Document ID: EPA-HQ-OPP-2006-0038-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-02-15T05:00Z

Page
1
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49
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
November
23,
2005
MEMORANDUM
SUBJECT:
Triadimenol:
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
PC
Code:
127201,
CAS
Reg.
No.
55219­
65­
3,
DP
Barcode:
D314964.

Regulatory
Action:
Tolerance
Reassessment
Eligibility
Decision
Risk
Assessment
Type:
Single
Chemical/
Aggregate
FROM:
Christina
Jarvis,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

AND
Judy
Facey,
Toxicologist
Yvonne
Barnes,
Product
Chemist
Samuel
Ary,
Residue
Chemist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
John
Pates,
Jr.,
Chemical
Review
Manager
Reregistration
Branch
III
Special
Review
and
Reregistration
Division
(
7508C)

TABLE
OF
CONTENTS
Page
2
of
49
1.0
SUMMARY
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2.0
INGREDIENT
PROFILE
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2.1
Registered
Uses
/
Products
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2.2
Use
Patterns
/
Rates
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Page
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2.3
Percent
Treatment
of
Registered
Crops
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2.4
Structure
/
Physicochemical
Properties
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Page
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2.5
Data
Requirements
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Page
10
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3.0
METABOLISM
ASSESSMENT
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Page
10
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49
3.1
Metabolism
in
the
Rat
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3.2
Metabolism
in
Plants
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Page
12
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3.3
Metabolism
in
Livestock
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Page
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3.4
Metabolism
/
Degradation
in
the
Environment
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Page
13
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3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
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3.5.1
Tabular
Summary
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Page
15
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49
4.0
HAZARD
CHARACTERIZATION
/
ASSESSMENT
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Page
15
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49
4.1
Hazard
Profile
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Page
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49
4.2
FQPA
Hazard
Considerations
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Page
21
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4.2.1
Adequacy
of
the
Toxicity
Data
Base
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Page
21
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4.2.1.1
Studies
available
and
considered
(
animal,
human,
and
general
literature)
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Page
21
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49
4.2.1.2.
Evidence
of
Neurotoxicity
(
Mode
of
action,
metabolism,
toxicokinetic
data)
.
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Page
22
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4.2.2
Toxicological
Effects
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Page
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4.2.3
Dose­
Response
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Page
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4.2.4
Developmental
Toxicity
Studies
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Page
27
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4.2.5
Reproductive
Toxicity
Studies
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Page
30
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49
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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Page
31
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4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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Page
31
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49
4.4
Special
FQPA
Safety
Factor(
s)
Required
and
Rationale
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Page
31
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49
4.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
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Page
31
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49
4.5.1
Acute
Reference
Dose
(
aRfD)
­
General
Population
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Page
31
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49
4.5.2
Chronic
Reference
Dose
(
cRfD)
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Page
33
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4.5.3
Classification
of
Carcinogenic
Potential
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Page
33
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4.6
Endocrine
Disruption
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Page
34
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5.0
PUBLIC
HEALTH
DATA.
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Page
34
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5.1
Incident
Reports
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Page
34
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Page
3
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49
6.0
EXPOSURE
CHARACTERIZATION
/
ASSESSMENT
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Page
34
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6.1
Dietary
Exposure
/
Risk
Pathway
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Page
34
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49
6.1.2
Acute
and
Chronic
Dietary
Exposure
/
Risk
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Page
40
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49
7.0
AGGREGATE
RISK
ASSESSMENT
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Page
43
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49
8.0
CUMULATIVE
RISK
ASSESSMENT
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Page
44
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49
9.0
HUMAN
INCIDENT
DATA
REVIEW
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Page
45
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49
10.0
DATA
REQUIREMENTS
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Page
46
of
49
Page
4
of
49
1.0
SUMMARY
This
chapter
represents
the
Health
Effects
Division's
(
HED's)
chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
document
for
triadimenol.
A
TRED
is
prepared
for
pesticides
registered
after
1984,
and
reports
on
FQPA
tolerance
reassessment
progress.
As
such,
a
TRED
does
not
include
an
assessment
of
occupational
uses
of,
and
occupational
risk
to,
a
particular
pesticide.

Triadimenol
[$­(
4­
chlorophenoxy)­"­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol]
is
a
systemic
fungicide
registered
for
use
in
the
United
States
as
a
seed
treatment
for
barley,
corn,
cotton,
oats,
rye,
sorghum,
and
wheat.
Additionally,
an
import
tolerance
on
bananas
has
been
established.
Triadimenol
end­
use
products
are
marketed
in
the
U.
S.
under
the
trade
name
Baytan
®
.
The
reregistration
of
triadimenol
is
being
supported
by
Bayer
Corporation,
the
basic
producer,
and
by
Gustafson,
Inc.
The
triadimenol
formulations
registered
for
food/
feed
uses
include
emulsifiable
concentrate
(
EC),
wettable
powder
(
WP),
flowable
concentrate
(
FlC),
and
soluble
concentrate
(
SC)
formulations.

Tolerances
are
established
for
residues
of
triadimenol
and
its
butanediol
metabolite
(
KWG
1342,
calculated
as
triadimenol)
in/
on
various
plant
commodities.
The
established
tolerances
for
plant
commodities
range
from
0.01
ppm
(
sorghum
grain
and
fodder)
to
2.5
ppm
(
green
forage
of
oats,
rye,
and
wheat).
Tolerances
are
established
for
residues
of
triadimenol
and
its
metabolites
containing
the
chlorophenoxy
moiety
(
calculated
as
triadimenol)
in/
on
animal
commodities
at
0.01
ppm
(
milk,
and
poultry
commodities)
and
0.1
ppm
(
fat,
meat,
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep).
Triadimenol
and
its
butanediol
metabolite
are
also
regulated
as
metabolites
of
the
fungicide
triadimefon.

The
toxicological
database
for
triadimenol
contains
acceptable
/
guideline
toxicity
studies
including
acute,
subchronic
(
rats
and
dogs),
developmental
(
rats
and
rabbits),
chronic
(
dog),
two
carcinogenicity
(
mice)
studies,
a
chronic/
carcinogenicity
study
in
rats,
a
15­
day
dermal
study
in
rats,
a
two
year
reproduction
study
in
rats,
and
a
central
nervous
effects
study
in
mice
and
rats.
The
database
is
also
supported
by
substantial
data
from
the
literature,
including
some
studies
performed
by
EPA
scientists,
that
support
the
mode
of
toxic
action
and
endpoint
selection.

Triadimenol
shows
low
toxicity
for
acute
oral,
dermal,
and
inhalation
exposures
(
toxicity
Category
III
or
IV)
and
is
not
a
skin
sensitizer.
Triadimenol
is
an
eye
irritant
with
irritation
clearing
in
21
days
or
longer
(
toxicity
Category
II),
and
is
a
mild
dermal
irritant
(
toxicity
Category
IV).
For
the
purposes
of
reregistration,
the
database
is
adequate
although
there
are
data
gaps
(
lack
of
acute
and
subchronic
neurotoxicity
studies).

There
was
no
evidence
for
quantitative
and
qualitative
susceptibility
following
oral
or
dermal
exposures
to
rats
in
utero
or
oral
exposure
to
rabbits
in
utero.
The
degree
of
concern
for
preand
or
post­
natal
susceptibility
is
low.
Page
5
of
49
HED's
Cancer
Assessment
Review
Committee
(
CARC)
has
classified
triadimenol
as
a
category
C,
"
possible
human
carcinogen."
This
classification
is
based
on
increased
incidence
of
hepatocellular
adenomas
in
females.
However,
it
was
concluded
that
a
quantified
carcinogenic
risk
assessment
for
triadimenol
is
not
appropriate
and
risk
assessment
will
be
based
on
the
chronic
population
adjusted
dose
(
cPAD)
and
margin
of
exposure
(
MOE)
approaches
only.

The
special
Food
Quality
Protection
Act
(
FQPA)
safety
factor
of
10x
is
not
required
since
the
current
developmental
and
reproductive
toxicity
studies
do
not
suggest
that
the
young
are
more
sensitive
than
adult
animals,
and
the
lack
of
a
developmental
neurotoxicity
study
is
addressed
by
the
FQPA
database
uncertainty
factor
of
10x.
The
FQPA
Safety
Factor
is
1x.

No
appropriate
acute
and
chronic
endpoint
could
be
determined
from
the
triadimenol
database;
therefore,
the
triadimefon
subchronic
neurotoxicity
study
in
rats
was
chosen
as
the
basis
for
the
acute
and
chronic
Reference
Doses
(
aRfD/
cRfD).
The
Lowest­
Observed­
Adverse­
Effect­
Level
(
LOAEL)
of
54.6%
and
68.7&
mg/
kg/
day
is
based
on
hyperactivity.
The
No­
Observed­
Adverse­
Effect­
Level
(
NOAEL)
is
3.4%
and
4.3&
mg/
kg/
day.
For
acute
and
chronic
dietary
risk
assessments,
the
uncertainty
factor
is
1,000X
(
10X
for
interspecies
extrapolation,
10X
for
interspecies
variation,
and
10X
FQPA
database
uncertainty
factor).
Since
the
special
FQPA
safety
factor
is
reduced
to
1X,
the
aRfD/
cRfD
of
0.0034
mg/
kg/
day
is
equivalent
to
the
acute/
chronic
population
adjusted
dose
(
aPAD/
cPAD).

The
Agency
has
determined
that
the
residues
of
concern
for
tolerance
expression
and
risk
assessment
are
likely
to
be
triadimenol,
the
metabolite
KWG
1342,
and
the
metabolite
KWG
1732
in/
on
cereal
grains
(
barley,
corn,
oats,
rye,
and
wheat)
and
cotton.
The
residues
of
concern
for
tolerance
expression
and
risk
assessment
for
bananas
are
triadimenol
and
the
metabolite
KWG
1342.
Based
on
an
analysis
of
the
structural
relationship
of
the
above
metabolites
to
parent
triadimefon,
the
toxicity
of
metabolites
is
not
expected
to
exceed
the
parent
compound,
and
an
assumption
of
equal
toxicity
is
made
for
aggregate
risk
assessment.

Acute
and
chronic
dietary
(
food
and
water)
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
acute
dietary
risk
assessment
utilizes
anticipated
residue
estimates
for
bananas,
tolerance
level
residues
for
all
other
commodities,
a
default
processing
factor
for
dried
bananas,
available
data
from
processing
studies,
and
a
100%
crop
treated
assumption,
as
well
as
peak
surface
water
concentration
values.
For
all
supported
commodities,
the
acute
dietary
(
food
+
water)
risk
estimates
do
not
exceed
HED's
level
of
concern
(
less
than
100%
of
the
aPAD)
at
the
95th
exposure
percentile
for
the
U.
S.
population
and
all
populations
subgroups.
The
highest
exposed
population
subgroup
is
children
1­
2
years
of
age
at
29%
of
the
aPAD.

A
chronic
dietary
exposure
assessment
was
conducted,
using
existing
tolerance
level
residues,
a
default
processing
factor
for
dried
bananas,
available
data
from
processing
studies,
an
assumption
Page
6
of
49
of
100%
crop
treated,
and
the
highest
1
in
10
year
annual
mean
drinking
water
concentration.
For
all
supported
commodities,
the
chronic
dietary
risk
estimates
(
food
+
water)
do
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
and
all
population
subgroups.
The
highest
exposed
population
subgroup
is
children
1­
2
years
of
age
at
23%
of
the
cPAD.

A
Tier
II
drinking
water
assessment
was
conducted
by
OPP's
Environmental
Fate
and
Effects
Division
(
EFED),
based
on
parent
triadimenol.
Parent
triadimenol
was
the
major
residue
found
in
the
available
triadimefon
aerobic
soil
metabolism
study.
Estimated
environmental
concentrations
(
EECs)
of
triadimenol
in
surface
water
were
generated
by
the
PRZM­
EXAMS
model
and
were
based
on
the
maximum
calculated
application
rate
of
triadimenol
as
a
seed
treatment
for
each
crop.
For
drinking
water
derived
from
surface
water,
acute
and
chronic
(
non­
cancer)
concentrations
are
as
follows:

°
393
ng/
L
(
acute)
and
194
ng/
L
(
chronic)
for
wheat,
barley,
oats,
and
rye
°
95
ng/
L
(
acute)
and
34
(
chronic)
for
corn
°
133
ng/
L
(
acute)
and
27
ng/
L
(
chronic)
for
cotton
Chronic
concentrations
for
drinking
water
derived
from
surface
water
are
128
ng/
L
(
wheat,
barley,
oats,
and
rye),
22
ng/
L
(
corn),
and
14
ng/
L
(
cotton).

EFED
conducted
a
Tier
1
assessment
of
estimated
ground
water
concentrations
of
triadimenol,
using
the
SCI­
GROW2
model.
For
drinking
water
derived
from
ground
water,
the
EECs
are
63
ng/
L,
18
ng/
L,
and
10
ng/
L,
respectively.
No
water
monitoring
data
are
available
for
this
compound
for
comparison
to
modeled
values.

There
are
no
residential
uses
of
triadimenol;
therefore,
a
non­
occupational
(
residential)
assessment
has
not
been
conducted.
The
aggregate
risk
assessment
includes
combined
exposure
from
food
and
drinking
water
only.
Aggregate
risks
from
combined
exposure
to
food
and
drinking
water
are
below
HED's
level
of
concern
(<
100%
of
the
aPAD/
cPAD).
Page
7
of
49
2.0
INGREDIENT
PROFILE
2.1
Registered
Uses
/
Products
Triadimenol
[$­(
4­
chlorophenoxy)­"­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol]
is
a
systemic
fungicide
registered
for
use
in
the
United
States
as
a
seed
treatment
for
barley,
corn,
cotton,
oats,
rye,
sorghum,
and
wheat.
Triadimenol
end­
use
products
are
marketed
in
the
U.
S.
under
the
trade
name
Baytan
®
.
The
reregistration
of
triadimenol
is
being
supported
by
Bayer
Corporation,
the
basic
producer,
and
by
Gustafson,
Inc.
The
triadimenol
formulations
registered
for
food/
feed
uses
include
emulsifiable
concentrate
(
EC),
soluble
concentrate
(
SC),
wettable
powder
(
WP),
and
flowable
concentrate
(
FlC)
formulations.

Table
1:
Triadimenol
End­
use
Products
(
EPs)
Registered.

EPA
Reg.
No.
Formulation1
Registrant
Product
Name
264­
742
25%
WP
Bayer
CropScience
Baytan
®
Seed
Treatment
Fungicide
264­
760
28.3%
FlC
Bayer
CropScience
Baytan
®
2.6
FS
Seed
Treatment
Fungicide
264­
939
5%
EC
Bayer
CropScience
Gustafson
RTU
®
­
Baytan
®
­
Thiram
Fungicide
264­
941
30%
FlC
Bayer
CropScience
Gustafson
Baytan
®
30
Fungicide
264­
980
13.33
SC
Bayer
CropScience
Protege
Allegiance
Bayton
®
W.
P.
Fungicide
2935­
459
30%
FlC
Wilbur­
Ellis
Company
Wilbur­
Ellis
Baytan
®
Flowable
1.
WP=
Wettable
Powder,
FlC=
Flowable
Concentrate,
EC=
Emulsifiable
Concentrate,
and
SC=
Soluble
Concentrate.

