Document ID: EPA-HQ-OPP-2006-0333-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-07T04:00Z

FILE
NAME:
company.
wpt
(
1/
1/
2005)
(
xml)
Template
Number
P25
Kresoxim­
methyl:
Tolerance
on
cucurbits:
April,
2006
ATTENTION:

All
commodity
terms
must
comply
with
the
Food
and
Feed
Commodity
Vocabulary
database
(
http://
www.
epa.
gov/
pesticides/
foodfeed/).

All
text
in
blue
font
(
instructions
for
preparing
the
document),
should
be
removed
prior
to
sending
the
document
to
the
Federal
Register
Staff.
Instructional
text
and
prompts
in
green
font
should
also
be
removed.

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
1/
1/
2005)

EPA
Registration
Division
contact:
Barbara
Madden,
IR­
4
Liaison,
703­
305­
6463
INSTRUCTIONS:
Please
utilize
this
outline
in
preparing
tolerance
petition
documents.
In
cases
where
the
outline
element
does
not
apply
please
insert
"
NA­
Remove"
and
maintain
the
outline.
The
comment
notes
that
appear
on
the
left
margin
represent
hidden
typesetting
codes
designed
to
expedite
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processing
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Register
document.
Please
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not
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Simply
replace
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that
appear
in
italics
and
brackets,
i.
e.,
"[
insert
company
name],"
with
the
information
specific
to
your
action.

TEMPLATE:

[
Interregional
Research
Project
No.
4,
Rutgers,
the
State
University
of
New
Jersey]

[
PP
3E6594]
EPA
has
received
a
pesticide
petition
(
PP
3E6594)
from
[
Interregional
Research
Project
No.
4,
Rutgers,
the
State
University
of
New
Jersey
],
[
681
U.
S.
Highway
No.
1,
South
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.

Options
(
pick
one)

by
establishing
a
tolerance
for
combined
residues
of
[
kresoxim­
methyl
(
methyl
(
E)­
methoxyimino­
2­[
2­(
o­
toloxymethyl)
phenyl]
acetate)
and
the
glycoside
conjugates
of
its
metabolites
2­[
o­(
o­
hydroxymethylphenoxymethyl)
phenyl]­
2­
(
methoxyimino)
acetic
acid
and
2­[
o­(
p­
hydroxy­
o­
methylphenoxymethyl)
phenyl]­
2­
(
methoxyimino)
acetic
acid
]
in
or
on
the
raw
agricultural
commodity
[
cucurbits]
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.
[
Based
on
previous
actions
approved
by
EPA,
the
metabolism
in
plants
and
animals
is
understood]

2.
Analytical
method.
[
The
proposed
analytical
method
involves
extraction,
enzyme
hydrolysis,
partition,
clean­
up
and
detection
of
residues
by
HPLC/
UV
detection.]

3.
Magnitude
of
residues.
[
Eight
cucumber
residue
trials
were
conducted
in
seven
states.
Residues
of
kresoxim­
methyl
and
its
two
metabolites
were
measured
by
HPLC/
UV.
The
analytical
method
had
a
limit
of
detection
of
0.05
ppm
for
each
of
the
three
analytes.
Residues
ranged
from
<
0.15
ppm
to
0.22
ppm.

Six
melon
residue
trials
were
conducted
in
4
states.
Residues
of
kresoxim­
methyl
and
its
two
metabolites
were
measured
by
HPLC/
UV.
The
analytical
method
had
a
limit
of
detection
of
0.05
ppm
for
each
of
the
three
analytes.
Residue
of
parent
and
metabolites
ranged
<
0.15
to
0.26
ppm.

Five
squash
residue
trials
were
conducted
in
five
states.
Residues
of
kresoxim­
methyl
and
its
two
metabolites
were
measured
by
HPLC/
UV.
The
analytical
method
had
a
limit
of
detection
of
0.05
ppm
for
each
of
the
three
analytes.
Residues
of
parent
plus
metabolites
ranged
from
<
0.15
to
0.32
ppm.]

