
systemic
toxicity
was
reported.
NOAEL
for
skin
lesions
not
established
870.3700a
Developmental
Toxicity­
Rat
40425001(
1987)
Acceptable/
guideline
0,
30,
90
or
300
mg/
kg/
day
Maternal
Toxicity
LOAEL
=
300
mg/
kg/
day
based
on
severe
clinical
toxicity
(
ataxia,
coma,
lethargy,
prostation,
labored
respiration
and
salivation)
NOAEL
=
90
mg/
kg/
day
Developmental
Toxicity
LOAEL
=
90
mg/
kg/
day
based
on
increased
incidence
of
rudimentary
ribs,
cleft
palate
malformations
(
0.3%)
unossified
sternebrae,
as
well
as
increased
incidence
of
shortened
and
absent
renal
papillae.
NOAEL
=
30
mg/
kg/
day
Page
37
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Non­
guideline
Developmental
Toxicity­
Rat
40425002
(
1987)
Acceptable/
nonguideline
0
or
300
mg/
kg/
day
cleft
palate:
2/
2064
fetuses
of
dosed
animals
vs.
0/
1222
controls
(
lab.
hist.
control
incidence:
was
0/
5431).
This
confirms
findings
of
cleft
palate
noted
in
above
study.
Severe
clinical
toxicity
in
the
treated
animals
(
ataxia,
coma,
lethargy,
prostation,
labored
respiration
and
salivation)

870.3700b
Developmental
Toxicity­
Rabbit
40425004
(
1986)
Acceptable/
guideline
0,
100,
250
or
400
mg/
kg/
day
Maternal
Toxicity
LOAEL
=
250
mg/
kg/
day
based
on
reduced
dam
body
weight
gain
and
decreased
food
consumption
during
the
dosing
period
NOAEL
=
100
mg/
kg/
day
Developmental
Toxicity
LOAEL
=
400
mg/
kg/
day
based
on
increased
incidence
of
fetuses
/
litters
with
13thrib
and
increased
abortions.
NOAEL
=
250
mg/
kg/
day
870.3800
2­
Generation
reproduction­
Rat
00151514
(
1985)
Acceptable/
guideline
0,
100.
500
or
2500
ppm
Parental
Toxicity
LOAEL
=
500
ppm
(
42
mg/
kg/
day)
based
on
increased
incidence
of
hepatic
clear
cell
change
NOAEL
=
8
mg/
kg/
day
Reproductive
Toxicity
LOAEL
=>
2500
ppm
(>
263
mg/
kg/
day,
HDT)
Offspring
Toxicity
LOAEL
=
2500
ppm
(
192­
263
mg/
kg/
day
based
on
decreased
offspring
survival
and
body
weights
and
an
increased
incidence
of
hepatic
cellular
swelling
NOAEL
=
500
ppm
(
43­
52
mg/
kg/
day)

870.4100
12­
Month
Chronic
Oral
Toxicity
(
dietary)
­
Dogs
00151515
(
1985)
Acceptable/
guideline
0,
5,
50
or
250
ppm
(
0,
0.12,
1.25,
or
6.25
mg/
kg/
day)
LOAEL
=
250
ppm
(
6.25
mg/
kg/
day),
based
on
hypermia
of
the
stomach
in
males
(
indicating
mild
irritation
of
the
mucosa).
NOAEL
is
50
ppm
(
1.25
mg/
kg/
day)

870.4100
24­
Month
Chronic/
Carcinog
enicity
Feeding­
Rats
00129918
(
1982)
Acceptable/
guideline
0,
100,
500
or
2500
ppm
(
male
3.6,
18.1
and
96.4
 
,
female
4.6,
23.3
and
100.6
 
mg/
kg/
day)
LOAEL
=
2500
ppm
(
96.4
mg/
kg/
day)
based
on
liver
lesions
(
vacuolation
of
hepatocytes
in
males,
ballooned
cells
in
the
liver
of
males,
foci
of
enlarged
hepatocytes
in
females,
and
increased
incidence
of
luminal
dilation
of
the
uterus)
and
reduced
body
weight
gain
in
both
males
and
females.
NOAEL
=
500
ppm
(
18.1
mg/
kg/
day).
The
test
material
was
not
carcinogenic
at
the
doses
tested.
Page
38
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.4200
24­
Month
Carcinogenicity
in
Mice
00129570
(
1982
)
Acceptable/
guideline
0,
100,
500
or
2500
ppm
(
M:
10.0,
49.4,
and
344.3
F:
10.8,
55.6
and
340.3
mg/
kg/
day
LOAEL
=
500
ppm
(
49.5
mg/
kg/
day)
based
on
nonneoplastic
liver
effects
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly)).
The
NOAEL
was
100
ppm
(
10
mg/
kg/
day).
Liver
tumors
at
2500
ppm
in
male
mice.

870.4200
18
­
month
oncogenicity
study
­
male
CD­
1
mice
44381401
(
1997)
Acceptable/
guideline
0,
100,
500
or
850
ppm
(
0,
11,
59
or
108
mg/
kg/
day)
LOAEL=
500
ppm
(
59.0
mg/
kg/
day)
for
males,
based
on
hepatotoxicity
(
increased
liver
weight,
hepatocellular
hypertrophy,
liver
necrosis)
and
body
weight
gain
effects
observed
at
the
interim
and
terminal
sacrifices.
NOAEL=
100
ppm
(
11.0
mg/
kg/
day)
for
males.
Treatment
related
increase
in
hepatocellular
adenoma
and
total
hepatocellular
neoplasia
at
the
850
ppm
exposure
level
compared
to
concurrent
controls,
but
were
within
the
range
of
the
inadequate
historical
control
data
submitted
with
the
study
report.
Adequate
dosing
based
on
body
weight
gain
and
hepatotoxic
effects
seen
at
500
and
850
ppm.
Subsequently,
the
Registrant
submitted
additional
control
data
on
five
groups
of
CD­
1
male
mice
generated
within
the
approximate
time
frame
of
the
original
study
and
in
the
same
testing
facility
under
similar
experimental
conditions
(
MRID
45215804)
concerning
the
spontaneous
occurrence
of
liver
tumors.
The
tumor
incidence
observed
in
male
livers
at
the
850
ppm
dose
is
within
the
range
of
the
new
historical
data.

870.6200
Acute
neurotoxicity
in
rats
46604601
(
2005)

Acceptable/
guideline
0,
30,
100
or
300
mg/
kg
by
gavage
LOAEL
=
100
mg/
kg
based
on
clinical
signs
of
toxicity
(
piloerection,
diarrhea,
tiptoe
gait).

NOAEL
=
30
mg/
kg.

LOAEL
for
neurobehavioral
toxicity
=
300
mg/
kg
based
on
reduced
motor
activity.

NOAEL
for
neurobehavioral
toxicity
=
100
mg/
kg
870­
5100
Bacterial
reverse
mutation
00058601
(
1979)
Unacceptable
25­
2025

g/
plate
Negative
in
Salmonella
strains
with
or
without
S­
9
activation.
Test
material
purity
not
specified,
not
tested
up
to
cytotoxic
dose.
Page
39
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870­
5300
In
vitro
cell
transformation
assay
(
BALB/
3T3)
00133349
(
1982)
Acceptable/
guideline
1.16­
18.5

g/
ml
Did
not
cause
a
measurable
increase
in
transformation
of
BALB/
T3
cells.
Highest
dose
produced
25%
reduction
in
colony
forming
ability.

870­
5385
(
bone
marrow
chromosomal
aberration)
­
Chinese
hamsters
00058603
(
1979)
Acceptable/
guideline
0,
251,
502
or
1004
mg/
kg
Negative
for
induction
of
micronuclei
in
bone
marrow
cells
at
all
levels
tested.

870­
5550
Unscheduled
DNA
synthesis
in
human
fibroblasts,
00133347
(
1982)
Acceptable/
guideline
Negative
for
inducing
Unscheduled
DNA
Synthesis
at
concentrations
up
to
and
including
9.32
µ
g/
ml.
Highest
dose
tested
to
allow
at
least
25%
cell
viability
870­
5550
Unscheduled
DNA
synthesis
in
primary
rat
hepatocytes
00133348
(
1982)
Acceptable/
guideline
Negative
for
inducing
Unscheduled
DNA
Synthesis
at
concentrations
up
to
and
including
83.5
µ
g/
ml.
Highest
dose
tested
to
allow
at
least
25%
cell
viability
870­
5575
Mitotic
gene
conversion
assay
(
Saccharomyces
cerevisiae)
00133343
(
1982)
Acceptable/
guideline
10,
30,
90
or
270

g/
ml
No
increase
in
convertants
or
revertants
(
did
not
induce
mutation)
with
or
without
activation.
Concentrations
of
 
30

g/
ml
had
inhibitory
effect
on
yeast
cell
growth.

870.5450
Dominant
lethal
assay
in
mice
00058602
(
1979)
Acceptable/
guideline
165
or
495
mg/
kg
single
dose
oral
gavage,
No
evidence
of
dominant
lethal
effects
was
observed
in
the
progeny
of
mice
treated
with
propiconazole.

870.7485
Metabolism
and
pharmacokinetics
(
Rat)
42403901
(
1983)
Acceptable/
guideline
male
rats:
single
oral
31.4
mg/
kg
­
14C
at
the
triazole­[
3,5]
position
Rapidly
metabolized:
96%
excreted
in
urine
and
feces
(
5:
4
ratio)
after
3
days.
Extensively
metabolized
by
hydroxylation,
oxidation
and
conjugation.
Page
40
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
(
Rat)
41326701
(
1989)
Acceptable/
guideline
0.5
mg/
kg
oral
or
iv
(
U­
14C)­
Phenyl
label
or
0.5
mg/
kg/
day
unlabeled
for
14
days
followed
with
0.5
mg/
kg
labeled
or
single
oral
dose
50
mg/
kg
labeled
Oral
or
iv
routes
resulted
in
similar
patterns
of
14C
elimination
suggesting
biliary
excretion.
>
90%
of
14C
excreted
after
168
hours
mostly
within
the
48
hrs.
Females
eliminated
more
in
the
urine
than
in
the
feces
and
vice
versa
for
males
in
the
orally
dosed
groups.
No
significant
differences
were
seen
in
the
excretion
pattern
or
were
seen
between
the
low
and
high
dose
groups
or
the
repeated
dosing
groups.
Extensively
metabolized
(
oxidative):
24
and
47
metabolites
in
urine
and
feces,
respectively.
Parent
(
27­
30%
of
AD)
only
detected
in
the
urine
of
iv
animals.

870.7485
Metabolism
and
pharmacokinetics
(
Rat)
00074506
(
1979)
00074507
(
1981)
Acceptable/
guideline
triazole­[
3,5­
14C]
labeled
single
oral
dose
of
31.4
mg/
kg
or
phenyl­[
U­
14C]
single
oral
dose
of
32.5
mg/
kg
to
male
rats.
Study
focused
on
urinary
and
fecal
metabolites.
Similar
metabolic
profiles
for
the
two
labels
suggesting
that
the
bridge
between
the
phenyl
ring
and
the
triazole
ring
remained
intact.
Metabolic
pathway:
cleavage
of
dioxolane
ring
through
the
oxidation
of
the
propyl
side
chain,
with
subsequent
dechlorination
and
conjugation
and
through
the
oxidation
of
the
propyl
side
chain.
Urinary
and
fecal
metabolites
except
the
presence
of
parent
in
feces.

870.7485
Metabolism
and
pharmacokinetics
(
Mouse)
00164795
(
1986)
Acceptable/
nonguideline
Male
and
female
mice
fed
in
the
diet
for
21
days
at
5,
100
or
2500
ppm
propiconazole
followed
by
phenyl­[
U­
14C]
single
oral
dose
at
corresponding
levels.
Two
male
rats
given
single
oral
dose
9.4
mg/
kg
of
the
phenyl­[
U­
14C]
compound
Mice
pre­
treated
with
the
unlabeled
CGA
64250
excreted
83­
103%
of
the
administered
14C
radioactivity
within
96
hours
(
mostly
within
the
first
24­
48
hours)
in
the
urine
and
feces
(
mostly
in
urine:
1.5­
3.7x
of
the
feces).
The
male
rats
excreted
nearly
equal
amounts
of
the
radioactivity
in
urine
(
48%)
and
feces
(
54%).
Mouse
urinary
metabolites
15­
30.
The
major
metabolic
pathway
in
mice
proceeds
via
elimination
of
the
dioxolane
ring.
In
males
this
represents
30%
of
the
AD
whereas
in
the
females
it
represents
15%
of
the
AD.
Mice
cleaved
the
dioxolane
ring
to
a
greater
extent
(
70%
&
and
40%
for
males
and
females,
respectively)
than
do
male
rats
(
30%).

870.7600
Dermal
penetration
(
Rat)
42415701
(
1986)
Acceptable/
guideline
Propiconazole
14C
at
the
triazole­[
3,5]
position
0.01,
0.1,
1.0
mg/
cm2
The
average
dermal
absorption
of
propiconazole
over
a
10
hour
period
at
an
exposure
level
of
0.01
mg/
cm2
is
approximately
40%
Page
41
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Non­
guideline
Special
study
00151517
(
1984)
Acceptable
Tumor
promotion­
rat
2000
ppm
dietary
up
to
8
weeks
Propiconazole
caused
proliferative
changes,
with
or
without
pretreatment
with
an
initiator
(
DENA;
nitrosodiethylamine),
in
the
rat
liver
similar
to
phenobarbital
(
500
ppm),
a
known
liver
tumor
promoter.

Non­
guideline
Special
study
Mechanistic
studies:
Hepatic
biochemical
parameters
­
Mouse
45215803
(
1998)
Male
CD­
1
mice,
6/
dose
propiconazole
at
0,
850
or
2500
ppm
(
0,
149,
578
mg/
kg/
day)
for
14
days.
Phenobarbital
850
ppm
(
145
mg/
kg/
day)
to
one
group
Total
cytochrome
P450
activity
increased
significantly
(
3­
3.9x
of
the
controls)
at
 
850
ppm
propiconazole.
7­
ethoxyresorufin
activity,
indicative
of
CYP1A1
induction
was
increased
slightly
but
not
to
the
extent
observed
following
true
induction.
Lauric
acid
hydroxylation,
specifically
a
result
of
peroxisome
proliferation,
was
not
induced
by
propiconazole.
However,
the
activity
of
7­
pentoxyresorufin­
Odealkylase
associated
with
CYP2B
or
PB­
type
induction,
was
clearly
increased
30­
55­
fold
by
propiconazole
Microsomal
coumarin
7­
hydroxylase,
associated
with
enzymes
belonging
to
the
subfamily
CYP2A
was
also
induced
by
propiconazole
treatment
consistent
with
PB­
like
induction.
The
microsomal
activities
of
epoxide
hydrolase
and
UDPGT
and
the
cytosolic
activity
of
GST
were
slightly
increased
with
propiconazole
treatment.
The
pattern
of
microsomal
and
cytosolic
enzyme
induction
determined
biochemically
was
entirely
consistent
with
PB­
type
induction.
Propiconazole
resulted
in
a
marked
increase
of
total
testosterone
oxidation.
The
results
from
the
determination
of
microsomal
and
cytosolic
enzyme
activities,
testosterone
hydroxylation,
and
immunoblot
analyses
show
that
propiconazole
is
not
a
3­
MC
or
mixed
type
inducer,
but
causes
a
pure
PB­
type
induction
of
cytochrome
P450
activity.
The
effects
of
propiconazole
treatment
on
mouse
liver
weights
and
liver
enzymes
were
comparable
to
those
produced
by
phenobarbital,
a
known
liver
enzyme
inducer
and
liver
tumor
promoter.
The
authors
concluded
that
propiconazole
can
thus
be
considered
a
strong
phenobarbital­
type
inducer
of
xenobiotic
metabolizing
enzymes
in
the
mouse.
Page
42
of
112
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile:
Propiconazole
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Non­
guideline
Special
study
Mechanistic
studies:
Hepatocellular
proliferation
­
Mouse
45215802
(
1999)
Male
CD­
1
mice
40/
dose
propiconazole
at
0,
850
or
2500
ppm
(
0,
127,
353
mg/
kg/
day)
for
up
to
60
days.
A
group
of
40
mice
given
850
ppm
PB.
Five
mice/
group
were
sacrificed
on
days
1,
2,
3,
4,
7,
28,
or
60
(
IP
injection
of
100
mg/
kg
BrdU
two
hours
prior
to
sacrifice)
Test
material
and
Phenobarbital
(
PB)
induced
a
doserelated
increase
in
absolute
and
relative
liver
weights.
All
mice
developed
hepatocellular
hypertrophy
(
primarily
in
the
centrilobular
hepatocytes
with
mild
effects
in
the
midzonal
hepatocytes).
Liver
necrosis
and
cytoplasmic
vacuolation
were
noted.
Increased
mitotic
activity
was
observed
in
all
groups.
Minimal
to
moderate
hepatocellular
nerosis
of
hypertrophic
single
or
focal
cells
was
found
predominately
in
the
high
dose
and
PB
group.
Treatment
with
propiconazole
or
PB
induced
a
>
1000%
increase
in
BrdU­
staining
hepatocellular
nuclei
within
24
hours
from
the
start
of
the
study
that
peaked
at
a
>
3600%
increase
by
48
hours.
Thereafter,
the
number
of
BrdU­
stained
nuclei
decreased
dramatically
and
was
not
biologically
different
from
controls
7
days
after
the
start
and
through
the
remainder
of
the
study.
For
all
treatment
groups,
the
BrdU­
staining
nuclei
were
found
primarily
in
the
centrilobular/
midzonal
portions
of
the
liver.
These
data
support
the
conclusion
that
propiconazole
induced
an
initial
time­
and
dose­
related
proliferation
in
the
liver
followed
by
a
sustained
treatment­
related
hypertrophy
in
a
manner
similar
to
the
known
hypertrophic
agent
PB.
The
hepatomegaly
was
attributed
to
a
sharp
and
transient
induction
of
hepatocellular
proliferation
as
well
as
to
a
time­
and
dose­
related
increase
in
the
severity
of
hepatocellular
hypertrophy.
Page
43
of
112
4.2
FQPA
Hazard
Considerations
HIARC
(
February
13,
2003)
concluded
that
the
toxicology
database
for
propiconazole
is
complete
for
FQPA
assessment.
The
HIARC
concluded
that
there
is
low
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
propiconazole.
In
the
developmental
toxicity
study
in
rats,
the
HIARC
considered
the
fetal
effects
observed
in
this
study
at
a
dose
lower
than
that
evoking
maternal
toxicity
to
be
quantitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
propiconazole.
In
the
developmental
toxicity
study
in
rabbits,
the
HIARC
determined
that
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
propiconazole
was
observed
in
this
study.
In
the
2­
generation
reproduction
study
in
rats,
the
HIARC
determined
that
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
neonates
(
as
compared
to
adults)
to
pre­
and/
or
postnatal
exposure
to
propiconazole
was
observed
in
this
study.
Since
there
was
quantitative
evidence
of
increased
susceptibility
of
the
young
following
exposure
to
propiconazole
in
the
developmental
rat
study,
HIARC
performed
a
Degree
of
Concern
Analysis
and
concluded
that
the
degree
of
concern
for
the
effects
observed
in
this
study
was
low
and
no
residual
uncertainties
were
identified.
The
FQPA
factor
is
thus
1X.

4.2.1
Adequacy
of
the
Toxicity
Data
Base
HIARC
(
February
13,
2003)
concluded
that
the
toxicology
database
for
propiconazole
is
complete
for
FQPA
assessment.
The
database
was
adequate
to
characterize
any
potential
for
prenatal
or
postnatal
risk
for
infants
and
children.

4.2.2
Evidence
of
Neurotoxicity
Although
there
is
no
evidence
of
neurotoxicity,
neuropathology
or
abnormalities
in
the
development
of
the
fetal
nervous
system
from
the
available
developmental
and
reproductive
studies
conducted
with
propiconazole,
neurotoxic
effects
(
ataxia,
lethargy,
salivation,
rales)
were
noted
in
pregnant
rats
administered
high
propiconazole
doses
(
360
mg/
kg/
day)
during
gestation
period.
In
view
of
the
neurotoxic
effects
observed
in
pregnant
rats,
the
HIARC
(
February
13,
2003)
determined
that
an
acute
neurotoxicity
(
ACN)
study
was
required.
HIARC
determined
that
for
acute
(
single
dose)
and
short­
term
exposure
scenarios
a
3X
database
uncertainty
factor
(
UFDB)
was
adequate
to
account
for
the
lack
of
the
ACN.

In
July,
2005,
the
ACN
study
in
the
rat
was
submitted
and
reviewed
by
the
Agency
(
MRIDs
46604601
&
46604602).
The
study
confirmed
that
propiconazole
at
doses
of
300
mg/
kg
in
rats
produces
severe
clinical
signs
of
toxicity
as
was
demonstrated
in
the
developmental
rat
study
at
360
mg/
kg.
This
ACN
study
also
demonstrated
that
the
clinical
signs
of
toxicity
were
not
accompanied
by
nervous
tissue
damage
and
neurobehavioral
effects
were
minimal.
Therefore,
the
propiconazole
risk
assessment
team
concludes
that
the
ACN
study
satisfies
the
data
gap
imposed
by
HIARC
and
the
3X
factor
for
the
data
base
uncertainty
factor
can
be
removed.
Page
44
of
112
4.2.3
Developmental
Toxicity
Studies
DEVELOPMENTAL
­
RAT
In
an
acceptable/
guideline
developmental
toxicity
study
(
MRID
40425001),
CGA
64250
technical(
92.1%
purity
propiconazole,
Batch
no.
FL
850083)
was
administered
to
24
CL:
COBS
CD
(
SD)
BR
VAF/
PLUS
virgin
female
rats/
dose
by
oral
gavage
in
aqueous
suspensions
(
3%
corn
starch
containing
0.5%
Tween
80)
at
dose
levels
of
0,
30,
90
or
300
mg/
kg/
day
from
days
6
through
16
of
gestation.
High
dose
animals
initially
received
360
mg/
kg/
day
up
to
five
days,
but
because
of
severe
symptoms
it
was
reduced
to
300
mg/
kg/
day.
Severe
compound­
related
maternal
toxicity
was
observed
at
the
high
dose
level
during
the
first
five
days
of
dosing
beginning
on
day
8
of
gestation
at
360
mg/
kg/
day.
These
included
statistically
significant
increases
in
the
incidence
of
lethargy,
ataxia,
salivation,
and
biologically
significant
increases
in
rales,
prostration,
hypothermia
and
bradypnea.
The
incidence
of
these
effects
versus
control
is
as
follows:
lethargy
(
9/
23
vs.
0/
24
in
controls),
salivation
(
4/
23
vs.
0/
24
in
controls)
and
ataxia
(
3/
23
vs.
0/
24
in
controls).
After
lowering
the
dose
to
300
mg/
kg/
day
on
day
6,
the
severity
and
frequency
of
these
effects
decreased
rapidly.
At
the
lower
doses
with
the
exception
of
one
animal
of
the
90
mg/
kg/
day
group
exhibiting
rales
,
there
were
no
treatment
related
clinical
observations.
Mean
food
consumption
was
significantly
reduced
(
p<
0.05)
in
the
300
mg/
kg/
day
group
on
days
7­
8,
8­
9
and
9­
10
and
in
the
90
mg/
kg/
day
group
on
days
8­
9
and
10­
11.
Maternal
body
weights
were
not
affected
by
the
treatments.
Maternal
body
weight
gains
were
significantly
decreased
(
p<
0.05)
in
the
90
mg/
kg/
day
group
(
44%
of
controls)
and
in
the
high
dose
group
(
38%
of
controls)
during
gestation
days
6­
8
only.
This
effect
was
considered
to
be
temporary
and
not
treatment
related.
No
significant
treatment­
related
effects
on
uterine
weights,
corpora
lutea,
live
and
dead
fetuses,
fetal
weights,
and
resorption
were
reported.
The
maternal
toxicity
LOAEL
of
propiconazole
is
300
mg/
kg/
day,
based
on
severe
clinical
toxicity.
The
maternal
toxicity
NOAEL
is
90
mg/
kg/
day.
Fetotoxic
effects
observed
included
a
high
incidence
of
rudimentary
ribs,
though
not
statistically
significant
but
part
of
dose
related
trend
(
0.7%,
3%
and
39%
in
the
30,
90
and
300
mg/
kg/
day
groups,
respectively
vs.
0%
in
the
controls),
a
high
incidence
of
un­
ossified
sternebrae
(
57%,
p<
0.05
in
the
90
mg
group,
and
72%,
p<
0.01
in
the
300
mg
group
vs.
38%
in
the
controls),
as
well
as
increased
incidence
of
shortened
renal
papillae
(
26%
in
the
90
mg
group
(
not
statistically
significant)
and
39%
in
the
300
mg
group,
p
<
0.01
vs.
23%
in
the
controls)
and
absent
renal
papillae
(
5%
in
the
90
mg
group
(
not
statistically
significant)
and
11%
in
the
300
mg
group,
p
<
0.01
vs.
3%
in
the
controls)
and
dilated
ureter
(
43%
in
the
300
mg
group,
p
<
0.01
vs.
27%
in
the
controls).
External
and
visceral
examination
revealed
a
very
low
incidence
of
cleft
plate
malformations
in
the
90
mg
group
(
0.3%)
and
in
the
300
mg
group
(
0.7%)
and
considered
to
be
"
probably
compound
related".
Historical
controls
in
19
teratology
studies
from
this
laboratory
had
no
incidence
of
cleft
palate.
The
cleft
palate
incidence
in
the
current
study
was
probably
under
reported
because
only
half
of
the
fetuses
were
examined
viscerally.
It
was
also
concluded
that
the
low
incidence
of
this
finding
along
with
skeletal
anomalies
was
indicative
of
delayed
development.
The
cleft
palate
finding
at
300
mg/
kg/
day
was
also
confirmed
in
a
separate
study
(
MRID
40425002)
where
propiconazole
was
administered
to
pregnant
rats
at
0
or
300
mg/
kg/
day
during
the
gestation
period.
The
developmental
toxicity
LOAEL
of
propiconazole
is
90
mg/
kg/
day,
based
on
increased
incidence
of
rudimentary
ribs,
un­
ossified
sternebrae,
as
well
as
increased
Page
45
of
112
incidence
of
shortened
and
absent
renal
papillae
and
increased
cleft
palate.
The
developmental
toxicity
NOAEL
is
30
mg/
kg/
day.