2.2
Use
Patterns
/
Rates
Triadimenol
is
used
as
a
seed
treatment
on
wheat,
barley,
oats,
rye,
corn,
and
cotton.
The
maximum
use
rates,
adjusted
for
planting
rate,
range
from
0.006
to
0.0375
lb
ai/
A
(
0.007­
0.042
kg
ai/
ha)
for
one
season
(
see
Table
2
below).
Page
8
of
49
Table
2:
Maximum
Application
/
Seeding
Rates
End­
uses
(
planting
depth)
Max.
Label
Rates
(
lb
ai/
100
lb
seed)
#
Apps
Seeding
Rates
(
lbs/
A)
1
Seasonal
Max.
Rate
(
kg
ai/
Ha,
including
planting
rates)

Baytan
2.6
FS
Wheat
Barley
Oats
0.03
(
all
crops)
1
1
1
70­
125
60­
80
(
Plains)
80­
100
(
CA)
50­
60
(
drier
areas)

60­
100
0.024­
0.042
0.02­
0.027
0.027­
0.034
0.017­
0.02
0.02­
0.034
Gustafson
(
RTU­
Baytan­
Thiram),
0.43
lb
triadimenol/
gallon
Wheat
Barley
Oats
Rye
0.015­
0.03
(
all
crops)
1
1
1
1
70­
125
60­
80
(
Plains)
80­
100
(
CA)
50­
60
(
drier
areas)

60­
100
41
(
CO)­
86
(
GA)
0.024­
0.042
0.02­
0.027
0.027­
0.034
0.017­
0.02
0.02­
0.034
0.013­
0.029
Cotton
(
acid
delinted)
0.01­
0.04
1
102
0.002­
0.007
Baytan
30
(
2.65
lb
ai/
gallon)

Wheat
Barley
Oats
Rye
0.015­
0.03
1
1
1
1
70­
125
60­
80
(
Plains)
80­
100
(
CA)
50­
60
(
drier
areas)

60­
100
41
(
CO)­
86
(
GA)
0.024­
0.042
0.02­
0.027
0.027­
0.034
0.017­
0.02
0.02­
0.034
0.013­
0.029
Corn
0.06
1
193
0.012
Cotton
0.021­
0.06
1
102
0.002­
0.007
1
Unless
otherwise
noted,
the
information
comes
from
Considine,
D.
M.
and
G.
D.
Considine.
Foods
and
Food
Production
Handbook.
1982.
Van
Nostrand
Reinhold
Company.
2
Based
on
http://
www.
agctr.
lsu.
edu/
cotton/
SEEDRATE.
html
3
Iowa
Extension
Service
Page
9
of
49
Cl
O
N
N
N
OH
2.3
Percent
Treatment
of
Registered
Crops
Based
on
pesticide
usage
data
for
the
years
1992
through
2001,
total
annual
domestic
usage
of
triadimenol
averaged
approximately
24,000
pounds
of
active
ingredient
(
a.
i.)
for
over
12,000,000
acres
treated.
Use
on
cotton
accounted
for
approximately
75
%
of
the
total
pounds
of
a.
i.
applied
annually.
Corn
and
wheat
accounted
for
approximately
20%
and
5%,
respectively.
About
80%
of
U.
S.
acreage
planted
to
cotton
is
treated
with
triadimenol,
and
less
than
1
%
of
corn
and
wheat
acres
are
treated
(
F.
Hernandez
memo,
8/
5/
02).

2.4
Structure
/
Physicochemical
Properties
Table
3:
Triadimenol
Nomenclature.

Chemical
structure
Common
name
Triadimenol
Molecular
formula
C14H18ClN3O2
Molecular
weight
295.77
g/
mol
IUPAC
name
(
1RS,
2RS;
1RS,
2SR)­
1­(
4­
chlorophenoxy)­
3,3­
dimethyl­
1­(
1H­
1,2,4­
triazol­
1­
yl)­
butan­
2­
ol
CAS
name
$­(
4­
chlorophenoxy)­"­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol
CAS
number
55219­
65­
3
PC
Code
127201
Current
supported
food/
feed
sites
barley,
cotton,
corn,
oats,
rye,
and
wheat
Table
4:
Physicochemical
Properties
of
Triadimenol
Parameter
Value
Reference
Melting
point/
range
109­
115
°
C
MRID
00125399
pH
Not
available
­­

Density
at
20
°
C
1.22
g/
mL
MRID
00125399
Water
solubility
at
20
°
C
0.012
g/
100g
of
water
MRID
00125399
Solvent
solubility
at
20
°
C
Triadimenol
is
insoluble
in
aliphatic
hydrocarbons.
1
to
5
g/
100g
of
toluene
10
to
20
g/
100g
of
methylene
chloride
40
to
60
g/
100g
of
cyclohexanone
MRID
00125399
Vapor
pressure
at
20
°
C
<
1
mPa
MRID
00125399
Dissociation
constant,
pKa
Not
available
 
Table
4:
Physicochemical
Properties
of
Triadimenol
Parameter
Value
Reference
Page
10
of
49
Octanol/
water
partition
coefficient
Not
available
­­

UV/
visible
absorption
spectrum
Not
available
 

Triadimenol
contains
two
optically
active
carbons,
and
consists
of
four
optically
active
isomers.
The
registrant
has
stated
that
the
product
consists
of
two
pairs
of
enantiomers,
one
pair
of
which
is
five
times
more
active
than
the
other.
The
product
is
manufactured
to
maximize
the
fraction
of
the
more
pesticidally
active
enantiomer
pair.

2.5
Data
Requirements
The
following
product
chemistry
data
requirements
are
identified
for
triadimenol:

°
OPPTS
Guideline
830.6313,
Normal
and
elevated
temperatures,
and
upon
exposure
to
metals
and
metal
ions
°
OPPTS
Guideline
830.7000,
pH
°
OPPTS
Guideline
830.7050,
UV/
VIS
Absorption
°
OPPTS
Guidelines
830.7550,
830.7560,
or
830.7570,
N­
octanol/
water
partition
data
°
OPPTS
Guideline
830.7840
or
830.7860,
water
solubility
3.0
METABOLISM
ASSESSMENT
Two
triadimenol
specific
metabolism
studies
(
wheat
and
sugar
beets)
have
recently
been
submitted
and
are
currently
under
review
by
the
Agency.
Metabolism
studies
with
triadimefon
have
been
received
and
reviewed,
and
are
used
to
determine
residues
of
concern
in/
on
apples,
grapes,
pears,
pineapples,
and
raspberries.
The
Agency
believes
that
the
use
of
triadimefon
metabolism
data
for
triadimenol
is
appropriate
in
this
case,
given
that
triadimenol
is
a
major
metabolite
of
triadimefon,
and
given
that
the
two
compounds
are
structurally
similar.

The
exception
to
this
is
for
cereal
grains
and
cotton.
HED
has
determined
that
the
translation
of
metabolism
data
from
triadimefon
to
triadimenol
is
not
appropriate
for
existing
uses
on
cereal
grains
and
cotton,
since
metabolism
studies
with
triadimefon
were
conducted
using
a
foliar
application
and
triadimenol
is
used
only
as
a
seed
treatment.

The
triadimefon/
triadimenol
metabolite,
1,2,4­
triazole,
occurs
in
other
triazole
pesticides
and
a
risk
assessment
specific
to
1,2,4,­
triazole
is
currently
being
conducted
by
the
Agency.
It
should
also
be
noted
that,
except
for
1,2,4­
triazole,
specific
toxicological
data
are
not
available
for
the
other
triadimefon/
triadimenol
metabolites
(
KWG
1323,
KWG
1342,
and
KWG
1732)
identified
in
metabolism
studies.
However,
based
on
an
analysis
of
the
structural
relationship
of
the
above
Page
11
of
49
metabolites
to
triadimefon/
triadimenol,
the
toxicity
of
metabolites
is
not
expected
to
exceed
the
parent
compound,
and
an
assumption
of
equal
toxicity
is
made
for
aggregate
risk
assessment.

3.1
Metabolism
in
the
Rat
In
a
rat
metabolism
study,
[
14C]
triadimefon
(
radiochemical
purity
not
reported)
in
50%
aqueous
ethanol
was
administered
as
a
single
gavage
dose
at
24.5­
25.0
mg/
kg
to
12
Sprague
Dawley
rats/
sex
to
determine
tissue
distribution
and
to
12
rats/
sex
to
determine
the
excretion
profile.
Radioactivity
was
not
detected
in
the
expired
air
of
animals.
Over
a
7
day­
period,
recovery
in
the
urine
was
29.8%
dose
in
males
and
39.9%
in
females,
and
recovery
in
feces
was
52.7%
in
males
and
34.5%
in
females.
Thus,
based
on
urinary
excretion,
absorption
was
at
least
29.8%
dose
in
all
animals.
Plasma
levels
of
radioactivity
were
highest
1­
2
hours
post­
dose
(
2.5­
3.2
ppm),
and
the
half­
life
was
approximately
4
hours.
Tissue
concentrations
in
males
were
generally
similar
to
females.
The
highest
concentrations
of
radioactivity
were
found
in
the
fat
(
43.5­
45.0
ppm)
at
4­
8
hours
post­
dose.
Approximately
50%
of
the
radiolabeled
compound
in
the
fat
of
males
was
unchanged
triadimefon
and
50%
was
isomeric
forms
of
the
2­
butanol
derivative
(
triadimenol);
over
90%
was
triadimefon
in
females.
In
addition,
relatively
high
concentrations
of
radioactivity
were
observed
in
the
liver
(
26.2­
28.4
ppm)
and
skin
(
21­
22
ppm)
at
2
hours
post­
dose.
Tissue
concentrations
were
<
0.14
ppm
at
7
days
post­
dose.
In
the
urine,
the
major
component
of
the
acidified
extract
was
KWG
0519
acid
(
6.1­
7.7%
dose).
In
the
direct
extract
of
urine,
3
minor
metabolites
were
identified:
p­
chlorophenol,
KWG
1323,
and
KWG
1342
(
two
isomers).
In
the
direct
extract
of
the
feces,
KWG
1323,
KWG
1342,
and
KWG
0519
acid
(
5.7­
20.0%
dose)
were
identified.
KWG
1323
was
the
predominant
metabolite
in
the
feces
of
females
(
12.7%
dose),
and
KWG
0519
acid
was
the
predominant
metabolite
in
the
feces
of
males
(
20.0%
dose).
Thus,
the
major
metabolites
were
the
alcohol
and
acid
of
triadimefon,
which
were
formed
by
the
sequential
hydroxylation
and
oxidation
of
the
methyl
group
of
the
t­
butyl
chain.

In
a
second
rat
metabolism
study,
[
14C]
triadimefon
(
99.3%
radiochemical
purity)
in
polyethylene
glycol
was
administered
to
5
Wistar
rats/
sex/
dose
as
a
single
gavage
dose
at
5
or
50
mg/
kg
or
as
a
single
gavage
dose
at
5
mg/
kg
following
14
daily
doses
of
unlabeled
triadimefon
at
5
mg/
kg.
In
addition,
triadimefon
was
administered
to
a
group
3
of
male
rats
as
a
single
gavage
dose
of
50
mg/
kg
in
a
preliminary
study.
Radioactivity
was
not
detected
in
the
expired
air.
The
overall
recovery
of
radioactivity
was
97­
112%.
The
compound
was
predominantly
excreted
(
90­
98%
dose)
within
4
days.
The
excretion
profile
of
the
repeated
low­
dose
group
was
similar
to
the
single
low­
dose
group;
however,
the
excretion
profiles
were
sex­
dependent.
Over
a
4­
day
period,
recovery
in
the
urine
was
24­
28%
dose
in
males
and
57­
66%
in
females,
and
recovery
in
feces
was
63­
66%
in
males
and
32­
40%
in
females.
Thus,
based
on
urinary
excretion,
absorption
was
at
least
24%
dose
in
males
and
57%
in
females.
Less
than
1%
dose
remained
in
the
body
4
days
after
treatment.
Bioaccumulation
was
not
indicated.
Tissue
residues
were
highest
in
the
liver
(
0.088­
1.94
ppm)
and
kidney
(
0.041­
0.38
ppm),
and
were
generally
slightly
higher
in
males
than
in
females.
RP­
HPLC
analyses
revealed
the
presence
of
15
radioactive
components
in
the
urine
and
12
in
the
feces.
The
4
major
metabolites
(
1­
14%
dose,
each)
in
the
urine
of
both
sexes
were:
KWG
0519
acid
(
2
isomers),
KWG
1323­
gluc,
HO­
DeME­
KWG
1342
(
2
isomers),
and
DeMe
Page
12
of
49
KWG
132­
gluc
(
2
isomers).
The
5
major
metabolites
(
1­
15%
dose,
each)
in
the
feces
of
both
sexes
were:
KWG
0519
acid
(
2
isomers),
KWG
1323­
gluc,
KWG
1323,
KWG
1342,
and
KWG
0519
dehydrate.
Thus,
metabolism
of
this
compound
proceeded
along
several
pathways,
such
as:
(
i)
hydroxylation
at
the
t­
butyl
moiety
and
oxidation
to
the
acid
or
glucuronidation;
(
ii)
reduction
of
the
keto
group
and
subsequent
reactions
(
including
sulfate
conjugation);
and
(
iii)
desmethylation
followed
by
glucuronidation.

3.2
Metabolism
in
Plants
The
reregistration
requirements
for
plant
metabolism
have
not
been
fulfilled.
Two
metabolism
studies
with
triadimenol
(
wheat
and
sugar
beets)
have
been
submitted
and
are
currently
under
review
by
the
Agency.
Additionally,
metabolism
studies
with
triadimefon
(
grapes,
cucumbers,
tomatoes,
and
wheat)
have
been
received
and
reviewed.
The
Health
Effects
Division
(
HED)
has
examined
the
results
of
these
studies
and
determined
that
the
triadimefon
residues
of
concern
in/
on
apples,
grapes,
pears,
pineapples,
and
raspberries
for
tolerance
expression
are
triadimefon
and
triadimenol.
The
residues
of
concern
for
risk
assessment
are
triadimefon,
triadimenol,
KWG
1323,
and
KWG
1342.
Of
these
compounds,
triadimenol
and
KWG
1342
are
currently
regulated
for
plant
commodities.

HED
has
determined
that
the
translation
of
metabolism
data
from
triadimefon
to
triadimenol
is
not
appropriate
for
existing
uses
on
cereal
grains
and
cotton.
The
metabolism
studies
with
triadimefon
were
conducted
using
a
foliar
application,
while
triadimenol
is
used
only
as
a
seed
treatment.
Additionally,
in
the
submitted
triadimenol
seed
treatment
wheat
study,
residues
in
grain
were
not
identifiable
due
to
the
low
activity
found
in
wheat
grain.
Therefore,
HED
concludes
the
nature
of
the
residue
in
cereal
grains
and
cotton
is
not
adequately
understood;
however,
based
on
chemical
structure
and
the
probable
metabolic
pathway
of
triadimenol,
the
residues
of
concern
for
tolerance
expression
and
risk
assessment
are
likely
to
be
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
cereal
grains
(
barley,
corn,
oats,
rye,
and
wheat)
and
cotton.
Separate
metabolism
studies
with
triazole­
14C
and
phenyl­
14C
labeled
triadimenol
applied
as
a
seed
treatment
to
corn
or
wheat
and
cotton
should
be
conducted
to
confirm
the
residues
of
concern.

The
residues
of
concern
for
tolerance
expression
and
risk
assessment
for
bananas
are
triadimenol
and
KWG
1342,
based
on
the
available
metabolism
data
conducted
with
triadimefon,
applied
to
an
established
grape
vine,
and
the
field
trial
data
conducted
with
triadimenol
applied
to
the
soil
of
banana
groves.

3.3
Metabolism
in
Livestock
The
metabolism
of
triadimefon/
triadimenol
in
livestock
is
adequately
understood
based
on
acceptable
goat
and
poultry
metabolism
studies
submitted
to
support
reregistration
of
triadimefon.

For
the
ruminant
study,
a
lactating
goat
received
[
phenyl­
14C]
triadimefon
at
86.4
ppm
for
three
consecutive
days
in
feed.
Triadimefon
was
detected
at
low
levels
in
milk
and
fat
(<
5%
TRR)
but
Page
13
of
49
was
not
detected
in
kidney,
liver,
or
muscle.
The
major
residue
identified
was
KWG
1342
glucuronide
(
6­
47%
TRR).
Triadimenol
and
its
conjugates
comprised
a
major
portion
of
the
residue
in
tissues
and
milk
(
totals
of
9­
42%
TRR).
The
remainder
of
the
radioactivity
was
identified
as
KWG
1323
glucuronide
(
19­
22%
TRR)
and
KWG
1342
(
1­
6%
TRR)
and
its
sulfate
(
1­
15%
TRR
in
tissues,
43%
TRR
in
milk).

For
the
poultry
study,
16
laying
hens
received
[
phenyl­
14C]
triadimefon
at
28.7
ppm
for
three
consecutive
days
in
feed.
Triadimefon
was
identified
in
fat
and
eggs
(
4­
17%
TRR)
but
was
not
detected
in
liver
or
muscle.
Triadimenol
and
its
related
compounds
were
the
major
metabolites
identified
(
totals
of
41­
49%
TRR).
The
remainder
of
the
radioactivity
was
identified
as
KWG
1342
and
its
related
compounds
(
totals
of
10­
36%
TRR),
p­
chlorophenol
(
liver
and
fat
only
at
2­
4%
TRR),
chlorophenoxytriazolyl
acetic
acid
(
muscle
only
at
3%
TRR),
and
KWG
1323
(
eggs
and
fat
only
at
3­
5%
TRR).

HED
concludes
that
the
supported
uses
on
barley,
corn,
cotton,
oats,
rye,
and
wheat
result
in
a
40
CFR
180.6(
a)(
3)
situation
for
livestock
commodities;
i.
e,
there
is
no
reasonable
expectation
of
finite
residues
in
livestock
commodities.
Additional
data
on
the
transfer
of
residues
to
meat,
milk,
poultry,
and
eggs
are
not
required
and
all
tolerances
for
livestock
commodities
should
be
revoked
pending
results
from
the
requested
corn
and
wheat
metabolism
studies.
If
registration
on
additional
commodities
and
livestock
feed
items
are
requested,
then
triazole
and
phenyl­
labeled
livestock
metabolism
studies
would
be
required.
Such
data
may,
in
turn,
trigger
the
need
for
magnitude
of
the
residue
(
feeding)
studies
in
livestock.

