Document ID: EPA-HQ-OPP-2005-0258-0014
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-02-15T05:00Z

1
of
94
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
February
7,
2006
MEMORANDUM
SUBJECT:
1,2,4­
Triazole,
Triazole
Alanine,
Triazole
Acetic
Acid:
Human
Health
Aggregate
Risk
Assessment
in
Support
of
Reregistration
and
Registration
Actions
for
Triazole­
derivative
Fungicide
Compounds.
Risk
Assessment
Type:
Single
Chemical
Aggregate
PC
Code:
600074
 
1,2,4­
Triazole
600011
 
Triazole
Alanine
600082
 
Triazole
Acetic
Acid
DP
Number:
322215
FROM:
Michael
Doherty,
Ph.
D.,
Chemist,
RAB
2;
Kathleen
Raffaele,
Ph.
D.,
Toxicologist,
RAB
3;
Kit
Farwell,
DVM,
Toxicologist,
RRB
1;
Steve
Dapson,
Ph.
D.,
Branch
Senior
Scientist,
RAB
3;
Kelly
Schumacher,
M.
S.,
Toxicologist,
RAB
2;
Jack
Arthur,
Environmental
Health
Scientist,
RAB
3;
David
Hrdy,
Biologist,
CEB;
Health
Effects
Division
(
7509C)

Iwona
Maher,
Chemist,
ERB
1
Environmental
Fate
and
Effects
Division
(
7507C)

THROUGH:
Richard
Loranger,
Ph.
D.,
Branch
Senior
Scientist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

TO:
Tamue
Gibson/
Cynthia
Giles­
Parker,
FB
Registration
Division
(
7505C)

Michael
Goodis,
RRB
3
Special
Review
and
Reregistration
Division
(
7508C)

Susan
Lewis,
RRB
1
Special
Review
and
Reregistration
Division
(
7508C)
2
of
94
Table
of
Contents
1.0
Executive
Summary.....................................................................................................
5
Preface
and
General
Information.................................................................................................
7
2.0
Chemical
Profile..........................................................................................................
8
2.1
Summary
of
Registered/
Proposed
Uses
Considered
in
These
Assessments
..............
8
3.0
Metabolism
Assessment
............................................................................................
12
3.1
Comparative
Metabolic
Profile
..............................................................................
12
1,2,4­
Triazole
...........................................................................................................................
13
4.0
Hazard
Characterization/
Assessment
.........................................................................
13
4.1
Hazard
Characterization.........................................................................................
13
4.2
FQPA
Hazard
Considerations
................................................................................
17
4.2.1
Adequacy
of
the
Toxicity
Data
Base
..............................................................
17
4.2.2
Evidence
of
Neurotoxicity..............................................................................
17
4.2.3
Developmental
Toxicity
Studies.....................................................................
18
4.2.4
Reproductive
Toxicity
Study..........................................................................
18
4.2.5
Additional
Information
from
Literature
Sources.............................................
18
4.2.6
Pre­
and/
or
Postnatal
Toxicity.........................................................................
18
4.2.6.1
Determination
of
Susceptibility..................................................................
18
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Postnatal
Susceptibility
....................................................................................................
19
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study..................................
19
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study..........
20
4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study....
20
4.3.2.1
Rationale
for
the
UFDB
(
when
a
DNT
is
recommended)..............................
21
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
..........................................
21
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49........................................
21
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population.......................................
21
4.4.3
Chronic
Reference
Dose
(
cRfD).....................................................................
21
4.4.4
Incidental
Oral
Exposure
(
Short­
Term)
..........................................................
22
4.4.5
Incidental
Oral
Exposure
(
Intermediate­
Term)
...............................................
22
4.4.6
Dermal
Absorption.........................................................................................
22
4.4.7
Dermal
and
Inhalation
Exposure
(
Short­
Term)...............................................
23
4.4.8
Dermal
and
Inhalation
Exposure
(
Intermediate­
and
Long­
Term)...................
23
4.4.9
Margins
of
Exposure
and
Levels
of
Concern..................................................
23
4.4.10
Recommendation
for
Aggregate
Exposure
Risk
Assessments.........................
23
4.4.11
Classification
of
Carcinogenic
Potential
.........................................................
24
4.5
Special
FQPA
Safety
Factor
..................................................................................
25
4.6
Endocrine
disruption..............................................................................................
26
5.0
Public
Health
Data.....................................................................................................
27
6.0
Exposure
Characterization/
Assessment......................................................................
27
6.1
Dietary
Exposure/
Risk
Pathway.............................................................................
27
6.1.1
Residue
Profile
..............................................................................................
27
6.1.1.1
Residues
in
Food........................................................................................
27
3
of
94
6.1.1.2
Residues
in
Water
......................................................................................
32
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk...............................................
32
6.2
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway.......................................
34
6.2.1
Home
Uses
....................................................................................................
34
6.2.1.1
Application
Scenarios
................................................................................
34
6.2.1.2
Postapplication
Scenarios...........................................................................
37
6.2.2
Recreational
Use
Sites
...................................................................................
40
6.2.3
Other
(
Spray
Drift,
etc.)
.................................................................................
40
6.2.4
Pharmaceutical
Uses
......................................................................................
41
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
............................................
41
7.1
Short­
term
Aggregate
Risk
....................................................................................
42
7.2
Intermediate­
term
Aggregate
Risk
.........................................................................
42
8.0
Cumulative
Risk
Characterization/
Assessment
..........................................................
43
9.0
Occupational
Exposure/
Risk
Pathway........................................................................
44
10.0
Data
Needs
and
Label
Requirements
.........................................................................
44
10.1
Toxicology
............................................................................................................
44
10.2
Residue
Chemistry.................................................................................................
44
10.3
Occupational
and
Residential
Exposure
.................................................................
44
11.0
Hazard
Characterization/
Assessment
............................................................................
45
11.1
Hazard
Characterization.........................................................................................
45
11.1.1
Database
Summary
........................................................................................
45
11.1.1.1
Studies
available
and
considered
...............................................................
45
11.1.1.2
Mode
of
action,
metabolism,
and
toxicokinetic
data
..................................
45
11.1.1.3
Sufficiency
of
studies/
data
........................................................................
46
11.1.2
Toxicological
Effects
.....................................................................................
47
11.1.2.1
Acute
toxicity
..............................................................................................
47
11.1.2.2
Subchronic,
Chronic,
and
Other
Toxicity
....................................................
48
11.1.3
Dose­
Response
..............................................................................................
51
11.2
FQPA
Hazard
Considerations
................................................................................
61
11.2.1
Adequacy
of
the
Toxicity
Data
Base
..............................................................
61
11.2.2
Evidence
of
Neurotoxicity..............................................................................
61
11.2.3
Developmental
Toxicity
Studies.....................................................................
62
11.2.3.1
Developmental
Toxicity
Study
in
Rats
......................................................
62
11.2.3.2
Developmental
Toxicity
Study
in
Rabbits
.................................................
62
11.2.4
Reproductive
Toxicity
Study..........................................................................
62
11.2.5
Additional
Information
from
Literature
Sources.............................................
63
11.2.6
Pre­
and/
or
Postnatal
Toxicity.........................................................................
63
11.2.6.1
Determination
of
Susceptibility.................................................................
63
11.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre­
and/
or
Postnatal
Susceptibility..............................................................................................
63
11.3
Recommendation
for
a
Developmental
Neurotoxicity
Study..................................
64
11.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
Study.........
64
11.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
Study...
64
11.3.2.1
Rationale
for
the
UFDB
..............................................................................
64
11.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
..........................................
64
11.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
(
13
to
49
years
of
age)
....................
64
4
of
94
11.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population.......................................
65
11.4.3
Chronic
Reference
Dose
(
cRfD).....................................................................
65
11.4.4
Incidental
Oral
Exposure................................................................................
66
11.4.5
Dermal
Absorption.........................................................................................
66
11.4.6
Dermal
Exposure
(
Short­,
Intermediate­,
and
Long­
term)...............................
66
11.4.7
Inhalation
Exposure
(
Short­,
Intermediate­,
and
Long­
term)...........................
66
11.4.8
Margins
of
Exposure
and
Levels
of
Concern..................................................
66
11.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments.........................
67
11.4.10
Classification
of
Carcinogenic
Potential
.....................................................
67
11.5
Special
FQPA
Safety
Factor
..................................................................................
67
11.6
Endocrine
Disruption.............................................................................................
69
12.0
Public
Health
Data.....................................................................................................
69
13.0
Exposure
Characterization/
Assessment......................................................................
69
13.1
Dietary
Exposure/
Risk
Pathway.............................................................................
69
13.1.1
Residue
Profile
..............................................................................................
69
13.1.1.1
Residues
in
Food.......................................................................................
69
13.1.1.2
Residues
in
Drinking
Water
......................................................................
71
13.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk...............................................
72
13.2
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway.......................................
72
14.0
Aggregate
Risk
Assessments
and
Risk
Characterization
............................................
72
15.0
Cumulative
Risk
Characterization/
Assessment
..........................................................
72
16.0
Occupational
Exposure/
Risk
Pathway........................................................................
73
17.0
Data
Needs
and
Label
Requirements
.........................................................................
73
17.1
Toxicology
............................................................................................................
73
17.2
Residue
Chemistry.................................................................................................
73
17.3
Occupational
and
Residential
Exposure
.................................................................
73
References
................................................................................................................................
73
Attachment
1:
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
...........................
75
Attachment
2:
Second
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
...............
82
Attachment
3:
Triazole
Summaries
­
Additional
Data
Summaries/
Literature
Articles...............
87
5
of
94
1.0
Executive
Summary
The
Office
of
Pesticide
Program's
Health
Effects
Division
(
HED)
has
conducted
aggregate
human
health
risk
assessments
for
1,2,4­
triazole
and
triazole
conjugates
(
triazole
alanine
and
triazole
acetic
acid).
These
assessments
include
evaluation
of
risks
for
various
population
subgroups,
including
those
comprised
of
infants
and
children.
1,2,4­
Triazole
and
its
conjugates
are
common
metabolites
to
the
class
of
compounds
know
as
the
triazoles
(
a.
k.
a.
triazolederivative
fungicides,
T­
D
fungicides,
conazoles).
These
compounds
all
have
a
triazole
ring
with
nitrogen
atoms
at
the
1,
2,
and
4
positions.
In
2000,
the
Agency
delayed
granting
registration
of
any
new
triazole
pesticides
or
new
uses
of
already
registered
triazole
pesticides
pending
resolution
of
a
number
of
toxicological,
occupational/
residential,
and
dietary
exposure
concerns,
and
issued
data
call
ins
for
a
number
of
studies.
At
this
time
sufficient
data
are
available
to
support
a
risk
assessment
for
these
metabolites.
Based
on
the
toxicological
information
available
at
this
time,
HED
has
conducted
two
assessments:
one
for
1,2,4­
triazole
(
1,2,4­
T)
and
one
for
combined
exposure
to
triazole
alanine
(
TA)
and
triazole
acetic
acid
(
TAA).
Both
assessments
are
highly
conservative,
screening­
level
evaluations
in
terms
of
the
hazards
associated
with
these
compounds
(
e.
g.,
use
of
the
maximum
combination
of
uncertainty
factors)
and
potential
dietary
and
non­
dietary
exposures
(
i.
e.,
high­
end
estimates
of
both
dietary
and
non­
dietary
exposures).

Triazole
alanine
and
triazole
acetic
acid
residues
are
primarily
associated
with
plant
commodities
whereas
1,2,4­
triazole
is
associated
with
rats
and
livestock,
with
lesser
amounts
being
found
in
plants.
All
three
metabolites
may
occur
in
the
environment,
with
their
relative
proportions
depending
on
a
variety
of
environmental
conditions.
The
degree
of
formation
of
these
metabolites
in
plants,
animals,
and
the
environment
is
highly
dependent
on
the
properties
of
the
various
parent
triazole
pesticides.

Available
studies
indicate
that
1,2,4­
triazole
affects
the
central
and
peripheral
nervous
systems,
reproductive
tissues
of
both
sexes,
and
the
hematological
system.
Developmental
and
reproductive
effects
have
been
noted
for
this
compound.
Based
on
the
available
metabolism
data
from
rats
and
livestock,
1,2,4­
triazole
may
form
in
humans
following
exposure
to
parent
triazole
compounds.
In
estimating
exposures,
HED
has
included
direct
exposure
to
residues
of
1,2,4­
triazole
as
well
as
indirect
exposure
via
exposure
to
parent
triazole
pesticides
and
subsequent
conversion
to
1,2,4­
triazole.
Triazole­
derivative
fungicides
(
T­
D
fungicides)
have
registered
or
requested
uses
for
a
number
of
food
commodities
as
well
as
registered
and
proposed
uses
for
turf
and
ornamental
plantings.
HED
has
assessed
potential
dietary
and
non­
dietary
exposures.
The
assessments
are
based
on
health­
protective
assumptions
regarding
the
toxicology
of
and
exposure
to
1,2,4­
triazole.
For
all
individual
exposure
pathways
as
well
as
for
aggregate
exposure,
risk
estimates
fall
below
HED's
level
of
concern
for
all
population
subgroups.

Relative
to
triazole
alanine,
fewer
studies
are
available
depicting
the
toxicological
effects
of
the
triazole
conjugates.
For
purposes
of
this
risk
assessment,
HED
has
assumed
that
the
triazole
conjugates
are
all
toxicologically
equivalent
to
triazole
alanine.
The
available
studies
found
developmental
skeletal
effects,
decreased
body
weight
and
body
weight
gain,
and
decreased
leukocytes
and
triglycerides.
The
triazole
conjugates
are
generally
not
found
in
animal
metabolism
studies;
therefore,
HED
has
only
assessed
the
direct
exposure
to
these
compounds.
Furthermore,
residues
of
TA
and
TAA
are
formed,
and
remain,
within
plant
structures,
making
6
of
94
them
unavailable
for
dermal
or
hand­
to­
mouth
exposures.
Therefore,
HED
has
assessed
exposure
to
the
triazole
conjugates
for
the
dietary
pathway
only.
Exposure
estimates
for
the
triazole
conjugates
indicate
that
risk
associated
with
these
compounds
is
below
HED's
level
of
concern.
The
exposure
estimates
are
based
on
health­
protective
assumptions
regarding
residues
of
the
triazole
conjugates.

Based
on
the
available
information
and
on
conservative
estimates
of
hazard
and
exposure,
there
are
no
human
health
risk
issues
associated
with
1,2,4­
triazole
or
its
metabolites
that
would
preclude
re­
registration
of
the
triazole­
derivative
fungicides
registered
to
date
or
conditional
registration
of
the
triazole­
derivative
fungicide
uses
that
have
been
proposed
as
of
September
1,
2005.
HED
recommends
that
resolution
of
the
following
issues
be
a
condition
of
registration
for
new
uses
and
new
active
ingredients.

 
Chemistry:
­
Final
two­
year
storage
stability
study
with
1,2,4­
triazole;
­
Resolution
of
concerns
regarding
the
prevalence
of
conjugated
residues
of
TA
and
the
ability
of
the
analytical
method
to
quantify
them.
 
Toxicology:
­
Free
triazole:

 
Developmental
neurotoxicity
study
in
rats;

 
Chronic
toxicity/
oncogenicity
study
in
male
rats
and
female
mice
[
This
study,
included
in
the
original
data
call­
in,
has
not
been
submitted.
A
previous
waiver
request
for
this
study
was
denied;
a
new
waiver
request
submitted
in
August,
2005,
is
under
review];

 
Acute
neurotoxicity
study
in
rats
[
This
study,
included
in
the
original
data
call­
in,
was
placed
in
reserve
pending
the
results
of
the
combined
subchronic/
neurotoxicity
study,
in
response
to
a
previous
waiver
request.
A
new
waiver
request
for
this
study
was
submitted
in
August
2005,
and
is
under
review.];
­
Triazole
alanine:

 
Developmental
toxicity
study
in
rabbits;

 
Chronic
toxicity
study
in
rats,
conducted
according
to
current
guidelines
that
include
neurobehavioral
assessments,
with
additional
neuropathology
evaluations
conducted
according
to
the
neurotoxicity
guidelines;
­
Triazole
acetic
acid:

 
Developmental
toxicity
study
in
rabbits;

 
Combined
90­
day
feeding/
neurotoxicity
study
in
rats;
 
Occupational/
Residential
Assessment:
­
None.
HED
has
agreed
to
waive
previous
requirements
for
dislodgeable
foliar
and
turftransferable
residue
studies.

New
uses
for
triazole
pesticides
should
also
be
examined
in
terms
of
potential
residues
of
1,2,4­
triazole
and
its
conjugates.
This
assessment
may
require
revision
if
new
uses
are
for
sites
not
already
addressed
by
the
current
list
of
registered
or
proposed
uses,
if
the
formation
of
the
metabolites
exceeds
the
estimates
used
herein,
or
if
required
toxicity
data
raise
concerns
not
addressed
by
the
current
risk
assessment.
7
of
94
Preface
and
General
Information
This
document
addresses
human
health
risks
associated
with
metabolites
that
are
common
to
the
class
of
compounds
know
as
triazoles.
These
compounds
all
contain
a
triazole
ring
with
nitrogen
atoms
at
the
1,2,
and
4
positions
(
Figure
1.1).
The
HED
has
identified
1,2,4­
triazole
(
1,2,4­
T)
and
its
conjugates,
triazole
alanine
(
TA),
triazole
acetic
acid
(
TAA),
triazole
pyruvic
acid,
and
triazole
lactic
acid
as
compounds
with
potentially
significant
toxicological
properties.
The
occurrence
of
triazole
pyruvic
acid
and
triazole
lactic
acid
in
metabolism
studies
is
low;
therefore,
those
two
metabolites
have
not
been
explicitly
included
in
this
risk
assessment.
In
2000
the
Agency
delayed
granting
the
registration
of
any
new
triazole­
derivative
fungicides
(
T­
D
fungicides)
or
new
uses
of
registered
T­
D
fungicides
pending
resolution
of
issues
regarding
toxicology,
dietary
exposure,
and
non­
dietary
exposure.
At
this
time,
the
HED
has
enough
information
to
proceed
with
risk
assessments
for
these
compounds,
conditional
on
submission
of
additional
toxicological
and
residue
chemistry
data
as
discussed
in
Sections
10
and
17.

This
risk
assessment
is
intended
to
serve
as
a
support
document
for
registration
and
reregistration
activities
of
the
triazole­
derivative
fungicides.
There
are
large
number
of
new
active
ingredients
and
new
uses
that
are
pending
for
this
class
of
compounds
due
to
the
five­
year
period
that
has
elapsed
since
the
Agency
noted
1,2,4­
triazole
and
its
conjugates
as
residues
of
concern.
This
assessment
takes
into
consideration
the
compounds
and
use
sites
that
are
being
evaluated
for
reregistration,
as
well
as
the
new
compounds
and
new
use
sites
that
have
been
submitted
to
the
Agency
(
as
of
9/
1/
05).
OPP
is
expecting
to
receive
a
significant
number
of
additional
new
active
ingredient
and
new
use
requests.
HED
has
designed
the
assessments
presented
herein
to
be
extremely
conservative
so
that
the
assumptions
associated
with
the
risk
estimates
will
remain
valid
for
the
majority
of
these
expected
requests.
Reexamination
of
the
risk
estimates
for
1,2,4­
triazole,
triazole
alanine,
and
triazole
acetic
acid
will
be
required:
 
For
crops
or
use
sites
that
have
not
been
included
in
the
current
established/
requested
set
of
uses
(
e.
g.,
potatoes)
 
Upon
review
of
metabolic
information
for
a
new
compound
or
a
new
use
showing
formation
of
1,2,4­
triazole,
triazole
alanine,
triazole
acetic
acid,
and/
or
labile
conjugates
that
exceeds
the
maxima
assumed
in
this
assessment.
 
Upon
review
of
the
required
toxicology
data
for
1,2,4­
triazole
and
its
conjugates
as
discussed
below.

In
examining
exposure
to
1,2,4­
triazole,
HED
has
considered
both
direct
exposure
to
this
compound
and
indirect
exposure
resulting
from
the
in­
vivo
formation
of
1,2,4­
triazole
following
exposure
to
parent
triazole­
derivative
compounds.
At
this
time,
the
degree
to
which
the
pharamcokinetics
(
PK)
and
pharamacodynamics
(
PD)
of
exogenous
1,2,4­
triazole
are
the
same
as
the
PK
and
PD
of
1,2,4­
triazole
formed
following
in
vivo
metabolism
is
unknown.
Specifically,
this
analysis
assumes
that
the
target
tissue,
the
dose
at
the
target
tissue,
and
timing
of
exposure
and
toxic
effect
are
similar
between
the
exogenous
and
internally
generated
forms
of
1,2,4­
triazole.
As
the
purpose
of
the
current
risk
assessment
is
to
provide
high­
end,
screening
level
risk
estimates,
HED
has
made
the
conservative
assumption
that
the
direct
and
indirect
exposures
can
occur
simultaneously
and
are
toxicologically
equivalent.
8
of
94
2.0
Chemical
Profile
Following
application
of
a
triazole­
derivative
fungicide,
biological
and/
or
chemical
processes
may
cause
the
triazole
ring
to
be
released
from
the
parent
compound.
In
rats
and
livestock,
1,2,4­
triazole
is
relatively
stable
and
is
the
terminal
form
of
the
triazole
ring.
In
plants,
the
1,2,4­
triazole
molecule
may
become
conjugated
to
serine.
The
resulting
compound,
triazole
alanine,
may
be
oxidized
to
form
triazole
acetic
acid.
Triazole
alanine
and
triazole
acetic
acid
are
the
primary
terminal
forms
of
the
triazole
ring
in
plants,
though
some
1,2,4­
triazole
may
remain.
All
three
compounds
were
identified
in
environmental
fate
studies
and
there
is
evidence
that
in
the
environment
there
is
significant
conversion
between
all
three
forms.
The
degree
of
formation
of
any
given
form
of
the
triazole
ring
is
highly
dependent
on
the
nature
and
properties
of
the
parent
compound.
Although
other
triazole
conjugates
such
as
triazole
lactic
acid
and
triazole
pyruvate
have
been
observed
in
plant
metabolism
studies,
HED
has
concluded
that
TA
and
TAA
are
the
predominant
conjugates
that
need
to
be
included
in
the
dietary
risk
assessment.

NH
N
N
1,2,4­
Triazole
(
a.
ka.
1,2,4­
T;
free
triazole)
CAS
No.
288­
88­
0
PC
Code:
600074
Molecular
wgt.:
69.07
N
N
N
NH2
O
OH
Triazole
Alanine
(
a.
ka.
TA)
CAS
No.
86362­
20­
1
PC
Code:
600011
Molecular
wgt.:
156.15
N
N
N
O
OH
Triazole
Acetic
Acid
(
a.
k.
a.
TAA)
CAS
No.
28711­
29­
7
PC
Code:
600082
Molecular
wgt.:
127.10
Figure
1.1.
Chemical
structures
for
1,2,4­
triazole,
triazole
alanine,
and
triazole
acetic
acid
Based
on
the
currently
available
toxicology
data,
the
toxicological
effects
of
1,2,4­
T
are
sufficiently
different
from
those
of
the
conjugates
(
TA,
TAA)
that
it
is
appropriate
to
consider
their
risks
separately.
As
such,
this
document
consists
of
two
risk
assessments,
one
for
1,2,4­
T
(
Sections
4
 
10)
and
one
for
combined
residues
of
TA
and
TAA
(
Sections
11
 
17).

We
note
that
in
conducting
these
assessments
we
have
used
maximum
metabolic
conversion
factors
and
have
not
made
an
effort
to
maintain
mass
balance
with
respect
to
residues
of
1,2,4­
T
versus
TA/
TAA.
As
a
result,
a
summation
of
the
residue
estimates
used
in
these
assessments
results
in
a
total
residue
estimate
that
may
be
greater
than
physically
possible
based
on
conservation
of
mass.

2.1
Summary
of
Registered/
Proposed
Uses
Considered
in
These
Assessments
At
this
time,
there
are
13
registered
triazole­
derivative
fungicides
with
53
uses
on
foods
and
11
uses
on
non­
foods
(
i.
e.,
ornamental
plants,
turf,
etc.).
Additionally,
the
Agency
has
been
petitioned
to
establish
registrations
for
14
triazole­
derivative
fungicides
with
69
food
uses
and
4
non­
food
uses.
This
risk
assessment
addresses
all
registered
and
requested
uses
as
of
September
1,
2005.
These
uses
are
summarized
in
Table
2.1.
9
of
94
Table
2.1.
Summary
of
Triazole­
derivative
Fungicides
and
Uses
Addressed
in
these
Risk
Assessments.

Sorted
by
Active
Ingredient
Sorted
by
Use
Site
Active
Ingredient
Use
Site
Use
Site
Active
Ingredient
Bitertanol
Banana
Fenbuconazole
Banana
Myclobutanil
Ornamentals
Almond
Propiconazole
Bromuconazole
Turf
Apple
Difenoconazole
Coffee
Myclobutanil
Soybean
Artichoke
Triadimefon
Cyproconazole
Turf
Myclobutanil
Apple
Tebuconazole
Banana
Asparagus
Triadimefon
Barley
Bitertanol
Canola
Bromuconazole
Grape
Difenoconazole
Sweet
Corn
Epoxiconazole
Difenoconazole
Wheat
Fenbuconazole
Epoxiconazole
Banana
Hexaconazole
Almond
Metconazole
Banana
Myclobutanil
Blueberry
Propiconazole
Citrus
Fruit
Group
Tebuconazole
Cranberry
Tetraconazole
Grape
Banana
Triadimenol
Ornamentals
Difenoconazole
Peanut
Prothioconazole
Pecan
Tebuconazole
Pome
Fruit
Group
Barley
Triticonazole
Stone
Fruit
Group
Berry
Group
Propiconazole
Sugarbeat
Blueberry
Fenbuconazole
Turf
Propiconazole
Fenbuconazole
Wheat
Bulb
Vegetable
Group
Tebuconazole
Flusilazole
Soybean
Myclobutanil
Hexaconazole
Banana
Caneberry
Triadimefon
Cucurbit
Vegetable
Group
Difenoconazole
Ornamentals
Canola
Prothioconazole
Sweet
Corn
Carrot
Propiconazole
Ipconazole
Turf
Celery
Propiconazole
Banana
Propiconazole
Metconazole
Soybean
Cereal
Grain
Group
Triadimenol
Almond
Fenbuconazole
Artichoke
Citrus
Fruit
Group
Propiconazole
Asparagus
Cyproconazole
Myclobutanil
Banana
Coffee
Tebuconazole
10
of
94
Table
2.1.
Summary
of
Triazole­
derivative
Fungicides
and
Uses
Addressed
in
these
Risk
Assessments.

Sorted
by
Active
Ingredient
Sorted
by
Use
Site
Active
Ingredient
Use
Site
Use
Site
Active
Ingredient
Caneberry
Triadimefon
Cotton
Propiconazole
Cucurbit
Vegetable
Group
Tebuconazole
Currant/
Gooseberry
Corn
Triadimenol
Grape
Myclobutanil
Hops
Tebuconazole
Mayhaw
Cotton
Triadimenol
Ornamentals
Fenbuconazole
Peppermint/
Spearmint
Cranberry
Propiconazole
Peppers
Ipconazole
Pome
Fruit
Group
Myclobutanil
Snap
Bean
Cucurbit
Vegetable
Group
Tebuconazole
Stone
Fruit
Group
Myclobutanil
Strawberry
Currant/
Gooseberry
Propiconazole
Sugar
Beet
Prothioconazole
Tomato
Dry
Bean
and
Pea
Group
Tebuconazole
Turf
Difenoconazole
Ornamentals
Fenbuconazole
Paclobutrazol
Turf
Myclobutanil
Almond
Tebuconazole
Banana
Grape
Triadimefon
Berry
Group
Propiconazole
Bulb
Vegetable
Group
Grass
Grown
for
Seed
Tebuconazole
Carrot
Myclobutanil
Celery
Hops
Tebuconazole
Cereal
Grain
Group
Lychee
Tebuconazole
Citrus
Fruit
Group
Mango
Tebuconazole
Corn
Myclobutanil
Cranberry
Mayhaw
Triadimefon
Currant/
Gooseberry
Oats
Tebuconazole
Grass
Grown
for
Seed
Okra
Tebuconazole
Ornamentals
Bromuconazole
Peanut
Fenbuconazole
Pecan
Ipconazole
Pineapple
Myclobutanil
Pistachio
Paclobutrazole
Sorghum
Propiconazole
Soybean
Tebuconazole
Stone
Fruit
Group
Ornamentals
Triadimefon
Strawberry
Fenbuconazole
Sugar
Beet
Propiconazole
Propiconazole
Sugarcane
Peanut
Prothioconazole
11
of
94
Table
2.1.
Summary
of
Triazole­
derivative
Fungicides
and
Uses
Addressed
in
these
Risk
Assessments.

Sorted
by
Active
Ingredient
Sorted
by
Use
Site
Active
Ingredient
Use
Site
Use
Site
Active
Ingredient
Turf
Tebuconazole
Wild
Rice
Tetraconazole
Barley
Fenbuconazole
Canola
Pecan
Propiconazole
Dry
Bean
and
Pea
Group
Peppermint/
Spearmint
Myclobutanil
Peanut
Peppers
Myclobutanil
Rice
Propiconazole
Soybean
Pineapple
Triadimefon
Prothioconazole
Wheat
Propiconazole
Asparagus
Pistachio
Tebuconazole
Banana
Fenbuconazole
Barley
Myclobutanil
Bulb
Vegetable
Group
Tebuconazole
Coffee
Pome
Fruit
Group
Triadimefon
Corn
Rice
Prothioconazole
Cotton
Snap
Bean
Myclobutanil
Cucurbit
Vegetable
Group
Propiconazole
Dry
Bean
and
Pea
Group
Sorghum
Triadimenol
Grape
Cyproconazole
Grass
Grown
for
Seed
Flusilazole
Hops
Metconazole
Lychee
Propiconazole
Mango
Prothioconazole
Oats
Tebuconazole
Okra
Soybean
Tetraconazole
Ornamentals
Fenbuconazole
Peanut
Myclobutanil
Pistachio
Propiconazole
Pome
Fruit
Group
Stone
Fruit
Group
Tebuconazole
Soybean
Myclobutanil
Stone
Fruit
Group
Strawberry
Propiconazole
Sunflower
Myclobutanil
Tree
Nuts
Group
Propiconazole
Turf
Tetraconazole
Turnip
Sugar
Beet
Fenbuconazole
Tebuconazole
Wheat
Sugarcane
Propiconazole
Banana
Sunflower
Tebuconazole
Peanut
Difenoconazole
Soybean
Sweet
Corn
Ipconazole
Sugar
Beet
Tomato
Myclobutanil
Tetraconazole
Turf
Tree
Nuts
Group
Tebuconazole
Triadimefon
Artichoke
Turf
Bromuconazole
12
of
94
Table
2.1.
Summary
of
Triazole­
derivative
Fungicides
and
Uses
Addressed
in
these
Risk
Assessments.

Sorted
by
Active
Ingredient
Sorted
by
Use
Site
Active
Ingredient
Use
Site
Use
Site
Active
Ingredient
Asparagus
Cyproconazole
Caneberry
Fenbuconazole
Coffee
Ipconazole
Grape
Myclobutanil
Mayhaw
Paclobutrazole
Ornamentals
Propiconazole
Pineapple
Tebuconazole
Pome
Fruit
Group
Tetraconazole
Turf
Triadimefon
Banana
Triticonazole
Cereal
Grain
Group
Turnip
Tebuconazole
Corn
Difenoconazole
Cotton
Fenbuconazole
Triadimenol
Sorghum
Prothioconazole
Barley
Tebuconazole
Turf
Wheat
Triticonazole
Triticonazole
Wheat
Wild
Rice
Propiconazole
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
1,2,4­
Triazole;
triazole
alanine;
and
triazole
acetic
acid
are
common
metabolites
to
the
class
of
compounds
known
as
triazoles.
In
plants,
1,2,4­
T
is
rapidly
conjugated
with
serine
to
form
TA.
The
TA
can
then
be
oxidized
to
form
TAA.
The
extent
to
which
1,2,4­
T,
TA,
and/
or
TAA
forms
in
a
given
plant
or
animal
is
primarily
dependent
on
the
parent
triazole­
derivative
fungicide.
Across
the
various
parent
compounds,
maximum
formation
of
1,2
4­
T
in
plants
ranges
from
0%
of
the
total
radioactive
residue
(
TRR)
to
17%
TRR,
with
the
majority
of
compounds
yielding
1,2,4­
T
at
around
5­
10%
TRR.
In
rats,
goats,
and
hens,
maximum
1,2,4­
T
formation
ranges
from
0
to
77%
TRR.
Formation
of
1,2,4­
T
in
the
rat
is
less
than
20%
TRR
for
the
majority
(
approximately
80%)
of
the
triazole­
derivative
fungicides
for
which
data
are
available.
Formation
of
TA
ranges
from
0
to
89%
TRR
in
plants.
Triazole
acetic
acid
formation
in
plants
ranges
from
0
to
76%
TRR.
Triazole
alanine
and
triazole
acetic
acid
have
generally
not
been
found
to
be
significant
metabolites
in
rats,
lactating
goats,
or
laying
hens.
The
exception
to
this
appears
to
be
fenbuconazole.
In
studies
with
radio­
labeled
fenbuconazole
fed
to
goats
and
hens,
TA
formation
ranges
from
0
to
35%
TRR;
formation
of
TA
from
fenbuconazole
was
not
noted
in
the
rat
metabolism
studies.
There
is
evidence
from
toxicological
studies
that
there
can
be
limited
reduction
of
TA
to
1,2,4­
T
following
oral
exposure
to
TA.

In
environmental
fate
studies,
all
three
forms
of
triazole
(
1,2,4­
T,
TA,
and
TAA)
have
been
found
and
there
is
evidence
that
the
three
can
inter­
convert
in
soil
and
aquatic
systems.
At
this
time,
there
are
not
reliable
data
available
for
making
general
descriptions
about
the
relative
rates
of
formation
of
these
compounds
or
any
steady­
state
equilibria
that
may
occur.
13
of
94
1,2,4­
Triazole
4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
1,2,4­
triazole
(
free
triazole)
is
a
metabolite
common
to
a
number
of
triazole­
derivative
pesticides,
and
is
found
in
both
mammalian
(
rat)
and
plant
metabolism
studies.
Although
for
most
pesticides,
mammals
convert
only
a
small
proportion
to
free
triazole
(
less
than
25%),
two
compounds
(
tetraconazole
and
flusilazole)
demonstrate
relatively
high
conversion
(
68­
77%)
in
rat
metabolism
studies.
As
a
plant
metabolite,
and
given
the
wide
use
of
triazole­
derivative
pesticides
(
used
as
fungicides
on
many
crops
as
well
as
on
turf)
free
triazole
is
found
in
a
variety
of
food
commodities,
including
animal
byproducts.
1,2,4­
triazole
appears
to
be
relatively
stable
in
the
environment,
and
may
be
found
in
rotational
crops
as
well
as
in
water.

