Document ID: EPA-HQ-OPP-2005-0053-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-09-22T04:00Z

Page
1
of
55
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
August
3,
2006
MEMORANDUM
Subject:
Fenbuconazole:
Human
Health
Risk
Assessment
for
Proposed
Uses
on
Almonds,
Apples,
Bananas,
Bushberries,
Citrus
Fruit,
Cranberries,
Grapes,
Peanuts,
Pecans,
Stone
Fruits,
Sugar
Beets,
and
Wheat.
PC
Code:
129011,
DP
Barcode:
D316607
Petition
Nos.
(
see
below).

Regulatory
Action:
Section
3
Registration
Action
Risk
Assessment
Type:
Single
Chemical
Aggregate
From:
Margarita
Collantes,
Risk
Assessor,
Biologist
Michael
Doherty,
Chemist
Kim
Harper,
Toxicologist
Registration
Action
Branch
2
Health
Effects
Division
(
7509P)

Through:
Richard
Loranger,
Branch
Senior
Scientist
Registration
Action
Branch
2
Health
Effects
Division
(
7509P)

Christina
Swartz,
Branch
Chief
Registration
Action
Branch
2
Health
Effects
Division
(
7509P)

To:
John
Bazuin,
PM25
Fungicide
Branch
Registration
Division
(
7505P)

The
following
petition
numbers
are
addressed
within
this
risk
assessment:
2F4127;
2F4135;
7F4887;
7F4900;
3H5663;
9F6024;
1F3989;
1F3995;
2F4154;
0E6208;
3F4194;
4H5689;
4F6879;
1F3989;
1E6252;
9E5041
Page
2
of
55
Table
of
Contents
1.0
Executive
Summary
........................................................................................................
4
2.0
Ingredient
Profile
............................................................................................................
7
2.1
Summary
of
Registered/
Proposed
Uses........................................................................
8
2.2
Structure
and
Nomenclature
......................................................................................
11
2.3
Physical
and
Chemical
Properties
..............................................................................
13
3.0
Metabolism
Assessment
................................................................................................
11
3.1
Comparative
Metabolic
Profile
..................................................................................
11
3.2
Nature
of
the
Residue
in
Foods..................................................................................
13
3.2.1.
Description
of
Primary
Crop
Metabolism...........................................................
12
3.2.2
Description
of
Livestock
Metabolism.................................................................
12
3.2.3
Description
of
Rotational
Crop
Metabolism.......................................................
13
3.3
Environmental
Degradation.......................................................................................
13
3.4
Tabular
Summary
of
Metabolites
and
Degradates......................................................
13
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates...............................................
15
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
......................
15
3.6.1
Tabular
Summary
..............................................................................................
15
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates.......................................
16
4.0
Hazard
Characterization/
Assessment..................................................................................
16
4.1
Hazard
Characterization
............................................................................................
17
4.2
FQPA
Hazard
Considerations
....................................................................................
28
4.2.1
Adequacy
of
the
Toxicity
Data
Base
..................................................................
28
4.2.2
Evidence
of
Neurotoxicity
.................................................................................
28
4.2.3
Developmental
Toxicity
Studies
........................................................................
28
4.2.4
Reproductive
Toxicity
Study..............................................................................
28
4.2.5
Additional
Information
from
Literature
Sources.................................................
29
4.2.6
Pre­
and/
or
Postnatal
Toxicity...............................................................................
29
4.2.6.1
Determination
of
Susceptibility......................................................................
29
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Postnatal
Susceptibility
........................................................................................................
29
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study......................................
29
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
..............................................
29
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
................................................
29
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
4.4.3
Chronic
Reference
Dose
(
cRfD).........................................................................
30
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
...................................
30
4.4.5
Dermal
Absorption
............................................................................................
30
4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)
.....................................
30
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
.................................
31
4.4.8
Margins
of
Exposure..........................................................................................
31
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
............................
31
4.4.10
Classification
of
Carcinogenic
Potential.............................................................
31
4.5
Special
FQPA
Safety
Factor
......................................................................................
34
4.6
Endocrine
disruption
.................................................................................................
34
Page
3
of
55
5.0
Public
Health
Data
........................................................................................................
32
5.1
Incident
Reports
........................................................................................................
32
6.0
Exposure
Characterization/
Assessment
..............................................................................
32
6.1
Dietary
Exposure/
Risk
Pathway.................................................................................
32
6.1.1
Residue
Profile
..................................................................................................
32
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk...................................................
36
6.2
Water
Exposure/
Risk
Pathway...................................................................................
35
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway...........................................
36
6.3.1
Other
(
Spray
Drift,
etc.)
.....................................................................................
36
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
................................................
36
7.1
Acute
Aggregate
Risk................................................................................................
39
7.2
Short­
Term
Aggregate
Risk.......................................................................................
37
7.3
Intermediate­
Term
Aggregate
Risk............................................................................
37
7.4
Long­
Term
Aggregate
Risk
.......................................................................................
37
7.5
Cancer
Risk...............................................................................................................
38
8.0
Cumulative
Risk
Characterization/
Assessment
..............................................................
38
9.0
Occupational
Exposure/
Risk
Pathway
...........................................................................
39
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk.............................................................
39
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk..................................................
49
10.0
Data
Needs
and
Label
Requirements
.............................................................................
52
10.1
Toxicology
................................................................................................................
52
10.2
Residue
Chemistry
....................................................................................................
52
10.3
Occupational
and
Residential
Exposure
.....................................................................
53
References:
...............................................................................................................................
54
Appendices
...............................................................................................................................
55
Page
4
of
55
1.0
EXECUTIVE
SUMMARY
A
human
health
risk
assessment
has
been
conducted
to
support
the
proposed
new
uses
of
fenbuconazole
and
associated
tolerances
submitted
for
a
Section
3
registration
on
almonds,
apples,
bushberries,
citrus,
cranberries,
grapes
(
tolerance
only),
peanuts,
pecans,
stone
fruit,
sugar
beets,
and
wheat.
Fenbuconazole,
(
alpha­(
2­(
4­
chlorophenyl)­
ethyl)­
alpha­
phenyl­
3­(
1H­
1,2,4­
triazole)­
1­
propanenitrile),
is
a
broad­
spectrum,
triazole
fungicide.
It
is
formulated
in
wettable
powder
(
WP,
75%
a.
i.)
and
flowable
concentrate
(
FlC,
2
lb
a.
i./
gal)
forms.
Fenbuconazole
may
be
applied
by
groundboom,
airblast
or
aerial
equipment.
The
application
rates
as
specified
on
proposed
registered
labels
vary
from
0.062
to
0.19
lbs
a.
i./
acre
depending
on
the
crop.

Toxicology
The
Health
Effects
Division
(
HED)
has
evaluated
the
toxicity
data
submitted
by
the
petitioner
and
has
found
it
to
be
of
sufficient
scope
and
quality
to
assess
the
human
health
hazards
associated
with
fenbuconazole,
including
potential
developmental,
reproductive
and
neurotoxic
effects.
Fenbuconazole
targets
the
liver
and,
to
a
lesser
degree,
the
thyroid.
Fenbuconazole
is
classified
as
"
Group
C"
carcinogen
based
on
increased
incidence
of
liver
and
thyroid
cancers
in
mice
and
rats,
respectively.
Developmental
and
reproductive
studies
show
that
there
is
no
evidence
of
increased
qualitative
or
quantitative
susceptibility
of
the
offspring
to
fenbuconazole.
There
is
no
evidence
that
fenbuconazole
affects
the
endocrine
system.
There
are
no
data
gaps
associated
with
the
toxicological
database.

Metabolic
Profile
Adequate
studies
are
available
depicting
the
metabolism
of
[
14C]
fenbuconazole
in
rats,
primary
crops
(
peaches,
peanuts,
wheat,
sugar
beets),
rotational
crops
(
collards,
turnips,
wheat),
and
livestock
(
lactating
goats,
laying
hens).
Based
on
these
studies,
HED
has
determined
that
the
residues
of
concern
for
risk
assessment
are
fenbuconazole
and
the
following
metabolites:
RH­
9129,
RH­
9130,
RH­
4911(
peanut
only),
and
RH­
7905
(
peanut
only).
The
current
analytical
enforcement
method
has
been
validated
for
the
analysis
of
fenbuconazole,
RH­
9129,
and
RH­
9130,
which
are
the
residues
of
concern
for
tolerance
enforcement.
Additionally,
the
HED
has
identified
the
common
triazole
metabolites
(
1,2,4­
triazole,
triazolylalanine,
and
triazolylacetic
acid)
as
residues
of
concern
for
risk
assessment.
Risks
associated
with
exposure
to
these
compounds
have
been
addressed
in
a
separate
assessment
(
M.
Doherty,
et
al.,
D322215,
2/
7/
06).

Residue
Chemistry,
Environmental
Fate
and
Drinking
Water
HED
also
evaluated
the
residue
chemistry
database
for
fenbuconazole.
The
residue
chemistry
data
are
sufficient
to
evaluate
the
nature
and
magnitude
of
residues
in
crops
and
livestock,
although
there
are
minor
data
gaps.
To
evaluate
acute,
chronic,
and
cancer
dietary
risks,
HED
used
information
in
the
residue
chemistry
database
along
with
modeled
estimates
of
fenbuconazole
in
drinking
water
to
conduct
dietary
(
food
+
water)
exposure
assessments.
Results
of
those
analyses
indicate
that
dietary
exposures
do
not
present
risks
of
concern
for
the
U.
S.
population
or
any
population
subgroups.
There
are
minor
data
gaps
associated
with
the
residue
chemistry
database.
Page
5
of
55
Residential
Exposure:
Currently
there
are
no
registered
residential
uses
associated
with
fenbuconazole.

Aggregate
Exposure:
There
are
no
residential
uses
associated
with
fenbuconazole.
Consequently,
dietary
sources
are
the
only
sources
of
exposure
to
fenbuconazole
and
a
separate
aggregate
assessment
is
not
required.

Occupational
Exposure:

Based
on
the
number
of
seasonal
applications
indicated
on
this
product
label
and
information
provided
by
the
registrant,
handler
exposures
for
the
proposed
new
uses
are
expected
to
be
shortand
intermediate­
term
in
duration.
Both
cancer
and
non­
cancer
risks
were
estimated.
All
noncancer
mixer/
loader,
applicator
and
flagger
inhalation
MOEs
were
greater
than
the
level
of
concern
(
MOE
>
100)
at
baseline.

EPA
considers
handler
cancer
risk
estimates
greater
than
one
in
ten
thousand
(
1
x
10­
4)
to
be
of
concern,
and
attempts
to
mitigate
such
exposures
so
that
cancer
risk
estimates
are
reduced
to
one
in
one
million
(
1
x
10­
6)
or
less,
where
feasible.
The
cancer
risk
for
private
farmers
ranged
from
6.1
x
10­
9
to
1.3
x
10­
6
,
while
the
cancer
risk
for
commercial
farmers
ranged
from
1.8
x
10­
8
to
4.0E
x
10­
6
using
either
baseline
or
PPE
(
single
layer
clothing
and
gloves)
mitigation.
HED
does
not
consider
any
of
these
scenarios
as
a
risk
to
workers.

Long­
term
dermal
exposure
as
a
result
of
postapplication
activities
is
not
expected.
Therefore
a
non­
cancer
postapplication
exposure
assessment
was
not
required.
All
cancer
risks
were
lower
than
1
x
10­
6
and
therefore
were
not
a
risk
concern.

Restricted
Entry
Interval
The
restricted
entry
interval
(
REI)
is
based
on
the
acute
toxicity
of
fenbuconazole
technical
material
which
is
classified
as
Category
III
and
IV.
Acute
toxicity
Category
III
and
IV
chemicals
require
a
12
hour
REI.
Therefore
the
12­
hour
REI
which
appears
on
the
Enable
2F
Fungicide
and
Indar
75WSP
labels
are
adequate.

Environmental
Justice
Considerations:

Potential
areas
of
environmental
justice
concerns,
to
the
extent
possible,
were
considered
in
this
human
health
risk
assessment,
in
accordance
with
U.
S.
Executive
Order
12898,
"
Federal
Actions
to
Address
Environmental
Justice
in
Minority
Populations
and
Low­
Income
Populations,"
http://
www.
eh.
doe.
gov/
oepa/
guidance/
justice/
eo12898.
pdf).

As
a
part
of
every
pesticide
risk
assessment,
OPP
considers
a
large
variety
of
consumer
subgroups
according
to
well­
established
procedures.
In
line
with
OPP
policy,
HED
estimates
risks
to
population
subgroups
from
pesticide
exposures
that
are
based
on
patterns
of
that
subgroup's
food
and
water
consumption,
and
activities
in
and
around
the
home
that
involve
Page
6
of
55
pesticide
use
in
a
residential
setting.
Extensive
data
on
food
consumption
patterns
are
compiled
by
the
USDA
under
the
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII)
and
are
used
in
pesticide
risk
assessments
for
all
registered
food
uses
of
a
pesticide.
These
data
are
analyzed
and
categorized
by
subgroups
based
on
age,
season
of
the
year,
ethnic
group,
and
region
of
the
country.
Additionally,
OPP
is
able
to
assess
dietary
exposure
to
smaller,
specialized
subgroups
and
exposure
assessments
are
performed
when
conditions
or
circumstances
warrant.
Whenever
appropriate,
nondietary
exposures
based
on
home
use
of
pesticide
products
and
associated
risks
for
adult
applicators
and
for
toddlers,
youths,
and
adults
entering
or
playing
on
treated
areas
postapplication
are
evaluated.
Further
considerations
are
currently
in
development
as
OPP
has
committed
resources
and
expertise
to
the
development
of
specialized
software
and
models
that
consider
exposure
to
bystanders
and
farm
workers
as
well
as
lifestyle
and
traditional
dietary
patterns
among
specific
subgroups.

Review
of
Human
Research:

This
risk
assessment
does
not
rely
on
any
data
from
studies
in
which
human
subjects
were
intentionally
exposed
to
a
pesticide
or
other
chemical.

Conclusion
Based
on
our
analysis
of
the
available
data
and
on
estimates
of
risk,
HED
is
recommending
that
a
conditional
registration
for
fenbuconazole
be
granted
and
that
permanent
tolerances
be
established
for
combined
residues
of
fenbuconazole
[
 ­[
2­(
4­
chlorophenyl)­
ethyl]­
 ­
phenyl­
3­(
1H­
1,2,4­
triazole)­
1­
propanenitrile]
and
its
metabolites,
cis­
5­(
4­
chlorophenyl)­
dihydro­
3­
phenyl­
3­(
1H­
1,2,4­
triazole­
1­
ylmethyl)­
2­
3H­
furanone
(
RH­
9129)
and
trans­
5­
(
4­
chlorophenyl)
dihydro­
3­
phenyl­
3­(
1H­
1,2,4­
triazole­
1­
ylmethyl)­
2­
3H­
furanone
(
RH­
9130)
as
follows:

Almond                  .
0.05
Almond,
hulls                
1.0
Apple                   .
0.4
Apple,
wet
pomace..             ..
1.0
Banana                  ...
0.3
Bushberry
subgroup
13B
          ..
0.3
Fruit,
citrus,
group
10
            .
1.0
Citrus,
oil                 .
40.0
Citrus,
dried
pulp
              .
5.0
Cranberry                 ..
0.5
Grape*                   .
1.0
Peanut                   
0.1
Pecan                   .
0.05
Fruit,
stone,
group
12
             .
1.0
Beet,
sugar,
roots
               
0.3
Beet,
sugar,
tops
               .
9.0
Beet,
sugar,
dried
pulp...            ..
1.0
Beet,
sugar,
molasses
             .
0.4
Wheat,
grain      ..          ..
0.1
Page
7
of
55
Wheat,
forage                
4.0
Wheat,
hay                 .
8.0
Wheat,
straw                ..
8.0
Grain,
aspirated
fractions     ..      
6.0
Meat
byproducts
of
cattle,
horses,
goats,
and
sheep ..
0.05
*
The
CFR
entry
should
indicate
that
there
is
no
U.
S.
registration
on
grapes
as
of
the
date
of
the
Federal
Notice
establishing
the
tolerance.