3.4
Metabolism
/
Degradation
in
the
Environment
Based
on
laboratory
studies
and
the
submitted
field
dissipation
study,
triadimenol
is
stable
in
sterile
water
and
to
photodegradation
on
soil,
but
may
photodegrade
in
shallow,
well­
mixed
surface
water
that
is
not
shaded
or
contains
a
significant
sediment
load.
The
primary
route
of
triadimenol
degradation
appears
to
be
microbial
activity.
Triadimenol
degraded
slowly
in
aerobic
soil
in
the
laboratory,
with
a
calculated
half­
life
of
238
days.
Triadimenol
does
not
degrade
under
anaerobic
conditions
and
appears
to
be
mobile
in
soil
(
Kd=
2.4­
5.3).
Since
triadimenol
is
a
seed
treatment
only,
and
applied
below
the
soil
surface,
runoff
to
surface
water
may
be
reduced
but
the
potential
for
groundwater
contamination
may
be
increased.
Page
14
of
49
Cl
O
N
N
N
OH
Cl
O
N
N
N
OH
OH
Cl
O
N
N
N
O
Cl
O
N
N
N
O
OH
Cl
O
N
N
N
O
OH
Table
5:
Chemical
Names
and
Structures
of
Triadimenol
and
Its
Metabolites.

Common
name
and
chemical
name
Chemical
structure
Triadimenol
(
KWG
0519)

$­(
4­
chlorophenoxy)­"­(
1,1­
dimethylethyl)­
1H­
1,2,4­
triazole­
1­
ethanol
KWG
1342
1­(
4­
chlorophenoxy)­
3,3­
dimethyl­
3­
hydroxymethyl­
1­(
1H­
1,2,4­
triazole­
1­
yl)­
2­
butanol
Triadimefon
1­(
4­
chlorophenoxy)­
3,3­
dimethyl­
1­(
1H­
1,2,4­
triazole­
1­
yl)­
2­
butanone
KWG
1323
1­(
4­
chlorophenoxy)­
3,3­
dimethyl­
3­
hydroxymethyl­
1­(
1H­
1,2,4­
triazole­
1­
yl)­
2­
butanone
KWG
1732
1­(
4­
chlorophenoxy)­
1­(
1H­
1,2,4­
triazole­
1­
yl)
ethanoic
acid
Page
15
of
49
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.5.1
Tabular
Summary
Table
6:
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
Primary
crop
­
cereal
grains
and
cotton
triadimenol,
KWG
1342,
and
KWG
1732
triadimenol,
KWG
1342
and
KWG
1732
Primary
crop
­
bananas
triadimenol
and
KWG
1342
triadimenol
and
KWG
1342
Rotational
crop
triadimenol,
KWG
1342,
and
KWG
1732
triadimenol,
KWG
1342,
and
KWG
1732
Livestock
Ruminant
NA
NA
Poultry
NA
NA
Drinking
Water
triadimenol
NA
NA
=
Not
Applicable
4.0
HAZARD
CHARACTERIZATION
/
ASSESSMENT
4.1
Hazard
Profile
Table
7:
Acute
Toxicity
Profile
­
Triadimenol
Technical
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.1100
Acute
oral
­
rat
00125411
LD50
=
689
mg/
kg
(
males)
LD50
=
752
mg/
kg
(
females)
III
870.1200
Acute
dermal
­
rabbit
00145086
LD50
>
2000
mg/
kg
III
870.1300
Acute
inhalation
­
rat
00145087
LC50
>
2.58
mg/
L
(
Limit
Dose)
IV
870.2400
Acute
eye
irritation
­
rabbit
00145088
eye
irritant.
Irritation
cleared
in
21
days
or
longer.
II
870.2500
Acute
dermal
irritation
­
rabbit
00145088
mild
skin
dermal
irritation
IV
Page
16
of
49
870.2600
Skin
sensitization­
guinea
pig
00125413
Not
a
skin
sensitizer
Not
Applicable
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
(
rats)
00127769
(
1977)
Acceptable/
guideline
0,
150,
600,
or
2400
ppm
M:
0,
12.16,
49.23,
203.07
mg/
kg/
day
F:
0,
17.07,
71.33,
236.60
mg/
kg/
day
42192701
(
1983)
Acceptable/
guideline
0,
120,
600,
or
3000
ppm
M:
0,
8.0,
39.6,
208.5
mg/
kg/
day
F:
0,
9.4,
46.4,
221.1
mg/
kg/
day
NOAEL
is
600
ppm
(
equivalent
to
49.23/
71.33
mg/
kg/
day
[
M/
F]).
The
LOAEL
is
2400
ppm
(
equivalent
to
203.07/
236.60
mg/
kg/
day
[
M/
F])
based
on
initial
body
weight
decreases
in
both
sexes.

NOAEL
is
120
ppm
(
equivalent
to
8.0/
9.4
mg/
kg/
day
in
the
males/
females).
The
LOAEL
for
this
study
is
600
ppm
(
equivalent
to
39.6/
46.4
mg/
kg/
day
in
the
males/
females)
based
on
increased
liver
weights
and
incidences
of
liver
hypertrophy
in
the
males
and
females
and
on
fatty
changes
in
the
liver
in
the
females.

870.3150
90­
Day
oral
toxicity
(
nonrodents
dogs)
00125420
(
1977)
Acceptable/
guideline
0,
150,
600,
or
2400
ppm
M:
0,
44.2,
178.5,
or
717.0
mg/
kg/
day
F:
0,
44.8,
179.0
or
702.1
mg/
kg/
day
NOAEL
is
600
ppm
(
equivalent
to
44.2/
44.8
mg/
kg/
day
in
the
males/
females).
The
LOAEL
for
this
study
is
2400
ppm
(
equivalent
to
717.0/
702.1
mg/
kg/
day
in
the
males/
females)
based
on
decreased
body
weights
and
body
weight
gains
in
the
females,
increased
alkaline
phosphatase,
cholesterol,
absolute
kidney
weights,
and
renal
cysts
in
the
males,
and
increased
N­
demethylase
and
relative
liver
weights
in
the
males
and
females.

870.3150
6
months
oral
toxicity
(
non­
rodents­
dogs)
00151247
(
1984)
Acceptable/
guideline
0,
10,
30,
or
100
ppm
0,
0.25,
0.75,
or
2.5
mg/
kg/
day
NOAEL
is
100
ppm
(
approximately
equivalent
to
2.5
mg/
kg/
day).
The
LOAEL
was
not
observed.
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
17
of
49
870.3200
15­
Day
dermal
toxicity
(
rabbits)
00151246
(
1984)
Acceptable/
guideline
0,
50,
or
250
mg/
kg/
day
NOAEL
is
250
mg/
kg/
day
for
males
and
females.
The
LOAEL
was
not
observed.

870.3465
21­
Day
inhalation
toxicity
(
rats)
00125421
(
1976)
Unacceptable/
not
ungradable
0,
30,
68,
or
230
mg/
m3
0,
0.030,
0.068,
or
0.230
mg/
L
NOAEL
is
0.230
mg/
L/
day,
the
highest
dose
tested.
The
LOAEL
was
not
observed.

870.3700a
Prenatal
developmental
in
(
rats)
41498401
(
1990)
Acceptable/
guideline
0,
5,
15,
25,
or
60
mg/
kg/
day
40307804
&
40887702
(
1987)
Acceptable/
guideline
0,
30,
60,
or
120
mg/
kg/
day
Maternal
NOAEL
is
5
mg/
kg/
day
and
the
LOAEL
is
15
mg/
kg/
day
based
on
decreased
body
weights
and
adjusted
(
for
gravid
uterine
weight)
body
weight
gains.

Developmental
NOAEL
is
25
mg/
kg/
day
and
the
LOAEL
is
60
mg/
kg/
day
based
on
increased
incidences
of
extra
ribs,
a
variation.

Maternal
NOAEL
is
30
mg/
kg/
day
and
the
LOAEL
is
60
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.

Developmental
NOAEL
is
30
mg/
kg/
day
and
the
LOAEL
is
60
mg/
kg/
day
based
on
increased
incidences
of
supernumerary
ribs.
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
18
of
49
870.3700b
Prenatal
developmental
in
(
rabbits)
42365001
(
1992)
Acceptable/
guideline
0,
5,
25,
or
125
mg/
kg/
day
40307805
&
40887703
(
1987)
Acceptable/
guideline
0,
8,
40,
or
200
mg/
kg/
day
Maternal
NOAEL
is
25
mg/
kg/
day
and
the
LOAEL
is
125
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.

Developmental
NOAEL
is
125
mg/
kg/
day
(
HDT).
The
developmental
LOAEL
was
not
observed.

Maternal
NOAEL
is
40
mg/
kg/
day
and
the
LOAEL
is
200
mg/
kg/
day
based
on
clinical
signs
of
toxicity,
decreased
body
weights
and
food
consumption,
and
increased
post­
implantation
loss
and
early
resorptions.

Developmental
NOAEL
is
40
mg/
kg/
day
and
the
LOAEL
is
200
mg/
kg
based
on
skeletal
abnormalities.

870.3800
Reproduction
and
fertility
effects
(
rats)
00151248
(
1984)
Acceptable/
guideline
0,
20,
100,
or
500
ppm
(
0,
1,
5
or
25
mg/
kg/
day)
Parental/
Systemic
toxicity
NOAEL
is
5
mg/
kg/
day
and
the
LOAEL
is
25
mg/
kg/
day
based
on
decreased
body
weights
and
body
weight
gains
in
the
F1b
generation.

Offspring
toxicity
NOAEL
is
5
mg/
kg/
day
and
the
LOAEL
is
5
mg/
kg/
day
based
on
decreased
pup
weight.

Reproductive
toxicity
NOAEL
appears
to
be
5
mg/
kg/
day
The
LOAEL
for
reproductive
performance
was
not
observed.

870.4100b
Chronic
toxicity
(
dog)
00150484
&
00159012
(
1984)
Acceptable/
non­
guideline
0,
150,
600,
or
2400
ppm
0,
3.8,
15.0,
or
60.0
mg/
kg/
day
The
NOAEL
is
3.8
mg/
kg/
day
and
the
LOAEL
is
15
mg/
kg/
day
based
on
changes
in
enzyme
levels.
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
19
of
49
870.4200
Carcinogenicity
(
mice)
44740901
(
1998)
Unacceptable/
guideline
0,
80,
400,
or
2000
ppm
M:
0,
11.3,
60.2,
or
340.3
mg/
kg/
day
F:
0,
17.2,
91.3
or
472
mg/
kg/
day
NOAEL
in
males
is
80
ppm
(
equivalent
to
11.3
mg/
kg/
day)
and
in
females
is
400
ppm
(
equivalent
to
91.3).

LOAEL
in
males
is
400
ppm
(
equivalent
to
60.2
mg/
kg/
day)
based
on
hepatic
changes
and
increased
relative
food
consumption.
The
chronic
LOAEL
in
females
is
2000
ppm
(
equivalent
to
472.0
mg/
kg/
day)
based
on
decreased
body
weights
and
body
weight
gains,
increased
relative
food
consumption,
and
hepatic
changes.

No
evidence
of
carcinogenicity
870.4200
Carcinogenicity
(
mice)
00126259
(
1982)
Acceptable/
guideline
0,
125,
500,
or
2000
ppm
0,
19,
75,
or
300
mg/
kg/
day
The
NOAEL
is
125
ppm
(
equivalent
to
19
mg/
kg/
day).

The
LOAEL
is
500
ppm
(
equivalent
to
75
mg/
kg/
day),
based
on
increased
alanine
aminotransferase
levels
in
both
sexes
and
aspartate
aminotransferase
in
females.

At
the
doses
tested,
the
carcinogenic
potential
of
KWG
0519
is
positive
at
500
ppm.
Hepatic
neoplastic
lesions
occurred
in
females
due
to
treatment.
The
incidence
of
adenomas
increased
dose­
dependently
(
2­
10%
treated
vs
0%
concurrent
controls
and
4%
historical
controls).
The
incidence
of
hepatic
carcinoma
was
increased
at
500
and
2000
ppm
(
4­
6%
treated
vs
2%
concurrent
controls).
The
incidence
of
combined
hepatic
adenomas
and
carcinomas
was
also
increased
at
500
and
2000
ppm
(
10­
16%
treated
vs
2%
controls).
The
Toxicology
Branch
Peer
Review
Committee
(
TXR
#
006772,
dated
July
6,
1988)
concluded
that
KWG
0519
should
be
classified
as
a
Group
C
carcinogen.
Dosing
was
considered
adequate
based
on
decreased
body
weights,
and
increased
blood
levels
of
hepatic
enzymes
and
liver
weights,
and
increased
incidences
of
gross
and
microscopic
abnormalities.
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
20
of
49
870.4300
Combined
Chronic/
Carcinogenicity
(
rats)
00126260
(
1982)
Acceptable/
guideline
0,
125,
500,
or
2000
ppm
0,
6.25,
25,
or
100
mg/
kg/
day
The
NOAEL
is
125
ppm
(
approximately
equivalent
to
6.25
mg/
kg/
day).
The
LOAEL
is
500
ppm
(
approximately
equivalent
to
25
mg/
kg/
day),
based
on
increased
glutamate
dehydrogenase
and
liver
bile
duct
vacuolization
in
males;
and
aspartate
and
alanine
aminotransferase
levels
in
females.

no
evidence
of
carcinogenicity
870.5100
Bacterial
system,
mammalian
activation
gene
mutation
00126264
(
1979)
Unacceptable/
guideline
0,
4,
20,
100,
500,
or
2500
µ
g/
plate
(+
S9)
and
2500
µ
g/
plate
(­
S9)
Negative
870.5300
In
Vitro
Mammalian
Cell
Gene
Mutation
00126269
(
1982)
Acceptable/
guideline
7.8,
15.6,
31.3,
62.5,
or
125.0
µ
g/
mL
(­
S9)
3.91,
7.81,
15.6,
31.3,
or
62.5
µ
g/
mL
(+
S9)
Negative
870.5450
Cytogenetics
dominant
lethal
assay
00126266
(
1978)
Unacceptable/
up­
gradable
0
or
500
mg/
kg
Negative
870.5500
Other
Genotoxicity
DNA
damage
00126271
(
1981)
Acceptable/
guideline
0,
62.5,
125,
250,
500,
or
1000
µ
g/
plate
Negative
no
evidence
that
DNA
damage
was
induced
870.5550
Other
Genotoxicity
Unscheduled
DNA
Synthesis
00126271
(
1982)
Acceptable/
guideline
0,
0.25,
0.5,
1,
2.5,
5,
10,
25,
50,
100,
or
250
µ
g/
mL.
Negative
no
evidence
that
unscheduled
DNA
synthesis
870.
5900
Other
Effects
In
vitro
Sister
Chromatid
Exchange
Assay
40815901
(
1987)
Acceptable/
guideline
0,
100,
125,
150,
175,
or
200
µ
g/
mL
(+
S9)
0,
38,
75,
150,
225,
or
300
µ
g/
mL
(­
S9)
Negative
Table
8:
Triadimenol
Technical
Toxicology
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
21
of
49
Other
Studies
Central
Nervous
Effects
(
mouse)
00145083
(
1983)
3.75
to
60
mg/
kg
In
mice,
KWG
0519
(
3.75
to
60
mg/
kg)
stimulated
the
spontaneous
motility,
increased
their
irritability
and
escape
response
and
augmented
certain
reflexes;
dose
of
15
and
60
mg/
kg
potentiated
the
effect
of
amphetamine;
and
doses
of
12
to
48
mg/
kg
antagonized
that
of
reserpin.
The
substance
prolonged
the
hexobartital
sleeping
time
at
15
and
60
mg/
kg.
In
rats,
the
dose
of
48
mg/
kg
had
an
excitatory
effect.