The
available
toxicology
database
for
1,2,4­
triazole
consists
of
2
developmental
toxicity
studies
(
in
rats
and
rabbits),
a
reproductive
toxicity
study
(
in
rats),
a
combined
subchronic/
neurotoxicity
study
(
in
rats),
and
28­
and
90­
day
toxicity
studies
in
mice.
Two
additional
non­
guideline
studies
in
rats
(
a
30­
day
gavage
study
and
an
unacceptable
90­
day
subchronic
study)
provide
limited
additional
information.
No
reliable
data
are
available
for
dogs
(
an
incomplete
study
examining
ocular
toxicity
only
was
submitted,
but
included
very
limited
procedural
information),
and
no
chronic
or
oncogenicity
studies
have
been
submitted.
Although
limited
chronic
toxicity
data
(
chronic
toxicity/
oncogenicity
studies
in
male
rats
and
female
mice)
were
called
in
by
RD
in
2002
(
see
TXR
#
0052011),
these
studies
have
not
been
conducted
and
a
new
request
to
waive
those
studies
has
been
recently
submitted
(
August
2005).
HED
has
not
yet
completed
an
evaluation
of
the
request
and,
to
date,
the
data
requirement
remains.
A
previous
waiver
request,
submitted
by
USTTF
in
March
2003
[
DP
Barcode
289197],
was
reviewed
by
an
HED
peer
review
committee
in
June
2003,
and
was
denied
[
see
attached
memorandum,
August
5,
2003,
K.
Raffaele
to
Bob
Tomerlin,
TXR#
0052012].

Available
unacceptable
metabolism
studies
indicate
that
1,2,4­
triazole
is
rapidly
absorbed
after
oral
administration
and
widely
distributed
in
all
evaluated
tissues.
Excretion
occurs
mostly
via
the
urine,
largely
as
unchanged
parent
(
80­
95%),
although
biliary
canulation
results
suggest
the
possibility
of
some
enterohepatic
recirculation.
With
an
estimated
half­
life
of
8­
10
hours,
excretion
is
largely
completed
within
48
hours
of
administration
of
a
single
dose.

Limited
acute
toxicity
data
for
1,2,4­
triazole
are
available,
but
no
complete
guideline
studies
have
been
submitted
(
Table
4.1).
Available
acute
data
indicate
that
1,2,4­
triazole
is
slightly
toxic
by
the
oral
route
(
Category
III,
with
oral
LD50
values
ranging
from
666
mg/
kg
in
rabbits
to
3650
mg/
kg
in
mice)
and
slightly
to
moderately
toxic
by
the
dermal
route
(
dermal
LD50s
were
less
than
2000
mg/
kg
in
rabbits,
and
3000­
4000
mg/
kg
in
rats).
Limited
available
information
indicates
that
1,2,4­
triazole
is
slightly
irritating
or
non­
irritating
to
the
skin,
but
severely
irritating
to
the
eye.
Based
on
the
limited
acute
toxicity
data,
as
well
as
the
available
developmental
toxicity
data
(
see
below),
it
appears
that
rabbits
may
be
substantially
more
susceptible
to
1,2,4­
triazole
than
are
rats
or
mice.
14
of
94
In
spite
of
the
limitations
of
the
available
database,
a
number
of
target
organs
and
critical
effects
have
been
identified.
1,2,4­
triazole
targets
the
nervous
system,
both
central
and
peripheral,
as
brain
lesions
(
most
notably
in
the
cerebellum)
were
seen
in
both
rats
and
mice,
and
peripheral
nerve
degeneration
was
also
seen
in
the
subchronic
neurotoxicity
study
in
rats.
In
addition,
brain
weight
decreases
were
seen
in
several
studies,
including
in
the
offspring
in
the
reproductive
toxicity
study.
In
the
subchronic/
neurotoxicity
study,
there
is
evidence
that
effects
progress
over
time,
with
an
increase
in
incidence
of
clinical
signs
(
including
tremors
and
muscle
fasciculations)
during
weeks
8
and
13
that
were
not
seen
during
earlier
evaluations.
Effects
were
also
seen
on
reproductive
organs
in
both
sexes,
most
notably
ovaries
(
in
rats)
and
testes
(
in
rats
and
mice),
in
both
the
reproductive
toxicity
and
subchronic
toxicity
studies.
Hematological
changes,
including
slightly
decreased
hemoglobin
and/
or
hematocrit,
have
also
been
seen
in
multiple
studies
and
species
(
in
rats
at
doses
of
33
mg/
kg/
day
and
above,
and
in
mice
at
doses
of
487
mg/
kg/
day
and
above).
Studies
depicting
the
effects
of
chronic
exposure
to
free
triazole
or
its
conjugates
are
not
currently
available.
A
request
to
waive
chronic/
oncogenicity
studies
has
been
received
by
the
Agency
and
is
currently
under
review.

1,2,4­
triazole
also
causes
developmental
toxicity
in
both
rats
and
rabbits,
including
malformations,
at
doses
similar
to
those
inducing
maternal
toxicity
(
decreased
body
weight
gain
in
rats
and
clinical
signs
and
mortality
in
rabbits).
Developmental
toxicity
was
also
seen
in
the
reproductive
toxicity
study,
with
offspring
showing
adverse
effects
on
multiple
endpoints
(
including
decreased
brain
and
body
weight)
at
doses
lower
than
those
at
which
effects
were
seen
in
parents.
In
addition,
reproductive
toxicity
was
seen
in
both
sexes:
at
the
highest
dose
(
3000
ppm),
only
two
F1
litters
(
one
pup/
litter)
were
produced,
and
neither
survived
to
adulthood.

No
data
are
available
to
directly
evaluate
the
potential
for
carcinogenicity
of
1,2,4­
triazole.
Available
mutagenicity
data
are
limited
(
salmonella
assays
submitted
by
the
USTTF
and
a
Russian
literature
report
(
MRID
45284011)
of
chromosomal
aberrations
in
rat
marrow
cells),
but
negative.
A
large
number
of
parent
triazole­
derivative
pesticides
have
been
classified
as
carcinogens
(
most
also
non­
mutagenic),
but
the
relevance
of
that
finding
to
expected
effects
of
free
triazole
may
be
limited.
The
types
of
tumors
associated
with
exposure
to
the
parent
chemicals
are
most
commonly
hepatocellular
adenomas/
carcinomas
in
mice.
Other
tumor
types
vary
considerably
(
including
liver
tumors,
thyroid
tumors,
ovarian
tumors,
testicular
tumors,
and
bladder
tumors).
None
of
the
tumor
types
are
clearly
associated
with
the
proportion
of
free
triazole
formed
in
available
rat
metabolism
studies.
The
previous
HED
peer
review
committee
concluded
that
it
was
not
possible
to
predict
toxicity
of
free
triazole
based
on
toxicity
seen
with
parent
compounds:
these
conclusions
and
their
rationale
are
discussed
in
the
memoranda
from
those
meetings
(
see
TXR
Nos.
0052011
and
0052012,
attached).
This
conclusion
is
supported
by
the
recently
submitted
subchronic
and
reproductive
toxicity
studies
for
free
triazole,
identifying
effects
not
consistently
seen
in
toxicity
studies
with
parent
compound
(
including
pathologic
lesions
in
the
nervous
system
and
reproductive
failure
seen
at
the
high
dose
in
the
reproductive
toxicity
study).
15
of
94
Table
4.1.
Acute
Toxicity
Profile
 
1,2,4­
Triazole.
Note
that
values
on
this
table
are
based
on
submitted
summary
data;
full
study
reports
are
not
available.
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.1100
Acute
oral
[
rat]
45284004,
45284001
LD50
=
1648­
3080
mg/
kg
III
870.1100
Acute
oral
[
mice]
45284001
LD50
=
3650
mg/
kg
III
870.1100
Acute
oral
[
rabbit]
45324301
LD50
=
666
mg/
kg
III
870.1200
Acute
dermal
[
rat]
45284004
LD50
=
3129­
4200
mg/
kg
III
870.1200
Acute
dermal
[
rabbit]
45324301,
45284006
LD50
=
<
2000
mg/
kg
II
870.1300
Acute
inhalation
[
mice]
45284011
LC50
4
h
=
2200
mg/
m3
870.1300
Acute
inhalation
[
rats]
45284011
LC50
4
h
=
2050
mg/
m3
870.2400
Acute
eye
irritation
[
rabbit]
45284004,
45324301,
45284006
severe
870.2500
Acute
dermal
irritation
[
rabbit]
45284004,
45324301,
45284006
not
irritating
to
slightly
irritating
IV
870.2600
Skin
sensitization
[
species]
No
studies
available
unknown
TABLE
4.2
Toxicity
Profile
for
1,2,4
triazole.
Gdln
Study
Type/
Classification
MRID
Number
Doses
Results
870.3050
28­
Day
oral
toxicity
in
mice
Acceptable/
nonguideline
46467301
0,
50,250,
500,
2000
ppm
M:
9,
47,
90,
356
mkd
F:
12,
60,
120,
479
mkd
NOAEL:
90
mg/
kg/
day
LOAEL:
356
mg/
kg/
day
(
male)
based
on
testicular
degeneration
870.3100
90­
Day
oral
toxicity
in
mice
Acceptable/
guideline
46467302
0,
500,
1000,
3000,
6000
ppm
M:
80,
161,
487,
988
mkd
F:
105,
215,
663,
1346
mkd
NOAEL:
80
mg/
kg/
day
LOAEL:
161
mg/
kg/
day
based
on
 
testicular
wt
and
microscopic
testicular
changes
At
487
mg/
kg/
day,
also
tremors,
 
brain
wt,
slight
hematology
changes.
At
988
mg/
kg/
day,
also
cerebellar
degeneration.
870.3050
30­
Day
oral
toxicity
in
rats
­
gavage
Acceptable/
nonguideline
45537401
0,
8,
57,
400
mg/
kg/
day
NOAEL:
<
8
mg/
kg/
day
LOAEL:
8
mg/
kg/
day
based
on
 
adrenal
wt
At
57
mg/
kg/
day,
also
slight
hematology
changes.
At
400
mg/
kg/
day,
also
clinical
signs
(
staggering,
tremors,
hunched)
 
BW
870.3100
90­
Day
oral
toxicity
in
rats
Unacceptable
45284007
0,
100,
500,
2500
ppm
M:
8,
38,
212
mg/
kg/
day
F:
10,
54,
267
mg/
kg/
day
NOAEL:
38
mg/
kg/
day
LOAEL:
212
mg/
kg/
day
based
on
 
BW,
convulsions,
fatty
infiltration
of
liver
in
males
870.3100
870.6200
90­
Day
oral
toxicity/
neurotoxicity
in
rats.
Acceptable/
guideline
46467303
0,
250,
500,
3000,
1000/
4000
ppm
M:
16,
33,
183,
210
mkd
F:
19,
41,
234,
275
mkd
NOAEL:
16
mg/
kg/
day
LOAEL:
33
mg/
kg/
day
(
male)
based
on
 
TSH
Also
at
183
mg/
kg/
day
and
above:
 
BW,
tremors
and
other
FOB,
 
brain
wt,
neuropath
in
peripheral
nerves
and
brain
(
most
prominently
cerebellum);
also
slight
 
hematology,
sl
 
CL.
870.3150
90­
day
oral
toxicity
study
in
nonrodents
­­­
­­­
No
study
available
16
of
94
TABLE
4.2
Toxicity
Profile
for
1,2,4
triazole.
Gdln
Study
Type/
Classification
MRID
Number
Doses
Results
870.3200
21/
28­
Day
dermal
toxicity
(
species)
­­­
­­­
No
study
available
870.3250
90­
Day
dermal
toxicity
(
species)
­­­
­­­
No
study
available
870.3465
90­
Day
inhalation
toxicity
(
species)
­­­
­­­
No
study
available
870.3700
Developmental
toxicity
in
rats
Acceptable/
guideline
45223401
45223402
0,
100,
200
mg/
kg/
day
0,
10,
30,
100
mg/
kg/
day
Maternal
NOAEL:
30
mg/
kg/
day
Maternal
LOAEL:
100
mg/
kg/
day
based
on
 
BW
gain
Developmental
NOAEL:
30
mg/
kg/
day
Developmental
LOAEL:
100
mg/
kg/
day
based
on
 
fetal
BW,
skeletal
variations,
undescended
testes
Also
at
200,
increased
resorptions
and
decreased
number
of
viable
fetuses,
cleft
palate,
hydronephrosis,
increased
incidence
of
major
malformations
870.3700
Developmental
toxicity
in
rabbits
Acceptable/
guideline
46492903
0,
5,
15,
30,
45
mg/
kg/
day
Maternal
NOAEL:
30
mg/
kg/
day
Maternal
LOAEL:
45
mg/
kg/
day
based
on
mortality
and
clinical
signs
( 
motor
activity,
head
tilt,
lacrimation,
drooping
eyelids,
diarrhea,
salivation)
Developmental
NOAEL:
30
mg/
kg/
day
Developmental
LOAEL:
45
mg/
kg/
day
based
on
 
fetal
wt
and
urinary
tract
malformations
870.3800
Reproduction
and
fertility
effects
Acceptable
46467304
0,
250,
500,
3000
ppm
M:
15,
31,
189
mkd
F:
18,
36,
218
mkd
Parental
NOAEL:
<
15
mg/
kg/
day
Parental
LOAEL:
15
mg/
kg/
day
(
male)
based
on
 
BW
and
BWG
in
F1
males,
 
spleen
weight
in
F1
females
At
218
mg/
kg/
day:
cerebellar
lesions,
 
brain
weight,
 
thyroid
weight,
Offspring
NOAEL:
<
19
mg/
kg/
day
Offspring
LOAEL:
19
mg/
kg/
day
based
on
 
BW,
BWG
and
brain
wt
in
F2
pups,
 
spleen
weight
in
F2
female
pups.
Repro
NOAEL:
15
mg/
kg/
day
Repro
LOAEL:
31
mg/
kg/
day
based
on
abnormal
sperm
and
 #
of
CL
in
F1
females
At
218
mg/
kg/
day,
reproductive
failure
(
no
viable
offspring),
 
CL
in
F0
parental
females
870.4100a
Chronic
toxicity
(
rodent)
­­­
­­­
No
study
available
870.4100b
Chronic
toxicity
(
dog)
­­­
­­­
No
study
available
870.4200
Carcinogenicity
(
rat)
­­­
­­­
No
study
available
870.4300
Carcinogenicity
(
mouse)
­­­
­­­
No
study
available
870.[
]
Gene
Mutation
­­­
­­­
See
attached
summaries
17
of
94
TABLE
4.2
Toxicity
Profile
for
1,2,4
triazole.
Gdln
Study
Type/
Classification
MRID
Number
Doses
Results
870.[
]
Cytogenetics
­­­
­­­
No
study
available
870.[
]
Other
Effects
­­­
­­­
No
study
available
870.6200a
Acute
neurotoxicity
screening
battery
­­­
­­­
No
study
available
870.6200b
Subchronic
neurotoxicity
screening
battery
­­­
­­­
See
combined
subchronic/
neurotoxicity
study
(
above)

870.6300
Developmental
neurotoxicity
­­­
­­­
No
study
available
870.7485
Metabolism
and
pharmacokinetics
­
rat
Unacceptable/
guideline
45284018
intraduodenal
1
mg/
kg
i.
v.
0.1
­
100
mg/
kg
oral
0.4
­
866
mg/
kg
Oral
absorption
of
80­
95%.
Excreted
in
urine
(
80­
95%)
and
feces
(<
15%),
biliary
excretion
of
10%
with
enterohepatic
recirculation.
Unchanged
triazole
accounted
for
~
95%
of
radioactivity.
870.7600
Dermal
penetration
(
species)
­­­
­­­
No
study
available
Special
studies
­­­
­­­
­­­
See
Attachment
3
4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
available
toxicity
data
base,
including
developmental
toxicity
studies
in
two
species,
a
rat
2­
generation
reproductive
toxicity
study,
and
a
subchronic/
neurotoxicity
study
in
rats,
is
adequate
to
evaluate
the
potential
for
increased
toxicity
in
infants
and
children.

4.2.2
Evidence
of
Neurotoxicity
The
available
toxicity
data
base
includes
substantial
evidence
that
exposure
to
1,2,4­
triazole
causes
neurotoxicity,
including:
neuropathological
lesions
in
the
brain
(
seen
in
the
90­
day
subchronic
toxicity
studies
in
both
mice
and
rats,
and
in
the
reproductive
toxicity
study
in
rats
[
at
doses
of
183
mg/
kg/
day
and
above]);
neuropathological
lesions
in
the
peripheral
nervous
system
(
seen
in
the
subchronic
neurotoxicity
study
in
rats
at
doses
similar
to
those
causing
brain
lesions);
and
decreases
in
brain
weight
in
several
studies
in
both
rats
and
mice
(
including
decreases
in
brain
weight
of
offspring
in
the
reproductive
toxicity
study
at
doses
not
causing
similar
effects
in
F0
parents
[
see
below]).
In
addition,
effects
indicating
potential
neurotoxicity
were
seen
in
the
FOB
and
motor
activity
evaluations
in
the
subchronic
neurotoxicity
study
in
rats
(
including
tremors,
muscle
fasciculations,
decreased
arousal,
decreased
rearing,
and
decreased
motor
activity
[
at
doses
similar
to
those
causing
brain
lesions]),
and
in
the
developmental
toxicity
study
in
rabbits
(
decreased
motor
activity,
excessive
salivation,
hyperpnea,
lacrimation,
and
head
tilt
[
seen
in
does
at
doses
of
45
mg/
kg/
day
and
above]).
18
of
94
4.2.3
Developmental
Toxicity
Studies
There
is
evidence
of
developmental
toxicity
in
available
studies
in
rats
and
rabbits.
In
rats,
reduced
fetal
body
weight,
an
increased
incidence
of
runts,
an
increase
in
skeletal
variations
and
an
increase
in
incidence
of
undescended
testes
were
seen
at
the
LOAEL
of
100
mg/
kg/
day,
a
dose
also
causing
decreased
body
weight
gain
in
dams.
At
200
mg/
kg/
day
in
rats,
there
was
an
increase
in
malformations,
including
cleft
palate
and
hydronephrosis,
accompanied
by
an
increase
in
post­
implantation
loss.
In
rabbits,
there
was
a
decrease
in
fetal
weight
and
an
increase
in
incidence
of
urinary
tract
malformations
at
doses
causing
severe
effects
in
does
(
weight
loss,
multiple
clinical
signs,
and
increased
mortality).
The
dose­
response
in
rabbits
appears
to
be
very
steep,
with
no
effects
seen
at
30
mg/
kg/
day,
and
mortality
seen
at
45
mg/
kg/
day
(
only
15
mg/
kg/
day
higher).
In
summary,
there
was
no
increase
in
quantitative
severity
in
either
species.
There
was
an
increase
in
qualitative
sensitivity
(
more
severe
effects)
in
rats,
but
not
in
rabbits.

4.2.4
Reproductive
Toxicity
Study
There
is
evidence
of
increased
offspring
sensitivity,
both
quantitative
and
qualitative,
in
the
reproductive
toxicity
study
in
rats.
In
adult
(
F1)
male
offspring,
decreases
in
body
weight
and
brain
weight
were
seen
at
doses
of
15­
16
mg/
kg/
day
and
36
mg/
kg/
day,
respectively.
Similar
effects
were
seen
in
parental
(
F0)
animals
only
at
the
highest
dose
of
189
mg/
kg/
day.
Similarly,
decreased
brain
weight
and
body
weight
were
seen
at
(
parental)
doses
of
18.9
mg/
kg/
day
in
F2
pups,
doses
below
those
causing
similar
effects
in
F0
animals
(
189
mg/
kg/
day).
Decreases
in
corpora
lutea
were
seen
in
F1
females
at
36
mg/
kg/
day;
similar
effects
were
not
seen
in
F0
females
(
increases
in
corpora
lutea
were
seen
at
the
high
dose
of
218
mg/
kg/
day;
no
changes
were
seen
in
mid­
dose
F0
females).

4.2.5
Additional
Information
from
Literature
Sources
None.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
Toxicity
was
seen
in
offspring
in
all
studies
in
which
they
were
evaluated.
Pre­
natal
findings
include
malformations
as
well
as
decreases
in
body
weight.
Findings
in
the
reproductive
toxicity
study
included
effects
on
multiple
organ
systems,
including
decreases
in
body
and
brain
weight
and
changes
in
reproductive
organs
(
including
testes
and
ovaries).
It
is
not
possible
to
determine
whether
the
effects
seen
in
the
reproductive
toxicity
study
were
due
to
pre­
or
post­
natal
exposure.

4.2.6.1
Determination
of
Susceptibility
Available
data
indicate
evidence
of
increased
qualitative
sensitivity
in
the
rat
developmental
toxicity
study
(
malformations
seen
at
doses
causing
only
decreased
body
weight
gain
in
dams),
and
of
quantitative
sensitivity
in
the
rat
reproductive
toxicity
study
(
similar
effects
seen
at
lower
19
of
94
doses
in
offspring).
No
increase
in
qualitative
or
quantitative
sensitivity
was
seen
in
the
rabbit,
with
malformations
occurring
at
doses
causing
severe
maternal
toxicity.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
Although
a
developmental
neurotoxicity
study
is
unavailable,
available
data
(
including
nervous
system
lesions
seen
in
adults
and
decreased
brain
weight
in
offspring)
raise
concern
regarding
developmental
effects
on
the
nervous
system.
In
an
attempt
to
address
this
concern,
additional
brain
evaluations,
including
morphometric
measures
in
weanlings,
were
performed
in
the
available
reproductive
toxicity
study.
Although
no
effects
were
seen
in
either
the
qualitative
or
quantitative
evaluations
performed
in
pups,
similar
evaluations
were
not
conducted
in
adult
animals,
in
spite
of
evidence
(
decreases
in
brain
weight
in
F1
adults)
of
persistent
effects
on
the
central
nervous
system.
It
is
also
important
to
note
that
the
highest
dose
evaluated
in
offspring,
approximately
32
mg/
kg/
day,
was
substantially
lower
than
that
causing
nervous
system
lesions
in
adults
not
developmentally
dosed
(
approximately
183
mg/
kg/
day
in
males
in
the
subchronic/
neurotoxicity
study
and
189
mg/
kg/
day
in
F0
parents
in
the
reproductive
toxicity
study).
Although
lesions
were
found
in
the
peripheral
nervous
system
(
PNS)
in
adults
in
the
subchronic
neurotoxicity
study,
there
has
been
no
evaluation
of
PNS
tissues
in
offspring.
In
addition,
behavioral
evaluations
of
pups
are
not
available;
in
the
subchronic/
neurotoxicity
study
in
adult
rats,
behavioral
effects
were
detected
during
FOB
and
motor
activity
evaluations
that
were
not
seen
in
routine
clinical
observations.
It
is
possible
similar
effects
could
occur
in
offspring
during
development,
that
would
not
have
been
detected
in
the
reproductive
toxicity
study.
Although
the
toxicity
seen
in
offspring
in
the
reproductive
toxicity
study
indicates
that
offspring
were
exposed,
the
degree
of
lactational
transfer,
and
thus
the
relative
exposure
of
pups
and
adults,
is
unknown.

In
addition
to
the
nervous
system
lesions,
1,2,4­
triazole
also
appears
to
impact
the
function
of
the
endocrine
system,
based
on
reproductive
failure
at
the
high
dose
and
delays
in
sexual
maturation
seen
in
the
reproductive
toxicity
study,
and
on
lesions
in
reproductive
organs
and
changes
in
corpora
lutea
counts
seen
in
various
studies
in
rats
and/
or
mice.

The
HED
Risk
Assessment
Review
Committee
(
RARC)
found
the
residual
concern
for
the
above­
described
effects
to
be
low,
since
the
endpoint
of
concern
(
effects
in
the
offspring
at
the
LOAEL
in
the
reproductive
toxicity
study)
is
being
used
as
the
basis
for
the
current
risk
assessment,
and
the
appropriate
uncertainty
factors
are
being
used
to
account
for
the
residual
uncertainty
(
RARC
Meeting
10/
4/
05;
see
below).

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
triazole
toxicology
team
determined
that
a
Developmental
Neurotoxicity
study
is
required
based
on
multiple
nervous
system
and
endocrine­
related
findings
in
available
studies,
including
effects
seen
in
offspring
at
doses
not
causing
toxicity
in
F0
parental
animals.
20
of
94
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
Pathological
lesions
of
the
nervous
system
have
been
seen
in
all
evaluated
species,
in
multiple
studies:
 
Cerebellar
lesions
in
the
90­
day
study
in
mice
at
487/
663
and
988/
1346
mg/
kg/
day
(
males/
females).
 
Brain
and
peripheral
nervous
system
lesions
and
behavioral
effects
in
rats
at
183/
234
and
210/
275
mg/
kg/
day
in
the
subchronic/
neurotoxicity
study.
 
Decreases
in
brain
weight
and
cerebellar
lesions
in
both
sexes
of
F0
adults
in
the
rat
reproductive
toxicity
study
at
188/
218
mg/
kg/
day
(
M/
F).
 
Decreases
in
brain
weight
in
adult
offspring
and
weanlings
in
the
rat
reproductive
toxicity
study
at
doses
of
16/
19
and
33/
41
mg/
kg/
day
(
M/
F).
 
Slight
increases
in
incidence
of
retinal
degeneration
in
the
90­
day
subchronic/
neurotoxicity
study
in
rats,
at
183/
234
and
210/
275
mg/
kg/
day
(
M/
F).
 
Possible
changes
in
lens
biochemistry
were
seen
in
an
ocular
toxicity
study
in
dogs.

Clinical
signs,
indicative
of
neurobehavioral
effects
have
been
seen
in
multiple
studies:
 
Effects
were
seen
during
FOB
evaluations
(
including
tremors,
muscle
fasciculations,
and
decreases
in
rearing)
and
motor
activity
evaluations
in
the
subchronic/
neurotoxicity
study
in
rats,
at
183/
234
and
210/
275
mg/
kg/
day
(
M/
F).
 
Clinical
signs,
including
gait
and
postural
changes,
tremors,
and
slight
convulsions,
were
seen
in
two
older
rat
toxicity
studies
(
30­
day
gavage
and
90­
day
dietary).
 
Clinical
signs
indicative
of
neurotoxicity
were
seen
in
does
in
the
rabbit
developmental
toxicity
study.

Possible
endocrine­
mediated
effects
have
been
seen
in
multiple
studies
and
species:
 
Testicular
changes
in
mice
(
28­
and
90­
day
mouse
studies),
sperm
abnormalities
in
rats
(
reproductive
toxicity
study),
decreases
in
testes
weight
in
old
rat
30­
and
90­
day
toxicity
studies.
 
Ovarian
changes
in
rats
(
90­
day
subchronic
rat
and
reproductive
toxicity
study
in
rats).
 
Delays
in
sexual
maturation
in
rat
reproductive
toxicity
study.
 
Reproductive
failure
at
high
dose
in
rat
reproductive
study
(
only
two
litters
produced,
with
no
pups
surviving
lactation).
 
Increased
incidence
of
undescended
testicle
in
rat
developmental
toxicity
study.
 
Dose­
related
decreases
in
TSH
at
33
mg/
kg/
day
and
above
in
male
rats
in
the
subchronic/
neurotoxicity
study.

4.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
study
 
No
effects
were
seen
in
morphometric
evaluation
of
weanling
rats
in
the
reproductive
toxicity
study.

 
No
CNS
malformations
were
seen
in
available
developmental
toxicity
studies
in
rats
and
rabbits.
21
of
94
4.3.2.1
Rationale
for
the
UFDB
(
when
a
DNT
is
recommended)

Based
on
the
evidence
described
in
Section
4.3.1
regarding
the
concern
for
neurotoxic
effects
in
developing
offspring,
as
well
as
other
data
gaps
(
lack
of
chronic
studies,
oncogenicity
studies,
non­
rodent
toxicity
studies),
the
triazole
toxicology
team
determined
that
a
database
UF
should
be
set
at
10x.
The
need
for
this
factor
will
be
re­
evaluated
upon
receipt
of
the
additional
required
toxicology
data
(
see
Section
10.1).
A
larger
factor
will
be
used
for
some
endpoints
due
to
failure
to
identify
a
NOAEL
in
the
reproductive
toxicity
study
(
see
below).

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
Study
Selected:
Developmental
Toxicity
study
in
rabbits
MRID
Number:
MRID
46492903
Dose
and
Endpoint
for
Establishing
aRfD:
30
mg/
kg/
day,
based
on
urinary
tract
malformations
seen
at
the
LOAEL
of
45
mg/
kg/
day
Uncertainty
Factor(
s):
UF=
1000
(
10x
for
inter­
species
variability,
10x
for
intra­
species
variability,
and
10x
for
data
gaps
and
FQPA
concerns)
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Identified
developmental
toxicity
suitable
for
this
exposure
duration.
Although
changes
in
birth
weight
and
in
weanling
brain
weight
were
seen
in
offspring
from
the
reproductive
toxicity
study,
these
were
seen
at
the
LOAEL
in
the
F2
generation
only,
and
thus
are
unlikely
to
occur
following
a
single
exposure.

Acute
RfD
=
30
mg/
kg/
day
(
NOAEL)
÷
1000
(
UF)
=
0.03
mg/
kg/
day
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
Study
Selected:
Developmental
Toxicity
study
in
rabbits
MRID
Number:
MRID
46492903
Dose
and
Endpoint
for
Establishing
aRfD:
NOAEL=
30
mg/
kg/
day,
based
on
clinical
signs
and
mortality
in
does
seen
at
the
LOAEL
of
45
mg/
kg/
day,
Uncertainty
Factor(
s):
UF=
1000
(
10x
for
inter­
species
variability,
10x
for
intra­
species
variability,
and
10x
for
data
gaps
and
FQPA
concerns)
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Effects
in
does
were
seen
starting
on
Gestation
Day
6
or
7,
and
are
therefore
suitable
for
this
exposure
duration.

Acute
RfD
=
30
mg/
kg/
day
(
NOAEL)
÷
1000
(
UF)
=
0.03
mg/
kg/
day
4.4.3
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Reproductive
toxicity
study
in
rats
(
MRID
46467304)
MRID
Number:
MRID
46467304
Dose
and
Endpoint
for
Establishing
cRfD:
LOAEL=
15
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
in
F1
males,
decreased
body
weight,
body
weight
gain,
and
brain
22
of
94
weight
in
F2
pups.
A
NOAEL
was
not
established
for
this
study
(
NOAEL=
less
than
15
mg/
kg/
day).

Uncertainty
Factor(
s):
UF=
3000
(
10x
for
intraspecies,
10x
for
interspecies,
10x
for
data
gaps
(
lack
of
DNT,
chronic
studies,
oncogenicity
studies,
non­
rodent
toxicity
studies),
3x
for
extrapolation
from
LOAEL
to
NOAEL).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Longest
duration
study
available,
with
lowest
effect
level,
in
available
database.

Chronic
RfD
=
15
mg/
kg/
day
(
LOAEL)
÷
3000
(
UF)
=
0.005
mg/
kg/
day
4.4.4
Incidental
Oral
Exposure
(
Short­
Term)

Study
Selected:
Developmental
Toxicity
study
in
rabbits
MRID
Number:
MRID
46492903
Dose
and
Endpoint:
NOAEL=
30
mg/
kg/
day,
based
on
clinical
signs
and
mortality
in
does
seen
at
the
LOAEL
of
45
mg/
kg/
day,
Uncertainty
Factor(
s):
UF=
1000
(
10x
for
inter­
species
variability,
10x
for
intra­
species
variability,
and
10x
for
data
gaps
and
FQPA
concerns)

Comments
about
Study/
Endpoint/
MOE:
Duration
appropriate
for
this
time
frame
(
up
to
28
days).
MOE=
1000
(
10x
for
intraspecies,
10x
for
interspecies,
10x
for
data
gaps
and
FQPA
concerns).

4.4.5
Incidental
Oral
Exposure
(
Intermediate­
Term)

Study
Selected:
Reproductive
toxicity
study
in
rats
MRID
Number:
46467304
Dose
and
Endpoint:
LOAEL=
15
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
in
F1
males,
decreased
body
weight,
body
weight
gain,
and
brain
weight
in
F2
pups.
A
NOAEL
was
not
established
in
this
study
(
less
than
15
mg/
kg/
day).

Comments
about
Study/
Endpoint/
MOE:
Duration
appropriate
for
this
time
frame
(
28
days
to
6
months).
MOE=
3000
(
10x
for
intraspecies,
10x
for
interspecies,
10x
for
data
gaps
(
lack
of
DNT,
chronic
studies,
oncogenicity
studies,
non­
rodent
toxicity
studies),
3x
for
extrapolation
from
LOAEL
to
NOAEL).

4.4.6
Dermal
Absorption
No
data
are
available
regarding
dermal
absorption
of
1,2,4­
triazole,
therefore
if
direct
dermal
exposure
to
1,2,4­
triazole
is
anticipated,
a
default
assumption
of
100%
dermal
absorption
should
be
used.
For
evaluation
of
risk
from
estimated
exposure
to
1,2,4­
triazole
occurring
as
a
result
of
metabolism
following
dermal
exposure
to
parent
conazole
compounds,
dermal
absorption
estimates
for
parent
compounds
should
be
used.
23
of
94
4.4.7
Dermal
and
Inhalation
Exposure
(
Short­
Term)

Study
Selected:
Developmental
Toxicity
study
in
rabbits
MRID
Number:
MRID
46492903
Dose
and
Endpoint:
NOAEL=
30
mg/
kg/
day,
based
on
clinical
signs
and
mortality
in
does
seen
at
the
LOAEL
of
45
mg/
kg/
day,
Uncertainty
Factor(
s):
UF=
1000
(
10x
for
inter­
species
variability,
10x
for
intra­
species
variability,
and
10x
for
data
gaps
and
FQPA
concerns)

Comments
about
Study/
Endpoint/
MOE:
Duration
appropriate
for
this
time
frame
(
up
to
28
days).
MOE=
1000
(
10x
for
intraspecies,
10x
for
interspecies,
10x
for
data
gaps
and
FQPA
concerns).

4.4.8
Dermal
and
Inhalation
Exposure
(
Intermediate­
and
Long­
Term)

Study
Selected:
Reproductive
toxicity
study
in
rats
MRID
Number:
46467304
Dose
and
Endpoint:
LOAEL=
15
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
in
F1
males,
decreased
body
weight,
body
weight
gain,
and
brain
weight
in
F2
pups.
NOAEL
was
not
established
in
this
study
(
less
than
15
mg/
kg/
day).