In
an
acceptable/
non­
guideline
developmental
toxicity
study
(
MRID
40425002),
CGA
64250
technical
(
92.1%
purity,
Batch
No.
FL
850083)
was
administered
to
CL:
COBS
CD
(
SD)
BR
VAF/
PLUS
virgin
female
rats
by
oral
gavage
in
aqueous
suspensions
(
3%
corn
starch
containing
0.5%
Tween
80)
at
dose
levels
of
0
or
300
mg/
kg/
day
from
days
6
through
15
of
gestation.
The
control
group
comprised
178
sperm
positive
animals
and
the
compound
treated
group
comprised
189
sperm
positive
animals.
The
study
was
intended
to
confirm
the
finding
of
cleft
palate
in
the
previous
study
(
MRID
40425001).
The
death
of
two
dams
from
the
treated
group
was
considered
incidental.
Severe
maternal
toxicity
was
observed
during
the
treatment
period
beginning
on
gestation
day
6
and
included
a
statistically
significant
increase
in
the
incidence
of
ataxia
(
42%
vs.
0
in
controls),
coma
(
9%
vs.
0
in
controls),
lethargy
(
44%
vs.
0
in
controls),
prostration
(
3%
vs.
0
in
controls),
audible
respiration
(
4%
vs.
0
in
controls),
labored
respiration
(
11%
vs.
0
in
controls),
and
salivation
(
20%
vs.
0
in
controls)
in
addition
to
a
biologically
significant
incidence
of
ptosis
(
0.5%
vs.
0
in
controls),
lacrimation
(
2%
vs.
0
in
controls),
pale
color
(
2%
vs.
0
in
controls)
and
death
(
1%
vs.
0
in
controls).
Mean
food
consumption
was
significantly
lower
(
60­
92%
of
the
control
values,
p<
0.05)
in
the
treated
group
during
the
dosing
period.
Body
weight
gains
were
significantly
lower
(
68%
of
controls,
p<
0.05)
in
dosed
animals
during
GD
6­
16.
There
were
no
significant
differences
between
dosed
and
control
animals
with
respect
to
fetal
sex
ratio
or
mean
number
of
corpora
lutea,
implantation
sites
and
dead
fetuses.
The
mean
number
of
live
fetuses
was
significantly
(
95%
of
controls,
p<
0.05)
lower
in
dosed
animals,
due
to
lower
mean
implantation
sites,
and
higher
mean
total
resorption
in
the
dosed
animals,
although
not
significantly
different
from
controls.
Mean
fetal
weights
for
both
males
and
females
(
95%
of
controls,
p<
0.001)
were
significantly
lower
in
dosed
animals.
Fetuses
were
examined
for
external
abnormalities
only
and
there
were
no
statistically
significant
treatmentrelated
external
gross
observations
among
fetuses.
Cleft
palate
was
reported
in
2/
2064
fetuses
of
dosed
animals
and
0/
1222
of
control
fetuses.
The
incidence
of
cleft
palate
in
controls
for
all
teratology
studies
(
not
including
this
one)
conducted
at
this
laboratory
during
1983­
1985
was
0/
5431.
This
study
confirms
the
findings
of
cleft
palate
in
the
previous
guideline
study
(
MRID
40425001).

DEVELOPMENTAL
­
RABBIT
In
a
developmental
toxicity
study
(
MRID
00265796),
CGA
64250
technical
(
92.1%
purity
propiconazole)
was
administered
to
groups
(
19/
group)
of
artificially
inseminated
New
Zealand
white
rabbits
by
oral
gavage
in
aqueous
suspensions
(
3%
corn
starch
containing
0.5%
Tween
80)
at
dose
levels
of
0,
100,
250
or
400
mg/
kg/
day
from
days
7
through
19
of
gestation.
One
animal
from
each
of
the
mid­
dose
groups
was
found
dead.
In
high­
dose
animals,
5/
19
does
were
sacrificed
early
due
to
abortion
or
early
delivery
(
statistically
significant,
p<
0.05
compared
to
control
1/
19).
In
the
mid
dose
(
250
mg/
kg/
day)
group,
one
doe
aborted
early.
One
control
animal
delivered
early.
Among
animals
of
the
high
dose
group,
an
increased
incidence
of
stool
alterations
(
decreased/
no/
soft;
18/
19
vs.
11/
19
in
controls,
p<
0.05)
was
observed,
possibly
compound
related.
During
the
dosing
period
(
days
7­
19),
the
high
and
mid
dose
animals
had
a
significant
(
p<
0.05)
decrease
in
food
intake
(
43
­
63%
of
the
controls
and
58­
78%
of
the
controls
Page
46
of
112
in
the
high­
and
mid­
dose
groups,
respectively)
and
a
severe
decrease
in
the
maternal
body
weight
gain,
but
rebounded
to
normal
after
withdrawal
of
the
test
compound.
During
GD
7­
10,
the
maternal
animals
had
a
weight
loss
of
0.047
and
0.111
kg
at
250
and
400
mg/
kg,
respectively,
compared
to
a
weight
gain
of
0.018
kg
in
controls.
The
weight
gains
during
GD
10­
20
were
67­
77%
and
11­
43%
of
controls
at
250
and
400
mg/
kg/
day,
respectively.
An
increased
incidence
of
the
formation
of
13th
rib
was
observed
at
400
mg/
kg/
day.
The
incidence
of
this
finding
on
fetuses/
litter
basis
was
2.7,
3.9,
4.1
and
5.3
at
0,
100,
250
and
400
mg/
kg/
day,
respectively.
The
incidence
of
fetuses
at
400
mg/
kg/
day
with
this
finding
was
statistically
significant.
Therefore,
this
finding
was
considered
to
be
treatment­
related.
The
increase
in
the
number
of
resorptions
at
400
mg/
kg/
day
was
caused
by
the
resorption
of
an
entire
litter.
At
400
mg/
kg/
day
there
was
also
an
increased
incidence
of
abortions.
The
maternal
toxicity
LOAEL
of
propiconazole
in
the
rabbit
is
250
mg/
kg/
day,
based
on
reduced
maternal
body
weight
gains
and
decreased
food
consumption
during
the
dosing
period.
The
maternal
toxicity
NOAEL
is
100
mg/
kg/
day.
The
developmental
toxicity
LOAEL
was
400
mg/
kg/
day
based
on
increased
incidence
of
fetuses/
litters
with
13th
rib
and
increased
abortions.
The
developmental
toxicity
NOAEL
was
250
mg/
kg/
day.

4.2.4
Reproductive
Toxicity
Study
In
an
acceptable/
guideline
2­
generation
reproduction
study
(
MRID
00151514),
CGA
64250
technical
(
89.7%
purity
propiconazole,
FL­
830377)
was
administered
to
15
male
and
30
female
Charles
river
CD
rats
at
dose
levels
of
0,
100,
500
or
2500
ppm
(
mean
doses
of
8,
42
and
192
mg/
kg/
day
for
F0
males,
9.4,
43,
223
mg/
kg/
day
for
F0
females,
9.2,
48,
238
mg/
kg/
day
for
F1
males
and
10,
52,
263
mg/
kg/
day
for
F1
females)
in
the
diet.
Test
diets
were
administered
to
both
F0
and
F1
generation
rats
during
pre­
mating
period
and
throughout
gestation
and
lactation
periods.
Parental
Toxicity:
No
compound­
related
clinical
observations
or
mortality
were
reported.
Female
body
weights
in
the
F0
and
F1
generation
were
significantly
reduced
in
the
high
dose
group
at
most
of
the
body
weight
intervals(
82­
94%
of
the
controls,
p<
0.05
and
0.01);
body
weight
gains
were
also
significantly
reduced
during
pre­
mating
(
12
weeks)
as
well
as
gestation
and
lactation
periods(
77­
85%
of
controls,
p<
0.01).
Correspondingly,
high
dose
females
also
had
significantly
reduced
food
intake
(
83­
88%
of
controls).
In
the
F0
and
F1
generation
male
body
weights
were
reduced
in
the
high
dose
groups
compared
to
controls
(
not
statistically
significant);
body
weight
gains
in
this
group
was
91­
94%
of
controls
for
the
pre­
mating
period
and
during
the
entire
duration
of
the
study
(
7
months).
Food
consumption
was
reduced
significantly
in
high
dose
F0
males
at
week
1
(
65%
of
the
control,
p<
0.01)
and
week
7
(
86%
of
the
control,
p<
0.01)
and
in
high
dose
F1
males
and
females
at
week
2,
6
and
10
(
84­
88%
of
controls).
Histological
examinations
revealed
that
hepatic
"
cellular
swelling"
was
significantly
increased
in
mid­
dose
males
and
high­
dose
males
and
females
of
the
F0
generation.
In
the
F1
parental
animals,
increase
in
the
incidence
of
this
finding
was
significant
for
both
sexes
in
the
mid­
and
high­
dose
groups.
The
incidence
of
"
hepatic
clear­
cell
change"
was
significantly
increased
in
F0
high­
dose
males,
F1
mid­
dose
and
high­
dose
males
and
F1
high­
dose
females
(
p<
0.05).
The
LOAEL
for
parental
toxicity
is
500
ppm
(
42
mg/
kg/
day)
based
on
increased
hepatic
clear­
cell
change
and
the
NOAEL
for
parental
toxicity
is
100
ppm
(
8
mg/
kg/
day).
Reproductive
parameters
(
mating,
fecundity,
gestation,
male
and
female
fertility
indices,
litter
resorptions
and
gestation
duration)
were
comparable
in
all
groups.
Offspring
Toxicity:
The
number
and
percent
of
viable
Page
47
of
112
pups
at
birth
and
surviving
through
weaning
were
comparable
between
the
dose
groups
and
controls
for
both
the
F1a
and
F1b
litters.
In
the
F2a
litters,
however,
the
number
of
pups
delivered,
delivered
viable
and
surviving
to
day
4
of
lactation
were
significantly
(
p<
0.01)
reduced
in
the
high­
dose
group.
The
percentages
of
high­
dose
pups
delivered
viable
and
surviving
to
day
4
were
also
reduced
(
not
statistically
significant).
The
F2b
litters
of
these
dams
had
significantly
reduced
survival
rates
(
both
number
and
percent
of
surviving
pups)
at
lactation
days
7,
14,
and
21.
The
mean
body
weights
of
high­
dose
progeny
were
significantly
reduced
at
days
14
and
21
for
pups
of
both
generations
(
72­
81%
of
controls).
Reductions
were
also
significant
on
days
4
and
7
(
except
for
F1b
litters)
and
at
birth
(
F2b
litters
only).
At
necropsy,
no
treatment
related
anomalies,
organ
weight
changes
and
gross
pathology
findings
were
noted
in
pups.
Histopathological
evaluation
of
selected
organs
from
F1b
and
F2b
progeny
revealed
significantly
(
p<
0.01)
increased
incidences
of
hepatic
"
cellular
swelling"
in
high­
dose
males
and
females.
This
was
considered
to
be
a
compound
related
effect.
The
LOAEL
and
NOAEL
for
offspring
toxicity
are
at
2500
ppm
(
192­
263
mg/
kg/
day)
and
500
ppm
(
43­
52
mg/
kg/
day),
respectively,
based
on
decreased
offspring
survival
and
body
weights
and
an
increased
incidence
of
hepatic
lesions
(
cellular
swelling)
at
2500
ppm.

4.2.5
Additional
Information
from
Literature
Sources
In
a
published
study,
propiconazole
(
Tilt
100
EC
in
the
form
of
10%
solution)
was
administered
to
groups
of
pregnant
female
albino
rats
(
15/
dose)
at
0,
75.85
or
151.70
mg
(
ai)/
kg/
day
on
days
6­
15
of
gestation
(
Hassan,
1993.
Embryotoxic
and
teratogenic
effects
of
the
organic
fungicide
tilt
in
albino
rats.
Bull.
Fac.
Pharm.,
Cairo
University
31(
3):
459­
463).
Rats
were
sacrificed
on
day
20
of
gestation.
Post­
implantation
deaths,
resorption
sites
and
dead
fetuses
were
counted.
Fetuses
were
examined
for
morphological,
visceral
and
skeletal
malformations.
Propiconazole
was
fetotoxic
at
both
doses
causing
significant
(
p<
0.05)
increased
fetal
resorptions
(
8
and
21%
at
the
low
and
high
dose
vs.
0%
in
the
control),
increased
fetal
deaths
(
10
and
24%
at
the
low
and
high
doses
vs.
2%
in
the
control)
and
decreased
fetal
weight).
The
mean
number
of
stunted
fetuses
was
significantly
higher
(
p<
0.05)
at
both
doses
(
1.43
and
3.57)
at
the
low
and
high
dose
vs.
0.13
in
the
control),
noting
incomplete
ossification
of
the
skull,
caudal
vertebrae
and
digits,
extra
rib
(
14th
rib)
and
missing
sternebrae.
Malformations
of
the
lung
and
kidneys
were
reported.
No
maternal
toxicity
was
reported
at
either
dose.
The
LOAEL
for
developmental
toxicity
in
this
study
is
76
mg/
kg/
day
(
the
lowest
dose
tested).
A
NOAEL
is
not
established.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
concluded
that
there
is
low
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
propiconazole.
In
the
developmental
toxicity
study
in
rats,
the
HIARC
considered
the
fetal
effects
observed
in
this
study
at
a
dose
lower
than
that
evoking
maternal
toxicity
to
be
quantitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
propiconazole.
In
the
developmental
toxicity
study
in
rabbits,
the
HIARC
determined
that
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
propiconazole
was
observed
in
this
study.
In
the
2­
generation
reproduction
study
in
rats,
the
HIARC
determined
that
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
Page
48
of
112
of
neonates
(
as
compared
to
adults)
to
pre­
and/
or
postnatal
exposure
to
propiconazole
was
observed
in
this
study.

4.2.6.1
Determination
of
Susceptibility
The
HIARC
concluded
that
there
is
low
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
Propiconazole.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Since
there
is
quantitative
evidence
of
increased
susceptibility
of
the
young
following
exposure
to
propiconazole
in
the
developmental
rat
study,
HIARC
performed
a
Degree
of
Concern
Analysis
to:
1)
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identify
any
residual
uncertainties
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
If
residual
uncertainties
are
identified,
HIARC
examines
whether
these
residual
uncertainties
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
In
the
developmental
rat
study,
quantitative
susceptibility
was
evidenced
as
increased
incidence
of
rudimentary
ribs,
unossified
sternebrae,
as
well
as
increased
incidence
of
shortened
and
absent
renal
papillae
and
increased
cleft
palate
at
(
90
mg/
kg/
day)
a
dose
lower
than
that
evoking
maternal
toxicity
(
severe
clinical
toxicity
at
300
mg/
kg/
day).
Considering
the
overall
toxicity
profile
and
the
doses
and
endpoints
selected
for
risk
assessment
for
propiconazole,
the
HIARC
characterized
the
degree
of
concern
for
the
effects
observed
in
this
study
as
low,
noting
that
there
is
a
clear
NOAEL
and
well­
characterized
dose
response
for
the
developmental
effects
observed.
No
residual
uncertainties
were
identified.
The
NOAEL
for
developmental
effects
in
this
study
(
30
mg/
kg/
day)
is
used
as
the
basis
for
the
acute
Reference
dose
(
aRfD)
for
the
female
13­
50
population
subgroup
as
well
as
for
short­
term
incidental
oral,
dermal
and
inhalation
endpoints.
For
all
other
toxicity
endpoints
established
for
propiconazole,
a
NOAEL
lower
than
this
developmental
NOAEL
is
used.
Based
upon
the
above­
described
data,
no
special
FQPA
safety
factor
is
needed
(
i.
e.
1X).

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
On
December
11,
2001
(
reaffirmed
February
13,
2003
and
December
9,
2003),
HIARC
recommended
that
the
decision
on
the
need
for
a
developmental
neurotoxicity
study
conducted
with
propiconazole
is
held
in
reserve
pending
submission
and
evaluation
of
an
acute
neurotoxicity
study
in
the
rat.
In
December,
2005,
the
Propiconazole
RED
risk
assessment
team,
based
on
all
of
the
data
available
(
including
the
acute
neurotoxicity
study),
recommended
that
a
developmental
neurotoxicity
study
in
the
rat
not
be
required
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
Neurotoxic
effects
(
ataxia,
lethargy,
salivation,
rales)
were
noted
in
pregnant
rats
administered
high
propiconazole
doses
(
360
mg/
kg/
day)
during
gestation.
In
view
of
this,
the
HIARC
determined
that
an
acute
neurotoxicity
(
ACN)
study
was
required
and
added
a
3X
database
Page
49
of
112
uncertainty
factor
(
UFDB)
for
acute
and
short
term
exposure
scenarios.
The
rat
acute
neurotoxicity
study
submitted
in
July,
2005,
confirmed
the
clinical
signs
seen
at
relatively
high
doses
of
propiconazole.

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
There
is
no
evidence
of
neurotoxicity,
neuropathology
or
abnormalities
in
the
development
of
the
fetal
nervous
system
from
the
available
toxicity
studies
conducted
with
propiconazole.
In
the
rat
acute
neurotoxicity
study,
there
was
evidence
of
mild
neurobehavioral
effects
at
300
mg/
kg,
but
no
evidence
of
neuropathology
from
propiconazole
administration.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
On
February
13,
2003,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reassessed
FQPA
requirements
(
TXR
0052277)
for
propiconazole
in
response
to
questions
posed
by
the
Natural
Resources
Defense
Council
(
NRDC).
No
new
data
have
been
reviewed
and
no
changes
were
made
to
the
toxicology
endpoints
previously
selected
for
Propiconazole
(
TXR
0050439
&
0051703).
Based
on
the
rat
acute
neurotoxicity
study
submitted
in
July,
2005,
a
new
acute
reference
dose
for
the
general
population
was
determined.
The
rat
acute
neurotoxicity
study
also
serves
as
the
basis
for
short
term
incidental
oral,
dermal
and
inhalation
scenarios.

4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
The
end
point
selected
was
based
on
a
developmental
NOAEL
of
30
mg/
kg/
day
from
the
developmental
toxicity
study
in
rats
(
MRID
40425001)
where
developmental
toxicity
was
manifested
as
increased
incidence
of
rudimentary
ribs,
unossified
sternebrae,
as
well
as
increased
incidence
of
shortened
and
absent
renal
papillae
and
increased
cleft
palate
at
the
LOAEL
of
90
mg/
kg/
day.
An
Uncertainty
Factor
(
UF):
100
(
10X
for
inter­
species
extrapolation,
10X
for
intraspecies
variability)
was
applied.
The
developmental
effects
are
presumed
to
occur
after
a
single
exposure
and
are
appropriate
for
the
population
of
concern
(
females
13­
49).

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
The
endpoint
selected
was
based
on
a
NOAEL
of
30
mg/
kg/
day
from
the
acute
neurotoxicity
study
in
rats
(
MRID
46604601)
where
clinical
signs
of
toxicity
(
piloerection
in
one
male,
diarrhea
in
one
female,
tip
toe
gait
in
3
females)
occurred
after
administration
of
100
mg/
kg/
day
propiconazole.
An
Uncertainty
Factor
(
UF)
of
100
(
10X
for
inter­
species
extrapolation
and
10X
for
intra­
species
variability)
was
applied.
Acute
RfD
(
Females
13­
49
years
old)
=
30
mg/
kg
(
NOAEL)
=
0.3
mg/
kg
100
(
UF)
Page
50
of
112
4.4.3
Chronic
Reference
Dose
(
cRfD)

A
24­
month
propiconazole
dietary
oncogenicity
acceptable/
guideline
study
(
MRIDs
00129570
and
93194037)
in
CD­
1
mice
was
selected
by
the
HIARC
for
deriving
the
chronic
RfD.
This
study
is
described
in
detail
at
the
end
of
this
section.
The
endpoint
selected
for
establishing
the
Chronic
RfD
was
based
on
non­
neoplastic
liver
effects
(
increased
liver
weight
in
males
and
increase
in
liver
lesions:
masses/
raised
areas/
swellings/
nodular
areas
mainly)
occurring
at
50
mg/
kg/
day
with
a
NOAEL
of
10
mg/
kg/
day.
An
Uncertainty
Factor
(
UF)
of
100
(
10X
for
interspecies
extrapolation,
10X
for
intra­
species
variability)
was
applied.
This
dose
was
considered
appropriate
since
effects
occurred
after
chronic
exposures.
The
HIARC
noted
that
the
NOAEL
of
2.7
mg/
kg/
day
in
a
3­
month
oral
feeding
toxicity
study
in
mice
is
lower
than
the
10
mg/
kg/
day
selected
for
this
risk
assessment.
The
HIARC
did
not
select
the
lower
NOAEL
(
2.7
mg/
kg/
day)
because:
a)
of
the
wide
dose
spread
between
the
NOAEL
(
2.7
mg/
kg/
day)
and
the
LOAEL
(
65
mg/
kg/
day)
in
that
study;
b)
the
LOAEL
(
50
mg/
kg/
day)
in
the
selected
study
is
lower
than
the
LOAEL
(
65
mg/
kg/
day)
of
the
3­
month
mouse
oral
feeding
study;
and
c)
the
liver
toxicity
seen
in
this
study
is
consistent
with
that
seen
in
an
18­
month
mice
and
2­
generation
reproduction
studies.
In
an
18­
month
oncogenicity
study
in
mice,
the
NOAEL
for
liver
toxicity
was
11
mg/
kg/
day
and
the
LOAEL
59
mg/
kg/
day).
In
a
24­
month
feeding
study
in
rats,
the
NOAEL
for
liver
toxicity
was
18
mg/
kg/
day
and
the
LOAEL
96
mg/
kg/
day).
In
2­
generation
reproduction
study
in
rats,
the
NOAEL
for
liver
toxicity
was
8
mg/
kg/
day
and
the
LOAEL
42
mg/
kg/
day).
The
HIARC
did
not
select
the
dog
study
since
stomach
irritations
were
attributed
to
local
effects
and
not
systemic
toxicity,
and
target
organ
(
liver)
toxicity
seen
in
mice
and
rats
was
not
seen
in
dogs.

4.4.4.1
Incidental
Oral
Exposure
(
Short
Term
1­
30
days)
The
endpoint
selected
was
based
on
a
NOAEL
of
30
mg/
kg/
day
from
the
acute
neurotoxicity
study
in
rats
(
MRID
46604601)
where
clinical
signs
of
toxicity
(
piloerection
in
one
male,
diarrhea
in
one
female,
tip
toe
gait
in
3
females)
occurred
after
administration
of
100
mg/
kg/
day
propiconazole.
An
Uncertainty
Factor
(
UF)
of
100
(
10X
for
inter­
species
extrapolation
and
10X
for
intra­
species
variability)
was
applied.
This
endpoint
is
relevant
to
the
population
of
concern
(
infants
and
children).