An
comparison
with
caffeine
showed
that
the
effect
fo
the
dose
of
2.5
mg
caffeine/
kg
corresponded
approximately
to
that
of
12
to
15
mg/
KWG
0519/
kg,
in
the
amphetamine
potentiation
test
that
of
4
mg
KWG
0519/
kg,
in
the
antagonism
of
ptosis
10
mg
caffeine/
kg
and
12
mg
KWG
0519/
kg
were
comparable.
The
no­
effect
dose
was
ca.
1
mg/
kg.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
4.2.1.1
Studies
available
and
considered
(
animal,
human,
and
general
literature)

The
toxicological
database
for
triadimenol
contains
acceptable
/
guideline
toxicity
studies
including
acute,
subchronic
(
rats
and
dogs),
developmental
(
rats
and
rabbits),
chronic
(
dog),
two
carcinogenicity
(
mice)
studies,
a
chronic/
carcinogenicity
study
in
rats,
a
15­
day
dermal
study
in
rats,
a
two
year
reproduction
study
in
rats,
and
a
central
nervous
effects
study
in
mice
and
rats.
The
database
is
also
supported
by
substantial
data
from
the
literature,
including
some
studies
performed
by
EPA
scientists,
that
support
the
mode
of
toxic
action
and
endpoint
selection.

Triadimenol
shows
low
toxicity
for
acute
oral,
dermal,
and
inhalation
exposures
(
toxicity
Category
III
or
IV)
and
is
not
a
skin
sensitizer.
Triadimenol
is
an
eye
irritant
with
irritation
clearing
in
21
days
or
longer
(
toxicity
Category
II),
and
is
a
mild
dermal
irritant
(
toxicity
Category
IV).
For
the
purposes
of
reregistration,
the
database
is
adequate
although
there
are
data
gaps
(
lack
of
acute
and
subchronic
neurotoxicity
studies).

The
endpoint
of
concern
is
neurotoxicity.
Although
there
is
a
central
nervous
effect
study
conducted
with
triadimenol,
the
study
is
not
a
comprehensive
study.
Based
on
the
available
data
on
the
similar
effects,
similar
structure,
and
similar
mode
of
action
of
triadimefon
and
triadimenol,
Page
22
of
49
the
current
triadimefon
neurotoxicity
studies
(
acute
(
ACN)
and
subchronic
neurotoxicity
(
SCN)
studies)
will
be
used
to
establish
the
triadimenol
acute
and
chronic
reference
doses.
Please
see
section
4.2.1.2
through
4.2.3
below
for
more
detail.

4.2.1.2.
Evidence
of
Neurotoxicity
(
Mode
of
action,
metabolism,
toxicokinetic
data)

The
active
ingredient,
triadimenol,
is
a
neurotoxic,
triazole
fungicide
and
is
the
subject
of
this
risk
assessment
document.
Triadimenol
is
also
a
major
mammalian
and
plant
metabolite
of
triadimefon,
another
neurotoxic
triazole
fungicide.
The
mode
of
toxic
action
for
both
triadimenol
and
triadimefon
involves
blocking
the
re­
uptake
of
dopamine
which
leads
to
increased
motor
activity
and
hyperactivity
in
rodents.
These
pesticides
act
as
indirect
dopamine
agonists
by
binding
to
the
dopamine
transporter
and
increasing
levels
of
synaptic
dopamine.

Triazole
fungicide
pesticides,
in
general,
are
believed
to
exhibit
their
fungicidal
activity
through
an
inhibition
of
ergosterol
biosynthesis,
leading
to
an
inhibition
of
cell
wall
percursors.
Crofton
(
1996)
evaluated
the
potential
for
14
triazole
fungicides
and
structurally
related
compounds.
The
purpose
was
to
screen
these
compounds
to
determine
whether
central
nervous
system
toxicity,
particularly
increased
motor
activity,
is
characteristic
of
other
triazole
fungicides.
Crofton
(
1996)
showed
that
of
the
chemicals
tested,
only
triadimefon
and
triadimenol
were
able
to
induce
hyperactivity;
none
of
the
other
triazoles
or
related
compounds
tested
produced
this
effect.
The
author
hypothesized
that
the
ether
oxygen
component
of
the
triadimenol
and
triadimefon
molecules
appears
to
be
an
important
structural
requirement
for
induction
of
hyperactivity
in
rats.
As
such,
at
this
time,
although
the
fungicidal
activity
of
triadimefon
and
triadimenol
may
be
through
the
inhibition
of
sterol
synthesis,
the
primary
mode
of
toxicity
in
mammals
appears
to
be
neurotoxicity
mediated
through
an
indirect
monoaminergic
mechanism
that
appears
to
be
specific
to
triadimefon
and
triadimenol
only.

It
is
also
noted
that
triadimefon
and
triadimenol
share
toxicological
properties
with
methylphenidate.
Methylphenidate
is
a
central
nervous
system
stimulant
approved
by
the
Food
and
Drug
Administration
for
the
treatment
of
attention
deficit
hyperactivity
disorder
(
ADHD)
and
narcolepsy
in
persons
six
years
and
older.
d,
l­
Methylphenidate
is
marketed
under
the
names
Ritalin
®
,
Metadate
®
,
and
Concerta
®
.
Methylphenidate
is
believed
to
block
re­
uptake
of
norepinephrine
and
dopamine
by
the
presynaptic
neuron,
thus
increasing
levels
of
monoamine
neurotransmitters
in
the
extra
neuronal
space.
As
methylphenidate
is
a
commonly
prescribed
human
drug,
there
is
extensive
metabolism
and
toxicity
data
in
humans
and
animals.
An
expert
panel
of
scientists
recently
reviewed
the
available
toxicity
and
metabolism
studies
regarding
methylphenidate
(
Golub
et
al,
2005).
Because
of
the
similar
toxicological
profiles
between
methylphenidate,
triadimefon
and
triadimenol,
at
present
time,
the
Agency
is
evaluating
the
extent
to
which
the
data
in
methylphenidate
may
be
used
to
inform
interspecies
extrapolation.
The
Agency
historically
uses
a
10X
factor
for
extrapolating
between
animals
and
humans.
This
10X
is
expected
to
account
for
differences
in
both
pharmacokinetic
and
pharmacodynamic
characteristics.
In
some
cases
where
the
mode
of
toxic
action
is
understood,
the
Page
23
of
49
pharmacodynamics
are
believed
to
be
similar
for
animals
and
humans,
and
the
pharmacokinetic
differences
are
not
expected
to
exceed
3X,
so
the
interspecies
extrapolation
factor
may
be
reduced
to
3X.
The
current
risk
assessment
has
applied
the
default
10X
interspecies
extrapolation
factor.
The
Agency
is
currently
reviewing
the
available
pharmacokinetic
and
pharmacodynamic
properties
of
methylphenidate,
triadimefon
and
triadimenol
and
may
in
the
future
reconsider
the
magnitude
of
the
interspecies
factor.
However,
in
the
interim,
the
default
10X
interspecies
extrapolation
factor
will
be
utilized.

4.2.2
Toxicological
Effects
As
mentioned
above,
triadimenol
is
known
to
cause
neurotoxic
effects.
In
a
central
nervous
effects
study
in
mice
(
MRID
00145083),
neurotoxicity
was
observed
when
KWG
0519
(
Triadimenol)
at
doses
ranging
from3.75
to
60
mg/
kg
stimulated
spontaneous
mobility,
increased
irritability
and
escape
response
and
augmented
certain
reflexes.
In
addition,
doses
of
15
and
60
mg/
kg
potentiated
the
effect
of
amphetamine
while
doses
of
12
to
48
mg/
kg
antagonized
the
reserpin
response.
Triadimenol
also
prolonged
the
hexobartital
sleeping
time
at
15
and
60
mg/
kg.
Similarly,
rats
exposed
to
48
mg/
kg
triadimenol
elicited
an
excitatory
effect.
A
comparison
with
caffeine
(
doses
of
2.5
and
10
mg/
kg)
showed
that
the
effect
of
2.5
mg/
kg
caffeine
corresponded
approximately
to
that
of
12
to
15
mg/
kg
KWG
0519,
in
the
amphetamine
potentiation
test
2.5
mg/
kg
caffeine
elicited
a
similar
response
as
4
mg/
kg
KWG
0519,
while
in
the
antagonism
of
ptosis
10
mg/
kg
caffeine
and
12
mg/
kg
KWG
0519
were
comparable.
The
noeffect
dose
was
1
mg/
kg
for
caffeine.
The
findings
of
this
study
point
to
a
potential
for
stimulation
of
Central
Nervous
System
(
CNS).

In
addition,
following
exposure
to
triadimefon,
acute
neurotoxic
signs
observed
in
mice,
rats,
and
rabbits
consisted
of
"
apathy,
labored
breathing,
increased/
decrease
mobility,
staggering
and
cramped
posture,
aggressiveness,
and
self­
mutilation"
(
MRID
00149331).
The
formulation
Bayleton
50%
Wettable
Powder,
has
been
shown
to
cause
hyperactivity,
biting
and
antagonism
behavior
in
rats,
and
the
durations
of
these
effects
were
dose­
related.
(
Mobay
Report
No.
88,
submitted
in
FIFRA
88,
Phase
III).
Baytan
(
triadimenol),
the
major
metabolite
of
triadimefon,
is
also
known
to
cause
CNS­
related
excitatory
effects
in
rats
and
mice
[(
from
the
memo
dated
February
27,
1992:
Triadimefon.
Section
18,
Reissuance
of
Emergency
Exemption
for
the
use
of
Bayleton
50%
Dry
Flowable
Fungicide
(
EPA
Reg.
No.
3125­
320)
to
control
powdery
mildew
on
artichokes
in
the
state
of
California)]).

The
neurotoxic
endpoint
seen
with
triadimefon
and
triadimenol
is
supported
by
the
results
of
numerous
studies
reported
in
the
open
literature.
In
fact,
the
motor
behavior
stimulant
effect
of
triadimefon
has
been
sufficiently
characterized
such
that
the
compound
was
used
as
a
prototype
in
an
interlaboratory
comparison
of
behavioral
toxicology
methods
(
Crofton
et
al.,
1991;
Moser
and
MacPhail,
1992).
In
addition,
triadimefon
is
used
in
contract
laboratories
as
a
positive
control
for
motor
activity
in
adults
animals
(
Crofton
et
al,
2004).
Doses
of
triadimefon
(
50­
100
mg/
kg)
have
been
reported
to
increase
locomotion
and
rearing
in
rats
(
Walker
et
al.,
1990).
The
highest
dose
of
triadimefon
tested
in
this
study
(
200
mg/
kg)
induced
three
stereotypic
behaviors:
head
Page
24
of
49
weaving,
circling,
and
backward
locomotion
(
Walker
et
al.,
1990).
Crofton
et
al.
(
1991)
reported
hyperactivity
in
rats
following
oral
exposure
to
triadimefon
with
LOAELs
ranging
from
50
to
100
mg/
kg.
Walker
and
Mailman
(
1996)
reported
that
acute
administration
of
triadimefon
and
triadimenol
resulted
in
a
neurotoxic
syndrome
in
rats
characterized
by
increased
motor
activity,
stereotyped
behaviors,
and
altered
monamine
metabolism.

To
reiterate,
the
endpoint
of
concern
is
neurotoxicity
seen
after
acute
exposure
to
both
triadimefon
and
triadimenol.
Upon
reviewing
the
toxicological
database
for
the
fungicidally
active
ingredient
triadimenol,
it
is
noted
that
the
CNS
study
(
MRID
00145083)
was
not
a
comprehensive
study
and
the
primary
reason
for
conducting
it
was
to
establish
whether
the
compound
had
a
centrally
stimulating
effect.
Based
on
the
available
data
on
the
similar
structure,
effects
and
mode
of
action
of
triadimefon
and
triadimenol,
the
current
triadimefon
neurotoxicity
data
(
ACN
and
SCN)
will
be
used
to
establish
the
triadimenol
acute
and
chronic
reference
doses.

As
described
below,
NOAELs
and
LOAELs
for
both
acute
and
subchronic
(
90
day)
exposures
in
guideline
studies
are
similar,
suggesting
that
the
neurotoxicity
resulting
from
exposure
to
triadimefon
does
not
accumulate.
Similarly,
no
accumulation
of
toxicity
was
observed
in
studies
by
Crofton
et
al.
(
1988)
and
Moser
et
al.
(
1995)
following
seven
and
14
days
of
exposure,
respectively.
Further
evidence
is
also
provided
by
Ikaiddi
et
al.
(
1997)
who
showed
lack
of
accumulation
of
neurotoxicity
following
14
days
of
dosing
with
some
tolerance
on
aminergic
endpoints.
The
Agency
notes
that
the
dose
spacing
between
the
NOAEL
and
LOAELs
in
the
guideline
acute
and
subchronic
neurotoxicity
studies
are
fairly
large
(>
10­
fold).
This
large
dose
spacing
may
contribute
to
the
conservative
nature
of
the
current
risk
assessment.
As
the
Agency
refines
its
preliminary
risk
assessment
for
triadimenol
in
the
coming
months,
dose­
response
studies
from
the
literature
may
provide
additional
information
for
the
hazard
characterization
of
triadimenol.

In
the
available
chronic
studies,
FOBs
and
motor
activity
were
not
measured
and
as
such,
hyperactivity
was
generally
not
observed.
Liver
toxicity
was
noted
in
subchronic
(
dog
and
rats)
and
chronic
(
rats,
mice,
and
dogs)
studies.
Specifically,
changes
in
liver
enzymes
were
noted
in
the
chronic
dog
and
mouse
studies.
Changes
in
liver
weights
were
noted
in
dog
and
rat
subchronic
studies.
Increased
incidence
of
hepatocellular
hypertrophy
in
both
sexes
were
noted
in
rats.

4.2.3
Dose­
Response
Acute
neurotoxicity:
In
an
acute
oral
neurotoxicity
study
(
MRID
43936101),
twelve
Wistar
(
Hsd
Win:
WU)
rats/
sex/
group
were
dosed
by
gavage
with
nominal
dose
of
0,
2,
35,
450
(
females
only),
or
600
(
males
only)
mg/
kg
of
triadimefon
(
MEB
6447;
95.8%
a.
i.;
Lot
No.:
203480004)
in
polyethylene
glycol
400
(
5
mL/
kg).
Analytically
confirmed
doses
were
0,
2,
31.2,
424.4
(
females
only)
and
587.4
(
males
only).
The
animals
were
monitored
for
a
14­
day
observation
period.
All
twelve
rats/
sex/
group
were
tested
in
the
functional
observational
battery
(
FOB)
and
motor
activity
(
MA)
measurements,
and
six
rats/
sex/
group
were
perfused
for
neuropathology.
Page
25
of
49
Within
two
days
after
dosing,
one
high­
dose
male
and
four
high­
dose
females
died.
Clinical
signs
were
observed
in
the
mid­
and
high­
dose
males
and
high­
dose
females.
Mid­
dose
males
exhibited
moderate
hyperactivity.
High
dose
rats
showed
signs
of
severe
hyperactivity,
stereotypic
behavior,
self­
mutilation,
diarrhea,
and
increased
rearing.
Decreased
body
weights
were
observed
on
Day
7
in
high­
dose
males
(­
7.6%;
p<
0.05)
and
females
(­
4.5%;
n.
s.).

Dose­
related
effects
were
observed
in
the
Functional
Operational
Battery
in
mid­
and
high­
dose
males
and
females.
On
day
0,
hyperactivity
was
indicated
by
affected
posture
and
gait,
increased
mobility,
searching
and
cleaning
gestures,
stereotypy,
increased
arousal,
and
increased
open
field
rearing
incidence.
Hyperactivity,
indicated
by
an
increased
incidence
of
open
field
rearing,
was
still
observed
at
day
7
or
day
14
in
mid­
or
high­
dose
males,
respectively.
In
mid­
dose
females,
rearings
were
increased
at
day
7
with
complete
reversibility
at
day
14.
Body
temperatures
were
significantly
(
p<
0.05)
increased
in
high­
dose
males
and
females
compared
to
controls.

Grip
strength
was
marginally
decreased
in
high­
dose
males
and
females
on
days
7
and
14
(
males
only).
Hindlimb
foot
splay
was
decreased
in
high­
dose
males
on
days
0
and
7.
Functional
Operational
Battery
effects
were
completely
reversible
until
the
end
of
the
study
in
females
and
largely
reversible
in
males.

On
day
0,
mid­
and
high­
dose
males
and
females
exhibited
statistically
significant
increases
(
226.9­
317.5%)
in
motor
activity.
On
day
7,
mid­
dose
males
still
had
a
statistically
significant
increase
(
33.6%)
in
motor
activity
(
interval
50­
60
minutes),
while
a
nonstatistically
significant
increase
(
26.2%)
was
present
on
day
14
(
intervals
30­
60
minutes).
Mid­
dose
females
exhibited
marginal
increases
in
motor
activity
on
days
7(
46.7%)
and
14
(
34.2%).

Statistically
significant
increases
(
326.7­
485.6%)
in
locomotor
activity
were
observed
in
mid­
and
high­
dose
males
and
females
on
day
0
persisting
until
the
end
of
the
study
period
(
Day
14)
though
to
a
lesser
extent
(
28.1­
50.2%).
Statistically
significantly
decreased
habituation
was
noted
in
midand
high­
dose
the
males
and
females
on
day
0.
This
continued
to
a
smaller
degree
for
mid­
dose
males
and
females
on
day
7
and
for
mid­
and
high­
dose
males
on
day
14.
The
blind
alley
and
figure­
eight
activities
were
increased
for
mid­
and
high­
dose
males
and
females
on
day
0.