Comments
about
Study/
Endpoint/
MOE:
Duration
appropriate
for
this
time
frame
(
28
days
to
lifetime).
No
longer­
term
study
is
available.
MOE=
3000
(
10x
for
intraspecies,
10x
for
interspecies,
10x
for
data
gaps
(
lack
of
DNT,
chronic
studies,
oncogenicity
studies,
non­
rodent
toxicity
studies),
3x
for
extrapolation
from
LOAEL
to
NOAEL)

4.4.9
Margins
of
Exposure
and
Levels
of
Concern
The
levels
of
concern
(
LOC)
for
residential
and
occupational
risk
assessment
are
as
follows:

Table
4.3.
Summary
of
Levels
of
Concern
for
Residential
and
Occupational
Risk
Assessments
for
1,2,4­
triazole.
Duration
of
Exposure
Route
of
Exposure
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1­
6
Months)
Long­
Term
(>
6
Months)
Occupational
Exposure
Dermal
1000
3000
3000
Inhalation
1000
3000
3000
Residential
Exposure
Incidental
Oral
1000
3000
3000
Dermal
1000
3000
3000
Inhalation
1000
3000
3000
4.4.10
Recommendation
for
Aggregate
Exposure
Risk
Assessments
For
a
given
duration
of
exposure,
the
same
study
and
endpoint
is
being
used
for
all
exposure
pathways;
therefore,
HED
is
assuming
that
the
toxicological
effects
following
exposure
via
those
routes
are
the
same.
Exposure
from
all
routes
should
be
aggregated.
24
of
94
4.4.11
Classification
of
Carcinogenic
Potential
There
are
no
available
cancer
bioassay
studies
on
1,2,4­
triazole.
1,2,4­
triazole
and
its
conjugate
(
triazole
alanine),
however,
are
not
mutagenic.
The
mutagenicity
data
on
the
parent
triazole
fungicides
(
i.
e.,
the
conazoles)
indicate
that
this
class
of
compounds
also
generally
lacks
genotoxic
potential.
Some
parent
triazole
fungicides
have
been
shown
to
be
carcinogenic
in
rodents,
in
particular
some
have
produced
mouse
liver
tumors
while
other
have
produced
rat
thyroid
tumors,
and
a
few
produced
both
tumor
types.
Other
tumor
types
noted
with
several
individual
triazoles
include
ovarian
tumors,
testicular
tumors,
and
bladder
tumors.
For
the
last
several
years,
the
EPA's
National
Health
and
Environmental
Effects
Research
Laboratory
(
NHEERL)
has
been
conducting
research
on
the
potential
mode
of
carcinogenic
action
underlying
the
rodent
hepatic
and
thyroid
follicular
cell
tumor
responses
found
for
the
parent
triazole
fungicides.
The
NHEERL
cancer
mechanistic
studies
on
fluconazole,
myclobutanil,
propiconazole,
and
triadimefon
are
just
beginning
to
appear
in
the
scientific
literature
(
Sun
et
al.,
2004;
Wolf
et
al.,
2005;
Allen
et
al.,
2005;
Goetz
et
al.,
2005;
Hester
et
al.,
2005;
Ren
et
al.,
2005;
Ward
et
al.,
2005).
NHEERL
used
both
traditional
toxicology
endpoints
and
DNA
microarrays
to
profile
gene
expression
in
their
investigations
on
potential
modes
of
carcinogenic
action.
This
recent
evidence
indicates
that
the
parent
triazole
compounds
appear
to
result
in
a
tumor
response
subsequent
to
perturbation
of
liver
metabolism,
specifically
xenobiotic
and
fatty
acid
metabolic
pathways.
Some
of
the
altered
pathways
are
regulated
by
CAR,
PXR,
and
other
nuclear
receptors.
In
addition
the
thyroid
response
appears
to
be
secondary
to
perturbation
of
thyroid
homeostasis.
Thus,
the
conazoles
appear
to
drive
a
tumor
response
secondary
to
epigenetic
effects
and
not
from
direct
interaction
with
the
DNA.
An
epigenetic
mode
of
action
would
be
consistent
with
a
nonlinear
process.

The
toxicity
profile
of
1,2,4­
triazole
is
not
similar
to
those
of
related
conazole
pesticides
showing
a
high
rate
of
metabolic
conversion
to
1,2,4­
triazole
(
see
Appendix).
Unlike
the
conazoles
currently
being
studied
by
NHEERL,
1,2,4­
triazole
did
not
alter
thyroid
hormones
and
did
not
cause
any
of
the
pre­
neoplastic
changes
in
liver
or
thyroid
typically
observed
following
subchronic
exposures.
There
were
decreases
in
liver
weights
reported
in
the
30­
day
and
2­
generation
reproductive
rat
studies
but
these
effects
were
not
associated
with
preneoplastic
changes.
Also,
a
decrease
in
serum
TSH
was
reported
in
a
subchronic
neurotoxicity
study
which
is
inconsistent
with
the
mode
of
thyroid
carcinogenic
action
which
requires
increased
circulating
TSH
and
subsequent
thyroid
follicular
cell
hyperplasia.
The
available
toxicity
studies
on
1,2,4­
triazole
indicate
that
the
nervous
system
and
reproductive
tissue
are
primary
targets
and
thus
those
toxicities
should
be
considered
in
the
risk
assessment.

In
summary,
because
a
chronic
cancer
study
is
not
available,
it
is
recommended
that
a
margin
of
exposure
or
RfD
approach
based
on
the
most
sensitive
toxicity
endpoint
with
the
inclusion
of
a
database
uncertainty
factor
to
account
for
the
absence
of
chronic
toxicity
studies
should
be
used.
This
approach
should
be
adequately
protective
of
human
health
and
would
be
consistent
with
the
recently
reported
cancer­
related
findings
for
a
series
of
triazole­
derivative
fungicides.
25
of
94
4.5
Special
FQPA
Safety
Factor
Based
on
the
hazard
data,
the
RARC
recommended
the
special
FQPA
SF
be
reduced
to
1x
because
there
are
low
residual
concerns
and
no
residual
uncertainties
with
regard
to
pre­
and/
or
postnatal
toxicity.
The
1,2,4­
triazole
risk
assessment
team
evaluated
the
quality
of
the
exposure
data
and,
based
on
these
data,
recommended
that
the
special
FQPA
SF
be
reduced
to
1x.
The
recommendation
is
based
on
the
following:

 
The
dietary
exposure
assessment
is
based
on
100%
CT
information
for
all
food
commodities
and
conservatively
estimated
anticipated
residue
levels.
Estimates
for
drinking
water
were
generated
by
models
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.
By
using
these
screening­
level
assessments,
dietary
exposures/
risks
will
not
be
underestimated.

 
The
residential
exposure
assessment
is
based
on
high­
end
assumptions
regarding
incidental
oral
and
dermal
exposures
to
1,2,4­
T.

Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
females
13­
49)
NOAEL
=
30
mg/
kg
UF=
1000
Acute
RfD=
0.03
mg/
kg
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.03
mg/
kg/
day
Developmental
Toxicity
study
in
rabbits
LOAEL=
45
mg/
kg
based
on
urinary
tract
malformations
in
fetuses
Acute
Dietary
(
general
population)
NOAEL
=
30
mg/
kg
UF=
1000
Acute
RfD=
0.03
mg/
kg
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.03
mg/
kg/
day
Developmental
Toxicity
study
in
rabbits
LOAEL=
45
mg/
kg
based
on
clinical
signs
and
mortality
in
does
starting
on
Gestation
Day
6
or
7
Chronic
Dietary
(
all
populations)
LOAEL
=
15
mg/
kg/
day
UF
=
3000
Chronic
RfD
=
0.005
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.005
mg/
kg/
day
Reproductive
Toxicity
study
in
rats
LOAEL
=
15
mg/
kg/
day
based
on
decreased
body
weight
in
adult
males,
decreased
body
weight
and
brain
weight
in
offspring
Incidental
Oral
Short­
term
(
1­
30
days)
NOAEL
=
30
mg/
kg/
day
FQPA
SF
=
1
LOC=
1000
Developmental
Toxicity
study
in
rabbits
LOAEL=
45
mg/
kg/
day
based
on
clinical
signs
and
mortality
in
does
starting
on
Gestation
Day
6
or
7
26
of
94
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Incidental
Oral
Intermediate­
or
Long­
term
(
30
days
to
6
months)
LOAEL
=
15
mg/
kg/
day
FQPA
SF
=
1
LOC=
3000
Reproductive
Toxicity
study
in
rats
LOAEL
=
15
mg/
kg/
day
based
on
decreased
body
weight
in
adult
males,
decreased
body
weight
and
brain
weight
in
offspring
Dermal
Short­
term
(
1­
30
days)
NOAEL
=
30
mg/
kg/
day
LOC=
1000
Developmental
Toxicity
study
in
rabbits
LOAEL=
45
mg/
kg/
day
based
on
clinical
signs
and
mortality
in
does
starting
on
Gestation
Day
6
or
7
Dermal
Intermediate­
or
Long­
term
(
30
days
to
6
months)
LOAEL
=
15
mg/
kg/
day
LOC=
3000
Reproductive
Toxicity
study
in
rats
LOAEL
=
15
mg/
kg/
day
based
on
decreased
body
weight
in
adult
males,
decreased
body
weight
and
brain
weight
in
offspring
Inhalation
Short­
term
(
1
­
30
days)
LOAEL
=
15
mg/
kg/
day
LOC=
3000
Reproductive
Toxicity
study
in
rats
LOAEL
=
15
mg/
kg/
day
based
on
decreased
body
weight
in
adult
males,
decreased
body
weight
and
brain
weight
in
offspring
Inhalation
Intermediate­
or
Long­
term
(
30
days
to
6
months)
LOAEL
=
15
mg/
kg/
day
LOC=
3000
Reproductive
Toxicity
study
in
rats
LOAEL
=
15
mg/
kg/
day
based
on
decreased
body
weight
in
adult
males,
decreased
body
weight
and
brain
weight
in
offspring
Cancer
(
oral,
dermal,
inhalation)
Classification:
Not
determined.
Evaluate
by
RfD
approach.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
4.5
4.6
Endocrine
disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
27
of
94
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

Effects
were
observed
in
tests
which
indicated
potential
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.

 
Testicular
changes
in
mice
(
28­
and
90­
day
mouse
studies),
sperm
abnormalities
in
rats
(
reproductive
toxicity
study),
decreases
in
testes
weight
in
old
rat
30­
and
90­
day
toxicity
studies.
 
Ovarian
changes
in
rats
(
90­
day
subchronic
rat
and
reproductive
toxicity
study
in
rats).
 
Delays
in
sexual
maturation
in
rat
reproductive
toxicity
study.
 
Reproductive
failure
at
high
dose
in
rat
reproductive
study
(
only
two
litters
produced,
with
no
pups
surviving
lactation).
 
Increased
incidence
of
undescended
testicle
in
rat
developmental
toxicity
study.
 
Dose­
related
decreases
in
TSH
at
33
mg/
kg/
day
and
above
in
male
rats
in
the
subchronic/
neurotoxicity
study.

When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
1,2,4­
triazole
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
No
incidents
involving
1,2,4­
triazole
were
found
from
a
search
of
the
Incident
Data
System
(
1992
to
present),
the
Poison
Control
Center
Data
(
1993­
2003),
California
(
1982­
2003,
or
NIOSH
(
1998­
2003).

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
(
M.
Doherty,
DP
322238,
11/
1/
05)

6.1.1
Residue
Profile
6.1.1.1
Residues
in
Food
Exposure
to
1,2,4­
triazole
may
occur
through
direct
or
indirect
means.
For
purposes
of
this
assessment,
direct
exposure
is
defined
as
exposure
to
residues
of
1,2,4­
triazole,
per
se.
Indirect
exposure
to
1,2,4­
triazole
may
occur
when
there
is
exposure
to
a
triazole­
derivative
fungicide.
Indirect
exposure
is
defined
as
exposure
to
1,2,4­
triazole
that
occurs
from
exposure
to
a
triazole
fungicide
and
subsequent
metabolic
conversion
of
the
parent
compound
to
1,2,4­
triazole
within
the
human
system.
For
assessing
direct
and
indirect
dietary
exposure,
residue
levels
of
1,2,4­
triazole
were
estimated
from
parent
triazole­
derivative
fungicide
tolerances.
For
each
food/
parent
fungicide
tolerance
combination,
a
residue
estimate
was
calculated
by
multiplying
the
tolerance
by
a
metabolic
conversion
factor
and
by
a
molecular
weight
conversion
factor.
Direct­
exposure
residue
levels
used
the
metabolic
factors
from
plant
metabolism
studies
for
crop
28
of
94
commodities
and
from
livestock
metabolism
studies
for
livestock
commodities.
Indirectexposure
residue
levels
used
metabolic
factors
from
rat
metabolism
studies.
For
some
compounds
metabolic
conversion
factors
were
not
readily
available
and
the
maximum
factors
from
the
entire
class
of
compounds
were
used
(
20%
for
plants,
77%
for
livestock).

Through
a
joint
effort
by
the
U.
S.
Triazole
Task
Force
(
USTTF)
and
USDA's
Pesticide
Data
Program
(
PDP),
monitoring
data
depicting
residues
of
1,2,4­
triazole
are
available
for
apples,
peaches,
wheat
flour,
bananas,
eggs,
peanut
butter,
soybeans,
finished
water,
strawberry,
milk,
grapes,
and
tomato.
Most
of
the
monitoring
data
for
1,2,4­
triazole
were
reported
as
being
below
the
level
of
quantification.

The
following
rules
were
used
to
select
residues
for
the
dietary
exposure
analysis:
1.
If
no
monitoring
data
were
available
for
the
crop,
or
from
a
representative
commodity,
the
calculated
residue
value
was
used.
2.
If
the
monitoring
dataset
contains
values
that
are
greater
than
the
LOQ,
the
monitoring
data
were
used.
3.
If
the
monitoring
data
are
all
less
than
the
reported
LOQ
and
the
calculated
residue
value
is
less
than
½
LOQ,
the
calculated
residue
values
were
used.
4.
If
the
monitoring
data
are
less
than
the
reported
LOQ
and
the
calculated
residue
value
is
greater
than
the
LOQ,
a
value
of
½
LOQ
was
used.
5.
Average
residue
estimates
from
the
indirect
exposure
pathway
were
added
to
either
the
maximum
direct
residue
estimate
for
acute
assessments
or
the
average
direct
residue
estimate
for
chronic
assessments.

For
the
indirect­
exposure
part
of
the
analysis,
average
indirect­
residue
estimates
were
used
for
both
the
acute
and
chronic
assessments.
The
average
value
was
selected
due
to
the
fact
that
this
indirect
exposure
is
addressed,
at
least
in
part,
by
the
toxicology
studies
and
risk
assessment
for
the
various
triazole­
derivative
parent
fungicides.
A
summary
of
the
values
used
in
the
assessments
and
their
sources
is
shown
in
Table
6.1.
Field
trial
studies
for
some
triazolederivative
fungicides
include
analyses
for
1,2,4­
triazole.
These
data
could
be
used
to
refine
the
exposure
and
risk
estimates;
however,
due
to
timing
issues,
resource
constraints,
and
the
various
stages
of
review
of
the
submissions,
they
were
not
considered
for
these
assessments.

1,2,4­
Triazole
is
not
currently
listed
in
40
CFR
Section
180,
nor
is
it
included
in
the
tolerance
expression
for
any
triazole­
derivative
fungicide.
Due
to
the
multiple
potential
sources
of
1,2,4­
triazole
and
its
occurrence
in
the
environment,
HED
believes
that
1,2,4­
triazole
is
not
an
appropriate
analyte
for
tolerance­
enforcement
purposes
and
is
not
recommending
that
tolerances
for
this
compound
be
established.
29
of
94
Table
6.1.
Summary
of
Direct
and
Indirect
Residue
Estimates
Used
to
Assess
Dietary
Exposure
to
1,2,4­
Triazole.

Direct
Exposure
2
Dietary
Model
Input,
ppm
1
Selected
Residue
Estimate,
ppm
3
Calculated
Data,

ppm
4
Monitoring
Data,
ppm
5
Item
Acute
Chronic
Acute
Acute
Source
Chronic
Chronic
Source
Max.
Avg.
LOQ
Max.
Avg.
Average
Indirect
Residue
Estimate,
ppm
6
Pome
Fruit
(
Apple)
0.0253
0.0253
0.0100
1/
2
LOQ
0.0100
1/
2
LOQ
0.0470
0.0182
0.02000
0.02000
0.02000
0.0153
Artichoke
0.0753
0.0655
0.0478
Max.
Calc'd
0.0380
Avg.
Calc'd
0.0478
0.0380
­­­
­­­
­­­
0.0275
Asparagus
0.0099
0.0056
0.0071
Max.
Calc'd
0.0028
Avg.
Calc'd
0.0071
0.0028
­­­
­­­
­­­
0.0028
Banana
0.0238
0.0238
0.0050
1/
2
LOQ
0.0050
1/
2
LOQ
0.1913
0.0279
0.01000
0.00315
0.00036
0.0188
Dry
Bean
0.0230
0.0137
0.0202
Max.
Calc'd
0.0109
Avg.
Calc'd
0.0202
0.0109
­­­
­­­
­­­
0.0028
Succulent
Bean
0.0568
0.0291
0.0478
Max.
Calc'd
0.0201
Avg.
Calc'd
0.0478
0.0201
­­­
­­­
­­­
0.0090
Blueberry
0.0462
0.0321
0.0404
Max.
Calc'd
0.0263
Avg.
Calc'd
0.0404
0.0263
­­­
­­­
­­­
0.0058
Caneberry
0.1495
0.1305
0.0957
Max.
Calc'd
0.0767
Avg.
Calc'd
0.0957
0.0767
­­­
­­­
­­­
0.0538
Canola
0.0100
0.0082
0.0040
Max.
Calc'd
0.0022
Avg.
Calc'd
0.0040
0.0022
­­­
­­­
­­­
0.0060
Carrot
0.0101
0.0101
0.0081
Max.
Calc'd
0.0081
Avg.
Calc'd
0.0081
0.0081
­­­
­­­
­­­
0.0020
Leafy
Petioles
0.2523
0.2523
0.2018
Max.
Calc'd
0.2018
Avg.
Calc'd
0.2018
0.2018
­­­
­­­
­­­
0.0505
Barley
0.0055
0.0043
0.0040
Max.
Calc'd
0.0028
Avg.
Calc'd
0.0040
0.0028
­­­
­­­
­­­
0.0015
Oats
0.0056
0.0046
0.0040
Max.
Calc'd
0.0030
Avg.
Calc'd
0.0040
0.0030
­­­
­­­
­­­
0.0016
Rice
0.3073
0.1236
0.2826
Max.
Calc'd
0.0989
Avg.
Calc'd
0.2826
0.0989
­­­
­­­
­­­
0.0247
Rye
0.0058
0.0050
0.0040
Max.
Calc'd
0.0032
Avg.
Calc'd
0.0040
0.0032
­­­
­­­
­­­
0.0018
Wheat
0.0053
0.0040
0.0040
Max.
Calc'd
0.0027
Avg.
Calc'd
0.0040
0.0027
­­­
­­­
­­­
0.0013
Wheat
Flour
0.0053
0.0040
0.0040
Max.
Calc'd
0.0027
Avg.
Calc'd
0.0040
0.0027
0.01000
0.01000
0.01000
0.0013
Wild
Rice
0.0252
0.0252
0.0202
Max.
Calc'd
0.0202
Avg.
Calc'd
0.0202
0.0202
­­­
­­­
­­­
0.0050
Citrus
Group
0.0436
0.0436
0.0410
Max.
Calc'd
0.0410
Avg.
Calc'd
0.0410
0.0410
­­­
­­­
­­­
0.0026
Coffee
0.0411
0.0005
0.0410
Max.
Calc'd
0.0004
Avg.
Calc'd
0.0410
0.0004
­­­
­­­
­­­
0.0001
Field
Corn
0.0052
0.0035
0.0040
Max.
Calc'd
0.0023
Avg.
Calc'd
0.0040
0.0023
­­­
­­­
­­­
0.0012
Sweet
Corn
0.0051
0.0033
0.0040
Max.
Calc'd
0.0022
Avg.
Calc'd
0.0040
0.0022
­­­
­­­
­­­
0.0011
Cotton
0.0965
0.0300
0.0898
Max.
Calc'd
0.0233
Avg.
Calc'd
0.0898
0.0233
­­­
­­­
­­­
0.0067
Cranberry
0.0460
0.0266
0.0404
Max.
Calc'd
0.0210
Avg.
Calc'd
0.0404
0.0210
­­­
­­­
­­­
0.0056
Cucurbits
0.0126
0.0100
0.0096
Max.
Calc'd
0.0070
Avg.
Calc'd
0.0096
0.0070
­­­
­­­
­­­
0.0030
Curant
0.1844
0.1328
0.1435
Max.
Calc'd
0.0919
Avg.
Calc'd
0.1435
0.0919
­­­
­­­
­­­
0.0409
Elderberry
0.0505
0.0505
0.0404
Max.
Calc'd
0.0404
Avg.
Calc'd
0.0404
0.0404
­­­
­­­
­­­
0.0101
Grape
0.0500
0.0337
0.0213
Max.
Mon.
0.0050
Avg.
Mon.
0.2244
0.0727
0.01000
0.02130
0.00150
0.0287
30
of
94
Table
6.1.
Summary
of
Direct
and
Indirect
Residue
Estimates
Used
to
Assess
Dietary
Exposure
to
1,2,4­
Triazole.

Direct
Exposure
2
Dietary
Model
Input,
ppm
1
Selected
Residue
Estimate,
ppm
3
Calculated
Data,

ppm
4
Monitoring
Data,
ppm
5
Item
Acute
Chronic
Acute
Acute
Source
Chronic
Chronic
Source
Max.
Avg.
LOQ
Max.
Avg.
Average
Indirect
Residue
Estimate,
ppm
6
Raisin
0.5932
0.5132
0.4800
Max.
Calc'd
0.4000
Avg.
Calc'd
0.4800
0.4000
­­­
­­­
­­­
0.1132
Hops
1.5278
1.5278
1.3460
Max.
Calc'd
1.3460
Avg.
Calc'd
1.3460
1.3460
­­­
­­­
­­­
0.1818
Lychee
0.0855
0.0855
0.0673
Max.
Calc'd
0.0673
Avg.
Calc'd
0.0673
0.0673
­­­
­­­
­­­
0.0182
Mango
0.0114
0.0114
0.0090
Max.
Calc'd
0.0090
Avg.
Calc'd
0.0090
0.0090
­­­
­­­
­­­
0.0024
Mayhaw
0.0419
0.0419
0.0335
Max.
Calc'd
0.0335
Avg.
Calc'd
0.0335
0.0335
­­­
­­­
­­­
0.0084
Bulb
Vegetables
0.0142
0.0104
0.0121
Max.
Calc'd
0.0083
Avg.
Calc'd
0.0121
0.0083
­­­
­­­
­­­
0.0021
Green
Onion
0.3350
0.3350
0.3229
Max.
Calc'd
0.3229
Avg.
Calc'd
0.3229
0.3229
­­­
­­­
­­­
0.0121
Okra
0.0570
0.0570
0.0449
Max.
Calc'd
0.0449
Avg.
Calc'd
0.0449
0.0449
­­­
­­­
­­­
0.0121
Peanut
0.0097
0.0053
0.0081
Max.
Calc'd
0.0037
Avg.
Calc'd
0.0081
0.0037
­­­
­­­
­­­
0.0016
Peanut
Butter
0.0779
0.0266
0.0763
Max.
Mon.
0.0250
Avg.
Mon.
0.0081
0.0037
0.01000
0.07630
0.02500
0.0016
Peppers
0.0717
0.0717
0.0478
Max.
Calc'd
0.0478
Avg.
Calc'd
0.0478
0.0478
­­­
­­­
­­­
0.0239
Peppermint
0.2153
0.2153
0.1435
Max.
Calc'd
0.1435
Avg.
Calc'd
0.1435
0.1435
­­­
­­­
­­­
0.0718
Pineapple
0.2192
0.1507
0.1411
Max.
Calc'd
0.0726
Avg.
Calc'd
0.1411
0.0726
­­­
­­­
­­­
0.0781
Sorghum
0.0094
0.0056
0.0081
Max.
Calc'd
0.0043
Avg.
Calc'd
0.0081
0.0043
­­­
­­­
­­­
0.0013
Soybean
0.0145
0.0145
0.0050
1/
2
LOQ
0.0050
1/
2
LOQ
0.0807
0.0290
0.01000
0.00290
0.00060
0.0095
Spearmint
0.2153
0.2153
0.1435
Max.
Calc'd
0.1435
Avg.
Calc'd
0.1435
0.1435
­­­
­­­
­­­
0.0718
Stone
Fruit­
no
cherry
0.1158
0.0858
0.0957
Max.
Calc'd
0.0657
Avg.
Calc'd
0.0957
0.0657
0.21000
0.21000
0.21000
0.0201
Cherry
0.2863
0.1824
0.2392
Max.
Calc'd
0.1353
Avg.
Calc'd
0.2392
0.1353
­­­
­­­
­­­
0.0471
Strawberry
0.0315
0.0315
0.0180
1/
2
LOQ
0.0180
1/
2
LOQ
0.0605
0.0422
0.03600
0.03600
0.03600
0.0135
Sugar
Beet
0.0152
0.0092
0.0121
Max.
Calc'd
0.0061
Avg.
Calc'd
0.0121
0.0061
­­­
­­­
­­­
0.0031
Sugar
Beet
Molasses
0.1520
0.0920
0.1210
Max.
Calc'd
0.0610
Avg.
Calc'd
0.1210
0.0610
­­­
­­­
­­­
0.0310
Sunflower
0.0028
0.0028
0.0022
Max.
Calc'd
0.0022
Avg.
Calc'd
0.0022
0.0022
­­­
­­­
­­­
0.0006
Tomato
0.0122
0.0122
0.0050
1/
2
LOQ
0.0050
1/
2
LOQ
0.0144
0.0144
0.01000
0.01000
0.01000
0.0072
Turnip
0.0228
0.0228
0.0180
Max.
Calc'd
0.0180
Avg.
Calc'd
0.0180
0.0180
­­­
­­­
­­­
0.0048
Turnip
Greens
0.3638
0.3638
0.3590
Max.
Calc'd
0.3590
Avg.
Calc'd
0.3590
0.3590
­­­
­­­
­­­
0.0048
Tree
Nuts
0.0048
0.0039
0.0040
Max.
Calc'd
0.0031
Avg.
Calc'd
0.0040
0.0031
­­­
­­­
­­­
0.0008
Almond
0.0186
0.0120
0.0164
Max.
Calc'd
0.0098
Avg.
Calc'd
0.0164
0.0098
­­­
­­­
­­­
0.0022
Pecan
0.0049
0.0049
0.0041
Max.
Calc'd
0.0041
Avg.
Calc'd
0.0041
0.0041
­­­
­­­
­­­
0.0008
Pistachio
0.0048
0.0039
0.0040
Max.
Calc'd
0.0031
Avg.
Calc'd
0.0040
0.0031
­­­
­­­
­­­
0.0008
31
of
94
Table
6.1.
Summary
of
Direct
and
Indirect
Residue
Estimates
Used
to
Assess
Dietary
Exposure
to
1,2,4­
Triazole.

Direct
Exposure
2
Dietary
Model
Input,
ppm
1
Selected
Residue
Estimate,
ppm
3
Calculated
Data,

ppm
4
Monitoring
Data,
ppm
5
Item
Acute
Chronic
Acute
Acute
Source
Chronic
Chronic
Source
Max.
Avg.
LOQ
Max.
Avg.
Average
Indirect
Residue
Estimate,
ppm
6
Poultry
Meat
0.0073
0.0051
0.0045
Max.
Calc'd
0.0023
Avg.
Calc'd
0.0045
0.0023
­­­
­­­
­­­
0.0028
Poultry
Fat
0.0064
0.0038
0.0045
Max.
Calc'd
0.0019
Avg.
Calc'd
0.0045
0.0019
­­­
­­­
­­­
0.0019
Poultry
Meat
Byprod.
0.0063
0.0036
0.0045
Max.
Calc'd
0.0018
Avg.
Calc'd
0.0045
0.0018
­­­
­­­
­­­
0.0018
Poultry
Liver
0.0073
0.0056
0.0045
Max.
Calc'd
0.0028
Avg.
Calc'd
0.0045
0.0028
­­­
­­­
­­­
0.0028
Egg
0.0073
0.0056
0.0045
Max.
Calc'd
0.0028
Avg.
Calc'd
0.0045
0.0028
0.01000
0.00370
0.00050
0.0028
Cattle
Meat
0.0644
0.0254
0.0517
Max.
Calc'd
0.0127
Avg.
Calc'd
0.0517
0.0127
­­­
­­­
­­­
0.0127
Cattle
Fat
0.0644
0.0323
0.0517
Max.
Calc'd
0.0196
Avg.
Calc'd
0.0517
0.0196
­­­
­­­
­­­
0.0127
Cattle
Meat
Byprod.
0.0644
0.0253
0.0517
Max.
Calc'd
0.0126
Avg.
Calc'd
0.0517
0.0126
­­­
­­­
­­­
0.0127
Cattle
Liver
0.6834
0.2236
0.5716
Max.
Calc'd
0.1118
Avg.
Calc'd
0.5716
0.1118
­­­
­­­
­­­
0.1118
Cattle
Kidney
0.0675
0.0316
0.0517
Max.
Calc'd
0.0158
Avg.
Calc'd
0.0517
0.0158
­­­
­­­
­­­
0.0158
Milk
0.0080
0.0052
0.0053
Max.
Mon.
0.0025
Avg.
Mon.
0.0071
0.0027
0.00500
0.00530
0.00140
0.0027
1
Values
used
in
the
dietary
exposure
assessment
are
a
sum
of
the
selected
acute
or
chronic
residue
estimate
and
the
average
indirect
residue
estimate.

2
Values
used
to
estimate
direct
ingestion
of
residues
of
1,2,4­
triazole.
Values
were
selected
from
calculated
data
or
monitoring
data
as
indicated.

3
Residue
estimates
and
sources
selected
from
calculated
data
or
monitoring
data
using
the
criteria
discussed
in
Section
6.1.1.1.

4
Maximum
or
average
residue
estimates
based
on
parent
triazole­
derivative
fungicide
tolerances
after
compensating
for
metabolic
and
molecular
weight
factors.

5
Residue
data
for
1,2,4­
triazole
from
USDA
Pesticide
Data
Program
or
U.
S.
Triazole
Task
Force
monitoring
data.

6
Average
indirect
residue
estimates
based
on
parent
triazole­
derivative
fungicide
tolerances
after
compensating
for
rat
metabolic
and
molecular
weight
factors.
32
of
94
6.1.1.2
Residues
in
Water
(
I.
Maher,
DP
320682,
In
Preparation)

Residues
of
1,2,4­
triazole
in
drinking
water
were
provided
to
HED
by
the
Environmental
Fate
and
Effects
Division.
The
Tier
II
PRZM/
EXAMS
(
surface
water)
and
SCIGROW
(
groundwater)
residue
estimates
are
summarized
in
Table
6.2.
The
estimated
surface
water
concentrations
were
used
directly
in
the
acute
and
chronic
dietary
exposure
model.
A
small­
scale
prospective
groundwater
monitoring
study
was
conducted
in
New
Jersey
for
parent
triadimefon
(
1997).
In
that
study,
the
average
maximum
concentration
(
663­
day
mean)
of
1,2,4­
T
in
pore
water
at
a
depth
of
9
ft
was
0.0167
ppm.
That
level
is
significantly
greater
than
the
SCIGROW
estimate.
HED
notes
that
there
were
no
detections
of
1,2,4­
triazole
in
any
of
the
271
water
samples
analyzed
by
PDP.
The
limit
of
quantification
for
those
analyses
is
730
parts­
per­
trillion
(
0.73
ppb,
0.00073
ppm),
more
than
two
orders
of
magnitude
less
than
the
modeled
surface
water
residue
estimates.

Table
6.2.
Summary
of
Tier
II
Modeled
Concentrations
of
Triazole
Metabolites
in
Drinking
Water.
Exposure
Duration
Surface
Water
Concentration,
ppm
Groundwater
Concentration,
ppm
Acute
0.041
0.001
Chronic
0.011
0.001
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Acute
and
chronic
dietary
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
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.
A
separate
cancer
dietary
assessment
was
not
conducted.
Although
there
is
some
concern
regarding
the
carcinogenicity
of
1,2,4­
T,
HED
believes
that
the
chronic
dietary
exposure
assessment
is
sufficiently
protective
of
any
cancer­
related
effects.

The
acute
and
chronic
assessments
include
direct
dietary
exposure
to
1,2,4­
triazole
as
well
as
indirect
exposure
that
may
occur
due
to
food­
borne
residues
of
parent
triazole­
derivative
fungicide
and
the
subsequent
in­
vivo
conversion
of
parent
compound
to
1,2,4­
trizole
within
the
human
system.
For
both
direct
and
indirect
exposures,
residue
estimates
were
derived
from
parent­
compound
tolerance
values,
taking
into
consideration
any
monitoring
data
that
were
available
for
1,2,4­
triazole.
Both
acute
and
chronic
assessments
make
the
conservative
assumption
that
100%
of
foods
with
triazole­
derivative
fungicide
registrations
(
active,
pending,
and
requested)
were
treated
with
a
triazole­
derivative
fungicide.
Both
assessments
are
deterministic
and
include
residue
estimates
for
water.

Acute
exposure
estimates
for
1,2,4­
triazole
range
from
0.0025
to
0.0096
mg/
kg/
day
at
the
95th
percentile
of
exposure.
The
maximum
exposure
estimate
is
for
infants
less
than
1
year
of
age
and
corresponds
to
a
risk
estimate
of
32%
of
the
acute
Population­
adjusted
Dose
(
aPAD).
Chronic
exposure
estimates
range
from
0.0005
to
0.00196
mg/
kg/
day.
For
the
chronic
exposure
estimates,
the
maximum
is
for
children
aged
1
to
2
years.
The
risk
estimate
associated
with
that
group
is
39%
of
the
chronic
PAD
(
cPAD).
HED
is
generally
concerned
when
risk
estimates
for
any
representative
population
subgroup
exceed
100%
of
the
PAD.
The
risk
estimates
associated
with
1,2,4­
triazole
are
below
HED's
level
of
concern.
These
assessments
are
considered
to
be
33
of
94
conservative
because
(
1)
the
food
residue
estimates
are
derived
from
parent­
compound
tolerances
or
from
high­
end
residues
in
monitoring
data,
(
2)
the
residue
in
drinking
water
is
based
on
conservatively
modeled
estimates,
(
3)
all
food
and
water
in
the
analysis
are
assumed
to
have
high­
end
levels
of
residue,
and
(
4)
the
inclusion
of
the
indirect
exposure
pathway
is
already
partially
addressed
by
the
dietary
exposure
and
risk
analyses
for
the
various
parent
compounds.
As
shown
in
Table
6.3,
risk
estimates
for
all
population
subgroups
are
below
HED's
level
of
concern
at
all
presented
percentiles
of
exposure.
Based
on
the
conservative
nature
of
this
assessment,
the
95th
percentile
is
the
most
appropriate
for
regulatory
purposes.