B.
Toxicological
Profile
A.
Acute/
Subchronic
Toxicology:
Based
on
available
acute
toxicity
data,
kresoximmethyl
does
not
pose
any
acute
toxicity
risks.
Acute
toxicology
studies
place
technical­
grade
kresoxim­
methyl
in
Toxicity
Category
IV
for
acute
oral
and
Category
III
for
acute
dermal
and
acute
inhalation
toxicity.
The
material
is
not
an
eye
irritant,
a
primary
dermal
irritant
or
a
skin
sensitizer.
Additionally,
in
acute
and
subchronic
neurotoxicity
studies,
kresoxim­
methyl
did
not
show
any
signs
of
neurotoxicity
at
dose
levels
up
to
and
including
2000
and
1267
mg/
kg/
day,
respectively.

B.
Chronic
Toxicology:
Based
on
review
of
the
available
data,
BASF
believes
the
Reference
Dose
(
RfD)
for
kresoxim­
methyl
will
be
based
on
the
2­
year
feeding
study
in
rats
with
a
threshold
NOEL
of
36
mg/
kg/
day
in
males
and
47
mg/
kg/
day
in
females.
Using
an
uncertainty
factor
of
100,
the
RfD
is
calculated
to
be
0.36
mg/
kg/
day.
The
following
are
summaries
of
the
pertinent
toxicity
data
supporting
kresoxim­
methyl
tolerances:

i.
Chronic
Feeding
­
Nonrodent
A
12
month
feeding
study
in
the
dog
with
doses
of
29,
142,
and
738
mg/
kg/
day
was
performed
with
a
NOAEL
of
138
mg/
kg/
day
for
males
and
761
mg/
kg/
day
for
females.
The
only
effect
observed
was
reduced
body
weights
in
male
dogs
at
the
highest
dose
tested.

ii.
Chronic
Feeding/
Oncogenicity
­
Rats
A
24
month
chronic
feeding/
oncogenicity
study
in
the
rat
with
doses
at
9,
36,
370,
and
746
mg/
kg/
day
for
males
and
12,
48,
503,
and
985
mg/
kg/
day
for
females
was
performed
with
a
NOAEL
of
36
mg/
kg/
day
in
males
and
47
mg/
kg/
day
in
females.
Reduced
body
weight
changes
were
observed
in
male
and
female
rats
in
the
highest
two
dose
groups.
Histopathologically,
changes
in
the
liver
were
observed
in
either
or
both
of
the
highest
two
dose
groups
for
male
and
female
rats.
These
changes
consisted
of
increased
liver
weight,
increased
hepatocellular
hypertrophy,
increased
incidence
and
severity
of
eosinophilic
foci
of
hepatocellular
alterations,
and
increased
incidence
and
degree
of
severity
of
bile
duct
proliferation.
Associated
with
the
liver,
an
increase
of
serum
 ­
glutamyltransferase
values
was
observed.
A
statistically
significant
increase
in
liver
tumors
was
observed
in
both
male
and
female
animals
at
370
mg/
kg/
day
and
985
mg/
kg/
day,
respectively.
With
regard
to
the
liver
tumors,
kresoxim­
methyl
is
not
a
genotoxic
agent
and
is
not
an
initiator
of
the
carcinogenic
process.
The
increased
incidence
of
liver
tumors
in
rats
is
the
result
of
liver
tumor
promoting
properties
of
the
test
substance.
Based
on
the
available
data,
the
mechanism
of
promotion
is
the
induction
of
liver
cell
proliferation
of
the
test
substance.
The
data
available
also
indicate
that
dose
levels
which
do
not
induce
liver
toxicity
neither
induce
cell
proliferation
nor
enhance
the
carcinogenic
process.
Therefore,
a
threshold
for
liver
carcinogenicity
in
rats
can
be
defined
to
be
 
40
mg/
kg/
day.