No
effect
on
the
absolute
or
relative
brain
weights
was
observed.
No
treatment­
related
gross
effects
or
histopathology
were
observed.

The
LOAEL
for
systemic/
neurobehavioral
findings
is
31.2
mg/
kg
based
on
clinical
signs,
FOB,
rearing,
body
temperature,
MA,
habituation,
and
spatial
distribution
in
males
and
females.
The
NOAEL
is
2
mg/
kg.

Subchronic
neurotoxicity:
In
a
subchronic
neurotoxicity
study
(
MRID
44153501),
triadimefon
(
MEB
6477)
technical
(
95.8­
95.9%
a.
i.)
was
administered
in
the
diet
to
18
Wistar
rats/
sex/
dose
at
levels
of
0,
50,
800,
or
2,200
ppm
(
0,
3.4,
54.6
and
149.8
mg/
kg/
day
for
males
and
0,
4.3,
68.7,
and
189.7
mg/
kg/
day
for
females)
for
13­
weeks.
Six
rats/
sex/
dose
level
were
subjected
to
Page
26
of
49
neuropathological
evaluations
at
the
end
of
the
exposure
period
and
the
remaining
12
rats/
sex/
dose
level
were
observed
for
another
4
(
males)
or
10
(
females)
weeks
to
investigate
the
persistence
of
the
toxicological
effects.

At
800
ppm
(
54.6%
and
68.7&
mg/
kg/
day)
there
were
increases
in
rearing
(
both
sexes)
and
motor
and
locomotor
activity
(
females
only)
and
other
indications
of
hyperactivity
especially
in
females
including
clinical
signs
(
mobility,
digging,
and
spilling
food
and
water);
body
weight
and
weight
gain
were
also
decreased
(
9%
%
and
14%
&)
in
both
sexes
in
the
initial
four
weeks
of
dosing.
There
were
also
slight
(
not
statistical
significant)
increases
in
male
brain
relative
weight
and
grip
strength.
At
2200
ppm
(
149.8%
and
189.7&
mg/
kg/
day)
there
was
stereotypy
(
pacing
only
in
a
few
rats),
and
increased
relative
brain
weight
(
18%
both
sexes).
Increased
landing
foot
splay
and
grip
strength
were
also
evident.
The
effects
were
considered
slowly
reversible,
however,
there
was
some
evidence
of
hyperactivity
persisting.
The
LOAEL
for
neurotoxicity
is
800
ppm
(
54.6%
and
68.7&
mg/
kg/
day)
based
largely
on
hyperactivity.
The
NOAEL
is
50
ppm
(
3.4%
and
4.3&
mg/
kg/
day).

Similar
signs
/
effects
were
seen
in
the
triadimefon
developmental
toxicity
study
(
MRID
00089023)
where
the
maternal
NOAEL
is
10
mg/
kg/
day
and
the
LOAEL
is
50
mg/
kg/
day
based
on
dose­
related
increase
in
both
degree
and
duration
of
motor
activity
and/
or
depression
of
maternal
weight.

Additional
Information
from
Literature
Sources:

1)
Crofton,
KM.,
Boncek,
VM.,
and
Reiter,
LW.
1988.
Hyperactivity
induced
by
triadimefon,
a
triazole
fungicide.
Fundam.
Appl.
Toxicol.
10,
459­
465.

2)
Crofton,
KM.,
Boncek,
VM.,
and
MacPhail,
RC.
1989.
Evidence
for
monoaminergic
involvement
in
triadimefon
­
induced
hyperactivity,
Psychopharmacology
97,
326­
330.

3)
Moser,
VC
and
MacPhail,
RC.
1989.
Neurobehavioral
effects
of
triadimefon,
a
triazole
fungicide,
in
male
and
female
rats.
Neurotoxicol.
Teratol.
11,
285­
293.

4)
Crofton,
KM.,
Howard,
JL.,
Moser,
VC.,
Gill,
MW.,
et
al.
1991.
Interlaboratory
comparison
of
motor
activity
experiments:
implications
for
neurotoxicological
assessments.
Neurotoxicol.
Teratol.
13
(
6):
599­
609.

5)
Moser,
VC
and
MacPhail,
RC.
1992.
International
validation
of
the
neurobehavioral
screening
battery:
The
IPCS/
WHO
collaborative
study.
Toxicol.
Lett.
64­
65
Spec.
No.,
217­
223.

6)
Moser,
VC.,
Cheek,
BM.,
and
MacPhail,
RC.
1995.
A
multidisciplinary
approach
to
toxicological
screenings:
III.
Neurobehavioral
toxicity.
Journal
Toxicol
Environ
Health
Jun
45(
2):
173­
210.
Page
27
of
49
7)
Crofton,
KM.
1996.
A
structure­
activity
relationship
for
the
neurotoxicity
of
triazole
fungicites.
Toxicol.
Lett
84
(
3):
155­
159.

8)
Walker,
QD
and
Mailman,
RB.
1996.
Triadimefon
and
triadimenol:
effects
on
monoamine
uptake
and
release.
Toxicol.
Appl.
Pharmacol.
139
(
2):
227­
233.

9)
Ikaiddi,
MU.,
Akunne,
HC.,
and
Soliman,
KE.
1997.
Behavioral
and
neurochemical
effects
of
acute
and
repeated
administration
of
triadimefon
in
the
male
rat.
Neurotoxicology
18(
3):
771­
80.

10)
Crofton,
KM.,
Makris,
SL.,
Sette,
WF.,
Mendez,
E.,
and
Raffaele,
KC.
2004.
A
qualitative
retrospective
analysis
of
positive
control
data
in
developmental
neurotoxicity
studies.
Neurotoxicology
and
Teratology
26;
345­
352.

11)
Golub,
M.,
Costa,
L.,
Crofton,
K.,
Frank,
D.,
Fried,
P.,
Gladen,
B.,
Henderson,
R.,
Liebelt,
E.,
Lusskin,
S.,
Marty,
S.,
Rowland,
A.,
Scialli,
J.,
and
Vore,
M.
2005.
NTPCERHR
expert
panel
report
on
the
reproductive
and
developmental
toxicity
of
methylphenidate.
Birth
Defects
Research
(
part
B)
74:
300­
381.

4.2.4
Developmental
Toxicity
Studies
Rabbit
Developmental:
In
a
developmental
toxicity
study
(
MRID
40307805),
triadimenol
(
97%
a.
i.)
was
administered
in
0.5%
Cremophor
EL
orally,
via
gavage,
in
a
dosing
volume
of
4
mL/
kg,
to
16
female
Chinchilla
rabbits/
group,
at
dose
levels
of
0,
8,
40,
or
200
mg/
kg/
day,
on
gestation
days
(
GD)
6
through
18.
All
surviving
does
were
sacrificed
on
GD
28
and
their
fetuses
were
removed
by
cesarean
and
examined.

When
compared
to
concurrent
controls,
no
treatment­
related
changes
were
observed
in
maternal
mortality,
the
number
of
live
and
dead
fetuses,
fetal
weights,
or
maternal
pathology.
At
200
mg/
kg,
all
does
appeared
excited
approximately
30
minutes
post­
dosing
from
GD
10
until
study
termination.
In
addition,
several
animals
in
this
group
suffered
a
loss
of
hair
on
the
forepaws
and
toes.
Decreased
(
p<=
0.05)
body
weights
were
noted
in
the
200
mg/
kg
does
during
GDs
7­
24
(
decr.
7­
14%).
In
addition,
mean
maternal
food
consumption
was
decreased
(
p<=
0.05)
in
these
animals
during
GDs
6­
19
(
decr.
22­
61%),
with
the
greatest
decreases
occurring
at
dose
initiation.
Increased
post­
implantation
loss
(
12.8%
treated
vs.
3.8
%
controls)
and
early
resorptions
per
doe
(
0.7
treated
vs.
0.1
controls)
were
observed
at
200
mg/
kg.
Neither
of
these
cesarean
findings
was
statistically
significant.

The
maternal
LOAEL
is
200
mg/
kg/
day
based
on
clinical
signs
of
toxicity,
decreased
body
weights
and
food
consumption.
The
maternal
NOAEL
is
40
mg/
kg/
day.
At
200
mg/
kg,
the
number
of
fetuses
(
7/
95
treated
vs.
0/
128
controls)
and
litters
(
6/
14
treated
vs.
0/
16
controls)
affected
with
skeletal
abnormalities
was
greater
(
p<=
0.01)
than
controls.
These
abnormalities
Page
28
of
49
involved
rib,
vertebral,
and/
or
sternal
elements.
The
developmental
toxicity
LOAEL
is
200
mg/
kg
based
on
skeletal
abnormalities
and
increased
post­
implantation
loss
and
early
resorptions.
The
developmental
toxicity
NOAEL
is
40
mg/
kg/
day.

Prenatal
Developmental
/
Rat:
In
a
prenatal
developmental
toxicity
study
(
MRIDs
40307804
and
40887702),
Baytan
(
triadimenol;
97%
a.
i.,
Lot/
Batch
#
203
519
123)
in
0.5%
(
w/
v)
aqueous
Cremophor
EL
was
administered
to
pregnant
Wistar/
HAN,
Kfm:
WIST
outbred,
SPF
rats
(
25/
dose)
via
gavage
in
a
dosing
volume
of
10
mL/
kg
at
concentrations
of
0,
30,
60,
or
120
mg/
kg/
day
on
GDs
6
through
15.
All
dams
were
sacrificed
on
GD
21
and
their
uterine
contents
examined.

There
were
no
unscheduled
deaths
during
the
study.
When
compared
to
concurrent
controls,
there
were
no
effects
of
treatment
on
maternal
clinical
observations,
gross
pathology,
numbers
of
dead
fetuses,
sex
ratios,
or
fetal
weights.
Maternal
body
weights
were
significantly
decreased
during
GDs
8­
17
at
60
mg/
kg
and
GDs
7­
18
at
120
mg/
kg.
Body
weight
gains
were
decreased
during
dosing
in
the
60
mg/
kg
(
decr.
6­
14%)
and
120
mg/
kg
(
decr.
15­
41%)
dams.
Corrected
(
for
gravid
uterine
weight)
body
weight
gains
were
decreased
(
decr.
23%;
not
significant)
in
the
120
mg/
kg
dams.
Food
consumption
was
significantly
decreased
during
treatment
in
the
60
mg/
kg
(
decr.
6­
11%)
and
120
mg/
kg
(
decr.
8­
20%)
dams.
The
mean
number
of
resorptions
was
increased
from
0.8
in
controls
to
1.5
at
120
mg/
kg.
Likewise,
the
percent
post­
implantation
loss
was
increased
in
this
group
(
11.8%
treated
vs
5.9%
controls).

The
maternal
LOAEL
is
60
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
The
maternal
NOAEL
is
30
mg/
kg/
day.
Dose­
dependent
increases
(
p<=
0.01)
in
fetal
and
litter
incidences
of
supernumerary
ribs
were
observed
at
60
and
120
mg/
kg/
day.

The
following
information
was
taken
from
the
memorandum
(
TXR#
007290):
"
The
issue
of
supernumerary
ribs
was
discussed
with
L.
Chitlik
(
HED)
on
several
occasions
in
April
and
May
1989.
In
a
meeting
between
R.
Engler
(
HED)
and
L.
Chitlik
on
May
4,
1989,
it
was
concluded
that
30
mg/
kg/
day
may
be
a
threshold
for
this
variation
because
of
the
apparent
trend.
Furthermore,
in
TXR#
007290
it
was
indicated
that
the
low
dose
concern
may
not
just
be
limited
to
supernumerary
ribs.
Therefore,
a
definite
NOAEL
could
not
be
established
for
developmental
toxicity,
and
consequently
the
study
was
classified
as
Core
Supplementary.
The
registrant
is
requested
to
submit
a
new
teratogenicity
study
in
the
same
strain
of
rats
to
define
the
NOAEL
for
the
developmental
toxicity."

A
subsequent
developmental
toxicity
study
in
the
rat
(
MRID
41498401;
TXR#
008269
&
009704),
conducted
in
1990,
was
submitted,
reviewed,
and
found
acceptable
with
a
LOAEL
of
60
mg/
kg/
day
based
on
supernumerary
ribs
and
a
NOAEL
of
25
mg/
kg/
day.
The
developmental
LOAEL
is
60
mg/
kg/
day
based
on
increased
incidences
of
supernumerary
ribs.
The
developmental
NOAEL
is
30
mg/
kg/
day.
Page
29
of
49
Prenatal
Developmental/
Rat:
In
a
prenatal
developmental
toxicity
study
(
MRID
41498401),
Baytan
(
triadimenol;
95%
a.
i.,
Lot/
Batch
#
6­
03­
0140)
in
0.5%
(
w/
v)
aqueous
carboxymethylcellulose
and
0.4%
(
w/
v)
aqueous
Tween
80
NF
was
administered
to
pregnant
Crl:
CD
BR
rats
(
28/
dose)
via
gavage
in
a
dosing
volume
of
10
mL/
kg
at
concentrations
of
0,
5,
15,
25,
or
60
mg/
kg/
day
on
gestation
days
(
GDs)
6
through
15.
All
dams
were
sacrificed
on
GD
20
and
their
uterine
contents
examined.

There
were
no
unscheduled
deaths
during
the
study.
When
compared
to
concurrent
controls,
there
were
no
effects
of
treatment
on
maternal
clinical
observations,
clinical
chemistry,
liver
weights,
gross
pathology,
numbers
of
abortions,
live
or
dead
fetuses,
resorptions,
sex
ratio,
or
fetal
weight.
Maternal
body
weights
were
decreased
(
decr.
13­
24%;
p<=
0.05)
during
dosing
(
GDs
6­
16)
in
the
15,
25,
and
60
mg/
kg
dams.
Likewise,
adjusted
(
for
gravid
uterine
weight)
body
weight
gains
were
decreased
in
the
15
(
decr.
16%;
p<=
0.01),
25
(
decr.
9%;
not
significant),
and
60
(
decr.
22%;
p<=
0.01)
mg/
kg
dams.
The
lack
of
statistical
significance
at
25
mg/
kg
is
likely
due
to
the
inclusion
of
data
from
dam
#
1862,
which
had
only
one
implant
and
a
uterine
weight
of
only
7.7
grams.
A
transient
decrease
(
p<=
0.05)
in
food
consumption
was
observed
on
day
7
in
the
15
and
60
mg/
kg
dams.
Placental
weight
was
increased
(
incr.
21%;
p<=
0.01)
at
60
mg/
kg.

The
maternal
LOAEL
is
15
mg/
kg/
day
based
on
decreased
body
weights
and
adjusted
(
for
gravid
uterine
weight)
body
weight
gains.
The
maternal
NOAEL
is
5
mg/
kg/
day.
The
incidence
of
extra
ribs,
a
variation,
was
increased
(
p<=
0.01)
at
60
mg/
kg/
day
(
21.2%
fetal
incidence;
71.4%
litter
incidence)
compared
to
concurrent
controls
(
0.5%
fetal
incidence;
3.6%
litter
incidence).
Incidences
of
this
variation
exceeded
historical
controls
(
0.5­
18.6%
fetal
incidence;
3.7­
65.2%
litter
incidence).
The
developmental
LOAEL
is
60
mg/
kg/
day
based
on
increased
incidences
of
extra
ribs,
a
variation.
The
developmental
NOAEL
is
25
mg/
kg/
day.

Prenatal
Developmental
/
Rabbit:
In
a
prenatal
developmental
toxicity
study
(
MRID
42365001),
Baytan
(
triadimenol;
96.0%
a.
i.,
Lot/
Batch
#
PF8741)
in
0.5%
(
w/
v)
aqueous
carboxymethylcellulose
and
0.4%
(
w/
v)
aqueous
Tween
80
NF
was
administered
to
pregnant
New
Zealand
White
rabbits
(
20/
dose)
via
gavage
in
a
dosing
volume
of
5
mL/
kg
at
concentrations
of
0,
5,
25,
or
125
mg/
kg/
day
on
gestation
days
(
GDs)
6
through
18.
All
does
were
sacrificed
at
the
end
of
the
exposure
period
and
their
uterine
contents
examined.