4.4.4.2
Incidental
Oral
Exposure
(
Intermediate
Term
1­
6
months)
A
24­
month
propiconazole
dietary
oncogenicity
acceptable/
guideline
study
(
MRIDs
00129570
and
93194037)
in
CD­
1
mice
was
selected
by
the
HIARC
for
deriving
this
endpoint
with
a
NOAEL
of
10
mg/
kg/
day.
Acute
RfD
(
General
Pop.)
=
30
mg/
kg
(
NOAEL)
=
0.3
mg/
kg
100
(
UF)

Chronic
RfD
=
10
mg/
kg/
day
(
NOAEL)
=
0.1
mg/
kg/
day
100
(
UF)
Page
51
of
112
4.4.5
Dermal
Absorption
HIARC
selected
a
40%
dermal
absorption
factor
based
on
the
average
dermal
absorption
of
propiconazole
over
a
10
hour
exposure
period
in
rats
at
an
exposure
level
of
0.01
mg/
cm2
(
MRID's
42415701,
45345901).
Although
another
dermal
absorption
factor
for
propiconazole
of
1%
was
used
in
a
recent
Section
18
risk
assessment,
it
is
not
clear
what
the
basis
for
the
lower
absorption
factor
was.
Since
the
current
factor
of
40%
is
based
on
a
dermal
absorption
study
in
the
rat,
the
propiconazole
risk
assessment
team
believes
that
this
value
is
the
appropriate
one
to
use.

4.4.6.1
Dermal
Exposure
(
Short
Term
1­
30)
HIARC
had
selected
a
developmental
NOAEL
of
30
mg/
kg/
day
from
the
developmental
rat
study
(
MRID
40425001)
to
assess
short
term
dermal
risks
to
females
13­
49,
and
a
maternal
NOAEL
of
90
mg/
kg/
day
from
the
developmental
rat
study
to
assess
dermal
risks
to
all
other
population
subgroups.
The
propiconazole
risk
assessment
team
recommends
that
the
recently
submitted
rat
acute
neurotoxicity
study
(
MRID
46604601)
with
a
NOAEL
of
30
mg/
kg/
day
is
appropriate
for
assessing
risks
of
this
exposure
duration
and
is
applicable
to
all
population
subgroups.
Since
an
oral
study
was
selected,
a
40%
dermal
absorption
factor
is
used
for
route
to
route
extrapolation
4.4.6.3
Dermal
Exposure
(
Intermediate
1­
6
months
and
long
term
>
6
months
HIARC
selected
NOAEL
of
10
mg/
kg/
day
based
on
non­
neoplastic
liver
effects
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly))
at
50
mg/
kg/
day
of
propiconazole
administration
derived
from
a
chronic/
oncogenicity
study
in
mice
(
MRID
00129570
and
93194037).

4.4.7.1
Inhalation
Exposure
(
Short
Term
1­
30
days)

HIARC
had
selected
a
developmental
NOAEL
of
30
mg/
kg/
day
based
on
increased
incidence
of
rudimentary
ribs,
unossified
sternebrae
and
shortened
and
absent
renal
papillae,
and
increased
cleft
palate
seen
at
the
developmental
LOAEL
of
90
mg/
kg/
day
in
a
developmental
rat
study
(
MRID
40425001).
The
propiconazole
risk
assessment
team
recommends
that
the
recently
submitted
rat
acute
neurotoxicity
study
(
MRID
46604601)
with
a
NOAEL
of
30
mg/
kg/
day
is
appropriate
for
assessing
inhalation
risks
of
this
exposure
duration
and
is
applicable
to
all
population
subgroups.
An
inhalation
absorption
factor
of
100%
(
default
value
assuming
equivalent
inhalation
and
oral
absorption)
will
be
used
for
route­
to­
route
extrapolation.

4.4.7.2
Inhalation
Exposure
(
Intermediate
1­
6
months
and
long
term
>
6
months)

HIARC
selected
NOAEL
of
10
mg/
kg/
day
based
on
non­
neoplastic
liver
effects
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly))
at
50
mg/
kg/
day
of
propiconazole
administration
derived
from
a
chronic/
oncogenicity
study
in
mice
(
MRID
00129570
and
93194037).
An
inhalation
absorption
factor
of
100%
Page
52
of
112
(
default
value
assuming
equivalent
inhalation
and
oral
absorption)
will
be
used
for
route­
to­
route
extrapolation.

4.4.8
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment
as
recommended
by
HIARC.

Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
100
100
100
Residential
(
Non­
Dietary)
Exposure
Oral
100
100
NA
Dermal
100
100
100
Inhalation
100
100
100
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
The
toxicity
endpoints
selected
for
these
routes
of
exposure
may
be
aggregated
as
follows.
°
For
the
General
Population,
including
infants
and
children,
the
short
term
oral
exposure
can
be
aggregated
with
the
short­
term
dermal
and
inhalation
due
to
a
common
toxicological
endpoint
(
clinical
signs
in
the
ACN
study).
°
A
common
toxicological
endpoint
was
identified
for
intermediate­
and
long­
term
oral,
dermal
(
oral
equivalent)
and
inhalation
(
oral
equivalent)
routes.
These
routes
can
be
aggregated
for
these
scenarios
for
the
appropriate
population.

4.4.10
Classification
of
Carcinogenic
Potential
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
classified
propiconazole
as
Group
C
­
possible
human
carcinogen
and
recommended
that
for
the
purpose
of
risk
characterization
the
reference
Dose
(
RfD)
approach
should
be
used
and
would
be
protective
(
HED
Doc.
No.
009771,
April
15,
1992
meeting).
This
classification
was
based
on
increased
hepatocellular
adenomas
and
combined
adenomas/
carcinomas
(
increased
trend
and
pairwise
comparison,
p<
0.01)
and
increased
hepatocellular
carcinomas
(
increased
trend,
p<
0.05)
in
male
mice
at
the
high
dose
(
2500
ppm)
in
an
oral
feeding
oncogenicity
study
(
MRID
00129570).
There
was
no
treatment
related
increased
tumor
response
in
female
mice.
In
a
rat
study
conducted
with
acceptable
doses
of
propiconazole
(
0,
100,
500,
or
2500
ppm),
no
tumorogenic
response
was
observed
either
(
MRID
00250784).
The
CPRC
determined
that
the
high
dose
of
2500
used
in
the
mouse
study
was
excessively
toxic
(
based
on
survival,
liver
clinical
pathology,
histopathology,
and
body
Page
53
of
112
weight
and
body
weight
gains)
but
that
the
other
doses
(
100
&
500
ppm)
were
not
adequate
for
assessing
the
carcinogenic
potential
of
propiconazole.
The
2500
ppm
used
in
the
oncogenicity
study
exceeded
the
MTD
demonstrated
in
the
90
day
study
(
MRID
42050501
&
42050502)
based
on
the
endpoint
of
hepatic
necrosis.

Subsequently
the
Registrant
conducted
an
18­
month
oncogenicity
study
in
male
CD­
1
mice
at
0,
100,
500
or
850
pm
(
MRID
44381401).
There
was
a
treatment
related
increase
in
hepatocellular
adenoma
incidences
(
20
%,
p<
0.05)
and
total
hepatocellular
neoplasia
(
adenomas
and
carcinomas)
of
24%,
p<
0.05,
at
the
850
ppm
exposure
level
when
compared
to
concurrent
controls
which
had
unusually
low
incidence
of
2%
of
adenomas
and
a
4%
of
total
neoplasia
.
Based
on
HED
standard
statistical
computations,
there
was
a
significant
dose­
related
increasing
trend,
and
a
significant
difference
in
the
pair­
wise
comparison
of
the
850
ppm
dose
group
with
the
concurrent
controls,
for
liver
adenomas
and/
or
carcinomas
combined,
both
at
p
<
0.01
(
Memo:
Feb.
1,
1999
from
Lori
L.
Brunsman,
Statistician
to
SanYvette
Williams­
Foy,
Veterinary
Toxicologist).
However,
this
increase
in
the
total
neoplasm
was
driven
primarily
by
the
adenomas.
Dosing
was
considered
adequate
based
on
the
body
weight
gain
and
hepatotoxic
effects
seen
at
500
and
850
ppm.
The
percentage
adenomas
and
carcinomas
were
within
the
range
of
the
inadequate
historical
control
data
(
the
collection
dates
were
not
specified
and
were
not
collected
in
the
testing
facility)
submitted
with
the
study
report.
Subsequently,
the
Registrant
submitted
additional
control
data
on
five
groups
of
CD­
1
male
mice
generated
within
the
approximate
time
frame
of
the
original
study
and
in
the
same
testing
facility
under
similar
experimental
conditions
(
MRID
45215804)
concerning
the
spontaneous
occurrence
of
liver
tumors.
The
new
data
demonstrated
primary
neoplastic
lesions
including
hepatocellular
adenoma
(
6­
18%)
and
hepatocellular
carcinoma
(
8­
16%)
corresponding
to
14­
30%
male
CD­
1
mice
bearing
hepatocellular
neoplasia,
hemangioma
(
2%)
and
hemangiosarcoma
(
2%),
and
foci
of
cellular
alteration
(
2­
4%)
were
observed
in
the
livers
of
males.
These
new
data
are
more
consistent
with
previous
historical
control
data
for
the
CD
mouse
and
indicate
that
the
study
control
in
the
second
mouse
study
may
be
low.
The
tumor
incidence
observed
in
male
livers
at
the
850
ppm
dose
is
within
the
range
of
the
new
historical
data.
However,
propiconazole
will
continue
to
be
classified
as
possible
human
carcinogen
(
group
C)
and
for
the
purpose
of
risk
characterization
the
reference
Dose
(
RfD)
approach
will
continue
to
be
used.

Mechanistic
studies
have
been
conducted
demonstrating
that
propiconazole
is
a
strong
phenobarbital­
type
inducer
of
xenobiotic
metabolizing
enzymes
in
the
mouse
(
MRID
45215803)
and
causes
hepatocellular
proliferation
in
a
manner
similar
to
that
of
phenobarbital
(
MRID
45215802).
Based
on
the
findings
in
these
studies
and
the
scientific
published
literature,
the
Registrant
advanced
a
mechanism
for
the
tumor
induction
in
male
mice
based
on
the
combined
mitogenic,
excessive
P450
inductive
and
hepatotoxic
effects
of
propiconazole
leading
to
early
hepatocyte
damage
(
accumulation
of
irreversibly
altered
cells)
leading
to
progressive
preneoplastic
changes
(
clonal
expansion
of
pre­
neoplastic
cells)
and
eventually
leading
to
hepatocellular
tumor
formation
at
excessive
doses
and
that
propiconazole
should
continue
to
be
regulated
by
a
margin­
of­
exposure
approach
(
MRID
45215805).
While
we
have
not
referred
completely
this
new
data
to
our
CARC,
the
rationale
supported
by
the
registrant
seems
reasonable
and
consistent
with
our
previous
classification
of
possible
human
carcinogen
using
the
RfD
for
risk
assessment
and
as
being
protective
of
the
carcinogenic
effect.
Page
54
of
112
Table
4.4a.
Data
Requirements
for
Propiconazole
Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity
...............................................................
870.1200
Acute
Dermal
Toxicity...........................................................
870.1300
Acute
Inhalation
Toxicity.......................................................
870.2400
Primary
Eye
Irritation
............................................................
870.2500
Primary
Dermal
Irritation.......................................................
870.2600
Dermal
Sensitization               
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
Rodent)
......................................................
870.3150
Oral
Subchronic
(
Non­
Rodent)...............................................
870.3200
21­
Day
Dermal
......................................................................
870.3250
90­
Day
Dermal
......................................................................
870.3465
28­
Day
Inhalation
               
yes
yes
yes
no
yes
yes
yes
yes
no
­
870.3700a
Developmental
Toxicity
(
Rodent)
..........................................
870.3700b
Developmental
Toxicity(
Non­
rodent)....................................
870.3800
Reproduction                 
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
Rodent)
.....................................................
870.4100b
Chronic
Toxicity
(
Non­
rodent)...............................................
870.4200a
Oncogenicity
(
Rat).................................................................
870.4200b
Oncogenicity
(
Mouse)............................................................
870.4300
Chronic/
Oncogenicity
             ..
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial...............................
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian..........................
870.5395
Mutagenicity 
Structural
Chromosomal
Aberrations
.............
870.5450
Mutagenicity 
Dominant
Lethal
Assay..................................
870.5550
Mutagenicity 
Unscheduled
DNA
Synthesis
........................
870.5575
Mutagenicity 
Gene
Mutation
 
bacterial
     
 
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
Hen)
.............................................
870.6100b
90­
Day
Neurotoxicity
Hen)
....................................................
870.6200a
Acute
Neurotoxicity.
Screening
Battery
(
Rat).........................
870.6200b
90
Day
Neurotoxicity
Screening
Battery
(
Rat)........................
870.6300
Develop.
Neurotoxicity             .
no
no
yes
no
no
­
yes
­

870.7485
General
Metabolism...............................................................
870.7600
Dermal
Penetration
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects.............................................................
Acute
Oral
(
Rat)
....................................................................
Subchronic
Oral
(
Rat)
............................................................
Six­
month
Oral
(
Dog)
    .
no
no
no
­
­
­
Page
55
of
112
Table
4.4b.
Summary
of
Toxicological
Doses
and
Endpoints
for
Propiconazole
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
49)
Dev.
NOAEL
=
30
mg
ai/
kg/
day
UF
=
100
Acute
RfD
=
0.3
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.3
mg/
kg/
day
Developmental
Toxicity
Study
­
Rats.
Developmental
toxicity:
increased
incidence
of
rudimentary
ribs,
cleft
palate
malformations
(
0.3%)
unossified
sternebrae,
as
well
as
increased
incidence
of
shortened
and
absent
renal
papillae.

Acute
Dietary
(
General
Population
including
infants
and
children)
NOAEL
=
30
mg
kg/
day
UF
=
100
Acute
RfD
=
0.3
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.3
mg/
kg/
day
Acute
Neurotoxicity
Study
 
Rats.

Clinical
signs
(
piloerection,
diarrhea,
tiptoe
gait).

Chronic
Dietary
(
All
populations)
NOAEL
=
10
mg
ai/
kg/
day
UF
=
100
Chronic
RfD
=
0.1
mg/
kg/
day
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.1
mg/
kg/
day
24
Month
Oncogenicity
Study
­
Mice.
Liver
toxicity
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly)

Short­
Term
(
1­
30
days)
Incidental
Oral
NOAEL
=
30
mg
kg/
day
Residential
MOE
=
100
Occupational
=
NA
Acute
Neurotoxicity
Study
 
Rats.

Clinical
signs
(
piloerection,
diarrhea,
tiptoe
gait).

Intermediate­
Term
(
1
­
6
months)
Incidental
Oral
NOAEL=
10
mg
ai/
kg/
day
Residential
MOE
=
100
Occupational
=
NA
24
Month
Oncogenicity
Study
­
Mice.
Liver
toxicity
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly)

Short­
Term
(
1
­
30
days)
Dermal
NOAEL=
30
mg
ai/
kg/
day
Dermal
absorption
rate
=
40%
Residential
MOE
=
100
Occupational
MOE
=
100
Acute
Neurotoxicity
Study
 
Rats.

Clinical
signs
(
piloerection,
diarrhea,
tiptoe
gait).
Page
56
of
112
Intermediate­
Term
dermal
(
1
­
6
months)
and
Long­
Term
dermal
(>
6
months)
Oral
NOAEL=
10
mg
ai/
kg/
day
(
Dermal
absorption
rate
=
40%)
Residential
MOE
=
100
Occupational
MOE
=
100
24
Month
Oncogenicity
Study
­
Mice.
Liver
toxicity
(
increased
liver
weight
in
males
and
increase
in
liver
lesions)
(
masses/
raised
areas/
swellings/
nodular
areas
mainly)

Short­
Term
(
1
­
30
days)
Inhalation
NOAEL=
30
mg/
kg/
day
(
Inhalation
absorption
rate
=
100%)
Residential
MOE
=
100
Occupational
MOE
=
100
Acute
Neurotoxicity
Study
 
Rats.

Clinical
signs
(
piloerection,
diarrhea,
tiptoe
gait).

Intermediate­
Term
(
1
­
6
months)
and
Long­
Term
Inhalation
(>
6
months)
Oral
NOAEL=
10
mg/
kg/
day
(
Inhalation
absorption
rate
=
100%)
Residential
MOE
=
100
Occupational
MOE
=
100
24
Month
Oncogenicity
Study
­
Mice.
Liver
toxicity
(
increased
liver
weight
in
males
and
increase
in
liver
lesions
(
masses/
raised
areas/
swellings/
nodular
areas
mainly)

Cancer
(
Oral,
dermal,
inhalation)
Group
C,
possible
human
carcinogen,
RfD
approach
for
risk
characterization.

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
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

4.5
Special
FQPA
Safety
Factor
Based
upon
the
above­
described
data,
no
special
FQPA
safety
factor
is
needed
(
i.
e.
1X)
since
there
are
no
residual
uncertainties
for
pre
and/
or
post
natal
toxicity.
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

4.6
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
Page
57
of
112
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
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

In
the
available
toxicity
studies
on
propiconazole,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.

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

5.0
Public
Health
Data
5.1
Incident
Reports
(
HED
memo
of
J.
Blondell,
D319239,
07/
26/
05)

From
the
review
of
the
Incident
Data
System,
it
appears
that
a
majority
of
cases
involved
skin
symptoms
such
as
rash,
itching,
and
skin
irritation
and
respiratory
effects
such
as
difficulty
breathing.
Poison
Control
Center
data
would
tend
to
support
the
Incident
Data
System
results;
dermal
irritation,
erythema,
and
difficulty
breathing
were
among
the
most
common
effects
reported.

Measures
to
limit
skin
and
respiratory
exposure
are
recommended
for
this
pesticide.
Appropriate
personal
protective
equipment
to
protect
the
skin
is
also
recommended
for
both
handlers
and
field
workers
who
are
likely
to
have
substantial
contact
with
propiconazole.

6.0
EXPOSURE
CHARACTERIZATION/
ASSESSMENT
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
Propiconazole
[
1­[[
2­(
2,4­
dichlorophenyl)­
4­
propyl­
1,3­
dioxolan­
2­
yl]
methyl]­
1H­
1,2,4­
triazole]
is
a
systemic
broad­
spectrum
fungicide
registered
for
treatment
of
disease
in/
on
a
variety
of
crops.
Propiconazole
end­
use
products
are
marketed
in
the
United
States
under
the
trade
names
Tilt
®
,
Alamo
®
,
Banner
®
,
and
Orbit
®
.
Recently,
propiconazole
is
also
registered
for
use
on
a
variety
of
crops
under
the
trade
names
of
Stratego
 
Twin­
Pak
 
and
Stratego
 
,
which
are
end­
use
products
containing
a
mixture
of
trifloxystrobin
and
propiconazole.
The
amount
of
active
ingredient
range
from
11.4%
to
45%.
The
propiconazole
formulations
registered
for
food/
feed
uses
include
emulsifiable
concentrate
(
EC)
and
flowable
concentrate
(
FlC)
formulations.
Except
for
pineapple
and
sugarcane
(
seed
pieces),
all
uses
are
pre­
harvest
Page
58
of
112
foliar
application,
ground
or
air.
Pineapple
and
sugarcane
uses
are
post­
harvest
uses.
The
application
rates
range
from
0.081
lbs
ai/
A/
season
(
such
as
wheat)
to
0.90
lbs
ai/
A/
season
(
grass
grown
for
seed).

Available
plant
metabolism
data
(
primary
and
rotated
crops)
show
that
plants
absorb,
metabolize
and
translocate
propiconazole
throughout
the
plant.
A
major
metabolic
pathway
in
plants
appears
to
be
hydroxylation
(
primarily
of
the
beta­
carbon)
of
the
n­
propyl
group
on
the
dioxolane
ring
of
the
cis/
trans
isomers
of
propiconazole.
These
metabolites
appear
to
readily
form
sugar
conjugates.
The
majority
of
TRR
was
found
in
the
stalks,
such
as
peanut
stalk,
wheat
forage
and
straw,
grape
leaves,
and
celery
stalks.
A
possible
alternative
pathway
involves
reductive
deketalization
of
the
dioxolane
ring
and
sugar
conjugation
of
the
resulting
metabolite.
The
alkyl
bridge
between
the
phenyl
and
triazole
rings
is
metabolized
and
free
triazole,
as
1H­
1,2,4­
triazole,
is
released.
The
free
triazole
is
readily
conjugated
with
the
amino
acid,
serine/
alanine,
forming
triazole
aniline
which
is
further
metabolized
to
triazole
acetic
acid
possibly
through
the
intermediate
formation
of
triazole
lactic
acid.
As
mentioned
earlier,
the
triazole
issue
will
be
addressed
separately.
The
HED
MARC
concluded
that
for
plants
and
animals,
residues
of
propiconazole
and
all
its
metabolites
containing
the
2,4­
dichlorophenyl
moiety
(
2,4­
DCBA),
including
conjugates,
are
of
concern
and
should
be
included
in
the
dietary
(
food)
risk
assessments,
propiconazole
per
se
should
be
included
in
the
dietary
(
water)
risk
assessments.
For
tolerance
expression,
MARC
concluded
that
the
current
tolerance
expression
for
propiconazole
should
be
amended
to
include
residues
of
propiconazole
per
se
only.
For
enforcement
purpose,
the
Multiresidue
Methods
Section
302
(
Luke
Method;
Protocol
D)
picks
up
parent
propiconazole.

Tolerances
are
established
for
residues
of
propiconazole
and
its
metabolites
determined
as
2,4­
dichlorobenzoic
acid
and
expressed
as
parent
compound
in/
on
various
plant
and
animal
commodities
[
40
CFR
§
180.434].
The
reassessed
tolerances
will
be
expressed
as
propiconazole
per
se.
As
a
result,
in
some
cases
the
tolerance
levels
will
be
over
estimated,
due
to
the
fact
that
the
analytical
data
collection
method
is
a
moiety
method
that
detects
all
residues
convertible
to
2,4­
DCBA,
and
the
field
data
were
reported
as
propiconazole
and
all
its
metabolites
containing
the
2,4­
DCBA,
as
a
result,
HED
is
unable
to
separate
out
the
parent
residue
from
the
metabolites
at
this
time.
HED
recommends
that
the
registrant
analyze
parent
and
metabolites
separately
in
all
future
field
trials,
so
that
more
realistic
tolerances
can
be
set
in
the
future.
With
the
exception
of
sunflower,
the
re­
registration
requirements
for
magnitude
of
the
residue
in/
on
all
the
raw
agricultural
commodities
(
RACs),
based
on
the
currently
registered
use
patterns,
will
be
fulfilled
pending
label
revisions
and/
or
tolerance
adjustments:
barley,
rye,
rice,
wheat,
sweet
corn;
field
and
pop
corn,
oat,
peanut,
pineapple,
stone
fruits,
and
aspirated
grain
fractions.
As
a
result
of
this
review,
new
tolerances
are
being
proposed
on
several
commodities.
The
re­
registration
requirements
for
magnitude
of
the
residue
in
the
processed
commodities
have
been
fulfilled,
except
for
pineapple
(
juice).
The
re­
registration
requirements
for
data
depicting
the
magnitude
of
propiconazole
residues
of
concern
in
meat,
milk,
poultry,
and
eggs
have
been
fulfilled.
The
maximum
theoretical
dietary
burden
to
livestock
has
been
recalculated
due
to
added
new
uses.
Tolerances
in
ruminant
commodities
were
reassessed
at
the
existing
level,
while
tolerances
for
poultry
commodities
are
not
required.
Plantback
restrictions
have
been
established
for
propiconazole
products
registered
for
use
on
rotatable
crops
based
on
the
confined
rotational
crop
studies.
Table
10
is
the
tolerance
reassessment
summary
for
propiconazole.
Page
59
of
112
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
(
Food
and
Water)
(
HED
memo
of
06/
15/
06,
Yan
Donovan,
D329667)

Acute
and
chronic
dietary
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCIDJ,
Version
2.02)
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.

Acute
Dietary
Exposure
Results
and
Characterization
An
acute
dietary
analysis
for
propiconazole
was
conducted
using
tolerance
levels
and
100
%
CT
for
all
existing
and
proposed
uses.
The
acute
PAD
for
all
population
subgroups,
including
females
13­
49
years
is
0.3
mg/
kg/
day.
The
results
of
the
analysis
indicate
that
acute
risk
from
dietary
exposure
to
propiconazole
from
the
requested
use
did
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.
The
exposure
to
the
U.
S.
population
was
3%
aPAD
at
the
95th
percentile,
the
highest
exposure
was
to
all
infants
<
1
yrs
old,
at
8%
aPAD.
The
exposure
to
females
13­
49
yrs
old
is
at
2
%
aPAD.

Chronic
Dietary
Exposure
Results
and
Characterization
A
chronic
dietary
analysis
for
propiconazole
was
conducted
using
tolerance
levels
and
100
%
CT
for
all
existing
and
proposed
uses.
The
results
of
the
analysis
indicated
that
chronic
risk
from
the
dietary
exposure
to
propiconazole
from
the
requested
use
did
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
or
any
population
subgroup.
The
exposure
to
the
U.
S.
population
was
3%
cPAD
and
the
most
highly
exposed
subgroup,
Children
1­
2
yrs
old,
at
8%
cPAD.

Cancer
Dietary
Exposure
Results
and
Characterization
The
HIARC
classified
propiconazole
as
a
Group
C
­
possible
human
carcinogen,
nonquantifiable
For
the
purpose
of
risk
characterization
the
reference
Dose
(
RfD)
approach
should
be
used
and
would
be
protective.