The
recommendation
for
a
conditional
registration
is
due
to
the
residue
chemistry
data
gaps
associated
with
fenbuconazole
as
detailed
in
Section
10.2.
In
addition,
as
specified
in
HED's
February
7,
2006
risk
assessment
(
M.
Doherty
et
al,
DP#
322215)
for
1,2,4­
triazole
and
its
metabolites
triazole
alanine
and
triazole
acetic
acid,
HED
recommended
that
resolution
of
various
issues
be
a
condition
of
registration
for
new
uses
of
triazole­
derivative
fungicides
and
for
new
active
ingredients
which
contain
the
1,2,4­
triazole
ring.
The
requirement
for
a
chronic
toxicity/
oncogenicity
study
in
male
rats
and
female
mice
in
the
2/
7/
2006
memo
was
later
modified
by
HED
to
a
1­
year
chronic
study
in
male
and
female
rats
(
Kit
Farwell,
DP#
321328,
5/
10/
2006).
Therefore,
HED
recommends
that
the
registration
of
the
proposed
new
uses
of
fenbuconazole
also
be
conditioned
upon
resolution
of
the
following
issues:

°
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
 
1
year
chronic
rat
study
in
males
and
females
 
Acute
neurotoxicity
study
in
rats
[
This
study,
included
in
the
original
data
requirements,
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.
Page
8
of
55
2.0
INGREDIENT
PROFILE
Fenbuconazole
is
a
broad­
spectrum,
triazole­
type
fungicide.
It
is
formulated
in
wettable
powder
(
WP,
75%
a.
i.)
and
flowable
concentrate
(
FlC,
2
lb
a.
i./
gal)
forms.
The
requested
uses
for
fenbuconazole
are
summarized
in
Table
2.1.

2.1
Summary
of
Registered/
Proposed
Uses
Table
2.1.
Summary
of
Directions
for
the
Proposed/
Requested
Uses
of
Fenbuconazole
Application
Timing,
Type,
and
Equip.
1
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
2
Almond
Broadcast
foliar
applications
beginning
at
pink
bud
stage
through
petal
fall.
Ground
or
aerial
equipment
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
0.094
3
0.282
160
A
minimum
retreatment
interval
(
RTI)
of
10
days
is
specified.

A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Apple
Broadcast
foliar
Unspecified
equipment
2
lb/
gal
FlC
[
62719­
416]
0.12
4
0.5
14
A
minimum
retreatment
interval
of
7
days
is
specified.
The
grazing
of
livestock
in
treated
areas
is
prohibited.
The
use
of
a
non­
ionic
surfactant
in
the
spray
mix
is
recommended.
Banana
Broadcast
foliar
applications
beginning
when
leaves
first
appear
Ground
or
aerial
equipment
2
lb/
gal
FlC
[
62719­
416]
0.094
8
0.75
0
A
minimum
RTI
of
14
days
is
specified.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix,
and
the
use
of
an
emulsifiable
spray
oil
is
recommended.
Bushberry,
Subgroup
13B
Broadcast
foliar
applications
beginning
at
bud
break
(
green
tip)
through
fruit
development.
Ground
or
aerial
equipment
75%
WP
[
62719­
421]
0.094
5
0.47
30
A
minimum
retreatment
interval
of
10
days
specified.
Do
apply
through
any
type
of
irrigation
system.
For
ground
and
aerial
applications,
apply
in
a
minimum
volume
of
10
and
20
gal/
A,
respectively.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Citrus,
Group
10
Broadcast
foliar
Unspecified
equipment
2
lb/
gal
FlC
[
62719­
416]
0.125
3
0.375
0
A
minimum
retreatment
interval
is
not
specified.
The
grazing
of
livestock
in
treated
areas
is
prohibited.
The
use
Page
9
of
55
Table
2.1.
Summary
of
Directions
for
the
Proposed/
Requested
Uses
of
Fenbuconazole
Application
Timing,
Type,
and
Equip.
1
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
2
of
a
non­
ionic
surfactant
in
the
spray
mix
is
recommended.
Cranberry
Broadcast
foliar
applications
beginning
when
50%
of
shoots
show
3
inch
of
new
growth,
through
fruit
development.
Ground
or
aerial
equipment
75%
WP
[
62719­
421]
0.188
5
0.94
30
A
minimum
retreatment
interval
of
7
days
is
specified.
Do
apply
through
any
type
of
irrigation
system.
For
aerial
applications,
apply
in
a
minimum
volume
of
10
gal/
A.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Grape
(
Central
and
South
America)
Broadcast
foliar
application
at
flowering.
Ground
equipment
2
lb/
gal
FlC
0.30
1
0.30
None
Grapes
(
Europe)
Broadcast
foliar
applications
beginning
at
6­
7
leaves
unfolded
through
berry
development.
Ground
equipment
50
g/
l
EC
0.01­
0.06
8
0.36
14
The
supported
minimum
retreatment
interval
is
14
days.

Peanut
Broadcast
foliar
beginning
4
weeks
after
planting
or
when
disease
first
appears.
Ground
or
aerial
equipment
1
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
0.125
8
1.0
14
A
minimum
retreatment
interval
of
10
days
is
specified.
Do
not
feed
hay
or
threshings
or
allow
livestock
to
graze
in
treated
areas.
The
minimum
specified
application
volumes
are
20
and
5
gal/
A
for
ground
and
aerial
applications,
respectively.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Pecan
Broadcast
foliar
applications
beginning
at
bud
break
up
to
shuck
split.
Ground
or
aerial
equipment
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
[
62719­
443]
0.125
NS
0.75
28
Minimum
RTIs
are
10
days
for
applications
between
budbreak
and
pollination,
and
14
days
for
cover
sprays.
Do
not
apply
after
shuck
split
or
within
28
days
of
harvest.
A
non­
ionic
surfactant
should
Page
10
of
55
Table
2.1.
Summary
of
Directions
for
the
Proposed/
Requested
Uses
of
Fenbuconazole
Application
Timing,
Type,
and
Equip.
1
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
2
be
used
in
the
spray
mix.
Stone
Fruit,
Group
12
Broadcast
foliar
applications
beginning
at
early
red
bud
stage
through
to
crop
maturity.
Ground
or
aerial
equipment
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
0.094
4
0.75
(
0.38)
3
0
A
minimum
RTI
of
7
days
is
specified.

A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.

Sugar
Beet
Broadcast
foliar
applications
when
disease
first
appears.
Ground
or
aerial
equipment
4
2
lb/
gal
FlC
[
62719­
416]
0.125
4
0.5
14
A
minimum
retreatment
interval
of
10
days
is
specified.
Do
not
feed
treated
tops
to
livestock.
The
minimum
specified
application
volumes
are
20
and
5
gal/
A
for
ground
and
aerial
applications,
respectively.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Wheat
Broadcast
foliar
applications
through
heading
(
Feekes
growth
stage
10.3­
10.5)
Ground
or
aerial
equipment
4
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
0.063
2
0.125
35
A
minimum
retreatment
interval
of
7
days
is
specified.
Do
not
apply
after
completion
of
flowering
(
Feekes
growth
stage
10.5)
or
within
35
days
of
harvest.
Do
not
graze
livestock
in
treated
areas
or
cut
the
green
crop
for
hay
or
silage.
The
minimum
specified
application
volumes
are
20
and
5
gal/
A
for
ground
and
aerial
applications,
respectively.
A
non­
ionic
surfactant
should
be
used
in
the
spray
mix.
Seed
treatment
5
2
lb/
gal
FlC
[
62719­
416]

75%
WP
[
62719­
421]
0.063
lb
ai/
100
lb
seed
(
625
ppm)
1
NA
NA
Treated
seed
should
be
dyed
and
labeled
to
indicate
that
the
seed
have
been
treated
with
fenbuconazole,
and
must
not
be
used
for
food
or
feed
purposes
1
All
use
directions
prohibit
the
grazing
of
livestock
in
treated
areas
and
the
feeding
of
cover
crops
grown
in
treated
areas
to
livestock.
Page
11
of
55
2
Applications
should
be
made
in
a
minimum
of
10
gal/
A
for
aerial
applications
and
50
gal/
A
for
ground
applications.
3
The
most
recently
proposed
use
directions
for
stone
fruits
(
plums/
prunes)
specifies
a
seasonal
maximum
of
0.38
lb
ai/
A.
4
Ground
applications
can
include
the
use
of
chemigation
using
the
following
types
of
irrigation
systems:
center
pivot,
lateral
move,
end
tow,
side
(
wheel)
roll,
traveler,
solid
set,
or
hand
move
systems.
5
The
seed
treatment
use
is
based
on
copies
of
proposed
labels
submitted
in
1997.

2.2
Structure
and
Nomenclature
Table
2.2.
Nomenclature
of
Fenbuconazole
and
its
Regulated
Metabolites
Compound
N
N
N
Cl
CN
Common
name
Fenbuconazole
Company
experimental
names
RH­
7592
IUPAC
name
(
RS)­
4­(
4­
chlorophenyl)­
2­
phenyl­
2­(
1H­
1,2,4­
triazol­
1­
ylmethyl)
butyronitrile
CAS
name
 ­[
2­(
4­
chlorophenyl)
ethyl]­
 ­
phenyl­
1H­
1,2,4­
triazole­
1­
propanenitrile
Molecular
weight
336.8
CAS
registry
number
114369­
43­
6
(
119611­
00­
6,
racemate)

End­
use
products/
EP
2
lb/
gal
FlC
and
75%
WPs
Metabolite
Common
name
cis
lactone
metabolite
Company
experimental
names
RH­
9129
IUPAC
names
(
3R,
5R)­
5­(
4­
chlorophenyl)­
3­
phenyl­
3­(
1H­
1,2,4­
triazol­
1­
ylmethyl)
dihydrofuran­
2(
3H)­
one
CAS
names
cis­
5­(
4­
chlorophenyl)
dihydro­
3­
phenyl­
3­(
methyl­
1­
H,
2,4­
triazole­
1­
yl­
2­(
3H)­
furanone
Molecular
weight
353.8
CAS
registry
number
146887­
38­
9
O
N
N
N
O
Cl
Page
12
of
55
Table
2.2.
Nomenclature
of
Fenbuconazole
and
its
Regulated
Metabolites
Metabolite
O
N
N
N
O
Cl
Common
name
trans
lactone
metabolite
Company
experimental
names
RH­
9130
IUPAC
names
(
3S,
5R)­
5­(
4­
chlorophenyl)­
3­
phenyl­
3­(
1H­
1,2,4­
triazol­
1­
ylmethyl)
dihydrofuran­
2(
3H)­
one
CAS
names
trans­
5­(
4­
chlorophenyl)
dihydro­
3­
phenyl­
3­(
methyl­
1­
H,
2,4­
triazole­
1­
yl­
2­
(
3H)­
furanone
Molecular
weight
353.8
CAS
registry
number
146887­
37­
8
2.3
Physical
and
Chemical
Properties
Table
2.3.
Physicochemical
Properties
of
the
Technical
Grade
Fenbuconazole
Parameter
Value
Reference
Melting
point
126.5 
127.0
°
C
pH
Not
available
Bulk
Density
0.50
g/
mL
Water
solubility
at
22
°
C
3.8
mg/
L
Solvent
solubility
(
g/
L)
at
25
°
C
Acetonitrile
231
Cyclohexanone
445
Ethyl
alcohol
39
1­
octanol
13
Aromatic
200
77
Ethyl
acetate
159
Heptane
1.0
Vapor
pressure
at
25
°
C
(
PAI)
0.37
×
10­
7
mm
Hg
(
4.9
×
10­
6Pa)

Dissociation
constant
(
pKa)
(
PAI)
Not
expected
to
dissociate
in
water
Octanol/
water
partition
coefficient
Log(
KOW)
3.22
UV/
visible
absorption
spectrum
 
max
(
nm)
196
262
268
275
 
(
L
·
mol­
1
·
cm­
1)
53,000
750
740
480
PMRA
Regulatory
Note
(
REG2003­
03)
on
Fenbuconazole,
4/
28/
03
Page
13
of
55
3.0
METABOLISM
ASSESSMENT
3.1
Comparative
Metabolic
Profile
Adequate
studies
are
available
depicting
the
metabolism
of
[
14C]
fenbuconazole
in
rats,
primary
crops
(
peaches,
peanuts,
wheat,
sugar
beets),
rotational
crops
(
collards,
turnips,
wheat),
and
livestock
(
lactating
goats,
laying
hens).
Major
residues
consistently
noted
in
these
studies
include
parent
fenbuconazole
and
the
lactone
metabolites
RH­
9129,
RH­
9130,
and
RH­
6467.
The
common
triazole
metabolites
1,2,4­
triazole,
triazolylalanine,
and
triazolylacetic
acid
were
observed
in
all
of
the
metabolism
studies,
with
the
degree
of
metabolite
formation
highly
dependent
on
the
species
being
studied.

In
rats,
fenbuconazole
is
rapidly
absorbed
and
excreted
within
96
hours
following
a
single
low
or
high
dose
or
following
repeated
low
doses.
Low
bioaccumulation
of
both
the
parent
compound
and
metabolites
was
indicated
by
low
levels
in
the
tissues.
Elimination
occurred
primarily
by
biliary
excretion
since
the
majority
of
the
administered
dose
was
recovered
in
the
bile
three
days
after
exposure
or
in
the
feces
four
days
after
exposure.
There
were
no
sex­
or
dose­
related
differences
in
absorption,
distribution,
or
elimination;
these
processes
were
also
similar
regardless
of
whether
single
or
multiple
exposure
regimens
were
used.
Extensive
metabolism
of
fenbuconazole
occurred,
with
sex­
and
dose­
related
differences.
Very
low
(
2­
5%)
parent
compound
was
recovered
in
the
feces
following
single
or
repeated
low
doses,
but
a
higher
percentage
(
21­
37%)
was
found
following
a
single
high
dose.
More
sulfate
metabolites
were
found
in
female
excreta
compared
to
males,
and
more
ketoacid
metabolites
were
found
in
male
urine
compared
to
females.

Based
on
the
peach
and
wheat
studies,
the
Metabolism
Committee
(
N.
Dodd
and
W.
Wassell,
3/
9/
94)
concluded
that
the
residues
of
concern
for
uses
on
stone
fruit,
wheat,
pecans,
bananas,
apples
and
almonds
are
fenbuconazole
and
its
lactone
metabolites,
RH­
9129
and
RH­
9130.
This
conclusion
was
contingent
upon
the
petitioner
providing
data
showing
that
RH­
4911
is
only
a
minor
residue
in
these
crops.
The
petitioner
subsequently
fulfilled
this
requirement
by
providing
data
from
the
wheat
and
peach
metabolism
studies
showing
that
conjugates
of
RH­
4911
accounted
for
<
5%
of
the
TRR
in
peaches
and
wheat
straw
(
D200171,
N.
Dodd,
4/
5/
94).
The
Metabolism
Committee
also
noted
that
the
iminolactone
metabolite
(
RH­
6468)
would
be
included
de
facto
in
the
residues
of
concern
as
this
compound
is
converted
to
the
lactones
by
the
analytical
methodology.
After
reviewing
the
sugar
beet
data,
HED
has
also
determined
that
fenbuconazole
and
it
lactone
metabolites
are
the
residues
of
concern
for
uses
on
sugar
beets
(
D241864,
PP#
7F4887).
Metabolite
studies
with
peanuts
show
that
RH­
7905
and
RH­
4911
are
significant
residues
of
concern
in
that
crop.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
degree
of
metabolism
of
fenbuconazole
varies
depending
on
the
primary
crop.
Overall,
three
routes
of
metabolism
appear
to
be
important:
(
i)
initial
cleavage
of
the
triazole
ring
can
Page
14
of
55
lead
to
terminal
residues
of
triazolylalanine
and/
or
triazolylacetic
acid;
(
ii)
hydroxylation
of
the
chlorophenyl
ring
leads
to
glycoside
conjugates
of
the
parent
molecule,
seen
primarily
in
peanut
as
the
glucose
conjugate
of
RH­
4911;
and
(
iii)
hydroxylation
of
the
alkyl
chain
results
in
formation
of
the
ketone
(
RH­
6467),
lactone
(
RH­
9129
and
RH­
9130),
and
iminolactone
(
RH­
6468)
metabolites.
Relative
amounts
of
these
metabolites
are
summarized
in
Table
3.4.