There
were
no
unscheduled
deaths
during
the
study.
When
compared
to
concurrent
controls,
there
were
no
effects
of
treatment
on
maternal
clinical
signs,
liver
enzymes,
liver
weights,
gross
pathology,
litter
size,
numbers
of
live
fetuses,
dead
fetuses,
or
resorptions,
post­
implantation
loss,
sex
ratio,
fetal
weight,
or
placental
weight.
Mean
litter
size
was
decreased
in
the
25
mg/
kg
(
decr.
32%)
and
125
mg/
kg
(
decr.
26%).
However,
the
decreased
in
litter
size
was
due
to
decreases
in
the
numbers
of
corpora
lutea
(
19­
20%)
and,
thus,
implantations
(
decr.
25­
32%)
in
these
groups
occurring
prior
to
initiation
of
treatment.

At
125
mg/
kg/
day,
maternal
body
weights
were
decreased
(
decr.
6%;
p<=
0.05)
during
GDs
13­
Page
30
of
49
16.
Body
weight
gains
were
decreased
during
the
dosing
period,
GDs
6­
18,
(­
0.07
kg
treated
vs
0.12
kg
in
controls;
p<=
0.01)
and
for
the
entire
gestation
period
(
decr.
29%;
p<=
0.05).
Food
consumption
was
decreased
(
p<=
0.05)
on
GDs
7
(
decr.
6%),
12
(
decr.
26%),
and
15
(
decr.
24%).
The
maternal
LOAEL
is
125
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
The
maternal
NOAEL
is
25
mg/
kg/
day.
The
developmental
LOAEL
was
not
observed.
The
developmental
NOAEL
is
125
mg/
kg/
day
(
HDT).
Increased
fetal
(
p<=
0.05)
and
litter
(
not
significant)
incidences
of
the
following
skeletal
findings
were
observed
in
the
125
mg/
kg
fetuses
compared
to
concurrent
controls:
(
i)
incomplete
ossification
of
the
skull;
(
ii)
enlarged
fontanelle
in
the
skull;
(
iii)
presence
of
calcified
body
on
the
skull;
(
iv)
irregular
spinous
process
on
the
scapula;
and
(
v)
incomplete
ossification
of
the
posterior
phalanges.

4.2.5
Reproductive
Toxicity
Studies
In
a
two­
generation
reproduction
toxicity
study
(
MRID
00151248)
triadimenol;
97.5%
a.
i.)
was
administered
continuously
in
the
diet
to
SPF
rats
(
10
males
and
20
females/
dose)
at
nominal
dose
levels
of
0,
20,
100,
or
500
ppm
(
0,1,5,
or
25
mg/
kg/
day).
The
P
parental
animals
were
given
test
diets
for
approximately
10
weeks
before
they
were
mated
to
produce
the
F1a
litters.
Two
weeks
after
their
litters
were
weaned,
the
P
animals
were
mated
for
a
second
time
to
produce
the
F1b
litters.
The
F1b
parental
animals
were
randomly
selected
to
become
the
parents
of
the
F2
generation
5
days
after
birth.
Following
weaning,
the
F1a
parents
received
the
test
diets
for
approximately
12
weeks
before
they
were
mated
to
produce
the
F2a
and
F2b
litters.
The
F1a,
F2a,
and
F2b
litters
were
weaned
after
four
weeks
and
then
sacrificed.

Mortality,
clinical
signs,
gross
pathology,
and
histopathology
in
the
parental
animals
and
their
offspring
were
unaffected
by
treatment.
Additionally,
parental
food
consumption
(
premating),
reproductive
performance,
and
organ
weights
were
not
affected
by
treatment.
Reproductive
function,
sexual
maturation,
and
pup
organ
weights
were
not
evaluated.
At
25
mg/
kg/
day
in
the
F1b
generation,
body
weights
were
slightly
decreased
(
p<=
0.05)
during
premating
week
15
in
the
males
and
during
most
of
premating
in
the
females
(
decr.
6­
8%).
During
gestation,
body
weights
were
decreased
(
p<=
0.05)
during
GDs1­
6
of
the
first
mating
and
GDs
1­
15
of
the
second
mating
(
decr.
8­
10%).
During
lactation,
body
weights
were
decreased
(
p<=
0.05)
during
LDs
14­
21
of
the
first
mating
and
LDs
7­
21
of
the
second
mating
(
decr.
6­
10%).
Body
weight
gains
during
lactation
were
decreased
for
both
matings
(
decr.
32­
50%).
No
treatment­
related
findings
were
noted
at
the
1
or
5
mg/
kg/
day
dose
levels.

The
LOAEL
for
parental
toxicity
is
25
mg/
kg/
day
based
on
decreased
body
weights
and
body
weight
gains
in
the
F1b
generation.
The
NOAEL
is
5
mg/
kg/
day.
At
25
mg/
kg/
day,
decreased
(
p<=
0.05)
pup
weights
were
observed
in
the
F1a
and
F1b
litters
during
early
lactation
and
in
the
F2a
litters
during
late
lactation
(
decr.
12­
18%).
No
treatment­
related
findings
were
noted
at
1
or
5
mg/
kg/
day
dose
levels.

The
LOAEL
for
offspring
toxicity
is
25
mg/
kg/
day
based
on
decreased
pup
weight.
The
NOAEL
Page
31
of
49
is
5
mg/
kg/
day.
This
study
was
classified
acceptable/
guideline.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
There
was
no
evidence
for
quantitative
and
qualitative
susceptibility
following
oral
or
dermal
exposures
to
rats
in
utero
or
oral
exposure
to
rabbits
in
utero.
The
degree
of
concern
for
preand
or
post­
natal
susceptibility
is
low
because
the
rabbit
NOAEL
(
20
mg/
kg/
day)
is
adequate
due
to
dose
spacing.
The
endpoint
used
for
risk
assessment
purposes
(
NOAEL
of
3.4
mg/
kg/
day
from
the
subchronic
neurotoxicity
study)
is
10x
lower
than
the
rabbit
NOAEL
and
it
is
accounted
for
in
the
overall
FQPA
database
uncertainty
factor
of
10x
for
the
lack
of
a
DNT.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
mode
of
toxic
action
for
triadimenol
involves
blocking
the
re­
uptake
of
dopamine.
These
pesticides
act
as
indirect
dopamine
agonists
by
binding
to
the
dopamine
transporter
and
increasing
levels
of
synaptic
dopamine.
The
toxicological
impact
of
blocking
this
re­
uptake
following
exposure
to
triadimenol
during
development
is
not
known.
A
developmental
neurotoxicity
study
with
triadimenol
is
not
required
at
this
time,
pending
the
outcome
of
an
acute
and/
or
subchronic
neurotoxicity
study(
ies).

4.4
Special
FQPA
Safety
Factor(
s)
Required
and
Rationale
Based
on
the
above
data,
the
special
FQPA
safety
factor
of
10x
is
not
required
since
the
current
developmental
and
reproductive
toxicity
studies
do
not
suggest
that
the
young
are
more
sensitive
than
adult
animals,
and
the
lack
of
a
DNT
is
addressed
by
the
FQPA
database
uncertainty
factor
of
10x.
Therefore,
the
FQPA
Safety
Factor
is
1x.

4.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.5.1
Acute
Reference
Dose
(
aRfD)
­
General
Population
No
appropriate
acute
endpoint
could
be
determined
from
the
triadimenol
database
(
see
Section
4.2.1).
Therefore,
the
Triadimefon
subchronic
neurotoxicity
study
in
rats
(
MRID
44153501)
was
chosen
for
the
acute
Reference
Dose
(
aRfD).
Triadimefon
(
MEB
6477)
technical
(
95.8­
95.9%
a.
i.)
was
administered
in
the
diet
to
18
Wistar
rats/
sex/
dose
at
levels
of
0,
50,
800,
or
2,200
ppm
(
0,
3.4,
54.6
and
149.8
mg/
kg/
day
for
males
and
0,
4.3,
68.7,
and
189.7
mg/
kg/
day
for
females)
for
13
weeks.
Six
rats/
sex/
dose
level
were
subjected
to
neuropathological
evaluations
at
the
end
of
the
exposure
period
and
the
remaining
12
rats/
sex/
dose
level
were
observed
for
another
4
(
males)
or
10
(
females)
weeks
to
investigate
the
persistence
of
the
toxicological
effects.

At
800
ppm
(
54.6%
and
68.7&
mg/
kg/
day)
there
were
increases
in
rearing
(
both
sexes)
and
motor
and
locomotor
activity
(
females
only),
as
well
as
other
indications
of
hyperactivity
(
especially
in
Page
32
of
49
Acute
RfD
=
3.4
mg/
kg/
day
(
NOAEL)
=
0.0034
mg/
kg/
day
1000
(
UF)
females).
Indications
of
hyperactivity
include
clinical
signs
(
motility,
digging,
spilling
food
and
water);
body
weight
and
body
weight
gain
(
9%
%
and
14%
&)
were
also
decreased
in
both
sexes
in
the
initial
four
weeks
of
dosing.
There
were
also
slight
(
not
significant)
increases
in
male
brain
relative
weight
and
grip
strength.

At
2200
ppm
(
149.8%
and
189.7&
mg/
kg/
day)
there
was
stereotypy
(
pacing
only
in
a
few
rats),
relative
brain
weight
(
18%
both
sexes)
and
increased
frequency
and
intensity
of
the
symptoms
noted
at
800
ppm.
Increased
landing
foot
splay
and
grip
strength
(
believed
to
be
associated
with
the
decrease
in
body
weight)
were
evident.
The
effects
were
considered
slowly
reversible
since
body
weight
recovered
slowly
and
there
was
some
evidence
of
hyperactivity
persisting.
The
LOAEL
for
neurotoxicity
is
800
ppm
(
54.6%
and
68.7&
mg/
kg/
day)
based
largely
on
hyperactivity.
The
NOAEL
is
50
ppm
(
3.4%
and
4.3&
mg/
kg/
day).

For
the
acute
dietary
risk
assessment,
the
Uncertainty
Factor
(
UF)
is
1000x:
10
x
for
interspecies
extrapolation,
10x
for
intraspecies
variations,
and
10x
for
FQPA
database
uncertainty
(
lack
of
an
acute
and/
or
subchronic
neurotoxicity
studies).

The
triadimefon
subchronic
neurotoxicity
study
was
used
to
established
the
aRfD,
although
an
acceptable
triadimefon
acute
neurotoxicity
study
is
available.
The
endpoint
of
concern
is
neurotoxicity
seen
both
after
acute
gavage
and
repeated
dietary
exposure.
The
clinical
signs
include
increase
rearing,
motor
activity,
stereotypy,
and
self
mutilation.
It
is
noted
that
the
acute
neurotoxicity
study
NOAEL
of
2
mg/
kg/
day
is
lower
than
the
3.4
NOAEL
in
the
SCN
selected
for
the
overall
risk
assessment
.
The
NOAEL
of
the
ACN
study
appears
to
be
an
artifact
of
dose
selection
(
large
spacing
between
the
doses
i.
e.,
2,
31.2,
424.4
and
587.4
mg/
kg);
thus,
use
of
the
NOAEL
of
3.4
mg/
kg
from
the
SCN
is
considered
appropriate
for
this
risk
assessment.

Again,
the
Agency
notes
that
the
dose
spacing
between
the
NOAEL
and
LOAELs
in
the
guideline
acute
and
subchronic
neurotoxicity
studies
are
fairly
large
(>
10­
fold).
This
large
dose
spacing
may
contribute
to
the
conservative
nature
of
the
current
risk
assessment.
As
the
Agency
refines
its
preliminary
risk
assessment
for
triadimenol
in
the
coming
months,
dose­
response
studies
from
the
literature
may
provide
additional
information
for
the
hazard
characterization
of
triadimenol.

4.5.2
Chronic
Reference
Dose
(
cRfD)

The
subchronic
neurotoxicity
study
in
rats
(
MRID
44153501)
is
chosen
for
the
cRfD.
Please
see
Section
4.5.1.

For
the
chronic
dietary
risk
assessment,
the
Uncertainty
Factor
(
UF)
is
as
follows:
1000X
(
10x
for
interspecies
extrapolation,
10x
for
intraspecies
variations,
and
10x
for
FQPA
database
uncertainty
Page
33
of
49
Chronic
RfD
=
3.4
mg/
kg/
day
(
NOAEL)
=
0.0034
mg/
kg/
day
1000
(
UF)
(
lack
of
an
acute
and/
or
subchronic
neurotoxicity
and
inhalation
studies).

The
triadimefon
subchronic
neurotoxicity
study
was
used
to
established
the
cRfD,
although
acceptable
triadimenol
chronic,
reproductive,
combined
chronic/
carcinogenicity
and
carcinogenicity
studies
are
available.
Using
the
subchronic
neurotoxicity
study
accounts
for
the
most
sensitive
species
and
endpoints
(
rat
vs.
chronic
dog
study
(
MRID
00150484)).
The
endpoint
of
concern
is
neurotoxicity
(
SCN)
and
liver
toxicity
for
the
chronic
studies.
An
extra
factor
will
not
be
used
for
using
a
short­
term
factor
(
SCN)
in
a
long­
term
risk
assessment
because
the
NOAEL
available
for
the
long­
term
studies
(
reproductive
study
MRID
00151248),
carcinogenicity
(
MRIDs
00126259
and
00126260)
and
chronic
(
MRID
00150484)
is
higher
than
the
NOAEL
selected
for
this
risk
assessment
(
3.8
­
19
mg/
kg/
day
vs.
3.4
mg/
kg/
day).

4.5.3
Classification
of
Carcinogenic
Potential
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July
1999),
the
Cancer
Assessment
Review
Committee
(
CARC)
classified
Triadmenol
into
the
category
C
"
possible
human
carcinogen."
This
classification
is
based
on
increased
incidence
of
hepatocellular
adenomas
in
females.

Table
9:
Summary
of
Toxicological
Doses
and
Endpoints
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
population)
NOAEL
=
3.4
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.0034
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.0034
mg/
kg/
day
Subchronic
neurotoxicity
study
in
rats.
LOAEL
=
54.6/
68.7
mg/
kg/
day
based
largely
on
hyperactivity.

Chronic
Dietary
(
all
populations)
NOAEL
=
3.4
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.0034
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.0034
mg/
kg/
day
Subchronic
neurotoxicity
study
in
rats.
LOAEL
=
54.6/
68.7
mg/
kg/
day
based
largely
on
hyperactivity.

Cancer
(
oral,
dermal,
inhalation)
Classification:
Category
C
"
possible
human
carcinogen"
based
on
increased
incidence
of
hepatocellular
adenomas
in
females.

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.
Page
34
of
49
*
Refer
to
Section
4.5
4.6
Endocrine
Disruption
EPA
is
required
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

5.0
PUBLIC
HEALTH
DATA
5.1
Incident
Reports
For
a
review
of
human
incident
data
for
triadimenol
and
triadimefon,
please
refer
to
Section
9.0.

6.0
EXPOSURE
CHARACTERIZATION
/
ASSESSMENT
6.1
Dietary
Exposure
/
Risk
Pathway
6.1.1
Residue
Profile
Tolerances
are
established
for
residues
of
triadimenol
and
its
butanediol
metabolite,
4­(
4­
chlorophenoxy)­
2,2­
dimethyl­
4­(
1H­
1,2,4­
triazol­
1­
yl)­
1,3­
butanediol]
(
calculated
as
triadimenol)
in/
on
various
plant
commodities
[
40
CFR
§
180.450(
a)].
The
established
tolerances
in
plant
commodities
range
from
0.01
(
sorghum
grain
and
fodder)
to
2.5
ppm
(
green
forage
of
oats,
rye,
and
wheat).
Tolerances
are
established
for
residues
of
triadimenol
and
its
metabolites
containing
the
chlorophenoxy
moiety
(
calculated
as
triadimenol)
in
livestock
commodities
at
0.01
ppm
(
milk
and
poultry
commodities)
and
0.1
ppm
(
fat,
meat,
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep).

Triadimenol
and
its
butanediol
metabolite
(
KWG
1342)
are
also
regulated
as
metabolites
of
the
fungicide
triadimefon
(
40
CFR
§
180.410).
In
addition,
40
CFR
§
180.3(
d)(
13)
specifies
that
Page
35
of
49
where
tolerances
are
established
for
residues
of
both
1­(
4­
chlorophenoxy)­
3,3­
dimethyl­
1­(
1H­
1,2,4­
triazol­
1­
yl)­
2­
butanone
(
triadimefon)
and
triadimenol
including
its
butanediol
metabolite,
4­(
4­
chlorophenoxy)­
2,2­
dimethyl­
4­(
1H­
1,2,4­
triazol­
1­
yl)­
1,3­
butanediol
(
KWG
1342),
in
or
on
the
same
raw
agricultural
commodity
and
its
products
thereof,
the
total
amount
of
such
residues
shall
not
yield
more
residue
than
that
permitted
by
the
higher
of
the
two
tolerances.
Currently,
triadimefon
and
triadimenol
do
not
share
any
uses,
so
40
CFR
§
180.3(
d)(
13)
should
be
deleted.

