Document ID: EPA-HQ-OPP-2006-0667-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-09-13T04:00Z

1
EPA
Registration
Division
contact:
Tom
Harris
 
(
703)
308­
9423
Barbara
Madden
 
(
703)
305­
6463
Bayer
CropScience
and
Interregional
Research
Project
No.
4
(
IR­
4)

PP#
5E6901
and
6F7039
EPA
has
received
a
pesticide
petition
(
PP#
5E6901)
from
Interregional
Research
Project
No.
4
(
IR­
4),
Rutgers,
The
State
University
of
New
Jersey,
500
College
Road
East,
Suite
201
W
Princeton,
NJ
08540,
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
180.607
by
amending
established
tolerances
for
combined
residues
of
spiromesifen
(
2­
oxo­
3­(
2,4,6­
trimethylphenyl)­
1­
oxaspiro[
4.4]
non­
3­
en­
4­
yl
3,3­
dimethylbutanoate)
and
its
enol
metabolite
(
4­
hydroxy­
3­
(
2,4,6­
trimethylphenyl)­
1­
oxaspiro[
4.4]
non­
3­
en­
2­
one),
calculated
as
the
parent
compound
equivalents
in
or
on
the
raw
agricultural
commodities
vegetable,
fruiting,
group
8
at
0.45
parts
per
million
(
ppm)
and
a
pesticide
petition
(
PP#
6F7039)
from
Bayer
CropScience,
2
T.
W.
Alexander
Drive,
Research
Triangle
Park,
NC
27709
by
establishing
tolerances
for
rotational
crops
for
the
inadvertent
or
indirect
combined
residues
of
spiromesifen
(
2­
oxo­
3­(
2,4,6­
trimethylphenyl)­
1­
oxaspiro[
4.4]
non­
3­
en­
4­
yl
3,3­
dimethylbutanoate),
its
enol
metabolite
(
4­
hydroxy­
3­(
2,4,6­
trimethylphenyl)­
1­
oxaspiro[
4.4]
non­
3­
en­
2­
one),
and
its
metabolites
containing
the
4­
hydroxymethyl
moiety
(
4­
hydroxy­
3­[
4­(
hydroxymethyl)­
2,6­
dimethylphenyl]­
1­
oxaspiro[
4.4]
non­
3­
en­
2­
one),
calculated
as
the
parent
compound
equivalents
in
or
on
the
raw
agricultural
commodities
oats,
forage;
oats,
fodder
and
oats,
straw
at
0.25
ppm,
and
in
or
on
oats,
grain
at
0.03
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
uptake
and
metabolism
of
spiromesifen
in
primary
crops
is
adequately
understood.
Radiolabeled
studies
have
been
conducted
in
various
plants
all
showing
similar
results.
The
residues
of
concern
are
spiromesifen
and
its
enol
metabolite.
The
uptake
and
metabolism
of
spiromesifen
in
rotational
crops
is
adequately
understood.
Studies
have
been
conducted
in
various
rotational
crops,
all
showing
similar
results.
The
residues
of
concern
are
spiromesifen,
the
enol
metabolite
(
cleavage
of
the
ester
bond
of
spiromesifen)
and
the
4­
hydroxmethyl
metabolite
(
hydroxylation
of
the
4­
methyl
group
of
the
enol)
and
its
conjugates.

2.
Analytical
method.
2
Adequate
analytical
methodology
using
LC/
MS/
MS
detection
is
available
for
enforcement
purposes.

3.
Magnitude
of
residues.
The
magnitude
of
the
residue
on
vegetable,
fruiting,
group
8,
has
already
been
established.
Based
on
an
adequate
database,
inadvertent
tolerances
exist
for
residue
in
wheat
and
barley
under
the
same
rotational
practices
as
are
being
proposed
for
oats.
It
is
proposed
that
the
data
from
wheat
and
barley
is
appropriate
data
to
use
in
establishing
tolerances
for
inadvertent
residues
in
the
raw
agricultural
commodities
from
oats.
The
data
supports
establishing
the
requested
tolerances.