iii.
Oncogenicity
­
Mice
A
mouse
oncogenicity
study
using
dosage
levels
at
60,
304,
and
1305
mg/
kg/
day
for
males
and
81,
410,
and
1662
mg/
kg/
day
for
females
was
performed
with
a
NOAEL
of
304
mg/
kg/
day
for
males
and
81
mg/
kg/
day
for
females,
with
no
evidence
of
oncogenicity.
Body
weight
changes
were
observed
in
both
male
and
female
mice
in
the
highest
dose
group
and
only
in
the
females
in
the
410
mg/
kg/
day
group.
Histopathology
was
limited
only
to
the
highest
dose
group
and
consisted
of
increased
incidence
renal
papillary
necrosis
for
both
male
and
female
mice
and
increased
incidence
and
higher
degree
of
severity
of
liver
amyloidosis
in
females
only.

iv.
Two­
Generation
Reproduction
­
Rats
A
two­
generation
reproductive
study
in
the
rat
with
doses
at
5,
100,
407,
and
1625
mg/
kg/
day
was
performed
with
a
NOAEL
of
100
mg/
kg/
day
for
parental
and
developmental
toxicity,
and
a
NOAEL
of
1625
mg/
kg/
day
for
reproduction
toxicity.
Decreased
body
weight
was
seen
in
both
the
pups
and
parents.
Reduced
serum
 ­
glutamyltransferase
was
seen
in
F0
males
and
both
sexes
of
the
F1
generation,
and
reduced
kidney
weights
were
seen
in
the
F1
generation
at
the
407
and
1625
mg/
kg/
day
dose
levels.
Decreased
fat
storage
was
observed
in
F0
and
F1
male
livers
at
the
407
and
1625
mg/
kg/
day
dose
levels.

C.
Subchronic
Toxicology:

i.
Teratology
­
Rat
A
teratogenicity
study
in
the
rat
with
doses
at
100,
400,
and
1000
mg/
kg/
day
by
gavage
was
performed
with
a
maternal
NOAEL
of
1000
mg/
kg/
day
and
fetal
NOAEL
of
1000
mg/
kg/
day.

ii.
Teratology
­
Rabbits
A
teratogenicity
study
in
the
rabbit
with
doses
at
100,
400,
and
1000
mg/
kg/
day
by
gavage
was
performed
with
a
maternal
NOAEL
of
1000
mg/
kg/
day
and
fetal
NOAEL
of
1000
mg/
kg/
day.

D.
Mutagenicity
Modified
Ames
Test
(
2
Studies;
point
mutation):
Negative;
In
Vitro
CHO/
HGPRT
(
point
mutation):
Negative;
In
Vitro
Cytogenetics
Chromosome
Damage
Human
Lymphocytes:
Negative;
In
Vivo
Chromosome
Mouse
Micronucleus:
Negative;
In
Vitro
DNA
Damage
&
Repair
Rat
Hepatocytes:
Negative;
UDS
ex
Vivo
DNA
Damage
&
Repair
Wistar
Rats
(
Single
Oral
Dose):
Negative;
UDS
ex
Vivo
DNA
Damage
&
Repair
Wistar
Rats
(
3­
Week
Feeding):
Negative.

3.
Threshold
effects
Based
on
review
of
the
available
data,
BASF
believes
the
Reference
Dose
(
RfD)
for
kresoximmethyl
will
be
based
on
the
2­
year
feeding
study
in
rats
with
a
threshold
NOEL
of
36
mg/
kg/
day
in
males
and
47
mg/
kg/
day
in
females.
Using
an
uncertainty
factor
of
100,
the
RfD
is
calculated
to
be
0.36
mg/
kg/
day.

