Document ID: EPA-HQ-OPP-2006-0521-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-05T04:00Z

1
EPA
Registration
Division
contact:

Barbara
Madden
(
703)
305­
6463
Interregional
Research
Project
Number
4
PP
6E7052
EPA
has
received
a
pesticide
petition
(
6E7052)
from
Interregional
Research
Project
Number
4
(
IR­
4),
681
U.
S.
Highway
#
1
South,
North
Brunswick,
NJ
08902­
3390,
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180.362
by
establishing
a
tolerance
for
residues
of
hexakis
(
2­
methyl­
2­
phenylpropyl)­
distannoxane
(
also
know
as
Fenbutatin­
oxide,
Bis
[
tris
(
2­
methyl­
2­
phenylpropyl)
tin]
oxide)
in
or
on
the
raw
agricultural
commodity
pistachio
at
0.5
parts
per
million
(
ppm).
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
The
qualitative
nature
of
the
residue
in
plants
is
adequately
understood.
Studies
with
apples
and
oranges
indicate
that
residues
are
primarily
found
on
the
fruits'
surface.
Since
the
parent
compound
comprises
the
majority
of
the
terminal
residue
in
plants,
only
the
parent
will
be
included
in
the
tolerance
expression
for
plant
commodities.
(
MRID
00113018)

2.
Analytical
method.
An
adequate
enforcement
method
is
available
for
fenbutatin­
oxide
residues
in
plants
and
animals.
The
GLC/
FPD
method
MMS­
R­
494­
2
has
successfully
undergone
Agency
method
validation
for
plants
and
animals
and
has
satisfied
the
requirements
of
PR
Notice
88­
5
concerning
independent
laboratory
validation.
Method
MMS­
R­
494­
2
individually
quantifies
each
analyte
to
a
detection
limit
of
0.05
ppm.
A
spectrophotometric
method
for
determining
total
organotin
and
a
GLC/
EC
method
(
MMS­
R­
391­
1)
for
determining
the
parent
compound
are
published
in
PAM,
Vol.
II
as
Methods
I
and
II,
respectively.
These
methods
are
inadequate
for
both
data
collection
and
enforcement
purposes.
In
addition,
the
TLC
methods
MMS­
R­
391­
1,
published
in
PAM,
Vol.
II
as
Method
A,
and
MMS­
R­
345­
1
(
the
section
for
SD­
31723
analysis
only),
are
adequate
only
for
confirming
GLC
results.
(
MRID's
41110901
and
41520701)

3.
Magnitude
of
residues.
The
tolerances
listed
in
40
CFR
§
180.362(
a)
are
for
the
residues
of
fenbutatin­
oxide.
Sufficient
data
are
available
to
ascertain
the
adequacy
of
the
established
tolerances
listed
for:
almonds;
almonds,
hulls;
apples;
cherries,
sour;
cherries,
sweet;
2
citrus
fruits;
cucumbers;
eggplant;
grapes;
papayas;
peaches;
pears;
pecans;
plums;
prunes;
strawberries;
and
walnuts.
Certain
commodity
definitions
of
the
above
tolerances
are
not
in
accordance
with
the
definitions
listed
in
the
Commodity
Index
Report
dated
10/
28/
92;
see
the
table
and
discussion
below
for
modifications
in
commodity
definitions.
The
individual
tolerances
for
"
almonds"
(
0.5
ppm),
"
pecans"
(
0.5
ppm),
and
"
walnuts"
(
0.5
ppm)
should
be
revoked,
and
a
tolerance
for
residues
in
or
on
"
tree
nuts
group"
should
be
established
at
0.5
ppm.
The
available
data
from
almonds,
pecans,
and
walnuts
will
support
this
crop
group
tolerance.