Water
Contribution
The
Agency
used
PRZM­
EXAMS
and
SCI­
GROW
screening
models
to
determine
the
EECs
of
propiconazole
in
surface
and
ground
water,
respectively.
Based
on
the
PRZM­
EXAMS
and
SCIGROW
models,
for
surface
water,
the
highest
estimated
environmental
concentrations
(
EECs)
of
propiconazole
for
acute
exposure
is
86.4
parts
per
billion
(
ppb)
(
rice
use),
and
for
chronic
exposure
is
37.5
ppb
(
turf
use).
For
ground
water,
the
highest
EEC
for
acute
and
chronic
exposure
is
0.7
ppb.
The
highest
estimates
from
surface
water
(
acute,
86.4
ppb
and
chronic,
37.5
ppb)
were
used
in
the
DEEM
analysis.

6.2
Water
Exposure/
Risk
Pathway
Drinking
water
Assessment;
James
Lin
(
D312353,
06/
29/
05)
Revised
Drinking
Water
Assessment;
James
Lin
(
D323440,
06/
07/
06)

Based
on
U.
S.
Geological
Survey
National
Water
Assessment
Data
Warehouse
(
link:
Page
60
of
112
http://
infotrek.
er.
usgs.
gov/
servlet/
page?_
pageid=
543&_
dad=
portal30&_
schema=
PORTAL30),
there
are
not
many
samples
analyzed
for
propiconazole.
Among
the
samples
analyzed,
none
of
the
samples
exceed
the
detection
limits
(
from
0.001
to
0.021
µ
g/
L).

Models,
Scenarios,
and
Input
Parameters
Used
To
Estimate
Concentrations
of
Propiconazole
With
the
exception
of
rice
use,
estimated
drinking
water
concentrations
from
surface
water
sources
were
calculated
using
Tier
II
PRZM
(
Pesticide
Root
Zone
Model)
and
EXAMS
(
Exposure
Analysis
Modeling
System).
PRZM
is
used
to
simulate
pesticide
transport
as
a
result
of
runoff,
erosion,
and
off­
target
spray
drift
from
an
agricultural
field
and
EXAMS
estimates
environmental
fate
and
transport
of
pesticides
in
surface
water.
These
models
are
run
using
the
linkage
program
shell,
PE4V01,
which
incorporates
the
standard
scenarios
developed
by
EFED.

For
use
on
rice,
the
Policy
for
Estimating
Aqueous
Concentrations
from
Pesticides
Labeled
for
Use
on
Rice,
dated
October
29,
2002,
was
followed
in
estimating
drinking
water
concentrations.
Since
propiconazole
degrades
quickly
in
the
rice
paddy
environment
with
a
half­
life
of
5
days,
which
is
equivalent
to
a
first
order
degradation
rate
of
0.
l39/
day,
this
degradation
rate
was
used
in
simulating
the
continuing
degradation
in
the
rice
paddy
environment.

Several
of
EFED's
standard
scenarios
were
simulated
for
this
drinking
water
assessment.
For
each
specific
use,
drinking
water
concentrations
were
estimated
assuming
the
maximum
allowable
label
rate.
The
final
estimated
drinking
water
concentrations
were
then
adjusted
with
the
proper
percent
crop
treated
area
(
PCA).
The
default
PCA
of
0.87
was
used,
except
for
the
uses
on
sweet
corn
(
0.46)
and
wheat
(
0.56).
There
is
no
PCA
correction
for
rice
use.

Drinking
Water
Estimates
from
Surface
Water
Sources
The
estimated
drinking
water
concentrations
of
propiconazole
in
surface
water
were
calculated.
In
general,
the
higher
use
rate
produces
the
higher
drinking
water
concentrations.
Rice
use
results
in
the
highest
peak
(
acute)
drinking
water
concentration
(
86.49
ug/
L)
among
all
scenarios
assessed.
The
highest
chronic
values
are
37.5
and
26.5
ug/
L,
respectively
for
PA
and
FL
turf
scenarios.
The
high
values
are
the
results
of
high
application
rate
(
up
to
7.2
lb
ai/
ac
per
year).

Drinking
Water
Estimates
from
Ground
Water
Sources
Since
the
input
value
of
604
for
soil
adsorption
Koc
used
in
SCIGROW
runs
is
outside
the
model
development
range
of
32
to
180
mL/
g,
the
uncertainties
of
these
estimated
values
are
great.
For
these
SCIGROW
runs,
all
the
fate
input
parameters
are
identical,
except
the
propiconazole
application
information.
The
higher
estimated
drinking
water
concentrations
are
associated
with
the
higher
rate.
Turf
and
ornamentals
uses
have
the
highest
concentration
of
0.72
µ
g/
L
(
ppb),
whereas
barley
use
has
the
lowest
value
of
0.01
µ
g/
L.

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Chemical.
Propiconazole
parent
compound
Exposure
Duration
Surface
water
(
ppb)
Ground
water
(
ppb)
Acute
86.5
0.7
Chronic
(
non­
cancer)
37.5
0.7
Page
61
of
112
Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Chemical.
Propiconazole
parent
compound
Exposure
Duration
Surface
water
(
ppb)
Ground
water
(
ppb)
Chronic
(
cancer)
N/
A
N/
A
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Propiconazole:
Revised
Occupational
and
Residential
Exposure
Assessment;
James
Miller,
Environmental
Scientist
(
D329393,
6/
15/
06)
Propiconazole
Occupational
and
Residential
Exposure
Assessment
of
the
Antimicrobial
Uses;
Timothy
Leighton
(
D326306,
2/
1/
2006)
Amendment
to
the
Propiconazole
RED
for
Children's
Post­
application
Exposure
from
Treated
Structures;
Tim
Leighton
(
D330159,
06/
20/
06)

Residential
Handler
Exposure
Assessment
The
anticipated
use
patterns
and
current
labeling
indicate
three
major
residential
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
can
potentially
be
used
to
make
propiconazole
applications.
The
quantitative
exposure/
risk
assessment
developed
for
residential
handlers
is
based
on
these
scenarios:

 
Mixer/
Loader/
applying
liquids
and
wettable
powder
in
water
soluble
packets
via
1)
Low
Pressure
Handwand,
and
2)
Hose­
End
Sprayer.
 
Applying
treated
paint
using
airless
sprayer
and
Hose­
end
spray.

Residential
handler
exposure
scenarios
are
considered
to
be
short­
term
only
due
to
the
infrequent
uses
associated
with
homeowner
products.

A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
residential
handler
risk
assessments.
Each
assumption
and
factor
is
detailed
below.
In
addition
to
these
factors,
unit
exposures
were
used
to
calculate
risk
estimates.
Mostly,
these
unit
exposures
were
taken
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
and
the
Outdoor
Residential
Exposure
Task
Force
(
ORETF)
studies.

HED
believes
that
the
scenarios
assessed
in
this
document
represent
worse­
case
exposures
and
risks
resulting
from
use
of
propiconazole
in
residential
environments.
It
should
also
be
noted
that
there
were
many
other
scenarios
where
medium
to
low
quality
PHED
data
were
used
to
complete
the
assessment.
Data
quality
should
be
considered
in
the
interpretation
of
the
uncertainties
associated
with
each
risk
presented.

 
Short­
term
risks
for
residential
handlers
are
presented
below
in
Table
6.3a.
All
risks
are
below
HED's
level
of
concern
(
i.
e.,
MOEs
are
>
100)
assuming
handlers
are
wearing
short­
sleeve
shirt,
short
pants,
shoes,
and
socks.
Page
62
of
112
Table
6.3a:
Summary
of
Residential
Handler
Exposure
Estimates
Max
Appl.
Rate
¹
Daily
Area
Treated
²
Handler
Scenario
Short­
Term
MOE
Application.
Equip.
Crop(
s)/
Site
Lb
ai/
Acre
or
%
in
paint*
Acre/
day
Or
gal/
day*
M/
L/
A
Derml+
Inhln
Baseline
(
Liquids)
4400
Low
Pressure
Handwand
5*

(
WP/
WSP)
N/
A
(
Liquids)
40,000
Hose­
end
Sprayer
Ornamentals
(
woody
and
flowering
plants),
Shade
Trees,
Woody
Shrubs
and
Vines
0.0024
5*
(
WP/
WSP)
N/
A
(
Liquids)
1300
Low
Pressure
Handwand
0.023
(
WP/
WSP)
N/
A
(
Liquids)
530
Hose­
end
Sprayer
Turf
(
Lawns)
1.8
0.5
(
WP/
WSP)
N/
A
Brush/
Roller3
0.35%
15*
(
Paint)
330
Airless
Sprayer3
Applying
treated
paint
2*
(
Paint)
120
Notes:
¹
Application
rates
are
the
maximum
rates
provided
for
propiconazole
in
all
cases.
²
Amount
handled
per
day
values
are
HED
estimates
of
area
treated
or
gallons
applied
based
on
Exposure
SAC
SOP
#
12
"
Recommended
Revisions
to
the
Standard
Operating
Procedures
for
Residential
Exposure
Assessments,"
HED
estimates
and
AD
Standard
Assumptions.
3
Paint
exposure
scenarios
are
from
the
AD
Occupational
and
Residential
Exposure
Assessment
(
T.
Leighton,
2/
1/
2006,
D326306).
The
density
of
paint
is
assumed
to
be
10
lb/
gal.

None
of
the
residential
handler
exposure
scenarios
exceeded
HED's
level
of
concern.
[
Note:
Although
the
risk
for
mixing/
loading/
applying
propiconazole
with
a
low
pressure
handwand
is
not
a
concern,
(
MOE
=
1300)
it
is
important
to
note
that
most
labels
identify
a
hose­
end
sprayer
as
the
method
of
application.
Additionally,
all
risk
calculations
were
conducted
using
the
maximum
turf
application
rate
(
1.8
lb
ai/
acre).
However,
a
turf
application
rate
of
0.51
lb
ai/
acre
was
identified
on
a
residential­
use
product
label
(
100­
773).
This
lower
application
rate
may
better
represent
homeowner
use.

Residential
Post­
application
Exposures
and
Risks
The
residential
use
patterns
result
in
post
application
dermal
exposures
to
adults,
and
dermal
and
oral
exposures
to
infants
and
children.
These
exposures
are
considered
short
term
only,
due
to
the
fact
that:
1)
Post­
application
exposures
were
calculated
using
Propiconazole
as
the
parent
compound;
2)
Compound
specific
TTR
data
indicates
that
at
the
Indiana,
California,
and
Page
63
of
112
Pennsylvania
test
sites,
average
total
propiconazole
residues
declined
to
below
the
minimum
quantifiable
limit
(
MQL)
by
DAT
=
14,
DAT
=
10,
and
DAT
=
8
respectively.
These
dissipation
rates,
combined
with
label
specific
use
rates
and
frequency
of
use
specifications,
reinforce
the
hand
to
mouth
short­
term
exposure
scenario;
3)
For
short
term
exposure
to
Children
1­
2
years
old,
the
driving
factors
for
this
risk
assessment
are
hand
to
mouth,
object
to
mouth,
and
dermal
exposure.
Soil
ingestion
is
insignificant
(
MOE>
300,000)
compared
to
these
factors,
indicating
that
the
post
application
scenario
should
be
short
term
only
In
addition
to
using
HED's
SOP
for
residential
assessment,
the
study
specific
turf
transferable
residue
(
TTR)
was
used
in
the
calculation.
A
summary
of
risk
estimates
for
residential
postapplication
risks
for
adults
and
children
is
provided
in
the
following
tables.
HED
combines
risk
values
resulting
from
separate
post­
application
exposure
scenarios
when
it
is
likely
they
can
occur
simultaneously
based
on
the
use­
pattern
and
the
behavior
associated
with
the
exposed
population
(
see
Table
6.3c),
and
all
MOEs
are
above
100,
and
not
of
concern.
[
Note:
Propiconazole
is
classified
as
a
non­
volatile
chemical;
therefore
a
residential
inhalation
postapplication
assessment
is
not
required].
The
assumptions
used
for
each
of
the
scenarios
separately
are
already
high
(
i.
e.,
time
spent
outdoors,
dislodgeable
residues).
So,
combining
all
these
activities
together
is
extra
conservative.

Table
6.3b:
Adult
Residential
Risk
Estimates
for
Post­
application
Exposure
to
Propiconazole
Exposure
Scenario
TC
cm
²
/
hr
Route
of
Exposure
Application
Rate
MOE
at
Day
0
Outdoors
Residential
Turf
(
Gen.
High­
Contact
Activities)
70000
Dermal
1.8
lb
ai/
acre
350
Residential
Turf
(
Mowing)
500
Dermal
1.8
lb
ai/
acre
50,000
Level
of
Concern:
MOE
=
100
Table
6.3c:
Toddler
Residential
Risk
Estimates
for
Post­
application
Exposure
to
Propiconazole
Exposure
Scenario
TC
cm
²
/
hr
Route
of
Exposure
Application
Rate
MOE
at
Day
0
Combined
MOE
Outdoors
Hand
to
Mouth
Activity
on
Turf
N/
A
Oral
1.8
lb
ai/
acre
1100
Object
to
Mouth
Activity
on
Turf
N/
A
Oral
1.8
lb
ai/
acre
4500
Soil
Ingestion
N/
A
Oral
1.8
lb
ai/
acre
330,000
Turf
 
General
High­
Contact
Activities
25000
Dermal
1.8
lb
ai/
acre
210
170
Note:
Combined
MOE
=
NOAEL/(
ADDhand­
to­
mouth
+
ADDobject­
to­
mouth
+
ADDincidental
soil
ingestion
+
ADDdermal)
Level
of
Concern:
MOE
=
100
Page
64
of
112
Residential
post­
application
scenarios
from
antimicrobial
uses
were
also
assessed.
No
postapplication
exposure
to
adult
is
expected
because
of
propiconazole's
low
vapor
pressure
(
therefore,
no
inhalation
exposure)
and
the
registrants'
deletion
of
the
only
other
use
(
i.
e.,
materials
preservative
in
fabrics,
textiles,
are
carpet
fibers).
Propiconazole
is
used
on
many
different
types
of
wood
including
1)
green
or
fresh
cut
lumber,
poles,
posts,
and
timbers;
2)
manufactured
wood
products
such
as
logs
(
including
for
log
home
construction),
wood
chips/
sawdust,
plywood
veneer,
and
particle
board;
3)
dry
lumber;
and
4)
finished
wood
products
such
as
millwork,
shingles,
shakes,
siding,
plywood,
and
structural
lumber
and
composites.
Except
"
dry
lumber"
uses,
the
other
3
groupings
would
result
in
minimal
dermal
and/
or
incidental
oral
exposure.
Inhalation
exposure
(
e.
g.,
in
log
homes
treated
with
propiconazole)
is
also
expected
to
be
negligible
based
on
the
low
vapor
pressure.
For
"
dry
lumber"
uses,
if
propiconazole­
treated
lumber
is
used
to
build
residential
decks
and/
or
play
sets,
then
there
is
the
potential
for
dermal
and
incidental
oral
exposures
to
treated
lumber
used
in
decks
and
or
play
sets.
AD
assessed
the
risk
to
children
playing
on
propiconazole­
treated
structures
using
screening
level
assessment.
Table
6.3d
shows
the
result
of
aggregate
risk
from
incidental
oral
and
dermal
exposure
from
propiconazole
treated
wood.
This
risk
assessment,
based
on
high
end
screening­
level
assumptions,
indicates
no
risk
of
concern.
Confirmatory
data
for
the
surface
residues
are
needed
to
verify
this
screening­
level
assessment.

Table
6.3
d.
Propiconazole
Assessment
of
Children
Playing
on
Treated
Structures.
MOEs
(
Target
=
100)
b
Exposure
Dose
(
mg/
kg/
day)
a
Short­
term
Intermediate
Dermal
Contact
0.0675
450
150
Incidental
Oral
0.00563
5,300
1,800
Aggregate
0.0731
410
140
a
Aggregate
dose
=
dermal
dose
+
oral
dose.
b
MOEs
=
ST
and
IT
NOAELs
(
mg/
kg/
day)
/
Dose
(
mg/
kg/
day).
Where
ST
NOAEL
=
30
mg/
kg/
day
and
IT
NOAEL
=
10
mg/
kg/
day.
Target
MOE
=
100.

7.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.

For
most
pesticide
active
ingredients,
water
monitoring
data
are
considered
inadequate
to
determine
surface
and
ground
water
drinking
water
exposure
estimates,
so
model
estimates
have
been
used
to
estimate
residues
in
drinking
water
(
EDWCs).
In
order
to
determine
if
aggregate
risks
are
of
concern,
HED
then
calculates
drinking
water
levels
of
comparison,
or
DWLOCs.
The
DWLOC
is
the
maximum
amount
of
a
pesticide
in
drinking
water
that
would
be
acceptable
in
light
of
combined
exposure
from
food
and
residential
pathways.
The
calculated
DWLOCs
are
then
compared
to
the
EDWCs
provided
by
EFED;
if
model­
derived
EDWCs
exceed
the
Page
65
of
112
DWLOCs
for
surface
or
ground
water,
there
may
be
a
concern
for
dietary
exposure
to
residues
in
drinking
water,
and
monitoring
data
may
be
required.

In
order
to
fully
implement
the
requirements
of
FQPA,
HED
and
EFED
have
been
working
toward
refining
the
screening­
level
DWLOC
approach
to
conducting
aggregate
risk
assessments
that
combine
exposures
across
all
pathways.
As
part
of
this
process,
EFED
and
HED
have
agreed
that
chronic
and
cancer
EDWCs
can
be
used
directly
in
chronic/
cancer
dietary
exposure
assessments,
to
calculate
aggregate
dietary
(
food
+
water)
risk.
This
is
done
by
using
the
relevant
PRZM­
EXAMS
value
as
a
residue
for
water
(
all
sources)
in
the
dietary
exposure
assessment.
The
principal
advantage
of
this
approach
is
that
the
actual
individual
body
weight
and
water
consumption
data
from
the
CSFII
are
used,
rather
than
assumed
weights
and
consumption
for
broad
age
groups.
This
refinement
has
been
used
for
propiconazole
acute
and
chronic
aggregate
risk
assessments.

Aggregate
exposure
risk
assessments
were
performed
for
the
following:
acute
aggregate
exposure
(
food
+
drinking
water)
and
chronic
aggregate
exposure
(
food
+
drinking
water).
Short­
term
aggregate
(
food
+
water+
residential
exposure)
risk
assessments
was
also
performed.

7.1
Acute
Aggregate
Risk
Since
the
DEEM
has
included
water
exposure
in
the
acute
analysis,
the
result
of
acute
aggregate
is
as
shown
in
Table
7.4
in
Section
7.4
below.

7.2
Short­
Term
Aggregate
Risk
Short­
intermediate
term
aggregate
exposure
takes
into
account
residential
exposure
plus
average
exposure
levels
to
food
and
water
(
considered
to
be
a
background
exposure
level).
Based
on
the
residential
use
pattern,
post­
application
exposure
to
propiconazole
for
adults
are
from
dermal
exposure
only,
for
infants
and
children
are
from
dermal
and
oral
routes.
Table
7.2a
aggregates
the
short
term
risk
for
Toddlers
from
incidental
oral,
dermal,
and
food
and
water
(
as
a
background).
Although
both
residential
and
antimicrobials
uses
result
in
incidental
oral
and
dermal
exposure
to
children,
the
highest
incidental
oral
and
dermal
exposure
scenarios
are
from
residential
use
on
turf,
which
were
used
in
the
short
term
aggregate
risk
assessment.
The
short
term
aggregate
risk
does
not
exceed
HED's
level
of
concern.
This
assessment
is
considered
very
conservative
in
that
the
residential
incidental
oral
post­
application
exposure
is
highly
conservative
because
it
is
combining
three
screening
level
assessments
(
which
by
themselves
already
have
conservative
estimates).
HED
also
did
a
back­
calculation
to
estimate
room
available
in
the
risk
cup
for
short
term
aggregate
risk.
In
order
to
obtain
a
short
term
aggregate
MOE
 
100,
the
MOE
resulting
from
additional
short
term
exposures
to
Children
1­
2
(
from
possible
dermal
and
incidental
oral
exposure
from
treated
wood
or
other
sources)
needs
to
be
 

270.
As
stated
above
in
Section
6.3,
the
MOE
from
antimicrobial
use
of
propiconazole
(
in
treated
wood)
for
Toddler
is
410,
which
is
greater
than
270.

Table
7.2a
:
Short­
term
Aggregate
Risk
Estimates
to
Propiconazole
for
Toddler
(
Children
1­
2years)

Exposure
Scenario
Target
MOE
Route
of
Exposure
Exposure
NOAELs
MOE
at
Day
0
Combined
MOE5
Page
66
of
112
Average
Food
and
Water
(
as
background)
N/
A
Food
and
water
0.0078
30
3800
2
Hand
to
Mouth
Activity
on
Turf
100
1
Oral
0.0269
30
1100
3
Object
to
Mouth
Activity
on
Turf
100
1
Oral
0.0067
30
4500
3
Soil
Ingestion
100
1
Oral
0.00009
30
330,000
3
Turf
 
General
High­
Contact
Activities
100
1
Dermal
0.1410
30
210
4
160
Note:
1
Target
MOE=
100,
Developmental
rat­
severe
maternal
clinical
toxicity.
NOAEL=
30
2
MOE
food
=
[(
short­
term
oral
NOAEL)/(
chronic
dietary
exposure)]
3
MOE
oral
=
[(
short
­
term
oral
NOAEL)/(
hand­
to­
mouth
residential
exposure)]
4
MOE
dermal
=
[(
short
­
term
dermal
NOAEL)/(
high­
end
dermal
residential
exposure)]
5
Aggregate
Combined
MOE
(
food,
water,
and
residential)
=
1
÷
[(
1
÷
MOE
food
and
water)
+
(
1
÷
MOE
oral)
+
(
1
÷
MOE
dermal)
].

Table
7.2b
aggregates
the
short­
term
risk
fro
adults
from
residential
post
application,
and
average
food
and
water
(
as
a
background).
Based
on
the
low
vapor
pressure
of
propiconazole,
no
post
application
inhalation
exposure
is
anticipated
to
occur.
No
post­
application
exposures
are
expected
to
occur
with
antimicrobial
uses.
The
highest
post
application
exposure
from
residential
use
on
turf
was
used
in
the
short
term
aggregate.
The
aggregate
MOE
is
340,
which
is
greater
than
the
target
MOE
of
100.
This
aggregate
exposure
assessment
is
considered
very
conservative
because
the
assumptions
used
for
each
of
the
scenarios
separately
are
already
high
end
(
i.
e.,
time
spent
outdoors,
dislodgeable
residues).

Table
7.2b
:
Short­
term
Aggregate
Risk
Estimates
to
Propiconazole
for
Adults
from
Post­
Application
Activities
Exposure
Scenario
Target
MOE
Route
of
Exposure
Exposure
Or
Daily
dose
NOAELs
MOE
at
Day
0
Combined
MOE4
Average
Food
and
Water
(
as
background)
N/
A
Food
and
water
0.0031
30
9700
2
Residential
Post­
application
(
Residential
Turf
Gen.
High­
Contact
Activities))
100
1
Dermal
0.085
30
350
3
340
Note:
1
Target
MOE=
100,
Developmental
rat­
increase
incidence
of
rudimentary.
NOAEL
=
30
2
MOE
food
and
water
=
[(
short­
term
oral
NOAEL)/(
chronic
dietary
exposure)]
3
MOE
dermal
=
[(
short
­
term
dermal
NOAEL)/(
high­
end
dermal
residential
exposure)]
4
Aggregate
Combined
MOE
(
food,
water,
and
residential)
=
1
÷
[(
1
÷
MOE
food
and
water)
+
(
1
÷
MOE
post
appl.
dermal)].

Propiconazole
also
has
homeowner
uses.
Homeowners
can
be
exposed
to
propiconazole
through
dermal
and
inhalation
routes
while
applying
home
use
products.
Table
7.2c
aggregates
the
short
Page
67
of
112
term
risk
for
homeowner/
residential
handlers
from
residential
exposure
and
average
food
and
water
(
as
a
background).
The
highest
residential
handler
exposure
(
Hose­
end
sprayer,
MOE
of
530)
is
used
for
the
aggregate
exposure
assessment.