4.
Non­
Threshold
effects
Carcinogenicity
Kresoxim­
methyl
was
shown
to
be
non­
carcinogenic
in
mice.
In
the
rat
carcinogenicity
study,
a
statistically
significant
increase
in
liver
tumors
was
observed
in
both
male
and
female
animals
at
370
and
746
mg/
kg/
day
and
503
and
985
mg/
kg/
day
dose
levels,
respectively.
Kresoxim­
methyl
is
not
a
genotoxic
agent
and
mechanistic
studies
have
shown
that
the
increased
incidence
of
liver
tumors
in
rats
is
the
result
of
liver
tumor
promoting
properties
of
the
test
substance.
Kresoxim
methyl
is
not
an
initiator
of
the
carcinogenic
process.
Based
on
the
available
data,
the
mechanism
of
promotion
is
the
induction
of
liver
cell
proliferation
of
the
test
substance.
The
data
available
also
indicate
that
dose
levels
which
do
not
induce
liver
toxicity
neither
induce
cell
proliferation
nor
enhance
the
carcinogenic
process.
Therefore,
a
threshold
for
liver
carcinogenicity
in
rats
can
be
defined
to
be
 
40
mg/
kg/
day.

Based
on
the
results
of
the
carcinogenicity
study
in
mice,
the
results
of
genotoxicity
testing,
the
results
of
the
24
month
chronic
feeding/
oncogenicity
study
in
rats;
and
auxiliary
mechanistic
data
showing
that
kresoxim­
methyl
is
not
an
initiator
of
the
carcinogenic
process,
BASF
believes
that
the
threshold
approach
to
regulating
kresoxim­
methyl
is
appropriate.

C.
Aggregate
Exposure
1.
Dietary
exposure.
Exposure
assessments
were
conducted
to
evaluate
the
potential
risk
due
to
chronic
dietary
exposure
of
the
U.
S.
population
to
residues
of
kresoximmethyl
This
fungicide
and
its
three
metabolites
as
follows:
(
E)­
2­[
2­(
2­
methylphenoxy)
methyl]­
phenyl­
2­(
methoxyimido)
acetic
acid;
(
E)­
2­[
2­(
2­
hydroxymethylphenoxy)
methyl]­
phenyl­
2­
(
methoxyimido)
acetic
acid
(
free
and
glucose
conjugated),
and
(
E)­
2­[
2­(
4­
hydroxy­
2­
methylphenoxy)­
methyl]
phenyl­
2­(
methoxyimido)
acetic
acid
(
free
and
glucose
conjugated)
in
or
on
raw
agricultural
commodities
and
meat
byproducts
were
expressed
as
the
parent
compound.
The
tolerance
values
previously
established
for
apple
pomace,
pome
fruit,
grapes,
raisins,
pecans,
and
meat
byproducts
(
cattle,
goat,
and
sheep)
are
listed
in
the
U.
S.
EPA
final
rule
published
in
the
U.
S.
40
CFR
§
180.554.
This
analysis
included
all
current
registered
uses
and
cucurbit
vegetables
(
crop
group
9).

i.
Food.
Acute
Dietary
Exposure
Assessment
Toxicology
studies
have
shown
that
kresoxim­
methyl
poses
no
acute
dietary
risk.
Therefore
an
acute
dietary
exposure
assessment
was
not
required.

Chronic
Dietary
Exposure
Assessment
The
chronic
dietary
exposure
estimates
were
based
on
tolerance
values,
default
process
factors,
and
%
crop
treated
values
based
on
market
share
for
the
current
registered
uses
and
anticipated
residues
and
100%
crop
treated
values
for
cucurbit
vegetables
(
crop
group
9).
The
consumption
data
was
from
the
USDA
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII
1994
­
1996,
1998)
and
the
EPA
Food
Commodity
Ingredient
Database
(
FCID)
using
Exponent's
Dietary
Exposure
Evaluation
Module
(
DEEM­
FCID
 
)
software.
The
chronic
population
adjusted
dose
(
cPAD)
used
for
U.
S.
population
and
all
sub­
populations
is
0.36
mg/
kg
bw/
day.
Considering
the
exposure
assumptions
discussed
above,
kresoxim­
methyl
chronic
dietary
exposure
from
food
for
the
U.
S.
population
and
all
subpopulations
was
less
than
0.11%
of
the
cPAD.
The
results
of
the
chronic
dietary
assessment
are
presented
in
Table
1.