B.
Toxicological
Profile
1.
Acute
toxicity.
In
a
rat
acute
oral
study,
the
LD50
of
fenbutatin
oxide
was
4400
mg/
kg.
The
dermal
LD50
in
rabbits
was
>
2000
mg/
kg,
the
highest
dose
tested.
Rat
4­
hour
inhalation
LC50
values
ranged
from
0.06­
0.23
mg/
L.
Fenbutatin
oxide
was
a
severe
eye
irritant
and
a
mild
skin
irritant
in
rabbits,
but
did
not
produce
skin
sensitization
in
guinea
pigs.
In
an
acute
neurotoxicity
study
in
rats,
the
NOEL
was
20
mg/
kg
based
on
minimally
decreased
motor
activity
in
male
rats
at
100
mg/
kg
and
effects
on
body
weight,
nutritional
parameters,
clinical
signs
of
toxicity
and
effects
on
motor
activity
in
both
sexes
at
1000
mg/
kg.
There
were
no
effects
on
neuropathology
at
any
dose
(
highest
dose
tested
2000
mg/
kg).

2.
Genotoxicty.
Fenbutatin
oxide
was
negative
in
a
battery
of
genotoxicity
assay
including
Salmonella
or
Chinese
hamster
ovary
cells
with
or
without
activation.
It
did
not
induce
chromosome
aberrations
in
human
lymphocytes.
Fenbutatin
oxide
did
not
produce
an
increase
in
micronucleated
polychromatic
erythrocytes
in
the
bone
marrow
of
mice
at
dose
up
to
and
including
5000
mg/
kg.
It
did
not
produce
unscheduled
DNA
synthesis
in
rat
hepatocytes.

3.
Reproductive
and
developmental
toxicity.
A
two­
generation
rat
reproduction
study
was
conducted
at
dietary
concentrations
of
0,
40,
75,
250,
and
750
ppm.
The
NOAEL
for
maternal
and
reproductive
toxicity
were
both
75
ppm
(
5
mg/
kg/
day)
based
on
effects
on
body
weight
and
nutritional
parameters
in
parental
animals
and
body
weight
effects
in
pups
at
250
ppm
(
20
mg/
kg/
day).

In
a
developmental
toxicity
study,
pregnant
female
rats
were
administered
fenbutatin
oxide
at
0,
15,
30,
or
60
mg/
kg/
day
on
days
6
to
15
of
gestation.
The
NOAEL
for
maternal
toxicity
was
15
mg/
kg/
day
based
on
diarrhea
and
reduced
body
weight
at
30
mg/
kg/
day.
The
developmental
NOAEL
was
60
mg/
kg/
day,
the
highest
dose
tested.

Pregnant
female
rabbits
were
administered
fenbutatin
oxide
at
0,
1,
5,
or
10
mg/
kg/
day
on
days
6
to
18
of
gestation.
Rabbits
dosed
with
5
mg/
kg/
day
exhibited
anorexia
and
lesions
of
the
gastrointestinal
tract
but
without
any
effect
on
body
weight.
Rabbits
dosed
with
10
mg/
kg/
day
had
anorexia,
reduced
body
weight,
gastric
lesions,
maternal
mortality,
and
increased
abortions.
The
NOAEL
for
developmental
effects
was
10
mg/
kg/
day,
the
highest
dose
tested.
3
4.
Subchronic
toxicity.
A
90­
day
feeding
study
was
conducted
in
rats
at
dietary
concentrations
from
50
to
600
ppm.
Effects
on
body
weight,
nutritional
parameters,
and
clinical
chemistry
occurred
at
300
ppm
and
higher.
Blood
urea
nitrogen
levels
were
also
increased
in
females
at
100
ppm.
There
were
no
treatment­
related
gross
or
microscopic
pathologic
effects
at
any
dietary
concentration.

A
90­
day
neurotoxicity
study
in
rats
was
conducted
at
the
same
dietary
concentrations.
The
NOAEL
was
100
ppm
(
7.63
mg/
kg/
day)
for
females
and
300
ppm
(
18.8
mg/
kg/
day)
for
males
based
on
effects
on
body
weight
and
nutritional
parameters
at
higher
dietary
levels.
There
were
no
treatment­
related
effects
on
neurobehavioral
endpoints
or
neuropathology
at
any
dietary
concentration.