Table
7.2c
:
Short­
term
Aggregate
Risk
Estimates
to
Propiconazole
for
Adult
Residential
Handlers
Exposure
Scenario
Target
MOE
Route
of
Exposure
Exposure
Or
Daily
dose
NOAELs
MOE
at
Day
0
Combined
MOE4
Average
Food
and
Water
(
as
background)
N/
A
Food
and
water
0.0031
30
9700
2
Residential
handler
(
Hoseend
sprayer)
100
Dermal
&
Inhalation
0.057
30
530
3
500
Note:
1
Target
MOE=
100,
Developmental
rat­
increase
incidence
of
rudimentary.
NOAEL
=
30
2
MOE
food
and
water
=
[(
short­
term
oral
NOAEL)/(
chronic
dietary
exposure)]
3
MOE
dermal
/(
inhalation)
=
[(
short
­
term
dermal/
inhalation
NOAEL)/(
high­
end
dermal/
inhalation
residential
exposure)]
4
Aggregate
Combined
MOE
(
food,
water,
and
residential)
=
1
÷
[(
1
÷
MOE
food
and
water)
+
(
1
÷
MOE
handler
dermal)].

Table
7.2d
aggregates
the
short­
term
risk
from
residential
handlers
of
paint
(
antimicrobial)
use
and
average
food
and
water
(
as
a
background).
The
highest
residential
handler
exposure
(
Painting­
airless
spray,
MOE
of
120)
is
used
for
the
aggregate
exposure
assessment.

Table
7.2d
:
Short­
term
Aggregate
Risk
Estimates
to
Propiconazole
for
Adult
Residential
Handlers
of
Paint
(
antimicrobial
use)

Exposure
Scenario
Target
MOE
Route
of
Exposure
Exposure
Or
Daily
dose
NOAELs
MOE
at
Day
0
Combined
MOE4
Average
Food
and
Water
(
as
background)
N/
A
Food
and
water
0.0031
30
9700
2
Residential
Handler
(
Painting­
airless
spray)
100
Dermal
&
Inhalation
0.25
30
120
3
120
Note:
1
Target
MOE=
100,
Developmental
rat­
increase
incidence
of
rudimentary.
NOAEL
=
30
2
MOE
food
and
water
=
[(
short­
term
oral
NOAEL)/(
chronic
dietary
exposure)]
3
MOE
dermal
/(
inhalation)
=
[(
short
­
term
dermal
/
inhalation
NOAEL)/(
high­
end
dermal/
inhalation
residential
exposure)]
4
Aggregate
Combined
MOE
(
food,
water,
and
residential)
=
1
÷
[(
1
÷
MOE
food
and
water)
+
(
1
÷
MOE
handler
dermal
+
inhalation)].

7.3
Intermediate­
Term
Aggregate
Risk
The
only
residential
use
scenario
that
will
result
in
potential
intermediate
term
exposure
to
propiconazole
is
post
application
exposure
to
Children
from
wood
treatment
(
antimicrobial
use).
Page
68
of
112
Table
7.3
shows
the
aggregate
risk
for
intermediate
term
exposure
to
Children
1­
2
years
old.
The
aggregate
MOE
is
130,
which
is
greater
than
the
target
MOE
of
100.

Table
7.3
:
Intermediate
­
term
Aggregate
Risk
Estimates
to
Propiconazole
for
Toddler
(
Children
1­
2years)

Exposure
Scenario
Target
MOE
Route
of
Exposure
Exposure
NOAELs
MOE
at
Day
0
Combined
MOE5
Average
Food
and
Water
(
as
background)
N/
A
Food
and
water
0.0078
10
1300
2
Incidental
oral
100
1
Oral
0.0056
10
18003
Dermal
Contact
Activities
100
1
Dermal
0.068
10
150
4
130
Note:
1
Target
MOE=
100,
24
Month
oncogenicity
study.
NOAEL=
10
2
MOE
food
=
[(
intermediate­
term
oral
NOAEL)/(
chronic
dietary
exposure)]
3
MOE
oral
=
[(
intermediate
­
term
oral
NOAEL)/(
hand­
to­
mouth
residential
exposure)]
4
MOE
dermal
=
[(
intermediate
­
term
dermal
NOAEL)/(
high­
end
dermal
residential
exposure)]
5
Aggregate
Combined
MOE
(
food,
water,
and
residential)
=
1
÷
[(
1
÷
MOE
food
and
water)
+
(
1
÷
MOE
oral)
+
(
1
÷
MOE
dermal)
].

7.4
Long­
Term
Aggregate
Risk
Since
there
are
no
residential
uses
that
will
likely
to
result
in
chronic
exposure
to
propiconazole,
chronic
aggregate
includes
food
and
water
only.
Water
exposure
has
been
included
in
the
DEEM
analysis,
therefore,
the
result
of
chronic
aggregate
is
as
shown
in
Table
7.4
below.
Propiconazole
does
not
possess
a
separate
cancer
dietary
endpoint 
the
RfD
approach
is
considered
protective;
therefore,
the
results
of
only
the
acute
and
chronic
analyses
are
given.

Table
7.4.
Summary
of
Dietary
Exposure
and
Risk
for
Propiconazole
FOOD
PLUS
WATER.

Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Cancer
Population
Subgroup*
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
Risk
General
U.
S.
Population
0.009650
3.2
0.003113
3.1
All
Infants
(<
1
year
old)
0.02352
7.8
0.006597
6.6
Children
1­
2
years
old
0.01843
6.1
0.007753
7.8
Children
3­
5
years
old
0.01556
5.2
0.006464
6.5
Children
6­
12
years
old
0.01074
3.6
0.004314
4.3
Youth
13­
19
years
old
0.00700
2.3
0.002627
2.6
Adults
20­
49
years
old
0.00730
2.4
0.002510
2.5
N/
A
Page
69
of
112
Table
7.4.
Summary
of
Dietary
Exposure
and
Risk
for
Propiconazole
FOOD
PLUS
WATER.

Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Cancer
Population
Subgroup*
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
Risk
Adults
50+
years
old
0.00700
2.3
0.002490
2.5
Females
13­
49
years
old
0.00725
2.4
0.002434
2.4
7.5
Cancer
Risk
The
HIARC
classified
propiconazole
as
a
Group
C
­
possible
human
carcinogen,
RfD
approach
will
be
protective."

8.0
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
made
a
common
mechanism
of
toxicity
finding
as
to
propiconazole
and
any
other
substances.
Propiconazole
is
among
the
group
of
chemicals
which
generates
a
common
metabolite
called
1,2,4­
Triazole
and
conjugates.
A
separate
document
will
be
available
to
address
this
common
metabolite
issue.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
propiconazole
has
a
common
mechanism
of
toxicity
with
other
substances.
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/.

9.0
OCCUPATIONAL
EXPOSURE/
RISK
PATHWAY
Revised
Occupational
and
Residential
Exposure
Assessment;
James
Miller,
(
D329393,
6/
15/
06)

9.1
Short/
Intermediate­
Term
Handler
Risk
There
is
potential
for
exposure
to
propiconazole
in
occupational
scenarios
from
handling
propiconazole
products
during
the
application
process
(
i.
e.,
mixer/
loaders,
applicators,
flaggers,
and
mixer/
loader/
applicators)
and
a
potential
for
post­
application
worker
exposure
from
entering
into
areas
previously
treated
with
propiconazole.
As
a
result,
risk
assessments
have
been
completed
for
occupational
handler
scenarios.
HED
uses
the
term
"
handlers"
to
describe
those
individuals
who
are
involved
in
the
pesticide
application
process.
HED
believes
that
there
are
distinct
job
functions
or
tasks
related
to
applications
and
that
exposures
can
vary
depending
on
the
specifics
of
each
task.
Job
requirements
(
e.
g.,
amount
of
chemical
to
be
used
in
an
application),
the
kinds
of
equipment
used,
the
target
being
treated,
and
the
level
of
protection
used
by
a
handler
can
cause
exposure
levels
to
differ
in
a
manner
specific
to
each
application
Page
70
of
112
event.
Occupational
handler
exposure
assessments
are
completed
by
HED
using
different
levels
of
personal
protection.
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
handler
risk
assessments.
No
chemical
specific
information
was
available
for
propiconazole
handler
exposure
assessments,
all
analyses
were
completed
using
acceptable
surrogate
exposure
data
for
the
scenario
in
question.

There
are
short­
and
intermediate­
term
non­
cancer
occupational
handler
scenarios
for
propiconazole
that
have
risks
of
concern;
however,
these
risks
are
at
baseline
PPE,
whereas
all
labels
call
for
baseline
plus
glove
levels
of
PPE.

In
order
to
refine
this
occupational
risk
assessment,
exposure
studies
for
many
equipment
types
that
lack
data
or
that
are
not
well
represented
in
PHED
(
e.
g.,
because
of
low
replicate
numbers
or
data
quality)
should
be
considered
based
on
the
data
gaps
identified
in
Section
10.2.
A
summary
of
the
combined,
dermal
plus
inhalation
short­,
and
intermediate­
term
risks
for
each
exposure
scenario
are
presented
in
Table
9.1.
Page
71
of
112
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Propiconazole
Occupational
Handler
Non­
cancer
Risk
Estimates
S­
Term
MOE
(
Dermal+
Inhalation)
I­
Term
MOE
(
Dermal+
Inhalation)
Exposure
Scenario
Crops
Appl.
Rate
(
lb
ai/
acre
or
lb
ai/
gallon)
Area
Treated
(
acre/
day
or
2
gal/
day)
Baseline
Baseline
+
Gloves
Baseline
Baseline
+
Gloves
Mixer/
Loader
­
Liquid
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
1200
13
1500
4.5
500
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
350
46
5100
15
1700
Non­
bearing
Citrus,
Pecans,
Non­
bearing
Hazelnuts,
Peanuts
0.225
350
23
2600
7.7
850
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Wild
Rice
0.225
350
23
2600
7.7
850
Sod­
farm
turf
1.8
350
2.9
320
1.0
110
Wheat
0.08
1200
19
2100
6.3
700
Aerial
Rice
0.28
1200
5.4
600
1.8
200
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
200
80
9000
27
3000
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
80
200
22000
67
7500
Non­
bearing
Citrus,
Nonbearing
Hazelnuts,
Pecans,
Peanuts
0.225
80
100
11000
33
3700
Grasses
grown
for
seed
(
forage
and
fodder
grasses)
0.225
80
100
11000
33
3700
Sod
farm
turf
80
13
1400
4.2
470
Golf
Course
turf
1.8
40
25
2800
8.4
930
Groundboom
Wheat
0.08
200
110
13000
38
4200
Pecans,
Non­
bearing
Citrus
0.225
40
200
22000
67
7500
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum)
0.1125
40
400
45000
130
15000
Ornamental
(
Flowering
and
Woody
plants)
0.37
40
120
14000
41
4500
Airblast
Bananas
and
Plantains
0.084
40
540
60000
180
20000
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower,
Celery
0.1125
350
46
5100
15
1700
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Non­
bearing
citrus,
Peanut
0.225
350
23
2600
7.7
850
Wheat
0.08
350
65
7200
22
2400
Chemigation
Rice
0.28
350
18
2100
6.2
690
Page
72
of
112
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Propiconazole
Occupational
Handler
Non­
cancer
Risk
Estimates
S­
Term
MOE
(
Dermal+
Inhalation)
I­
Term
MOE
(
Dermal+
Inhalation)
Exposure
Scenario
Crops
Appl.
Rate
(
lb
ai/
acre
or
lb
ai/
gallon)
Area
Treated
(
acre/
day
or
2
gal/
day)
Baseline
Baseline
+
Gloves
Baseline
Baseline
+
Gloves
Handgun
Sprayer
Turf
1.8
100
10
1100
3.3
370
Mixer/
Loader
­
Wettable
Powder
in
Water
Soluble
Packets
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
1200
1800
3700
600
1200
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
350
6200
13000
2100
4300
Non­
bearing
Citrus,
Pecans,
Non­
bearing
Hazelnuts,
Peanuts
0.225
350
3100
6400
100
2100
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Wild
rice
0.225
350
3100
6400
100
2100
Sod­
farm
turf
1.8
350
390
800
130
270
Wheat
0.08
1200
2500
5300
840
1800
Aerial
Rice
0.28
1200
720
1500
240
500
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
200
11000
22000
3600
7500
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
80
27000
56000
9000
19000
Non­
bearing
Citrus,
Nonbearing
Hazelnuts,
Pecans,
Peanuts
0.225
80
14000
28000
4500
9300
Grasses
grown
for
seed
(
forage
and
fodder
grasses)
0.225
80
14000
28000
4500
9300
Sod
Farm
turf
80
1700
3500
560
1200
Golf
Course
turf
1.8
40
3400
7000
110
2300
Groundboom
Wheat
0.08
200
15000
32000
5100
11000
Pecans,
Non­
bearing
Citrus
0.225
40
27000
56000
9000
19000
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum)
0.1125
40
54000
110000
18000
37000
Ornamental
(
Flowering
and
Woody
plants)
0.37
40
16000
34000
5500
11000
Airblast
Bananas
and
Plantains
0.084
40
72000
150000
24000
50000
Chemigation
Barley,
Rye,
Oats,
Wheat
0.1125
350
6200
13000
2100
4300
Page
73
of
112
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Propiconazole
Occupational
Handler
Non­
cancer
Risk
Estimates
S­
Term
MOE
(
Dermal+
Inhalation)
I­
Term
MOE
(
Dermal+
Inhalation)
Exposure
Scenario
Crops
Appl.
Rate
(
lb
ai/
acre
or
lb
ai/
gallon)
Area
Treated
(
acre/
day
or
2
gal/
day)
Baseline
Baseline
+
Gloves
Baseline
Baseline
+
Gloves
(
Past
Feekes
8),
Corn,
Sunflower,
Celery
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Non­
bearing
citrus,
Peanut
0.225
350
3100
6400
1000
2100
Wheat
0.08
200
8700
18000
2900
6000
Rice
0.28
350
2500
5200
830
1700
Handgun
Sprayers
Turf
1.8
100
1400
2800
450
930
Applicator
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
1200
7500
16000
2500
5500
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
350
26000
56000
8600
19000
Non­
bearing
Citrus,
Pecans,
Non­
bearing
Hazelnuts,
Peanuts
0.225
350
31000
28000
4300
9400
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Wild
rice
0.225
350
31000
28000
4300
9400
Sod­
farm
turf
1.8
350
1600
3500
540
1200
Wheat
0.08
1200
11000
23000
3500
7700
1
Aerial
Rice
0.28
1200
3000
6600
1000
2200
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
0.1125
200
15000
15000
4900
4900
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
80
37000
37000
12000
12000
Non­
bearing
Citrus,
Nonbearing
Hazelnuts,
Pecans,
Peanuts
0.225
80
18000
18000
6100
6100
Grasses
grown
for
seed
(
forage
and
fodder
grasses)
0.225
80
18000
18000
6100
6100
Sod
Farm
turf
1.8
80
2300
2300
770
770
Groundboom
(
Open
Cab)

Wheat
0.08
200
21000
21000
6900
6900
Pecans,
Non­
bearing
Citrus
0.225
40
1600
2300
520
770
Airblast
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
0.1125
40
3100
4600
1000
1500
Page
74
of
112
Table
9.1:
Summary
of
Short­
and
Intermediate­
Term
Propiconazole
Occupational
Handler
Non­
cancer
Risk
Estimates
S­
Term
MOE
(
Dermal+
Inhalation)
I­
Term
MOE
(
Dermal+
Inhalation)
Exposure
Scenario
Crops
Appl.
Rate
(
lb
ai/
acre
or
lb
ai/
gallon)
Area
Treated
(
acre/
day
or
2
gal/
day)
Baseline
Baseline
+
Gloves
Baseline
Baseline
+
Gloves
Plum)

Ornamental
(
Flowering
and
Woody
plants)
0.37
40
960
1400
320
470
Bananas
and
Plantains
0.084
40
4200
6200
1400
2100
Flagger
Barley,
Rye,
Oats,
Wheat
(
Past
Feekes
8),
Corn,
Sunflower
Celery,
Stone
Fruits
(
Apricots,
Cherry,
Nectarine,
Peach,
Plum),
Mint,
Triticale
0.1125
350
11000
10000
3700
3500
Non­
bearing
Citrus,
Pecans,
Non­
bearing
Hazelnuts,
Peanuts
Grasses
grown
for
seed
(
forage
and
fodder
grasses),
Wild
rice
0.225
350
5600
5200
1900
1700
Sod­
farm
turf
1.8
350
700
650
230
220
Wheat
0.08
350
16000
15000
5300
4900
1
Aerial
applications
Rice
0.28
350
4500
4200
1500
1400
Mixer/
Loader/
Applicator
(
Liquid
formulations)

High
Pressure
Handwand
Non­
bearing
Fruits
and
Nuts,
Ornamental
Woody
and
Flowering
plants
2
1000
NA
780
NA
260
Low
Pressure
Handwand
Non­
bearing
Fruits
and
Nuts,
Ornamental
Woody
and
Flowering
plants
0.0024
2
40
550
110000
180
36000
Handgun
Sprayer
Turf
1.8
5
NA
12000
NA
390
Seed
piece
Dip
Sugarcane
(
HI
only)
.00021
21000
8600
960000
2900
320000
Notes:
Baseline
PPE
=
(
long
sleeve
shirt,
long
pants,
no
gloves,
and
no
respirator)
MOE
=
NOAEL/
Daily
Dose
where
the
NOAEL
for
both
dermal
and
inhalation
is
30.0
mg/
kg/
day
for
Short­
term
and
10.0
mg/
kg/
day
for
Intermediate/
Long­
term
exposures.
The
target
MOE
is
100
for
Short­
and
Intermediate­
term
Dermal/
Inhalation
exposure.
¹
Application
and
Flagging
for
Aerial
scenarios
are
accessed
without
gloves;
therefore
data
is
(
N/
A).
2
Area
treated:
(
gal/
day)
Page
75
of
112
9.2
Short/
Intermediate­
Term
Post­
application
Risk
HED
uses
the
term
"
post­
application"
to
describe
exposures
to
individuals
that
occur
as
a
result
of
being
in
an
environment
that
has
been
previously
treated
with
a
pesticide
(
also
referred
to
as
re­
entry
exposure).
HED
believes
that
there
are
distinct
job
functions
or
activities
that
occur
in
previously
treated
areas.
These
job
functions
(
e.
g.,
the
kinds
of
jobs
to
cultivate
a
crop),
the
nature
of
the
crop
or
target
that
was
treated,
and
the
how
chemical
residues
degrade
in
the
environment
can
cause
exposure
levels
to
differ
over
time.
Propiconazole
use
is
varied
as
it
can
be
used
on
a
wide
variety
of
agricultural
crops
(
food,
feed,
ornamentals,
and
turf).
As
a
result,
a
wide
array
of
individuals
can
potentially
be
exposed
by
working
in
areas
that
have
been
previously
treated.
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
post­
application
worker
risk
assessments
for
agricultural
scenarios.
A
total
of
six
residue
dissipation
studies
are
available.
These
studies
described
residue
dissipation
and
exposure
for
corn,
peaches,
rice,
pecans,
ornamentals
and
turf.
The
corn
data
have
been
used
to
complete
all
assessments
for
the
following
agronomic
crop
groups:
Tall
field/
row
crop:
corn
(
field/
pop/
sweet),
sunflowers
breeder's
seed.
The
peach
data
have
been
used
to
complete
all
assessments
for
the
following
agronomic
crop
groups:
Tree
fruit,
stone
fruit,
bunch/
bundle,
and
ornamentals.
The
rice
data
have
been
used
to
complete
all
assessments
for
field/
row
crops,
low/
medium:
peanuts,
wheat,
barley,
mint,
rice.
The
pecan
data
have
been
used
to
complete
all
assessments
for
tree
nuts.
The
turf
TTR
data
have
been
used
to
complete
all
assessments
for
turf:
sod­
farm,
recreational
areas
and
golf
courses.
The
transfer
coefficients
used
in
this
assessment
are
from
an
interim
transfer
coefficient
policy
developed
by
HED's
Science
Advisory
Council
for
Exposure
using
proprietary
data
from
the
Agricultural
Re­
entry
Task
Force
(
ARTF)
database
(
policy
#
3.1).

All
agricultural
scenarios
were
evaluated
using
propiconazole­
specific
DFR/
TTR
dissipation
data.
A
summary
of
the
post­
application
risks
for
each
crop/
activity
combination
are
shown
in
Table
9.2.
All
short­
term
occupational
risks
are
below
HED's
level
of
concern
(
i.
e.,
MOEs
>
100)
at
day
0.
The
occupational
post­
application
risks
that
exceed
HED's
level
of
concern
(
i.
e.,
MOE's
<
100
at
Day
=
0)
are
as
follows:

 
Intermediate­
Term
post­
application
hand­
harvesting
(
cut
flowers),
risks
are
of
concern
on
the
day
of
application
(
DAT
=
0)
and
do
not
reach
the
target
MOE
of
100
until
1day
after
treatment
(
DAT
=
1)

o
Day
0
(
MOE
=
97)
o
Day
1
(
MOE
=
104)

[
Note:
The
day­
0
intermediate­
term
MOE
of
concern
(
97)
for
hand­
harvesting
cut
flowers
were
calculated
using
the
average
of
day­
0
residues
and
represents
a
conservative
estimate].

HED
has
used
the
latest
information
to
complete
this
post­
application
risk
assessment
for
propiconazole.
Several
data
gaps
exist
such
as
a
lack
of
post­
application
studies
in
different
crop
groupings
and
lack
of
exposure
data
on
mechanized
or
partially
mechanized
cultural
practices
where
there
is
a
potential
for
exposure.
Page
76
of
112
Table
9.2:
Summary
of
Propiconazole
Non­
cancer
Post­
application
Worker
Risk
Estimates
Crop
Activity
TC
cm2/
hr
Max.
App.
Rate
(
lb
ai/
A)
DAT
(
days)
DFR
ug/
cm2
(
adjusted)
Short­
Term
MOE
1Int­
Term
MOE
irrigating,
scouting,
handweeding
100
0
0.184
36000
12000
irrigating,
scouting
1500
0
0.184
2400
800
Celery,
Mint,
Wild
rice,
(
MN
only),
Barley,
Oats,
Rye,
Wheat,
Rice,
Peanuts
hand­
harvesting
2500
0.28
0
0.184
1400
500
hand­
weeding
100
0
0.059
110000
37000
irrigating,
scouting
1000
0
0.059
1100
3700
Corn
(
field,
pop,
sweet),
Sunflower
detasseling,
handharvesting
17000
0.1125
0
0.059
700
220
irrigating,
scouting
1000
0
0.254
2600
860
hand­
weeding,
hand
harvesting,
hand­
pruning,
1500
0
0.254
1700
570
Stone
Fruits,
Peaches,
Nonbearing
Apples,

thinning
3000
0.1125
0
0.254
860
290
irrigation,
scouting,
handweeding
1000
0
0.508
1300
430
Non­
bearing
Citrus
hand­
pruning,
thinning
3000
0.225
0
0.508
430
140
irrigation,
hand­
weeding
100
0
0.190
35000
12000
scouting,
irrigation
1300
0
0.190
2700
900
Bananas,
Plantains
hand­
harvesting,,
thinning,
hand­
weeding/
pruning
2000
0.084
0
0.190
1700
600
scouting,
hand­
weeding/
pruning,
irrigation,
thinning
400
0
0.382
4300
1400
Non­
bearing
Blueberries
hand­
pruning
1500
0.169
0
0.382
1200
380
pruning,
tying
110
0
0.835
7100
2040
Ornamentals
(
Woody
and
Herbaceous)
plants
transporting,
moving
potted
plants
400
0
0.835
2000
560
0
0.835
150
97
Cut
Flowers
hand­
harvesting
S­
Term
5100
I­
term
2700
0.37
1
.778
165
104
hand­
weeding,
thinning,
irrigating,
scouting
500
0
0.255
5200
1700
Pecans,
Nonbearing
Hazelnuts
hand­
pruning,
thinning
2500
0.225
0
0.255
1000
340
Page
77
of
112
Table
9.2:
Summary
of
Propiconazole
Non­
cancer
Post­
application
Worker
Risk
Estimates
Crop
Activity
TC
cm2/
hr
Max.
App.
Rate
(
lb
ai/
A)
DAT
(
days)
DFR
ug/
cm2
(
adjusted)
Short­
Term
MOE
1Int­
Term
MOE
Turf
maintenance
3400
1.8
0
0.0106
1800
600
Turf
(
grasses
grown
for
seed,
golf
courses,
sod
farms)
hand­
weeding/
harvesting
transplanting,
handharvest
mech­
harvesting
6800
1.8
0
0.0106
900
300
10.0
DATA
NEEDS
AND
LABEL
REQUIREMENTS
10.1
Residue
Chemistry
Data
Needs
 
Amend
the
product
labels
for
the
41.8%
EC
formulations
to
indicate
the
propiconazole
concentration
in
terms
of
lb
ai/
gal.
In
addition,
the
following
products
have
label
restrictions
prohibiting
the
feeding
of
treated
forage
and/
or
hay
of
cereals
and
corn
to
livestock:
the
41.8%
EC
(
100­
617
and
100­
737)
and
the
45%
WP
(
100­
780)
formulations.
Such
restrictions
are
no
longer
permitted
and
must
be
removed.