3.2.2
Description
of
Livestock
Metabolism
Metabolism
studies
with
lactating
goats
and
laying
hens
show
that
the
majority
of
the
administered
dose
is
excreted
and
only
a
small
portion
(
1­
2%)
is
absorbed.
In
the
goat
study,
 

0.4%
of
the
administered
dose
was
excreted
in
the
milk.
Overall,
the
metabolism
of
fenbuconazole
in
ruminants
appears
to
proceed
via
three
pathways
involving
either:
(
i)
oxidation
at
the
unsubstituted
phenyl
ring
to
yield
the
4­
phenol
metabolite
(
RH­
1311);
(
ii)
oxidation
at
the
benzylic
position
of
the
chlorinated
phenyl
ring
leading
to
the
formation
of
the
benzylic
alcohol
metabolite
(
RH­
6648)
and
the
iminolactone
(
RH­
6468),
lactones
(
RH­
9130
and
RH­
9129),
keto
acid
(
RH­
1745)
metabolites
and
the
benzylic
conjugates
(
sulfate
and
glucuronide
conjugates
of
RH­
6648);
or
(
iii)
cleavage
of
the
parent
molecule
eliminating
the
triazole
ring
to
yield
RH­
7968,
1,2,4­
triazole
and
lesser
amounts
of
triazolylalanine.
To
date,
the
Agency
has
not
received
an
acceptable
poultry
metabolism
study.
Based
on
the
information
available
at
this
time,
a
40
CFR
180.6(
a)(
3)
situation
exists
for
poultry
(
i.
e.,
no
expectation
of
finite
residues);
therefore,
the
lack
of
acceptable
poultry
metabolism
data
is
not
a
significant
data
gap.
If
future
new
uses
are
sought
for
significant
poultry
feed
items,
then
an
acceptable
poultry
metabolism
study
will
likely
be
required.

3.2.3
Description
of
Rotational
Crop
Metabolism
Fenbuconazole
appears
to
be
extensively
metabolized
in
the
environment
prior
to
uptake
of
residues
by
rotational
crops.
The
major
residues
observed
in
rotational
crops
are
triazolylalanine
and
triazolylacetic
acid.
Studies
using
radiolabeled
fenbuconazole
reveal
that
parent
compound,
RH­
9129,
RH­
9130,
and
RH­
6467
may
be
found
in
rotational
crop
matrices,
but
only
in
very
small
amounts.

3.3
Environmental
Degradation
Fenbuconazole
is
considered
to
be
moderately
persistent
to
persistent
in
the
environment
and
slightly
mobile
to
mobile
in
soils.
Because
of
its
adsorption
to
soil,
the
potential
for
fenbuconazole
to
leach
to
ground
water
appears
to
be
slight.
However,
the
potential
to
contaminate
groundwater
may
be
greater
at
vulnerable
sites,
i.
e.,
where
soils
have
low
organic
matter
and
where
groundwater
is
relatively
close
to
the
surface.
The
long
half­
lives
of
fenbuconazole
in
aerobic
soil
and
terrestrial
field
dissipation
studies
indicate
that
when
fenbuconazole
is
applied
over
multiple
growing
seasons,
soil
residue
accumulation
may
result.
These
residues
may
be
available
for
rotational
crop
uptake
or
may
be
transported
with
sediments
during
runoff
events.
For
purposes
of
human
health
risk
assessment,
the
residue
of
concern
in
water
is
fenbuconazole,
per
se.
Page
15
of
55
3.4
Tabular
Summary
of
Metabolites
and
Degradates
Table
3.4.
Summary
of
Metabolites
and
Degradates
of
Fenbuconazole.
Common
name/
code
Chemical
name
Major
Metabolite
Minor
Metabolite
Chemical
structure
Fenbuconazole
RH­
7592
 ­[
2­(
4­
chlorophenyl)
ethyl]­
 ­
phenyl­
1H­
1,2,4­
triazole­
1­
propanenitrile
Peach
Peanut
Vine
Sugar
beet
Wheat
Ruminants
Poultry
Water
Rotational
Crops
N
N
N
Cl
CN
Iminolactone
Metabolite
RH­
6468
5­(
4­
chlorophenyl)­
3­
phenyl­
3­(
1H­
1,2,4­
triazol­
1­
ylmethyl)
dihydrofuran­
2(
3H)­
imine
 
Ruminants
Poultry
O
N
N
N
N
H
Cl
Lactone
A
and
B
Metabolites
RH­
9129
and
RH­
9130
trans­
or
cis­
5­(
4­
chlorophenyl)
dihydro­
3­
phenyl­
3­(
1H­
1,2,4­
triazol­
1­
ylmethyl)­
2(
3H)­
furanone
Peach
Poultry
Ruminant
Peanut
Sugar
beet
Wheat
Rotational
Crops
O
N
N
N
O
Cl
Benzylic
Alcohol
Metabolite
RH­
6648
4­(
4­
chlorophenyl)­
4­
hydroxy­
2­
phenyl­
2­
(
1H­
1,2,4­
triazol­
1­
ylmethyl)
butanenitrile
 
Poultry
N
N
N
Cl
CN
OH
Ketone
Metabolite
RH­
6467
4­(
4­
chlorophenyl)­
4­
oxo­
2­
phenyl­
2­(
1H­
1,2,4­
triazol­
1­
ylmethyl)
butanenitrile
Peanut
Wheat
Rotational
Crops
N
N
N
Cl
CN
O
4­
Phenol
Metabolite
RH­
1311
4­(
4­
chlorophenyl)­
2­
(
4­
hydroxyphenyl)­
2­
(
1H­
1,2,4­
triazol­
1­
ylmethyl)
butanenitrile
 
Ruminants
Poultry
Egg
N
N
N
CN
O
H
Page
16
of
55
Table
3.4.
Summary
of
Metabolites
and
Degradates
of
Fenbuconazole.
Common
name/
code
Chemical
name
Major
Metabolite
Minor
Metabolite
Chemical
structure
Glucosyl
conjugate
of
RH­
4911
RH­
7905
 ­[
2­[
4­
chloro­
3­(
Dglucopyranosyloxy
phenyl]
ethyl]­
 ­
phenyl­
1H­
1,2,4­
triazole­
1­
propanenitrile
Peanut
Peach
Wheat
N
N
N
O
Cl
CN
O
OH
O
H
O
H
OH
Cleaved
Alcohol
Metabolite
RH­
7968
4­(
4­
chlorophenyl)­
2­
(
hydroxymethyl)­
2­
phenylbutanenitrile
 
Ruminants
Eggs
Cl
CN
OH
Triazole
RH­
0118
1H­
1,2,4­
triazole
Eggs
Poultry
Rat
Ruminant
Milk
NH
N
N
Triazolylalanine
TAA
RH­
3968
2­
amino­
3­(
1H­
1,2,4­
triazol­
1­
yl)
propanoic
acid
Peach
Peanut
Wheat
Rotational
Crops
Milk
N
N
N
NH
2
HOOC
Triazolylacetic
acid
TA
RH­
3779
RH­
4098
1H­
1,2,4­
triazol­
1­
yl
acetic
acid
Wheat
Rotational
Crops
Peach
N
N
N
COOH
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Toxicological
data
specific
to
1,2,4­
triazole,
triazolylalanine,
and
triazolylacetic
acid
have
been
submitted
to
the
Agency.
Risks
associated
with
exposure
to
1,2,4­
triazole,
triazolylalanine,
and
triazolylacetic
acid
are
the
subject
of
a
separate
risk
assessment
(
M.
Doherty
et
al.,
D322215,
2/
7/
06).
For
major
metabolites
of
fenbuconazole
other
than
those
three
compounds,
toxicological
data
are
not
available.
Structural
similarities
between
fenbuconazole
and
the
metabolites
RH­
9129,
RH­
9130,
and
RH­
4911
lead
HED
to
believe
that
these
compounds
may
have
similar
toxicity.
HED
also
has
concern
regarding
the
potential
toxicity
of
RH­
7905
since
cleavage
of
the
labile
sugar
moiety
results
in
the
formation
of
RH­
4911.

3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression*
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Page
17
of
55
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression*
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Primary
Crop
Fenbuconazole
+
RH­
9129
+
RH­
9130
+
RH­
7905
(
peanut
only)
+
RH­
4911
(
peanut
only)
Fenbuconazole
+
RH­
9129
+
RH­
9130,
expressed
as
fenbuconazole
Plants
Rotational
Crop
Not
Applicable
at
this
time
Not
Applicable
at
this
time
Ruminant
Fenbuconazole
+
RH­
9129
+
RH­
9130
Fenbuconazole
+
RH­
9129
+
RH­
9130,
expressed
as
fenbuconazole
Livestock
Poultry
Not
Applicable
at
this
time
Not
Applicable
at
this
time
Drinking
Water
Fenbuconazole
Not
Applicable
*
The
common
triazole
metabolites
1,2,4­
triazole,
triazolylalanine,
and
triazolylacetic
acid
have
been
identified
as
residues
of
concern
for
risk
assessment.
Separate
assessments
addressing
these
compounds
have
been
conducted
(
see.
M.
Doherty,
et
al.,
D322215,
2/
7/
06).

3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
HED
has
determined
that
the
residues
of
concern
for
risk
assessment
are
fenbuconazole
and
the
following
metabolites:
RH­
9129,
RH­
9130,
RH­
4911(
peanut
only),
and
RH­
7905
(
peanut
only).
RH­
9129
and
RH­
9130
are
cis/
trans
isomers
of
the
lactone
metabolite
of
fenbuconazole
and
may
account
for
approximately
one
third
of
the
total
fenbuconazole
residues.
RH­
9129
and
RH­
9130
are
residues
of
concern
for
both
risk­
assessment
and
tolerance­
enforcement
purposes.
RH­
7905
is
a
minor
metabolite
except
in
peanut.
In
animals,
the
glucoside
conjugate
(
RH­
7905)
will
be
cleaved
to
yield
RH­
4911.
Although
RH­
4911,
being
a
hydroxy­
derivative
of
fenbuconazole,
is
likely
to
be
less
toxic
than
the
parent,
we
have
no
specific
toxicological
information
for
this
compound.
Because
it
shares
structural
features
with
the
parent,
HED
is
assuming
that
it
has
the
same
toxicity
as
fenbuconazole.
Therefore,
RH­
7905
and
RH­
4911
are
being
included
as
residues
of
concern
for
risk
assessment
(
peanuts
only).
The
current
analytical
enforcement
method
has
been
validated
for
the
analysis
of
fenbuconazole
as
well
as
RH­
9129
and
RH­
9130.

4.0
HAZARD
CHARACTERIZATION/
ASSESSMENT
4.1
Hazard
Characterization
Acute
studies
were
conducted
on
both
the
technical
material
and
end­
use
product
(
25%
a.
i.).
Technical
grade
fenbuconazole
has
low
acute
toxicity
(
Category
III
for
acute
oral
and
inhalation
exposures
and
Category
IV
for
acute
dermal
exposure).
The
end­
use
product
also
has
low
acute
toxicity
(
Category
III
for
acute
inhalation
exposure
and
Category
IV
for
acute
oral
and
dermal
exposures).
Neither
the
technical
material
nor
the
end­
use
product
are
skin
or
eye
irritants
(
Category
IV),
and
neither
are
dermal
sensitizers.
Table
4.1a
summarizes
both
the
acute
toxicity
for
the
technical
and
end­
use
product
of
fenbuconazole.
Page
18
of
55
Table
4.1a
­
Acute
Toxicity
of
Fenbuconazole
­
Technical
and
End­
Use
Product
Guideline
No.
Study
Type
MRID
Results
Toxicity
Category
870.1100
Acute
Oral
­
Rats
41031209
Oral
LD50
(
M)
>
2000
mg/
kg
III
870.1100
Acute
Oral
­
Rats
41031207
Oral
LD50
(
M
and
F)
>
2000
mg/
kg
III
870.1100
Acute
Oral
­
Rats
41031221
Oral
LD50
(
M)
>
5000
mg/
kg
IV
870.1100
Acute
Oral
­
Rats
41031222
Oral
LD50
(
F)
>
5000
mg/
kg
IV
870.1200
Acute
Dermal
­
Rats
41031208
LD50
(
M
and
F)
>
5000
mg/
kg
IV
870.1200
Acute
Dermal
­
Rats
41031223
LD50
(
M)
>
5000
mg/
kg
IV
870.1200
Acute
Dermal
­
Rats
41031224
LD50
(
F)
>
5000
mg/
kg
IV
870.1300
Acute
Inhalation
­
Rats
41398201
LC50
(
M
and
F)
>
2.1
mg/
L
Particle
size
too
large.
Requirement
was
waived
due
to
problem
in
generating
respirable
dust
particles
or
liquid
aerosol.
III
870.1300
Acute
Inhalation
­
Rats
41031225
LC50
(
M
and
F)
>
2.1
mg/
L
III
870.2400
Primary
Eye
Irritation­
Rabbits
41031211
Not
irritating
to
unwashed
eyes
IV
870.2400
Primary
Eye
Irritation­
Rabbits
41031226
Not
irritating
to
the
eyes
IV
870.2500
Primary
Dermal
Irritation­
Rabbits
41031212
Not
irritating
to
the
skin
IV
870.2500
Primary
Dermal
Irritation­
Rabbits
41031227
Not
irritating
to
the
skin
IV
870.2600
Dermal
Sensitization­
Guinea
pigs
41031213
Is
not
a
sensitizer
under
conditions
of
study.
N/
A
870.2600
Dermal
Sensitization­
Guinea
pigs
41031228
Is
not
a
sensitizer
under
conditions
of
study.
N/
A
Subchronic
and
chronic
feeding
studies
were
conducted
in
the
rat,
mouse,
and
dog.
In
these
studies,
the
liver
was
the
main
target
of
toxicity
in
all
three
species.
At
the
LOAEL
in
the
subchronic
studies,
there
were
changes
in
liver
histopathology,
predominantly
hepatocellular
hypertrophy.
At
doses
higher
than
the
LOAEL
in
the
rat,
the
thyroid
was
a
secondary
target
organ
with
increased
follicular
cell
size.
In
the
chronic
studies,
liver
effects
were
seen
(
including
hepatocellular
hypertrophy
and
vacuolization,
changes
in
liver
enzymes,
and
increased
liver
weights),
as
well
as
decreased
body
weight
gains
in
all
three
species.
Again,
in
the
chronic
rat
study,
the
thyroid
was
a
secondary
target
with
increased
thyroid
and
parathyroid
weights
and
thyroid
follicular
cell
hypertrophy.
In
addition,
increased
mean
T4
and
decreased
TSH
were
Page
19
of
55
found
in
the
high­
dose
rats
near
the
end
of
the
study.
In
the
chronic
dog
study,
kidney
and
adrenal
weights
were
also
increased.
Males
and
females
throughout
the
studies
appeared
to
be
equally
sensitive
to
fenbuconazole
toxicity,
except
in
the
chronic
mouse
study,
where
male
mice
appeared
to
be
more
sensitive
than
the
females.

In
the
rat
and
rabbit
developmental
toxicity
studies
and
the
two
generation
study
in
rats,
all
effects
in
the
pups
occurred
in
the
presence
of
maternal
toxicity,
including
changes
in
body
weight
and
body
weight
gains
in
rats
and
decreased
food
consumption
and
clinical
signs
in
rabbits.
Developmental
effects
included
increased
post­
implantation
loss
and
decreased
fetuses
per
dam
in
the
rat
developmental
study;
increased
early
resorptions
in
the
rabbit
developmental
study;
and
decreased
mean
pup
body
weight,
increased
number
of
stillborn
pups,
decreased
number
of
total
offspring
delivered,
and
decreased
viability
index
of
pups
in
the
two
generation
study
in
rats.
No
increased
qualitative
or
quantitative
susceptibility
was
observed
in
any
of
the
studies.
There
was
no
evidence
of
neurotoxicity
in
any
of
the
studies
available
in
the
toxicology
database.
Therefore,
a
developmental
neurotoxicity
study
is
not
required
at
this
time.