Skin
irritation
but
no
systemic
toxicity
occurred
in
rabbits
in
a
21­
day
dermal
study
in
which
fenbutatin
oxide
was
administered
at
doses
up
to
5
mg/
kg/
day.

5.
Chronic
toxicity.
Fenbutatin
oxide
was
not
carcinogenic
in
rats
or
mice.
In
a
two­
year
feeding
study,
rats
were
administered
up
to
600
ppm
in
the
diet.
The
NOAEL
was
100
ppm
(
5
mg/
kg/
day)
based
on
decreased
body
weight,
reduced
total
white
cells
in
males,
increased
serum
alkaline
phophatase,
and
organ
weight
changes
at
300
ppm
(
15
mg/
kg/
day).

Mice
were
fed
up
to
600
ppm
fenbutatin
oxide
in
the
diet
for
18­
months.
The
only
significant
treatment­
related
effect
was
a
reduction
in
body
weight
at
300
ppm
(
45
mg/
kg/
day).
There
were
hematologic,
clinical
chemical,
or
pathologic
effects
at
any
level.
The
NOAEL
was
100
ppm
(
15
mg/
kg/
day).

Dog
were
administered
fenbutatin
oxide
by
gelatin
capsule
up
to
60
mg/
kg/
day
for
two
years.
The
NOAEL
was
5
mg/
kg/
day
based
up
clinical
observations
of
vomiting
and
diarrhea
at
the
LOEL
of
15
mg/
kg/
day.
There
were
no
specific
compound­
related
histopathologic
changes
at
any
dose.

6.
Animal
metabolism.
In
a
rat
metabolism
study,
fenbutatin
oxide
was
excreted
virtually
unchanged
from
the
feces.
Only
a
very
small
amount
(~
1%)
of
fenbutatin
oxide
was
absorbed
from
the
gastrointestinal
tract
producing
two
minor
metabolites.
Over
a
5­
day
period,
83­
100%
of
the
radioactivity
was
found
in
the
feces
or
urine
indicating
the
potential
for
bioaccumulation
is
minimal.
Metabolism
studies
were
conducted
in
goats
and
laying
hens.
In
goats,
fenbutatin
oxide
was
extensively
eliminated
in
the
feces
as
parent
material.
Small
amounts
of
radioactivity
were
found
in
the
tissues.
Concentrations
of
radioactivity
in
the
milk
were
below
levels
of
detection.
In
study
with
laying
hens,
the
majority
of
administered
radioactive
dose
was
found
in
the
excreta
as
intact
parent
compound.
Very
small
amounts
of
radioactivity
were
found
in
tissue
and
eggs.

7.
Metabolite
toxicology.
The
nature
of
the
residues
in
plants
and
animals
are
adequately
understood.
The
tolerance
expression
for
plants
is
for
fenbutatin
oxide
only.
EPA
has
determined
4
residues
to
be
regulated
for
meat,
milk,
poultry,
and
eggs
are
the
combined
residues
of
parent
and
two
metabolites
calculated
as
parent
­­
hexakis
(
2­
methyl­
2­
phenylpropyl)
distannoxane.

8.
Endocrine
disruption.
There
are
no
apparent
estrogenic
effects
from
fenbutatin
oxide
based
on
the
collective
findings
from
developmental,
two­
generation
reproduction,
subchronic,
and
chronic
toxicity
studies
conducted
in
multiple
species,
including
histopathological
evaluation
of
the
reproductive
tract
and
other
endocrine
organs.

C.
Aggregate
Exposure
1.
Dietary
exposure.
An
assessment
was
conducted
to
determine
the
acute
and
chronic
exposure
of
all
population
groups
to
fenbutatin­
oxide.
Tolerance
values
have
previously
been
established
for
all
crops
except
pistachio.
This
analysis
included
all
crops
and
animal
commodities
with
established
tolerance
values
and
the
proposed
crop
of
pistachio.