Table
1.
Results
for
Kresoxim­
methyl
Chronic
Dietary
Exposure
Analysis
Considering
all
Current
and
Proposed
Tolerances
for
Cucurbit
Vegetables
using
DEEM­
FCID
Population
Exposure
Estimate
%
cPAD
Subgroups
(
mg/
kg
b.
w./
day)

U.
S.
Population
0.000079
0.02
All
Infants
(<
1
year
old)
0.000122
0.03
Children
(
1­
2
years
old)
0.000371
0.10
Children
(
3­
5
years
old)
0.000246
0.07
Children
(
6­
12
years
old)
0.000098
0.03
Youth
(
13­
19
years
old)
0.000052
0.01
Females
(
13­
49
years
old)
0.000051
0.01
Adults
(
20­
49
years
old)
0.000048
0.01
Adults
(
50+
years
old)
0.000067
0.02
cPAD
=
chronic
population
adjusted
dose
*
Exposure
estimates
based
on
tolerance
values,
default
processing
factor,
and
considering
%
crop
treated
values
based
on
market
share
for
current
registered
uses
and
anticipated
residues
and
100%
CT
for
crop
group
9
The
results
of
the
analysis
show
that
for
all
sub­
populations,
the
exposures
are
well
below
a
level
of
concern
(<
100%
cPAD).
Additional
refinements
in
the
chronic
dietary
risk
assessment
(
i.
e.
utilizing
anticipated
residue
values
for
registered
commodities,
process
factors,
%
CT
for
crop
group
9)
would
further
reduce
the
estimated
exposure
values.

ii.
Drinking
water.
Based
on
values
listed
in
the
Federal
Register
(
Volume
64,
Number
111,
June
10,
1999)
the
peak
EDWCs
of
kresoxim­
methyl
for
acute
and
chronic
exposure
are
estimated
to
be
5
ug/
L
(
ppb)
in
surface
water
and
4.1
ug/
L
in
shallow
ground
water.

Drinking
water
contributions
were
assessed
based
on
the
maximum
estimated
kresoxim­
methyl
water
concentrations
(
5
ug/
L),
and
water
consumption
and
body
weights
reported
in
CSFII,
using
DEEM­
FCID
software.
The
chronic
estimated
water
exposure
values
are
summarized
in
Table
2.
Minimal
exposure
of
kresoxim­
methyl
occurs
through
drinking
water
with
<
0.1%
the
cPAD
for
all
subpopulations.
Toxicology
studies
have
shown
that
kresoxim­
methyl
poses
no
acute
dietary
risk.
Therefore
an
acute
dietary
exposure
assessment
for
drinking
water
was
not
required.

Table
2.
Results
for
Kresoxim­
methyl
Chronic
Water
Exposure
Analysis
Considering
the
Maximum
Estimated
Chronic
Drinking
Water
Concentration
using
DEEM­
FCID
Population
Water
Exposure
Estimate
%
cPAD
Subgroups
(
mg/
kg
b.
w./
day)

U.
S.
Population
0.000097
0.03
All
Infants
(<
1
year
old)
0.00025
0.07
Children
(
1­
2
years
old)
0.000145
0.04
Children
(
3­
5
years
old)
0.00014
0.04
Children
(
6­
12
years
old)
0.000095
0.03
Youth
(
13­
19
years
old)
0.000073
0.02
Females
(
13­
49
years
old)
0.000091
0.03
Adults
(
20­
49
years
old)
0.000091
0.03
Adults
(
50+
years
old)
0.000095
0.03
cPAD
=
chronic
population
adjusted
dose
Based
on
estimated
chronic
surface
water
value
of
5
ug/
L
Acute
Aggregate
Exposure
and
Risk
(
Food
and
water)

Toxicology
studies
have
shown
that
kresoxim­
methyl
poses
no
acute
dietary
risk.
Therefore
an
acute
aggregate
exposure
assessment
was
not
required.

