Document ID: EPA-HQ-OPP-2005-0245-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-14T04:00Z

TITLE:

Notice
of
Filing
to
Support
the
Uses
of
Fenhexamid
(
Elevate
50
WDG,
TM­
402)
on
Ginseng,
Pomegranate,
Non­
bell
Pepper,
and
Cilantro
AUTHOR:
Doina
Bujor
REPORT
COMPLETION
DATE:
August
13,
2004
SUBMITTER:
TM­
402
(
KBR
2738)
Fungicide
Task
Force
Comprised
of
Arvesta
Corporation
and
Bayer
Corporation
EPA
Consortium
No.
69436
STATEMENT
OF
NO
DATA
CONFIDENTIALITY
CLAIMS
No
claims
of
confidentiality
are
made
for
any
information
in
this
study
on
the
basis
of
its
falling
within
the
scope
of
FIFRA
§
10(
d)(
1)(
A),
(
B),
or
(
C).

This
report
is
the
property
of
Arvesta
Corporation
Company
Agent:
_____________________________________
________________________

Doina
Bujor
Date
Project
Manager
Registrations
and
Regulatory
Affairs
Arvesta
Corporation
GOOD
LABORATORY
PRACTICE
STATEMENT
This
summary
is
not
subject
to
the
requirements
of
40
CFR
Part
160.

Submitter:
_____________________________________
________________________

Doina
Bujor
Date
Project
Manager
Registrations
and
Regulatory
Affairs
Arvesta
Corporation
For:

TM­
402
(
KBR
2738)
Fungicide
Task
Force
EPA
Registration
Division
contact:
[
insert
name
and
telephone
number
with
area
code]

[
3E6799]

Summary
of
Petitions
EPA
has
received
pesticide
petitions
(
xxxxx)
from
the
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
by
establishing
a
tolerance
for
residues
of
N­(
2,3­
dichloro­
4­
hydroxyphenyl)­
1­
methyl­
cyclohexane
carboxamide
in
or
on
the
following
raw
agricultural
commodity:
ginseng
at
0.3
parts
per
million
(
ppm),
pomegranate
at
3.0
parts
per
million
(
ppm),
non­
bell
pepper
at
0.02
parts
per
million
(
ppm)
and
cilantro
(
as
part
of
the
Crop
Sub­
group
4A)
at
30.0
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
fenhexamid
residues
in
plants
is
adequately
understood.
2.
Analytical
method.
An
adequate
method
for
purposes
of
enforcement
of
the
proposed
fenhexamid
tolerances
in
plant
commodities
is
available.
3.
Magnitude
of
Residues.
The
magnitude
of
residues
for
fenhexamid
on
the
proposed
commodity
is
adequately
understood.

B.
Toxicological
Profile
1.
Acute
toxicity.
The
acute
oral
toxicity
study
resulted
in
a
lethal
dose
(
LD
50)
of
>
5,000
mg/
kg
for
both
sexes.
The
acute
dermal
toxicity
in
rats
resulted
in
an
LD
50
of
>
5,000
mg/
kg
for
both
sexes.
The
acute
inhalation
was
investigated
in
two
studies
in
rats.
Inhalation
by
aerosol
at
the
maximum
technically
possible
concentration
of
0.322
milligram/
liter
(
mg/
L)
resulted
in
no
deaths
or
symptoms
(
LC
50
>
0.322
mg/
L).
A
dust
inhalation
study
resulted
in
an
LC
50
>
5.057
mg/
L.
Fenhexamid
was
not
irritating
to
the
skin
or
eyes
after
a
4­
hour
exposure
period.
The
Buehler
dermal
sensitization
study
in
guinea
pigs
indicated
that
fenhexamid
is
not
a
sensitizer.
Based
on
these
results
fenhexamid
technical
is
placed
in
toxicity
Category
IV
and
does
not
pose
any
acute
dietary
risks.
2.
Genotoxicty.
The
potential
for
genetic
toxicity
of
fenhexamid
was
evaluated
in
six
assays
including
two
Ames
tests,
an
HGPRT
forward
mutation
assay,
a
unscheduled
DNA
synthesis
(
UDS)
assay,
an
in
vitro
chromosomal
aberration
assay
in
Chinese
hamster
ovary
(
CHO)
cells,
and
a
micronucleus
test
in
mice.
The
compound
was
found
to
be
devoid
of
any
mutagenic
activity
in
each
of
these
assays;
including
those
tests
that
investigated
the
absence
or
presence
of
metabolic
activating
systems.
The
weight
of
evidence
indicates
that
fenhexamid
technical
does
not
pose
a
risk
of
mutagenicity
or
genotoxicity.