B.
Toxicological
Profile
1.
Acute
toxicity.
Oral
and
dermal
LD50
values
were
>
2000
mg/
kg
bw.
Inhalation
LC50
values
were
>
4873
mg/
m3
air.
Spiromesifen
was
not
irritating
to
rabbit
skin
or
eyes
but
did
cause
skin
sensitization
in
the
Magnusson/
Kligman
maximization
test
in
guinea
pigs.
Acute
toxicity
studies
for
spiromesifen
support
an
overall
toxicity
Category
III.

2.
Genotoxicty.

Several
genotoxicity
tests
were
conducted
to
test
for
point­
mutagenic
activity,
chromosome
aberration
in
vitro
and
in
vivo,
and
for
DNA
repair.
All
tests
conducted
were
negative,
indicating
no
evidence
of
mutagenic
or
genotoxic
potential.

3.
Reproductive
and
developmental
toxicity.
An
oral
developmental
toxicity
study
in
rat
did
not
reveal
any
evidence
of
teratogenic
potential.
The
maternal
and
developmental
NOAELs
were
10
mg/
kg
bw/
day.
An
oral
developmental
toxicity
study
in
rabbits
demonstrated
a
maternal
NOAEL
of
5
mg/
kg
bw/
day,
a
developmental
NOAEL
of
35
mg/
kg
bw/
day
and
did
not
reveal
any
teratogenic
potential.
A
two­
generation
study
in
rats,
with
a
parental
systemic
toxicity
NOAEL
of
3.3
mg/
kg
bw/
day
for
males
and
4.6
mg/
kg
bw/
day
for
females
(
based
on
the
F1
generation),
did
not
reveal
evidence
of
a
primary
reproductive
toxicity
potential.
The
reproductive
NOAEL
was
36.6
mg/
kg
bw/
day
for
males
and
14.2
mg/
kg
bw/
day
in
females.

4.
Subchronic
toxicity.
A
subchronic
toxicity
feeding
study
with
rats
over
90
days
demonstrated
a
NOAEL
of
6.3
and
7.7
mg/
kg
bw/
day
for
males
and
females,
respectively,
based
on
reduced
body
weights,
effects
on
the
lipid
metabolism
(
decrease
of
triglycerides
and
cholesterol)
and
thyroid
effects
(
colloidal
alteration,
hypertrophy)
at
the
higher
dose
levels.
A
subchronic
feeding
study
in
mice
over
14
weeks
demonstrated
a
NOAEL
of
3.2
and
5.1
mg/
kg
bw/
day
based
on
effects
on
lipid
metabolism
(
decrease
of
cholesterol)
and
adrenal
effects
(
cytoplasmic
eosinophilia).
A
14­
week
feeding
study
in
dogs
demonstrated
a
NOAEL
of
9.2
and
9.3
mg/
kg
bw/
day
based
on
liver
effects
(
enzyme
induction,
increased
liver
weights
and
cytoplasmic
change)
and
thyroid
effects
(
decreased
T4).
3
5.
Chronic
toxicity.
A
12­
month
chronic
feeding
study
in
rats
demonstrated
a
NOAEL
of
6.5
and
19.3
mg/
kg
bw/
day
for
males
and
females,
respectively.
A
24­
month
oncogenicity
study
in
rats
demonstrated
a
NOAEL
of
6.1
and
19.5
mg/
kg
bw/
day
for
males
and
females,
respectively.
An
oncogenicity
study
in
the
mouse
revealed
a
NOAEL
of
3.3
and
3.8
mg/
kg
bw/
day
for
males
and
females,
respectively
based
on
macroscopic
and
microscopic
adrenal
effects.
There
was
no
indication
in
the
rat
or
mouse
for
an
oncogenic
effect
of
spiromesifen.
A
one­
year
feeding
study
with
dogs
demonstrated
a
NOAEL
of
11.5
and
10.8
mg/
kg
bw
day
for
males
and
females,
respectively
based
on
decreased
body
weights,
liver
effects
(
increased
liver
weight,
hepatocellular
cytoplasmic
change,
vacuoles)
adrenal
effects
(
increased
incidence
of
small
cell
types).