Although
these
dietary
exposure
assessments
are
principally
based
on
anticipated
residues,
the
data,
selection
criteria,
and
assumptions
that
serve
as
the
source
of
those
residues
are
conservative
in
nature.
HED
has
assumed
that
application
of
multiple
triazole­
derivative
fungicides
will
not
occur
for
any
given
crop
during
a
single
growing
season.
Although
such
a
scenario
is
not
currently
prohibited
via
product
labeling,
HED
believes
that
such
practices
will
be
unlikely
due
to
economic
and
resistance­
management
issues.
Overall,
this
assessment
likely
overestimates
actual
direct
and
indirect
dietary
exposure
to
1,2,4­
triazole.
Even
with
the
conservatisms
in
the
dietary
assessments,
risk
estimates
for
the
general
U.
S.
population
and
all
representative
population
subgroups,
including
those
of
infants
and
children,
are
well
below
HED's
level
of
concern.
Reviewed
field
trial
data
depicting
measured
residues
of
1,2,4­
triazole
in
foods
are
likely
to
be
available
as
HED
progresses
with
evaluation
of
new­
use
and
new­
activeingredient
petitions.
Use
of
these
data,
as
well
as
incorporation
of
the
entire
distribution
of
monitoring
data,
will
result
in
more
realistic
dietary
exposure
and
risk
estimates
and
may
be
useful
if
exposure
and
risk
estimates
require
refinement.

Table
6.3.
Dietary
(
Food
+
Water)
Direct
and
Indirect
Exposure
and
Risk
Estimates
for
1,2,4­
Triazole.
Exposure
Estimate,
mg/
kg/
day
Risk
Estimate,
%
aPADa
Population
Subgroup
aPAD,
mg/
kg/
day
95th
%
ile
99th
%
ile
99.9th
%
ile
95th
%
ile
99th
%
ile
99.9th
%
ile
Acute
U.
S.
Population
(
total)
0.03
0.0036
0.0060
0.0108
12
20
36
All
infants
(<
1
year)
0.03
0.0096
0.0130
0.0212
32
44
71
Children
1­
2
yrs
0.03
0.0072
0.0107
0.0145
24
36
48
Children
3­
5
yrs
0.03
0.0059
0.0085
0.0144
20
28
48
Children
6­
12
yrs
0.03
0.0038
0.0055
0.0082
13
18
27
Youth
13­
19
yrs
0.03
0.0027
0.0044
0.0067
9
15
22
Adults
20­
49
yrs
0.03
0.0028
0.0044
0.0069
9
15
23
Adults
50+
yrs
0.03
0.0025
0.0034
0.0056
8
11
19
Females
13­
49
yrs
0.03
0.0028
0.0043
0.0067
9
14
22
Chronic
Population
Subgroup
cPAD,
mg/
kg/
day
Exposure
Estimate,
mg/
kg/
day
Risk
Estimate,
%
cPADa
U.
S.
Population
(
total)
0.005
0.00069
14
All
infants
(<
1
year)
0.005
0.00156
31
Children
1­
2
yrs
0.005
0.00196
39
Children
3­
5
yrs
0.005
0.00149
30
Children
6­
12
yrs
0.005
0.00088
18
Youth
13­
19
yrs
0.005
0.00054
11
Adults
20­
49
yrs
0.005
0.00055
11
Adults
50+
yrs
0.005
0.00055
11
Females
13­
49
yrs
0.005
0.00054
11
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
a
Reported
to
2
significant
figures.
34
of
94
6.2
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
(
J.
Arthur,
DP
322240,
12/
9/
05)

6.2.1
Home
Uses
There
is
a
potential
for
exposure
to
1,2,4­
T
for
homeowners
in
residential
settings
during
the
application
of
T­
D
fungicide
products
on
lawns
(
turf)
and
from
subsequent
contact
during
activities
in
such
treated
areas.
As
a
result,
risk
assessments
have
been
completed
for
both
residential
handler
and
postapplication
scenarios.

Toddlers
can
be
exposed
directly
to
1,2,4­
T
by
ingesting
soil
where
T­
D
fungicides
have
been
applied
due
to
environmental
degradation
of
the
parent
compound
to
1,2,4­
T.
Indirect
exposure
to
1,2,4­
T
for
toddlers
can
occur
from
dermal
contact
and
absorption
of
T­
D
fungicide
residues
on
treated
turf,
with
subsequent
internal
metabolism
to
1,2,4­
T.
Similarly,
indirect
exposure
also
can
occur
through
incidental
ingestion
of
parent
residues
from
hand­
to­
mouth
and
object­
tomouth
activities
on
T­
D
fungicide­
treated
turf.
Indirect
1,2,4­
T
exposure
can
occur
for
adults
following
direct
dermal
and
inhalation
exposure
to
T­
D
fungicides
while
applying
these
products
to
home
lawns.
Indirect
exposure
may
also
occur
after
application
via
the
dermal
route
from
subsequent
contact
with
treated
lawns.
HED
believes
that
formation
of
1,2,4­
T
in
plants
will
occur
within
the
structures
of
the
plant
or
result
from
uptake
from
soil.
Therefore
surface,
dislodgable
residues
will
not
be
available
and
direct
hand­
to
mouth,
object­
to­
mouth,
or
dermal
exposure
to
1,2,4­
T
are
unlikely.

1,2,4­
T
exposure
is
determined
by
certain
key
characteristics
specific
to
the
parent
T­
D
fungicide
from
which
it
is
formed.
These
characteristics
can
be
different
for
each
parent
T­
D
fungicide
and
include
application
rate,
environmental
and
metabolic
conversion
rates,
molecular
weight,
and
dermal
absorption
factors.
HED
has
based
its
assessment
of
residential
exposure
on
the
currently
registered
turf­
use
T­
D
fungicide
that
results
in
the
highest
1,2,4­
T
exposure
(
i.
e.,
triadimefon)

6.2.1.1
Application
Scenarios
Non­
occupational
exposure
is
likely
during
the
handling
of
T­
D
fungicides
in
the
treatment
of
residential
lawns.
The
major
residential
exposure
scenarios
are
mixer/
loader/
applicators
using
a
hose­
end
sprayer
or
a
low­
pressure
hand
wand.

The
following
assumptions
and
factors
are
specific
to
the
residential
assessment:

 
Residential
handler
exposure
scenarios
are
limited
to
short­
term
duration
due
to
the
episodic
uses
associated
with
homeowner
products.
 
Homeowner
handler
assessments
are
based
on
individuals
wearing
shorts
and
shortsleeved
shirts.
 
Homeowner
handlers
are
expected
to
complete
all
tasks
associated
with
the
use
of
a
pesticide
product
including
mixing/
loading,
if
needed,
as
well
as
the
application.
 
The
Agency
always
considers
the
maximum
application
rates
allowed
by
labels
in
its
risk
35
of
94
assessments
to
consider
what
is
legally
possible
based
on
the
label.
 
The
Agency
based
calculations
on
what
would
reasonably
be
treated
by
homeowners
such
as
the
size
of
a
lawn,
or
the
size
of
a
garden.
 
A
70­
kg
body
weight
is
used
for
adults
because
the
toxicity
endpoint
is
not
genderspecific

Residential
handlers
may
be
exposed
dermally
and
by
inhalation
during
mixing,
loading
and
application
of
T­
D
fungicides
for
short­
term
durations.
Because
a
common
toxicity
endpoint
was
identified
for
both
dermal
and
inhalation
routes,
a
combined
risk
from
both
routes
of
exposure
is
assessed.
Results
from
these
risk
calculations
for
residential
handlers
are
seen
in
Table
6.4
for
triadimefon.
36
of
94
Table
6.4.
Non­
occupational
Handler
Exposure
and
Risk
Estimates
for
1,2,4­
Triazole
from
Triadimefon
Application
to
Turf.

Exposure
Scenario
Personal
Protective
Equipment
Exposure
Route
Applic.

Rate,

lb
ai/
A
Absorption
Rate,
%
Amount
Treated
per
day,
acre
Unit
Exposure,

mg/
lb
ai
Data
Confidence
Daily
Dose,
1
mg/
kg/
day
MOE
2
Total
Daily
Dose,

mg/
kg/
day
Total
MOE3
Dermal
8
114
High
0.00091
33,000
M/
L/
A
Liquids:

hose­
end
sprayer
short
sleeves
short
pants
no
gloves
Inhalation
2.75
100
0.5
0.0164
High
0.000017
1.8E+
6
0.00093
32,000
Dermal
8
565
Low
0.00021
140,000
M/
L/
A
Liquids:

lowpressure
hand
wand
short
sleeves
short
pants
no
gloves
Inhalation
2.75
100
0.023
(
1000
ft2)
0.00385
Medium
0.00000018
1.7E+
8
0.00021
140,000
1
Daily
Dose
=
[
Application
Rate
*
MW
Ratio
(
0.24)
*
Metabolic
Rate
(
0.22)
*
Absorption
Rate
*
Amount
Treated
*
Unit
Exposure)]/
Body
Weight
(
70
kg)

2
MOE
=
NOAEL/
Daily
Dose.
The
dermal
and
inhalation
NOAEL
=
30
mg/
kg/
day,
was
used
for
all
calculations.
The
LOC
=
1000.

3
Total
MOE
=
NOAEL/(
dermal
daily
dose
+
inhalation
daily
dose)

4
Unit
exposure
values
taken
from
ORETF
study
(
OMA004),
"
Mixer/
Loader/
Applicator:
Hose­
end
Sprayer.
Mix
your
own."

5
Unit
exposure
values
taken
from
ORETF
study
(
OMA005),
"
Resident
Mixer/
loader/
applicator
­
Handheld
Pump
Sprayer:
Fruit
Trees
and
Ornamentals."
37
of
94
Residential
handler
risk
estimates
from
exposure
to
1,2,4­
T
do
not
exceed
HED's
LOC
for
lawn
use
of
triadimefon.
Dermal
absorption
factors
used
in
this
assessment
were
taken
from
the
May
2005
assessment
(
MRID
46553701)
provided
by
the
U.
S.
Triazole
Task
Force
(
USTTF).

6.2.1.2
Postapplication
Scenarios
Individuals
of
varying
ages
can
potentially
be
exposed
from
activities
on
treated
turf.
Potential
routes
of
exposure
include
dermal
and
incidental
ingestion
(
toddlers
only).
Residential
uses
of
T­
D
fungicides
may
result
in
short­
term
(
1
to
30
days)
postapplication
exposures.
Available
data
for
1,2,4­
T
and
various
parent
T­
D
fungicides
indicates
that
residues
of
these
compounds
may
persist
long
enough
to
warrant
assessment
of
intermediate­
term
exposures
(>
30
days
to
180
days).

The
HED
Standard
Operating
Procedures
for
Residential
Exposure
Assessments
(
Draft,
December
18,
1997)
were
used
as
a
guideline
for
performing
the
residential
postapplication
assessment.
Also
used
in
the
assessment
were
interim
changes
to
these
SOPs
which
were
adopted
by
the
HED
Exposure
Science
Advisory
Council
regarding
standard
values,
including,
for
turf
transferrable
residues,
turf
transfer
coefficients
and
hand­
to­
mouth
activities
(
Policy
11,
February
22,
2001).
The
exposure
and
risk
estimates
for
the
four
residential
exposure
scenarios
are
assessed
for
the
day
of
application
(
day
"
0")
because
it
is
assumed
that
adults
and
toddlers
could
contact
the
lawn
immediately
after
application.
On
the
day
of
application,
it
was
assumed
that
5
percent
of
the
application
rate
is
available
from
the
turf
grass
as
transferable
residue
(
20
percent
for
object­
to­
mouth
activities).

Assessment
of
residential
postapplication
exposure
was
performed
using
the
same
approach
as
was
used
for
handler
exposure
above
using
the
T­
D
fungicide
triadimefon.

A
summary
of
the
estimated
exposures
and
risks,
along
with
the
algorithms
used
for
each
turf
exposure
scenario
are
presented
below
in
Tables
6.5
 
6.8
for
triadimefon.
38
of
94
Table
6.5.
Dermal
Exposure
and
Risk
for
Adults
and
Children
from
Treated
Lawns
(
Triadimefon)

Subgroup
exposed
Applicati
on
Rate,

lb
ai/
A
Fraction
of
ai
Available
Turf
Transferrable
Residue
at
Day
"
0"

(
ug/
cm2)
1
Dermal
Transfer
Coefficient,

cm2/
hr
Exposure
Time,

hrs/
day
Absorption
Factor
Body
Weight,

kg
Daily
Dose,
2
mg/
kg/
day
MOE3
Adult
5.4
0.05
2.94
14,500
2
8%
70
0.0051
5,900
Children
5.4
0.05
2.94
5200
2
8%
15
0.0086
3,500
1
Turf
Transferrable
Residue
(
ug/
cm2)
=
Application
rate
(
lb
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
2
Daily
Dose
=
(
Turf
Transferrable
Residue
x
Absorption
Factor
x
1E­
3
mg/
ug
x
Dermal
Transfer
Coefficient
x
Exposure
Time
x
MW
ratio
(
0.24)
x
Metab.

Conv.
Rate
(
0.22))/
Body
weight
3
MOE
=
Dermal
NOAEL
(
30
mg/
kg/
day)
/
Daily
Dose.
LOC
=
1000.

Table
6.6.
Oral
Hand­
to­
mouth
Exposure
and
Risk
for
Children
from
Treated
Lawns
(
Triadimefon)

Application
Rate,

lb
ai/
A
Fraction
of
ai
Available
Turf
Transferrable
Residue
at
Day
"
0",

(
ug/
cm2)
1
Exposure
Time,

hrs/
day
Extraction
by
saliva
Hand
Surface
Area,

cm2/
event
Frequency,

events/
hr
Body
Weight,

kg
Daily
Dose,
2
mg/
kg/
day
MOE3
5.4
0.05
2.94
2
0.5
20
20
15
0.0041
7,300
1Turf
Transferrable
Residue
(
ug/
cm2)
=
Application
rate
(
lb
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
2
Daily
Dose
=
(
Turf
Transferrable
Residue
x
Extraction
by
Saliva
x
Hand
Surface
Area
x
Frequency
x
1E­
3
mg/
ug
x
Exposure
Time
x
MW
ratio
x
Metab.

Conv.
Rate)/
Body
Weight.

3
MOE
=
Oral
NOAEL
(
30
mg/
kg/
day)
/
Daily
Dose.
LOC
=
1000.

Table
6.7.
Oral
Object­
to­
mouth
(
Turfgrass)
Exposure
and
Risk
for
Children
from
Treated
Lawns
(
Triadimefon)

Application
Rate,

lb
ai/
A
Fraction
of
ai
Available
Grass
Residue
at
Day
"
0",

(
ug/
cm2)
1
Surface
Area
Mouthed,

cm2/
day
Body
Weight,

kg
Daily
Dose,
2
mg/
kg/
day
MOE3
5.4
0.2
11.6
25
15
0.001
30,000
1Grass
Residue
(
ug/
cm2)
=
Application
rate
(
lb
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
2
Daily
Dose
=
(
Grass
residue
x
Surface
Area
Mouthed
x
1E­
3
mg/
ug
x
MW
ratio
(
0.24)
x
Metab.
Conv.
Rate
(
0.22))/
Body
Weight.

3
MOE
=
Oral
NOAEL
(
30
mg/
kg/
day)
/
Daily
Dose.
LOC
=
1000.
39
of
94
Table
6.8
Exposure
and
Risk
for
Children
from
Ingestion
of
Soil
from
Treated
Lawns
(
Triadimefon)

Application
Rate,

lb
ai/
A
Fraction
of
ai
Available
Soil
Residue
at
Day
"
0",

(
ug/
g)
1
1,2,4­
T
to
Parent
MW
Ratio
Max.
Soil
Conversion
Rate
to
1,2,4­
T,
%
Ingestion
Rate,

mg/
day
Body
Weight,

kg
Daily
Dose,
2
mg/
kg/
day
MOE3
5.4
1
39.4
0.24
30.7
100
15
0.000019
1,600,000
1
Soil
residue
(
ug/
g)
=
[
Application
Rate
(
lbs
ai/
A)
x
Fraction
of
ai
Available
x
4.54E+
8
ug/
lb
x
2.47E­
8
A/
cm2
x
0.67
cm3/
g
soil]

2
Daily
Dose
=
[
Soil
residue
(
ug/
g)
x
Ingestion
rate
(
mg/
day)
x
1E­
6
g/
ug]
x
Soil
Conversion
Rate
x
MW
ratio
/
[
Body
Weight
(
kg)]

3
MOE
=
Oral
NOAEL
(
30
mg/
kg/
day)
/
Daily
Dose.
LOC
=
1000.
40
of
94
The
MOEs
for
postapplication
exposure
to
the
T­
D
fungicide
turf
product,
triadimefon
are
all
>
1000
for
individual
routes
of
exposure,
and
therefore
do
not
exceed
HED's
level
of
concern.
FQPA
requires
residential
exposures
that
could
reasonably
be
expected
to
occur
on
the
same
day
be
combined
and
compared
to
the
appropriate
toxicity
endpoint.
Toddler
dermal
and
incidental
ingestion
by
hand­
to­
mouth,
object­
to­
mouth
and
soil
ingestion
activities
may
co­
occur.
When
the
exposure
estimates
from
these
routes
are
combined,
the
MOE
is
2200.
As
with
the
individual
route
MOEs,
the
aggregate
MOE
does
not
exceed
HED's
LOC.

HED
has
considered
only
ingestion
of
soil­
borne
residues
in
assessing
intermediate­
term
risk.
Although
residues
of
parent
T­
D
fungicides
may
persist
on
turf
(
environmental
half­
lives
are
on
the
order
of
1­
3
months),
the
act
of
mowing
the
lawn
removes
residues
from
the
lawn
surface
and
makes
them
unavailable
for
hand­
to­
mouth,
object­
to­
mouth,
and
dermal
exposures.
The
exposure
estimate
of
0.00013
mg/
kg/
day
from
short­
term
soil
ingestion
is
being
used
as
a
highly
conservative
estimate
for
intermediate­
term
exposure
as
well.
Applying
the
intermediate­
term
NOAEL
of
15
mg/
kg/
day
gives
a
MOE
of
approximately
120,000,
which
is
significantly
greater
than
the
LOC
of
3000.
Therefore,
the
estimated
intermediate­
term
risk
is
below
HED's
level
of
concern.

The
exposure
estimates
in
this
assessment
are
based
on
some
upper­
percentile
(
i.
e.,
maximum
application
rate)
and
some
central
tendency
(
i.
e.,
surface
area,
hand­
to­
mouth
activity,
and
body
weight)
assumptions
and
are,
therefore,
considered
to
be
representative
of
central
to
high­
end
exposures.
The
uncertainties
associated
with
this
assessment
stem
from
the
use
of
an
assumed
amount
of
pesticide
available
from
turf,
and
assumptions
regarding
transfer
of
chemical
residues,
and
hand­
to­
mouth
activity.
Dermal
absorption
factors
used
in
the
assessments
were
taken
from
the
May
2005
assessment
(
MRID
46553701)
provided
by
the
USTTF.

6.2.2
Recreational
Use
Sites
T­
D
fungicides
may
be
used
on
turf
at
recreational
use
sites
and,
therefore
may
result
in
postapplication
exposure
to
adults
and
children
involved
in
recreational
activities.
Exposures
to
adults
and
children
from
the
use
of
T­
D
fungicides
at
recreational
use
sites
are
assumed
to
be
the
same
as
those
assessed
for
residential
use
sites,
and
therefore,
a
separate
recreational
exposure
assessment
was
not
included.
Results
from
the
residential
turf
exposure
assessment
are
considered
upper
percentile
risk
estimates.
Therefore,
it
is
not
expected
that
the
high­
end
residential
exposure
scenario
would
occur
on
the
same
day
as
a
high­
end
recreational
exposure
scenario.
Exposures
from
the
residential
and
recreational
scenarios
are
not
aggregated.
Rather,
the
residential
risk
estimate
should
serve
as
a
high­
end
estimate
for
both
residential
and
recreational
exposure.

6.2.3
Other
(
Spray
Drift,
etc.)

While
the
drifting
of
agricultural
spray
applications
of
T­
D
fungicides
to
nearby
residential
settings
is
possible,
the
T­
D
funcgicide
turf
uses
addressed
in
the
above
residential
risk
assessment
are
considered
to
be
conservative,
worst
case
scenarios,
that
would
cover
any
potential
1,2,4­
T
risks
from
agricultural
spraying
operations.
41
of
94
Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
groundboom
application.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
The
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
and
risks
associated
with
aerial
as
well
as
other
application
types
where
appropriate.

6.2.4
Pharmaceutical
Uses
Triazole
fungicides
have
proved
to
be
useful
tools
in
combating
systemic
fungal
infections
in
humans.
Examples
of
these
compounds
include
fluconazole,
itraconazole,
voriconazole,
and
posaconazole.
The
Food
and
Drug
Administration
(
FDA)
approves
uses
of
pharmaceutical
products
under
FFDCA.
EPA
is
currently
working
with
FDA
to
derive
appropriate
exposure
assessment
methodology
to
determine
how
the
pharmaceutical
uses
of
triazole
fungicides
should
be
considered
in
the
aggregate
risk
assessments
for
1,2,4­
triazole
and
the
triazole
conjugates
(
triazole
alanine
and
triazole
acetic
acid).
A
supplementary
exposure
analysis
will
be
completed,
and
the
incremental
impact
of
exposure
to
pharmaceutical
uses
of
the
triazole
fungicides
will
be
considered
in
the
Agency's
reregistration
decisions
for
propiconazole,
triadimefon,
and
triadimenol.
For
additional
information,
please
refer
to
the
EPA
memorandum
to
FDA
regarding
the
pharmaceutical
uses
of
triazole
fungicides
(
included
in
the
dockets
for
propiconazole,
triadimefon,
and
triadimenol).

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
assessing
acute
and
chronic
risk
from
aggregate
exposure
to
1,2,4­
triazole,
the
only
scenarios
appropriate
for
consideration
are
dietary
exposure
(
all
non­
dietary
exposures
are
short­
to
intermediate­
term
in
duration).
Water
was
included
in
the
dietary
exposure
estimates;
therefore,
the
acute
and
chronic
aggregate
risk
estimates
are
the
same
as
those
presented
in
Section
6.1.2.
Risk
estimates
for
those
durations
were
all
less
than
HED's
level
of
concern.
As
previously
noted,
the
chronic
risk
assessment
is
believed
to
be
protective
of
any
carcinogenic
effects
attributable
to
1,2,4­
T
and
a
separate
cancer
risk
assessment
has
not
been
completed.
Risk
estimates
for
short­
and
intermediate­
term
aggregate
exposure
are
presented
below.
Evaluation
of
short­
and
intermediate­
term
risk
includes
exposures
from
non­
dietary
sources
coupled
with
chronic
dietary
exposure
estimates,
as
an
approximation
of
background­
level
exposure
by
the
dietary
route.
HED
notes
that
this
approach
implicitly
assumes
that
the
non­
dietary
and
dietary
exposures
are
constantly
co­
occurring
during
the
short­
or
intermediate­
term
duration
being
evaluated.
The
approach
does
not
take
into
account
the
temporal
variability
inherent
in
exposures
from
these
different
pathways.
Triadimefon
use
on
turf
is
being
used
to
cover
nondietary
exposures
for
all
T­
D
fungicides.
42
of
94
7.1
Short­
term
Aggregate
Risk
In
assessing
short­
term
aggregate
risk,
HED
has
combined
estimates
of
dietary
exposure
(
direct
and
indirect),
dermal
exposure
(
indirect),
hand­
to­
mouth
exposure
(
indirect,
toddlers
only),
object­
to­
mouth
exposure
(
indirect,
toddlers
only)
and
soil
ingestion
(
direct,
toddlers
only).
These
short­
term
aggregate
risk
estimates
are
considered
to
be
very
conservative.
The
pathwayspecific
exposure
estimates
are
derived
from
high­
end,
health­
protective
assumptions.
In
aggregating
these
exposure
estimates,
HED
has
made
the
further
conservative
assumption
that
the
exposures
co­
occur
for
the
duration
of
the
exposure
interval
(
1­
30
days).
The
exposure
estimates
and
resulting
aggregate
MOE
are
summarized
in
Table
7.1.
Aggregate
MOEs
are
greater
than
the
LOC
of
1000
for
all
population
subgroups.
Therefore,
the
estimated
risks
are
not
of
concern.

Table
7.1.
Short­
term
Aggregate
Exposure
and
Risk
Estimates
for
1,2,4­
Triazole.
Exposure
Estimate,
mg/
kg/
day
Population
Subgroup
Dietary
Dermal
(
M/
L/
A)
Dermal
(
Post­
Applic.)
Hand­
to­
Mouth
Objectto
Mouth
Soil
Ingestion
Aggregate
Aggregate
MOE1
U.
S.
Population
(
total)
0.00069
0.00183
0.0051
N/
A
N/
A
N/
A
0.00762
3,900
All
infants
(<
1
year)
0.00156
N/
A
0.0086
0.0041
0.0010
0.000019
0.01528
2,000
Children
1­
2
yrs
0.00196
N/
A
0.0086
0.0041
0.0010
0.000019
0.01568
1,900
Children
3­
5
yrs
0.00149
N/
A
0.0086
0.0041
0.0010
0.000019
0.01521
2,000
Children
6­
12
yrs
0.00088
N/
A
0.0086
N/
A
N/
A
N/
A
0.00948
3,200
Youth
13­
19
yrs
0.00054
0.00183
0.0051
N/
A
N/
A
N/
A
0.00747
4,000
Adults
20­
49
yrs
0.00055
0.00183
0.0051
N/
A
N/
A
N/
A
0.00748
4,000
Adults
50+
yrs
0.00055
0.00183
0.0051
N/
A
N/
A
N/
A
0.00748
4,000
Females
13­
49
yrs
0.00054
0.00183
0.0051
N/
A
N/
A
N/
A
0.00747
4,000
1
Aggregate
MOE
=
NOAEL
(
30
mg/
kg/
day)
÷
Aggregate
Exposure
Estimate
(
mg/
kg/
day).
LOC
=
1000.

7.2
Intermediate­
term
Aggregate
Risk
In
assessing
intermediate­
term
aggregate
risk,
HED
has
combined
dietary
exposure
(
direct
and
indirect)
with
soil
ingestion
(
direct,
toddlers
only).
Other
sources
of
non­
dietary
exposure
have
not
been
included.
As
noted
in
Section
6.2,
many
T­
D
fungicides
are
relatively
stable
(
half­
lives
on
the
order
of
1­
3
months).
Although
residues
may
persist
into
an
intermediate­
term
timeframe,
they
will
not
be
available
for
hand­
to­
mouth,
object­
to­
mouth,
or
dermal
exposure.
Therefore,
intermediate­
term
aggregate
risk
estimates
only
include
pathways
of
dietary
exposure
and
soil
ingestion.
Aggregate
MOEs
for
infants
and
children
ages
1
to
2
years
are
well
above
the
intermediate­
term
LOC
of
3000
and,
therefore,
represent
risks
that
are
below
HED's
level
of
43
of
94
concern.
Aggregate
risk
estimates
for
older
populations,
where
soil
ingestion
is
not
an
issue,
are
equivalent
to
the
dietary
risk
estimates
presented
in
Section
6.1.

Table
7.2.
Intermediate­
term
Aggregate
Exposure
and
Risk
Estimates
for
1,2,4­
Triazole.
Exposure
Estimate,
mg/
kg/
day
Population
Subgroup
Dietary
Soil
Ingestion
Aggregate
Aggregate
MOE1
U.
S.
Population
(
total)
0.00069
N/
A
0.00069
22,000
All
infants
(<
1
year)
0.00156
0.000019
0.00158
9,500
Children
1­
2
yrs
0.00196
0.000019
0.00198
7,600
Children
3­
5
yrs
0.00149
0.000019
0.00151
9,900
Children
6­
12
yrs
0.00088
N/
A
0.00088
17,000
Youth
13­
19
yrs
0.00054
N/
A
0.00054
28,000
Adults
20­
49
yrs
0.00055
N/
A
0.00055
27,000
Adults
50+
yrs
0.00055
N/
A
0.00055
27,000
Females
13­
49
yrs
0.00054
N/
A
0.00054
28,000
1
Aggregate
MOE
=
NOAEL
(
15
mg/
kg/
day)
÷
Aggregate
Exposure
Estimate
(
mg/
kg/
day).
LOC
=
3000.

8.0
Cumulative
Risk
Characterization/
Assessment
FQPA
(
1996)
stipulates
that
when
determining
the
safety
of
a
pesticide
chemical,
EPA
shall
base
its
assessment
of
the
risk
posed
by
the
chemical
on,
among
other
things,
available
information
concerning
the
cumulative
effects
to
human
health
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
other
substances
that
have
a
common
mechanism
of
toxicity.
The
reason
for
consideration
of
other
substances
is
due
to
the
possibility
that
low­
level
exposures
to
multiple
chemical
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
could
lead
to
the
same
adverse
health
effect
as
would
a
higher
level
of
exposure
to
any
of
the
other
substances
individually.
A
person
exposed
to
a
pesticide
at
a
level
that
is
considered
safe
may
in
fact
experience
harm
if
that
person
is
also
exposed
to
other
substances
that
cause
a
common
toxic
effect
by
a
mechanism
common
with
that
of
the
subject
pesticide,
even
if
the
individual
exposure
levels
to
the
other
substances
are
also
considered
safe.

HED
did
not
perform
a
cumulative
risk
assessment
as
part
of
this
assessment
for
the
triazole
metabolites.
Investigations
into
the
potential
cumulative
effects
of
1,2,4­
triazole,
triazole
alanine
and
triazole
acetic
acid,
and
parent
triazole­
derivative
fungicides
are
currently
being
undertaken
by
the
Office
of
Research
and
Development.
Additionally,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
regarding
the
triazole
metabolites
and
any
other
substances.
For
purposes
of
this
assessment,
EPA
has
assumed
that
1,2,4­
triazole
and
triazole
alanine/
triazole
acetic
acid
do
not
have
a
common
mechanism
of
toxicity
and
that
the
triazole
metabolites
do
not
have
a
common
mechanism
of
toxicity
with
other
substances.

Before
undertaking
a
cumulative
risk
assessment,
HED
will
follow
procedures
for
identifying
chemicals
that
have
a
common
mechanism
of
toxicity
as
set
forth
in
the
"
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity"
(
64
FR
5795­
5796,
February
5,
1999).
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
44
of
94
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

On
this
basis,
the
Registrant
must
submit,
upon
EPA's
request
and
according
to
a
schedule
determined
by
the
Agency,
such
information
as
the
Agency
directs
to
be
submitted
in
order
to
evaluate
issues
related
to
whether
the
triazole
metabolites
share
a
common
mechanism
of
toxicity
with
any
other
substances.
If
HED
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
the
triazole
metabolites,
HED
will
perform
aggregate
exposure
assessments
on
each
chemical
and
will
begin
to
conduct
a
cumulative
risk
assessment.

As
previously
noted,
this
assessment
does
take
into
consideration
the
multiple
parent
triazolederivative
fungicides
that
may
lead
to
dietary
and
non­
dietary
exposure
to
the
triazole
metabolites.

9.0
Occupational
Exposure/
Risk
Pathway
Occupational
exposure
to
1,2,4­
triazole
is
likely
to
occur
as
a
result
of
activities
associated
with
a
single
T­
D
compound.
The
risks
associated
with
occupational
exposure
to
this
compound
are
addressed
in
the
risk
assessments
for
the
parent
compounds.
Those
risk
estimates
inherently
include
risk
associated
with
occupational
exposure
to
1,2,4­
triazole.
Therefore,
an
occupational
exposure
and
risk
assessment
for
1,2,4­
triazole,
per
se,
is
not
warranted.
This
is
unlike
the
case
for
dietary
exposure
where
it
is
likely
that
multiple
T­
D
fungicides
simultaneously
lead
to
1,2,4­
triazole
exposure.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
 
Developmental
neurotoxicity
study
in
rats.
 
Chronic
toxicity/
oncogenicity
study
in
male
rats
and
female
mice
[
This
study,
included
in
the
original
data
call­
in,
has
not
been
submitted.
As
noted
above,
a
previous
waiver
request
for
this
study
was
denied.
A
new
waiver
request
submitted
in
August,
2005,
is
under
review.]
 
Acute
neurotoxicity
study
in
rats
[
This
study,
included
in
the
original
data
call­
in,
was
placed
in
reserve
pending
the
results
of
the
combined
subchronic/
neurotoxicity
study,
in
response
to
a
previous
waiver
request.
A
new
waiver
request
for
this
study
was
submitted
in
August
2005,
and
is
under
review.]

10.2
Residue
Chemistry
 
A
final
two­
year
storage
stability
study
with
1,2,4­
triazole
remains
outstanding.
An
interim
report,
depicting
residues
following
one
year
of
storage
indicates
that
1,2,4­
T
is
stable
in
frozen
food
commodities.

10.3
Occupational
and
Residential
Exposure
45
of
94
 
A
study
examining
dislodgeable
foliar
residues
of
the
T­
D
fungicide
metabolites
was
requested.
However,
the
USTTF
has
requested
that
the
Agency
waive
the
study,
arguing
that
any
residues
of
metabolites
would
be
contained
within
the
leaf
surface
and
therefore
not
dislodgeable.
The
waiver
request
has
been
reviewed
by
HED
and
recommended
to
be
granted
(
Jack
Arthur,
D319566,
12/
22/
05).

Triazole
Alanine
and
Triazole
Acetic
Acid
11.0
Hazard
Characterization/
Assessment
11.1
Hazard
Characterization
11.1.1
Database
Summary
11.1.1.1
Studies
available
and
considered
For
triazole
alanine,
acute
toxicity
was
evaluated
using
acute
oral
toxicity
studies
and
a
nonguideline
acute
intraperitoneal
toxicity
study.
Subchronic
studies
available
for
hazard
characterization
included
14­
day,
28­
day,
and
90­
day
oral
toxicity
studies
in
the
rat
and
a
90­
day
oral
toxicity
study
in
the
dog.
No
chronic
studies
were
submitted.
Developmental
toxicity
and
two­
generation
reproduction
studies
in
the
rat
were
evaluated;
a
developmental
toxicity
study
in
the
rabbit
was
not
available.
Multiple
mutagenicity
and
metabolism
studies
were
considered.

For
triazole
acetic
acid,
five
acceptable
studies
were
available
for
hazard
characterization:
an
acute
oral
toxicity
study,
a
non­
guideline
14­
day
oral
toxicity
study
in
the
rat,
a
bacterial
reverse
mutation
assay,
and
two
non­
guideline
metabolism
studies.