 
The
maximum
number
of
applications
for
peanuts
on
the
Stratego
 
label
is
not
very
clear.
After
discussing
with
RD
and
the
registrant,
it
is
understood
that
the
maximum
number
of
six
applications
is
intended
only
for
the
7.0
oz
ai/
A
rate,
while
the
restricted
number
of
application
at
14
oz
ai/
A
is
only
two.
HED
recommends
that
the
registrant
to
amend
the
Stratego
 
label
to
specify
these
instructions.

 
HED
is
translating
the
wheat
grain,
wheat
straw,
wheat
hay
and
forage
data
to
barley
and
rye
grain,
straw,
hay
and
forage.
The
product
labels
for
the
41.8%
EC
(
EPA
Reg.
Nos.
100­
617
and
100­
737)
and
the
45%
WP
(
EPA
Reg.
No.
100­
780)
formulations
must
be
modified
to
make
the
use
patterns
for
barley
and
rye
identical
to
wheat.

 
The
use
directions
for
rice
on
all
labels
should
be
amended
to
specify
a
45­
day
PHI
.

 
HED
recommends
increasing
the
wheat
grain
tolerance
to
0.3
ppm,
wheat
straw
to
15.0
ppm,
and
to
propose
new
tolerances
on
wheat
hay
and
forage
at
2.0
ppm,
and
on
wheat
bran
at
1.0
ppm.

 
HED
recommends
the
registrant
to
cancel
all
24C
uses
while
revising
the
Section
3
label
to
cover
these
24C
uses.

 
A
more
appropriate
level
for
the
oat
hay
tolerance
of
2.0
ppm
should
be
established
using
data
translated
from
wheat.
The
reassessed
tolerances
for
barley
grain
and
rye
Page
78
of
112
grain
should
be
0.3
ppm,
for
barley
and
rye
straw
should
be
15.0
ppm.
New
tolerances
for
barley
hay
and
rye
forage
should
be
established
at
2.0
ppm.

 
The
available
rice
residue
data
support
the
established
3.0
ppm
tolerance
for
propiconazole
residues
in/
on
rice
straw;
however,
the
data
also
indicate
that
the
registrant
should
propose
increasing
the
tolerance
for
residues
in/
on
rice
grain.
An
appropriate
level
for
residues
in/
on
rice
grain
would
be
0.3
ppm.
The
registrant
needs
to
propose
new
tolerances
on
rice
grain
at
0.3
ppm.
Based
on
the
Agency's
review
of
the
rice
processing
study,
the
registrant
needs
to
propose
new
tolerances
on
rice
bran
at
1.0
ppm,
and
rice
hulls
at
1.2
ppm.

 
HED
recommends
a
5.0
ppm
tolerance
on
aspirated
grain
fractions
for
propiconazole.

 
The
use
on
sunflower
for
seeds
can
not
be
considered
a
non­
food
use,
because
the
seed
is
a
food.
No
tolerance
can
be
established
on
sunflower
until
a
petition
and
field
trial
data
are
submitted.

 
A
pineapple
processing
study
is
required
to
determine
the
potential
for
concentration
in
pineapple
juice,
unless
a
field
trial
study
conducted
at
5x
the
maximum
application
rate
indicates
that
all
residue
levels
in/
on
pineapples
are
less
than
LOD.

 
HED
recommends
that
the
registrant
analyze
parent
and
metabolites
separately
in
all
future
field
trials,
so
that
more
realistic
tolerances
can
be
set
in
the
future.

10.2
ORE
Data
Needs
Occupational
handler
data
gaps
identified
for
this
assessment
include:

 
Seed
piece
dip
treatments
(
pineapples
and
sugarcane);
Note:
Labels
call
for
chemical
resistant
gloves,
apron
and
protective
eyewear.

 
Tree
injections;
Note:
Labels
call
for
chemical
resistant
gloves,
protective
eyewear/
face­
shield.

 
Mixing/
Loading/
Applying
wettable
powders
in
water­
soluble
packets
for
handheld
equipment.
Note:
Although
there
are
no
data
to
assess
this
scenario,
it
is
reasonable
to
assume
that
M/
L/
A
exposures
associated
with
this
formulation
are
lower
than
M/
L/
A
exposures
with
liquid
formulations.
This
rationale
is
based
on
the
assumption
that
the
"
application"
component
of
the
exposure
will
not
be
significantly
different
for
the
same
application
method
(
both
will
be
applied
as
a
spray);
however,
as
seen
in
scenarios
where
the
activities
are
separate,
the
"
mixing/
loading"
exposure
component
is
greater
for
liquid
formulations.
Page
79
of
112
10.3
Toxicology
Data
Needs
None.
Page
80
of
112
Table
10:
Tolerance
Reassessment
Summary
for
Propiconazole.

Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Tolerances
Established
Under
40
CFR
§
180.434(
a)

Bananas
0.2
0.2
[
Banana]

Barley,
grain
0.1
0.3
Translated
from
wheat
data.
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Barley,
straw
1.5
15.0
Translated
from
wheat
data.
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Cattle,
fat
0.1
0.1
0.08
ppm
combined
residues
in
fat
were
expected
from
MTDB.

Cattle,
kidney
2.0
2.0
1.01
ppm
combined
residues
in
kidney
were
expected
from
MTDB.
However,
several
new
uses
are
pending
which
may
increase
the
MTDB.

Cattle,
liver
2.0
2.0
1.33
ppm
combined
residues
in
liver
were
expected
from
MTDB.
However,
several
new
uses
are
pending
which
may
increase
the
MTDB.

Cattle,
meat
byproducts,
except
kidney
and
liver
0.1
0.1
(
see
comments
above
in
fat)

Cattle,
meat
0.1
0.1
0.04
ppm
combined
residues
in
meat
were
expected
from
MTDB.
However,
several
new
uses
are
pending
which
may
increase
the
MTDB.

Celery
5.0
5.0
Corn,
field,
stover
12
12
Expiration
date
11/
30/
08
[
Corn,
field,
stover]

Corn,
field,
forage
12
12
Expiration
date
11/
30/
08
[
Corn,
field,
forage]

Corn,
field,
grain
0.1
0.1
Expiration
date
11/
30/
08
[
Corn,
field,
grain]

Corn,
sweet,
kernels
plus
cobs
with
husks
removed
0.1
0.1
Expiration
date
11/
30/
08
[
Corn,
sweet,
kernels
plus
cobs
with
husks
removed]
Page
81
of
112
Table
10:
Tolerance
Reassessment
Summary
for
Propiconazole.

Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Eggs
0.1
Revoke
Feeding
study
data
indicate
that
tolerances
for
poultry
commodities
are
not
necessary.

Fruit,
Stone,
group
12
1.0
1.0
[
Fruit,
stone,
group
12]

Goat,
fat
0.1
0.1
(
see
comments
in
cattle)

Goat,
kidney
2.0
2.0
(
see
comments
in
cattle)

Goat,
liver
2.0
2.0
(
see
comments
in
cattle)

Goat,
meat
byproducts,
except
kidney
and
liver
0.1
0.1
(
see
comments
in
cattle)

Goat,
meat
0.1
0.1
(
see
comments
in
cattle)

Grass,
forage
0.5
0.5
Grass,
hay
(
straw)
40
40
[
Grass,
hay]

Grass,
straw
40
40
[
Grass,
straw]

Hog,
fat
0.1
0.1
(
see
comments
in
cattle)

Hog,
kidney
2.0
2.0
(
see
comments
in
cattle)

Hog,
liver
2.0
2.0
(
see
comments
in
cattle)

Hog,
meat
byproducts,
except
kidney
and
liver
0.1
0.1
(
see
comments
in
cattle)

Hog,
meat
0.1
0.1
(
see
comments
in
cattle)

Horse,
fat
0.1
0.1
(
see
comments
in
cattle)

Horse,
kidney
2.0
2.0
(
see
comments
in
cattle)

Horse,
liver
2.0
2.0
(
see
comments
in
cattle)

Horse,
mbyp
(
except
kidney
and
liver)
0.1
0.1
[
Horse,
meat
byproducts,
except
kidney
and
liver](
see
comments
in
cattle)

Horse,
meat
0.1
0.1
(
see
comments
in
cattle)

Milk
0.05
0.05
0.03
ppm
combined
residues
in
milk
were
expected
from
26.5ppm
MTDB.
Page
82
of
112
Table
10:
Tolerance
Reassessment
Summary
for
Propiconazole.

Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Mushroom
0.1
0.1
Use
of
propiconazole
on
mushrooms
is
being
supported
by
IR­
4.
Currently
there
are
no
registered
uses
of
propiconazole
on
mushrooms.
[
Mushroom]

Oat,
forage
10.0
10.0
[
Oat,
forage]

Oat,
grain
0.1
0.1
[
Oat,
grain]

Oat,
hay
30.0
2.0
Translated
from
wheat
hay.
[
Oat,
hay]

Oat,
straw
1.0
1.0
[
Oat,
straw]

Peanut
0.2
0.2
Expiration
date
11/
30/
08
[
Peanut].
Parent
accounted
30%
of
the
TRR
based
on
peanut
metabolism
(
MARC
memo
of
4/
4/
02,
D279299).

Peanut,
hay
20.0
20.0
Expiration
date
11/
30/
08
[
Peanut,
hay]

Pecans
0.1
0.1
Syngenta
has
proposed
removal
of
the
established
tolerance
for
pecans
on
establishment
of
the
proposed
tree
nut
crop
group
tolerance
(
pending
tolerance
petition
PP#
9F3470).

Pineapple
0.1
0.1
Expiration
date
11/
30/
08
Pineapple,
fodder
0.1
Revoke
Expiration
date
11/
30/
08;
no
longer
considered
a
significant
livestock
feed
item.

Plum,
prune,
fresh
1.0
Revoke
This
tolerance
has
been
replaced
by
the
stone
fruits
group
tolerance.

Rice,
grain
0.1
0.3
The
available
data,
reflecting
the
maximum
registered
use
pattern,
indicate
that
the
maximum
combined
residues
of
propiconazole
and
its
metabolites
determined
as
2,4­
DCBA
were
0.28
ppm
in/
on
rice
grain.
(
HED
memo
of
02/
23/
05,
T.
Morton,
D240856).
Page
83
of
112
Table
10:
Tolerance
Reassessment
Summary
for
Propiconazole.

Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Rice,
straw
3.0
3.0
(
HED
memo
of
02/
23/
05,
T.
Morton,
D240856).

Rye,
grain
0.1
0.3
Translated
from
wheat
data.
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Rye,
straw
1.5
15.0
Translated
from
data
for
wheat
straw.

Sheep,
fat
0.1
0.1
(
see
comments
in
cattle)

Sheep,
kidney
2.0
2.0
(
see
comments
in
cattle)

Sheep,
liver
2.0
2.0
(
see
comments
in
cattle)

Sheep,
meat
byproducts,
except
kidney
and
liver
0.1
0.1
(
see
comments
in
cattle)

Sheep,
meat
0.1
0.1
(
see
comments
in
cattle)

Wheat,
grain
0.1
0.30
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Wheat,
straw
1.5
15.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Tolerances
To
Be
Proposed
Under
40
CFR
§
180.434(
a)

Grain,
aspirated
fractions
20
(
sorghum)
1
5.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.
[
Grain,
aspirated
fraction]

Barley,
hay
None
established
2.0
Translate
from
wheat
hay
Corn,
pop,
grain
None
established
0.1
Translate
from
field
corn
Corn,
pop,
stover
None
established
12
Translate
from
field
corn
Corn,
sweet,
forage
None
established
12
Translate
from
field
corn
Corn,
sweet,
stover
None
established
12
Translate
from
field
corn
Rice,
bran
None
established
1.0
Concentration
factor
for
rice
bran
is
2.9x.
(
MRID45080811.
DER2)

Rice,
hulls
None
established
1.2
Concentration
factor
for
rice
hulls
is
3.8x.
(
MRID45080811.
DER2)

Rye,
forage
None
established
2.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.

Wheat
forage
None
established
2.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.
[
wheat,
forage]
Page
84
of
112
Table
10:
Tolerance
Reassessment
Summary
for
Propiconazole.

Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Wheat
hay
None
established
2.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.
[
Wheat,
hay]

Wheat
Bran
None
established
1.0
Memo
of
02/
02/
05,
Y.
Donovan,
D271790.
[
Wheat,
bran]

Tolerances
Established
Under
40
CFR
§
180.434(
b)

Blueberry
1.0
N/
A
Expiration
date
11/
31/
07.
Recommended
in
Agency
memo
of
02/
22/
05,
D.
Rate,
D313289.
[
Blueberry]

Cranberry
1.0
N/
A
Expiration
date
12/
31/
05
[
Cranberry]

Dry
bean
forage
8.0
N/
A
Expiration
date
12/
31/
05
[
Bean,
dry,
forage]

Dry
bean
hay
8.0
N/
A
Expiration
date
12/
31/
05
[
Bean,
dry,
hay]

Dry
bean
0.5
N/
A
Expiration
date
12/
31/
05
[
Bean,
dry]

Sorghum,
aspirated
grain
fractions
20
N/
A
Expiration
date
06/
30/
05
Sorghum,
grain,
grain
0.2
N/
A
Expiration
date
06/
30/
05
[
Sorghum,
,
grain,
grain]

Sorghum,
grain,
stover
1.5
N/
A
Expiration
date
06/
30/
05
Soybean,
bean
0.5
(
pending)
N/
A
Agency
memo
of
04/
14/
04,
J.
R.
Tomerlin,
D262299.

Soybean,
forage
8.0
(
pending)
N/
A
Agency
memo
of
04/
14/
04,
J.
R.
Tomerlin,
D262299.

Soybean,
hay
25.0
(
pending)
N/
A
Agency
memo
of
04/
14/
04,
J.
R.
Tomerlin,
D262299.
Page
85
of
112
Commodity
Current
Tolerance,
ppm
Reassessed
Tolerance,
ppm
Comment
[
Correct
Commodity
Definition]

Tolerances
Established
Under
40
CFR
§
180.434(
c)

Sunflower
None
established
TBD
2
Peppermint,
tops;
[
Spearmint,
tops
0.3
0.3
Regional
registration
for
use
west
of
the
Cascade
Mountains
only.
[
Peppermint,
tops]
[
Spearmint,
tops]

Rice,
wild
0.5
0.5
MN
[
Rice,
wild]
Note:
1
The
20­
ppm
tolerance
for
sorghum
aspirated
grain
fractions
is
a
time­
limited
tolerance
to
support
a
Section
18
Exemption.
2
Tolerance
can
not
be
established
until
field
data
are
submitted.
Page
86
of
112
CODEX
HARMONIZATION
The
Codex
Alimentarius
Commission
has
established
several
maximum
residue
limits
(
MRLs)
for
propiconazole
in/
on
various
raw
agricultural
commodities.
The
Codex
MRLs
are
expressed
in
terms
of
propiconazole
per
se,
which
is
in
harmonized
with
the
US
tolerance
expression.
HED
has
harmonized
tolerance
levels
on
most
commodities
that
have
Codex
MRLs
to
the
extend
possible.
A
numerical
comparison
of
the
Codex
MRLs
and
the
corresponding
reassessed
U.
S.
tolerances
is
presented
in
Table
11.

Table
11:
Codex
MRLs
for
Propiconazole
and
applicable
U.
S.
tolerances.

Codex
Commodity
(
As
Defined)
MRL
1
(
mg/
kg)
Step
Reassessed
U.
S.
Tolerance
(
ppm)
Recommendation
and
Comments
Almonds
0.05
CXL
­­
No
U.
S.
registration.

Banana
0.1
CXL
TBD
Barley
0.05
CXL
0.3
Coffee
beans
0.1
CXL
­­
No
U.
S.
registration.

Edible
offal
(
mammalian)
0.05
CXL
­­
No
U.
S.
registration.

Eggs
0.05
(*)
CXL
­­
No
U.
S.
registration.

Grapes
0.5
CXL
­­
No
U.
S.
registration
Mango
0.05
CXL
­­
No
U.
S.
registration.

Meat
(
from
mammals
other
than
marine)
0.05
(*)
CXL
0.1
Milks
0.01
(*)
CXL
0.05
Unable
to
harmonize
2
Oats
0.05
(*)
CXL
0.1
Peanut
0.05
CXL
0.1
Unable
to
harmonize
2
Peanut,
whole
0.1
CXL
 
Not
currently
regulated
by
U.
S.
EPA.

Pecan
0.05
CXL
0.1
Unable
to
harmonize
2
Poultry
meat
0.05
(*)
CXL
­­
No
U.
S.
registration.

Rape
seed
0.05
CXL
­­
No
U.
S.
registration.

Rye
0.05
(*)
CXL
0.3
Unable
to
harmonize
2
Stone
fruits
1
CXL
1.0
Sugar
beet
0.05
CXL
­­
No
U.
S.
registration.
Page
87
of
112
Table
11:
Codex
MRLs
for
Propiconazole
and
applicable
U.
S.
tolerances.

Codex
Commodity
(
As
Defined)
MRL
1
(
mg/
kg)
Step
Reassessed
U.
S.
Tolerance
(
ppm)
Recommendation
and
Comments
Sugar
beet
leaves
or
tops
0.5
CXL
­­
No
U.
S.
registration.

Sugar
cane
0.05
CXL
­­
Use
in
the
U.
S.
is
considered
a
non
food
use.

Wheat
0.05
(*)
CXL
0.30
Unable
to
harmonize
due
to
higher
use
rate
Note:
1
Asterisk
designates
MRL
set
at
the
limit
of
quantization.
2
Can
not
harmonize
because
current
use
patterns
in
the
United
States
supports
the
higher
value.
Page
88
of
112
APPENDICES
TOXICOLOGY
STUDIES
The
executive
summaries
of
toxicity
studies
not
discussed
in
previous
sections
are
provided
below.

Chronic
Oral
Toxicity
­
Dogs:
870.4100b
Chronic
Toxicity
 
Dog
In
a
chronic
toxicity
study
(
MRID
00151515),
propiconazole
was
fed
as
CGA­
64250
technical
(
90.2%
purity,
batch
#
FL­
831527)
to
beagle
dogs
(
7/
sex/
dose
(
control
and
high
dose)
and
5/
sex/
group
(
low
and
mid
dose
groups)
at
dietary
dose
levels
of
0,
5,
50
or
250
ppm
(
time
weighted
average
dietary
concentrations
based
on
mean
food
consumption
are:
0.2,
1.9,
8.4
mg/
kg/
day
for
males
and
0.2,
1.9
,
8.9
mg/
kg/
day
for
females,
respectively)
for
a
period
of
52
weeks.
These
doses
were
based
on
a
3­
month
study
in
dogs
fed
50,
250
or
1,250
ppm
where
a
LOAEL
of
250
ppm
was
set
based
on
changes
in
the
pyloric
region
of
the
stomach.
All
animals
were
sacrificed
after
52
weeks
except
for
two
males
and
two
females
of
the
control
and
250
ppm
were
sacrificed
after
a
four
week
recovery
period
during
of
which
these
dogs
were
fed
diets
free
of
CGA­
64250.

All
dogs
survived
the
12
month
treatment.
No
treatment
related
effects
were
noted
in
mean
body
weights,
body
weight
gains,
mean
food
consumption,
hematologic
and
clinical
chemistry,
opthalmological
findings,
electrocardiograms,
organ
weights
and
gross
pathological
findings.

Histopathologic
examinations
revealed
hypermia
of
the
mucosa
of
the
stomach
in
3/
5
of
the
250
ppm
males,
and
no
comparable
findings
were
seen
in
the
control
males.
Functional
hypertrophy
of
the
mammary
gland
was
reported
in
1/
5
control
females,
2/
5
receiving
50
ppm,
and
3/
5
receiving
250
ppm
of
the
test
material.
All
other
findings
including
the
necropsy
and
histopathological
examination
of
the
dogs
in
the
recovery
period
were
unremarkable.

Deficiencies
in
the
study
conduct
included
non
homogeneous
distribution
of
the
test
material
in
the
mid­
and
high­
dose
groups
during
weeks
14­
21.
Analytical
results
showed
the
mean
propiconazole
concentrations
for
the
50
ppm
diet
ranged
from
38
to
47
ppm
and
for
the
250
ppm
diet
ranged
from
161
to
518
ppm
during
this
period.
According
to
study
authors
this
was
due
to
mixing
problems
and
crystallization
of
the
test
material
during
refrigeration
storage.
The
test
material
was
reported
to
be
stable
at
room
temperature,
however,
it
was
stored
at
room
temperature
only
during
the
later
half
of
the
study
and
heated
to
50­
98o
C
prior
to
feed
preparation.
Nevertheless,
the
diet
analysis
data
indicated
the
test
material
was
stable
throughout
the
study.
Page
89
of
112
The
LOAEL
is
250
ppm
(
8.4
mg/
kg/
day),
based
on
hypermia
of
the
stomach
in
males
(
indicating
mild
irritation
of
the
mucosa).
The
NOAEL
is
50
ppm
(
1.9
mg/
kg/
day).
However
an
OHEA
and
OPP
work
group
(
May
25,
1987)
noted
a
mistake
in
the
estimation
of
NOAEL
dose
and
recommended
instead
the
usual
dose
conversion
factor
for
dogs
of
1
ppm
=
0.025
mg/
kg/
day.
This
revision
results
in
slightly
lower
NOAEL
of
1.25
mg/
kg/
day.
Accordingly
the
LOAEL
is
revised
to
6.25
mg/
kg/
day.
(
Acceptable/
Guideline)

SUBCHRONIC
­
RAT:
870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
subcronic
toxicity
study
(
MRID
00058606
&
93194032),
CGA
64250
(
90.0%
purity)
was
administered
to
Tif
(
RAIF)
SPF
rats,
approximately
four
weeks
of
age
(
20/
sex/
dose)
at
dietary
concentrations
of
0,
240,
1200,
or
6000
ppm
(
0,
15.85,
76.08
and
461.73
mg/
kg
bw/
day
in
males
and
0,
16.82,
77.59
and
400.90
mg/
kg
bw/
day
in
females,
respectively)
for
13
weeks.

No
clinical
symptoms
nor
any
signs
of
local
and/
or
systemic
toxicity
were
observed.
The
survival
and
mean
food
consumption
of
animals
was
unaffected
by
the
treatment.
The
body
weight
and
body
weight
gain
of
all
male
and
females
at
6000
ppm
was
significantly
decreased
from
weeks
2­
13
(
79%
and
80%
of
controls
body
weight
and
75%
and
73%
of
controls
body
weight
gain
at
week
13
for
males
and
females,
respectively).
The
body
weight
and
body
weight
gain
of
the
females
of
the
1200
ppm
group
was
significantly
decreased
from
weeks
9­
13
when
compared
to
the
control
(
92%
of
controls
body
weight
and
89%
of
the
controls
body
weight
gain
at
week
13).
Although
there
was
some
statistically
significant
reduction
(
2­
5%)
in
body
weight
gain
during
the
same
weeks
of
the
study
in
the
low­
dose
females,
the
slight
decrease
in
body
weight
gain
in
this
group
is
not
considered
biologically
significant.
For
all
animals
in
the
6000
ppm
groups,
absolute
organ
weights
(
heart,
kidney,
and
adrenal
glands
in
males;
kidneys
and
heart
in
females)
were
decreased
and
relative
organ
weights
to
body
weight
increased
and
to
brain
weight
mostly
decreased.

Ophthalmic,
auditory
and
hematological
findings
showed
no
evidence
of
treatment
related
effects.

Erythrocyte
count,
hematocrit
and
hemoglobin
concentration
were
found
to
be
significantly
lower
in
the
female
rats
of
the
high
dose
group
at
week
13.

The
only
clinical
chemistry
findings
noted
consisted
of
an
increase
in
alkaline
phosphatase
activity
in
the
high­
dose
female
rats
at
week
13
and
an
increase
in
the
 ­
glutamyl
transpeptidase
activity
in
male
and
female
rats
of
the
high­
dose
groups
at
weeks
4,
8,
and
13.

Histopathology
examination
of
the
spleen
of
all
female
rats
from
the
6000
ppm
group
showed
an
increase
in
hemosiderosis.

The
NOAEL
for
the
study
is
considered
1200
ppm
in
males
(
76
mg/
kg
bw/
day)
and
240
ppm
in
females
(
16.82
mg/
kg
bw/
day).
The
LOAEL
is
6000
ppm
in
males
(
462
mg/
kg
bw
/
day)
and
1200
ppm
in
females
(
77.59
mg/
kg
bw/
day)
based
on
reduced
body
weight
gain.
(
Acceptable/
Guideline)
Page
90
of
112
SUBCHRONIC
­
MOUSE:
870.3100
90­
Day
Oral
Toxicity
­
Mouse
In
a
subcronic
toxicity
study
(
MRID
42050501),
propiconazole
was
administered
as
CGA
64250
(
92.0%
purity,
batch
number
FL­
850083)
to
7­
week
old
Crl:
CD­
1
(
ICR)
BR
(
Swiss)
mice
(
20/
sex/
dose)
at
dietary
concentrations
of
0,
20,
500,
or
2500
ppm
(
0,
2.7,
65,
352
mg/
kg/
day
in
males
and
0,
3.4,
85,
434
mg/
kg/
day
in
females,
respectively)
for
17
weeks.
Two
additional
groups
of
male
mice
(
20/
group)
were
administered
the
test
material
at
850
or
1450
ppm
(
112,
194
mg/
kg/
day,
respectively).