i.
Food.
The
chronic
dietary
exposure
assessment
of
the
currently
approved
uses
of
fenbutatin­
oxide
and
the
proposed
use
on
pistachios
is
well
within
acceptable
limits
for
all
sectors
of
the
population.
The
chronic
module
of
the
Dietary
Exposure
Evaluation
Model
software
with
Food
Commodity
Intake
Database
(
DEEM­
FCIDTM
)
was
used
to
conduct
the
assessment
with
the
chronic
reference
dose
(
cRfD)
of
0.05
mg/
kg
body
wt/
day.
The
analysis
used
mean
residue
values
from
either
field
trials
or
from
the
USDA
Pesticide
Data
Program
(
PDP).
Percent
crop
treated
data
from
National
Agricultural
Statistics
Service
(
NASS)
and
Doane
Marketing
Research
were
used.
The
chronic
exposure
to
fenbutatin­
oxide
for
the
overall
US
population
is
0.000618
mg/
kg
body
wt/
day,
which
is
1%
of
the
cRfD.
The
exposure
of
the
most
sensitive
subgroup,
children
1­
2
years,
is
0.002469
mg/
kg
body
wt/
day,
which
utilizes
5%
of
the
cRfD.
There
are
large
margins
of
safety
for
all
population
groups.

The
acute
dietary
exposure
assessment
of
currently
approved
uses
of
fenbutatin­
oxide
and
the
proposed
use
on
pistachios
is
well
within
acceptable
limts
for
all
sectors
of
the
population.
The
acute
module
of
the
Dietary
Exposure
Evaluation
Model
software
with
Food
Commodity
Intake
Database
(
DEEM­
FCIDTM
)
was
used
to
conduct
the
assessment
with
the
proposed
acute
reference
dose
(
aRfD)
of
0.20
mg/
kg
body
wt/
day.
The
analysis
used
a
probabilistic
assessment
with
residue
data
from
USDA
PDP
and
field
trials.
Percent
crop
treated
data
from
NASS
and
Doane
Marketing
Research
were
used.
The
acute
exposure
to
fenbutatin­
oxide
at
the
99.9
percentile
for
the
overall
US
population
is
0.011824
mg/
kg
body
wt/
day,
which
is
6%
of
the
proposed
aRfD.
The
exposure
of
the
most
sensitive
subgroup,
children
1­
2
years,
is
0.031390
mg/
kg
body
weight/
day,
which
utilizes
16%
of
the
aRfD.
There
are
large
margins
of
safety
for
all
population
groups.

ii.
Drinking
water.
The
FIRST
and
SCI­
GROW
models
were
used
to
estimate
conservative
concentrations
of
fenbutatin­
oxide
in
surface
and
ground
water,
respectively.
The
peak
(
12.7
ppb)
and
average
annual
(
2.3
ppb)
surface
water
values
from
FIRST
were
5
used
in
the
DEEM­
FCIDTM
software
to
determine
aggregate
exposure
to
food
and
water
on
an
acute
and
chronic
basis,
respectively,
since
they
were
higher
than
the
ground
water
values.
The
resultant
aggregate
exposure
values
were
not
significantly
greater
than
the
exposure
values
determined
on
the
basis
of
food
alone.
The
margins
of
safety
for
all
population
groups
remain
large.

2.
Non­
dietary
exposure.
In
the
2002
document
"
Overview
of
Fenbutatin­
Oxide
Risk
Assessment"
HED
concluded
that
non­
occupational
(
residential)
risks
are
not
of
concern
for
fenbutatin­
oxide.

D.
Cumulative
Effects
It
is
not
necessary
at
this
time
to
consider
cumulative
effects
because
there
is
no
indication
that
toxic
effects
of
fenbutatin­
oxide
have
a
common
mechanism
with
those
of
any
other
chemical
compounds.

E.
Safety
Determination
1.
U.
S.
population.
Based
on
the
risk
assessments
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
general
population
from
the
aggregate
exposure
to
fenbutatin­
oxide.
No
additional
safety
factors
are
warranted.

2.
Infants
and
children.
Based
on
the
risk
assessments
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
infants
and
children
from
the
aggregate
exposure
to
fenbutatin­
oxide.
No
additional
safety
factors
are
warranted.

F.
International
Tolerances
International
tolerances
are
not
applicable
for
fenbutatin­
oxide.