3.
Reproductive
and
developmental
toxicity.
i.
In
a
2­
generation
reproduction
study
(
one
mating
per
generation),
30
Sprague­
Dawley
rats
per
sex
per
dose
were
administered
0,
100,
500,
5000,
or
20000
ppm
of
fenhexamid
in
the
diet.
The
reproductive
toxicity
no
observed
adverse
effect
level
(
NOAEL)
was
20,000
ppm.
The
neonatal
NOAEL
was
500
ppm,
and
the
lowest
observed
adverse
effect
level
(
LOAEL)
was
5,000
ppm
based
on
decreased
pup
body
weight.
The
parental
toxicity
NOAEL
was
500
ppm
based
on
lower
adult
pre­
mating
body
weights
at
5,000
and
20,000
ppm,
lower
gestation
body
weights
at
20,000
ppm,
lower
lactation
body
weights
at
5,000
and
20,000
ppm,
and
statistically
significant
changes
in
clinical
chemistry
parameters,
terminal
body
weights,
and
organ
weights
at
5,000
and
20,000
ppm.
Based
on
this
study,
it
is
clear
that
the
only
toxic
effects
in
the
neonates
occurred
at
parentally
toxic
doses.
ii.
In
rats,
fenhexamid
was
administered
by
gavage
at
doses
of
0
or
1000
mg/
kg
for
gestation
days
6­
15.
No
maternal
toxicity,
embryotoxicity,
fetotoxicity,
or
teratogenic
effects
were
observed
at
the
limit
dose
of
1000
mg/
kg/
day.
Therefore,
the
NOAEL
for
maternal
and
developmental
toxicity
was
1000
mg/
kg/
day.
iii.
In
rabbits,
fenhexamid
was
administered
by
gavage
at
doses
of
0,100,
300,
and
1000
mg/
kg
for
gestation
days
6­
18.
Body
weight
gain
and
feed
consumption
of
the
dams
were
reduced
at
the
two
top
doses.
One
abortion
occurred
in
each
of
the
top
two
dose
groups
and
two
total
resorptions
occurred
in
the
top
dose
group.
The
placental
weights
were
slightly
decreased
at
300
mg/
kg/
day
and
above.
In
the
1000
mg/
kg/
day
group,
slightly
decreased
fetal
weights
and
a
slightly
retarded
skeletal
ossification
were
observed.
All
other
parameters
investigated
in
the
study
were
unaffected.
Therefore,
the
NOAELs
for
maternal
and
developmental
toxicity
were
100
mg/
kg/
day
in
this
study.
Based
on
the
2­
generation
reproduction
study
in
rats,
fenhexamid
is
not
considered
a
reproductive
toxicant
and
shows
no
evidence
of
endocrine
effects.
The
data
from
the
developmental
toxicity
studies
on
fenhexamid
show
no
evidence
of
a
potential
for
developmental
effects
(
malformations
or
variations)
at
doses
that
are
not
maternally
toxic.
The
NOAEL
for
both
maternal
and
developmental
toxicity
in
rats
was
1000
mg/
kg/
day,
and
for
rabbits
the
NOAEL
for
both
maternal
and
developmental
toxicity
was
100
mg/
kg/
day.