The
reregistration
requirements
for
plant
metabolism
have
not
been
fulfilled.
Two
triadimenol
specific
metabolism
studies
(
wheat
and
sugar
beets)
have
recently
been
submitted
and
are
currently
under
review
by
the
Agency.
Metabolism
studies
with
triadimefon
have
been
received
and
reviewed,
and
are
used
to
determine
residues
of
concern
in/
on
apples,
grapes,
pears,
pineapples,
and
raspberries.
HED
has
examined
the
results
of
these
studies
and
determined
that
the
triadimefon
residues
of
concern
in/
on
apples,
grapes,
pears,
pineapples,
and
raspberries
for
tolerance
expression
are
triadimefon
and
triadimenol
and
for
risk
assessment
are
triadimefon,
triadimenol,
KWG
1323,
and
KWG
1342.
Of
these
compounds,
triadimenol
and
KWG
1342
are
currently
regulated
in
plant
commodities.

HED
has
determined
that
translation
of
metabolism
data
from
triadimefon
to
triadimenol
is
not
appropriate
for
the
existing
uses
on
cereal
grains
and
cotton.
The
metabolism
studies
with
triadimefon
were
conducted
using
a
foliar
application
whereas
triadimenol
is
used
only
as
a
seed
treatment.
Additionally,
in
the
submitted
triadimenol
seed
treatment
wheat
study,
residues
in
grain
were
not
identifiable
due
to
the
low
activity
found
in
wheat
grain.
Therefore,
HED
concludes
that
the
nature
of
the
residue
in
cereal
grains
and
cotton
is
not
adequately
understood;
however,
based
on
chemical
structure
and
the
probable
metabolic
pathway
of
triadimenol,
the
residues
of
concern
for
tolerance
expression
and
risk
assessment
are
likely
to
be
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
cereal
grains
(
barley,
corn,
oats,
rye,
and
wheat)
and
cotton.
Separate
metabolism
studies
with
triazole
[
14C]­
and
phenyl
[
14C]­
labeled
triadimenol
applied
as
a
seed
treatment
to
corn
or
wheat
and
cotton
should
be
conducted
to
confirm
the
residues
of
concern.
The
residues
of
concern
for
tolerance
expression
and
risk
assessment
for
bananas
are
triadimenol
and
KWG
1342.

Additionally,
the
Agency
does
have
concern
about
the
potential
toxicity
of
1,2,4­
triazole
and
two
conjugates,
triazole
alanine
and
triazole
acetic
acid,
which
are
metabolites
common
to
most
of
the
triazole
fungicides.
To
support
the
reassessment
of
existing
tolerances
and
granting
of
new
tolerances
for
parent
triazole­
derivative
fungicide,
EPA
will
be
conducting
separate
human­
health
assessments
reflecting
aggregate
exposure
to
1,2,4­
triazole.

The
reregistration
requirements
for
livestock
metabolism
are
fulfilled
based
on
acceptable
goat
and
poultry
metabolism
studies
submitted
to
support
reregistration
of
triadimefon.
HED
has
determined
that
the
residues
of
concern
for
tolerance
expression
and
risk
assessment
in
livestock
commodities
are
triadimenol
and
KWG
1342.
Page
36
of
49
The
Pesticide
Analytical
Manual
(
PAM)
Vol.
II
does
not
contain
a
listing
for
triadimenol
(
February
1997
Index).
However,
the
methods
listed
for
triadimefon
can
be
used
for
the
determination
of
triadimenol,
KWG
1323,
KWG
1342,
and
KWG
1732.
PAM
lists
two
gas
chromatographic
methods
with
mass
spectrometric
detection
(
GC/
MS)
(
Methods
I
and
II)
for
the
determination
of
triadimenol
and
its
free
and
conjugated
metabolites
in
plant
and
livestock
commodities.
Both
methods
are
common
moiety
methods.
The
reported
limit
of
quantitation
(
LOQ)
is
0.05
and
limit
of
detection
(
LOD)
is
0.01
ppm
for
both
methods.

In
conjunction
with
triadimefon
reregistration,
Bayer
has
proposed
a
GC/
MS
method
(
Report
No.
106549)
for
enforcement
of
tolerances
for
residues
of
triadimefon,
triadimenol,
KWG
1342,
KWG
1323,
and
KWG
1732
in/
on
barley,
corn,
cotton,
oat,
rye,
and
wheat
commodities.
The
method
has
been
successfully
radiovalidated
and
has
undergone
independent
laboratory
validation.
The
reported
method
LOQ
is
0.05
ppm
for
each
analyte
in
cereal
grains
and
0.02
ppm
in
each
analyte
in
cotton.
Additionally,
a
GC
method
using
a
nitrogen/
phosphorus
detector
(
NPD;
Report
No.
80488)
is
available
for
determination
of
residues
of
triadimenol,
KWG
1342,
and
KWG
1323
and
is
adequate
for
the
enforcement
of
the
banana
tolerance.
The
method
has
undergone
a
successful
Agency
method
validation
on
tomatoes
and
was
submitted
to
the
FDA
for
publication
in
PAM
Vol.
II.
The
reported
method
LOQ
is
0.01
ppm
for
each
analyte.

The
reregistration
requirements
for
multiresidue
method
testing
for
residues
of
triadimenol,
KWG
1342,
and
KWG
1732
are
satisfied.

The
reregistration
requirements
for
storage
stability
data
are
not
satisfied
for
field
corn,
sweet
corn,
cotton,
and
wheat
forage,
hay,
straw,
and
processed
commodities
pending
the
results
from
the
requested
metabolism
studies.

The
reregistration
requirements
for
data
depicting
the
magnitude
of
triadimenol
residues
of
concern
in
meat,
milk,
poultry,
and
eggs
have
been
fulfilled.
Acceptable
ruminant
and
poultry
feeding
studies
have
been
submitted
and
evaluated.
Triadimenol
is
not
registered
for
use
as
a
direct
livestock
treatment.
The
nature
of
the
residue
in
livestock
is
adequately
defined
for
the
current
uses.
HED
concludes
that
the
supported
uses
on
barley,
corn,
cotton,
oats,
rye,
and
wheat
result
in
a
40
CFR
§
180.6(
a)(
3)
situation
for
ruminant
commodities;
i.
e.,
there
is
no
reasonable
expectation
of
finite
residues
in
ruminant
commodities.
Therefore,
additional
data
on
the
transfer
of
residues
to
meat,
milk,
poultry,
and
eggs
are
not
required
and
all
tolerances
for
triadimenol
residues
in
livestock
commodities
should
be
revoked
pending
results
from
the
requested
corn
and
wheat
metabolism
studies.
If
foliar
uses
or
registration
on
additional
major
livestock
feed
items
are
requested,
then
triazole
and
phenyl­
labeled
livestock
metabolism
studies
would
be
required.
Such
data
may,
in
turn,
trigger
the
need
for
magnitude
of
the
residue
(
feeding)
studies
in
livestock.

The
reregistration
requirements
for
magnitude
of
the
residue
data
in/
on
bananas
are
fulfilled.
Additional
field
trials
conducted
with
field
corn
(
forage,
grain,
stover),
sweet
corn
(
forage,
K+
CWHR,
grain,
and
stover),
cotton
(
undelinted
seed
and
gin
byproducts),
and
wheat
(
forage,
Page
37
of
49
grain,
hay,
and
straw)
are
required
pending
the
results
from
the
requested
metabolism
studies.

The
reregistration
requirements
for
magnitude
of
the
residue
in
the
processed
commodities
of
field
corn
and
cotton
have
been
fulfilled.
A
wheat
processing
study
conducted
with
triadimenol
applied
to
wheat
as
a
seed
treatment
should
be
submitted
once
the
requested
wheat
metabolism
studies
have
been
submitted
and
reviewed.

No
data
pertaining
to
confined/
field
accumulation
of
triadimenol
residues
in
rotational
crops
have
been
submitted;
however,
confined
rotational
crop
data
for
triadimefon
have
been
submitted
and
translated.
The
reregistration
requirements
for
accumulation
in
rotational
crops
are
fulfilled,
pending
submission
of
the
requested
corn
or
wheat
and
corn
and
cotton
triazole
labeled
metabolism
studies
for
final
determination
of
the
metabolites
of
concern.
HED
has
concluded
that
limited
field
rotational
crop
studies
for
triadimenol
must
be
submitted.

A
general
summary
of
residue
chemistry
deficiencies
are
listed
below.

Regulatory
Recommendations
and
Residue
Chemistry
Deficiencies
°
Separate
metabolism
studies
with
triazole­
14C
and
phenyl­
14C
labeled
triadimenol
applied
as
a
seed
treatment
to
wheat
and
corn
should
be
conducted
to
confirm
the
residues
of
concern.

°
Storage
stability
data
for
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
field
corn,
sweet
corn,
cotton,
and
wheat
processed
commodities
are
required
pending
the
results
from
the
requested
metabolism
studies.
Storage
stability
data
for
KWG
1732
in/
on
wheat
forage,
hay,
and
straw
are
required
pending
the
results
from
the
requested
metabolism
studies.

°
Crop
field
trial
data
depicting
residues
of
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
field
corn
(
forage,
grain,
stover),
sweet
corn
(
forage,
K+
CWHR,
grain,
and
stover),
cotton
(
undelinted
seed
and
gin
byproducts),
and
wheat
(
forage,
grain,
hay,
and
straw)
grown
from
seed
treated
at
the
maximum
rate
are
required
pending
the
results
from
the
requested
metabolism
studies.

°
A
wheat
processing
study
conducted
with
triadimenol
applied
to
wheat
as
a
seed
treatment
should
be
submitted
once
the
requested
corn
or
wheat
metabolism
studies
have
been
submitted
and
reviewed.

°
Limited
field
rotational
crop
studies
for
triadimenol
must
be
submitted
pending
the
results
from
the
requested
metabolism
studies.

A
summary
of
the
triadimenol
tolerance
reassessment
and
recommended
modifications
in
commodity
definitions
is
presented
in
the
following
table:
Page
38
of
49
Table
10:
Tolerance
Reassessment
Summary
for
Triadimenol.

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

Tolerances
Established
Under
40
CFR
§
180.450
(
a)

Banana
(
whole)
1
0.2
0.2
Barley,
grain
0.05
TBD2
Barley,
straw
0.2
TBD
Corn,
forage
0.05
TBD
[
Corn,
field,
forage]
[
Corn,
sweet,
forage]

Corn,
fresh
(
including
sweet),
(
K+
CWHR)
0.05
TBD
[
Corn,
sweet,
K+
CWHR]

Corn,
grain
0.05
TBD
[
Corn,
field,
grain]
[
Corn,
pop,
grain]

Corn,
stover
0.05
TBD
[
Corn,
field,
stover]
[
Corn,
pop,
stover]
[
Corn,
sweet,
stover]

Cotton,
forage
0.02
Revoke
No
longer
considered
a
significant
livestock
feed
item.

Cotton,
undelinted
seed
0.02
TBD
Oat,
forage
2.5
TBD
Oat,
grain
0.05
TBD
Oat,
straw
0.2
TBD
Rye,
forage
2.5
TBD
Rye,
grain
0.05
TBD
Rye,
straw
0.1
TBD
Sorghum,
forage,
hay
0.05
Revoke
Bayer
does
not
intend
to
support
use
of
triadimenol
on
sorghum.

Sorghum,
grain
0.01
Revoke
Bayer
does
not
intend
to
support
use
of
triadimenol
on
sorghum.

Sorghum,
grain,
stover
0.01
Revoke
Bayer
does
not
intend
to
support
use
of
triadimenol
on
sorghum.

Wheat,
forage
2.5
TBD
Wheat,
grain
0.05
TBD
Table
10:
Tolerance
Reassessment
Summary
for
Triadimenol.

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

Page
39
of
49
Wheat,
straw
0.2
TBD
Tolerances
Established
Under
40
CFR
§
180.450
(
b)

Cattle,
fat
0.1
Revoke
The
available
data
indicate
that
tolerances
for
cattle
commodities
are
not
required.
Cattle,
meat
0.1
Cattle,
meat
byproducts
0.1
Egg
0.01
Revoke
The
available
data
indicate
that
a
tolerance
for
eggs
is
not
required.

Goat,
fat
0.1
Revoke
The
available
data
indicate
that
tolerances
for
goat
commodities
are
not
required.
Goat,
meat
0.1
Goats,
meat
byproducts
0.1
Hog,
fat
0.1
Revoke
The
available
data
indicate
that
tolerances
for
hog
commodities
are
not
required.
Hog,
meat
0.1
Hog,
meat
byproducts
0.1
Horse,
fat
0.1
Revoke
The
available
data
indicate
that
tolerances
for
horse
commodities
are
not
required.
Horse,
meat
0.1
Horse,
meat
byproducts
0.1
Milk
0.01
Revoke
The
available
data
indicate
that
a
tolerance
for
milk
is
not
required.

Poultry,
fat
0.01
Revoke
The
available
data
indicate
that
tolerances
for
poultry
commodities
are
not
required.
Poultry,
meat
0.01
Poultry,
meat
byproducts
0.01
Sheep,
fat
0.1
Revoke
The
available
data
indicate
that
tolerances
for
sheep
commodities
are
not
required.
Sheep,
meat
0.1
Sheep,
meat
byproducts
0.1
Table
10:
Tolerance
Reassessment
Summary
for
Triadimenol.

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

Page
40
of
49
Tolerances
To
Be
Proposed
Under
40
CFR
§
180.450
(
a)

Barley,
hay
None
established
TBD
Cotton,
gin
byproducts
None
established
TBD
Oat,
hay
None
established
TBD
Wheat,
hay
None
established
TBD
1.
40
CFR
§
180.450(
a)
states
that
there
are
no
U.
S.
registrations
for
banana
(
whole)
as
of
9/
22/
93.
2.
TBD
=
To
be
determined.

Codex
Harmonization
The
Codex
Alimentarius
Commission
(
Codex)
has
established
several
maximum
residue
limits
(
MRLs)
for
triadimenol
in/
on
various
raw
agricultural
commodities.
The
Codex
MRLs
are
expressed
in
terms
of
triadimenol
per
se.
The
MRLs
have
been
established
to
accommodate
triadimenol
residues
resulting
from
the
use
of
triadimefon
and/
or
triadimenol.
Compatibility
cannot
be
achieved
with
the
Codex
MRLs
because
these
levels
are
expressed
in
terms
of
triadimenol
only;
the
U.
S.
tolerances
for
plant
commodities
are
expressed
in
terms
of
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
cereal
grains
and
cotton
and
triadimenol
and
KWG
1342
in/
on
bananas.
Additionally,
all
U.
S.
livestock
tolerances
should
be
revoked.

6.1.2
Acute
and
Chronic
Dietary
Exposure
/
Risk
Dietary
risk
for
triadimenol
is
assessed
by
comparing
acute
(
one­
day)
and
chronic
dietary
exposure
estimates
(
in
mg/
kg/
day)
to
both
the
triadimenol
aPAD
and
cPAD,
with
dietary
risk
expressed
as
percentage
of
the
aPAD
and
cPAD.
Dietary
risk
is
estimated
for
the
general
U.
S.
population
and
population
sub­
groups
defined
by
sex,
age,
region,
and
ethnicity.
The
triadimenol
aPAD
(
general
population)
and
cPAD
(
all
population
subgroups)
are
both
0.0034
mg/
kg
bw/
day,
based
on
a
NOAEL
of
3.4
mg/
kg
bw/
day
and
an
uncertainty
factor
of
1,000X.

Acute
and
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
2.00
­
2.02),
which
incorporates
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
96,
98
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
(
as
consumed)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
For
chronic
exposure
Page
41
of
49
assessment,
consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups,
but
for
acute
exposure
assessment
data
are
retained
as
individual
consumption
events.
Based
on
analysis
of
the
1994­
96,
98
CSFII
consumption
data,
which
took
into
account
dietary
patterns
and
survey
respondents,
HED
concluded
that
it
is
most
appropriate
to
report
risk
for
the
following
population
subgroups:
the
general
U.
S.
population,
all
infants
(<
1
year
old),
children
1­
2,
children
3­
5,
children
6­
12,
youth
13­
19,
adults
20­
49,
females
13­
49,
and
adults
50+
years
old.

For
chronic
dietary
exposure
assessment,
an
estimate
of
the
residue
level
in
each
food
or
foodform
(
e.
g.,
orange
or
orange
juice)
being
considered
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form.
The
resulting
residue/
consumption
estimate
for
each
food/
food
form
is
summed
with
the
residue/
consumption
estimates
for
all
other
food/
food
forms
considered
to
arrive
at
a
total
(
average)
estimated
exposure.
Durations
of
chronic
exposure
vary
from
one­
year
as
represented
by
"
all
infants,"
to
lifetime
exposure
as
represented
by
the
general
U.
S.
population,
which
combines
all
population
subgroups
to
form
a
mean
exposure
value.
It
should
be
noted
that
all
parameters
of
chronic
dietary
exposure
estimates
are
averaged
values
(
i.
e.
average
food
consumption,
average
residue,
etc.).
Dietary
exposure
estimates
are
also
factored
by
the
estimated
weighted
average
usage,
or
"
percent
crop
treated"
data.