Twice
daily
inspections
of
the
animals
revealed
no
clinical
signs
and
mortality
attributable
to
the
administration
of
the
test
article.

There
were
no
treatment­
related
effects
on
the
body
weight,
body
weight
gain
and
food
consumption
in
treated
mice.

Ophthalmological
examinations
of
all
animals
at
the
termination
of
the
study
revealed
no
treatment­
related
eye
lesions.

Statistically
significant
increases
(
p
<
0.01)
in
liver
weights
(
absolute:
115%­
192%
of
control,
and
relative
to
body
weight:
113%­
204%
or
relative
to
brain
weight:
116%­
194%)
were
found
in
the
male
animals
at
$
500
ppm
and
in
the
female
mice
at
the
2500
ppm
(
179%
of
control,
184%
relative
to
body
weight
and
189%
relative
to
brain
weight).

Gross
pathological
examination
of
the
livers
from
the
male
mice
revealed
a
significant
increase
in
liver
enlargement
($
1450
ppm)
and
focal
discoloration
($
850
ppm).
The
female
mice
showed
a
significant
increase
in
liver
enlargement
at
2500
ppm;
focal
discoloration
was
present
at
2500
ppm.
The
increase
in
absolute
and
relative
liver
weights
also
correlated
well
with
histopathological
(
hypertrophy
and
necrosis)
and
clinical
chemistry
(
increases
in
both
ALT
and
AST)
findings.
Males
showed
significant
decreases
(
p<
0.01)
in
serum
cholesterol
at
$
1450
ppm
after
13
weeks
and
at
$
850
ppm.
Significant
increase
(
p<
0.01)
in
alanine
aminotransferase
occurred
after
17
weeks
in
males
at
$
1450
ppm
and
in
females
at
13
and
17
weeks
at
2500
ppm.
Aspartate
aminotransferase
increased
significantly
(
p<
0.01)
in
females
at
the
17
week
interval
at
2500
ppm.
Clinical
chemistry
analysis
was
limited
to
liver
only.
Hematology
was
not
performed.

Male
mice
showed
a
dose­
related
increase
in
both
the
incidence
and
severity
of
histopathological
lesions
of
the
liver,
while
the
females
showed
significant
increases
only
at
2500
ppm.
At
500
and
850
ppm
dose
levels,
all
diagnosed
hypertrophy
in
the
males
was
mild;
moderate
hypertrophy
was
present
in
9/
20
and
18/
20
for
animals
in
the
1450
and
2500
ppm
groups,
respectively.
In
females
at
the
2500
ppm
dose,
14/
20
showed
minimal
to
mild
hypertrophy,
while
3/
20
was
classified
as
moderate.
Necrosis
occurred
both
as
scattered
individual
cell
foci
and
multicellular
areas.
Necrosis
was
present
in
males
at
500
ppm
with
significant
increases
found
at
$
850
ppm.
The
severity
and
incidence
of
the
necrosis
for
males
in
the
1450
ppm
group
Page
91
of
112
was
minimal
for
2/
20,
mild
for
5/
20
and
moderate
for
1/
20.
At
2500
ppm
7/
20
and
5/
20
male
mice
showed
minimal
and
mild
necrosis,
respectively.
For
females
at
2500
ppm
6/
20
showed
mild
necrosis.
Cellular
necrosis
in
males
was
minimal
for
2/
20
at
1450
ppm
and
7/
20
at
2500
ppm
and
mild
for
5/
20
at
2500
ppm.

Vacuolation
also
occurred
as
scattered
individual
foci
and
multicellular
areas.
Significant
vacuolation
was
present
only
in
the
2500
ppm
group
where
2/
20,
7/
20
and
1/
20
showed
minimal,
mild
and
moderate
vacuolation,
respectively.
No
compound­
related
effect
was
found
when
sections
of
male
livers
were
stained
using
Oil
Red
0,
since
nearly
all
of
the
sections
(
including
the
controls)
were
stained
for
microvesicular
lipid.
Males
appeared
to
be
more
sensitive
to
the
test
article
than
females.

The
LOAEL
based
on
increase
in
absolute
and
relative
liver
weights
and
histopathological
changes
is
500
ppm
(
65
mg/
kg/
day)
in
males
and
2500
ppm
(
434
mg/
kg/
day)
in
females.
The
NOAEL
is
20
ppm
in
males
(
2.7
mg/
kg/
day)
and
500
ppm
in
females
(
85
mg/
kg/
day).
(
Acceptable/
Guideline)

In
a
subcronic
toxicity
study
(
MRID
42050502)
propiconazole
administered
as
CGA
64250
(
92.0%
purity,
batch
number
FL­
850083)
was
administered
to
37
days
old
Crl:
CD­
1
(
ICR)
BR
Swiss
male
mice
(
40/
dose)
at
dietary
concentrations
of
0,
20,
500,
850,
1450
or
2500
ppm
(
0,
2.7,
65,
112,
194,
352
mg/
kg/
day,
respectively)
for
13
weeks.
One
group
of
10
males/
dose
was
sacrificed
after
4
weeks,
a
second
group
of
10
males/
dose
after
8
weeks
and
the
third
group
of
20
males/
dose
was
sacrificed
after
13
weeks.
This
study
was
conducted
to
determine
the
maximum
tolerated
dose
(
MTD).

Twice
daily
inspections
of
the
animals
revealed
no
clinical
signs
and
mortality
attributable
to
the
administration
of
the
test
article.

Significant
differences
in
weekly
body
weights
between
the
control
and
treated
mean
body
weights
were
limited
to
animals
in
the
2500
ppm
group
during
the
first
8
weeks
of
the
study.
A
significant
difference
was
also
observed
in
the
1450
ppm
group
after
4
weeks.
The
mean
cumulative
body
weight
gains
showed
significant
decreases
(
p
<
0.01)
for
animals
in
the
2500
ppm
during
weeks
1,
2,
and
4(
36%,
70%,
70%
of
the
body
weight
gain
of
the
controls,
respectively);
by
week
8
the
decrease
in
body
weight
gain
was
11%.
Although
the
food
consumption
at
2500
ppm
was
comparable
to
controls,
the
males
at
2500
ppm
had
lower
food
efficiency
(­
0.7%
vs.
1.4%
in
controls).

There
were
no
treatment­
related
eye
lesions
noted.

Statistically
significant
(<
0.01)
increases
in
liver
weights
(
absolute:
116%­
182%
of
controls,
and
relative
to
body
weight:
118­
194%
of
controls,
and
relative
to
brain
weight:
119­
192%
of
control)
were
found
in
the
male
animals
at
$
500
ppm
at
the
end
of
the
treatment
period.
Gross
pathology
examinations
revealed
generalized
enlargement
and
focal
discoloration
of
the
livers.
Page
92
of
112
Hepatocellular
hypertrophy,
necrosis
and
vacuolation
of
the
liver
significantly
increased
at
$
500
ppm
at
all
sacrifice
times.
In
general,
the
severity
of
the
histopathological
lesions
was
dose
related
with
the
highest
incidence
of
mild
to
moderate
lesions
occurring
in
the
highest
dose
groups.
None
of
the
lesions
were
classified
as
either
marked
or
severe.

Serum
cholesterol
significantly
decreased
(
p<
0.01)
at
$
850
ppm
and
serum
alanine
aminotransferase
(
aserum
enzyme
associated
with
hepatic
necrosis)
and
sorbitol
dehydrogenate
increased
at
$
1450
ppm
and
$
850
ppm,
respectively.
Only
liver
enzymes
were
measured.

Hematology
was
not
performed.

The
LOAEL
is
500
ppm
(
65
mg/
kg/
day),
based
on
increase
in
absolute
and
relative
liver
weights
and
histopathological
liver
lesions.
The
NOAEL
is
20
ppm
(
2.7
mg/
kg/
day).
(
Acceptable/
Guideline)

SUBCHRONIC
­
DOG:
870.3150
90­
Day
Oral
Toxicity
­
Dog
In
a
sub­
chronic
toxicity
study
(
MRID
00058607,
93194033),
CGA
64250
technical(
88.0%
purity,
batch
number
35/
5)
was
administered
to
pure­
bred
Beagle
dogs
(
4/
sex/
dose)
at
dietary
concentrations
of
0,
50,
250,
or
1250
ppm
(
0,
1.5,
7.3,
36.0
mg/
kg/
day,
respectively)
for
13
weeks.
The
initial
age
of
the
dogs
was
19­
28
weeks
and
body
weights
ranged
from
7.9­
13.0
kg
for
males
and
6.0­
11.6
kg
for
females.
The
dogs
were
housed
in
kennels
equipped
with
underfloor
heating.

Some
animals
of
all
groups
including
controls
showed
slight
to
moderate
diarrhea
during
the
whole
study.
Survival,
body
weight
gain,
food
consumption,
clinical
chemistry,
urinalysis,
ophthalmic
and
auditory
examinations
and
organ
weights
revealed
no
treatment
related
effects.

Necropsy
showed
that
in
3/
4
of
male
dogs
from
the
highest
dosage
group
(
1250
ppm),
slightly
granular
surface
in
the
pyloric
and
propyloric
part
of
the
stomach
was
noted.
Apart
from
this
finding
no
gross
anatomical
changes
were
seen
neither
in
treated
nor
in
control
dogs.
Microscopically,
in
3
out
of
4
male
dogs
from
the
highest
dose­
group
and
1
out
of
4
female
dogs
from
the
250
ppm
group
slightly
increased
amount
of
lymphoid
follicles
in
the
mucous
membrane
of
the
pyloric
part
of
the
stomach
was
seen.
However,
this
was
not
seen
in
the
high
dose
females.
These
histological
findings
are
considered
compound­
related.

The
LOAEL
is
250
ppm
(
7.3
mg/
kg/
day)
based
on
the
finding
of
lymphoid
follicles
in
the
mucous
membrane
of
the
pyloric
part
of
the
stomach.
The
NOAEL
is
50
ppm
(
1.5
mg/
kg/
day).
(
Acceptable/
Guideline)

METABOLISM:
In
a
metabolism
study
[
MRID
42403901],
the
metabolism
and
excretion
of
propiconazole
labeled
with
14C
at
the
triazole­[
3,5]
position
was
investigated
in
TIF:
RIA
f
(
SPF)
male
rats
(
number
and
age
of
animals
not
given)
orally
gavaged
a
single
dose
of
31.4
mg/
kg,
Page
93
of
112
dissolved
in
water/
ethanol/
propylene
glycol
200
(
50/
30/
20
v/
v/
v).
Animals
were
house
individually
in
metabolism
cages.

This
study
focused
on
the
identification
of
the
urinary
and
fecal
metabolites.
Several
analytical
techniques
were
used
to
separate
the
various
metabolites
including
high
performance
liquid
chromatography,
thin
layer
chromatography,
methylation,
acetylation,
sylation
and
other
derivitization
techniques.

The
test
compound
was
rapidly
metabolized
with
81,
94
and
96%
of
the
radioactivity
appearing
in
the
urine
and
feces
1,2,
and
3
days,
respectively
after
dosing.
The
ratio
of
the
urine
to
feces
radioactivity
was
approximately
5:
4.
The
parent
compound
is
extensively
metabolized;
only
a
small
percentage
remained
unabsorbed
and
appeared
in
the
feces.
The
n­
propyl
side
chain
is
first
metabolized
to
 ­,
 ­
and
 ­
hydroxy
derivatives
and
then
to
 ,
 ­
and
 ,
 ­
diols.
The
 ,
 ­
diol
is
further
metabolized
to
 ­
hydroxy
carboxylic
derivative,
a
major
metabolite
(
metabolite
U8,
11%)
appearing
in
the
urine.
The
side
chain
is
sequentially
decarboxylated
to
yield
acetic
and
formic
acid
derivatives.
Once
the
dioxolane
derivative
ring
is
cleaved,
a
wide
variety
of
metabolic
reactions
occurs,
leading,
in
general,
to
the
hydroxylation
of
the
dichlorophenyl
and
triazole
rings.
Sulfation
appeared
to
be
the
preferential
route
of
secondary
metabolism
and
accounted
for
5.5%
of
the
dose.
(
Acceptable/
Guideline).
It
partially
satisfies
the
guideline
requirement
for
a
metabolism
study
(
870.7485,
§
85­
1)
because
absorption
and
tissue
distribution
of
radioactivity
were
not
determined
in
this
study.

In
another
metabolism
study
[
MRID
41326701],
the
absorption,
distribution,
metabolism
and
excretion
of
propiconazole
labeled
with
(
U­
14C)­
Phenyl
was
investigated
in
groups
of
(
5/
sex/
group)
Sprague­
Dawley
rats
(
Crl:
CD(
SD)
BR
strain)
following
oral
or
intravenous
(
iv)
administration
at
dose
levels
of
0.5
mg/
kg.
Additionally,
one
group
was
administered
daily
single
oral
dose
of
0.5
mg/
kg
of
the
non­
radiolabeled
compound
for
14
days
followed
with
a
single
oral
dose
of
0.5
mg/
kg
of
the
radiolabeled
material
24
hours
after
the
last
dose.
Another
group
was
administered
a
single
oral
dose
of
50
mg/
kg
of
the
radiolabeled
compound.
Animals
were
housed
individually
in
metabolism
cages.
Urine
and
feces
were
collected
at
regular
intervals
and
analyzed
by
two
dimensional
thin
layer
chromatography
and
autoradiography.
Tissues
were
collected
at
sacrifice
time
(
168
hours)
and
radio­
assayed.

Administration
of
0.5
mg/
kg
of
radiolabeled
CGA
64250
to
rats
by
oral
or
iv
routes
resulted
in
similar
patterns
of
elimination,
possibly
as
a
result
of
biliary
excretion.
Renal
elimination
data
suggest
that
35­
50%
of
the
oral
dose
was
absorbed.
More
than
90%
of
the
administered
radioactivity
was
eliminated
in
the
urine
and
feces
(
including
cage
washes)
after
168
hours
of
dosing.
Most
of
the
excreted
radioactivity
occurred
within
the
first
48
hours
of
treatment.
Traces
or
non
detectable
levels
were
seen
in
the
tissues
and
expired
air.
Female
rats
appeared
to
eliminate
more
of
the
radioactivity
in
the
urine
than
in
the
feces(
46.3%
vs
39.0%
in
the
orally
dosed;
43.8%
vs
37.0%
in
the
iv
dosed).
While
male
rats
eliminated
more
radioactivity
in
the
urine
than
in
the
feces
in
most
of
the
groups
except
for
the
iv
group
where
urine
and
fecal
elimination
were
about
equal.
No
significant
differences
in
the
excretion
pattern
were
seen
between
the
low
and
high
oral
dose
groups
or
the
repeated
dosing
group.
The
distribution
of
radioactivity
in
tissues
was
similar
in
low
and
high
dose
groups.
Page
94
of
112
Examination
of
the
pooled
urine
and
fecal
samples
indicated
that
(
U­
14C)­
Phenyl
labeled
CGA
64250
was
extensively
metabolized
into
24
and
47
different
radiolabeled
components,
respectively.
The
latter
may
reflect
a
difference
in
assay
sensitivity
as
well
as
a
dose
level
effect.
Within
each
sample
type,
the
pattern
of
metabolites
varied
according
to
sex
and
dose
group.
The
radiolabled
parent
compound
was
only
detected
in
the
urine
of
the
iv
group
males
and
females
(
27.1
and
29.9%
of
the
urine
radioactivity
in
males
and
females,
respectively).
In
the
iv
urine
radiolableled
material
co­
chromatographing
with
standards
CGA
188245
(
61.8%
in
males,
2.4%
in
females),
CGA
217495
(
8.9%
in
males,
58.3%
in
females),
CGA
91304
(
2.3%
in
males
only),
CGA
118244
(
3.6%
in
females
only).
These
metabolites
were
also
detected
to
varying
degrees
in
the
urine
of
the
orally
dosed
groups.
In
the
feces,
no
parent
material
was
detected
in
the
iv
group,
but
detected
in
the
other
groups
(
6.8­
17.6%
of
the
fecal
radioactivity
in
males
and
females).
Radiolabeld
materials
co­
chromatographing
with
standards
CGA
91305,
CGA
188245
and
CGA
177291
were
reported
ranging
from
0.5%
­
10.9%
of
the
fecal
radioactivity
in
males
and
females
or
in
one
sex
alone.
Most
of
the
fecal
radioactivity
was
not
characterized.

(
U­
14C)­
Phenyl
radiolabeled
is
extensively
metabolized
in
male
and
female
rats
following
oral
or
iv
administration.
The
proposed
metabolic
pathway
involves
initial
side
chain
oxidation
giving
the
hydroxylated
propel
derivative
or
replacement
of
the
propyl
group
by
carboxylic
acid.
The
alkyl
side
chain
attached
to
the
dioxolane
ring
in
CGA
64250
is
probably
attacked
with
the
possible
loss
of
the
dioxolane
ring
itself.
(
Acceptable/
Guideline).
However,
it
partially
satisfies
the
guideline
requirement
for
a
metabolism
study
(
85­
1)
because
most
of
the
metabolites
were
not
identified.

In
another
metabolism
study
[
MRID
00074506
&
00074507],
urinary
and
fecal
metabolites
of
(
U­
14C)­
phenyl
or
14C­
triazole
ring
labeled
propiconazole
administered
to
Tif:
RAI
F
(
SPF)
male
rats
were
investigated.
The
triazole­[
3,5­
14C]
CGA
64250
(
specific
activity
23.1
uCi/
mg)
was
given
to
20
male
rats
at
an
average
single
oral
dose
of
31.4
mg/
kg.
The
phenyl­[
U­
14C]
CGA
64250
(
specific
activity
38.9
uCi/
mg)
was
given
to
3
male
rats
at
an
average
single
oral
dose
of
32.5
mg/
kg.
Animals
were
kept
in
individual
metabolism
cages.
Urine
and
feces
were
collected
and
pooled
for
an
unspecified
period
of
time
and
analyzed
for
radioactivity.

The
study
mainly
focused
on
the
analysis
of
urinary
and
fecal
metabolites.
Within
3
days
>
95%
of
the
administered
triazole
labeled
dose
was
excreted
in
urine
(
52%)
and
feces
(
43%).
Animals
treated
with
the
phenyl
label
showed
a
similar
pattern
of
excretion
in
urine
(
51%)
and
feces
(
48%).

Examination
of
the
0­
24
hour
urine
by
two
dimensional
TLC
revealed
12
metabolites
in
both
the
triazole
and
phenyl
labeled
and
a
13th
metabolite
in
the
triazole
labeled
compound.
No
parent
material
was
detected.
When
the
urine
was
incubated
with
 
­
glucurodinase
or
with
 ­
glucurodinase/
aryl
sulfatase
certain
metabolite
fractions
disappeared
suggesting
the
presence
of
glucuronic
acid
and
sulfuric
acid
conjugates.
Two
other
fractions
co­
chromatographed
with
CGA
77502
and
CGA
58533.
High
voltage
electrophoresis
showed
80%
of
the
urinary
metabolites
to
be
acidic
and
fecal
metabolites
were
some
what
polar.
Page
95
of
112
The
percentages
of
fecal
metabolites
extracted
and
distributed
at
various
pH's
were
not
substantially
different
between
the
triazole
and
phenyl
labeld
CGA
64250.
TLC
of
the
fecal
extracts
revealed
at
least
8
metabolites,
which
were
less
polar
than
the
urinary
metabolites.
TLC
also
indicated
the
presence
of
metabolites
CGA
77502
and
CGA
58533
in
addition
to
unchanged
parent
material
(
5%
of
fecal
radioactivity).

The
similarities
in
the
excretion
pattern
and
metabolite
distribution
from
the
two
different
labels
suggest
that
the
bridge
between
the
phenyl
ring
and
the
triazole
ring
remained
intact.

The
proposed
major
metabolic
pathway
appears
to
involve
the
cleavage
of
the
dioxalone
ring
with
subsequent
dechlorination
and
conjugation
and
through
the
oxidation
of
the
propel
side
chain.
The
metabolic
profile
of
both
urine
and
feces
appear
to
be
similar
except
for
the
presence
of
parent
material
in
the
feces
while
the
urine
had
conjugated
phenolic
metabolites.
(
Acceptable/
Guideline).
However,
it
partially
satisfies
the
guideline
requirement
for
a
metabolism
study
(
870.7485,
§
85­
1)
because
it
did
not
provide
absorption
and
pharmacokinetic
data.

870.7485
Metabolism
­
Mouse
In
a
metabolism
study
[
MRID
00164795],
the
absorption,
distribution,
metabolism
and
excretion
of
(
U­
14C)­
phenyl
labeled
propiconazole
was
investigated
in
CD­
1
mice
and
Tif:
RAI
F
(
SPF)
rats.
Male
and
female
mice
(
5/
dose
level)
were
fed
ad
libitum
unlabeled
CGA
64250
(
Batch
No.
OP
412127,
91.1%
purity)
in
the
diet
for
21
days
at
levels
of
5,
100
or
2500
ppm
followed
by
a
single
oral
dose
of
the
radiolabeled
CGA
64250
(
Batch
No.
GAN­
VA­
43)
at
the
corresponding
levels
(
equivalent
to
0.81,
16.8
and
434
mg/
kg
for
males
and
1.02,
21.5
and
475
mg/
kg
for
the
females).
Three
female
mice
were
given
a
bolus
dose
of
600
mg/
kg
14C­
CGA
64250
without
pretreatment
of
unlabeled
compound
(
these
mice
showed
severe
signs
of
toxicity
and
two
died
48­
72
hours
post
dosing).
Two
male
rats
were
given
9.4
mg/
kg
single
oral
dose
of
the
14C­
CGA
64250
without
pretreatment
of
unlabeled
compound.
After
14C­
CGA
64250
dosing,
animals
were
kept
in
glass
metabolism
cages.
Urine
and
feces
were
collected
at
24
hour
intervals.
Animals
were
killed
4
days
post
14C
dosing.
Blood,
liver,
kidneys,
lungs
and
remaining
carcass
were
taken
for
analysis.

Excretion:
Mice
pre­
treated
with
the
unlabeled
CGA
64250
excreted
83­
103%
of
the
administered
14C
radioactivity
within
96
hours
(
mostly
within
the
first
24­
48
hours)
in
the
urine
and
feces.
More
radioactivity
(
particularly
at
the
higher
doses
of
100
and
2500
ppm)
was
excreted
in
the
urine
than
in
the
feces
(
1.5­
3.7x)
in
males
and
females.
The
high
dose
females
excreted
the
least
amount
(
83%
of
the
administered
dose
(
AD)).
Total
recovered
radioactivity
ranged
from
88­
106%
of
the
AD.
The
male
rats
excreted
nearly
equal
amounts
of
the
radioactivity
in
urine
(
48%)
and
feces
(
54%).

Tissue
Disribution:
Tissues
and
carcass
residues
were
less
than
0.55%
of
the
AD
in
treated
rats
and
mice.
Four
days
post
dosing
with
14C­
CGA
64250,
residues
were
detected
in
the
liver
in
rats
and
liver,
kidneys
and
carcass
in
mice.
Page
96
of
112
Urinary
Metabolites:
Two
dimensional
TLC
revealed
15­
30
metabolites
in
the
0­
24
urine
samples
(
identified
in
the
report
by
their
TLC
code).
Metabolites
U1,
U2,
U9,
U12,
U17,
U18
representing
5­
19%,
6­
73%,
2­
8%,
2­
22%,
2­
3%
and
1­
16%
of
the
urine
radioactivity,
respectively
were
the
most
predominant
in
the
two
species.
Metabolite
U2
was
highest
in
the
male
mice
urine
(
61­
73%).
Female
mice
urine
contained
29­
36%
while
the
male
rat
had
the
least
(
6%)
of
the
U2
metabolite.
The
U12
fraction
was
another
example
of
species
and
sex
difference
in
metabolic
products.
At
5
and
100
ppm
female
mice
(
and
the
male
rats)
excreted
more
of
the
U12
metabolite
than
in
the
other
groups
(
18
and
21%
in
female
mice,
respectively
and
22%
in
male
rats).
In
an
earlier
study
this
metabolite
was
identified
as
 ­
hydroxy­
carboxyacid
(
metabolite
CU).

When
mouse
urine
was
incubated
with
 ­
glucuronidase
then
75­
85%
of
the
U2
fraction
disappears
giving
rise
to
a
more
unpolar
U18
fraction.
In
rat
urine,
however,
the
most
polar
fraction
U1
completely
disappears
after
 ­
glucuronidase
incubation
and
forms
several
unpolar
fractions
while
the
U2
fraction
of
the
rat
urine
is
not
significantly
affected.
The
U18
fraction
consisted
of
at
least
two
compounds,
one
is
the
alcohol
CGA
91305
and
the
other
is
the
analogus
ketone
CGA
91304.
The
major
urinary
metabolite
isolated
from
the
U2
fraction
was
determined
to
be
Met
IU,
the
glucuronic
acid
conjugate
of
metabolite
CGA
91305.