6.
Animal
metabolism.
Metabolism
and
pharmacokinetic
studies
in
the
rat
demonstrate
that
spiromesifen
residues
are
rapidly
absorbed,
metabolized
and
eliminated.
There
was
no
evidence
of
accumulation
of
residues
in
any
tissues
or
organs.
The
primary
metabolites
are
the
enol,
which
is
formed
by
cleavage
of
the
alkyl
ester
group,
and
the
4­
hydroxymethyl
metabolite.
However,
several
other
metabolites
are
also
formed.

7.
Metabolite
toxicology.
The
residues
of
concern
are
spiromesifen,
its
enol
metabolite
and
the
4­
hydroxymethyl
metabolite
of
the
enol,
which
are
products
of
metabolism
in
mammalian
systems,
as
well
as
in
the
environment.
Since
both
products
are
major
metabolites
following
the
oral
administration
of
spiromesifen
to
rats,
toxicology
data
for
these
metabolites
are
completely
supported
by
data
obtained
for
spiromesifen.

8.
Endocrine
disruption.
There
is
no
evidence
to
suggest
that
spiromesifen
has
any
primary
endocrine
disruptive
potential.
Reproductive
and
developmental
findings
provided
no
evidence
of
an
enhanced
sensitivity
of
the
young.
All
prospective
endocrine
and
endocrine­
related
changes
which
were
noted
were
considered
a
function
of
the
chemical's
biological
mode
of
action,
the
degree
of
exposure,
a
response
secondary
to
other
changes
(
e.
g,
enhanced
liver
metabolism),
an
aging
or
strain­
specific
phenomenon,
or
some
combination
of
these
factors.

C.
Aggregate
Exposure
1.
Dietary
exposure.
Acute
dietary
exposure
limits
for
all
populations,
including
infants
and
children,
are
not
necessary
because
an
endpoint
of
concern
attributable
to
a
single
exposure
(
dose)
was
not
identified
from
the
oral
toxicity
studies.
In
addition,
there
are
no
developmental
concerns
based
on
rat
and/
or
rabbit
developmental
toxicity
studies
.
For
the
chronic
dietary
analysis,
the
chronic
reference
dose
(
cRfD),
of
0.033
mg/
kg/
day
was
derived
from
a
parental
systemic
NOAEL
of
3.3
mg/
kg/
day
(
based
on
the
F1
generation)
in
a
2­
generation
reproduction
toxicity
study
in
rats
and
4
the
application
of
an
UF
of
100.
As
the
toxicology
database
is
adequate
for
Food
Quality
Protection
Act
(
FQPA)
purposes
and
there
are
no
concerns
or
residual
uncertainties
for
pre­/
post­
natal
toxicity,
an
FQPA
safety
factor
of
1
was
applied
to
the
chronic
toxicology
values,
resulting
in
a
chronic
population
adjusted
dose
(
cPAD)
of
0.033
mg/
kg/
day.
As
a
conservative
measure,
the
cPAD
values
were
used
for
all
population
sub­
groups
when
conducting
the
assessments.

i.
Food.
Assessments
were
conducted
to
evaluate
the
potential
risks
due
to
chronic
dietary
exposure
of
the
entire
U.
S.
population
and
selected
population
subgroups
to
residues
of
spiromesifen.
These
assessments
cover
the
proposed
use
of
spiromesifen
on
brassica
(
head
and
stem,
broccoli
and
cabbage;
leafy,
mustard
greens),
corn
(
field),
cotton,
cucurbits
(
cantaloupe,
cucumbers,
and
summer
squash),
fruiting
vegetables
(
peppers
and
tomatoes),
leafy
greens
(
head
and
leaf
lettuce
and
spinach),
potatoes,
strawberries,
and
the
rotational
crops
of
alfalfa,
sugarbeets,
barley,
wheat
and
oats.
These
assessments
also
included
EPA's
established
tolerances
for
fat,
meat
byproducts,
and
milk
for
cattle,
goat,
horse
and
sheep.
Chronic
exposure
for
the
most
exposed
subpopulation,
Children
1­
2
years,
equated
to
1.1%
of
the
cPAD.
The
exposure
to
the
U.
S.
population
equated
to
0.3%
of
the
cPAD.
These
Tier
3
chronic
dietary
exposure
estimates,
incorporating
Bayer
CropScience
estimates
of
percent
crop
treated,
are
well
below
EPA's
level
of
concern
for
the
overall
U.
S.
population
as
well
as
the
various
population
subgroups.