4.
Subchronic
toxicity.
i.
Fenhexamid
was
administered
in
the
diet
to
rats
for
13
weeks
at
doses
of
0,
2500,
5000,
10000,
and
20000
ppm.
The
NOAEL
was
5000
ppm
(
415
mg/
kg/
day
in
males
and
549
mg/
kg/
day
in
females).
Reversible
liver
effects
were
observed
at
10,000
ppm.
ii.
Fenhexamid
was
administered
in
the
diet
to
mice
for
approximately
14
weeks
at
doses
of
0,
100,
1000,
and
10000
ppm.
The
NOAEL
was
1000
ppm
(
266.6
mg/
kg/
day
in
males
and
453.9
mg/
kg/
day
in
females).
Increased
feed
and
water
consumption
and
kidney
and
liver
effects
were
observed
at
10,000
ppm.
iii.
Fenhexamid
was
administered
in
the
diet
to
beagle
dogs
for
13
weeks
at
doses
of
0,
1000,
7000,
and
50000
ppm.
The
NOAEL
was
1000
ppm
(
33.9
mg/
kg/
day
in
males
and
37.0
mg/
kg/
day
in
females).
Increased
Heinz
bodies
were
observed
at
7000
ppm.

5.
Chronic
toxicity.
i.
Fenhexamid
was
administered
in
the
feed
at
doses
of
0,
500,
3500,
or
25000
ppm
to
4
male
and
4
female
beagle
dogs
per
group
for
52
weeks.
A
systemic
NOAEL
of
500
ppm
(
an
average
dose
of
17.4
mg/
kg/
day
over
the
course
of
the
study)
was
observed
based
on
decreased
food
consumption
and
decreased
body
weight
gain
at
25000
ppm,
decreased
erythrocyte,
hemoglobin
and
hematocrit
values
at
25000
ppm,
increased
Heinz
bodies
at
3500
ppm
and
above,
and
a
dose­
dependent
increase
of
alkaline
phosphatase
at
3500
ppm
and
above.
There
were
no
treatment
related
effects
on
either
macroscopic
or
histologic
pathology.
ii.
A
combined
chronic/
oncogenicity
study
was
performed
in
Wistar
rats.
Fifty
animals/
sex/
dose
were
administered
doses
of
0,
500,
5000,
or
20000
ppm
for
24
months
in
the
feed.
A
further
10
animals/
sex/
group
received
the
same
doses
and
were
sacrificed
after
52
weeks.
The
doses
administered
relative
to
body
weight
were
0,
28,
292,
or
1280
mg/
kg/
day
for
males
and
0,
40,
415,
or
2067
mg/
kg/
day
for
females.
The
NOAEL
in
the
study
was
500
ppm
(
28
mg/
kg/
day
for
males
and
40
mg/
kg/
day
for
females)
based
on
body
weight
decreases
in
females
at
5000
ppm
and
above,
changes
in
biochemical
liver
parameters
in
the
absence
of
morphological
changes
in
both
sexes
at
5000
ppm
and
above,
and
caecal
mucosal
hyperplasia
evident
at
5000
ppm
and
above.
The
NOAEL
in
the
chronic
dog
study
was
17.4
mg/
kg/
day
based
on
body
weight,
hematology
and
clinical
chemistry
effects.
The
lowest
NOAEL
in
the
2­
year
rat
study
was
determined
to
be
28
mg/
kg/
day
based
on
body
weight,
clinical
chemistry
parameters
in
the
liver,
and
caecal
mucosal
hyperplasia.

6.
Animal
metabolism.
i.
A
lactating
goat
was
dosed
at
10
milligrams
(
mg)
14Cfenhexamid
per
kilograms/
bodyweight
on
3
consecutive
days
at
24­
hour
intervals.
Fenhexamid
was
rapidly
and
almost
completely
absorbed,
distributed
and
eliminated
(
24.9%
in
urine,
38.6%
in
feces,
and
0.03%
in
milk).
The
half­
life
of
biliary­
fecal
elimination
(
primary
pathway)
was
0.5
hours.
The
primary
residues
in
tissues
were
unreacted
fenhexamid,
its
glucuronide
derivative
and
the
4­
hydroxy
derivative.
ii.
Rats
were
administered
radiolabeled
fenhexamid
(
a
single
oral
low
dose
of
1
mg/
kg,
a
single
oral
high
dose
of
100
mg/
kg,
or
15
repeated
low
doses
of
1
mg/
kg/
day).
Radiolabeled
fenhexamid
was
rapidly
eliminated
and
tissue
residues
declined
rapidly.
After
48
hours
the
total
radioactivity
residue
in
the
body
excluding
the
GI
tract,
was
<
0.3%
of
the
administered
dose
in
all
dose
groups.
Excretion
was
rapid
and
almost
complete
with
feces
as
the
major
route
of
excretion.
Approximately
62­
84%
of
the
recovered
radioactivity
was
found
in
feces,
and
15­
36%
in
urine
within
48
hours
post­
dosing.
Metabolite
characterization
studies
showed
that
the
main
components
detected
in
excreta
were
the
unchanged
parent
compound
(
62­
75%)
and
the
glucuronic
acid
conjugate
of
the
parent
compound
(
4­
23%).
The
proposed
major
pathway
for
biotransformation
is
via
conjugation
of
the
aromatic
hydroxyl
group
with
glucuronic
acid.
Identification
of
radioactive
residues
ranged
from
88%
to
99%
and
was
independent
of
dose
and
sex.

