Document ID: EPA-HQ-OPP-2005-0297-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-07T04:00Z

FILE
NAME:
Fenarimol
Filbert
NOF.
wpt
(
6/
20/
05)

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

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
7/
1/
2004)

EPA
Registration
Division
contact:
Mary
Waller,
(
703)
308­
9354
INSTRUCTIONS:
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utilize
this
outline
in
preparing
tolerance
petition
documents.
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cases
where
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Remove"
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specific
to
your
action.

[
PP#
5E4573]

Summary
of
Petition
EPA
has
received
a
pesticide
petition
(
PP
5E4573)
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
by
establishing
a
tolerance
for
residues
of
fenarimol
[
alpha­(
2­
chlorophenyl)­
alpha­(
4­
chlorophenyl)­
5­
pyrimidinemethanol]
in
or
on
the
raw
agricultural
commodity
filbert
at
0.02
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
nature
of
the
residue
in
fenarimol­
treated
filbert
has
not
been
directly
determined.
Radioactive
metabolism
studies
with
apples
and
cherries
indicate
that
fenarimol
is
the
only
significant
component
of
the
residue
in
apples
and
cherries.
The
residue
of
concern
in
filbert
is
fenarimol.
2
2.
Analytical
methodAnalytical
methodology
used
for
filbert
is
a
slight
modification
of
the
basic
PAM
II
method
for
fenarimol
(
Method
R039).
Residues
are
extracted
with
methanol.
Aqueous
sodium
chloride
(
5%)
is
added
and
the
extract
is
partitioned
with
dichloromethane.
Residues
are
cleaned
up
on
a
Florisil
column
and
detected
by
GC/
ECD.
Recoveries
ranged
from
84%
to
97%
in
samples
fortified
with
fenarimol
at
0.02
ppm
to
0.2
ppm.
The
limit
of
detection
via
this
method
is
<
0.02
ppm.
3.
Magnitude
of
residues.
IR­
4
data
from
4
residue
trials
show
residues
of
fenarimol
were
<
0.02
ppm
in
composite
samples
of
filbert
treated
at
0.09
pound
of
active
ingredient
per
acre
(
lb
ai/
A)
and
composite
samples
treated
at
0.18
lb
ai/
A
or
two
times
the
proposed
maximum
application
rate.
These
data
indicate
that
fenarimol
residues
would
not
be
expected
to
accumulate
to
significant
levels
in
filbert.
Based
on
these
results
and
for
purposes
of
this
petition,
it
is
appropriate
to
base
the
magnitude
of
total
terminal
residues
and
proposed
tolerance
only
on
residues
of
the
parent
compound,
fenarimol.
B.
Toxicological
Profile
1.
Acute
toxicity.
The
acute
oral
lethal
dose
(
LD
50
)
in
the
rat
is
2,500
milligrams
per
kilogram
(
mg/
kg)
and
the
acute
dermal
LD
50
in
the
rabbit
is
>
2,000
mg/
kg.
The
inhalation
lethal
concentration
(
LC
50
)
in
the
rat
is
>
2.04
mg/
liter
of
air,
which
is
the
highest
obtainable
respirable
aerosol
concentration.
Fenarimol
produced
no
indications
of
dermal
irritation
in
rabbits
or
sensitization
in
the
guinea
pig.
End
use
formulations
of
fenarimol
have
similar
low
acute
toxicity
profiles.
2.
GenotoxictyFenarimol
tested
negative
in
several
assay
systems
for
gene
mutation,
structural
chromosome
aberration
and
other
genotoxic
effects.
In
a
micronucleus
test
in
the
mouse,
fenarimol
did
produce
a
significant
increase
in
the
percent
of
polychromatic
erythrocytes
with
micronucleus
at
24
hours
but
not
at
48
or
72
hours.
Moreover,
a
second
test
run
at
a
higher
dosage,
which
produced
significant
toxicity
including
death,
was
unequivocally
negative.

3.
Reproductive
and
developmental
toxicityA
developmental
toxicity
study
in
rabbits
was
negative
for
teratogenic
effects
at
all
doses
tested
(
0,
5,
10,
and
35
mg/
kg).
A
developmental
toxicity
study
in
rats
demonstrated
hydronephrosis
at
35
mg/
kg
(
doses
tested
were
0,5,
10,
and
35
mg/
kg).
A
second
developmental
toxicity
study
in
rats,
with
a
postpartum
evaluation,
again
demonstrated
hydronephrosis
at
35
mg/
kg.
Maternal
toxicity
(
decreased
body
weight)
was
also
observed
at
the
35
mg/
kg/
day
dose
level.
The
no
observed
effect
level
(
NOEL)
for
hydronephrosis
and
maternal
toxicity
is
13
mg/
kg.