For
triazole
lactic
acid
and
triazole
pyruvate,
no
mammalian
toxicology
studies
were
available.

11.1.1.2
Mode
of
action,
metabolism,
and
toxicokinetic
data
Mode
of
action.
The
parent
triazole
fungicides
act
by
inhibiting
sterol
synthesis,
particularly
by
preventing
the
14­
demethylation
of
the
sterols.
The
sterols,
which
are
similar
to
cholesterol
in
mammals,
are
important
for
fungi
membrane
structure
and
function.
The
mode(
s)
of
action
for
mammalian
toxicity
associated
with
1,2,4­
triazole
and
the
triazole
conjugates
is
currently
unknown.

Metabolism
and
toxicokinetic
data.
Pharmacokinetic
studies
showed
that
triazole
alanine
is
rapidly
absorbed
and
excreted
following
single
oral
gavage
doses
of
0.5,
0.56,
5,
54,
56,
or
994
mg/
kg,
following
five
daily
oral
gavage
doses
of
approximately
48­
49
mg/
kg/
day,
and
following
a
single
dose
of
5
mg/
kg
by
i.
v.
injection.
Excretion
occurred
mostly
in
the
urine,
accounting
for
81­
85%
to
>
90%
of
the
administered
radioactivity
in
three
single
oral
and
i.
v.
injection
studies
and
~
55­
63%
in
the
multiple
oral
dose
study
at
168
hours.
Much
less
of
the
radioactivity
was
excreted
in
the
feces,
which
accounted
for
~
2­
5%
of
the
administered
radioactivity
in
the
single
dose
studies
and
~
11­
27%
in
the
multiple
oral
dose
study.
Volatiles
accounted
for
<
1%
of
the
46
of
94
radioactivity.
Tissue
residues
were
low
in
all
studies,
with
the
majority
of
the
radiolabel
found
in
tissues
located
in
the
liver
and
kidneys.

The
two
single
oral
dose
triazole
alanine
metabolism
studies
are
consistent,
since
both
found
high
amounts
of
unchanged
triazole
alanine
(
72­
93%
of
the
radioactivity)
recovered
in
the
urine
24
hours
after
exposure
to
0.56­
994
mg/
kg,
lesser
amounts
of
N­
acetyl
triazole
alanine
(
8­
30%),
and
a
small
percentage
of
unknown
metabolites.
There
was
no
mention
that
triazole
acetic
acid
or
1,2,4­
triazole
were
detected
in
these
urinary
samples.
(
Note
that
N­
acetyl
triazole
alanine
and
triazole
acetic
acid
are
structurally
different.)
From
the
fecal
samples
taken
24
hours
following
oral
exposure
to
56
mg/
kg,
a
high
proportion
of
the
recovered
radioactivity
was
unchanged
triazole
alanine
(
50%),
with
less
N­
acetyl
triazole
alanine
identified
(
16%),
similar
to
what
was
found
in
the
urine.
However,
30%
of
the
radioactivity
found
in
the
fecal
samples
consisted
of
an
unknown
component
that
did
not
appear
in
the
urinary
samples.

In
the
repeated
oral
dose
metabolism
study,
a
large
amount
(
63%)
of
the
radioactivity
recovered
in
the
urine
samples
taken
168
hours
following
5
doses
of
~
48­
49
mg/
kg/
day
triazole
alanine
was
identified
as
unchanged
triazole
alanine,
similar
to
what
was
seen
24
hours
after
a
single
dose.
However,
30%
of
the
urinary
radioactivity
was
identified
as
triazole
acetic
acid,
and
1.6%
was
identified
as
1,2,4­
triazole.
These
compounds
were
not
seen
in
the
single
dose
studies;
furthermore,
N­
acetyl
triazole
alanine,
which
was
seen
in
the
single
dose
studies,
was
not
seen
in
the
repeated
dose
study.
This
study
also
showed
that
the
same
three
components
seen
in
the
urine
were
found
in
the
feces.
However,
a
much
larger
percentage
of
the
radioactivity
recovered
in
the
feces
was
identified
as
triazole
acetic
acid
(
69%)
and
1,2,4­
triazole
(
11%),
with
significantly
less
excreted
as
unchanged
triazole
alanine
(
2%).
The
remaining
radioactivity
in
the
feces
was
made
up
of
three
unknown
conjugates,
none
of
which
was
greater
than
7%.

For
triazole
acetic
acid,
two
metabolism
and
pharmacokinetic
studies
showed
rapid
absorption
and
excretion
following
a
single
oral
dose
of
approximately
0.6,
59,
or
1035
mg/
kg
or
five
daily
oral
doses
of
approximately
50­
51
mg/
kg/
day.
Excretion
occurred
mainly
in
the
urine,
as
it
did
for
triazole
alanine,
accounting
for
~
90­
104%
of
the
administered
radiolabel
in
the
single
dose
study
and
~
66­
75%
of
the
radiolabel
in
the
multiple
dose
study
at
168
hours.
The
feces
accounted
for
much
less
of
the
administered
radiolabel:
~
1­
7%
in
the
single
dose
study
and
~
11­
32%
in
the
multiple
dose
study.
In
both
studies,
tissue
burdens
were
very
low.
Unlike
triazole
alanine,
the
sole
component
identified
in
both
the
urinary
and
fecal
extracts
from
these
two
studies
was
triazole
acetic
acid,
indicating
that
triazole
acetic
acid
administered
to
the
rat
is
excreted
intact
without
metabolic
conversion.

11.1.1.3
Sufficiency
of
studies/
data
Triazole
alanine.
The
partial
toxicology
database
available
for
triazole
alanine
is
insufficient
to
fully
characterize
the
hazards
associated
with
this
conjugate.
However,
it
was
possible
to
categorize
the
acute
toxicity
of
triazole
alanine,
to
identify
effects
following
subchronic
exposure,
to
begin
examination
of
the
differences
in
toxicity
associated
with
longer
duration
of
exposure
and
across
species
(
i.
e.,
rat
and
dog),
to
examine
potential
reproductive
toxicity,
to
evaluate
the
differences
in
susceptibility
between
rodent
parents
and
offspring,
and
to
examine
the
potential
of
triazole
alanine
to
cause
mutagenicity.
47
of
94
The
toxicity
resulting
from
exposures
to
triazole
alanine
longer
than
90
days
was
not
determined
because
no
chronic
studies
were
available.

Interspecies
differences
were
not
fully
examined
because
no
triazole
alanine
studies
were
conducted
in
rabbits
or
mice.
The
lack
of
a
developmental
toxicity
study
in
rabbits
is
a
particularly
important
data
gap,
because
mortality
and
clinical
signs
were
seen
in
adult
rabbits
following
a
single
dose
of
45
mg/
kg
1,2,4­
triazole
in
a
rabbit
developmental
study
(
MRID
46492903).
For
free
triazole,
the
rabbit
was
shown
to
be
the
most
sensitive
species;
in
the
absence
of
data
to
suggest
otherwise,
it
is
likely
that
rabbits
are
also
more
sensitive
to
triazole
alanine.

Triazole
acetic
acid.
The
toxicology
database
for
triazole
acetic
acid
consists
of
five
acceptable
studies,
including
three
non­
guideline
studies.
In
the
absence
of
additional
data,
the
studies
on
triazole
acetic
acid
were
compared
to
corresponding
studies
on
triazole
alanine
to
determine
potential
differences
in
potency
between
these
two
conjugates.

Other
triazole
conjugates.
No
mammalian
toxicology
studies
are
available
for
triazole
lactic
acid
or
triazole
pyruvate.
These
compounds
occur
only
infrequently
in
plant
metabolism
studies
and
have
not
been
included
in
the
quantitative
risk
assessment.

11.1.2
Toxicological
Effects
11.1.2.1
Acute
toxicity
Triazole
alanine.
The
acute
toxicity
of
triazole
alanine
is
low,
based
on
acute
oral
toxicity
studies
in
the
the
rat
and
mouse
(
Category
IV)
and
an
acute
intraperitoneal
toxicity
study
in
the
rat
(
LD50
>
5000
mg/
kg).
Although
triazole
alanine
was
classified
as
Category
III
according
to
results
from
one
acute
oral
toxicity
study
(
MRID
00138119),
this
was
because
inadequate
dose
levels
were
tested.
Note
that
although
the
acute
toxicity
of
1,2,4­
triazole
was
greater
in
the
rabbit
than
in
the
rat
or
mouse,
a
similar
comparison
of
the
acute
toxicity
of
triazole
alanine
across
species
could
not
be
made
since
acute
rabbit
studies
were
not
submitted
for
the
conjugate.

Triazole
acetic
acid.
The
acute
toxicity
of
triazole
acetic
acid
is
also
low,
based
on
an
acute
oral
toxicity
study
in
the
rat
(
Category
IV).

Table
11.1.
Acute
Toxicity
Profile
for
Triazole
Alanine
Test
Material
[%
ai]
Guideline
Number
Study
Type
MRID
Number
Results
Toxicity
Category
Triazole
alanine
[
not
specified]
870.1100
Acute
oral
­
rat
00138119
(
TXR
004766
Acc.
252132)
00133356
LD50
(
 
+
 
 
)
>
2000
mg/
kg
Unacceptable/
supplementary
III
Triazole
alanine
["
analytically
pure"]
870.1100
Acute
oral
­
rat
00138120
(
TXR
004766
Acc.
252132)
00133357
LD50
(
 
+
 
 
)
>
5000
mg/
kg
Acceptable/
guideline
IV
48
of
94
Table
11.1.
Acute
Toxicity
Profile
for
Triazole
Alanine
Test
Material
[%
ai]
Guideline
Number
Study
Type
MRID
Number
Results
Toxicity
Category
Triazole
alanine
["
analytically
pure"]
870.1100
Acute
oral
­
mouse
00138120
(
TXR
004766
Acc.
252132)
00133357
LD50
(
 
+
 
 
)
>
5000
mg/
kg
Acceptable/
guideline
IV
Triazole
alanine
[
99%]
870.1100
Acute
oral
­
dog
00138130
(
TXR
004766
Acc.
252132)
Both
dogs
vomited
a
portion
of
the
test
material
(
5000
mg/
kg)
within
4
hours
of
dosing.
No
other
signs
were
observed
in
the
male.
Slight
salivation,
slightly
unsteady
gait,
and
decreased
food
consumption
and
body
weight
were
seen
in
the
female.

Unacceptable
Not
determined
Triazole
alanine
["
analytical
pure"]
Non­
GDLN
Acute
intraperitoneal
­
rat
00138120
(
TXR
004766
Acc.
252132)
00133357
LD50
(
 
+
 
 
)
>
5000
mg/
kg
Acceptable/
non­
guideline
N/
A
Triazole
alanine
870.1200
Acute
dermal
­
rat
ND
ND
ND
Triazole
alanine
870.1300
Acute
inhalation
­
rat
ND
ND
ND
Triazole
alanine
870.2400
Acute
eye
irritation
­
rabbit
ND
ND
ND
Triazole
alanine
870.2500
Acute
dermal
irritation
­
rabbit
ND
ND
ND
Triazole
alanine
870.2600
Skin
sensitization
­
guinea
pig
ND
ND
ND
ND
=
Study
not
done
Table
11.2.
Acute
Toxicity
Profile
for
Triazole
Acetic
Acid
Test
Material
[%
ai]
Guideline
Number
Study
Type
MRID
Number
Results
Toxicity
Category
Triazole
acetic
acid
[>
99%]
870.1100
Acute
oral
­
rat
45596802
LD50
(
 
+
 
)
>
5000
mg/
kg
IV
Triazole
acetic
acid
870.1200
Acute
dermal
­
rat
ND
ND
ND
Triazole
acetic
acid
870.1300
Acute
inhalation
­
rat
ND
ND
ND
Triazole
acetic
acid
870.2400
Acute
eye
irritation
­
rabbit
ND
ND
ND
Triazole
acetic
acid
870.2500
Acute
dermal
irritation
­
rabbit
ND
ND
ND
Triazole
acetic
acid
870.2600
Skin
sensitization
­
guinea
pig
ND
ND
ND
ND
=
Study
not
done
11.1.2.2
Subchronic,
Chronic,
and
Other
Toxicity
Triazole
alanine.
The
toxicity
of
triazole
alanine
in
the
rat
was
examined
in
14­,
28­,
and
90­
day
oral
toxicity
studies,
a
developmental
toxicity
study,
and
a
two­
generation
reproduction
study.
Of
these
five
studies,
adverse
effects
in
adults
were
only
observed
in
the
90­
day
feeding
study.
49
of
94
These
effects
included
decreased
leukocytes
in
males
and
decreased
triglycerides
at
the
LOAEL
(
370/
400
mg/
kg/
day,
males/
females),
with
decreased
body
weight
and
body
weight
gain
(
males),
decreased
leukocytes
(
both
sexes),
and
decreased
triglycerides
(
both
sexes)
observed
at
1510/
1680
mg/
kg/
day
(
males/
females).

No
treatment­
related
effects
were
seen
in
the
14­
day
drinking
water
study,
in
which
male
rats
were
exposed
to
triazole
alanine
at
dose
levels
up
to
~
1500
mg/
kg/
day.
Because
hematological
and
clinical
chemistry
parameters
(
including
those
decreased
in
the
90­
day
study)
were
not
measured
in
this
study,
it
is
unknown
if
they
would
be
affected
by
two
weeks
exposure
to
triazole
alanine.
The
decreases
in
body
weight
and
body
weight
gain
seen
at
the
high
dose
in
the
90­
day
rat
study
were
not
observed
until
week
3,
so
it
is
not
unexpected
that
body
weight
measurements
remained
comparable
to
controls
in
this
two
week
study.

No
treatment­
related
effects
were
seen
in
the
28­
day
oral
toxicity
study,
in
which
rats
were
exposed
to
triazole
alanine
via
oral
gavage
at
dose
levels
up
to
400
mg/
kg/
day.
This
study
was
classified
unacceptable
due
to
the
lack
of
analytical
data
on
the
test
compound
and
incomplete
hematological,
clinical
chemistry,
and
histopathological
analyses.
Leukocyte
counts,
which
were
measured
in
this
study,
were
unaffected
following
28
days
exposure
to
triazole
alanine
by
gavage
(
vehicle
=
Cremophor
EL),
although
they
were
slightly
decreased
after
one
month
of
dietary
exposure
in
the
90­
day
feeding
study.
Triglycerides,
which
were
decreased
in
the
90­
day
study,
were
not
evaluated
in
this
study.
The
decreased
body
weights
and
body
weight
gains
observed
on
week
3
of
the
90­
day
study
were
not
seen
in
this
study,
which
is
not
unexpected
given
that
the
highest
dose
tested
in
the
28­
day
study
was
just
400
mg/
kg/
day
vs.
1510
mg/
kg/
day
in
the
90­
day
study.

Systemic
maternal/
paternal
toxicity
was
not
seen
in
the
developmental
toxicity
or
two­
generation
reproduction
studies
in
rats
at
dose
levels
up
to
~
1000
mg/
kg/
day.
Reproductive
toxicity
was
also
not
noted.
Because
hematology
and
clinical
chemistry
are
not
examined
in
developmental
or
reproduction
studies,
it
is
unknown
if
they
were
affected
as
in
the
90­
day
feeding
study.
Changes
in
body
weights
observed
in
the
90­
day
study
were
not
seen
in
either
of
these
studies;
however,
the
highest
dose
levels
tested
in
the
developmental
and
reproduction
studies
were
lower
than
those
which
produced
body
weight
effects
in
the
90­
day
study.

Differences
in
toxicity
due
to
increased
duration
of
exposure
to
triazole
alanine
could
not
be
confirmed
since
treatment­
related
effects
were
only
seen
in
the
90­
day
study
and
since
hematological
and
clinical
chemistry
parameters
were
not
measured
in
the
shorter
duration
studies.

Differences
between
routes
of
exposure
to
triazole
alanine
could
not
be
examined
because
dermal
and
inhalation
studies
were
not
available.

Differences
in
the
toxicity
of
triazole
alanine
across
mammalian
species
were
examined
by
comparing
the
90­
day
feeding
studies
in
the
rat
and
the
dog.
(
Studies
using
the
mouse
or
rabbit
were
not
available.
The
lack
of
a
rabbit
study
is
a
particularly
important
data
gap
because
the
rabbit
is
the
most
sensitive
species
to
free
triazole.
Mortality
and
clinical
signs
of
neurotoxicity
were
seen
in
adult
rabbits
following
a
single
gavage
dose
of
45
mg/
kg
1,2,4­
triazole
in
a
rabbit
50
of
94
developmental
study
[
MRID
46492903]).
As
stated
previously,
treatment­
related
effects
in
the
90­
day
rat
study
include
decreased
leukocytes
(
males)
and
triglycerides
(
females)
at
the
LOAEL
(
370/
400
mg/
kg/
day
in
males/
females),
as
well
as
decreased
leukocytes
and
triglycerides
in
both
sexes
and
decreased
body
weights
and
body
weight
gains
in
males
at
the
highest
dose
tested
(
1510/
1680
mg/
kg/
day
in
males).
Triazole
alanine
is
less
toxic
in
dogs.
The
only
treatmentrelated
effect
seen
in
the
90­
day
dog
study
was
a
10%
decrease
in
female
food
consumption
near
the
limit
dose
(
902
mg/
kg/
day),
with
no
effects
seen
in
males.

Increased
quantitative
and
qualitative
susceptibility
of
the
offspring
was
seen
in
the
developmental
toxicity
rat
study,
and
increased
quantitative
susceptibility
was
seen
in
the
twogeneration
reproduction
study.
In
the
developmental
toxicity
study,
increased
incidences
of
skeletal
findings
were
seen
in
the
offspring
at
the
mid
and
high
doses,
while
no
treatment­
related
effects
were
seen
in
the
dams
up
to
the
limit
dose.
These
skeletal
findings
include
unossified
odontoid
processes
at
300
and
1000
mg/
kg/
day,
with
partially
ossified
transverse
processes
of
the
7th
cervical
vertebra
(
bilateral),
unossified
5th
sternebra,
and
partially
ossified
13th
thoracic
centrum
observed
only
at
1000
mg/
kg/
day.
In
the
reproduction
study,
mean
litter
weights
were
decreased
approximately
10­
20%
for
both
generations
at
~
1000
mg/
kg/
day,
compared
to
controls,
but
parental
body
weights
were
unaffected
at
all
treatment
levels.

No
mutagenic
potential
was
noted
in
the
following
acceptable
mutagenicity
studies:
1.
bacterial
reverse
mutation
assays,
2.
in
vitro
mammalian
cell
gene
mutation
tests
conducted
in
BALB/
3T3
and
CHO
cells,
3.
mammalian
erythrocyte
micronucleus
tests
conducted
using
mice
and
Chinese
hamsters,
and
4.
bacterial
DNA
damage
and
repair
tests.
An
increased
number
of
transformed
colonies
was
seen
in
an
in
vitro
mammalian
cell
gene
mutation
test
conducted
in
baby
hamster
kidney
cells
(
MRID
00132914);
however,
this
study
was
classified
unacceptable/
inconclusive
due
to
severe
toxicity,
excessive
concentrations,
and
lack
of
information
regarding
test
material
purity.
Mutagenic
potential
was
also
seen
in
a
mammalian
erythrocyte
micronucleus
test
conducted
using
mice
(
MRID
0013912);
however,
this
study
was
classified
unacceptable/
inconclusive
because
effects
were
seen
only
at
24
hours
and
not
at
48
or
72
hours.
Finally,
triazole
alanine
inhibited
protein
biosynthesis
in
microorganisms
(
TXR
005841);
however,
this
study
was
classifed
unacceptable
due
to
inconsistent
results,
a
lack
of
individual
data,
not
enough
dose
levels
tested,
and
no
explanation
of
incubation
times
used.

Triazole
acetic
acid.
In
a
14­
day
toxicity
feeding
study
in
rats,
no
treatment­
related
effects
were
observed
up
to
the
highest
dose
tested
(
788/
703
mg/
kg/
day
in
males/
females).
No
other
studies
are
available
to
determine
the
target
organs
and
critical
effects
of
triazole
acetic
acid;
to
compare
toxicity
across
species,
routes
of
exposure,
or
duration
of
exposure;
or
to
examine
potential
developmental,
reproductive,
or
neurological
toxicity.
This
short­
term
study
is
comparable
to
the
14­
day
oral
triazole
alanine
study,
in
which
no
effects
were
seen
in
male
rats
up
to
1491
mg/
kg/
day,
and
to
the
28­
day
oral
triazole
alanine
study,
in
which
no
effects
were
seen
in
male
or
female
rats
up
to
400
mg/
kg/
day.
However,
since
no
effects
were
seen
in
the
available
shortterm
studies,
a
difference
in
toxicity
between
triazole
alanine
and
triazole
acetic
acid
could
not
be
evaluated.
51
of
94
Mutagenicity
was
not
seen
in
an
acceptable/
guideline
bacterial
reverse
mutation
assay
using
triazole
acetic
acid
or
in
the
available
mutagenicity
studies
for
triazole
alanine.
Therefore,
neither
compound
appears
mutagenic.

11.1.3
Dose­
Response
For
triazole
alanine,
greater
toxicity
was
seen
at
higher
doses.
At
the
mid
dose
(
LOAEL)
in
the
90­
day
feeding
study,
decreased
leukocytes
were
seen
in
males
only
and
decreased
triglycerides
were
seen
only
in
females
(
370/
400
mg/
kg/
day,
males/
females).
However,
at
the
high
dose,
decreased
leukocytes
and
triglycerides
were
each
seen
in
both
sexes,
along
with
decreased
body
weight
and
body
weight
gain
in
males
(
1510/
1680
mg/
kg/
day,
males/
females).
In
the
rat
developmental
toxicity
study,
more
types
of
skeletal
findings
were
observed
in
offspring
at
the
high
dose
(
1000
mg/
kg/
day),
compared
to
the
mid
dose
(
300
mg/
kg/
day).

For
triazole
acetic
acid,
dose­
response
could
not
be
evaluated
because
no
treatment­
related
effects
were
observed
in
the
available
toxicity
studies.

Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
Nonguideline
14­
Day
drinking
water
toxicity
in
rodents
­
rat
Acceptable/
nonguideline
00138121
(
TXR
004766
Accession
#
252132)
00133358
0,
3000,
10000
ppm
M:
0,
448,
1491
mg/
kg/
day
F:
not
tested
NOAEL
=
1491
mg/
kg/
day
(
M)
LOAEL
=
>
1491
mg/
kg/
day
(
M)

870.3050
28­
Day
oral
toxicity
in
rodents
­
rat
Unacceptable
00138122
(
TXR
004766
Accession
#
252132)
00133359
0,
25,
100,
400
mg/
kg/
day
NOAEL
=
400
mg/
kg/
day
(
M/
F)
LOAEL
=
>
400
mg/
kg/
day
(
M/
F)

Many
of
the
required
hematology,
clinical
chemistry,
and
microscopic
pathology
parameters
were
not
examined.
Dosages
administered
to
the
test
animals
were
not
analytically
quantitated.
52
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.3100
90­
Day
oral
toxicity
in
rodents
­
rat
Acceptable/
nonguideline
00164107
(
TXR
005532
005094)
0,
1250,
5000,
20000
ppm
M:
0,
90,
370,
1510
mg/
kg/
day
F:
0,
160,
400,
1680
mg/
kg/
day
NOAEL
=
90/
160
mg/
kg/
day
(
M/
F)
LOAEL
=
370/
400
mg/
kg/
day
(
M/
F)
based
on
decreased
leukocyte
counts
in
males
and
decreased
triglycerides
in
females.

At
1510/
1680
mg/
kg/
day
(
M/
F),
decreased
body
weight
(
M),
body
weight
gain
(
M),
leukocytes
(
M&
F),
and
triglycerides
(
M&
F)
were
seen.

There
was
no
assessment
of
motor
activity,
grip
strength,
or
sensory
reactivity
of
the
test
animals.
There
was
no
indication
of
how
often
fresh
batches
of
food
containing
the
test
material
were
given
to
the
animals.
870.3100
90­
Day
oral
toxicity
in
rodents
­
mouse
ND
ND
ND
870.3150
90­
Day
oral
toxicity
in
nonrodents
­
dog
Acceptable/
guideline
00164106
00154946
(
TXR
004469
005841
Accession
#
256058)
0,
3200,
8000,
20000
ppm
M:
0,
144,
322,
850
mg/
kg/
day
F:
0,
150,
345,
902
mg/
kg/
day
NOAEL
=
850/
345
mg/
kg/
day
(
M/
F)
LOAEL
=
>
850/
902
mg/
kg/
day
(
M/
F)
based
on
10%
decreased
food
consumption
in
females
only.

No
treatment­
related
effects
were
seen
in
males.
870.3200
21/
28­
Day
dermal
toxicity
ND
ND
ND
870.3250
90­
Day
dermal
toxicity
ND
ND
ND
870.3465
90­
Day
inhalation
toxicity
ND
ND
ND
870.3700
Prenatal
developmental
toxicity
in
rodents
­
rat
Acceptable/
guideline
00138128
(
TXR
004766
&
005155
Accession
#
252132)

00132915
00147889
(
TXR
0005155
Accession
#
252132)
0,
100,
300,
1000
mg/
kg/
day
Maternal
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
>
1000
mg/
kg/
day
Developmental
NOAEL
=
100
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day
based
on
increased
incidence
of
skeletal
findings
(
unossified
odontoid
process).

At
1000
mg/
kg/
day,
increased
incidences
of
partially
ossified
transverse
processes
of
the
7th
cervical
vertebra
(
bilateral),
unossified
5th
sternebra,
and
partially
ossified
13th
thoracic
centrum
were
also
seen.
53
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.3700
Prenatal
developmental
toxicity
in
nonrodents
ND
ND
ND
870.3800
Reproduction
and
fertility
effects
­
rat
Acceptable/
guideline
00164112
(
TXR
005841
&
008292
Accession
#
252132)

41326803
(
TXR
008292)

41326804
(
TXR
008292)
0,
500,
2000,
10000
ppm
M
(
F0/
F1):
0,
50/
47,
213/
192,
1098/
929
mg/
kg/
day
F
(
F0/
F1):
0,
51/
49,
223/
199,
1109/
988
mg/
kg/
day
Parental/
Systemic
NOAEL
=
929/
988
mg/
kg/
day
(
M/
F)
LOAEL
=
>
929/>
988
mg/
kg/
day
(
M/
F)

Reproductive
NOAEL
=
929/
988
mg/
kg/
day
(
M/
F)
LOAEL
=
>
929/>
988
mg/
kg/
day
(
M/
F)

Offspring
NOAEL
=
192/
199
mg/
kg/
day
(
M/
F)
LOAEL
=
929/
988
mg/
kg/
day
(
M/
F)
based
on
reduced
mean
litter
weights
in
both
generations.
870.4100
Chronic
toxicity
ND
ND
ND
870.4200
Carcinogenicity
ND
ND
ND
870.4300
Combined
chronic
toxicity/
carcinogenicity
ND
ND
ND
870.5100
Bacterial
reverse
mutation
assay
Acceptable/
guideline
00138123
00132911
(
TXR
004469
004562
004766
Accession
#
252132)
20,
100,
500,
2500,
12500
ug/
plate
for
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
(
±
S9)
Not
mutagenic
in
bacteria
(
Salmonella
typhimurium,
±
S9)
under
conditions
of
this
assay.

870.5100
Bacterial
reverse
mutation
assay
Acceptable
00164111
(
TXR
005841)
20­
5000
µ
g/
plate
for
Salmonella
typhimurium
strains
TA98,
TA100,
TA102,
TA1535,
and
TA1537
(
±
S9).
Not
mutagenic.
54
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.5300
In
vitro
mammalian
cell
gene
mutation
test
(
Baby
hamster
kidney
cells)

Unacceptable
00132914
00139576
(
TXR
004562
004766
Accession
#
252132)
­
S9:
0.5,
1,
2,
4,
8
mg/
ml
+
S9:
1,
2,
4,
8,
16
mg/
ml
Inconclusive.
­
S9:
LD39
=
8mg/
ml
(
HDT).
Transformation
frequency
was
39
vs
10
for
control.
An
increase
in
number
of
transformed
colonies.

+
S9:
LD50
=
5.2
mg/
ml.
Transformation
frequency
was
28
vs
0
for
the
control
at
16
mg/
ml.
Increase
in
number
of
transformed
colonies,
but
in
the
presence
of
severe
toxicity
and
excessive
concentrations.
In
addition,
the
lack
of
information
on
the
test
material
purity
raises
concerns
regarding
the
validity
of
the
response.
870.5300
In
vitro
mammalian
cell
gene
mutation
test
(
BALB/
3T3
cells)

Acceptable
00147892
(
TXR
005155
Accession
#
257997)
62.5,
125,
250,
500,
1000
ug/
ml
(
±
S9)
Not
mutagenic.
Triazole
alanine
did
not
induce
cell
transformations
at
levels
up
to
1000
µ
g/
ml.
The
HDT
of
1000
µ
g/
ml
is
the
highest
level
recommended
for
this
test
system.
The
increase
in
cell
transformation
frequency
in
the
presence
of
S9
was
not
significant.
870.5300
In
vitro
mammalian
cell
gene
mutation
test
(
CHO
cells)

Acceptable
00164108
41326801
(
TXR
005841
008292)
500,
1000,
2000,
4000,
6000,
8000,
10000
µ
g/
ml
Not
mutagenic
with
or
without
S9
activation.
Viability
of
cells
at
10000
µ
g/
ml
was
66­
67%
relative
to
control.
At
10000
µ
g/
ml,
a
3­
fold
increase
was
within
the
accepted
spontaneous
range
for
this
cell
line.
Stability
of
compound
was
confirmed.
870.5375
In
vitro
mammalian
chromosome
aberration
test
ND
ND
ND
870.5395
Mammalian
erythrocyte
micronucleus
test
(
mice)

Unacceptable
00132912
00138125
00138131
(
TXR
004562
004766
Accession
#
252131)
8000
mg/
kg,
single
oral
dose
to
15
mice/
sex
Inconclusive
because
effects
were
only
seen
at
24
hours.
No
clinical
or
cytotoxice
effects.
TA
caused
slight
induction
of
micronuclei
in
bone
marrow
PCEs
at
24
hrs,
but
not
at
48
or
72
hrs.
No
data
for
the
negative
control
at
these
two
intervals.
55
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.5395
Mammalian
erythrocyte
micronucleus
test
(
mice)

Acceptable/
guideline
00133361
00138124
(
TXR
004562
004766
Accession
#
252132)
2500
or
5000
mg/
kg,
by
intraperitoneal
injection
Not
mutagenic.
Under
the
conditions
of
this
test,
triazole
alanine
did
not
cause
induction
of
micronuclei
in
mouse
bone
marrow
PCE
stem
cells
when
administered
by
i.
p.
injection
at
2500
or
5000
mg/
kg.
The
effects
of
the
positive
control
were
clearly
demonstrated.
870.5395
Mammalian
erythrocyte
micronucleus
test
(
Chinese
hamster)

Acceptable
00164110
41326802
(
TXR
005841
008292)
5000
mg/
kg
(
limit
dose)

Preliminary
test:
200,
1000,
5000
mg/
kg
Not
mutagenic.
Based
on
scoring
1000
polychromatic
erythrocytes
per
animal
for
the
incidence
of
micronuclei,
TA
was
comparable
to
the
control.
The
best
5
slides
per
sex
were
scored.
870.5500
Bacterial
DNA
damage
test
Acceptable/
guideline
00132913
00138126
(
TXR
004469
004562
004766
Accession
#
252131)
62.5,
125,
250,
500,
1000
µ
g/
plate
(
±
S9)

E.
coli
p3478
(
polA­)
&
E.
coli
W3110
(
polA+)
Not
mutagenic.
No
measurable
inhibition
areolae
were
found
for
E.
coli
polA­
or
polA+
strains
(
±
S9).
Under
the
conditions
of
this
assay,
triazole
alanine
(
±
S9)
did
not
elicit
measurable
DNA
damage.

870.5550
Bacterial
DNA
repair
test
(
rat
hepatocytes)

Acceptable/
guideline
00164109
(
TXR
005841)
0.08,
0.4,
2,
10
mg/
ml
Induced
with
Arochlor
1254
Not
mutagenic.
No
evidence
that
unscheduled
DNA
synthesis
was
induced.