7.
Metabolite
toxicology.
As
the
primary
residues
found
in
rats
and
goat
were
the
parent
compound
fenhexamid
and
its
glucuronic
acid
conjugate,
no
additional
metabolite
toxicology
studies
are
warranted.

8.
Endocrine
disruption.
Fenhexamid
has
no
endocrine­
modulation
characteristics
as
demonstrated
by
the
lack
of
endocrine
effects
in
developmental,
reproductive,
subchronic,
and
chronic
studies.

C.
Aggregate
Exposure
1.
Dietary
exposure.

i.
Food.
Dietary
exposure
to
fenhexamid
is
limited
to
the
established
tolerances
for
residues
of
fenhexamid
on
grapes
(
at
4.0
ppm),
raisins
(
at
6.0
ppm),
strawberries
(
at
3.0
ppm),
almond
nutmeat
(
at
0.02
ppm),
almond
hulls
(
at
2.0
ppm),
stonefruit
except
plum,
prune,
fresh,
post­
harvest
(
at
10.0
ppm),
plum,
prune,
dried
(
at
2.5
ppm);
plum,
prune,
fresh
(
at
1.5
ppm);
pear
(
at
15
ppm),
bushberries
(
at
5.0
ppm),
caneberries
(
at
20
ppm),
pistachios
(
at
0.02
ppm);
cucumber
(
at
2.0
ppm);
fruiting
vegetables,
except
non­
bell
peppers
(
at
2.0
ppm);
kiwi,
postharvest
(
at
15.0
ppm);
leafy
greens,
except
spinach
(
at
30.0
ppm);
the
previously
proposed
tolerances
for
pome
fruit
(
at
10
ppm);
and
apple
pomace
(
at
25
ppm);
and
the
proposed
tolerances
through
this
petition
for
ginseng
(
at
0.3
ppm),
pomegranate
(
3.0
ppm),
non­
bell
pepper
(
0.02
ppm)
and
cilantro
(
30.0
ppm).

ii.
Drinking
water.
Review
of
the
environmental
fate
data
indicates
that
fenhexamid
is
relatively
immobile
and
rapidly
degrades
in
the
soil
and
water.
Fenhexamid
dissipates
in
the
environment
via
several
processes.
Therefore,
a
significant
contribution
to
aggregate
risk
from
drinking
water
is
unlikely.
2.
Non­
dietary
exposure.
There
is
no
significant
potential
for
non­
occupational
exposure
to
the
general
public.
The
proposed
uses
are
limited
to
agricultural
and
horticultural
use.

D.
Cumulative
Effects
Consideration
of
a
common
mechanism
of
toxicity
is
not
appropriate
at
this
time
since
it
has
a
unique
mode
of
action.
Moreover,
there
is
no
significant
toxicity
observed
for
fenhexamid.
Even
at
toxicology
limit
doses,
only
minimal
toxicity
is
observed
for
fenhexamid.
Therefore,
only
the
potential
risks
of
fenhexamid
are
considered
in
the
exposure
assessment.