ii.
Drinking
water.
Amending
tolerances
in
vegetables,
fruiting
and
adding
rotational
crop
tolerances
will
not
alter
exposure
to
residues
of
spiromesifen
or
its
degradates
through
drinking
water.
A
drinking
water
assessment
for
spiromesifen
has
been
conducted
based
on
PRZM/
EXAMS(
Pesticide
Root
Zone
Model/
Exposure
Analysis
Modeling
System)
to
calculate
the
surface
water
estimated
drinking
water
concentrations
(
EDWCs)
and
on
the
Screening
Concentration
in
Ground
Water
(
SCI­
GROW)
model
to
calculate
corresponding
EDWCs.
All
EDWCs
values
are
much
lower
than
the
drinking
water
level
of
comparison
(
DWLOC)
values
of
326:
g/
L
(
children
1­
2
years
old)
determined
for
the
chronic
scenario.
Therefore,
the
EDWCs
do
not
exceed
the
Agency's
level
of
concern.

2.
Non­
dietary
exposure.
There
are
no
indoor
or
outdoor
residential
uses
associated
with
this
product.

D.
Cumulative
Effects
Spiromesifen
represents
a
new
class
of
chemistry,
ketoenoles.
There
are
no
known
registered
chemicals
within
this
class.
Bayer
will
submit
information,
if
necessary,
for
EPA
to
consider
concerning
potential
cumulative
effects
of
spiromesifen
consistent
with
the
schedule
established
by
EPA
at
62
Federal
Register
42020
(
Aug.
4,
1997)
and
other
EPA
publications
pursuant
to
the
Food
Quality
Protection
Act.
5
E.
Safety
Determination
1.
U.
S.
population.
Based
on
the
exposure
assessments
described
above
and
on
the
completeness
and
reliability
of
the
toxicity
data,
it
can
be
concluded
that
total
aggregate
exposure
to
spiromesifen
from
all
label
uses
will
utilize
less
than
2
percent
of
the
RfD
for
chronic
dietary
exposures
to
the
U.
S.
population
and
all
population
subgroups
and
that
EDWCs
do
not
exceed
the
Agency's
level
of
concern
based
on
conservative
DWLOC
calculations.
EPA
generally
has
no
concerns
for
exposures
below
100
percent
of
the
RfD,
because
the
RfD
represents
the
level
at
or
below
which
daily
aggregate
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
Thus,
it
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
from
aggregate
exposure
to
spiromesifen
residues.

2.
Infants
and
children.

The
Agency
has
previously
concluded
that
the
toxicology
database
is
adequate
for
Food
Quality
Protection
Act
(
FQPA)
purposes
and
that
there
are
no
concerns
or
residual
uncertainties
for
pre­/
post­
natal
toxicity.
Therefore,
a
FQPA
factor
of
1X
was
selected.
Available
studies
include
developmental
toxicity
studies
in
rats
and
rabbits,
a
two­
generation
reproductive
toxicity
study
in
rats,
and
acute
and
subchronic
neurotoxicity
studies
in
rats.
In
the
prenatal
developmental
toxicity
studies
in
rats
and
rabbits
and
in
the
two­
generation
reproduction
study
in
rats,
developmental
toxicity
to
the
offspring
occurred
at
equivalent
or
higher
doses
than
maternal
toxicity.
There
are
no
neurotoxicity
concerns
based
on
acute
and
subchronic
neurotoxicitystudies.
The
most
highly
exposed
population
subgroup
was
children
1­
2
years
old,
with
a
dietary
exposure
equal
to
1.1%
of
the
cPAD.
EDWCs
do
not
exceed
the
Agency's
level
of
concern
based
on
conservative
DWLOC
calculations.
EPA
generally
has
no
concerns
for
exposures
below
100
percent
of
the
RfD,
because
the
RfD
represents
the
level
at
or
below
which
daily
aggregate
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
Thus,
it
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate
exposure
to
spiromesifen
residues.

F.
International
Tolerances
Codex
maximum
residue
levels
(
MRLs)
are
not
yet
established
for
spiromesifen.