Short­
and
Intermediate
Term
Aggregate
Exposure
and
Risk
(
food,
water,
and
residential)
Kresoxim­
methyl
is
not
registered
in
the
United
States
for
residential
use.
Toxicology
studies
have
shown
that
kresoxim­
methyl
poses
no
acute
dietary
risk.
Therefore
a
short
and
intermediate
term
aggregate
exposure
and
risk
assessment
was
not
required
Chronic
Aggregate
Exposure
and
Risk
(
food
and
water)
The
aggregate
chronic
risk
includes
residues
of
kresoxim­
methyl
from
food
and
water
(
Table
3).
Exposures
from
residential
uses
are
not
included
in
the
chronic
aggregate
assessment.
The
results
demonstrate
there
are
no
safety
concerns
for
any
subpopulation
based
on
established
and
new
uses,
and
that
the
results
clearly
meet
the
FQPA
standard
of
reasonable
certainty
of
no
harm.
Table
3.
Estimated
Chronic
Aggregate
Exposure
and
Risk
of
Kresoxim­
methyl
Population
Subgroup
cPAD
(
mg/
kg/
day)
Food
Exposure
(
mg/
kg/
day)
Water
Exposure
(
mg/
kg/
day)
Total
Exposure
(
mg/
kg/
day)
%
cPAD
U.
S.
Population
0.36
0.000079
0.000097
0.000176
0.05
All
Infants
(<
1
yr
old)
0.36
0.000122
0.00025
0.000372
0.10
Children
1­
2
years
0.36
0.000371
0.000145
0.000516
0.14
Children
3­
5
years
0.36
0.000246
0.00014
0.000386
0.11
Children
6
 
12
years
0.36
0.000098
0.000095
0.000193
0.05
Youth
13­
19
years
0.36
0.000052
0.000073
0.000125
0.03
Females
13­
49
years
0.36
0.000051
0.000091
0.000139
0.04
Adults
20­
49
years
0.36
0.000048
0.000091
0.000162
0.05
Adults
+
50
0.36
0.000067
0.000095
0.000142
0.04
Aggregate
Cancer
Risk
for
U.
S.
Population
The
aggregate
cancer
risk
(
considering
food
and
drinking
water)
was
calculated
for
kresoximmethyl
and
is
shown
in
Table
4.
The
results
demonstrate
there
are
no
safety
concerns
for
US
population
based
on
established
and
new
uses,
and
that
the
results
clearly
meet
the
FQPA
standard
of
reasonable
certainty
of
no
harm.

Table
4.
Aggregate
Cancer
Risk
of
Kresoxim­
methyl
to
the
U.
S.
Population
Population
*
q1
Food
Exposure
(
mg/
kg/
day)
Water
Exposure
(
mg/
kg/
day)
Total
Exposure
(
mg/
kg/
day)
Cum
Risk
(
Q*
x
exp)

U.
S.
Population
0.00290
0.000079
0.000097
0.000176
5.10E­
07
2.
Non­
dietary
exposure.
Kresoxim­
methyl
is
not
registered
in
the
United
States
for
residential
use.
Therefore
a
nondietary
exposure
and
risk
assessment
was
not
required
D.
Cumulative
Effects
The
EPA
is
currently
developing
methodology
to
perform
cumulative
risk
assessments.
At
this
time,
there
is
no
available
data
to
determine
whether
kresoxim­
methyl
has
a
common
mechanism
of
toxicity
with
other
substances
or
how
to
include
this
pesticide
in
a
cumulative
risk
assessment.

E.
Safety
Determination
1.
U.
S.
population.
Based
on
this
risk
assessment,
BASF
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
general
population
from
the
aggregate
exposure
to
kresoxim­
methyl
residues.

2.
Infants
and
children.
Based
on
this
risk
assessment,
BASF
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
or
children
from
the
aggregate
exposure
to
kresoxim­
methyl
residues.

F.
International
Tolerances
Codex
levels
(
MRL's)
have
been
established
for
residues
of
kresoxim­
methyl
on
cucurbits
at
0.5
ppm.