Fenbuconazole
is
not
mutagenic.
On
August
11,
1993,
the
Health
Effects
Division
Carcinogenicity
Peer
Review
Committee
(
CPRC)
determined
that
fenbuconazole
should
be
classified
as
Group
C
­
Possible
Human
Carcinogen
and
recommended
that
a
low
dose
extrapolation
model
applied
to
the
experimental
animal
tumor
data
should
be
used
for
quantification
of
human
risk
(
Q1*).
The
Q1*
established
for
use
in
cancer
risk
analysis
is
0.00359
(
mg/
kg/
day)­
1
in
human
equivalents.

A
dermal
absorption
study
was
conducted
in
rats.
The
majority
of
the
radio­
labeled
compound
could
be
recovered
in
a
skin
wash.
A
value
of
4.25%
dermal
absorption,
measured
10
hours
after
exposure,
has
been
selected
for
use
in
risk
assessment.

In
rats,
fenbuconazole
is
rapidly
absorbed
and
excreted
within
96
hours
following
a
single
low
or
high
dose
or
following
repeated
low
doses.
Low
bioaccumulation
of
both
the
parent
compound
and
metabolites
was
indicated
by
low
levels
in
the
tissues.

Table
4.1b
summarizes
the
toxicity
profile
of
fenbuconazole.
Page
20
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
­
rats
41073502
0,
20,
80,
400,
and
1600
ppm
(
Males:
0,
1.3,
5.1,
25.3,
and
103.0
mg/
kg/
day;
Females:
0,
1.5,
6.3,
31.1,
and
123.9
mg/
kg/
day)
NOAEL
=
1.3/
1.5
mg/
kg/
day
(
M/
F)
LOAEL
=
5.1/
6.3
mg/
kg/
day
(
M/
F)
based
on
liver
histopathology
870.3100
90­
Day
oral
toxicity
rodents
­
mice
41073503
0,
20,
60,
180,
and
540
ppm
(
Males:
0,
3.8,
11.1,
28.6,
and
99.1
mg/
kg/
day;
Females:
0,
5.7,
17.6,
50.4,
and
139.2
mg/
kg/
day)
NOAEL
=
3.8/
5.7
mg/
kg/
day
(
M/
F)
LOAEL
=
11.1/
17.6
mg/
kg/
day
(
M/
F)
based
on
liver
histopathology
870.3150
90­
Day
oral
toxicity
in
nonrodents
­
dogs
41073504
0,
30,
100,
400,
and
1600
ppm
(
Males:
0,
1.0,
3.3,
13.3,
and
50.4
mg/
kg/
day;
Females:
0,
1.1,
3.5,
14.0,
and
53.3
mg/
kg/
day)
NOAEL
=
3.3/
3.5
mg/
kg/
day
(
M/
F)
LOAEL
=
13.3/
14.0
mg/
kg/
day
(
M/
F)
based
on
liver
histopathology
870.3200
21/
28­
Day
dermal
toxicity
­
rats
41875013
42882701
0,
250,
625,
and
1000
mg/
kg/
day
NOAEL
=
1000
mg/
kg/
day
(
HDT)
LOAEL
=
>
1000
mg/
kg/
day
870.3250
90­
Day
dermal
toxicity
N/
A
N/
A
Not
performed
870.3465
90­
Day
inhalation
toxicity
N/
A
N/
A
Not
performed
870.3700
Prenatal
developmental
in
rodents
­
rats
41031214
41073505
0,
30,
75,
and
150
mg/
kg/
day
Maternal
NOAEL
=
30
mg/
kg/
day
Maternal
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
Developmental
NOAEL
=
30
mg/
kg/
day
Developmental
LOAEL
=
75
mg/
kg/
day
based
on
increased
postimplantation
loss
and
a
decrease
in
the
number
of
live
fetuses/
dam
Page
21
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.3700
Prenatal
developmental
in
nonrodents
­
rabbits
41875014
42882701
0,
10,
30,
and
60
mg/
kg/
day
Maternal
NOAEL
=
10
mg/
kg/
day
Maternal
LOAEL
=
30
mg/
kg/
day
based
on
decreased
food
consumption
and
increased
incidence
of
clinical
signs
(
soft/
scant/
no
feces
and
red
discharge)
Developmental
NOAEL
=
30
mg/
kg/
day
Developmental
LOAEL
=
60
mg/
kg/
day
based
on
increased
early
resorptions
870.3800
Reproduction
and
fertility
effects
­
rats
41875015
0,
8,
80,
and
800
ppm
(
0,
0.4,
4,
and
40
mg/
kg/
day)
Parental
systemic
NOAEL
=
4
mg/
kg/
day
Parental
systemic
LOAEL
=
40
mg/
kg/
day
based
on
maternal
death
during
delivery,
decreased
body
weight
and
food
consumption,
increased
number
of
dams
not
delivering
viable
or
delivering
nonviable
offspring,
and
increased
adrenal
and
thyroid/
parathyroid
weights
Reproductive
NOAEL
=
40
mg/
kg/
day
(
HDT)
Reproductive
LOAEL
=
>
40
mg/
kg/
day
Offspring
systemic
NOAEL
=
4
Offspring
systemic
LOAEL
=
40
mg/
kg/
day
based
on
decreased
mean
pup
body
weight,
increased
number
of
stillborn
pups,
decreased
number
of
total
offspring
delivered,
and
decreased
viability
index
870.4100
Chronic
toxicity
­
rodents
See
870.4300
870.4100
Chronic
toxicity
­
dogs
41875049
0,
15,
150,
and
1200
ppm
(
0,
0.38,
3.75,
and
30
mg/
kg/
day)
NOAEL
=
3.75/
0.38
mg/
kg/
day
(
M/
F)
LOAEL
=
30/
3.75
mg/
kg/
day
(
M/
F)
based
on
decreased
body
weight
gain
Note:
dose­
related
adaptive
liver
changes
were
observed
in
highdose
males
and
females.
Page
22
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.4200
Carcinogenicity
­
rats
See
870.4300
870.4200
Carcinogenicity
­
mice
41893301
41635303
Males:
0,
10,
200,
and
650
ppm
(
0,
1.43,
28.6,
and
92.9
mg/
kg/
day)
Females:
0,
10,
650,
and
1300
ppm
(
0,
1.43,
92.9,
and
186
mg/
kg/
day)
NOAEL
=
1.43
mg/
kg/
day
(
M
&
F)
LOAEL
=
28.6/
92.9
mg/
kg/
day
(
M/
F)
based
on
decreased
body
weight,
increased
relative
and
absolute
liver
weight,
and
hepatocellular
hypertrophy
and
vacuolization
Evidence
of
carcinogenicity
870.4300
Combined
chronic
toxicity/
carcinogenicity
­
rat
41635301
41635302
Control
­
0
ppm
Low
­
4
ppm
(
weeks
1
&
2),
6
ppm
(
weeks
3
&
4),
and
8
ppm
(
weeks
5­
term)

Mid
­
40
ppm
(
weeks
1
&
2),
60
ppm
(
weeks
3
&
4),
and
80
ppm
(
weeks
5­
term)

High
­
400
ppm
(
weeks
1
&
2),
600
ppm
(
weeks
3
&
4),
and
800
ppm
(
weeks
5­
term)

(
Males:
0,
0.31,
3.03,
and
30.62
mg/
kg/
day;
Females:
0,
0.4,
4.02,
and
43.07
mg/
kg/
day)
NOAEL
=
3.0/
4.0
mg/
kg/
day
(
M/
F)
LOAEL
=
30.6/
43.1
mg/
kg/
day
(
M/
F)
based
on
decreased
body
weight
gain
(
F),
hepatocellular
enlargement
and
vacuolization
(
F),
increased
thyroid
weight
(
M&
F),
and
histopathological
lesions
in
the
thyroid
gland
(
M)

Evidence
of
carcinogenicity
870.4300
Combined
chronic
toxicity/
carcinogenicity
­
rat
42021901
42055001
Control
­
0
ppm
Low
­
400
ppm
(
weeks
1
&
2),
600
ppm
(
weeks
3
&
4),
and
800
ppm
(
weeks
5­
term)

High
­
800
ppm
(
weeks
1
&
2),
1200
ppm
(
weeks
3
&
4),
and
1600
ppm
(
weeks
5­
term)

(
0,
30.4,
and
63.9
mg/
kg/
day)
NOAEL
=
Not
established
LOAEL
=
30.4
mg/
kg/
day
(
M)
based
on
decreased
body
weight
gain,
increased
liver
weight,
and
increased
thyroid
and
parathyroid
weights
Note:
only
males
were
used
in
this
study.

Insufficient
evidence
of
carcinogenicity
Page
23
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.5100
Gene
mutation
­
bacterial
reverse
mutation
assay
41031216
TA1535
­
30­
300
ug
TA1537
­
30­
300
ug
TA98
­
0.2­
20
ug
TA100
­
160­
1600
ug
No
mutagenic
activity
in
bacteria
(
Salmonella
typhimurium)
under
conditions
of
this
assay.

Note:
only
TA1535,
TA1537,
TA98,
and
TA100
were
tested.
This
study
is
classified
unacceptable.

870.5100
Gene
mutation
­
bacterial
reverse
mutation
assay
41031217
TA1535
­
30­
300
ug
TA1537
­
30­
300
ug
TA98
­
30­
300
ug
TA100
­
30­
300
ug
No
mutagenic
activity
in
bacteria
(
Salmonella
typhimurium)
under
conditions
of
this
assay.

Note:
only
TA1535,
TA1537,
TA98,
and
TA100
were
tested.
This
study
is
classified
unacceptable.

870.5300
Cytogenetics
­
in
vitro
mammalian
cell
gene
mutation
test
(
CHO
Cells)
41031218
15­
50
ug/
ml
without
S9
activation
35­
60
ug/
ml
with
S9
activation
No
increase
in
mutant
frequency
at
the
HGPRT
locus,
in
the
presence
or
absence
of
S9
activation.

870.5385
Cytogenetics
­
mammalian
bone
marrow
chromosomal
aberration
test
(
rats)
41031219
0,
0.25,
1.25,
and
2.5
g/
kg
No
increase
in
number
of
cells
with
aberrations
or
in
aberrations
per
cell.

870.5550
Other
effects
­
unscheduled
DNA
synthesis
in
mammalian
cells
in
culture
(
rats)
41031220
0,
7.5,
10.0,
12.5,
and
15.0
ug/
ml
No
evidence
(
or
a
dose
related
positive
response)
that
unscheduled
DNA
synthesis
was
induced.
Page
24
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
41875017
41875018
1)
1
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
2)
100
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
3)
1
mg/
kg
unlabelled,
14
days
in
the
diet,
PLUS
1
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
4)
1
mg/
kg
radiolabelled,
by
i.
v.
injection
The
mean
recovery
of
radioactivity
4
days
after
exposure
was
82.6­
93.0%
following
single
or
repeated
oral
doses
and
88.2­
99.2%
following
single
i.
v.
doses,
indicating
rapid
absorption,
distribution,
and
elimination.
Rapid
elimination
and
low
tissue
levels
indicate
low
bioaccumulation
of
the
parent
and
metabolites.

Elimination
occurred
primarily
by
biliary
excretion
because
recovery
of
radioactivity
was
mostly
in
the
feces:
75.6­
83.7%
following
oral
exposure
and
77.2­
91.4%
following
i.
v.
exposure.
In
urine,
radioactivity
recovery
was
5.5­
12.6%
for
all
dose
scenarios.
Peak
radioactivity
in
the
blood
occurred
3
hours
following
a
single
low
dose
and
3­
6
hours
after
a
single
high
dose,
indicating
biphasic
elimination.

Only
8.5­
14.8%
and
0.0­
2.7%
of
the
parent
compound
was
recovered
in
the
feces
and
urine,
respectively,
indicating
extensive
metabolism.
A
number
of
major
metabolites
were
identified;
however,
50%
and
20%
of
metabolites
in
the
feces
and
urine,
respectively,
were
not
identified.
Sex­
related
differences
include
a
greater
number
of
sulfate
metabolites
in
female
excreta
compared
to
males,
and
a
greater
number
of
ketoacid
metabolites
in
male
urine
compared
to
females.
Page
25
of
55
Table
4.1b
­
Toxicity
Profile
of
Fenbuconazole
Technical
Guideline
No.
Study
Type
MRID
Doses
Results
870.7485
Metabolism
and
pharmacokinetics
­
rat
42900801
1)
1
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
2)
100
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
3)
1
mg/
kg
unlabelled,
14
days
in
the
diet,
PLUS
1
mg/
kg
radiolabelled,
single
dose
by
oral
gavage
The
mean
recovery
of
radioactivity
3­
4
days
after
exposure
was
90.4­
104.5%
following
single
or
repeated
oral
doses,
indicating
rapid
absorption,
distribution,
and
elimination.
Bioaccumulation
of
the
parent
compound
and
metabolites
is
low.
There
were
no
major
sex­
or
doserelated
differences
in
absorption,
distribution,
or
elimination.

Elimination
occurred
primarily
by
biliary
excretion:
recovery
of
the
administered
dose
occurred
mainly
in
the
bile
(
79.1­
87.1%)
3
days
after
exposure
and
mostly
in
the
feces
(
78.7­
94.4%)
4
days
after
exposure.
In
contrast,
radioactivity
recovery
in
the
urine
was
3.2­
11.5%
at
3
and
4
days
after
exposure.

Extensive
metabolism
occurred;
numerous
metabolites
were
found
in
the
feces
and
urine.
There
is
a
dose­
related
difference
in
metabolism.
A
higher
amount
of
parent
compound
was
found
in
the
feces
following
the
single
high
dose
compared
to
the
single
or
repeated
low
dose(
s),
which
suggests
that
saturation
may
be
occurring
at
the
high
dose.

870.7600
Dermal
penetration
­
rat
41875019
0,
0.125,
1.25,
and
12.5
mg/
kg
Note:
End­
use
product
(
23.1%)
was
tested
Mean
%
of
the
dose
absorbed
(
sum
of
urine,
feces,
carcass,
and
skin)
after
10
hrs
of
exposure:

0.125
mg/
kg:
4.25%
1.25
mg/
kg:
2.08%
12.5
mg/
kg:
0.45%

4.2
FQPA
Hazard
Considerations
The
FQPA
safety
factor
was
removed
(
i.
e.,
reduced
to
1x)
in
assessing
the
risk
posed
by
fenbuconazole.
This
recommendation
was
based
on
the
following:
Page
26
of
55
 
There
are
no
data
gaps
for
the
assessment
of
the
effects
of
fenbuconazole
following
in
utero
and/
or
postnatal
exposure;
a
developmental
neurotoxicity
study
is
not
required.
 
There
is
no
indication
of
quantitative
or
qualitative
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
fenbuconazole
 
The
dietary
exposure
assessment
is
based
on
models
and
input
parameters
designed
to
be
protective
of
human
health.
 
At
this
time,
there
are
no
registered
residential
uses
for
fenbuconazole;
therefore,
this
type
of
exposure
to
infants
and
children
is
not
expected.

4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
is
complete
and
adequate
for
risk
assessment.

4.2.2
Evidence
of
Neurotoxicity
Acute
and
sub­
chronic
neurotoxicity
studies
are
not
required
for
fenbuconazole.
The
available
toxicology
studies
do
not
indicate
that
fenbuconazole
is
neurotoxic.
Neither
sub­
chronic
nor
chronic
toxicity
studies
in
rats
and
mice
nor
the
developmental
toxicity
studies
in
rats
or
rabbits
indicated
that
the
nervous
system
was
specifically
affected
by
treatment
with
fenbuconazole.