Nonguideline
Potential
inhibition
of
protein
biosynthesis
in
microorganisms
Unacceptable
No
MRID
TXR
005841
Accession
#
265203­
265209
1,
10,
100,
500
ppm
for
E.
coli,
S.
cerevisiae,
and
A.
flavus
TA
inhibited
protein
synthesis
in
all
three
microorganisms
in
the
presence
of
both
radiolabeled
phenylalanine
and
alanine
after
1
hr
of
incubation.
Growth
curve
of
E.
coli
indicated
that
maximum
period
of
protein
synthesis
was
~
1
hr
of
incubation.
Unacceptable
due
to
lack
of
individual
data,
not
enough
doses
of
TA
tested,
no
explanation
of
incubation
times
used,
inconsistent
results.
56
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
45607001
~
10.1
mg/
day*
radiolabeled,
5
days
by
oral
gavage,
to
1
rat/
sex
*
Approx.
48­
49
mg/
kg/
day,
based
on
given
body
weights
Triazole
alanine
is
readily
absorbed
and
excreted
within
48
hours
following
5
daily
doses
of
~
10
mg/
day
of
either
compound.
At
168
hours,
radioactivity
recovery
was
~
92­
98%
of
the
administered
dose.
Absorption
of
the
administered
doses
(
urine
and
cage
wash)
at
168
hours
was
~
71­
81%.
Urinary
excretion
accounted
for
~
55­
63%
of
the
administered
radioactivity;
fecal
excretion
accounted
for
~
11­
27%
of
the
administered
radioactivity.
Minor
gender­
related
quantitative
differences
were
observed,
but
because
only
1
rat/
sex/
compound
was
tested,
these
are
likely
due
to
individual
variability.
Tissue
burdens
were
negligible
at
72
hrs
post­
dosing.
Triazole
alanine,
triazole
acetic
acid,
free
triazole,
plus
three
additional
unknown
metabolites
were
detected
in
the
urine
and
feces.
The
investigators
propose
that
one
of
these
unknown
degradates
is
a
pyruvic
acid
derivative.
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
00138118
(
TXR
004766
Accession
#
252132)
00133354
0.5
or
56
mg/
kg
14Ctriazole
alanine,
single
dose
by
oral
gavage,
to
4
rats/
sex/
dose
For
both
dose
levels,
>
90%
of
the
administered
dose
was
excreted
in
urine
at
168
hours,
~
4­
5%
in
feces,
and
<
1%
in
volatiles,
with
most
excretion
in
the
first
24
hours.
At
the
low
dose,
no
radioactivity
was
detected
in
tissues.
At
the
high
dose,
0.002­
0.02
ppm
of
TA
equivalents
were
detected
in
tissues,
mostly
in
the
liver
and
kidneys.
TA
made
up
72%
and
80.3%,
and
N­
acetyl
TA
made
up
19.4%
and
12.7%
of
the
radioactivity
recovered
from
the
urine
of
low
dose
males
and
females,
respectively.
TA
made
up
83.4%
and
86.4%,
and
N­
acetyl
TA
made
up
10.6%
and
7.7%
of
the
radioactivity
recovered
from
the
urine
of
high
dose
males
and
females,
respectively.
57
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
Continuation
of
MRID
00138118
00139575
(
TXR
004766
Accession
#
252132)
00133355
56
mg/
kg
14C­
triazole
alanine
(
TA),
single
dose
by
oral
gavage,
to
4
rats/
sex/
dose
Urine
and
feces
samples
included
the
first
24
hours
after
exposure.
Triazole
alanine
is
completely
absorbed
and
rapidly
excreted.
The
major
route
of
excretion
is
urine.
Most
of
the
radiolabel
recovered
in
the
urine
sample
from
the
first
24
hours
was
unchanged
TA
(
72­
86%),
with
8­
19%
of
the
urinary
radioactivity
as
N­
acetyl
TA.
Two
or
three
minor
unknown
metabolites
(<
3%
each)
were
also
found
in
the
various
urine
samples.
About
50%
of
the
radiolabel
recovered
in
the
feces
was
TA,
16%
was
recovered
as
N­
acetyl
TA,
and
30%
was
not
identified
but
wasn't
found
in
the
urine.
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
00164114
(
TXR
005841)
0.56,
54.4
or
993.7
mg/
kg
14C
triazole
alanine,
single
dose
by
oral
gavage,
to
2
rats/
sex/
dose
Radioactivity
recoveries
at
168
hours
were
101.2%,
90.7%,
and
92.1%
for
the
low,
mid,
and
high
doses,
respectively.
There
were
no
major
sex
differences
in
excretion
patterns.
The
major
route
of
excretion
was
urine:
81­
82%
of
the
administered
dose
for
males
and
84­
85%
for
females.
Absorption
and
excretion
was
rapid:
within
24
hours
after
dosing,
76­
82%
of
the
administered
dose
in
males
and
71­
91%
in
females
was
eliminated
in
the
feces
and
urine.
Tissue
residues
were
low
(<
1%
for
both
sexes).
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
Continuation
of
MRID
00164114.
00164115
(
TXR
005841)
0.56,
54.4
or
993.7
mg/
kg
14C
triazole
alanine,
single
dose
by
oral
gavage,
to
2
rats/
sex/
dose
Urine
samples
included
the
first
24
hours
after
exposure.
Triazole
alanine
made
up
82­
93%
of
the
radioactivity
recovered
in
the
first
24
hours
urine
sample,
and
Nacetyl
triazole
alanine
made
up
13­
30%.
The
significance
of
an
apparent
decrease
in
the
percentage
of
N­
acetylation
at
the
high
dose
is
questionable.
58
of
94
Table
11.3.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Alanine
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
nonguideline
00138132
(
TXR
004766
Accession
#
252132)
Metabolism:
5
mg/
kg
14Ctriazole
alanine,
by
oral
gavage
or
i.
v.
injection,
to
5
males/
exposure
route
Autoradiography:
10
mg/
kg
14C­
triazole
alanine,
by
i.
v.
injection,
to
6
males
Absorption
and
excretion
was
rapid,
with
most
excretion
in
the
urine.
At
48
hours
after
oral
exposure,
94.5%
and
3.5%
of
the
administered
radiolabel
was
recovered
in
the
urine
and
feces,
respectively.
At
48
hours
after
i.
v.
exposure,
92.4%
and
2.1%
of
the
administered
radiolabel
was
recovered
in
the
urine
and
feces,
respectively.
Tissue
residues
were
low,
with
the
highest
residues
found
in
the
kidney
and
liver.
Following
oral
administration,
radioactivity
increased
in
the
plasma
and
a
maximum
was
attained
within
40
minutes.
Radioactivity
declined
in
a
biphasic
manner
with
half
lives
of
3
and
8
hours.
Following
iv
administration,
radioactivity
decreased
in
triphasic
manner
with
half
lives
of
15
minutes,
4.4
hours,
and
12.4
hours.
Whole
body
autoradiography
indicated
radioactivity
distribution
in
all
tissues
and
organs
except
the
compacts
of
the
bone.
ND
=
Study
not
done
Table
11.4.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Acetic
Acid
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
Nonguideline
14­
Day
oral
toxicity
in
rodents
­
rat
Acceptable/
non­
guideline
45596801
0,
100,
1000,
8000
ppm
M:
0,
10.6,
102.8,
788.3
mg/
kg/
day
F:
0,
10.1,
97.2,
703.5
mg/
kg/
day
NOAEL
=
788.3/
703.5
mg/
kg/
day
(
M/
F)
LOAEL
=
>
788.3/>
703.5
mg/
kg/
day
(
M/
F)

870.3050
28­
Day
oral
toxicity
in
rodents
ND
ND
ND
870.3100
90­
Day
oral
toxicity
in
rodents
ND
ND
ND
870.3150
90­
Day
oral
toxicity
in
nonrodents
ND
ND
ND
870.3200
21/
28­
Day
dermal
toxicity
ND
ND
ND
870.3250
90­
Day
dermal
toxicity
ND
ND
ND
870.3465
90­
Day
inhalation
toxicity
ND
ND
ND
870.3700
Prenatal
developmental
toxicity
in
rodents
ND
ND
ND
59
of
94
Table
11.4.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Acetic
Acid
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.3700
Prenatal
developmental
toxicity
in
nonrodents
ND
ND
ND
870.3800
Reproduction
and
fertility
effects
ND
ND
ND
870.4100
Chronic
toxicity
ND
ND
ND
870.4200
Carcinogenicity
ND
ND
ND
870.4300
Combined
chronic
toxicity/
carcinogenicity
ND
ND
ND
870.5100
Bacterial
reverse
mutation
assay
Acceptable/
guideline
45596803
20,
80,
320,
1280
and
5120
ug/
plate
for
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537
(
his­
)
No
mutagenic
activity
in
bacteria
(
Salmonella
typhimurium)
in
the
presence
or
absence
of
S9
activation.

870.5300
In
vitro
mammalian
cell
gene
mutation
test
ND
ND
ND
870.5375
In
vitro
mammalian
cell
chromosome
aberration
test
ND
ND
ND
870.5395
Mammalian
erythrocyte
micronucleus
test
ND
ND
ND
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cells
in
culture
ND
ND
ND
60
of
94
Table
11.4.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Acetic
Acid
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
non­
guideline
45596804
45596805
0.58,
58.63,
or
1034.69
mg/
kg
radiolabeled,
single
dose
by
oral
gavage.
Triazole
acetic
acid
was
readily
absorbed
and
excreted
within
48
hours
following
a
single
oral
dose
of
0.58,
58.63,
or
1034.69
mg/
kg.
Average
absorption
at
168
hours
was
nearly
complete
(~
93­
103%,
~
102­
104%,
and
~
92­
101%
of
the
administered
dose
for
the
males
and
females
in
the
low­,
mid­,
and
highdose
groups,
respectively)
and
did
not
appear
to
be
saturated
at
the
highest
dose.
Urinary
excretion
accounted
for
~
90­
104%
of
the
administered
radioactivity,
whereas
fecal
excretion
accounted
for
only
~
1­
7%
of
the
administered
radioactivity
in
all
treatment
groups.
Excretory
patterns
did
not
exhibit
gender­
related
variability.
Because
radioactivity
in
tissues
was
very
low,
neither
triazole
acetic
acid
nor
its
metabolites
appear
to
undergo
significant
sequestration.
The
urinary
metabolite
was
identified
as
triazole
acetic
acid,
indicating
that
the
parent
compound
was
excreted
intact
without
being
metabolized
in
the
rat.
61
of
94
Table
11.4.
Subchronic,
Chronic,
and
Other
Toxicity
Profile
for
Triazole
Acetic
Acid
Guideline
Number
Study
Type/
Classification
MRID
Number
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
Acceptable/
non­
guideline
45607001
~
10.5
mg/
day*
radiolabeled,
5
days
by
oral
gavage,
to
1
rat/
sex
*
Approx.
50­
51
mg/
kg/
day,
based
on
given
body
weights
Triazole
acetic
acid
is
readily
absorbed
and
excreted
within
48
hours
following
5
daily
doses
of
~
10.5
mg/
day.
At
168
hours,
radioactivity
recovery
was
~
101­
102%
of
the
administered
dose.
Absorption
of
the
administered
doses
(
urine
and
cage
wash)
at
168
hours
was
~
69­
91%.
Urinary
excretion
accounted
for
~
66­
75%
of
the
administered
radioactivity.
Fecal
excretion
accounted
for
~
11­
32%
of
the
administered
radioactivity.
Minor
gender­
related
quantitative
differences
were
observed,
but
because
only
1
rat/
sex/
compound
was
tested,
these
are
likely
due
to
individual
variability.
Tissue
burdens
were
negligible
at
72
hrs
post­
dosing.
The
sole
component
identified
in
extracts
of
feces
and
urine
from
radiolabeled­
triazole
acetic
acid­
fed
rats
was
triazole
acetic
acid,
which
indicates
excretion
without
metabolic
conversion
of
triazole
acetic
acid.
ND
=
Study
not
done
11.2
FQPA
Hazard
Considerations
11.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
for
triazole
alanine
is
considered
incomplete
in
terms
of
endpoint
studies
and
dose­
response
information
to
characterize
potential
pre­
and/
or
post­
natal
risk
for
infants
and
children.
Acceptable
developmental
toxicity
and
two­
generation
reproduction
studies
in
the
rat
were
evaluated,
but
a
developmental
toxicity
study
in
the
rabbit
was
not
available.

No
studies
on
triazole
acetic
acid,
including
rat
or
rabbit
developmental
toxicity
studies
or
a
twogeneration
reproduction
study
in
the
rat,
were
available
to
characterize
any
potential
pre­
and/
or
post­
natal
risk
for
infants
and
children.

11.2.2
Evidence
of
Neurotoxicity
There
is
no
evidence
that
exposure
to
triazole
alanine
results
in
neurotoxicity.
No
clinical
signs
of
neurotoxicity,
changes
in
brain
weights,
changes
in
brain
gross
or
microscopic
pathology,
or
any
other
neurotoxic
effects
were
observed
in
the
short­
term
rat
studies,
the
subchronic
rat
and
62
of
94
dog
feeding
studies,
the
rat
developmental
toxicity
study,
or
the
two­
generation
reproduction
study.
Slight
salivation
and
a
slightly
unsteady
gait
were
seen
in
the
female
dog
tested
in
an
acute
oral
dog
study;
however,
the
neurotoxicological
significance
of
this
effect
is
questionable,
since
the
effects
were
seen
at
an
extremely
high
dose
(
5000
mg/
kg),
and
similar
effects
were
not
seen
in
the
male
dog.
Spastic
gait,
piloerection,
lethargy,
and
diarrhea
were
initially
seen
in
rats
tested
in
an
acute
intraperitoneal
study;
however,
the
significance
of
these
effects
is
also
questionable
because
the
rats
were
exposed
to
an
extremely
high
dose
(
5000
mg/
kg),
and
similar
effects
were
not
seen
at
5000
mg/
kg
in
three
acute
oral
studies
of
triazole
alanine
in
rats.

While
the
available
repeated
dose
studies
show
no
evidence
for
triazole
alanine
to
adversely
affect
the
nervous
system,
there
is
some
concern
that
this
is
due
to
an
incomplete
database,
rather
than
a
true
inability
of
the
compound
to
produce
neurotoxicity.
For
instance,
no
acute
or
subchronic
neurotoxicity
tests
or
an
evaluation
of
perfused
brain
tissue
are
available
for
triazole
alanine.
Tremors,
decreased
brain
weight,
and
cerebellar
degeneration
were
seen
in
the
90­
day
mouse
study
on
1,2,4­
triazole;
however,
no
mouse
studies
on
triazole
alanine
are
available
for
comparison.
Clinical
signs
of
neurotoxicity
were
seen
in
adults
in
the
developmental
rabbit
study
on
1,2,4­
triazole,
including
decreased
motor
activity,
head
tilt,
lacrimation,
drooping
eyelids,
diarrhea,
salivation;
however
no
rabbit
studies
are
available
on
triazole
alanine.
Cerebellar
lesions
and
decreased
brain
weights
were
seen
at
the
highest
dose
tested
in
the
twogeneration
reproduction
study
on
free
triazole;
however,
brains
were
not
microscopically
examined
in
the
triazole
alanine
reproduction
study.

11.2.3
Developmental
Toxicity
Studies
11.2.3.1
Developmental
Toxicity
Study
in
Rats
For
triazole
alanine,
increased
quantitative
and
qualitative
susceptibility
was
seen
in
the
developmental
toxicity
study
in
rats.
(
See
section
A­
1.3.1
of
the
appendix
for
the
executive
summary
of
MRIDs
00138128
and
00147889).
In
this
study,
increased
incidences
of
skeletal
findings
were
seen
in
the
offspring
at
the
mid
and
high
doses,
while
no
treatment­
related
effects
were
seen
in
the
dams
up
to
the
limit
dose.
The
skeletal
findings
included
unossified
odontoid
processes
at
300
and
1000
mg/
kg/
day,
with
partially
ossified
transverse
processes
of
the
7th
cervical
vertebra
(
bilateral),
unossified
5th
sternebra,
and
partially
ossified
13th
thoracic
centrum
observed
only
at
1000
mg/
kg/
day.

A
developmental
toxicity
study
in
rats
was
not
submitted
for
triazole
acetic
acid.

11.2.3.2
Developmental
Toxicity
Study
in
Rabbits
A
developmental
toxicity
study
in
rabbits
was
not
submitted
for
either
triazole
alanine
or
triazole
acetic
acid.

11.2.4
Reproductive
Toxicity
Study
For
triazole
alanine,
increased
quantitative
susceptibility
was
seen
in
the
two­
generation
reproduction
study
in
rats.
(
See
section
A­
1.4.1
of
the
appendix
for
the
executive
summary
of
63
of
94
MRIDs
164112,
41326803,
and
41236804).
In
this
study,
mean
litter
weights
were
decreased
approximately
10­
20%
for
both
generations
at
~
1000
mg/
kg/
day,
compared
to
controls,
but
parental
body
weights
were
unaffected
at
all
treatment
levels
tested.
The
lowest
dose
associated
with
decreased
body
weights
and
body
weight
gains
in
adult
rats
was
1510
mg/
kg/
day,
from
the
90­
day
toxicity
study.

A
two­
generation
reproduction
study
in
rats
was
not
submitted
for
triazole
acetic
acid.

11.2.5
Additional
Information
from
Literature
Sources
No
relevant
specific
information
on
the
toxicity
of
triazole
alanine
or
triazole
acetic
acid
was
noted
in
the
open
scientific
literature.

11.2.6
Pre­
and/
or
Postnatal
Toxicity
11.2.6.1
Determination
of
Susceptibility
Increased
quantitative
and
qualitative
susceptibility
of
the
offspring
was
seen
in
the
developmental
toxicity
rat
study,
and
increased
quantitative
susceptibility
was
seen
in
the
twogeneration
reproduction
study.
In
the
developmental
toxicity
study,
increased
incidences
of
skeletal
findings
were
seen
in
the
offspring
at
the
mid
and
high
doses,
while
no
treatment­
related
effects
were
seen
in
the
dams
up
to
the
limit
dose.
These
skeletal
findings
include
unossified
odontoid
processes
at
300
and
1000
mg/
kg/
day,
with
partially
ossified
transverse
processes
of
the
7th
cervical
vertebra
(
bilateral),
unossified
5th
sternebra,
and
partially
ossified
13th
thoracic
centrum
observed
only
at
1000
mg/
kg/
day.
In
the
reproduction
study,
mean
litter
weights
were
decreased
approximately
10­
20%
for
both
generations
at
~
1000
mg/
kg/
day,
compared
to
controls,
but
parental
body
weights
were
unaffected
at
all
treatment
levels.

11.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre­
and/
or
Postnatal
Susceptibility
The
toxicology
database
for
triazole
alanine
is
incomplete
with
respect
to
pre­
and
post­
natal
toxicity
because
a
rabbit
developmental
toxicity
study
was
not
available,
and
the
existing
twogeneration
reproduction
study,
completed
in
1986,
did
not
meet
the
current
guideline
protocol.
Evidence
of
increased
qualitative
and
quantitative
susceptibility
in
the
offspring
was
seen
in
the
rat
developmental
toxicity
study
in
the
form
of
skeletal
findings
observed
in
the
offspring
at
dose
levels
that
produced
no
treatment­
related
effects
in
the
dams.
Evidence
of
increased
quantitative
susceptibility
was
also
seen
in
the
two­
generation
reproduction
study
as
a
reduction
in
mean
litter
weights
for
both
generations
at
dose
levels
that
produced
no
treatment­
related
effects
in
the
parents.
However,
the
concern
is
low
for
the
increased
susceptibilities
seen
in
these
studies,
as
well
as
for
the
residual
uncertainties
regarding
the
data
gaps,
because
the
doses
currently
used
for
dietary,
residential,
and
occupational
exposure
risk
assessments
are
similar
or
lower
than
the
doses
that
caused
the
effects.

For
triazole
acetic
acid,
the
toxicology
database
is
incomplete
with
respect
to
pre­
and
post­
natal
toxicity
because
no
rat
or
rabbit
developmental
toxicity
studies
or
a
two­
generation
reproduction
64
of
94
study
in
the
rat
are
available.
Increased
qualitative
and
quantitative
susceptibility
was
seen
for
both
triazole
alanine
and
1,2,4­
triazole.
Therefore,
there
is
residual
uncertainty
for
increased
pre­
and/
or
postnatal
susceptibility
following
exposure
to
triazole
acetic
acid,
but
this
uncertainty
is
addressed
by
retaining
the
10X
database
uncertainty
factor.

11.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
At
this
time,
a
developmental
neurotoxicity
study
on
the
triazole
conjugates
is
not
required.

11.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
Study
At
present,
there
is
no
evidence
to
support
requiring
a
Developmental
Neurotoxicity
Study.

11.3.2
Evidence
that
supports
not
requiring
a
Developmental
Neurotoxicity
Study
There
was
no
evidence
of
neurotoxicity
in
any
of
the
studies
available
in
the
toxicology
database
for
triazole
alanine
or
triazole
acetic
acid,
including
the
short­
term
rat
studies,
the
subchronic
rat
and
dog
feeding
studies,
the
rat
developmental
toxicity
study,
and
the
two­
generation
reproduction
study.

11.3.2.1
Rationale
for
the
UFDB
The
database
uncertainty
factor
is
10X,
based
on
the
lack
of
a
developmental
toxicity
study
in
rabbits
for
both
triazole
alanine
and
triazole
acetic
acid,
lack
of
a
chronic
study
in
rats
(
including
additional
neuropathological
and
neurobehavioral
measurements)
with
triazole
alanine,
and
lack
of
a
combined
90­
day/
subchronic
neurotoxicity
study
in
rats
for
triazole
acetic
acid.

11.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
Because
no
effects
were
seen
in
the
available
acute
oral
toxicity
studies
(
14­
day
oral
studies
in
rats
and
a
bacterial
reverse
mutation
assay),
a
difference
in
toxicity
between
triazole
alanine
and
triazole
acetic
acid
could
not
be
evaluated.
In
the
absence
of
data
to
suggest
otherwise,
the
endpoint
selection
discussed
in
the
following
sections
applies
to
all
triazole
conjugates
(
i.
e.,
triazole
alanine,
triazole
acetic
acid,
triazole
lactic
acid,
and
triazole
pyruvate).

11.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
(
13
to
49
years
of
age)

Study
Selected:
Prenatal
developmental
toxicity
in
rodents
­
rat
MRID
Number:
00138128
and
00147889
Dose
and
Endpoint
for
Establishing
aRfD:
100
mg/
kg/
day
(
NOAEL),
based
on
increased
incidence
of
skeletal
findings
(
unossified
odontoid
process)
at
300
mg/
kg/
day
(
LOAEL).
Uncertainty
Factor(
s):
1000
(
10X
for
interspecies
extrapolation,
10X
for
intraspecies
variations,
and
10X
for
database
uncertainty).
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Adverse
effects
seen
in
offspring
from
an
oral
developmental
study
are
appropriate
for
setting
an
acute
dietary
endpoint
for
women
of
65
of
94
childbearing
age.
There
is
some
uncertainty
as
to
whether
effects
on
ossification
are
due
to
a
single
dose.
Delays
in
ossification
can
indicate
an
effect
on
growth,
which
would
be
seen
with
repeated
exposure,
but
no
change
in
fetal
body
weights
was
observed
in
this
study.
However,
in
the
absence
of
a
developmental
rabbit
study,
which
is
the
most
sensitive
species
for
free
triazole,
this
dose
and
study
were
selected
for
this
risk
assessment.
In
accordance
with
current
FQPA
policy,
a
1000X
uncertainty
factor
is
applied,
which
includes
a
10X
database
UF
to
account
for
the
lack
of
developmental
toxicity
studies
on
triazole
alanine
and
triazole
acetic
acid
in
rabbits.

Acute
RfD
=
100
mg/
kg/
day
(
NOAEL)
÷
1000
(
UF)
=
0.1
mg/
kg/
day
11.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
In
2003,
the
Triazole
Peer
Review
Committee
(
PRC)
determined
that
the
acute
endpoint
for
the
triazole
conjugates
should
be
based
on
the
developmental
toxicity
study
in
rats
discussed
previously,
with
an
uncertainty
factor
of
300X
to
include
a
3X
database
UF
(
TXR
No.
0052011).
However,
reevaluation
of
the
triazole
alanine
database
showed
that
no
appropriate
endpoints
(
i.
e.,
effects
seen
in
adult
animals
following
a
single,
oral
dose)
were
available
to
set
an
acute
reference
dose
for
the
general
population.

11.4.3
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
90­
Day
oral
toxicity
in
rodents
­
rat
MRID
Number:
00164107
Dose
and
Endpoint
for
Establishing
cRfD:
90
mg/
kg/
day
(
NOAEL),
based
on
decreased
leukocyte
counts
in
males
at
370
mg/
kg/
day
(
LOAEL).
Uncertainty
Factor(
s):
1000
(
10X
for
interspecies
extrapolation,
10X
for
intraspecies
variations,
and
10X
for
database
uncertainty).
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
For
females,
the
NOAEL
is
160
mg/
kg/
day,
and
the
LOAEL
is
400
mg/
kg/
day,
based
on
decreased
triglycerides.
Out
of
the
available
toxicology
studies
on
the
triazole
conjugates,
the
two­
generation
reproduction
study
and
the
90­
day
studies
were
the
longest
in
duration.
Chronic
studies
in
rats,
mice,
or
dogs
were
not
available.
Additionally,
rabbits,
which
are
more
sensitive
than
rats
to
free
triazole,
were
not
used
in
any
of
the
available
toxicology
studies
on
the
triazole
conjugates.
Although
no
adverse
effects
were
seen
in
adults
in
the
reproduction
study,
fewer
endpoints
are
measured
in
this
study
compared
to
the
subchronic
feeding
studies.
Treatment­
related
effects
were
seen
in
both
the
90­
day
dog
and
rat
studies,
but
the
90­
day
rat
study
was
chosen
because
rats
were
more
sensitive
to
triazole
alanine
than
dogs.
The
10X
database
uncertainty
factor
used
for
the
chronic
endpoint
is
to
account
for
the
lack
of
a
developmental
toxicity
study
in
rabbits
for
both
triazole
alanine
and
triazole
acetic
acid,
the
lack
of
a
chronic
study
in
rats
(
including
additional
neuropathological
and
neurobehavioral
measurements)
with
triazole
alanine,
and
a
lack
of
a
combined
90­
day/
subchronic
neurotoxicity
bridging
study
on
triazole
acetic
acid.

In
2003,
the
Triazole
Peer
Review
Committee
(
PRC)
determined
that
the
chronic
endpoint
for
the
triazole
conjugates
should
be
based
on
the
developmental
toxicity
study
in
rats
discussed
above,
with
an
uncertainty
factor
of
300X
to
include
a
3X
database
UF
(
TXR
No.
0052011).
This
decision
was
made
prior
to
the
current
FQPA
policy;
to
the
receipt
of
the
90­
day/
subchronic
66
of
94
neurotoxicity
rat
study,
developmental
rabbit
toxicity
study,
and
reproduction
study
on
1,2,4­
triazole;
and
to
the
reevaluation
of
the
triazole
alanine
studies.
The
reanalysis
of
the
triazole
alanine
studies
resulted
in
a
change
in
chronic
dose
and
endpoint
selection.
The
subchronic
rat
study
is
a
more
appropriate
basis
for
a
chronic
endpoint
than
a
developmental
study.
The
change
in
FQPA
policy
and
receipt
of
additional
free
triazole
studies
resulted
in
an
increased
database
UF.

Chronic
RfD
=
90
mg/
kg/
day
(
NOAEL)
÷
1000
(
UF)
=
0.09
mg/
kg/
day
11.4.4
Incidental
Oral
Exposure
The
endpoint
for
short­
and
intermediate­
term
incidental
oral
exposure
is
based
on
changes
in
hematology
observed
in
the
90­
day
oral
feeding
study
in
rats
(
MRID
00164107),
which
is
discussed
earlier
in
section
11.4.3.
The
oral
route
of
exposure
used
in
this
study
and
the
type
of
effects
seen
are
considered
appropriate
for
short­
or
intermediate­
term
incidental
oral
endpoints.
Additionally,
the
NOAEL
from
the
90­
day
study
is
protective
of
the
offspring
toxicity
observed
in
the
developmental
rat
study.
The
90­
day
duration
of
the
study
is
most
appropriate
for
an
intermediate
term
endpoint.
However,
due
to
the
lack
of
studies
and
of
parameters
measured
in
the
available
studies
and
because
the
effects
seen
in
the
90­
day
rat
study
could
occur
with
shortto
long­
term
exposure,
this
study
was
used
as
the
basis
for
residential
and
occupational
endpoints
for
all
durations.

11.4.5
Dermal
Absorption
No
dermal
absorption
studies
on
triazole
alanine
or
triazole
acetic
acid
are
available
in
the
database.
Therefore,
there
are
no
data
to
support
a
dermal
absorption
factor
other
than
100%.

11.4.6
Dermal
Exposure
(
Short­,
Intermediate­,
and
Long­
term)

In
the
absence
of
dermal
studies,
the
endpoint
for
short­,
intermediate­,
and
long­
term
dermal
exposure
is
the
same
as
for
short
and
intermediate
term
incidental
oral
exposure.
See
section
11.4.4
for
more
details.

11.4.7
Inhalation
Exposure
(
Short­,
Intermediate­,
and
Long­
term)

In
the
absence
of
inhalation
studies,
the
endpoint
for
short­,
intermediate­,
and
long­
term
inhalation
exposure
is
the
same
as
for
short­
and
intermediate­
term
incidental
oral
exposure.
See
section
11.4.4
for
more
details.

11.4.8
Margins
of
Exposure
and
Levels
of
Concern
The
levels
of
concern
(
LOCs)
for
residential
and
occupational
exposure
and
risk
assessment
are
given
below.
Each
LOC
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
variation
and
10X
for
interspecies
extrapolation),
as
well
as
a
10X
database
uncertainty
factor
for
the
lack
of
a
developmental
toxicity
study
in
rabbits
for
both
triazole
alanine
and
triazole
acetic
acid,
the
lack
of
a
chronic
study
in
rats
(
including
additional
67
of
94
neuropathological
and
neurobehavioral
measurements)
with
triazole
alanine,
and
a
lack
of
a
combined
90­
day/
subchronic
neurotoxicity
study
in
rats
for
triazole
acetic
acid.

Table
11.5.
Summary
of
Levels
of
Concern
for
Residential
and
Occupational
Risk
Assessments
for
Triazole
Alanine
and
Triazole
Acetic
Acid.
Duration
of
Exposure
Route
of
Exposure
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1­
6
Months)
Long­
Term
(>
6
Months)
Occupational
Exposure
Dermal
1000
1000
1000
Inhalation
1000
1000
1000
Residential
Exposure
Incidental
Oral
1000
1000
1000
Dermal
1000
1000
1000
Inhalation
1000
1000
1000
11.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Because
the
same
endpoints
are
used
for
all
exposure
routes,
oral,
dermal,
and
inhalation
exposures
can
be
aggregated.

11.4.10
Classification
of
Carcinogenic
Potential
There
are
no
available
cancer
bioassay
studies
on
1,2,4­
triazole.
1,2,4­
triazole
and
its
conjugate
(
triazole
alanine),
however,
are
not
mutagenic.
For
a
further
discussion
of
carcinogenicity
and
triazole
metabolites,
see
Section
4.4.11.

11.5
Special
FQPA
Safety
Factor
The
special
FQPA
safety
factor
has
been
removed
(
i.
e.,
reduced
to
1X)
for
the
current
risk
assessment
on
the
triazole
conjugates
because
the
currently
selected
endpoints,
together
with
a
10X
database
uncertainty
factor,
are
protective
of
increased
susceptibility
of
infants
and
children
seen
in
the
available
studies.
Although
increased
qualitative
and
quantitative
susceptibility
of
the
offspring
was
seen
in
the
developmental
toxicity
and
two­
generation
reproduction
studies
in
rats
(
see
section
11.2.6),
the
currently
selected
dietary,
residential,
and
occupational
endpoints
are
all
based
on
NOAELs
that
are
protective
of
these
adverse
effects.
Additionally,
no
evidence
of
neurotoxicity
was
seen
in
the
available
toxicology
database,
so
a
developmental
neurotoxicity
study
is
not
recommended
at
this
time.
Finally,
while
the
current
recommendation
is
to
reduce
the
special
FQPA
safety
factor
to
1X,
residual
uncertainty
is
accounted
for
by
a
10X
database
uncertainty
factor.
This
10X
database
uncertainty
factor
is
retained
for
the
lack
of
developmental
toxicity
(
rabbit)
studies
with
triazole
alanine
and
triazole
acetic
acid,
lack
of
a
chronic
rat
study
(
with
additional
neuropathological
and
neurobehavioral
endpoints)
with
triazole
alanine,
and
lack
of
a
combined
90­
day/
subchronic
neurotoxicity
rat
study
for
triazole
acetic
acid.

Future
receipt
of
additional,
required
toxicology
studies
on
triazole
alanine
(
or
the
other
triazole
conjugates)
may
warrant
removal
of
the
database
uncertainty
factor
(
i.
e.,
reduction
to
1X).
At
68
of
94
that
time,
the
need
for
a
10X
special
FQPA
safety
factor
based
on
the
newly
available
toxicity
data
will
be
re­
evaluated.

Table
11.6.
Summary
of
Toxicological
Doses
and
Endpoints
for
Triazole
Conjugates
to
be
Used
in
Human
Health
Risk
Assessments.
Exposure
Scenario
Dose
Used
in
Risk
Assessment
and
UF
Special
FQPA
SF
*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
females
13­
49)
NOAEL
=
100
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.1
mg/
kg/
day
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.1
mg/
kg/
day
Prenatal
developmental
toxicity
in
rodents
­
rat
LOAEL
=
300
mg/
kg/
day
based
on
increased
incidence
of
skeletal
findings
(
unossified
odontoid
process).
Acute
Dietary
(
general
population,
including
infants
and
children)
None
None
No
appropriate
dose
and
endpoint
could
be
identified
for
these
population
groups.

Chronic
Dietary
(
all
populations)
NOAEL
=
90
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.09
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.09
mg/
kg/
day
90­
Day
oral
toxicity
in
rodents
­
rat
LOAEL
=
370/
400
mg/
kg/
day
(
M/
F)
based
on
decreased
leukocyte
counts
in
males
and
decreased
triglycerides
in
females.

Incidental
Oral
(
all
durations)
NOAEL
=
90
mg/
kg/
day
Residential
LOC
for
MOE
=
1000a
Occupational
=
NA
90­
Day
oral
toxicity
in
rodents
­
rat
LOAEL
=
370/
400
mg/
kg/
day
(
M/
F)
based
on
decreased
leukocyte
counts
in
males
and
decreased
triglycerides
in
females.
Dermal
(
all
durations)
NOAEL
=
90
mg/
kg/
day
(
dermal
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
1000a
90­
Day
oral
toxicity
in
rodents
­
rat
LOAEL
=
370/
400
mg/
kg/
day
(
M/
F)
based
on
decreased
leukocyte
counts
in
males
and
decreased
triglycerides
in
females.
Inhalation
(
all
durations)
NOAEL
=
90
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000a
Occupational
LOC
for
MOE
=
1000a
90­
Day
oral
toxicity
in
rodents
­
rat
LOAEL
=
370/
400
mg/
kg/
day
(
M/
F)
based
on
decreased
leukocyte
counts
in
males
and
decreased
triglycerides
in
females.
Cancer
(
oral,
dermal,
inhalation)
Classification:
Not
determined.
Evaluate
by
RfD
approach.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
11.5
a
Additional
10x
database
uncertainty
factor
for
lack
of
developmental
toxicity
(
rabbit)
studies
with
triazole
alanine
and
triazole
acetic
acid,
a
chronic
rat
study
(
with
additional
neuropathological
and
neurobehavioral
endpoints)
with
triazole
alanine,
and
a
combined
90­
day/
subchronic
neurotoxicity
rat
study
for
triazole
acetic
acid.
69
of
94
11.6
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

In
the
available
toxicity
studies
on
triazole
alanine
and
triazole
acetic
acid,
no
estrogen­,
androgen­,
and/
or
thyroid­
mediated
toxicity
was
observed.