For
acute
exposure
assessments,
one­
day
food
consumption
data
are
used
on
an
individual­
byindividual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
deterministic
exposure
assessment,
or
"
matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(
i.
e.,
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(
i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.

Estimated
Drinking
Water
Concentrations
(
EDWCs)
are
used
directly
in
dietary
exposure
assessments
to
calculate
aggregate
dietary
(
food
+
water)
risk.
This
is
done
by
using
the
relevant
model
value
as
a
residue
for
drinking
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
in
estimating
the
dietary
exposure
component
in
the
triadimenol
aggregate
risk
assessment.

EDWCs
are
provided
by
OPP's
Environmental
Fate
and
Effects
Division,
and
are
incorporated
into
the
following
categories
of
the
DEEM­
FCID
 
model:
"
water,
direct,
all
sources"
and
"
water,
indirect,
all
sources."
EDWCs
for
surface
water
are
moderately
refined,
and
calculated
using
the
PRZM­
EXAMS
model.
Estimated
ground
water
concentrations
for
triadimenol
are
unrefined
and
are
calculated
using
SCI­
GROW;
however,
ground
water
concentrations
were
not
used
in
this
assessment
as
residues
in
ground
water
are
lower
than
those
in
surface
water.

EDWCs
are
calculated
from
the
use
of
triadimenol
as
a
seed
treatment
to
wheat,
corn,
and
cotton.
Page
42
of
49
The
wheat
scenario
produced
the
highest
concentrations
and
is
used
in
this
dietary
assessment.
For
the
acute
assessment,
the
30­
year
annual
peak
surface
water
concentration
of
0.000393
ppm
was
used;
for
the
chronic
dietary
assessment,
the
1
in
10
year
annual
mean
surface
water
concentration
of
0.000194
ppm
was
used.

The
acute
dietary
assessment
utilizes
anticipated
residue
estimates
for
bananas
(
based
on
available
field
trial
data)
and
existing
tolerance
level
residues
for
the
remaining
commodities.
A
DEEM
Version
7.81
default
processing
factor
for
dried
bananas,
available
data
from
processing
studies,
and
an
assumption
of
100%
crop
treated
were
also
used
in
the
assessment.
For
all
supported
commodities,
the
acute
dietary
risk
estimates
(
food
plus
drinking
water)
do
not
exceed
HED's
level
of
concern
at
the
95th
exposure
percentile
for
the
U.
S.
population
(
15%
of
the
aPAD)
and
all
population
subgroups.
The
highest
exposed
population
subgroup
is
children
1­
2
years
of
age,
at
29%
of
the
aPAD.

The
chronic
dietary
assessment
utilizes
existing
tolerance
level
residues,
the
DEEM
Version
7.81
default
processing
factor
for
dried
bananas,
available
data
from
processing
studies,
and
an
assumption
of
100%
crop
treated.
For
all
supported
commodities,
the
chronic
dietary
risk
estimates
(
food
plus
drinking
water)
do
not
exceed
HED's
level
of
concern
for
the
U.
S.
population
(
7%
of
the
cPAD)
and
all
population
subgroups.
The
highest
exposed
population
subgroup
is
children
1­
2
years
of
age,
at
23%
of
the
cPAD.
The
results
of
the
acute
and
chronic
dietary
exposure
analysis
are
reported
in
the
following
table:

Table
11:
Summary
of
Acute
and
Chronic
Dietary
(
food
+
water)
Exposure
and
Risk
for
Triadimenol.

Population
Subgroup
Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.000501
15
0.000251
7
All
Infants
(<
1
year
old)
0.000798
23
0.000469
14
Children
1­
2
years
old
0.000981
29
0.000770
23
Children
3­
5
years
old
0.000871
26
0.000610
18
Children
6­
12
years
old
0.000639
19
0.000379
11
Youth
13­
19
years
old
0.000436
13
0.000224
7
Adults
20­
49
years
old
0.000329
10
0.000188
6
Adults
50+
years
old
0.000249
7
0.000178
5
Females
13­
49
years
old
0.000318
9
0.000181
5
The
bolded
values
represent
the
highest
exposed
populations
for
each
of
the
risk
assessments.
Page
43
of
49
The
acute
and
chronic
dietary
risk
estimates
from
food
only
(
not
including
drinking
water)
are
presented
in
the
following
table,
in
order
to
illustrate
the
minimal
contribution
of
drinking
water
to
overall
dietary
risk
from
triadimenol:

Table
12:
Summary
of
Acute
and
Chronic
Dietary
(
food
only)
Exposure
and
Risk
for
Triadimenol.

Population
Subgroup
Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.000494
15
0.000247
7
All
Infants
(<
1
year
old)
0.000763
22
0.000456
13
Children
1­
2
years
old
0.000961
28
0.000764
23
Children
3­
5
years
old
0.000862
25
0.000604
18
Children
6­
12
years
old
0.000633
19
0.000375
11
Youth
13­
19
years
old
0.000428
13
0.000221
7
Adults
20­
49
years
old
0.000320
9
0.000185
5
Adults
50+
years
old
0.000240
7
0.000174
5
Females
13­
49
years
old
0.000309
9
0.000177
5
7.0
AGGREGATE
RISK
ASSESSMENT
As
part
of
the
reregistration
eligibility
decision,
the
Agency
is
required
by
the
Food
Quality
Protection
Act
to
ensure
"
that
there
is
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
pesticide
chemical
residue,
including
all
anticipated
dietary
exposures
and
other
exposures
for
which
there
is
reliable
information."
As
there
are
no
residential
uses
associated
with
triadimenol,
the
aggregate
risk
assessment
includes
exposure
from
food
and
drinking
water
only.
Acute
and
chronic
aggregate
risks
(
food
+
drinking
water)
are
below
HED's
level
of
concern
for
all
population
subgroups.

Exposure
to
triadimenol
can
occur
following
the
application
of
triadimenol
as
an
active
ingredient
as
well
as
from
the
metabolism/
degradation
of
triadimefon.
The
current
risk
assessment
only
addresses
the
use
of
triadimenol
as
an
active
ingredient
per
se.
Exposures
from
the
pesticidal
uses
of
triadimenol
have
not
been
aggregated
with
triadimenol
exposures
reflecting
metabolism
and/
or
degradation
of
triadimefon
because
risks
attributable
to
uses
of
triadimefon
already
exceed
HED's
level
of
concern
and
because
the
resulting
apparent
increase
in
aggregate
risk
would
unduly
be
associated
with
the
registered
uses
of
triadimenol.
The
Agency
is
soliciting
comments
on
assumptions
used
in
the
current
risk
assessment.
Should
refinements
be
possible
in
the
future,
it
Page
44
of
49
may
be
appropriate
to
aggregate
multiple
routes
and
sources
of
exposures
for
these
chemicals.

At
this
time
the
Agency
has
decided
not
to
aggregate
the
exposures
resulting
from
the
independent
use
of
these
two
chemicals.
This
decision
not
to
aggregate
was
based
on
the
risks
associated
with
the
use
of
triadimefon,
as
the
risk
from
triadimefon
already
exceed
the
Agency's
level
of
concern
by
itself.
Furthermore,
the
Agency
feels
that
aggregating
the
metabolite
triadimenol
exposures
from
use
of
triadimefon
with
the
exposures
resulting
from
the
use
of
triadimenol
would
not
allow
for
the
proper
evaluation
of
the
use
of
triadimenol
active
ingredient
products.
Should
refinements
be
possible
in
the
future,
it
may
be
possible
and
appropriate
to
aggregate
multiple
routes
and
sources
of
exposures
for
these
chemicals.

8.0
CUMULATIVE
RISK
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
triadimenol
and
any
other
substances.
For
the
purposes
of
this
action,
therefore,
EPA
has
not
assumed
that
triadimenol
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
HUMAN
INCIDENT
DATA
REVIEW
The
following
data
bases
were
consulted
for
the
poisoning
incident
data
on
triadimefon/
triadimenol:

1)
OPP
Incident
Data
System
(
IDS):
reports
of
incidents
from
various
sources,
including
registrants,
other
federal
and
state
health
and
environmental
agencies
and
individual
consumers,
submitted
to
OPP
since
1992.

2)
Poison
Control
Centers:
as
the
result
of
a
data
purchase
by
EPA,
OPP
received
Poison
Control
Center
data
covering
the
years
1993
through
1998
for
all
pesticides.
Most
of
the
national
Poison
Control
Centers
(
PCCs)
participate
in
a
national
data
collection
system,
the
Toxic
Exposure
Surveillance
System
which
obtains
data
from
about
65­
70
centers
at
hospitals
and
universities.
PCCs
provide
telephone
consultation
for
individuals
and
health
care
providers
on
suspected
poisonings,
involving
drugs,
household
products,
pesticides,
etc.

There
were
nine
reports
of
occupational
exposure
to
triadimefon/
triadimenol
and
46
nonoccupational
exposures
from
1993
through
2003.
There
were
just
two
exposures
reported
from
Page
45
of
49
any
type
of
exposure
to
triadimefon/
triadimenol,
but
neither
had
medical
outcome
recorded
or
required
medical
care.
Of
the
46
non­
occupational
exposures,
13
occurred
in
children
under
six
years
of
age.
Of
the
total
20
cases
with
medically
determined
outcome,
11
reported
minor
medical
outcome.
Of
the
total
54
exposures
to
triadimefon/
triadimenol,
just
four
were
seen
in
a
health
care
facility
and
none
required
hospitalization.
A
review
of
symptoms
revealed
almost
exclusively
irritation
effects
(
including
rash
and
erythema)
to
skin,
mouth,
throat,
and
eyes.
These
effects
were
reported
a
total
of
24
times
with
some
patients
reporting
two
or
more
of
these
symptoms.
There
were
four
cases
reporting
headache
and
two
reported
cough.
No
other
significant
symptoms
were
reported.

3)
California
Department
of
Pesticide
Regulation:
California
has
collected
uniform
data
on
suspected
pesticide
poisonings
since
1982.
Physicians
are
required,
by
statute,
to
report
to
their
local
health
officer
all
occurrences
of
illness
suspected
of
being
related
to
exposure
to
pesticides.
The
majority
of
the
incidents
involve
workers.
Information
on
exposure
(
worker
activity),
type
of
illness
(
systemic,
eye,
skin,
eye/
skin
and
respiratory),
likelihood
of
a
causal
relationship,
and
number
of
days
off
work
and
in
the
hospital
are
provided.

The
majority
of
triadimefon/
triadimenol
incidents
(
92%)
occurred
prior
to
1990.
Most
of
the
triadimefon/
triadimenol
cases
(
73%)
involved
use
on
grapes
which
is
a
labor
intensive
crop
involving
high
exposure
to
foliar
residues.
Foliar
residues
accounted
for
half
of
the
illnesses
and
nearly
half
of
the
systemic
illnesses.
Although
most
of
the
symptoms
appeared
to
be
minor,
skin
and
eye
irritation,
and
rash
were
among
the
most
common
topical
symptoms.
The
most
common
systemic
effects
included
nausea,
headache,
sneezing,
congestion,
difficulty
breathing
and
other
allergic­
type
reactions.
There
were
three
reports
of
vomiting.

4)
National
Pesticide
Information
Center
(
NPIC):
NPIC
is
a
toll­
free
information
service
supported
by
OPP.
A
ranking
of
the
top
200
active
ingredients
for
which
telephone
calls
were
received
during
calendar
years
1984­
1991,
inclusive
has
been
prepared.
The
total
number
of
calls
was
tabulated
for
the
categories
human
incidents,
animal
incidents,
calls
for
information,
and
others.

On
the
list
of
the
top
200
chemicals
for
which
NPIC
received
calls
from
1984­
1991
inclusively,
triadimefon/
triadimenol
was
not
reported
to
be
involved
in
human
incidents.

5)
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR)
performs
standardized
surveillance
in
seven
states
from
1998
through
2002.
States
included
in
this
reporting
system
are
Arizona,
California,
Florida,
Louisiana,
Michigan,
New
York,
Oregon,
Texas,
and
Washington.
Reporting
is
very
uneven
from
state
to
state
because
of
the
varying
cooperation
from
different
sources
of
reporting
(
e.
g.,
workers
compensation,
Poison
Control
Centers,
emergency
departments
and
hospitals,
enforcement
investigations,
private
physicians,
etc.).
Therefore,
these
reports
should
not
be
characterized
as
estimating
the
total
magnitude
of
poisoning.
The
focus
is
on
occupationallyrelated
cases
not
residential
or
other
non­
occupational
exposures.
However,
the
information
Page
46
of
49
collected
on
each
case
is
standardized
and
categorized
according
the
certainty
of
the
information
collected
and
the
severity
of
the
case.

Out
of
5,899
reported
cases
from
1998­
2003,
one
involved
triadimefon/
triadimenol.
However,
this
case
was
a
duplicate
of
a
California
case
included
in
the
discussion
above.

Conclusion:
Both
California
and
Poison
Control
Center
data
show
a
clear
pattern
of
irritative,
but
usually
minor
symptoms
from
exposure
to
triadimefon/
triadimenol.
Irritation
to
skin,
eyes,
and
respiratory
passage
occur
readily
among
unprotected
handlers
(
applicators
and
mixer/
loaders)
and
among
those
who
have
substantial
contact
with
foliage
such
as
grape
harvesters
and
tenders.
It
was
unclear
whether
triadimefon/
triadimenol
might
also
be
a
sensitizer,
contributing
to
allergictype
reactions.

10.0
DATA
REQUIREMENTS
Product
Chemistry:
°
OPPTS
Guideline
830.6313
°
OPPTS
Guideline
830.7000
°
OPPTS
Guideline
830.7050
°
OPPTS
Guideline
830.7550,
830.7560,
or
830.7570
°
OPPTS
Guideline
830.7840
or
830.7860
Residue
Chemistry:
°
Separate
metabolism
studies
with
triazole­
14C
and
phenyl­
14C
labeled
triadimenol
applied
as
a
seed
treatment
to
wheat
and
corn
should
be
conducted
to
confirm
residues
of
concern.
°
Storage
stability
data
for
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
field
corn,
sweet
corn,
cotton,
and
wheat
processed
commodities
are
required
pending
the
results
from
the
requested
metabolism
studies.
Storage
stability
data
for
KWG
1732
in/
on
wheat
forage,
hay,
and
straw
are
required
pending
the
results
from
the
requested
metabolism
studies.
°
Crop
field
trial
data
depicting
residues
of
triadimenol,
KWG
1342,
and
KWG
1732
in/
on
field
corn
(
forage,
grain,
stover),
sweet
corn
(
forage,
K+
CWHR,
grain,
and
stover),
cotton
(
undelinted
seed
and
gin
byproducts),
and
wheat
(
forage,
grain,
hay,
and
straw)
grown
from
seed
treated
at
the
maximum
rate
are
required
pending
the
results
from
the
requested
metabolism
studies.
°
A
wheat
processing
study
conducted
with
triadimenol
applied
to
wheat
as
a
seed
treatment
should
be
submitted
once
the
requested
corn
or
wheat
metabolism
studies
have
been
submitted
and
reviewed.
°
Limited
field
rotational
crop
studies
for
triadimenol
must
be
submitted
pending
the
results
from
the
requested
metabolism
studies.

Toxicology:
Page
47
of
49
°
Acute
and
subchronic
neurotoxicity
studies
with
triadimenol
are
required.
Page
48
of
49
REFERENCES:

Samuel
Ary.
Triadimenol:
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
DP
Barcode
D314928.
November
18,
2005.

Samuel
Ary.
Triadimenol:
Summary
of
Analytical
Chemistry
and
Residue
Data
for
the
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document.
DP
Barcode
D314891.
November
17,
2005.

Yvonne
Barnes.
Summary
of
Product
Chemistry
Data
for
Tolerance
Reassessment
(
TRED)
Document.
DP
Barcode
D315152.
November
22,
2005.

James
Breithaupt.
TRED
for
Triadimenol
Drinking
Water
Assessment.
DP
Barcode
D312519.
February
9,
2005.
Page
49
of
49
APPENDIX
The
requirements
(
40
CFR
158.340)
for
food
for
Triadimenol
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Test
Technical
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
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
no
no
yes
yes
yes
yes
no
no
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
yes
no
yes
yes
no
yes
no
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­
­
no
no
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
n/
a
n/
a
n/
a