4.2.3
Developmental
Toxicity
Studies
No
quantitative
or
qualitative
susceptibility
was
observed
in
either
of
the
developmental
rat
or
rabbit
studies.
In
the
developmental
rat
study,
increased
post­
implantation
loss
and
decreased
live
fetuses
per
dam
were
noted
at
a
dose
level
in
which
decreased
maternal
body
weight
and
body
weight
gain
were
observed.
Since
the
developmental
effects
observed
in
the
rat
study
were
seen
in
the
presence
of
maternal
toxicity,
they
are
not
considered
to
be
qualitatively
more
severe
than
the
maternal
effects.
The
maternal
LOAEL
in
the
rabbit
study,
which
is
based
on
decreased
food
consumption
and
increased
clinical
signs,
is
a
lower
dose
level
than
the
developmental
LOAEL,
which
is
based
on
increased
early
resorptions.

4.2.4
Reproductive
Toxicity
Study
In
the
two­
generation
reproduction
study,
a
decrease
in
mean
pup
body
weight,
an
increased
number
of
stillborn
pups,
a
decreased
number
of
total
offspring
delivered,
and
a
decreased
viability
index
for
pups
were
seen
at
the
same
dose
level
that
produced
maternal
death
and
decreased
maternal
body
weights.
The
same
types
of
toxicity
were
seen
in
dams
and
in
pups
(
i.
e.,
death
and
body
weight
changes),
and
these
effects
were
seen
at
the
same
dose
level;
thus,
there
is
no
increase
in
qualitative
or
quantitative
susceptibility
in
the
two­
generation
reproduction
study.

4.2.5
Additional
Information
from
Literature
Sources
A
literature
search
was
not
conducted
at
this
time.
Page
27
of
55
4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
The
data
provided
no
indication
of
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
fenbuconazole.
In
the
prenatal
developmental
study
in
rats
and
rabbits
and
the
two
generation
study
in
rats,
effects
in
the
offspring
were
observed
only
at
or
above
those
treatment
levels
which
resulted
in
maternal
toxicity.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
The
degree
of
concern
for
infants
and
children
exposed
to
fenbuconazole
in
utero
and/
or
postnatally
is
low;
there
are
no
residual
uncertainties.
The
toxicology
database
for
fenbuconazole
is
complete
and
adequate
for
risk
assessment
purposes.
Acceptable
developmental
studies
in
rats
and
rabbits
and
the
two
generation
reproduction
study
in
rats
did
not
show
evidence
of
increased
susceptibility
in
offspring
exposed
to
fenbuconazole
in
utero
and/
or
postnatally.
While
the
toxicology
database
does
not
have
an
appropriate
endpoint
for
an
acute
dietary
assessment
for
the
general
population,
a
NOAEL
has
been
selected
for
the
subpopulation
Females
13­
49
based
on
developmental
effects
(
increased
resorptions
and
decreased
live
fetuses
per
dam)
seen
at
the
LOAEL
in
the
developmental
rat
study.
By
regulating
on
the
effect
of
concern
for
this
subpopulation,
the
risk
assessment
is
protective
of
potential
effects
to
infants
and
children.
There
are
currently
no
registered
or
proposed
residential
uses
for
fenbuconazole,
so
exposure
to
fenbuconazole
is
limited
to
dietary
exposure.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
available
toxicology
database
does
not
indicate
that
fenbuconazole
is
neurotoxic
to
rats,
rabbits,
or
dogs.
In
the
acceptable
rat
and
rabbit
developmental
studies
and
rat
reproduction
study,
there
was
no
evidence
of
increased
quantitative
or
qualitative
susceptibility
resulting
from
in
utero
and/
or
postnatal
exposure
to
fenbuconazole.
Therefore,
a
developmental
neurotoxicity
study
is
not
required.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
The
acute
dietary
endpoint
for
females
13­
49
is
based
on
increased
resorptions
and
decreased
live
fetuses
per
dam
observed
at
the
LOAEL
of
75
mg/
kg/
day
in
a
developmental
rat
study.
This
endpoint
is
considered
appropriate
for
this
population
subgroup
because
the
observed
developmental
effects
are
presumed
to
occur
following
a
single
oral
dose.
The
NOAEL
was
30
mg/
kg/
day,
resulting
in
an
acute
reference
dose
(
aRfD)
of
0.3
mg/
kg/
day
(
standard
10x
intraspecies
variation
and
10x
interspecies
extrapolation
safety
factors
were
applied).
Selection
of
this
dose
and
endpoint
is
supported
by
the
fact
that
the
NOAEL
in
the
developmental
rat
study
Page
28
of
55
is
equal
to
the
NOAEL
in
the
developmental
rabbit
study;
the
LOAEL
in
the
developmental
rabbit
study
is
based
on
increased
resorptions,
which
could
also
occur
following
a
single
oral
dose.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
The
current
toxicology
database
does
not
have
a
dose
and
endpoint
suitable
for
acute
dietary
exposure
assessment
for
the
general
population.
None
of
the
effects
seen
in
the
database
(
excluding
developmental
effects)
were
considered
to
occur
as
the
result
of
one
oral
dose.

4.4.3
Chronic
Reference
Dose
(
cRfD)

The
chronic
dietary
endpoint
is
based
on
effects
in
the
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat:
decreased
body
weight
gain,
increased
thyroid
weight,
and
histopathological
lesions
in
the
liver
and
thyroid
gland
observed
at
the
LOAEL
of
30.6/
43.1
mg/
kg/
day
(
M/
F).
Although
a
lower
NOAEL
is
identified
in
the
mouse
carcinogenicity
study
based
on
liver
effects,
the
mouse
study
was
not
chosen
as
a
basis
for
the
chronic
dietary
endpoint
because
it
was
compromised
by
a
hepatitis
infection
which
could
have
potentiated
liver
toxicity.
A
lower
NOAEL
was
also
identified
for
females
in
the
chronic
dog
study
based
on
decreased
body
weight
gain;
however,
the
rat
study
is
considered
more
robust
than
the
dog
study.
In
addition,
liver
toxicity
was
seen
at
a
similar
dose
in
both
the
rat
and
dog
studies.
The
NOAEL
was
3
mg/
kg/
day,
with
a
chronic
reference
dose
(
cRfD)
of
0.03
mg/
kg/
day
(
standard
10x
intra­
species
variation
and
10x
interspecies
extrapolation
safety
factors
were
applied).

4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Currently,
there
are
no
proposed
or
registered
residential
uses
for
fenbuconazole;
therefore,
an
incidental
oral
exposure
risk
assessment
is
not
necessary
at
this
time.

4.4.5
Dermal
Absorption
The
21­
day
dermal
absorption
study
in
rats
indicated
that
fenbuconazole
is
poorly
absorbed
through
the
skin,
as
there
was
no
dermal
or
systemic
toxicity
up
to
the
limit
dose.
Therefore,
a
4.25%
(
at
one
hour)
dermal
absorption
factor
was
selected
from
the
dermal
penetration
study
in
rats
and
should
be
applied
to
dermal
risk
assessments.

4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)

No
dermal
or
systemic
toxicity
was
seen
in
male
and
female
Sprague­
Dawley
rats
following
15
repeated
dermal
applications
of
fenbuconazole
up
to
the
limit
dose
in
the
21­
day
dermal
toxicity
study.
Because
toxicity
was
not
seen
following
dermal
exposure
over
this
time
frame
and
since
there
are
no
residential
uses
for
fenbuconazole
at
this
time,
short­
and
intermediate­
term
dermal
endpoints
were
not
selected.
Page
29
of
55
At
this
time,
current
and
proposed
uses
will
not
result
in
long­
term
dermal
exposure.
However,
for
future
long­
term
dermal
risk
assessments
involving
chronic
(
non­
cancer)
effects,
the
NOAEL
of
3
mg/
kg/
day
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
should
be
used
in
conjunction
with
the
4.25%
dermal
absorption
factor
described
in
section
4.4.5.
For
long­
term
dermal
risk
assessments
involving
carcinogenic
effects,
the
Q1
*
of
3.59
x
10­
3
should
be
used
since
fenbuconazole
has
been
classified
as
a
Group
C
carcinogen.

4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)

In
previous
risk
assessments,
inhalation
endpoints
were
not
selected
based
on
fenbuconazole's
low
inhalation
toxicity
and
previous
use
patterns.
However,
due
to
the
numerous
new
uses
which
require
application
of
fenbuconazole
by
airblast,
the
RAB2
Risk
Assessment
Team
selected
an
inhalation
endpoint
for
risk
assessment
purposes.
The
dose
and
endpoint
selected
for
all
durations
of
inhalation
risk
assessment
were
chosen
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats.
The
NOAEL
is
3.0
mg/
kg/
day,
based
on
decreased
body
weight
gain,
increased
thyroid
weights,
and
histopathological
lesions
in
the
liver
and
thyroid
glands
observed
at
the
LOAEL.
Body
weight
effects
were
evident
after
4
weeks
of
treatment
with
fenbuconazole
and
continued
throughout
the
study,
making
this
endpoint
suitable
for
all
durations
of
exposure.
A
sub­
chronic
inhalation
toxicity
study
has
not
been
submitted
for
this
chemical;
therefore
the
default
inhalation
absorption
factor
of
100%
should
be
applied
for
risk
assessment.

The
chronic
rat
study
is
considered
more
robust
than
either
the
chronic
mouse
or
dog
studies
(
see
section
4.4.3
for
more
details)
or
than
the
sub­
chronic
rat
study
for
the
purposes
of
risk
assessment.
Although
a
lower
NOAEL
was
noted
in
the
sub­
chronic
rat
toxicity
study,
based
on
histopathological
changes
in
the
liver,
this
dose
was
not
selected
for
short­
or
intermediate­
term
endpoints.
Liver
histopathology
was
the
basis
for
the
LOAEL
in
both
the
sub­
chronic
and
chronic
rat
studies.
Therefore,
the
chronic
NOAEL
(
3
mg/
kg/
day)
is
protective
of
this
effect,
and
the
lower
value
of
the
subchronic
rat
NOAEL
(
1.3
mg/
kg/
day)
is
considered
an
artifact
of
dose
selection.

4.4.8
Margins
of
Exposure
All
target
margins
of
exposure
are
100.

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
There
are
no
registered
or
proposed
residential
uses
for
fenbuconazole;
therefore,
the
aggregate
exposure
risk
assessment
should
be
based
on
dietary
and
drinking
water
exposure
only.

4.4.10
Classification
of
Carcinogenic
Potential
Under
the
1986
cancer
classification
scheme,
fenbuconazole
was
classified
as
a
Group
C
­
Possible
Human
Carcinogen,
with
a
low
dose
extrapolation
model
applied
to
the
animal
data
for
the
quantification
of
human
risk
(
Q1*).
This
was
based
on
increased
incidence
of
hepatocellular
Page
30
of
55
adenomas
and
carcinomas
in
male
and
female
mice
and
of
thyroid
follicular
adenomas
and
combined
adenomas/
carcinomas
in
male
rats.
Based
on
mechanistic
data,
quantification
of
risk
was
derived
using
combined
hepatocellular
adenomas/
carcinomas
in
female
mice.
The
upper
bound
estimate
of
unit
risk,
Q1*
(
mg/
kg/
day)­
1
is
3.59
x
10­
3
in
human
equivalents.

Table
4.4­
Summary
of
Toxicological
Dose
and
Endpoints
for
Fenbuconazole
for
use
in
Human
Risk
Assessment
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
years
of
age)
NOAEL
=
30
mg/
kg/
day
UF
=
100a
Acute
RfD
=
0.3
mg/
kg
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.3
mg/
kg
Developmental
rat
study
Developmental
LOAEL
=
75
mg/
kg/
day
based
on
increased
resorptions
and
decreased
live
fetuses
per
dam.

Acute
Dietary
(
General
population
including
infants
and
children)
None
None
Not
selected.

No
appropriate
dose
and
endpoint
could
be
identified
for
these
population
groups.

Chronic
Dietary
(
All
populations)
NOAEL=
3
mg/
kg/
day
UF
=
100a
Chronic
RfD
=
0.03
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.03
mg/
kg/
day
Combined
chronic
toxicity/
carcinogenicity
­
Rat
LOAEL
=
30.6/
43.1
(
M/
F)
mg/
kg/
day
based
on
decreased
body
weight
gain,
increased
thyroid
weight,
and
histopathological
lesions
in
the
liver
and
thyroid
gland
Incidental
Oral
(
All
durations)
None
None
Not
selected.

No
registered
uses
would
result
in
residential
exposure.

Long­
Term
Dermal
(
several
months
to
lifetime)
Oral
study
NOAEL=
3
mg/
kg/
day
(
dermal
absorption
rate
=
4.25%)
Residential
LOC
for
MOE
=
NA
Occupational
LOC
for
MOE
=
100a
Combined
chronic
toxicity/
carcinogenicity
­
Rat
LOAEL
=
30.6/
43.1
(
M/
F)
mg/
kg/
day
based
on
decreased
body
weight
gain,
increased
thyroid
weight,
and
histopathological
lesions
in
the
liver
and
thyroid
gland
Page
31
of
55
Table
4.4­
Summary
of
Toxicological
Dose
and
Endpoints
for
Fenbuconazole
for
use
in
Human
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Inhalation
(
All
durations)
Oral
study
NOAEL=
3
mg/
kg/
day
Absorption
factor
=
100%
Residential
LOC
for
MOE
=
NA
Occupational
LOC
for
MOE
=
100a
Combined
chronic
toxicity/
carcinogenicity
­
Rat
LOAEL
=
30.6/
43.1
(
M/
F)
mg/
kg/
day
based
on
decreased
body
weight
gain,
increased
thyroid
weight,
and
histopathological
lesions
in
the
liver
and
thyroid
gland
Cancer
(
oral,
dermal,
inhalation)
Classification:
Under
the
1986
cancer
classification
scheme,
fenbuconazole
was
classified
as
a
Group
C
­
Possible
Human
Carcinogen
with
a
low
dose
extrapolation
model
applied
to
the
animal
data
for
the
quantification
of
human
risk
(
Q1*).
This
was
based
on
increased
incidence
of
hepatocellular
adenomas
and
carcinomas
in
male
and
female
mice
and
of
thyroid
follicular
adenomas
and
combined
adenomas/
carcinomas
in
male
rats.
Based
on
mechanistic
data,
quantification
of
risk
was
derived
using
combined
hepatocellular
adenomas/
carcinomas
in
female
mice.
The
upper
bound
estimate
of
unit
risk,
Q1*
(
mg/
kg/
day)­
1
is
3.59
x
10­
3
in
human
equivalents.

UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
NA
=
Not
Applicable
a
Database
uncertainty
factor
reduced
to
1x.

4.5
FQPA
Safety
Factor
The
FQPA
safety
factor
has
been
removed
(
reduced
to
1x)
since:
1)
the
toxicology
database
is
complete;
2)
there
is
no
indication
of
increased
susceptibility
of
rat
or
rabbit
fetuses
to
in
utero
and/
or
postnatal
exposure
to
fenbuconazole
in
acceptable
developmental
and
reproductive
toxicity
studies;
3)
the
dietary
exposure
assessment
is
based
on
models
and
input
parameters
designed
to
be
protective
of
human
health;
and
4)
there
are
currently
no
registered
residential
uses
for
fenbuconazole;
therefore,
this
type
of
exposure
to
infants
and
children
is
not
expected.

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.
Page
32
of
55
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).

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

5.0
PUBLIC
HEALTH
DATA
5.1
Incident
Reports
There
are
no
clinical
acute
poisoning
cases
reported
in
the
literature
at
this
time
for
fenbuconazole.

6.0
EXPOSURE
CHARACTERIZATION/
ASSESSMENT
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
The
petitioner
has
submitted
adequate
studies
describing
residues
of
fenbuconazole
and
its
residues
of
concern
in
almond,
apple,
banana,
bushberry,
citrus,
cranberry,
grape,
peanut,
pecan,
stone
fruit,
sugar
beet,
and
wheat.
No
major
deficiencies
were
noted
in
the
residue
chemistry
database;
however,
a
number
of
minor
deficiencies
should
be
resolved
prior
to
establishing
tolerances.
These
deficiencies
are
listed
in
Section
10.