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

12.0
Public
Health
Data
None.

13.0
Exposure
Characterization/
Assessment
13.1
Dietary
Exposure/
Risk
Pathway
(
M.
Doherty,
D322239,
12/
20/
05)

13.1.1
Residue
Profile
13.1.1.1
Residues
in
Food
Through
a
joint
effort
by
the
U.
S.
Triazole
Task
Force
(
USTTF)
and
USDA's
Pesticide
Data
Program
(
PDP),
monitoring
data
depicting
residues
of
TA
and
TAA
are
available
for
apples,
peaches,
wheat
flour,
bananas,
eggs,
peanut
butter,
soybeans,
finished
water,
strawberry,
milk,
grapes,
and
tomato.
For
all
foods
addressed
by
these
assessments,
including
those
with
monitoring
data,
an
anticipated
residue
was
derived
by
converting
the
tolerance
value
for
each
parent
triazole­
derivative
fungicides
to
its
TA
equivalent
using
molecular
weight
conversion
factors.
For
the
acute
assessment,
the
highest
anticipated
residue
was
used
for
a
given
food;
for
the
chronic
assessment,
the
average
anticipated
residue
was
used.
For
foods
with
monitoring
data,
the
greater
of
the
maximum
monitoring
data
(
maximum
TA
plus
maximum
TAA)
or
the
anticipated
residue
was
used
in
the
assessment.
For
all
commodities
except
those
of
peanut
and
cereal
grain,
the
anticipated
residues
were
used.
For
peanut
commodities
the
maximum
monitored
residue
value
from
peanut
butter
was
used.
For
cereal
grain
commodities,
the
70
of
94
maximum
monitored
residue
value
from
wheat
flour
was
used.
The
assessments
include
default
processing
factors
from
DEEM
Version
7.81.
The
Agency
was
recently
made
aware
of
an
issue
with
the
analytical
method
for
TA
in
soybeans
in
which
the
method
underestimates
residues
by
4
to
12
fold.
That
issue
is
still
being
resolved.
In
order
to
ensure
that
this
assessment
does
not
underestimate
exposure
to
TA/
TAA
via
soybean,
all
inputs
for
soybean
were
multiplied
by
10
in
both
the
acute
and
chronic
analyses.
This
is
a
very
conservative,
higher­
end
deterministic
assessment.

Table
13.1.
Summary
of
Input
Residue
Values
for
the
Acute
and
Chronic
Dietary
Analyses
of
Triazole
Alanine
and
Triazole
Acetic
Acid.
DEEM
Input
Value,
ppm
Anticipated
Residue,
ppm
Food
Acute
Chronic
Acute
Chronic
Max.
Monitored
Residue,
ppm1
Remarks
Pome
Fruit
(
Apple)
0.53
0.23
0.53
0.21
0.23
 
Artichoke
0.54
0.43
0.54
0.43
 
 
Asparagus
0.80
0.03
0.80
0.03
 
 
Banana
2.16
0.57
2.16
0.32
0.57
 
Dry
Bean/
Pea
0.23
0.12
0.23
0.12
 
 
Succulent
Bean/
Pea
0.54
0.22
0.54
0.22
 
 
Blueberry
0.46
0.30
0.46
0.30
 
 
Caneberry
1.08
0.87
1.08
0.87
 
 
Canola
0.05
0.02
0.05
0.02
 
 
Carrot
0.09
0.09
0.09
0.09
 
 
Leafy
Petioles
2.28
2.28
2.28
2.28
 
 
Barley
0.55
0.55
0.046
0.31
 
From
wheat
flour
Oats
0.55
0.55
0.05
0.03
 
From
wheat
flour
Rice
3.19
1.11
3.19
1.11
 
 
Rye
0.55
0.55
0.05
0.04
 
From
wheat
flour
Wheat
0.55
0.55
0.05
0.03
 
From
wheat
flour
Wheat
Flour
0.55
0.55
0.05
0.03
0.55
 
Wild
Rice
3.19
1.11
0.23
0.23
 
From
rice
Citrus
Group
0.46
0.23
0.46
0.23
 
 
Coffee
0.005
0.005
0.005
0.005
 
 
Field
Corn
0.55
0.55
0.05
0.03
 
From
wheat
flour
Sweet
Corn
0.55
0.55
0.05
0.03
 
From
wheat
flour
Cotton
1.01
0.26
1.01
0.26
 
 
Cranberry
0.46
0.24
0.46
0.24
 
 
Cucurbits
0.11
0.08
0.11
0.08
 
 
Currant
1.62
1.04
1.62
1.04
 
 
Elderberry
0.46
0.46
0.46
0.46
 
 
Grape
2.53
0.82
2.53
0.82
0.29
 
Raisin
2.53
0.82
2.53
0.82
 
 
Hops
15.20
7.60
15.20
7.60
 
 
Lychee
0.76
0.76
0.76
0.76
 
 
Mango
0.10
0.10
0.10
0.10
 
 
Mayhaw
0.38
0.19
0.38
0.19
 
 
Bulb
Vegetables
0.14
0.09
0.14
0.09
 
 
Okra
0.51
0.51
0.51
0.51
 
 
Peanut
2.32
2.32
0.09
0.04
 
From
peanut
butter
Peanut
Butter
2.32
2.32
0.09
0.04
2.32
 
Peppers
0.54
0.54
0.54
0.54
 
 
Peppermint
1.62
1.62
1.62
1.62
 
 
71
of
94
Table
13.1.
Summary
of
Input
Residue
Values
for
the
Acute
and
Chronic
Dietary
Analyses
of
Triazole
Alanine
and
Triazole
Acetic
Acid.
DEEM
Input
Value,
ppm
Anticipated
Residue,
ppm
Food
Acute
Chronic
Acute
Chronic
Max.
Monitored
Residue,
ppm1
Remarks
Pineapple
1.59
0.82
1.59
0.82
 
 
Sorghum
0.55
0.55
0.09
0.05
 
From
wheat
flour
Soybean
9.1
3.3
0.91
0.33
0.12
10X
the
anticipated
residue
to
account
for
method
issue.
Spearmint
1.62
1.62
1.62
1.62
 
 
Stone
Fruit­
no
cherry
1.08
0.95
1.08
0.74
0.95
 
Cherry
2.70
1.53
2.70
1.53
 
 
Strawberry
0.68
0.48
0.68
0.48
0.13
 
Sugar
Beet
0.14
0.07
0.14
0.07
 
 
Sugar
Beet
Molasses
0.14
0.07
0.14
0.07
 
 
Sunflower
0.03
0.03
0.03
0.03
 
 
Tomato
0.16
0.16
0.16
0.16
0.09
 
Turnip
0.20
0.20
0.20
0.20
 
 
Turnip
Greens
2.28
2.28
2.28
0.04
 
From
Leafy
petiole
Tree
Nuts
0.19
0.11
0.19
0.11
 
 
Almond
0.19
0.11
0.19
0.11
 
 
Pecan
0.05
0.05
0.05
0.05
 
 
Pistachio
0.05
0.04
0.05
0.04
 
 
Poultry
Meat
0.03
0.02
0.03
0.02
 
 
Poultry
Fat
0.03
0.02
0.03
0.02
 
 
Poultry
Meat
Byprod.
0.03
0.02
0.03
0.02
 
 
Poultry
Liver
0.03
0.02
0.03
0.02
 
 
Egg
0.03
0.02
0.03
0.02
0.016
 
Cattle
Meat
0.53
0.13
0.53
0.13
 
 
Cattle
Fat
0.53
0.15
0.53
0.15
 
 
Cattle
Meat
Byprod.
0.53
0.14
0.53
0.14
 
 
Cattle
Liver
1.68
0.63
1.68
0.63
 
 
Cattle
Kidney
0.91
0.29
0.91
0.29
 
 
Milk
0.11
0.04
0.11
0.04
0.01
 
1
Residue
data
for
TA/
TAA
from
USDA
Pesticide
Data
Program
or
U.
S.
Triazole
Task
Force
monitoring
data.
Values
are
the
combined
maxima
for
TA
and
TAA
for
monitored
foods
and
do
not
reflect
the
maximum
combined
residue
of
TA
and
TAA
for
a
particular
sample.

13.1.1.2
Residues
in
Drinking
Water
As
noted
in
Section
6,
there
is
not
sufficient
information
available
to
model
potential
residues
of
the
triazole
conjugates
in
drinking
water.
As
a
surrogate
for
modeled
concentrations
of
TA
and
TAA,
HED
has
used
the
modeled
estimates
for
1,2,4­
T
(
Table
6.2)
in
the
TA/
TAA
dietary
exposure
assessment,
multiplying
the
values
by
2.26
to
correct
for
differences
in
molecular
weight.
Given
the
infrequent
and
very
low
residue
levels
reported
in
the
monitoring
data
(
Table
13.1),
the
use
of
1,2,4­
T
residue
estimates
in
drinking
water
is
highly
conservative.
72
of
94
13.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Table
13.2.
Dietary
(
Food
+
Water)
Exposure
and
Risk
Estimates
for
Triazole
Alanine
and
Triazole
Acetic
Acid.
Exposure
Estimate,
mg/
kg/
day
Risk
Estimate,
%
aPADa
Population
Subgroup
aPAD,
mg/
kg/
day
95th
%
ile
99th
%
ile
99.9th
%
ile
95th
%
ile
99th
%
ile
99.9th
%
ile
Acute
Females
13­
49
yrs
0.1
0.0274
27
0.0412
41
0.0827
83
Chronic
Population
Subgroup
cPAD,
mg/
kg/
day
Exposure
Estimate,
mg/
kg/
day
Risk
Estimate,
%
cPADa
U.
S.
Population
(
total)
0.09
0.0080
9
All
infants
(<
1
year)
0.09
0.0160
18
Children
1­
2
yrs
0.09
0.0239
27
Children
3­
5
yrs
0.09
0.0196
22
Children
6­
12
yrs
0.09
0.0121
13
Youth
13­
19
yrs
0.09
0.0073
8
Adults
20­
49
yrs
0.09
0.0062
7
Adults
50+
yrs
0.09
0.0054
6
Females
13­
49
yrs
0.09
0.0060
7
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
a
Reported
to
2
significant
figures.

Due
to
the
conservatism
of
the
assessment
inputs,
HED
believes
that
it
is
most
appropriate
to
base
regulatory
recommendations
on
results
at
the
95th
percentile
of
exposure
for
the
acute
assessment.
The
results
indicate
that
for
both
acute
and
chronic
exposure
durations
and
for
all
population
subgroups,
risk
estimates
are
well
below
HED's
level
of
concern.

13.2
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Triazole
alanine
is
formed
in
plants
by
the
conjugation
of
1,2,4­
T
to
serine.
The
TA
may
then
be
further
oxidized
to
form
TAA.
Because
of
the
nature
of
this
process,
HED
has
assumed
that
it
occurs
within
the
plant
itself
on
not
on
leaf
surfaces.
Therefore,
the
residues
are
not
available
for
dermal,
hand­
to­
mouth,
or
object­
to­
mouth
exposures
and
HED
has
not
conducted
a
residential
exposure
assessment
for
the
triazole
conjugates.
Residues
of
TA
and
TAA
may
occur
in
soil.
1,2,4­
Triazole
is
more
toxic
than
TA/
TAA
and
exposures
to
TA/
TAA
via
soil
ingestion
are
unlikely
to
exceed
those
of
1,2,4­
T.
The
assessment
for
soil
ingestion
of
1,2,4­
T
shows
that
risk
estimates
are
below
HED's
level
of
concern;
therefore,
risk
estimates
for
soil
ingestion
of
TA/
TAA
will
also
be
below
HED's
level
of
concern.

14.0
Aggregate
Risk
Assessments
and
Risk
Characterization
Dietary
exposure
is
the
only
pathway
of
concern
for
TA/
TAA;
therefore,
aggregate
risk
estimates
are
equivalent
to
those
discussed
for
dietary
risk
(
Section
13.1.2).
All
aggregate
risk
estimates
are
below
HED's
level
of
concern.

15.0
Cumulative
Risk
Characterization/
Assessment
See
Section
8.0.
73
of
94
16.0
Occupational
Exposure/
Risk
Pathway
Triazole
alanine
and
triazole
acetic
acid
are
not
present
in
pesticide
formulations;
therefore,
there
is
no
risk
from
exposure
to
these
chemicals
that
results
from
mixing,
loading,
or
application
activities.
Although
TA
and
TAA
are
significant
plant
metabolites,
the
residues
occur
inside
the
plant
structures
and
are
not
available
for
dermal
contact
(
see
Section
13.2).
Therefore,
there
is
no
significant
exposure
as
a
result
of
post­
application
activities
and
quantitative
occupational
exposure
and
risk
assessments
are
not
needed
for
TA
and
TAA.

17.0
Data
Needs
and
Label
Requirements
17.1
Toxicology
A
10X
database
uncertainty
factor
is
retained
for
the
lack
of
the
following
studies:

Triazole
alanine
 
Developmental
toxicity
study
in
rabbits
 
Chronic
toxicity
study
in
rats,
conducted
according
to
current
guidelines
that
include
neurobehavioral
assessments,
with
additional
neuropathology
evaluations
conducted
according
to
the
neurotoxicity
guidelines
Triazole
acetic
acid
 
Developmental
toxicity
study
in
rabbits
 
Combined
90­
day
feeding/
neurotoxicity
study
in
rats
17.2
Residue
Chemistry
 
Resolution
of
concerns
regarding
the
prevalence
of
conjugated
residues
of
TA
and
the
ability
of
the
analytical
method
to
quantify
them.

17.3
Occupational
and
Residential
Exposure
 
None.

References
Allen,
J.,
Wolf,
D.,
George,
M.
Hester,
S.,
Sun
G.,
Thai,
S­
F.,
Delker,
D.,
Nelson,
G.,
Winkfield,
E.
Roop,
B.,
Leavitt,
S.,
Ward,
W.,
and
Nesnow,
S.
(
2005)
Comparable
Liver
P450
Enzyme
Activity
and
Histopathology
in
Mice
Treated
With
the
Conazole
Fungicides:
Myclobutanil,
Propiconazole
and
Triadimefon.
The
Toxicologist.
Abstract.
No,
2146.

Goetz,
A.
K.,
Blystone,
C.,
Ren,
H.,
Schmid,
J.
E.,
Nichols,
H.
P.,
Bao,
W.,
Best,
D.
S.,
Narotsky,
M.
G.,
Wolf,
D.
C.,
Rockett,
J.
C.,
and
Dix,
D.
J.
(
2005)
Reproductive
Effects
of
Exposure
to
Conazole
Fungicides
in
the
Male
Rat.
The
Toxicologist.
Abstract
No
2148.
74
of
94
Hester,
S.,
Thai,
S.­
F.,
Wolf,
D.,
Ward,
W.,
and
Nesnow,
S.
(
2005)
Comparison
of
Gene
Expression
Profiles
from
Rats
Fed
Acute
Levels
of
Three
Toxicologically
Different
Conazoles.
The
Toxicologist.
Abstract
No.
2149.

Ren,
H.,
Schmid,
J.
E.,
Retief,
J.,
Turpaz,
Y.,
Zhang,
X.,
Jones,
P.
D.,
Newsted,
J.
L.,
Giesy,
J.
P.,
Wolf,
D.
C.,
Wood,
C.
R.,
Bao,
W.,
and
Dix,
D.
J.
(
2005)
Profiling
Gene
Expression
in
Human
H295R
Adrenocortical
Carcinoma
Cells
and
Rat
Testes
to
Identify
Pathways
of
Toxicity
for
Conazole
Fungicides.
The
Toxicologist.
Abstract
No.
2150.

Sun
G,
Thai
SF,
Tully
DB,
Lambert
GR,
Goetz
AK,
Wolf
DC,
Dix
DJ,
Nesnow
S:
Propiconazole­
induced
cytochrome
P450
gene
expression
and
enzymatic
activities
in
rat
and
mouse
liver.
Tox
Lett
155:
277­
287,
2004;
and
abstracts
from
the
2005
SOT
meeting,

Ward,
W.,
Delker,
D.,
Hester,
S.,
Thai,
S­
F.,
Allen,
J.,
Jones,
C.,
Wolf,
D.,
and
Nesnow,
S.
(
2005)
Comparison
of
Hepatic
Gene
Expression
Profiles
from
Mice
Exposed
to
Three
Toxicologically
Different
Conazoles.
The
Toxicologist.
Abstract
No.
2147.

Wolf,
D.
C.,
Allen,
J.,
Sun,
G.,
Thibodeaux,
J.,
George,
M.,
Hester,
S.
D.,
Thai,
S.­
F.,
Delker,
D.,
Nelson,
G.,
Winkfield,
E.,
Roop,
B.,
Leavitt,
S.,
Ward,
W.,
and
Nesnow,
S.
(
2005)
Triadimefon
Induces
Rat
Thyroid
Tumors
Through
a
Non­
TSH
Mediated
Mode
of
Action.
The
Toxicologist.
Abstract
No.
2144.

MRID
45284011.
Rakhmatov,
R.
M.,
V.
B.
Danilov,
U.
A.
Madzhidov,
and
S.
A.
Gamiyants.
(
1991).
Basis
data
for
setting
the
limiting
allowed
concentration
(
LAC)
of
1,2,4­
triazole
in
workplace
air.
Gigiena
i
Sanitariya
2:
30­
1.
[
Abstract
only].

MRID
46553701.
Heard,
N.
E.
(
2005).
1,2,4­
Triazole
Aggregate
Exposure
Assessment,
Syngenta
Study
T022748­
04,
May
20,
2005
Attachments:

1.
TXR
0052011.
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
2.
TXR
0052012.
Second
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
3.
Triazole
Summaries
­
Additional
Data
Summaries/
Literature
Articles
75
of
94
Attachment
1:
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
TXR
NO.
0052011
DATE:
August
5,
2003
MEMORANDUM
SUBJECT:
TRIAZOLES
­
Report
of
the
Ad
Hoc
HED
Peer
Review
Committee.

FROM:
Kathleen
Raffaele,
Toxicologist
Registration
Action
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Stephen
Dapson
Senior
Scientist,
Registration
Action
Branch
3
Health
Effects
Division
(
7509C)

TO:
Bob
Tomerlin
Registration
Division
(
7505C)

cc:
Margaret
Stasikowski,
HED
Elizabeth
Doyle,
OW
PC
Codes
(
include
but
are
not
limited
to):
004401;
120503;
128993;
128847;
123909;
129011;
128835;
128925;
128857;
125601;
122101;
120603;
128997;
109901;
127201;
128976
On
11/
4/
02,
an
ad
hoc
HED
committee
conducted
an
internal
Peer
Review
of
the
OPP
Triazole
Team's
7/
8/
02
analysis
of
the
Triazolylalanine
Group's
(
TAG)
1/
9/
02
document
entitled
"
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites"(
MRID#
45575501).
The
committee,
led
by
Elizabeth
Doyle,
addressed
toxicology
and
dietary
exposure
issues
associated
with
this
class
of
fungicides
and
its
metabolites/
degradates
of
concern.
The
conclusions
of
the
committee
with
respect
to
these
issues
are
presented
in
this
report.
76
of
94
Ad
Hoc
HED
Peer
Review
Committee
Members
in
Attendance
Elizabeth
Doyle
(
Chair),
Karl
Baetcke,
William
Burnam,
Vicki
Dellarco,
Steve
Knizner,
Nancy
McCarroll,
Alberto
Protzel,
Jess
Rowland,
and
Brenda
Tarplee
(
Executive
Secretary).

OPP
Triazole
Team
Members
in
Attendance
Steve
Dapson,
William
Hazel,
Rick
Loranger,
Kathleen
Raffaele,
Clark
Swentzel,
and
Jean
Holmes
(
EFED).

Also
in
attendance
were:
Rick
Keigwin
(
RD),
Timothy
McMahon
(
AD)

Chemistry
Data
Evaluation
/
Report
Presentation:
_______________________
Rick
Loranger,
Chemist
_______________________
William
Hazel,
Chemist
Toxicology
Data
Evaluation
/
Report
Presentation:
_______________________
Kathleen
Raffaele,
Toxicologist
77
of
94
INTRODUCTION
On
11/
4/
02,
an
ad
hoc
HED
committee
conducted
an
internal
Peer
Review
of
the
OPP
Triazole
Team's
7/
8/
02
analysis
of
the
Triazolylalanine
Group's
(
TAG)
1/
9/
02
document
entitled
"
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites"
(
MRID#
45575501).
The
committee,
led
by
Elizabeth
Doyle,
addressed
toxicology
and
dietary
exposure
issues
associated
with
this
class
of
fungicides
and
its
metabolites/
degradates
of
concern.

I.
DIETARY
EXPOSURE
CONCLUSIONS
The
conclusions/
recommendations
of
the
Peer
Review
Committee
(
PRC)
related
to
dietary
exposure
are
as
follows:

1.
The
PRC
agreed
with
the
OPP
Triazole
Team
that
there
will
be
dietary
exposure
to
1,2,4­
triazole
and
its
conjugates,
that
such
exposure
could
be
significant,
and
that
reliable
estimates
of
dietary
exposure
cannot
be
made
based
upon
available
data.

2.
The
PRC
had
no
issues
with
the
dietary
exposure
components
of
the
7/
8/
02
OPP
Triazole
Team's
evaluation
of
the
TAG's
1/
9/
02
risk
assessment
including
responses
to
TAG
conclusions
3
and
4.
The
OPP
Triazole
Team's
responses
were
as
follows
(
the
last
four
bullets
are
responses
to
TAG
conclusions
3
and
4):

3.
The
TAG
continues
to
exclude
1,2,4­
triazole
conjugates
from
dietary
exposure
which
the
Agency
currently
considers
to
be
residues
of
concern
for
the
triazole
fungicides.

4.
Exclusion
of
the
triazole
conjugates
results
in
a
great
underestimate
of
dietary
exposure.

5.
Even
if
found
to
be
less
toxic
than
free
1,2,4­
triazole,
the
much
higher
exposure
to
the
conjugates
is
expected
to
result
in
significant
risk.

6.
Calculation
of
free
triazole
residues
based
on
the
amount
of
parent
fungicide
at
harvest
also
is
expected
to
greatly
underestimate
dietary
exposure
(
the
soil
serves
as
a
reservoir).

7.
Exposure
to
free
and
conjugated
residues
in
rotational
crops,
often
with
some
of
the
highest
residues,
is
expected
to
result
in
significant
dietary
exposure
underestimation.

8.
Use
of
100%
crop
treated
and
95th
percentile
of
exposure
are
appropriate
assumptions
for
a
Tier
1
assessment
but
they
may
not
be
that
conservative
due
to
crop
rotation
and
the
soil
serving
as
a
reservoir
of
triazole
degradates/
metabolites.
78
of
94
9.
With
all
of
these
exposure
uncertainties,
hazard
uncertainties,
and
sources
of
potentially
great
exposure
underestimation,
risk
due
to
exposure
to
free
plus
conjugated
triazole
residues
is
likely
to
be
much
higher
than
the
TAG's
estimates
for
free
triazole
alone.

10.
The
TAG
states
that
free
triazole
formation
in
livestock
commodities
and
water
is
compound­
specific
and
should
be
considered
only
in
the
context
of
each
individual
triazole
fungicide's
risk.
The
first
statement
is
likely
correct,
but
the
law
requires
all
sources
of
exposure
be
considered
in
aggregate
risk
assessment.

11.
The
TAG
states
that
residues
of
free
triazole
in
plant
commodities
are
very
low
and
occur
in
<
15%
of
samples.
We
agree
there
are
low,
infrequent
residues
in
raw
crops,
but
effects
of
processing
on
triazole
formation
are
unknown.

12.
The
TAG
further
states
that
plant
residues
have
a
low
contribution
to
total
dietary
load.
We
believe
that
insufficient
data
exist
to
determine
relative
exposure
contributions
of
plant,
livestock
and
water
residues.

13.
The
TAG
also
believes
that
there
is
no
need
to
include
free
triazole
in
crop
residue
definitions.
We
agree
that
free
triazole
should
not
be
part
of
the
residue
definition
for
tolerance
enforcement
purposes
due
to
its
numerous
sources.
However,
from
a
risk
assessment
perspective,
both
free
triazole
and
its
conjugates
need
to
be
included
based
on
toxicological
properties.

3.
The
PRC
agreed
that
monitoring
of
1,2,4­
triazole
and
its
conjugates
in
the
U.
S.
food
supply
would
provide
representative
and
rapid
data
to
permit
assessment
of
human
dietary
risk
associated
with
this
class
of
fungicides
needed
for
risk
management
decisions
on
numerous
registration
actions
and
several
reregistration
eligibility
decisions.
Based
on
their
significance
as
major
food
consumption
items
(
particularly
for
children),
based
on
properties
of
free
triazole
and
its
conjugates,
and
based
on
the
need
to
represent
livestock
commodities
and
extensive
crop
rotation
practices,
it
was
highly
recommended
that
survey/
monitoring
data
be
generated
on
milk,
eggs,
and
soybean
protein
isolate.

4.
The
PRC
agreed
that
the
TAG
be
requested
to
perform
cooking
and
processing
studies
(
including
baking
studies
to
assess
flour
residues)
to
determine
the
potential
for,
and
extent
of,
conversion
of
parent
fungicides
and
triazole
conjugates
to
free
1,2,4­
triazole
at
elevated
pressure,
temperature,
and
at
the
pHs
of
various
processed
products
as
well
as
the
fractionation
of
the
various
residues
in
different
processed
products.
In
addition,
the
PRC
recommended
that
the
TAG
be
requested
to
perform
studies
in
which
livestock
are
fed
triazole
conjugates
to
determine
distribution
of
the
various
residues
in
tissues
and
milk
and
to
determine
79
of
94
the
likelihood
and
extent
of
conversion
of
triazole
conjugates
to
free
1,2,4­
triazole
in
livestock
(
metabolism
may
be
more
rapid
in
the
rumen).

II.
TOXICOLOGY
CONCLUSIONS
The
conclusions/
recommendations
of
the
Peer
Review
Committee
(
PRC)
related
to
toxicology
are
as
follows:

1.
The
PRC
concluded
that,
based
on
LD50
values,
the
acute
toxicity
of
free
triazole
and
triazole
alanine
are
comparable
to
the
parent
compounds.

2.
The
PRC
concluded
that
the
subchronic
toxicity
data
indicate
that
triazole
alanine
is
less
toxic
than
free
triazole;
however,
there
is
no
data
available
to
evaluate
neurotoxic
potential.

3.
The
PRC
concluded
that
there
is
no
need
for
additional
mutagenicity
data;
available
data
indicate
that
free
triazole
and
triazole
alanine
are
not
mutagenic.

4.
The
PRC
agreed
with
the
OPP
Triazole
Team
that
there
is
concern
for
toxicity
of
free
triazole,
triazole
alanine,
and
other
triazole
conjugates
5.
The
PRC
concurred
with
the
OPP
Triazole
Team
that
free
triazole
has
not
been
adequately
tested
in
toxicity
studies
with
the
parent
triazole
fungicides.

6.
The
PRC
determined
that
no
analogies
could
be
made
between
toxicity
of
parents
and
expected
toxicity
of
free
triazole
and
triazole
conjugates,
based
on
the
following
considerations:

°
Target
tissues
and
toxicological
effects
vary
across
parent
compounds,
with
some
overlap
but
no
consistent
pattern.

°
Carcinogenicity
also
varies
across
parent
compounds,
as
does
tumor
site
for
carcinogenic
parents.

°
The
relationship
between
toxicity
of
free
triazole,
triazole
conjugates,
and
parent
compounds
(
based
on
available
limited
data),
is
not
consistent;
e.
g.
some
parent
compounds
exhibit
toxicity
at
lower
doses
than
free
triazole,
others
at
higher
doses.

7.
The
PRC
determined
that
separate
risk
assessments
should
be
conducted
for
free
triazole
and
for
triazole
conjugates,
and
selected
endpoints
and
Uncertainty
Factors:
80
of
94
°
For
free
triazole,
the
developmental
toxicity
study,
with
a
NOAEL
of
30
mg/
kg
should
be
used
for
both
acute
and
chronic
risk
assessments;
UF=
1000
(
10x
intraspecies,
10x
interspecies,
10x
database).

°
For
triazole
alanine
and
other
triazole
conjugates,
the
developmental
toxicity
study,
with
a
NOAEL
of
100
mg/
kg,
should
be
used
for
both
acute
and
chronic
risk
assessments;
UF=
300
(
10x
intraspecies,
10x
interspecies,
3x
database).

°
The
developmental
endpoints
from
the
rat
developmental
toxicity
studies
for
free
triazole
and
triazole
alanine
were
selected
for
use
based
on
the
available
limited
database,
and
are
considered
to
be
protective
for
all
risk
assessment
scenarios,
in
the
absence
of
reliable
alternative
endpoints.

°
The
use
of
a
smaller
database
factor
(
3x)
for
triazole
alanine
and
other
triazole
conjugates
is
based
on
the
following
considerations:
°
Available
studies
for
triazole
alanine
showed
minimal
toxicity
in
adults
at
doses
approaching
the
limit
dose;
°
There
is
no
indication
of
neurotoxicity
in
the
available
triazole
alanine
studies;
°
If
additional
studies
were
requested
for
triazole
alanine,
they
would
likely
also
be
conducted
at
doses
approaching
the
limit
dose,
leading
to
endpoints
higher
than
that
selected
above
from
the
developmental
toxicity
study;
°
The
absence
of
a
developmental
toxicity
study
in
rabbits,
given
the
findings
in
the
developmental
toxicity
study
in
rats,
supports
the
use
of
an
additional
3x
database
factor.

8.
The
PRC
determined
toxicology
data
needs
for
free
triazole
and
triazole
alanine
(
following
evaluation
of
requested
studies,
it
is
possible
that
additional
data
may
be
needed):

°
For
free
triazole,
the
following
studies
should
be
required:
Acute
neurotoxicity
study
in
rat
Combined
90­
day/
subchronic
neurotoxicity
study
in
rat
Developmental
toxicity
study
in
rabbit
Reproductive
toxicity
study
in
rat
(
2­
generation)
Two­
year
chronic
toxicity/
oncogenicity
study
in
female
mice
and
male
rats
°
For
triazole
alanine,
requirements
for
additional
studies
should
be
reserved
pending
re­
review
of
previously
submitted
studies
or
results
of
monitoring
studies.
81
of
94
III.
REFERENCES
Triazolylalanine
Group
(
TAG).
January
9,
2002.
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites.
MRID#
45575501.

Review
of
"
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites".
Memorandum
from
C.
Swentzel
to
R.
Keigwin
dated
July
8,
2002.
82
of
94
Attachment
2:
Second
Report
of
the
Ad
Hoc
Triazole
HED
Peer
Review
Committee
TXR
NO.
0052012
DATE:
August
5,
2003
MEMORANDUM
SUBJECT:
TRIAZOLES
­
2nd
Report
of
the
Ad
Hoc
HED
Peer
Review
Committee.

FROM:
Kathleen
Raffaele,
Toxicologist
Registration
Action
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Stephen
Dapson
Senior
Scientist,
Registration
Action
Branch
3
Health
Effects
Division
(
7509C)

TO:
Bob
Tomerlin
Registration
Division
(
7505C)

PC
Codes
(
include
but
are
not
limited
to):
004401;
120503;
128993;
128847;
123909;
129011;
128835;
128925;
128857;
125601;
122101;
120603;
128997;
109901;
127201;
128976
On
11/
4/
02,
an
ad
hoc
HED
committee
conducted
an
internal
Peer
Review
of
the
OPP
Triazole
Team's
7/
8/
02
analysis
of
the
Triazolylalanine
Group's
(
TAG)
1/
9/
02
document
entitled
"
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites"(
MRID#
45575501).
The
committee,
led
by
Elizabeth
Doyle,
addressed
toxicology
and
dietary
exposure
issues
associated
with
this
class
of
fungicides
and
its
metabolites/
degradates
of
concern,
including
toxicology
data
needs
(
see
Memo
dated
July
10,
2003,
TXR#
0052011,
K.
Raffaele
to
Bob
Tomerlin).
On
June
16,
2003,
the
Committee
reconvened,
to
address
a
data
waiver
request
submitted
by
the
US
Triazole
Task
Force
(
USTTF,
DP
Barcode
289197),
requesting
that
data
requirements
for
the
acute
neurotoxicity
study,
the
rabbit
developmental
study,
and
the
chronic/
oncogenicity
studies
on
male
rats
and
female
mice
be
waived.
83
of
94
Ad
Hoc
HED
Peer
Review
Committee
Members
in
Attendance
Elizabeth
Doyle,
Karl
Baetcke,
William
Burnam,
Vicki
Dellarco,
George
Herndon
(
substituting
for
Steve
Knizner),
Alberto
Protzel,
Jess
Rowland,
and
Brenda
Tarplee
(
Executive
Secretary).

OPP
Triazole
Team
Members
in
Attendance
Kathleen
Raffaele,
Paula
Deschamp,
and
Mike
Metzger.

Also
in
attendance
were:
Timothy
McMahon
(
AD)

Toxicology
Data
Evaluation
/
Report
Presentation:
_______________________
Kathleen
Raffaele,
Toxicologist
84
of
94
INTRODUCTION
On
11/
4/
02,
an
ad
hoc
HED
committee
conducted
an
internal
Peer
Review
of
the
OPP
Triazole
Team's
7/
8/
02
analysis
of
the
Triazolylalanine
Group's
(
TAG)
1/
9/
02
document
entitled
"
Profile
of
the
Triazole­
derivative
Fungicide
Compounds
and
their
Common
Metabolites"
(
MRID#
45575501).
The
committee,
led
by
Elizabeth
Doyle,
addressed
toxicology
and
dietary
exposure
issues
associated
with
this
class
of
fungicides
and
its
metabolites/
degradates
of
concern,
including
toxicology
data
needs
(
for
conclusions
from
this
meeting,
see
TXR#
0052011).
On
June
16,
2003,
the
Committee
reconvened,
to
address
a
data
waiver
request
submitted
by
the
US
Triazole
Task
Force
(
USTTF,
DP
Barcode
289197),
proposing
that
data
requirements
for
the
acute
neurotoxicity
study,
the
rabbit
developmental
toxicity
study,
and
the
chronic/
oncogenicity
studies
on
male
rats
and
female
mice
be
waived.

BACKGROUND
In
their
meeting
on
11/
4/
02,
the
ad
hoc
Triazole
Peer
Review
Committee
(
PRC)
determined
toxicology
data
needs
for
free
triazole.
These
data
needs
were
transmitted
to
the
US
Triazole
Task
Force
(
USTTF)
in
November,
2002.
The
OPP
Triazole
Team
met
with
the
USTTF
to
discuss
toxicology
data
needs
on
February
20,
2003,
and
a
detailed
proposal
for
generation
of
toxicology
data,
including
a
rationale
for
waiver
of
several
studies,
was
submitted
by
the
USTTF
on
March
28,
2003.
This
proposal
was
reviewed
by
the
OPP
Triazole
Team,
and
the
PRC
was
reconvened
on
June
16,
2003
to
evaluate
the
proposed
waiver.

CONCLUSIONS
The
conclusions/
recommendations
of
the
Peer
Review
Committee
(
PRC)
regarding
the
toxicology
study
waiver
requests
are
as
follows:

1.
Acute
Neurotoxicity
Study
The
PRC
determined
that
the
data
requirement
for
the
acute
neurotoxicity
study
should
be
placed
in
reserve,
pending
the
outcome
of
the
combined
subchronic/
neurotoxicity
study
in
rats.
Upon
receipt
of
the
combined
subchronic/
neurotoxicity
study,
the
need
for
the
acute
neurotoxicity
study
will
be
reassessed.
In
the
absence
of
data
from
an
acute
neurotoxicity
study,
the
PRC
concluded
that
the
use
of
the
developmental
endpoint
from
the
developmental
toxicity
study
in
rats,
when
used
for
acute
risk
assessments
in
all
populations,
would
be
protective
for
effects
that
might
have
been
seen
in
the
acute
neurotoxicity
study.