E.
Safety
Determination
1.
U.
S.
population.
The
percent
of
the
cPAD
utilized
by
all
current
uses
(
almonds,
bushberries,
caneberries,
cucumbers,
fruiting
vegetables
(
except
non­
bell
peppers),
grapes,
kiwifruits,
leafy
greens
(
except
spinach),
pears,
pistachios,
raisins,
stonefruits,
strawberries)
was
estimated
by
EPA
to
be
9.9%
(
Federal
Register,
September
26,
2003).
Arvesta
Corporation
estimated
the
chronic
dietary
exposure
to
fenhexamid
resulting
from
the
use
on
pome
fruit,
ginseng,
pomegranate,
non­
bell
pepper
(
greenhouse
transplant)
and
pomegranate
using
the
DEEM­
FCIDTM
software
version
as
had
the
US
EPA
and
assuming
100
%
of
the
crop
treated
and
residues
equal
to
the
MRL.
The
percent
cPAD
utilized
by
all
current
and
proposed
uses
was
estimated
to
be
18%.
Therefore,
the
estimates
of
dietary
exposure
indicate
adequate
safety
margins
for
the
overall
U.
S.
population.

2.
Infants
and
children.
The
percent
of
the
cPAD
utilized
by
all
current
uses
(
almonds,
bushberries,
caneberries,
cucumbers,
fruiting
vegetables
(
except
non­
bell
peppers),
grapes,
kiwifruits,
leafy
greens
(
except
spinach),
pears,
pistachios,
raisins,
stonefruits
and
strawberries)
was
estimated
by
EPA
to
be
19.6%
(
infants
<
1
year)
and
21.8%
(
children
1
to
2
years)
(
Federal
Register,
September
26,
2003).
Arvesta
Corporation
estimated
the
chronic
dietary
exposure
to
fenhexamid
resulting
from
the
use
on
pome
fruit,
as
above.
There
is
no
exposure
to
infants
and
children
from
usind
fenhexamid
on
ginseng,
pomegranate,
non­
bell
peppers
and
cilantro.
The
percent
cPAD
utilized
by
all
current
and
proposed
uses
was
estimated
to
be
61.5%
(
infants
<
1
year)
and
60.0%
(
children
1
 
6
years).
Therefore,
the
estimates
of
dietary
exposure
indicate
adequate
safety
margins
for
children.
In
assessing
the
potential
for
additional
sensitivity
of
infants
and
children
to
residues
of
fenhexamid,
the
available
developmental
toxicity
and
reproductive
toxicity
studies
and
the
potential
for
endocrine
modulation
by
fenhexamid
were
considered.
Developmental
toxicity
studies
in
two
species
indicate
that
fenhexamid
does
not
impose
additional
risks
to
developing
fetuses
and
is
not
a
teratogen.
The
2­
generation
reproduction
study
in
rats
demonstrated
that
there
were
no
adverse
effects
on
reproductive
performance,
fertility,
fecundity,
pup
survival,
or
pup
development
at
non­
maternally
toxic
levels.
Maternal
and
developmental
NOAELs
and
LOAELs
were
comparable,
indicating
no
increase
in
susceptibility
of
developing
organisms.
No
evidence
of
endocrine
effects
was
noted
in
any
study.
It
is
therefore
concluded
that
fenhexamid
poses
no
additional
risk
for
infants
and
children
and
no
additional
uncertainty
factor
is
warranted.

F.
International
Tolerances
International
tomato
tolerances
are
in
effect
in
France,
Germany,
Greece,
Italy,
Slovenia,
Spain,
Turkey
(
1
ppm)
and
other
EU
countries
(
2
ppm).
Kiwi
tolerances
are
as
follows:
Greece,
Italy
and
Slovenia
(
10
ppm).
Stonefruit
tolerances
already
exist
in
the
USA
for
pre­
harvest
applications
as
well
as
in
Canada
(
6
ppm),
Austria
(
cherry,
5
ppm;
plum,
2
ppm);
Belgium
(
cherry,
5
ppm);
Germany
and
Slovenia
(
cherry,
5
ppm;
peach
and
plum,
2
ppm),
Italy
(
cherry,
5
ppm;
apricot,
peach
and
plum,
2
ppm);
Japan
(
peach,
1
ppm),
Switzerland
(
cherry,
2
ppm)
and
the
UK
(
plum,
1
ppm)
and
other
EU
countries
(
peach
and
plum,
1
ppm;
cherry,
5
ppm).