Crop
field
trials
with
the
above­
listed
commodities
resulted
in
measurable
residues
of
concern
for
all
crops,
though
the
relative
amounts
of
each
residue
of
concern
varies
based
on
the
crop.

Maximum
residue
limits
(
MRLs)
for
residues
of
fenbuconazole
have
been
established
by
Codex
Alimentarius,
Canada,
and
Mexico.
The
residue
definition
for
both
Codex
and
Mexico
is
fenbuconazole,
per
se,
and
the
Canadian
residue
definition
is
the
combined
residues
of
fenbuconazole
and
its
metabolites,
RH­
9129
and
RH­
9130,
each
expressed
as
parent
(
i.
e.,
the
same
as
the
U.
S.
tolerance
definition).
The
recommended
tolerance
levels,
international
MRLs,
and
processing
factors
associated
with
these
fenbuconazole
petitions
are
summarized
in
Table
6.1.
The
NAFTA
MRL
calculator
was
not
used
to
derive
the
recommended
tolerance
levels.

Table
6.1.1
Summary
of
Tolerances,
International
Maximum
Residue
Limits,
and
Processing
Factors
for
Fenbuconazole.
Crop
Commodity
Recommended
U.
S.
Tolerance,
ppm
International
Maximum
Residue
Limits,
ppm
Processing
Factor
Almond
Almond
0.05
 
 
Page
33
of
55
Table
6.1.1
Summary
of
Tolerances,
International
Maximum
Residue
Limits,
and
Processing
Factors
for
Fenbuconazole.
Crop
Commodity
Recommended
U.
S.
Tolerance,
ppm
International
Maximum
Residue
Limits,
ppm
Processing
Factor
Hulls
1.0
 
 
Apple
Fruit
Juice
Pomace
(
wet)
0.4
 
1.0
 
 
 
 
0.06h
2.46h
Banana
Banana
0.3
0.3d,
0.05e
 
Bushberry
Bushberrya
0.3
 
 
Citrus
Fruit
Oil
Pulp,
dried
1.0
40
5.0
 
 
 
 
61
6.9
Cranberry
Cranberry
0.5
 
 
Grape
Grape
Juice
Wine
Raisin
1.0
 
 
 
 
 
 
 
 
0.18
0.07
N/
Ai
Peanut
Peanut
0.1
 
 
Pecan
Pecan
0.05
0.05e
 
Stone
Fruit
Fruit
Plum,
dried
1.0
 
Multiplef
0.5g
 
3.4
Sugar
beet
Root
Top
Pulp,
dried
Molasses
0.3
9.0
1.0
0.4
 
 
 
 
 
 
5.4
1.8
Wheat
Grain
Forage
Hay
Straw
AGFb
0.1
4.0
8.0
8.0
6.0
0.1e
 
 
3.0e
 
 
 
 
 
69.2
Cattle,
goats,
horses,
sheep
Meat
Fat
MBPc
None
None
0.05
 
 
 
 
 
 
a
Includes
Juneberry,
Lingonberry,
and
Salal
b
AGF
=
Aspirated
Grain
Fractions
c
MBP
=
Meat
Byproducts
d
Mexican
MRL
on
plantains.
Residue
definition
is
fenbuconazole
e
Codex
MRL.
Residue
definition
is
fenbuconazole
only.
f
Codex:
Peach
 
0.5
ppm,
Cherry
 
1.0
ppm;
Canada:
Peach
 
0.5
ppm,
Cherry
 
0.8
ppm,
Plum
 
0.1
ppm
g
Canadian
MRL.
Residue
definition
is
fenbuconazole+
RH­
9129+
RH­
9130.
h
Draft
values
pending
evaluation
of
the
apple
processing
study
currently
under
review.
i
Due
to
the
low
amount
of
imported
grapes
processed
into
raisins,
a
processing
factor
for
raisins
is
not
required
for
this
petition.

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Fenbuconazole
Chronic
Dietary
Exposure
Assessment
for
the
Section
3
Registration
Action.
M.
Doherty,
D329595,
June
2006.

Acute,
chronic,
and
cancer
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.
Page
34
of
55
The
analyses
were
performed
to
estimate
the
dietary
exposures
and
risks
associated
with
the
uses
of
fenbuconazole
on
the
subject­
listed
commodities.
All
three
analyses
include
estimates
for
residues
of
fenbuconazole
in
water.

The
acute
dietary
(
food
+
water)
assessment
is
a
screening
level,
Tier
1
assessment.
It
is
based
on
tolerance­
level
residues
and
assumes
100%
crop
treated,
and
it
uses
the
EDWC
for
fenbuconazole
in
surface
water
(
20.3
ppb),
which
is
worst­
case
estimate
that
is
derived
from
the
requested
use
pattern
for
cherries.
As
such,
it
is
highly
conservative
with
respect
to
evaluating
potential
impacts
of
acute
dietary
exposure
to
fenbuconazole
on
human
health.
The
only
population
subgroup
that
is
relevant
for
this
acute
assessment
is
females
of
child­
bearing
age
(
13­
49
years
old).
The
acute
risk
estimate
that
results
from
this
analysis
is
3%
of
the
acute
population­
adjusted
dose
(
aPAD).
This
risk
estimate
is
much
less
than
HED's
level
of
concern
(
100%
of
the
aPAD).

The
chronic
(
non­
cancer)
dietary
assessment
includes
contributions
from
both
food
and
water.
This
analysis
is
more
refined
and
uses
average
residues
from
field
trials.
Due
to
the
manner
in
which
these
data
were
submitted
and
reviewed,
multiple
averages
were
calculated
for
many
of
the
crops.
For
these
crops,
the
highest
average
was
used
in
the
analysis.
The
non­
cancer
dietary
analysis
assumes
100%
crop
treated
and
the
annual
average
EDWC
from
the
cherry
use
(
16.5
ppb).
The
maximum
chronic
risk
estimate
is
7%
of
the
chronic
population­
adjusted
dose
(
cPAD)
and
is
for
the
infant
population
subgroup.
The
risk
estimates
for
all
other
population
subgroups
are
less
than
that
for
infants.
As
with
the
acute
assessment,
these
risk
estimates
are
all
well
below
HED's
level
of
concern.

The
cancer
dietary
analysis
uses
the
same
food
residue
inputs
as
those
of
the
non­
cancer
assessment.
The
cancer
analysis
is
further
refined
in
that
it
makes
use
of
percent­
crop­
treated
estimates
and
the
EDWC
from
the
30­
year
average
from
cherry
use
(
11.7
ppb).
The
cancer
risk
estimate
using
these
food
residue
inputs
and
a
worst­
case­
use­
pattern
assumption
for
water
is
1.61
x
10­
6.
For
fenbuconazole,
the
food­
only
risk
estimate
is
0.72
x
10­
6.

Cancer
risks
presented
in
this
assessment
are
expressed
to
one
significant
figure.
However,
it
should
be
noted
that,
in
general,
the
precision
which
can
be
assumed
for
cancer
risk
estimates
is
best
described
by
rounding
to
the
nearest
integral
order
of
magnitude
on
the
log
scale,
e.
g.
3.16
x
10­
7
to
3.16
x
10­
6,
expressed
as
10­
6.
Risks
are
generally
reported
to
one
significant
figure
in
HED
risk
assessments
to
allow
better
characterization
of
changes
in
risk
which
might
result
from
potential
risk
mitigation.
This
rounding
procedure
indicates
that
risks
should
generally
not
be
assumed
to
exceed
the
benchmark
level
of
concern
of
10­
6
until
the
calculated
risks
exceed
approximately
3
x
10­
6.
Discretion
should
be
used
in
interpreting
the
significance
of
these
calculated
risks
with
consideration
given
to
the
precision
in
the
risk
estimates.

Based
on
the
assumptions
used
in
the
cancer
analysis
and
the
available
information
in
the
fenbuconazole
residue
chemistry
database,
HED
does
not
believe
that
the
food
+
water
risk
estimate
represents
an
actual
risk
of
concern
for
the
U.
S.
population.
Therefore,
based
on
the
information
available
at
this
time,
there
are
no
dietary
exposure
concerns
that
would
preclude
Page
35
of
55
establishing
the
uses
of
and
tolerances
for
fenbuconazole
associated
with
the
subject­
listed
commodities.

Table
6.1.2.
Summary
of
Dietary
Exposure
and
Risk
Estimates
for
Fenbuconazole
Acute
Dietary
(
95th
Percentile)
Chronic
Dietary
Cancer
Population
Subgroup
Exposure
(
mg/
kg/
day)
%
aPAD
Exposure
(
mg/
kg/
day)
%
cPAD
Exposure
(
mg/
kg/
day)
Risk
General
U.
S.
Pop.
0.000666
2
0.0004494
1.61
x
10­
6
All
Infants
(<
1
year)
0.002016
7
Children
(
1­
2
years)
0.001795
6
Children
(
3­
5
years)
0.001408
5
Children
(
6­
12
years)
0.000783
3
Youth
(
13­
19
years)
0.000419
1
Adults
(
20­
49
years)
0.000525
2
Adults
(
50+
years)
Not
Applicable
0.000612
2
Females
(
13­
49
years)
0.009014
3
0.000539
2
Not
Applicable
6.2
Water
Exposure/
Risk
Pathway
(
Revised
Tier
II
Drinking
Water
Assessment
for
Fenbuconazole,
A.
Al­
Mudallal,
D330709,
July
7,
2006)

A
Tier
2
drinking
water
assessment
was
performed
using
PRZM
3.12/
EXAMS
2.7.97
modeling
with
index
reservoir
(
IR)
scenarios
and
percent
cropped
area
(
PCA)
adjustment
factors.
The
assessment
was
based
on
the
registered
use
rate
of
fenbuconazole
cherries.
The
Tier
II
modeling
for
cherries
predicts
that
the
concentrations
of
fenbuconazole
in
surface
water
are
not
likely
to
exceed
20.3
µ
g/
L
for
the
peak
concentration,
16.5
µ
g/
L
for
the
annual
average
concentration,
and
11.7
µ
g/
L
for
the
30
year
average
concentration.

Groundwater
concentrations
were
estimated
using
a
Tier
1
SCI­
Grow
model
(
version
2.2,
Nov.
1,
2001).
The
assessment
was
based
on
an
annual
use
rate
of
0.75
ai/
acre.
The
SCI­
GROW
model
predicts
the
acute
and
chronic
concentrations
of
fenbuconazole
in
shallow
ground
water
to
be
0.031
µ
g/
L.

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Fenbuconazole.
Fenbuconazole
Exposure
Duration
Surface
Water
Conc.,
ppb
a
Ground
Water
Conc.,
ppb
b
Acute
20.3
Chronic
(
non­
cancer)
16.5
0.031
Chronic
(
cancer)
11.7
a
From
the
Tier
II
PRZM­
EXAMS
­
Index
Reservoir
model.
Input
parameters
are
based
on
Michigan
Cherry
scenario
with
8
aerial
applications
of
0.094
lbs
a.
i./
acre,
7­
day
intervals.
A
default
PCA
factor
of
0.87
was
used.
b
From
the
SCI­
GROW
model
assuming
a
maximum
annual
use
rate
of
0.75
lb
ai/
A,
a
Koc
of
2884
ml/
g,
and
a
half­
life
of
393
days.
Page
36
of
55
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
There
are
currently
no
registered
residential
uses
associated
with
fenbuconazole.

6.3.1
Other
(
Spray
Drift,
etc.)

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
ground
application
method
employed
for
fenbuconazole.
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.
On
a
chemical
by
chemical
basis,
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
with
specific
products
with
significant
risks
associated
with
drift.

7.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.
There
are
no
residential
exposure
uses
associated
with
fenbuconazole.
Therefore,
for
purposes
of
this
assessment,
only
dietary
(
food)
and
drinking
water
sources
of
exposure
were
combined
to
obtain
an
estimate
of
potential
aggregate
risk.

For
most
pesticide
active
ingredients,
water
monitoring
data
are
considered
inadequate
to
determine
surface
and
ground
water
drinking
water
exposure
estimates,
so
model
estimates
have
been
used
to
estimate
residues
in
drinking
water
(
EDWCs).
The
Environmental
Fate
and
Effects
Division
(
EFED)
and
HED
have
agreed
that
acute,
chronic
and
cancer
EDWCs
can
be
used
directly
in
dietary
exposure
assessments
to
calculate
aggregate
dietary
(
food
+
water)
risk.
This
is
done
by
using
the
relevant
PRZM­
EXAMS
value
as
a
residue
for
water
(
all
sources)
in
the
dietary
exposure
assessment.
The
principal
advantage
of
this
approach
is
that
the
actual
individual
body
weight
and
water
consumption
data
from
the
CSFII
are
used,
rather
than
assumed
weights
and
consumption
for
broad
age
groups.

7.1
Acute
Aggregate
Risk
Page
37
of
55
Dietary
exposure
(
food
+
water)
is
the
only
source
of
exposure
to
fenbuconazole
that
is
expected
to
result
in
acute
exposure.
Therefore,
the
acute
aggregate
exposure
and
risk
estimate
is
equivalent
to
the
acute
dietary
exposure
and
risk
estimates
discussed
in
Sections
6.1.2
and
7.0.
Due
to
the
toxicology
of
fenbuconazole,
the
only
population
subgroup
of
concern
for
the
acute
assessment
is
females
13­
49
years
old.
The
data
are
shown
again
in
Table
7.1
for
convenience.

Table
7.1
Acute
Aggregate
Exposure
and
Risk
for
Fenbuconazole
Acute
Dietary
(
95th
Percentile)
Population
Subgroup
aPAD
Exposure
(
mg/
kg/
day)
%
aPAD
General
U.
S.
Pop.

All
Infants
(<
1
year)

Children
(
1­
2
years)

Children
(
3­
5
years)

Children
(
6­
12
years)

Youth
(
13­
19
years)

Adults
(
20­
49
years)

Adults
(
50+
years)
Not
Applicable
Females
(
13­
49
years)
0.3
0.009014
3
7.2
Short­
and
Intermediate­
Term
Aggregate
Risks
There
are
no
residential
uses
associated
with
fenbuconazole;
therefore
short­
and
intermediateterm
aggregate
risk
assessments
are
not
required.

7.3
Long­
Term
Aggregate
Risk
Dietary
exposure
(
food
+
water)
is
the
only
source
of
exposure
to
fenbuconazole
that
is
expected
to
be
long­
term
(
180­
365
days).
Therefore,
the
long­
term
aggregate
exposure
and
risk
estimates
are
equivalent
to
the
chronic
dietary
exposure
and
risk
estimates
discussed
in
Sections
6.1.2
and
7.0.
The
data
are
shown
again
in
Table
7.3
for
convenience.

Table
7.3
Aggregate
for
Long­
term
Exposure
to
Fenbuconazole
Chronic
Dietary
Population
Subgroup
cPAD
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Pop.
0.000666
2
All
Infants
(<
1
year)
0.002016
7
Children
(
1­
2
years)
0.001795
6
Children
(
3­
5
years)
0.001408
5
Children
(
6­
12
years)
0.000783
3
Youth
(
13­
19
years)
0.03
0.000419
1
Page
38
of
55
Table
7.3
Aggregate
for
Long­
term
Exposure
to
Fenbuconazole
Chronic
Dietary
Population
Subgroup
cPAD
Exposure
(
mg/
kg/
day)
%
cPAD
Adults
(
20­
49
years)
0.000525
2
Adults
(
50+
years)
0.000612
2
Females
(
13­
49
years)
0.000539
2
7.4
Cancer
Risk
Dietary
exposure
(
food
+
water)
is
the
only
source
of
exposure
to
fenbuconazole
that
is
expected
to
be
chronic
(
cancer
­
life­
time).
Therefore,
the
chronic
(
cancer)
aggregate
exposure
and
risk
estimates
are
equivalent
to
the
chronic
(
cancer)
dietary
exposure
and
risk
estimates
discussed
in
Sections
6.1.2
and
7.0.
The
data
are
shown
again
in
Table
7.4
for
convenience.