2.
Developmental
Toxicity
Study
in
Rabbits
The
PRC
reaffirmed
their
previous
decision
that
the
developmental
toxicity
study
in
rabbits
should
be
required.
Given
the
developmental
effects
seen
in
the
rat
study,
the
potential
for
developmental
toxicity
cannot
be
fully
evaluated
in
the
absence
of
a
study
in
rabbits
(
to
assess
the
possibility
that
the
rabbit
may
be
more
sensitive
than
the
rat).
Although
the
USTTF
argued,
85
of
94
based
on
results
from
parent
compounds,
that
the
rat
is
more
sensitive
to
developmental
toxicity
from
triazole­
derivative
compounds,
the
PRC
reaffirmed
its
previous
decision
that
the
toxicity
of
free
triazole
cannot
be
predicted
based
on
results
from
parent
compounds.
The
PRC
also
noted
that
the
results
from
studies
in
parent
compounds
were
mixed
with
respect
to
most
sensitive
species
for
developmental
effects
(
for
some
compounds,
lower
NOAELs
were
seen
in
rabbit
studies).

3.
Chronic
toxicity/
oncogenicity
studies
in
male
rats
and
female
mice
The
previous
recommendation
for
chronic
toxicity/
oncogenicity
studies
in
male
rats
and
female
mice
was
based
on
the
widespread
presence
and
persistance
of
free
triazole
in
the
environment
and
concerns
regarding
possible
carcinogenicity
of
free
triazole.
To
perform
an
adequate
assessment
of
carcinogenicity,
the
PRC
determined
that
both
rat
and
mouse
studies
were
needed.

The
USTTF
argued
that
chronic
toxicity
studies
for
free
triazole
are
not
needed;
they
suggested
that
chronic
endpoints
could
be
extrapolated
based
on
subchronic
data,
since
subchronic
and
chronic
endpoints
are
within
an
order
of
magnitude
for
parent
compounds.
As
mentioned
above,
the
PRC
previously
concluded
that
toxicity
of
free
triazole
could
not
be
predicted
based
on
results
of
studies
conducted
in
parent
compounds.
In
addition,
the
PRC
noted
that
the
relationship
between
subchronic
and
chronic
NOAELs/
LOAELs
has
much
to
do
with
dose
selection,
so
comparisons
of
NOAELs/
LOAELS
between
subchronic
and
chronic
studies
provides
limited
information.
The
PRC
also
noted
that
subchronic
studies
do
not
evaluate
the
potential
for
carcinogenicity,
which
is
seen
with
many
triazole­
derivative
compounds.

The
USTTF
stated
that
the
parent
triazole
compounds
are
not
mutagenic
or
genotoxic,
and
that
available
mutagenicity
data
for
free
triazole
are
also
negative,
mitigating
the
need
for
carcinogenicity
data.
The
PRC
agreed
that
available
mutagenicity
data
are
negative,
but
also
noted
that
many
triazole­
derivative
compounds
are
carcinogenic,
in
the
absence
of
mutagenicity
or
genotoxicity,
limiting
the
reliance
that
can
be
placed
on
these
negative
data.

The
USTTF
stated
that
there
was
no
indication
of
increased
toxicity
over
time
in
the
available
30­
and
90­
day
studies
with
free
triazole,
and
no
accumulation
of
free
triazole
was
seen
in
available
metabolism
studies.
The
PRC
concluded
that
differences
in
the
route
of
administration
(
gavage
vs.
dietary)
and
dose
selection,
and
limitations
on
the
endpoints
evaluated,
preclude
direct
comparison
of
results
across
the
30­
and
90­
day
studies
(
both
of
which
were
unacceptable,
with
multiple
deficiencies).
The
PRC
also
noted
that
the
length
of
the
cited
studies
was
not
substantially
different,
when
compared
to
the
duration
of
chronic
studies.
Regarding
the
metabolism
data,
the
PRC
noted
that
cumulative
toxicity
can
occur
due
to
repeated
insult,
without
need
for
bioaccumulation,
therefore
the
presence
or
absence
of
bioaccumulation
is
not
definitive.
In
addition,
the
estimated
half­
life
of
10­
12
h
from
these
available
metabolism
studies
does
not
preclude
the
possibility
of
bioaccumulation.
The
PRC
also
noted
that
the
available
metabolism
studies
for
free
triazole
are
limited
(
single
exposure
only),
and
have
been
classified
as
Unacceptable,
based
on
multiple
deficiencies
(
including
inadequate
methodological
information,
inadequate
characterization
of
test
substance,
etc.);
the
reliability
of
these
data
is
therefore
questionable.
86
of
94
The
USTTF
indicated
that
additional
endpoints
would
be
included
in
subchronic
rat
and
mouse
studies
to
address
possible
cancer
issues.
Based
on
review
of
submitted
protocols
by
the
Triazole
team,
the
added
endpoints
were
limited
(
retention
of
liver
tissue
for
possible
enzyme
analyses
[
criteria
for
performance
of
analyses
was
not
provided]
and
analysis
of
thyroid
hormone
levels
in
the
subchronic
rat
study).
No
mechanistic
data
were
proposed
or
provided,
nor
was
there
any
discussion
of
how
proposed
enzyme
analyses
(
if
performed)
or
thyroid
hormone
analyses
would
be
predictive
of
carcinogenicity.

In
conclusion,
the
PRC
determined
that
the
subchronic
studies
do
not
assess
carcinogenicity,
increased
severity
of
effects,
or
changes
in
dose/
response
curve,
which
may
occur
with
long
term
continuous
exposure.
In
the
absence
of
chronic
toxicity/
oncogenicity
studies,
long
term
risk
from
exposure
to
free
triazole,
including
possible
carcinogenic
effects,
cannot
be
evaluated.
The
requirement
for
chronic
toxicity/
oncogenicity
studies
in
male
rats
and
female
mice
was
reaffirmed.
87
of
94
Attachment
3:
Triazole
Summaries
­
Additional
Data
Summaries/
Literature
Articles
1.
O.
Hockwin
and
A.
Wegener.
(
1989).
Final
Expert
Opinion
on
the
In­
Vivo
examination
of
the
lens
using
slit­
lamp
microscope
and
Schiempflug
photography
and
post­
mortem
biochemistry
of
the
lenses
from
Bayer
Study
T
3
027
392
in
Beagle
Dogs.
Department
of
Exp.
Ophthalmology
of
the
Rheinische
Friedrich­
Wilhelm
University
Bonn,
Sigmund­
Freud
Street
25,
5300
Bonn
1,
Germany.
Laboratory
Project
ID
AC
Report
No.
109988.
MRID
45284013.
Unpublished.

This
document
contains
information
regarding
a
study
evaluating
ocular
effects
in
Beagle
dogs
during
exposure
to
several
Bayer
compounds,
including
tebuconazole
(
referred
to
in
the
document
as
HWG
1608)
and
triazole
(
1,2,4­
Triazole).
The
document
contains
no
information
regarding
the
study
protocol,
exposure
levels,
or
clinical
signs
in
the
exposed
animals.
Administered
doses
are
not
described
in
the
document,
although
a
listing
on
one
page
seems
to
indicate
doses
of
100
mg/
kg
for
both
triazole
and
tebuconazole.
The
report
does
contain
detailed
information
regarding
the
ocular
findings,
including
in
vivo
examinations
and
in
vitro
studies
of
changes
in
lens
biochemistry.
Statistically
significant
changes
were
found
on
some
parameters
for
both
tebuconazole
and
triazole.
Given
the
lack
of
procedural
information,
the
results
are
difficult
to
interpret.

Unless
additional
information
can
be
provided
for
this
study
(
for
example,
clinical
signs
or
necropsy
data,
and
a
more
adequate
explanation
of
the
procedures),
the
data
available
do
not
provide
information
usable
in
assessing
risk
from
triazole
exposure.

2.
J.
Thyssen
and
G.
Kimmerle.
(
1976).
1,2,4­
Triazole
Occupational
Toxicology
Study.
Bayer
AG,
Department
of
Toxicology,
Friedrich­
Ebert­
Strasse
217­
333,
D­
42096
Wuppertal,
Germany.
Bayer
AG
Report
No.
5926.
MRID
45284004.
Unpublished.

This
document
contains
short
summaries
of
several
acute
toxicity
studies
on
1,2,4­
triazole
(
studies
are
described
separately
below).
Very
little
information
was
provided
on
the
specific
procedures
used,
nor
was
there
analytical
data
on
the
test
substance.

Acute
oral
toxicity:
1,2,4­
triazole
was
administered
by
gavage
to
Wister
rats
(
size
of
most
dose
groups
was
15/
sex,
but
there
was
some
variation
among
doses).
Doses
ranged
from
250­
2500
mg/
kg
for
males,
100­
2500
mg/
kg
for
females;
there
were
9
dose
levels/
sex,
with
dose
intervals
usually
varying
by
250
mg/
kg.
Results
were
presented
as
the
number
of
animals/
group
who
died
or
showed
clinical
signs,
as
well
as
a
range
of
days
on
which
death
occurred
for
each
group.
An
LD50
was
also
calculated
separately
for
each
sex.

For
males,
clinical
signs
were
not
seen
at
250
mg/
kg,
but
were
seen
in
all
animals
for
all
other
dose
groups
(
starting
at
500
mg/
kg).
For
females,
clinical
signs
were
not
seen
at
100
mg/
kg,
but
were
seen
in
all
animals
for
all
dose
groups
starting
at
250
mg/
kg.
Clinical
signs
were
not
listed
for
individual
animals,
but
the
summary
listed
the
following
clinical
signs:
reduction
in
general
well­
being,
sedation,
and
breathing
disorders;
at
higher
doses,
lying
in
the
abdominal
or
side
position
(
doses
at
which
these
occurred
was
not
stated,
time
of
occurrence
was
given
as
"
within
88
of
94
an
hour
of
administration
and
...
for
a
maximum
of
up
to
13
days
after
administration"
[
study
report,
p.
6]).
The
lowest
dose
at
which
death
occurred
was
1250
mg/
kg
for
both
sexes,
with
the
death
occurring
on
the
day
of
dosing.
The
oral
LD50
was
similar
for
both
sexes
(
1650
mg/
kg
for
males,
1648
mg/
kg
for
females).

Dermal
toxicity:
1,2,4­
triazole
(
moistened
with
Cremophor
EL)
was
applied
to
the
shaven
dorsal
skin
of
male
and
female
Wistar
rats.
After
24
h,
substance
was
washed
off
(
with
soap
and
water).
Animals
were
observed
for
14
days.
The
summary
stated
that
studies
were
carried
out
using
the
occlusive
dressing
method
(
not
further
described,
although
a
citation
was
provided).
Group
size
varied
from
5
to
20,
with
most
groups
including
10
animals/
sex.
The
dose
range
was
1000­
5000
mg/
kg
for
males
(
4
dose
groups)
and
for
females
(
6
dose
groups).
Clinical
signs
were
seen
in
all
animals
from
all
treatment
groups.
Again,
individual
data
were
not
provided
but
the
summary
stated
that
the
symptoms
were
similar
to
those
seen
in
the
oral
studies.
Death
was
seen
at
the
2500
mg/
kg
dose
in
both
sexes;
time
of
death
varied
from
1­
9
days
after
treatment,
with
earlier
deaths
occurring
after
exposure
to
higher
dose
levels.
The
calculated
dermal
LD50
was
somewhat
lower
for
females
(
3129
mg/
kg)
than
for
males
(
4200
mg/
kg).

Inhalation:
No
effects
were
observed
in
the
inhalation
studies
(
using
5
male
rats
and
5
male
mice),
but
the
summary
also
states
that
"
no
substance
vaporized
or
atomized
in
the
4
and
6­
hr.
experiments",
so
it
is
not
clear
that
any
exposure
actually
occurred.

Dermal
irritation:
1,2,4­
triazole
was
applied
to
cellulose
patches
(
1.5
cm2,
500
mg/
patch).
The
patches
were
applied
for
24
h
to
the
hairless
skin
of
the
ears
of
2
rabbits.
Treated
skin
was
observed
for
7
days
following
removal
of
patches.
The
summary
stated
that
the
'
skin
revealed
no
changes'.

A
similar
study
was
also
performed
using
similar
treatment
on
the
human
forearm
(
specific
procedure
and
dose
not
provided),
with
exposure
from
2­
8
h
and
7
day
observation
periods
(
a
total
of
six
subjects,
1
female
and
5
male).
The
summary
stated
that
treated
skin
was
'
physiologically
normal'
after
removal
of
the
dressing
and
for
the
remainder
of
the
observation
period.

Ocular
irritation:
1,2,4­
triazole
was
applied
to
the
conjuctival
sac
of
the
left
eye
(
50
mg/
animal)
of
2
rabbits.
Intense
reddening
and
very
intense
swelling
of
the
eye
and
conjuctivae
were
observed
immediately
after
application
and
at
24
h.
After
5
days,
one
animal
had
returned
to
normal
but
the
other
still
had
some
redness
and
swelling
of
the
conjuctivae.
Effects
on
the
cornea
and
iris
were
also
observed
during
the
first
2
days
after
application.
The
test
substance
was
classified
as
a
severe
eye
irritant.

Summary:
The
report
concluded
that
1,2,4­
triazole
was
moderately
acutely
toxic
by
the
oral
and
dermal
route,
and
that
the
central
nervous
system
was
affected
at
high
oral
and
dermal
doses.

3.
P.
K.
Chan,
P.
M.
Fisher,
and
R.
D.
Morrison.
(
1981).
1,2,4­
Triazole
Acute
range­
finding
studies.
Rohm
and
Haas
Toxicology
Department,
727
Norristown
Rd.,
Spring
House,
PA
19477.
Rohm
and
Haas
Report
No.
81R
0057.
MRID
No.
45284006.
Unpublished.
89
of
94
and
K.
R.
Procopio
and
J.
D.
Hamilton.
(
1992).
1,2,4­
Triazole
Acute
range­
finding
studies.
Rohm
and
Haas
Company,
Toxicology
Department,
727
Norristown
Rd.,
Spring
House,
PA
19477.
Rohm
and
Haas
Report
No.
81R­
057A.
MRID
No.
45324301
(
Supplemental
submission
to
EPA
MRID
No.
45284006).
Unpublished.

Both
of
the
above­
cited
documents
provide
information
regarding
the
same
series
of
acute
toxicity
studies
on
1,2,4­
triazole,
with
the
second
submission
including
additional
information
not
provided
in
the
first
submission.

Acute
oral
toxicity:
1,2,4­
triazole
(
Sample
No.
TD
81­
112,
Lot
No.
113296,
92.8%
pure),
in
0.5%
methylcellulose,
was
administered
by
gavage
to
male
rats
(
Crl:
CDBR,
3/
group)
at
0.5
or
5
mg/
kg.
At
5.0
mg/
kg,
all
rats
died
within
10
min.
of
dosing;
at
0.5
mg/
kg,
all
rats
survived
and
no
clinical
signs
were
noted.

Acute
dermal
toxicity:
1,2,4­
triazole
(
lot
number
as
above),
was
moistened
with
saline
and
applied
to
shaven
intact
skin
of
rabbits
(
2
males/
dose
level)
at
0.2,
2.0,
and
5.0
g/
kg.
Application
sites
were
occluded.
After
24
hours,
covers
were
removed
and
site
was
wiped
with
paper
towels.
Animals
were
observed
for
14
days;
skin
irritation
was
also
recorded.

All
animals
treated
with
2.0
or
5.0
g/
kg
died;
the
higher
dose
animals
died
on
days
1
and
2,
the
lower
dose
animals
on
day
3
and
4.
Observed
clinical
signs
at
those
doses
included
passiveness,
scant
droppings,
soft
feces,
tremor,
ataxia,
salivation,
abdominal
breathing,
gasping,
and
nasal
discharges.
No
clinical
signs
were
seen
in
animals
treated
at
0.2
g/
kg.
Skin
irritation
was
noted
as
well
defined
erythema
and
very
slight
edema.
It
was
not
clear
at
which
dose(
s)
these
irritant
effects
were
observed.

Skin
irritation:
1,2,4­
triazole,
0.5
g/
patch,
was
moistened
with
saline
and
applied
to
the
skin
of
2
male
rabbits.
Two
patches
were
applied
to
each
rabbit,
1
on
intact
skin
and
1
on
abraded
skin.
Application
sites
were
occluded,
under
a
gauze
lined
patch
and
an
impervious
cuff,
for
24
h,
after
which
the
patches
were
removed
and
the
site
wiped
with
paper
towels.

No
edema
was
observed
for
either
site
on
either
rabbit.
Erythema,
scored
1
or
2,
was
observed
on
one
or
both
sites
for
both
rabbits.
Based
on
these
results,
1,2,4­
triazole
was
rated
as
'
slightly
irritating'
to
skin.

Eye
irritation:
1,2,4­
triazole,
0.1
g/
eye,
was
applied
to
the
conjunctival
sac
of
the
left
eye
of
two
male
rabbits.
Eye
irritation
was
evaluated
according
to
the
method
of
Draize,
for
up
to
14
days.
Effects
were
seen
on
the
cornea,
iris,
and
conjunctivae
starting
at
4
h.
By
day
7,
corneal
and
conjunctival
effects
had
cleared.
Iridal
effects
had
cleared
by
day
14.
Based
on
these
results,
1,2,4­
triazole
was
rated
as
'
substantially
irritating'
to
the
eye.

Summary:
Findings
in
this
series
of
studies
were
similar
to
those
in
the
previous
report.
The
only
notable
difference
was
that
there
were
no
clinical
signs
reported
in
the
current
acute
oral
90
of
94
study
at
0.5
g/
kg,
while
clinical
signs
were
seen
in
both
sexes
in
the
previous
acute
oral
study
at
500
mg/
kg
(
the
same
dose).
We
also
note
that
only
males
were
tested
in
the
current
study,
and
that
females
were
found
to
be
more
sensitive
in
the
previous
report.

4.
Wickramaratne,
G.
A.
de
S.
(
1987).
The
Chernoff­
Kavlock
Assay:
Its
validation
and
application
in
rats.
Teratogenesis,
Carcinogenesis,
and
Mutagenesis
7:
73­
83.
MRID
No.
45284010.

This
document
consists
of
a
copy
of
a
literature
article
reporting
on
a
study
intended
to
validate
the
use
of
an
abbreviated
Chernoff­
Kavlock
assay
in
rats
to
predict
chemicals
likely
to
cause
teratogenic
effects
(
testing
was
conducted
at
Central
Toxicology
Laboratory,
Imperial
Chemical
Industries
PLC,
Cheshire,
UK).
Test
substance
was
administered
to
pregnant
rats
(
Wistarderived
from
gestation
days
7­
17.
Maternal
observations
consisted
of
maternal
bodyweights
on
days
1,
7­
17,
and
22
of
gestation;
offspring
observations
included
only
litter
weights
of
live
pups
on
PNDs
1
and
5,
and
number
of
live
and
dead
pups
on
PNDs
1
and
5.

Triazole,
at
dose
of
25
and
100
mg/
kg,
was
included
as
one
of
the
many
substances
tested
in
this
assay.
Authors
reported
no
differences
between
triazole­
treated
animals
and
control
animals.

The
parameters
evaluated
and
reported
in
this
study
were
very
limited;
data
collected
in
the
rat
developmental
studies
conducted
by
Bayer
are
much
more
complete
and
would
supercede
those
reported
in
this
study.

5.
Wickings,
E.
J.,
M.
C.
Middleton,.
and
S.
G.
Hillier.
(
1987).
Non­
Steroidal
Inhibition
of
Granulosa
Cell
Aromatase
Activity
in
vitro.
J.
Steroid
Biochem.
26
(
6):
641­
646.
MRID
No.
45284014.

In
this
published
article,
a
substituted
triazole
(
R151885
[
1,1­
di(
4­
fluorophenyl)­
2­
1,2,4­
triazol­
1­
yl)­
ethanol)
was
evaluated
in
several
in
vitro
assays
for
effects
on
steroid
metabolism/
synthesis
(
including
granulosa
cell
estradiol
production,
progesterone
production,
and
testosterone
aromatization).
A
series
of
structurally
related
compounds
were
then
evaluated,
to
determine
which
structual
components
of
the
compound
were
responsible
for
aromatase
inhibition.
Results
indicated
that
imidazolyl
or
pyridyl
moieties,
when
replacing
the
triazolyl
substituent,
produced
more
potent
and
specific
inhibition.

These
results
appear
to
indicate
that
the
triazole
moiety
was
not
the
active
component
of
this
compound,
with
respect
to
inhibition
of
the
aromatase
enzyme
in
the
assay
used
in
this
study.

6.
Flucke,
W.
(
1978).
1,2,4­
Triazole.
Determination
of
Acute
Toxicity
(
LD50).
Bayer
AG,
Department
of
Toxicology,
Friedrich­
Ebert­
Strasse
217­
333,
D­
42096
Wuppertal,
Germany.
AC
Report
No.
109972.
MRID
No.
45284008.
Unpublished.

This
document
consists
of
a
one
page
report,
with
no
procedural
information
or
explanation
of
the
data.
It
appears
to
report
on
an
acute
oral
LD50
study;
doses
were
administered
to
male
rats
only,
10/
dose.
Doses
ranged
from
850­
2500
mg/
kg
(
8
dose
levels
tested).
It
appears
that
clinical
signs
(
not
described)
were
seen
in
all
animals
at
all
doses.
The
lowest
dose
at
which
death
91
of
94
occurred
was
1200
mg/
kg,
all
animals
died
at
2000
and
2500.
The
LD50
was
calculated
to
be
1375
mg/
kg
(
range
1273­
1485
mg/
kg).

The
findings
from
this
study
appear
to
be
similar
to
those
described
above.

7.
Rakhmatov,
R.
M.,
V.
B.
Danilov,
U.
A.
Madzhidov,
and
S.
A.
Gamiyants.
(
1991).
Basis
data
for
setting
the
limiting
allowed
concentration
(
LAC)
of
1,2,4­
triazole
in
workplace
air.
Gigiena
i
Sanitariya
2:
30­
1.
[
Abstract
only].
MRID
No.
45284011.

This
submission
consists
of
a
translated
Russian
abstract
that
describes
very
briefly
a
series
of
studies
conducted
for
use
in
setting
safe
exposure
levels
(
in
air)
for
1,2,4­
triazole.
Little
or
no
procedural
information
was
provided
for
the
various
studies.
The
results
reported
are
described
below.
­
Oral
LD50s
for
mice
(
3650
mg/
kg),
rats
(
3080
mg/
kg)
and
rabbits
(
666
mg/
kg).
Signs
reported
were
lethargy
and
ataxia,
with
death
on
the
'
first
day
of
observation.'
­
Inhalation
LC50
(
4
hour)
for
mice
(
2200
mg/
m3)
and
rats
(
2050
mg/
m3).
­
Skin
irritation
was
not
seen
upon
dermal
exposure
to
rats.
­
Eye
irritation
(
slight)
was
seen
in
rabbits.
­
Subacute
exposure
(
dose,
route,
and
duration
not
specified)
to
rats
demonstrated
some
potential
for
cumulative
toxicity.
Effects
seen
after
repeated
oral
exposure
were
described
as
'
macrovesicular
fatty
dystrophy
of
the
liver,
plethora
and
acirculatory
expansion
of
vessels
in
the
kidneys
with
filling
of
canal
loops
of
glomerulus
capillaries
by
blood,
and
shallow
hemorrhaging.'
­
Threshold
concentration
following
single
inhalation
exposure
(
duration
not
specified)
was
stated
as
226.6
±
10.5
mg/
m3,
with
findings
of
'
increased
methemoglobin
concentration
and
decreased
cholinesterase
activity
in
the
blood.'
­
Effects
of
aerosol
exposure
were
evaluated
in
rats
and
rabbits
at
doses
of
19.8
±
0.33
mg/
m3
and
4.9
±
0.08
mg/
m3.
Following
3
months
exposure
(
apparently
at
the
higher
dose),
decreased
levels
of
urea
in
urine
were
seen;
following
4
months,
decreased
cholinesterase
and
increased
methemoglobin
were
seen
in
blood.
No
effects
were
noted
at
the
lower
dose.
­
Mutagenic
(
as
represented
by
chromosome
aberrations
in
rat
marrow
cells)
or
'
embryotropic'
activity
(
not
further
described)
were
not
found
(
studies
not
described
but
conducted
using
inhalation
exposure
at
the
above
doses).

The
abstract
concluded
that
toxic
effects
of
the
compound
included
'
primarily
effects
on
the
liver,
kidneys,
and
CNS.'
A
LAC
of
5
mg/
m3
in
workplace
air
was
proposed.

8.
Saratikov,
A.
S.,
E.
M.
Trofimovich,
T.
P.
Novozheeva,
T.
A.
Zimina,
M.
R.
Ozhegina,
and
E.
L.
Morokova.
(
1986).
Toxicological
and
Health
Evaluation
of
1,2,4­
triazole
for
health
standards
in
aquifers.
Gigiena
i
Sanitariya
51
(
11):
65.
[
Abstract
only].
MRID
45284012.

This
submission
also
consists
of
a
translated
abstract,
describing
briefly
a
series
of
studies
conducted
for
use
in
evaluating
safe
levels
of
1,2,4­
triazole
in
aquifers.
It
was
stated
that
the
triazole
used
for
studies
was
98%
pure.
In
addition
to
toxicity,
several
properties
of
triazole
in
aqueous
solutions
were
evaluated.
92
of
94
Acute
toxicity
in
mice
and
rats
was
evaluated
following
intraperitoneal
administration
of
an
aqueous
solution.
Average
toxic
dose
was
stated
to
be
1350
mg/
kg
for
mice
and
1750
mg/
kg
for
rats,
with
clinical
signs
listed
as
decreased
motor
activity,
excitability,
muscle
cramp,
and
(
in
some
cases)
tremors
and
difficulty
breathing.

Irritancy
to
skin
was
evaluated
using
a
25%
solution,
eye
irritation
using
a
12.5%
solution;
no
irritant
effects
were
noted.

Cumulative
properties
were
also
evaluated,
and
it
was
stated
that
the
compound
has
moderatively
cumulative
properties,
but
insufficient
information
was
provided
to
interpret
the
stated
results.

A
six­
month
study
was
performed
in
male
white
rats
(
strain
not
specified),
using
i.
p.
doses
of
0.02,
0.20,
2.0
mg/
kg.
Evaluated
parameters
included
body
weights,
blood
cell
counts,
and
a
variety
of
clinical
chemistry
parameters;
apparently
no
histopathology
or
necropsy
data
were
collected.
Stated
results
included
an
increase
in
urine
protein
content,
changes
in
leukocytes,
and
changes
in
alkaline
phosphatase
activity
at
the
high
dose
(
no
other
description
provided).
No
changes
were
noted
at
the
two
lower
doses.
An
LAC
for
aquifers
was
recommended
at
4
mg/
dm3.

9.
Holzum,
B.
(
2000).
Developmental
toxicity
of
triazole­
fungicides,
Characterization
and
risk
assessment.
Bayer
AG,
Department
of
Toxicology,
Friedrich­
Ebert­
Strasse
217­
333,
D­
42096
Wuppertal,
Germany.
AC
Report
No.
109973.
MRID
No.
45284009.
Unpublished.

This
submission
consists
of
a
copy
of
a
presentation
by
a
Bayer
scientist,
regarding
common
developmental
toxicity
of
triazole
fungicides,
and
discussion
of
classification
of
developmental
effects
under
the
European
classification
and
labelling
requirements
(
used
within
the
European
Community).
Several
of
the
slide
copies
include
tables
listing
the
specific
types
of
developmental
toxicity
seen
following
exposure
to
triazole
fungicides
(
including
the
doses
at
which
effects
were
seen
maternally
and
in
offspring),
with
the
rat
and
rabbit
studies
compared
separately.

In
rats,
the
summary
notes
that
common
effects
generally
seen
include
embryolethality,
retarded
development,
and
supernumerary
ribs,
with
urinary
tract
variations
and
malformations
seen
in
a
subgroup
of
compounds.
In
rabbits,
the
only
general
effect
noted
was
embryolethality,
with
a
variety
of
malformations
again
seen
in
a
subgroup
of
compounds.

Included
in
the
summary
is
a
reference
to
developmental
toxicity
studies
using
triazole;
these
studies
have
been
reviewed
separately
and
the
results
will
not
be
discussed
here.

With
respect
to
common
toxicity
across
triazoles,
the
report
authors
concluded
"
we
may
conclude
that,
to
a
certain
extent,
a
typical
pattern
exists
for
triazole
developmental
toxicity
in
animals."
(
p.
9),
although
they
did
point
out
some
differences
in
the
patterns
of
abnormalities
across
studies.
The
report
author,
however,
attributes
developmental
effects
to
maternal
toxicity
for
this
group
of
compounds
(
perhaps
acting
via
maternal
hypoxia
or
adrenal
effects);
this
attribution
of
causation
appears
to
be
relevant
in
the
European
system
of
classification.
93
of
94
10.
Menegola,
E.,
M.
L.
Broccia,
F.
DiRenzo,
and
E.
Giavini.
(
date
not
provided).
Poster
Presentation:
In
Vitro
Comparative
Study
of
the
Teratogenic
Activity
of
Some
Triazoles.
University
of
Milan,
Dept.
of
Biology,
Milan­
Italy.
[
Copy
of
a
poster,
presentation
meeting
not
specified.]
MRID
No.
45344602.
Unpublished.

This
submission
consists
of
a
one
page
copy
of
a
poster.
Two
substituted
triazoles
(
Flusilazole
and
fluconazole)
and
triazole
were
evaluated
for
teratogenic
potential
in
vitro
in
48
h
whole
embryo
cultures
of
9.5
day
old
rat
embryos.
Methodological
details
regarding
the
culture
conditions
(
including
the
number
of
embryos
evaluated
in
each
condition)
and
analytical
procedures
were
not
provided.
The
results
stated
that
flusilazole
(
6.25­
250
µ
M)
and
fluconazole
(
125­
500
µ
M)
"
showed
abnormalities
at
the
branchial
apparatus
level
and
increased
cell
death
at
the
branchial
mesenchymes"
(
hypoplasia
of
I
and
II
branchial
arches
and
fusion
of
I­
II
branchial
arches)
without
indication
of
developmental
delays.
Exposure
to
triazole
(
2500­
5000
µ
M)
caused
slight
developmental
delays
and
severe
anemia
of
the
visceral
yolk
sac.
Authors
concluded
that
both
mono­
triazole
derivatives
showed
teratogenic
potential,
in
particular
for
cranio­
facial
abnormalities,
but
that
triazole
was
not
teratogenic.

We
note
that
insufficient
information
was
provided
for
us
to
evaluate
the
conclusions
stated
in
this
document,
and
that
the
conditions
of
exposure
for
this
in
vitro
study
may
not
represent
those
that
would
occur
in
vivo.
We
also
note
that
the
results
from
the
available
developmental
toxicity
study
in
rats
would
supercede
findings
from
this
study
with
respect
to
evaluating
teratogenic
effects
of
triazole.

Old
metabolism
studies
In
a
series
of
metabolism/
disposition
studies
(
MRID
45284018,
45284019,
and
45297202),
groups
of
male
and
female
Sprague­
Dawley
rats
were
given
a
single
intraduodenal
(
1
mg/
kg),
intravenous
(
0.1­
100
mg/
kg),
or
oral
dose
(
0.4­
866
mg/
kg)
of
14C­
labeled
triazole
(
MRID
45284018
 
Lot
No.
not
reported,
sp.
act.
470
µ
Ci/
mg,
purity
 
97%;
MRID
45284019
 
Lot
No.
CL­
V­
70,
sp.
act.
>
67
µ
Ci/
mg,
purity
>
98%;
MRID
45297202,
Lot
No.
CFQ
2458,
sp.
act.
103
µ
Ci/
mg,
purity
 
99%).
The
test
material
is
a
common
moiety
found
in
several
compounds
under
development
by
Ciba­
Geigy
at
the
time
these
studies
were
conducted.
Urine
and
feces
were
collected
up
to
7
days
postdose
and
expired
air
was
monitored
for
residual
activity.
Bile
samples
were
collected
up
to
24
hours
after
treatment
with
the
radiolabel.
Tissue/
carcass
burdens
were
investigated
at
selected
time
intervals
up
to
7
days
postdose.

No
treatment­
related
signs
of
toxicity
among
any
of
the
test
animals
were
reported.
Overall
recovery
of
administered
radioactivity
ranged
from
97­
105%.
Based
upon
urinary
and
biliary
excretion
and
tissue/
carcass
burden
data,
80%
­
95%
of
the
administered
dose
was
absorbed.
Elimination
of
administered
radioactivity
was
primarily
via
the
urine,
accounting
for
80­
95%
of
the
dose,
and
was
~
95%
complete
within
48
hours
after
treatment.
Elimination
via
expired
air
was
negligible
(<
0.1%).
Fecal
excretion
typically
accounted
for
<
15%
of
the
administered
radioactivity
and
was
essentially
complete
within
48
hours.
Biliary
excretion
accounted
for
approximately
10%
of
the
dose
during
the
24
hr
study
period,
and
the
results
were
suggestive
of
enterohepatic
circulation
and
diffusion/
secretion
by
the
stomach
mucosa.
94
of
94
The
only
compound
identified
in
the
urine
was
the
unchanged
parent
which
constituted
~
95%
of
the
radioactivity.
There
were
possibly
three
other
potential
polar
metabolites
in
the
urine,
each
constituted
<
3%
of
the
administered
dose.
Their
structures
were
not
elucidated,
but
all
three
seem
to
be
more
polar
than
triazole
as
judged
by
their
delayed
migration
relative
to
triazole
under
normal­
phase
TLC
separation
conditions.
Based
on
the
study
results,
triazole
was
nearly
completely
absorbed
and
rapidly
excreted
mostly
unchanged
in
the
urine.

These
metabolism/
disposition
studies
in
rats
are
Unacceptable/
Guideline
and
do
not
satisfy
the
requirements
for
a
Metabolism
and
Pharmacokinetics
Study
[
OPPTS
870.7485
(
§
85­
1)].
None
of
the
studies
were
described
in
detail
and
gave
the
impression
they
were
more
laboratory
notes
than
metabolic
study
reports.
Neither
the
care
and
treatment
of
the
animals
nor
the
test
material
were
adequately
described.
Details
concerning
dose
preparation,
such
as
stability
and
homogeneity
were
also
lacking.
Finally,
the
potential
metabolites
in
the
feces
were
not
identified,
particularly
in
those
instances
when
the
feces
contributed
>
5%
of
the
total
isotope
recovery
(
MRID
45284019).
The
study
can
be
upgraded
to
acceptable
if
it
can
be
shown
that
the
feces
also
contained
unchanged
parent
compound
and
if
more
information
were
provided
for
the
test
material
(
description,
purity,
stability,
homogeneity,
etc.).