Metabolic
Pathway:
It
was
concluded
that
the
major
metabolic
pathway
in
mice
proceeds
via
elimination
of
the
dioxolane
ring
leading
via
ketone
formation
(
CGA
91304)
to
the
corresponding
acid
to
yield
metabolite
CGA
91305.
In
males
this
represents
30%
of
the
Ad
whereas
in
the
females
it
represents
15%
of
the
AD.
In
rats,
the
unpolar
metabolite
fractions
U15
through
U18
represent
metabolites
where
the
dioxolane
ring
has
been
cleared.
In
conclusion
mice
cleaved
the
dioxolane
ring
to
a
greater
extent
(
70%
and
40%
for
males
and
females,
respectively)
than
do
male
rats
(
30%)."(
Acceptable/
Non­
Guideline).
Page
97
of
112
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH2
*
*
*

N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
N
HC
=

=
CH
N
N
CH2
CH
Cl
Cl
OH
CGA
64250,
triazole
label
CGA
64250,
phenyl
label
CGA
77502
CGA
58533
APPENDIX
1:
REFERENCE
COMPOUNDS
Page
98
of
112
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
N
HC
=

=
CH
N
N
CH2
CH
Cl
Cl
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH
CH2
OH
COOH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
CH2
CH
CH2
COOH
CH2
N
HC
=

=
CH
N
N
CH2
CH
Cl
Cl
OH
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
OH
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
OH
OH
Glucuronic
acid
Sulfuric
acid
Conjugates
CGA
64250
Appendix
2:
Proposed
major
metabolic
pathways
of
CGA
64250*

*
Chart
from
page
11
of
MRID
00074507:
14C­
triazole
or
phenyl
labeled
propiconazole
in
the
Rat
Page
99
of
112
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH2
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH
OH
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
COOH
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
C
COOH
CH2
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
COOH
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH
CH3
CH2
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH
CH3
CH
OH
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH
CH2
CH2
OH
CH2
C
Cl
Cl
O
O
CH2
CH
COOH
CH2
OH
N
HC
=

=
CH
N
N
Met.
H
F
(<
1%)

Met.
W
F
,
X
F
,
Y
F
(
1%)

Met.
Z
F7
(
1%)
Met.
U
F
(<
1%)

Met.
Eu
2
,
Ku,
Z
F
,
Z
F1
(
3%)
Met.
Cu,
Du,
Xu,
Wu,
TF
(
14%)

Met.
Eu3
(
2%)

Met.
Eu
1
(
2%)
2)
Appendix
1:
Proposed
Metabolic
Pathway
of
14C­
Triazole
Propiconazole
in
the
Rat
(
taken
from
of
study
MRID
42403901
(
Fig
16):
values
represent
percent
of
dose)
1)
Page
100
of
112
N
HC
=

=
CH
N
N
CH2
C
N
HC
=

=
CH
N
NH
Cl
Cl
Cl
Cl
HOOC
O
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
N
HC
=

=
CH
N
N
CH2
C
Cl
N
HC
=

=
CH
N
N
CH2
C
Cl
N
HC
=

=
CH
N
N
CH
2
Cl
Cl
N
HC
=

=
C
N
N
CH2
CH
Cl
Cl
OH
N
HC
=

=
CH
N
N
CH2
C
N
HC
=

=
CH
N
N
CH2
Cl
Cl
N
HC
=

=
N
N
CH2
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
C
OH
OH
CH
CH
CH
OH
Cl
OH
SCH3
SCH3
SCH3
SCH3
Met.
Zu16,
Zu36
(
2%)

Met.
LF
(<
1%)
Met.
Hu,
Zu18,
Zu23,
Zu32,
CF
(
3%)
5)

Met.
Lu,
Ru,
Zu7,
Zu11,
Zu20,
Zu22
SF
(
6%)
5)

Met.
Tu
(
1%)

Met.
Zu9
(<
1%)
Met.
Zu3,
Zu14,
Zu15
(<
1%)
5)
Met.
KF,
Zu13,
Zu4
Zu17
(
3%)
5)

Met.
Pu,
Zu,
Zu2
(
1%)
Met.
Zu19,
Zu27,
DF
(
3%)
5)

Met.
Z29a
(<
1%)
Met.
Zu6,
Zu10,
Zu12,
Zu24
Zu25,
Zu33,
Zu34,
Zu
29b
(
4%)
5)
4)
4)

1)
These
figures
are
based
on
the
amounts
of
metabolites
actually
isolated
2)
Hypothetical
intermediate
3)
Metabolite
Zu16
might
be
metabolically
formed
from
all
metabolites
above
4)
Artifacts
5)
Metabolites
partially
excreted
as
sulfuric
and/
or
glucuronic
acid
conjugate
3)
3)
3)
3)

N
HC
=

=
CH
N
N
CH2
CH
Cl
Cl
OH
OH
N
HC
=

=
C
N
N
CH2
CH
Cl
Cl
OH
OH
,
N
HC
=

=
CH
N
N
CH
2
CH
Cl
Cl
OH
Page
101
of
112
*
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH
CH3
CH2
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH2
OH
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
COOH
CH2
C
Cl
Cl
O
O
CH2
CH
COOH
CH2
N
HC
=

=
CH
N
N
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
N
HC
=

=
CH
N
N
CH2
CH
Cl
Cl
OH
Cl
Cl
HOOC
N
HC
=

=
CH
N
N
CH2
C
Cl
Cl
O
O
CH2
CH
CH2
CH3
CH2
CGA
64250
CGA
118244
CGA
118245
CGA
217495
CGA
217496
CGA
91304
CGA
91305
CGA
177291
APPENDIX:
REFERENCE
COMPOUNDS
Page
102
of
112
Page
103
of
112
Page
104
of
112
REFERENCES
00058591
Bathe,
R.
(
1978)
Report
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Acute
Oral
LD50
in
the
Rat
of
Technical
CGA
64250:
Project
No.
785244.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058596
Bathe,
R.
(
1979)
Report
on
Acute
Dermal
LD50
in
the
Rat
of
Technical
CGA
64250:
Project
No.
785245.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
G)

00058597
Sachsse,
K.;
Ullmann,
L.
(
1978)
Eye
Irritation
in
the
Rabbit
after
Single
Application
of
Technical
CGA
64250:
Project
No.
785248.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058598
Sachsse,
K.;
Ullmann,
L.
(
1978)
Skin
Irritation
in
the
Rabbit
after
Single
Application
of
Technical
CGA
64250:
Project
No.
785249.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
I)

00058599
Ullmann,
L.
(
1979)
Report
on
Acute
Aerosol
Inhalation
Toxicity
in
the
Rat
of
CGA
64250
EC
250
(
A­
6099
B):
Project
No.
790741.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058600
Ullmann,
L.
(
1979)
Report
on
Skin
Sensitizing
(
Contact
Allergenic)
Effect
in
Guinea
Pigs
of
Technical
CGA
64250:
Project
No.
785250.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058601
Arni,
P.;
Muller,
D.
(
1979)
Salmonella/
Mammalian­
Microsome
Mutagenicity
Test
with
CGA
64250:
No.
of
Experiment:
78/
2577.
(
Unpublished
study
received
Jan
28,
1981
under
100­
618;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
L)

00058602
Hool,
G.
(
1979)
Dominant
Lethal
Study:
CGA
64250:
Mouse:
No.
of
Experiment:
790034.
(
Unpublished
study
received
Jan
28,
1981
under
100­
618;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
M)

00058603
Hool,
G.;
Langauer,
M.
(
1979)
Nucleus
Anomaly
Test
in
Somatic
Interphase
Nuclei:
CGA
64250:
Chinese
Hamster:
No.
of
Experiment:
79­
0805.
(
Unpublished
study
received
Jan
28,
1981
under
100­
618;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
N)
Page
106
of
112
00058604
Fritz,
H.;
Becker,
H.
(
1979)
Report
on
CGA
64250
Tech.:
Teratology
Study
(
Seg.
II)
in
Rats:
Project
No.
790011.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
NC
00058605
Fritz,
H.;
Becker,
H.
(
1979)
Report
on
CGA
64250
Tech.:
Teratology
Study
(
Seg.
II)
in
Rabbits:
Project
No.
790009.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058606
Sachsse,
K.;
Suter,
P.;
Luetkemeier,
H.;
et
al.
(
1979)
CGA
64250
Techn.
Three
Months
Toxicity
Study
on
Rats:
Project
No.
790014.
Final
rept.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.

00058607
Sachsse,
K.;
Bathe,
R.;
Luetkemeier,
H.;
et
al.
(
1979)
CGA
64250
3­
Month
Toxicity
Study
on
Dogs.
Final
rept.
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
244271­
R)

00074505
Hambock,
H.
(
1979)
Distribution,
Degradation
and
Excretion
of
CGA
64250
in
the
Rat:
Project
Report
24/
79.
(
Unpublished
study
received
Jun
8,
1981
under
100­
EX­
69;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
070164­
K)

00074506
Muecke,
W.
(
1979)
Characterization
of
Urinary
and
Faecal
Metabolites
of
Rats
after
Oral
Application
of
CGA
64250:
Project
Report
35/
79.
(
Unpublished
study
received
Jun
8,
1981
under
100­
EX­
69;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
070164­
L)

00074507
Mucke,
W.
(
1981)
The
Major
Metabolic
Pathways
of
CGA
64250
in
the
Rat:
Project
Report
9/
81.
(
Unpublished
study
received
Jun
8,
1981
under
100­
EX­
69;
prepared
by
Ciba­
Geigy
Ltd.,
Switzerland,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
N.
C.;
CDL:
070164­
M)

00116591
Larson,
E.;
Matthews,
R.;
Naismith,
R.;
et
al.
(
1982)
21
Day
Dermal
Toxicity
Study
in
Rabbits:
[
CGA­
64250
Technical]:
PH
430­
CG­
001­
82.
Pharmakon
Research
International,
Inc.,
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
NC;.

00129570
Hunter,
B.;
Scholey,
D.;
Haywood,
R.;
et
al.
(
1982)
CGA
64250:
Long­
term
Feeding
Study
in
Mice:
CBG/
196/
81827.
Final
rept.
Unpublished.
Huntingdon
Research
Centre,
Eng.,
Ciba­
Geigy
Corp.,
Greensboro,
NC.

00129906
Simoneaux,
B.
(
1983)
Dermal
Absorption
of
Triazole­
14C­
CGA­
64250
by
Rats:
Report
No.
ABR­
82068.
(
Unpublished
study
received
Jul
21,
1983
under
100­
641;
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
250782­
G)
Page
107
of
112
00129918
Hunter,
B.;
Slater,
N.;
Heywood,
R.;
et
al.
(
1982)
CGA
64250:
Potential
Tumorigenic
and
Toxic
Effects
in
Prolonged
Dietary
Administration
to
Rats:
CBG
193/
8284
(
Test
No.
789023).
Final
rept.
Huntingdon
Research
Centre,
Eng.,
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
NC.

00131098
Simoneaux,
B.
(
1983)
Dermal
Absorption
of
Triazole­
14C­
CGA­
64250
by
Rats:
Report
No.
ABR­
82068.
(
Unpublished
study
received
Sep
8,
1983
under
100­
617;
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
251239­
I)

00132946
Simoneaux,
B.
(
1983)
Dermal
Absorption
of
Triazole­
14C­
CGA­
64250
by
Rats:
M5­
62­
2A:
Report
No.
ABR­
82068.
(
Unpublished.
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
072224­
V.

00133343
Arni,
P.
(
1982)
Saccharomyces
cerevisiae
D7/
Mammalian­
microsome
Mutagenicity
Test
in
vitro
with
CGA
64250
(
Test
for
Mutagenic
Properties
in
Yeast
Cells):
Experiment
No.
811558.
(
Unpublished
study
received
Dec
12,
1983
under
100­
617;
prepared
by
Ciba­
Geigy
Ltd.,
Switz.,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
072206­
C)

00133347
Puri,
E.
(
1982)
Autoradiographic
DNA
Repair
Test
on
Human
Fibroblasts:
CGA
64250
(
in
vitro
Test
for
DNA­
damaging
Properties):
Experiment
No.
811655.
(
Unpublished
study
received
Dec
12,
1983
under
100­
617;
prepared
by
Ciba­
Geigy
Ltd.,
Switz.,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
072206­
G)

00133348
Puri,
E.
(
1982)
Autoradiographic
DNA
Repair
Test
on
Rat
Hepatocytes:
CGA
64250
(
in
vitro
Test
for
DNA­
damaging
Properties):
Experiment
No.
811514.
(
Unpublished
study
received
Dec
12,
1983
under
100­
617;
prepared
by
Ciba­
Geigy
Ltd.,
Switz.,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
072206­
H)

00133350
Fritz,
H.;
Giese,
K.;
Zak,
F.
(
1981)
Report
on
CGA
64250
Tech.:
2­
Generation
Study
in
Rats:
Test
No.
79
0010.
(
Unpublished
study
received
Dec
12,
1983
under
100­
617;
prepared
by
Ciba­
Geigy
Ltd.,
Switz.,
submitted
by
Ciba­
Geigy
Corp.,
Greensboro,
NC;
CDL:
072206­
K)

00143454
Ciba­
Geigy
Corp.
(
1984)
Response
by
Ciba­
Geigy
to
the
April
12,
1984
Letter
Regarding
Rat
and
Rabbit
Teratology
Studies
with
CGA­
64250
Technical.
Unpublished.
467
p.
00151502
Ciba­
Geigy
Corp.
(
1985)
Response
to
EPA
Review
of
the
Two­
Year
Dietary
Oncogenicity
and
Chronic
Toxicity
Study
with
CGA­
64250
Technical:
Historical
Control
Data
and
an
Addendum
to
the
HRC
Report
No.
CBG
193/
8284.
Unpublished.
373
p.
Page
108
of
112
00151502
Ciba­
Geigy
Corp.
(
1985)
Response
to
EPA
Review
of
the
Two­
Year
Dietary
Oncogenicity
and
Chronic
Toxicity
Study
with
CGA­
64250
Technical:
Includes
Historical
Control
Data
and
an
Addendum
to
the
HRC
Report
No.
CBG
193/
8284.
Unpublished.
373
p.

00151503
Ciba­
Geigy
Corp.
(
1985)
Response
to
the
EPA
Review
of
the
Long­
Term
Feeding
Study
in
Mice
with
CGA­
64250
Technical:
Chemistry
Data
of
Test
Material,
Details
of
Diet
Preparation,
Summary
of
Incidence
of
Clinical
Signs,
and
Addendum
to
Report
CBG
196/
81827.
Unpublished.
214
p.

00151514
Borders,
C.;
Salamon,
C.
(
1985)
Two­
Generation
Reproduction
Study
in
Albino
Rats
with
CGA­
64250
Technical:
Toxigenics
Study
450­
1202.
Unpublished
study
prepared
by
Toxigenics,
Inc.
1886
p.

00151515
Johnson,
W.;
Thompson,
S.
(
1985)
One­
year
Subchronic
Oral
Toxicity
Study
in
Beagle
Dogs
with
CGA­
64250
Technical:
(
Final
Report):
FDRL
Study
No.
7737.
Unpublished.
Food
and
Drug
Research
Laboratories,
Inc.
570
p.

00151516
Waechter,
F.;
Bentley,
P.;
Staeubli,
W.
(
1984)
The
Effect
of
Propiconazole
on
Drug
Metabolizing
Enzymes
in
the
Liver
of
Male
Rats
and
Mice.
Unpublished.
Ciba­
Geigy
Ltd.
22
p.

00151517
Froehlich,
E.;
Bentley,
P.;
Staeubli,
W.;
et
al.
(
1984)
Promotion
Study
with
CGA
64250:
Study
on
the
Influence
of
CGA
64250
in
the
Formation
of
Focal
Proliferative
Changes
in
the
Rat
Liver:
GU
Exploratory
Research
Project
No.
834015.
Unpublished.
Ciba­
Geigy
Ltd.
553
p.

00163164
Salamon,
C.
(
1983)
Two­
generation
Reproduction
Study
in
Albino
Rats
Using
CGA­
64250
Technical:
Study
No.
450­
1202.
Unpublished
study
prepared
by
ToxiGenics,
Inc.
20
p.

00164469
Murphy,
T.;
Brown,
K.;
Doornheim,
D.;
et
al.
(
1986)
Dermal
Absorption
of
Carbon
14­
Propiconazole
in
Rats
after
a
Ten­
hour
Exposure
Period:
Report
No.
ABR­
86053.
Unpublished.
Ciba­
Geigy
Corp.
76
p.

00164794
Ballantine,
L.
(
1986)
Propiconazole
Animal
Metabolism
Update:
Metabolism
in
Mice:
Dermal
Absorption
in
the
Rat:
Report
No.
ABR­
86071.
Unpublished.
Ciba­
Geigy
Corp.
10
p.

00164794
Ballantine,
L.
(
1986)
Propiconazole
Animal
Metabolism
Update:
Metabolism
in
Mice:
Dermal
Absorption
in
the
Rat:
Report
No.
ABR­
86071.
Unpublished
compilation
prepared
by
Ciba­
Geigy
Corp.
10
p.

00164795
Bissig,
R.
(
1986)
The
Metabolism
of
C14­
phenyl­
CGA
64250
in
Mice
after
Pretreatment
with
Unlabelled
CGA
64
250:
Project
Report
6/
86.
Unpublished.
Ciba­
Geigy
Limited.
52
p.
Page
109
of
112
00164796
Hamboeck,
H.
(
1979)
Distribution,
Degradation
and
Excretion
of
CGA
64250
in
the
Rat:
Project
Report
24/
79.
Unpublished.
Ciba­
Geigy
Limited.
19
p.

00164797
Muecke,
W.
(
1981)
The
Major
Metabolic
Pathways
of
CGA
64250
in
the
Rat:
Project
Report
9/
81.
Unpublished
study
prepared
by
Ciba­
Geigy
Limited.
13
p.

00164798
Muecke,
W.
(
1983)
The
Metabolism
of
CGA
64250
in
the
Rats:
Project
Report
24/
83.
Unpublished.
Ciba­
Geigy
Limited.
145
p.

00164800
Raab,
D.;
Youreneff,
M.;
Giknis,
L.;
et
al.
(
1986)
CGA­
64250
Technical:
A
Teratology
Study
in
New
Zealand
White
Rabbits:
Toxicology/
Pathology
Report
86043
(
MIN
852172).
Unpublished.
Ciba­
Geigy
Corp.
437
p.

40425001
Giknis,
M.
(
1987)
CGA­
Technical:
Teratology
(
Segment
II)
Study
in
Rats:
Laboratory
Project
ID
86004.
Unpublished.
Ciba­
Geigy
Corporation.
425
p.

40425002
Mallows,
S.;
Levy,
E.;
Goknis,
M.;
et
al.
(
1987)
CGA­
64250:
A
Modified
Teratology
(
Segment
II)
Study
in
Albino
Rats
Laboratory
Project
ID
86189.
Unpublished.
Ciba­
Geigy
Corporation.
408
p.

40425004
Raab,
D.;
Youreneff,
M.;
Giknis,
M.;
et
al.
(
1987)
Propiconazole:
A
Teratology
Study
in
New
Zealand
Rabbits:
Final
Report
Amendment
No.
1:
Laboratory
Project
ID
86043.
Unpublished.
Ciba­
Geigy
Corporation.
125
p.

41178301
Stevens,
J.
(
1989)
Propiconazole
Technical:
Perspective:
Liver
Tumor
Response
Noted
in
Male
Mice
After
the
Administration
of
an
Excessive
Level
of
Propiconazole.
Unpublished.
Ciba­
Geigy
Corp.
23
p.

41326701
Cresswell,
D.
(
1989)
C14­
Phenyl
CGA
64250:
Absorption,
Distribution,
Metabolism
and
Excretion
in
the
Rat:
Lab
Project
Number:
380/
105.
Unpublished.
Hazleton
UK.
520
p.

41594801
Hartmann,
H.
(
1988)
CGA­
64250
Technical:
Acute
Aerosol
Inhalation
Toxicity
Study
in
Rats:
Lab
Project
Number:
871471.
Unpublished.
Ciba­
Geigy
Ltd.
22
p.

41594802
Deparade,
E.
(
1983)
CGA­
64250
Technical:
Salmonella/
Mammalian­
Microsome
Mutagenicity
Test:
Lab
Project
Number:
830121.
Unpublished
study
prepared
by
Ciba­
Geigy
Ltd.
31
p.

41594803
Strasser,
F.
(
1987)
CGA­
64250
Technical:
Micronucleus
Test
(
Chinese
Hamster):
Lab
Project
Number:
860359.
Unpublished
study.
Ciba­
Geigy
Ltd.
28
p.
Page
110
of
112
41594804
Cresswell,
D.
(
1989)
C14­
phenyl
CGA
64250:
Absorption,
Distribution,
Metabolism
and
Excretion
in
the
Rat:
Lab
Project
No.
380/
105.
Unpublished.
Hazleton
UK.
520
p.

42050501
Potrepka,
R.;
Turnier,
J.
(
1991)
Subchronic
Dietary
Toxicity
Study
with
CGA­
64250
in
Mice:
Lab
Project
Number:
F­
00098.
Unpublished.
Ciba­
Geigy
Corp.
302
p.

42050502
Potrepka,
R.;
Turnier,
J.
(
1991)
13­
Week
Dietary
Toxicity
Study
with
CGA­
64250
in
Male
Mice:
Lab
Project
Number:
F­
00107.
Unpublished.
Ciba­
Geigy
Corp.
226
p.

42050504
Ogorek,
B.
(
1983)
Intrasanguine
Host­
Mediated
Assay
with
S.
typhimurium:
CGA­
64250:
Lab
Project
Number:
830120.
Unpublished.
Ciba­
Geigy
Ltd.
21
p.

42050505
Strasser,
F.
(
1984)
Chromosome
Studies
on
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00058597.
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785248.
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93194030
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00058598.
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93194032
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Phase
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90­
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CIBA­
CEIGY
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13
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93194033
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00058607.
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785751.
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CIBA­
GEIGY
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12
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93194034
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Ciba­
Geigy
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00116591.
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430­
CG­
001­
82.
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Pharmakon
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93194035
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Ciba­
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00129918
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00074494,
00151502.
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193/
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15
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93194036
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Ciba­
Geigy
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Phase
3
Summary
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MRID
00151515.
One­
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13
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93194037
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Tisdel,
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Ciba­
Geigy
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Phase
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Summary
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MRID
00129570
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Related
MRIDs
00084153,
00151503,
00130844.
Long­
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Propiconazole:
Study
#
196/
81827.
14
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93194038
Gillis,
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Tisdel,
M.
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Ciba­
Geigy
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Phase
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Summary
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MRID
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CIBA­
GEIGY
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12
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93194039
Gillis,
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Geigy
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Phase
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Summary
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MRID
40425002.
Modified
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Propiconazole:
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#
MIN
862244.
Prepared
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CIBA­
GEIGY
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12
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93194040
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Ciba­
Geigy
Corp.
Phase
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Summary
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MRID
00164800
and
Related
MRIDs
40425004.
Teratology
Study
in
Rabbits:
Propiconazole:
Study
#
MIN
852172.
Prepared
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CIBA­
GEIGY
Corp.
12
p.

93194041
Tisdel,
M.
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Ciba­
Geigy
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Phase
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Summary
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MRID
00138167
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Related
MRIDs
00151514,
00163164.
Two­
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Study
#
450­
1202.
Prepared
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12
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93194042
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C.
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1990)
Ciba­
Geigy
Corp.
Phase
3
Summary
of
MRID
41594802.
Salmonella/
Mammalian­
Microsome
Mutagenicity
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Propiconazole:
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830121.
Unpublished.
Ciba­
Geigy
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12
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Ciba­
Geigy
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41594803.
Micronucleus
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­
Chinese
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Propiconazole:
Study
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860359.
Unpublished.
Ciba­
Geigy
Limited.
12
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93194044
Breckenridge,
C.
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1990)
Ciba­
Geigy
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Phase
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Summary
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00133348
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MRIDs
00151509.
DNA
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Propiconazole:
Study
#
811514.
Unpublished.
CIBA­
GEIGY
Limited.
12
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93194045
Hochman,
J.
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Ciba­
Geigy
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Summary
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MRID
41326701.
Propiconazole
­
Rat
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380/
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Hazleton
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Phase
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Reformat
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MRID
00058606.
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Propiconazole:
Study
#
790014.
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GEIGY
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93194084
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Geigy
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Reformat
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MRID
00058607.
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Propiconazole:
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Macclesfield,
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CTL
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648
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Macclesfield,
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CTL
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November
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9
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CC:
Yan
Donovan