Table
7.4
Aggregate
for
Chronic
(
Cancer)
Exposure
to
Fenbuconazole
Population
Q*
Exposure
(
mg/
kg/
day)
Cancer
Risk
U.
S.
Population
3.59e­
3
0.0004494
1.61
x
10­
6
8.0
CUMULATIVE
RISK
CHARACTERIZATION/
ASSESSMENT
Fenbuconazole
is
a
member
of
the
triazole­
containing
class
of
pesticides.
Although
conazoles
act
similarly
in
plants
(
fungi)
by
inhibiting
ergosterol
biosynthesis,
there
is
not
necessarily
a
relationship
between
this
pesticidal
activity
and
their
mechanism
of
toxicity
in
mammals.
Structural
similarities
do
not
constitute
a
common
mechanism
of
toxicity.
Evidence
is
needed
to
establish
that
the
chemicals
operate
by
the
same,
or
essentially
the
same
sequence
of
major
biochemical
events
(
EPA,
2002).
A
variable
pattern
of
toxicological
responses
are
found
for
conazoles.
Some
are
hepatotoxic
and
hepatocarcinogenic
in
mice.
Some
induce
thyroid
tumors
in
rats.
Some
induce
developmental,
reproductive,
and
neurological
effects
in
rodents.
Furthermore,
the
conazoles
have
a
diverse
range
of
biochemical
events
including
altered
cholesterol
levels,
stress
responses,
and
altered
DNA
methylation.
It
is
not
clearly
understood
whether
these
biochemical
events
are
directly
connected
to
the
toxicological
outcomes.
Thus,
there
is
currently
no
evidence
to
indicate
that
conazoles
share
common
mechanisms
of
toxicity
and
EPA
is
not
following
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity
for
the
conazoles.
For
information
regarding
EPA's
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
of
toxicity,
see
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

9.0
OCCUPATIONAL
EXPOSURE/
RISK
ASSESSMENT
PATHWAY
Page
39
of
55
(
Fenbuconazole:
Occupational
and
Residential
Exposure
Assessment
for
Section
3
Registration
for
use
of
Fenbuconazole
on
Almonds,
Apples,
Bananas,
Blueberries,
Citrus
Fruits,
Cranberries,
Pecans,
Peanuts,
Plums,
Prunes,
Sugar
Beets,
and
Wheat;
M.
Collantes;
DP
Barcode
328908;
June
2006)

9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
Fenbuconazole
may
be
applied
by
groundboom,
airblast
and
aerial
equipment.
Based
on
the
number
of
seasonal
applications
indicated
on
this
product
label,
and
information
provided
by
the
registrant,
handler
exposures
are
expected
to
be
short­
and
intermediate­
term
in
duration.

Chemical­
specific
data
for
assessing
exposure
during
pesticide
handling
activities
were
not
submitted
to
the
Agency
in
support
of
this
Section
3
application.
It
is
HED
policy
to
use
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1
to
assess
handler
exposures
for
regulatory
actions
when
chemical­
specific
data
are
not
available
(
HED
Science
Advisory
Council
for
Exposure,
SOP
Number
.007,
January
1999).

9.1.1
Non­
Cancer
Risk
HED's
level
of
concern
for
non­
cancer
risks
(
i.
e.,
target
level
of
Margins
of
Exposure
(
MOE))
is
defined
by
the
uncertainty
factors
that
are
applied
to
the
assessment.
HED
typically
applies
a
10X
factor
to
account
for
inter­
species
extrapolation
and
a
10X
factor
to
account
for
intra­
species
sensitivity.
The
total
uncertainty
factor
that
has
been
applied
to
the
non­
cancer
risk
assessment
for
fenbuconazole
is
100
for
occupational
exposure.
For
fenbuconazole,
non­
cancer
occupational
exposure
and
risk
estimates
resulting
in
MOEs
greater
than
or
equal
to
100
are
not
of
concern
to
HED.

Summaries
of
the
non­
cancer
(
MOEs)
risks
for
handlers
are
included
in
Table
9.1.1.
All
calculations
used
the
maximum
application
rate
to
estimate
worst
case
risk
scenario
for
handler
exposure
and
risk.
All
mixer/
loader,
applicator,
and
flagger
inhalation
MOEs
are
greater
than
100
at
baseline,
and
therefore
not
of
concern
to
HED.
Since
neither
a
short­
nor
intermediateterm
dermal
endpoint
was
selected
and
long­
term
dermal
exposure
to
handlers
is
not
expected,
a
handler
dermal
risk
assessment
was
not
required.

9.1.2
Cancer
Exposure
and
Risk
The
Agency
has
defined
a
range
of
acceptable
cancer
risks
for
occupational
carcinogenic
risk
("
Non­
Dietary
Cancer
Risk
Policy",
Dan
Barolo,
August
4,
1996).
In
summary,
this
policy
memo
indicates
occupational
carcinogenic
risks
that
are
1
x
10­
4
or
lower
require
no
risk
management
action.
EPA
considered
occupational
cancer
risk
estimates
greater
than
one
in
ten
thousand
(
1
x
10­
4)
to
be
of
concern,
and
attempts
to
mitigate
occupational
exposures
so
that
cancer
risk
estimates
are
one
in
one
million
(
1
x
10­
6)
or
less,
where
feasible.

To
estimate
the
carcinogenic
risk
from
absorbed
average
daily
dose,
the
values
were
amortized
over
the
working
lifetime
of
occupational
handlers.
Current
use
patterns
indicate
that
application
can
occur
numerous
times
during
a
year.
Based
on
use
scenario
and
use
patterns,
it
is
anticipated
that
commercial
applicators
would
apply
fenbuconazole
less
than
30
days
per
year.
It
Page
40
of
55
was
estimated
that
an
individual
farmer
would
handle
fenbuconazole
approximately
10
days
per
year.
As
a
result,
HED
considered
two
handler
populations
(
small,
medium,
and
large
scale
growers
as
well
as
commercial
applicators)
for
the
cancer
risk
assessment.
Finally,
a
35­
year
career
and
a
70­
year
lifespan
were
used
to
complete
the
calculations.

Table
9.1.2
summarizes
the
cancer
risk
for
handler
exposure.
All
cancer
calculations
use
the
maximum
application
rate
to
estimate
risk.
The
cancer
risk
for
private
and
commercial
farmers
(
i.
e.,
mixer/
loaders,
applicators
and
flaggers)
were
lower
than
1
x
10­
4
using
either
baseline
or
PPE
(
single
layer
clothing
and
gloves)
mitigation.
The
cancer
risk
for
private
farmers
ranged
from
6.1
x
10­
9
to
1.3
x
10­
6
,
while
the
cancer
risk
for
commercial
farmers
ranged
from
1.8
x
10­
8
to
4.0
x
10­
6
.

Table
9.1.1:
Non­
Cancer
Short­
and
Intermediate­
term
Handler
Risk
Scenario
Mitigation
Crops
Inhalation
Unit
Exposure
(
mg/
lb)
a
Application
Rate
b
(
lb
ai/
acre)
Acres
Treated
(
A/
day)
c
Inhalation
Dose
d
(
mg/
kg/
day)
Inhalation
MOEe
Mixer/
Loader
14,000
Wheat
0.062
200
0.00021
peanuts
and
sugar
beets
0.12
0.00016
19,000
ENABLE
2F
Groundboom
cranberries
0.19
80
0.00026
12,000
Almonds,
bananas,
blueberries,
plums,
prunes,
0.094
0.000064
47,000
ENABLE
2F
Airblast
Baseline
apples,
citrus
fruits,
grapefruit,
pecans,
0.12
40
0.000082
37,000
wheat
0.062
1200
0.0013
2,300
Almonds,
bananas,
blueberries,
plums,
prunes
0.094
0.00056
5,000
ENABLE
2F
Aerial
Baseline
apples,
citrus
fruits,
grapefruit,
pecans,
0.0012
0.12
350
0.00072
4,200
Page
41
of
55
Table
9.1.1:
Non­
Cancer
Short­
and
Intermediate­
term
Handler
Risk
Scenario
Mitigation
Crops
Inhalation
Unit
Exposure
(
mg/
lb)
a
Application
Rate
b
(
lb
ai/
acre)
Acres
Treated
(
A/
day)
c
Inhalation
Dose
d
(
mg/
kg/
day)
Inhalation
MOEe
cranberries
0.19
0.00114
2,600
Indar
75WSP
Airblast
Apricots,
cherries,
nectarines,
peaches
0.00024
0.09
40
0.0000123
240,000
Page
42
of
55
Indar
75WSP
Aerial
350
0.0001
30,000
Applicator
Enable
2F
wheat
0.00074
0.062
200
0.00013
23,000
Almonds,
bananas,
blueberries,
plums,
prunes
0.094
0.00024
13,000
Enable
2F
airblast
apples,
citrus
fruits,
grapefruit,
pecans,
0.0045
0.12
40
0.0003
10,000
wheat
0.062
1200
0.000072
42,000
Almonds,
bananas,
blueberries,
plums,
prunes
0.094
0.000032
94,000
apples,
citrus
fruits,
grapefruit,
pecans,
0.12
0.00004
75,000
Enable
2F
aerial
Cranberries
0.000068
0.19
350
0.000065
46,000
Indar
75
WSP
Airblast
0.0045
40
0.0000034
880,000
Indar
75
WSP
Aerial
Baseline
Apricots,
cherries,
nectarines,
peaches
0.000068
0.09
350
0.00003
100,000
Flagger
Enable
2F
wheat
0.062
1200
0.00037
8100
Baseline
Almonds,
bananas,
blueberries,
plums,
prunes
0.00035
0.094
350
0.000165
18,000
Page
43
of
55
apples,
citrus
fruits,
grapefruit,
pecans
0.12
0.00021
14,000
cranberry
0.19
0.00033
9100
Indar
75
WSP
Apricots,
cherries,
nectarines,
peaches
0.00035
0.09
350
0.00016
19,000
a.
PHED
Version
1.1
b.
Application
Rate
based
on
proposed
registered
label
for
fenbuconazole
products
c.
Acres
Treated
=
Science
Advisory
Council
Policy
#
9.1
d.
Short­
and
Intermediate­
term
Inhalation
Dose
(
mg/
kg/
day)
=
[
Rate
(
lb
ai/
A)
x
UE
(
mg
/
lb
ai
)
x
Acres
Treated
(
A/
day)]
/
BW
(
70
kg)
e.
Short­
and
intermediate­
term
Inhalation
MOE
=
Inhalation
NOAEL
(
3
mg/
kg/
day)/
Inhalation
Dose
(
mg/
kg/
day)
Page
44
of
55
Table
9.1.2
Handler
Cancer
Risk
for
Fenbuconazole
Scenario
Mitigation
Crop
Dermal
Dose
a
(
mg/
kg/
day)
Inhalation
Dose
a
(
mg/
kg/
day)
Combined
ADD
b
(
mg/
kg/
day)
Private
LADD
c
(
mg/
kg/
day)
Private
Cancer
Risk
d
Commerical
LADD
e
(
mg/
kg/
day)
Commercial
Cancer
Risk
f
Mixer/
Loader
wheat
0.02
0.00021
0.02
0.00027
9.9E­
7
0.00083
3.0E­
6
Peanuts,

sugar
beets
0.017
0.00016
0.0172
0.000235
8.4E­
7
0.0007
2.5E­
6
Enable
2F
Groundboom
cranberries
0.027
0.00026
0.0273
0.00037
1.3E­
6
0.0011
4.0E­
6
Almonds,

bananas,
blueberries,

plums,

prunes
0.0066
0.000064
0.0066
0.000091
3.3E­
7
0.00027
9.8E­
7
Enable
2F
Airblast
baseline
Apples,

citrus
fruits,

grapefruit,

pecans
0.0085
0.000082
0.0086
0.00118
4.2E­
7
0.00035
1.3E­
6
wheat
0.001
0.0013
0.0023
0.000032
1.1E­
7
0.000095
3.4E­
7
Enable
2F
Aerial
Baseline
­
Inhalation
Single
layer
&

gloves
­

Dermal
Almonds,

bananas,
blueberries,

plums,

prunes
0.0005
0.00056
0.001
0.000015
5.2E­
8
0.000044
1.6E­
7
Page
45
of
55
Table
9.1.2
Handler
Cancer
Risk
for
Fenbuconazole
Scenario
Mitigation
Crop
Dermal
Dose
a
(
mg/
kg/
day)
Inhalation
Dose
a
(
mg/
kg/
day)
Combined
ADD
b
(
mg/
kg/
day)
Private
LADD
c
(
mg/
kg/
day)
Private
Cancer
Risk
d
Commerical
LADD
e
(
mg/
kg/
day)
Commercial
Cancer
Risk
f
Apples,

citrus
fruits,

grapefruit,

pecans
Peanuts
and
sugar
beets
0.0006
0.00072
0.00132
0.000018
6.5E­
8
0.000054
1.9E­
7
cranberries
0.0009
0.00114
0.002
0.00003
9.9E­
8
0.000084
3.0E­
7
Indar
75WSP
airblast
0.0004
0.00114
0.00154
0.00002
7.5E­
8
0.000063
2.3E­
7
Indar
75WSP
aerial
Apricots,

cherries,
nectarines,

peaches
0.004
0.0000123
0.004
0.000055
1.9E­
7
0.000165
5.9E­
7
Applicator
wheat
0.0001
0.00013
0.00023
0.0000031
1.1E­
8
0.0000094
3.4E­
8
Apples,

citrus
fruits,

grapefruit,

pecans,
peanuts,
and
sugar
beets
0.000082
0.0001
0.00018
0.0000025
9E­
9
0.0000074
2.7E­
8
Enable
2F
Groundboom
baseline
cranberries
0.00013
0.00016
0.00029
3.9E­
6
1.4E­
8
0.000012
4.3E­
8
Page
46
of
55
Table
9.1.2
Handler
Cancer
Risk
for
Fenbuconazole
Scenario
Mitigation
Crop
Dermal
Dose
a
(
mg/
kg/
day)
Inhalation
Dose
a
(
mg/
kg/
day)
Combined
ADD
b
(
mg/
kg/
day)
Private
LADD
c
(
mg/
kg/
day)
Private
Cancer
Risk
d
Commerical
LADD
e
(
mg/
kg/
day)
Commercial
Cancer
Risk
f
Almonds,

bananas,
blueberries,

plums,

prunes
0.00082
0.00024
0.001
0.000015
5.2E­
8
0.000044
1.6E­
7
Enable
2F
airblast
Apples,

citrus
fruits,

grapefruit,

pecans
0.001
0.0003
0.0013
0.0000018
6.4E­
8
0.000053
1.9E­
7
wheat
0.00023
0.000072
0.0003
0.000004
1.5E­
8
0.0000123
4.5E­
8
Almonds,

bananas,
blueberries,

plums,

prunes
0.0001
0.000032
0.000132
0.0000018
6.5E­
9
0.0000054
1.9E­
8
Apples,

citrus
fruits,

grapefruit,

pecans,
peanuts,

sugar
beets
0.00013
0.00004
0.00017
0.0000023
8.4E­
9
0.000007
2.5E­
8
Enable
2F
aerial
cranberries
0.0002
0.000065
0.00027
0.0000036
1.3E­
8
0.000011
4E­
8
Indar
75
WSP
Airblast
Baseline
Apricots,

cherries,
nectarines,
0.0069
0.0000034
0.007
0.000095
3.4E­
7
0.0003
1E­
6
Page
47
of
55
Table
9.1.2
Handler
Cancer
Risk
for
Fenbuconazole
Scenario
Mitigation
Crop
Dermal
Dose
a
(
mg/
kg/
day)
Inhalation
Dose
a
(
mg/
kg/
day)
Combined
ADD
b
(
mg/
kg/
day)
Private
LADD
c
(
mg/
kg/
day)
Private
Cancer
Risk
d
Commerical
LADD
e
(
mg/
kg/
day)
Commercial
Cancer
Risk
f
Indar
75
WSP
Aerial
peaches
0.000095
0.00003
0.000125
0.0000017
6E­
9
0.000005
1.8E­
8
Flagger
Wheat
0.00049
0.00037
0.00086
0.000012
4.2E­
8
0.000035
1.3E­
7
Almonds,

bananas,
blueberries,

plums,

prunes
0.00022
0.000165
0.00038
0.00000513
1.8E­
8
0.0000156
5.6E­
8
Apples,

citrus
fruits,

grapefruit,

pecans,
peanuts,

sugar
beets
0.00028
0.00021
0.00049
0.0000066
2.4E­
8
0.00002
7.2E­
8
Enable
2F
cranberry
0.00044
0.00033
0.00077
0.00001
3.7E­
8
0.000032
1.1E­
7
Indar
75
WSP
Baseline
Apricots,

cherries,
nectarines,

peaches
0.00021
0.00016
0.00037
0.000005
1.8E­
8
0.000015
5.5E­
8
Notes:

a.
See
Table
5.1.2
of
June
2006
M.
Collantes
Occupational
Risk
Assessment
(
D328908)

b.
ADD
(
mg/
kg/
day)
=
[
Dermal
Dose
(
mg/
kg/
day)
x
4.25%
DA]+
Inhalation
Dose
(
mg/
kg/
day)

c.
Private
Farmer
LADD
(
mg/
kg/
day)
=
ADD
x
[(
10
days/
yr)/
(
365
days/
yr)]
x
(
35
yrs/
70yrs)
Page
48
of
55
d
Private
Farmer
Cancer
Risk
=
LADD
x
Q*
(
3.59
x
10­
3
mg/
kg/
day)­
1
e.
Commercial
Applicator
LADD
(
mg/
kg/
day)
=
ADD
x
[(
30
days/
yr)/
(
365
days/
yr)]
x
(
35
yrs/
70yrs)

f.
Private
Applicator
Cancer
Risk
=
LADD
x
Q*
(
3.59
x
10­
3
mg/
kg/
day)­
1
Page
49
of
55
9.2
Non­
Cancer
Short/
Intermediate/
Long­
Term
Postapplication
Risk
Neither
short­
nor
intermediate­
term
dermal
endpoints
were
selected
for
fenbuconazole.
Longterm
dermal
exposure
as
a
result
of
postapplication
activities
is
not
expected.
Therefore
a
noncancer
postapplication
exposure
assessment
was
not
required
9.2.1
Cancer
Postapplication
Risk
No
postapplication
data
were
submitted
in
support
of
this
registration
action.
Cancer
risk
and
exposures
resulting
from
postapplication
activities
were
estimated
using
dermal
transfer
coefficients
from
the
Science
Advisory
Council
For
Exposure
Policy
Number
3.1:
Agricultural
Transfer
Coefficients,
August
2000.
The
following
assumptions,
data
and
default
values
were
also
used:

Assumptions:
 
Application
Rate
=
ranges
from
0.064
lb
ai/
A
for
wheat
to
cranberries
at
0.19
lb
ai/
A
 
Exposure
Duration=
8
hours
per
day
 
Body
Weight
=
70
kg
 
Dermal
Absorption=
4.25%
for
long
term
exposure
 
Fraction
of
a.
i.
retained
on
foliage
is
assumed
to
be
20%
(
0.2)
on
day
zero
(=%
dislodgeable
foliar
residue,
DFR,
after
initial
treatment).
This
fraction
is
assumed
to
further
dissipate
at
the
rate
of
10%
(
0.1)
per
day
on
following
days.
These
are
default
values
established
by
HED's
Science
Advisory
Council
(
SAC)
for
Exposure.

The
Agency
has
defined
a
range
of
acceptable
cancer
risks
for
occupational
carcinogenic
risk
Occupational
carcinogenic
risks
that
are
1
x
10­
4
or
lower
require
no
risk
management
action.
EPA
considered
occupational
cancer
risk
estimates
greater
than
one
in
ten
thousand
(
1
x
10­
4)
to
be
of
concern,
and
attempts
to
mitigate
occupational
exposures
so
that
cancer
risk
estimates
are
one
in
one
million
(
1
x
10­
6)
or
less,
where
feasible.

In
determining
carcinogenic
risk
related
to
postapplication
exposure,
the
values
were
amortized
over
the
working
lifetime
of
occupational
workers.
Furthermore,
HED
considered
the
following
assumptions
and
data:
1.)
the
time
interval
between
reapplication
of
fenbuconazole
varies
between
7
days
and
30
or
more
days
for
the
proposed
uses,
2.)
residues
are
assumed
to
decrease
over
time
and
3.)
it
is
unlikely
that
workers
will
be
exposed
to
Day
0
residues
30
days
a
year.
Therefore,
HED
used
the
average
residue
over
30
days
to
estimate
cancer
risk.
All
cancer
risk
estimates
are
lower
than
1
x
10­
6
and
therefore
are
not
a
risk
concern.
Cancer
risk
estimates
are
summarized
in
Table
9.2.

Restricted
Entry
Interval
The
restricted
entry
interval
(
REI)
is
based
on
the
acute
toxicity
of
fenbuconazole
technical
material
which
is
classified
as
Category
III
and
IV.
Acute
toxicity
Category
III
and
IV
chemicals
require
a
12
hour
REI.
Therefore
the
12­
hour
REI
which
appears
on
the
Enable
2F
Fungicide
and
Indar
75WSP
labels
is
adequate.
Page
50
of
55
Table
9.2:
Postapplication
Cancer
Risk
and
Exposure
for
Fenbuconazole
Transfer
Coefficient
c
(
cm2/
hr)
Daily
Dose
d
(
mg/
kg/
day)
LADD
e
Cancer
Risk
f
Crop
DAT
a
DFR
b
(
ug/
cm2)
Low
High
Low
High
Low
High
Low
High
cranberry,
Avg
0.136
2.6E­
4
1.1E­
5
3.9E­
8
blueberry
Avg
0.067
400
NA
1.3E­
4
NA
5.4E­
6
NA
2.0E­
8
NA
wheat
Avg
0.044
2.2E­
5
3.2E­
4
8.8E­
7
1.3E­
5
3.2E­
9
4.8E­
8
sugar
beet,

and
peanut
Avg
0.086
100
1500
4.2E­
5
6.2­
4
1.74E­
6
2.6E­
5
6.0E­
9
9.2E­
8
apples
Avg
0.086
4.2E­
5
1.2E­
3
1.7E­
6
5.17E­
5
6.1E­
9
1.8E­
7
prunes
and
plums
Avg
0.064
3.1E­
5
9.4E­
4
1.3E­
6
3.8E­
5
4.6E­
9
1.4E­
7
apricots,
nectarines,

peaches
and
cherries
Avg
0.067
100
3000
3.3E­
5
9.3E­
4
1.3E­
6
4.0E­
5
4.8E­
9
1.4E­
7
grapefruits,

oranges
Avg
0.086
6.2E­
4
1.2E­
3
2.6E­
5
5.1E­
5
9.2E­
8
1.8E­
7
bananas
Avg
1500
3000
4.9E­
4
9.8E­
4
2.0E­
5
4.0E­
5
7.2E­
8
1.4E­
7
almonds
Avg
0.067
1.6E­
4
8.2E­
4
6.7E­
6
3.4E­
5
2.3E­
8
1.2E­
7
Pecans
Avg
0.086
500
2500
2.1E­
4
1.0E­
3
8.6E­
6
4.34E­
5
3.1E­
8
1.5E­
7
a.
DAT=
30
day
residue
average
b.
DFRt
(
µ
g/
cm2)
=
Application
Rate
(
lb
ai/
A)
x
F
x[[
1­(
1­
D)
30
]/[
1­(
1­
D)]}/
t
x
4.54E8
µ
g/
lb
x
24.7E­
9
A/
cm2
c.
Transfer
Coefficients
selected
in
accordance
with
SAC
for
Exposure
Policy
3.1
(
August
2000)

d.
Daily
Dose
(
mg/
kg/
day)
=
DFR
(
ug/
cm2)
x
0.001
mg/
ug
x
Tc
(
cm2/
hr)
x
DA
(
4.25%)
x
ET
(
8
hrs/
day)/
70
kg
Page
51
of
55
e.
LADD
(
mg/
kg/
day)
=
DD
x
[(
30
days/
yr)/
(
365
days/
yr)]
x
(
35
yrs/
70yrs)

f.
Cancer
Risk
=
LADD
x
Q*
(
3.59
x
10­
3
mg/
kg/
day)­
1
Page
52
of
55
10.
DATA
NEEDS
AND
LABEL
REQUIREMENTS
10.1
Toxicology
­
None
10.2
Residue
Chemistry
The
registrant
has
requested
a
large
number
of
new
uses
for
fenbuconazole.
Data
needs
and
label
requirements
are
presented
below
and
should
be
resolved
prior
to
establishing
tolerances,
except
where
items
are
noted
as
being
a
condition
of
registration.

General
(
All
Petitions)
 
The
petitioner
must
amend
Section
B
of
the
petitions
to
specify
whether
application
is
to
be
made
using
ground
and/
or
aerial
equipment,
and
to
specify
the
application
volumes
to
be
used
for
application.
These
Sections
B
need
to
be
modified
to
be
consistent
with
proposed
labels
(
i.
e.,
Enable
2F
and
Indar
75WSP)
which
state,
"
for
aerial
application
apply
a
minimum
of
5
gallons
of
water
per
acre
on
annual
crops
and
10
gallons
of
water
per
acre
on
perennial
tree
fruits
and
nuts"
and
"
for
aerial
application
apply
in
a
minimum
of
10
gallons
of
water
per
acre",
respectively.

 
The
analytical
reference
standards
for
the
two
fenbuconazole
metabolites,
RH
9129
and
RH
9130,
are
present
in
insufficient
quantities
at
the
Agency's
Analytical
Chemistry
Branch
repository.
The
registrant
must
submit
one
gram
each
of
the
reference
standards
for
the
two
fenbuconazole
metabolites,
RH
9129
and
RH
9130.

 
Prior
to
being
accepted
as
an
enforcement
method,
the
GC/
NPD
method
(
TR
34­
94­
142,
MRID
43524907)
for
determining
residues
in
livestock
commodities
must
undergo
a
Tolerance
Method
Validation
(
TMV).
HED
will
initiate
the
TMV.

7F4900/
4F6879
(
Citrus)
 
The
petitioner
must
amend
the
proposed
label
to
specify
a
minimum
retreatment
interval;
the
available
data
will
support
a
minimum
retreatment
interval
of
21
days.

 
The
petitioner
must
conduct
another
citrus
processing
study.
Samples
from
the
processing
study
must
be
analyzed
within
the
intervals
that
fenbuconazole
and
metabolite
residues
have
been
shown
to
be
stable
(
30
months
for
fruit
and
12
months
for
oil
and
dried
pulp).
The
required
study
does
not
need
to
include
the
analysis
of
juice
samples;
the
current
study
is
adequate
to
demonstrate
that
residues
of
fenbuconazole
and
its
metabolites
RH­
9129
and
RH­
9130
do
not
concentrate
in
citrus
juice.
Granting
of
a
registration
should
be
made
conditional
upon
resolution
of
this
issue.

2F4135
(
Apple)
 
The
petitioner
must
submit
a
revised
Section
F
to
specify
a
tolerance
expression
for
the
combined
residues
of
fenbuconazole
and
its
metabolites
RH­
9129
and
RH­
9130
Page
53
of
55
in
terms
of
parent
equivalents.
In
addition,
the
entry
for
apple
juice,
for
which
a
tolerance
level
of
"
not
required"
is
listed,
should
be
deleted
from
Section
F.

 
The
Agency
has
not
reviewed
an
acceptable
apple
processing
study
for
fenbuconazole.
Granting
of
a
registration
should
be
made
conditional
upon
resolution
of
this
issue.
We
note
that
MRID
43621001
is
under
review.

7F4887
(
Sugar
Beet)
 
The
proposed
label
must
be
amended
to
remove
the
prohibition
against
the
feeding
of
sugar
beet
tops
to
livestock,
as
the
Agency
does
not
allow
the
restriction
of
feeding
of
sugar
beet
tops.

1F3989,
1F3995,
2F4154
and
3F4194
(
Stone
Fruits,
Pecans,
Bananas
and
Almonds)
 
None
9E5041
(
Bushberries)
 
As
a
condition
of
registration,
two
additional
field
trials
are
required
for
blueberries,
one
each
from
Regions
2
and
5.

1E6252
(
Cranberries)
 
The
proposed
use
pattern
for
cranberries
should
be
amended
to
specify
a
minimum
retreatment
interval
of
10
days.

2F4127
(
Wheat)
 
Label
directions
for
uses
on
wheat
should
be
amended
to:
(
i)
remove
the
prohibition
against
the
grazing
or
feeding
of
forage
or
hay
to
livestock;
(
ii)
specify
a
minimum
PHI
for
forage
and
hay;
and
(
iii)
specify
rotational
crop
restrictions.
Although
limited,
the
available
data
indicate
that
a
14­
day
PHI
would
be
acceptable
for
wheat
forage
and
hay,
while
the
additional
field
trial
data
are
being
generated.
For
crops
without
primary
label
uses
(
i.
e.,
rotational
crops),
minimum
plantback
intervals
(
PBIs)
should
be
35
days
following
applications
totaling
 
0.188
lb
ai/
A
and
210
days
following
applications
totaling
0.2­
1.0
lb
ai/
A.

 
If
the
petitioner
is
continuing
to
support
seed
treatment
use
for
fenbuconazole
on
wheat,
then
copies
of
new
labels
must
be
submitted
with
directions
for
that
use.

 
A
complete
set
of
20
field
trials
are
required
on
wheat
forage
and
an
additional
12
tests
are
required
on
wheat
hay.
These
tests
should
be
conducted
using
the
currently
proposed
use
pattern,
which
reflects
one
application
on
forage
and
up
to
two
applications
on
hay
at
0.063
lb
ai/
A/
application.
Although
conditions
will
vary
between
test
sites,
the
sampling
intervals
for
forage
and
hay
should
be
consistent
enough
for
the
Agency
to
be
able
to
compare
residues
and
assess
an
appropriate
PHI.
Granting
of
a
registration
should
be
made
conditional
upon
resolution
of
this
issue.

10.3
Occupational
and
Residential
Exposure
­
None
Page
54
of
55
REFERENCES
1.
Revised
Tier
II
Drinking
Water
Assessment
for
Fenbuconazole,
A.
Al­
Mudallal,
D330709,
July
7,
2006
2.
Fenbuconazole
Acute,
Chronic
and
Cancer
Dietary
Exposure
Assessment
for
the
Section
3
Registration
Action
for
New
Uses.
M.
Doherty,
D329595,
June
2006.
3.
Occupational
and
Residential
Exposure
Assessment
for
Section
3
Registration
for
use
of
Fenbuconazole
on
Almonds,
Apples,
Bananas,
Blueberries,
Citrus
Fruits,
Cranberries,
Pecans,
Peanuts,
Plums,
Prunes,
Sugar
Beets,
and
Wheat.
M.
Collantes;
DP
Barcode
328908;
June
2006
4.
Fenbuconazole­
Report
of
the
Hazard
Identification
Assessment
Review
Committee,
February
26,
1998
5.
Carcinogenicity
Peer
Review
of
Fenbuconazole.
S.
Williams­
Foy
and
E.
Rinde;
March
15,
1996;
TXR
0011894
6.
HIARC
Report
for
Fenbuconazole.
S.
Williams­
Foy;
November
17,
1998;
TXR
0012971
Page
55
of
55
APPENDICES
1.0
TOXICOLOGY
DATA
REQUIREMENTS
HED
is
in
the
process
of
converting
existing
DERs
to
an
electronically
available
format
for
inclusion
into
subsequent
risk
assessments.

2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
HED
is
in
the
process
of
converting
existing
DERs
to
an
electronically
available
format
for
inclusion
into
subsequent
risk
assessments.

3.0
METABOLISM
CONSIDERATIONS
Since
fenbuconazole
is
not
a
new
active
ingredient
and
there
is
not
additional
information
other
then
what
has
already
been
stated
in
the
risk
assessment,
this
section
was
not
applicable.