4.
Subchronic
toxicity.

NA
­
Delete
5.
Chronic
toxicity.
A
2­
year
chronic
toxicity
and
carcinogenicity
study
in
rats
fed
diets
containing
0,
50,
130,
or
350
ppm
(
equivalent
to
2.5,
6.5,
or
17.5
mg/
kg/
day)
resulted
in
a
systemic
NOEL
of
130
ppm,
equivalent
to
6.5
mg/
kg/
day.
An
increase
in
fatty
liver
changes
was
observed
in
rats
fed
diets
containing
350
ppm.
There
were
no
carcinogenic
effects
observed
under
the
conditions
3
of
the
study.
A
second
2­
year
carcinogenicity
study
was
conducted
in
rats
fed
diets
containing
0,
12.5,
25,
or
50
ppm,
equivalent
to
0,
0.63,
1.25,
or
2.5
mg/
kg/
day.
There
was
no
apparent
effect
on
survival,
which
was
reduced
in
all
treatment
groups
due
to
chronic
respiratory
disease.
An
increased
incidence
of
fatty
changes
in
the
liver
was
observed
at
the
top
dose
level
of
50
ppm,
and
the
NOEL
was
established
as
25
ppm
(
1.2
mg/
kg/
day)
in
this
study.
A
third
2­
year
carcinogenicity
study
was
conducted
at
the
same
dose
levels
as
above.
The
incidence
of
liver
lesions
was
similar
in
the
treated
and
control
groups;
thus
the
NOEL
for
liver
effects
in
this
study
was
greater
than
50
ppm
(
2.5
mg/
kg/
day).
A
2­
year
feeding
study
was
conducted
in
mice
fed
diets
containing
concentrations
of
0,
50,
170,
or
600
ppm,
equivalent
to
0,
7,
24.3,
or
85.7
mg/
kg/
day.
The
600
ppm
dose
level
was
shown
to
increase
liver
weight.
There
was
no
increase
in
cancer,
and
no
toxicologically
significant
treatment
related
effects
were
observed
at
any
dose
level.
The
NOEL
was
determined
to
be
600
ppm
(
85.7
mg/
kg/
day).
In
a
1­
year
chronic
toxicity
study,
dogs
were
fed
diets
containing
0,
1.25,
12.5,
or
125
mg/
kg/
day.
The
NOEL
was
12.5
mg/
kg/
day
based
upon
an
increase
in
serum
alkaline
phosphatase,
increased
liver
weights,
an
increase
in
p­
nitroanisole
o­
demethylase
activity,
and
mild
hepatic
bile
stasis
at
the
high
dose
level
(
125
mg/
kg/
day).
Based
on
the
chronic
toxicity
data,
the
chronic
Reference
Dose
(
RfD)
for
fenarimol
is
established
at
0.0006
mg/
kg/
day.
The
RfD
for
fenarimol
is
based
on
a
2­
year
chronic
feeding
study
in
rats
with
a
NOEL
of
6.5
mg/
kg/
day
and
an
uncertainty
factor
of
1000.
For
short­
term
(<
35
day)
risk
assessments
to
females
13
­
50
years
old,
the
Agency
selected
a
LOAEL
of
35
mg/
kg/
day
based
upon
decreased
fertility
and
dystocia
in
rats
and
an
uncertainty
factor
of
3000.

6.
Animal
metabolism.
Metabolism
studies
conducted
in
rats
show
fenarimol
is
rapidly
metabolized
and
excreted.
Major
metabolic
pathways
were
oxidation
of
the
carbinol­
carbon
atom,
the
phenyl
rings
and
the
pyrimidine
ring.

7.
Metabolite
toxicology.
[
NA­
Remove]

8.
Endocrine
disruption.
In
a
3­
generation
reproduction
study
with
rats
and
in
subsequent
special
studies,
fenarimol
was
determined
to
be
a
weak
inhibitor
of
aromatase.
Rats
dosed
at
0,
12.5,
25
or
50
ppm
(
equivalent
to
0,
0.625,
1.25
or
2.5
mg/
kg/
day)
demonstrated
decreased
fertility
in
males
at
25
ppm
and
delayed
parturition
and
dystocia
in
females
at
25
and
50
ppm.
The
NOEL
for
reproductive
effects
was
12.5
ppm
(
0.625
mg/
kg/
day).
The
infertility
effect
in
males
is
considered
to
be
a
species­
specific
effect
mediated
by
the
inhibition
of
aromatase,
an
enzyme
which
catalyzes
the
conversion
of
testosterone
to
estradiol.
Estradiol
plays
an
essential
role
in
the
developmental
and
maintenance
of
sexual
behavior
in
rats.
Multigeneration
reproduction
studies
in
guinea
pigs
and
mice
were
negative
for
reproductive
effects
at
the
highest
dose
levels
tested,
35
mg/
kg/
day
and
20
mg/
kg/
day,
respectively.
A
NOEL
of
35
mg/
kg/
day
for
reproductive
effects
relevant
to
humans
was
established
based
on
the
NOEL
from
the
4
multigeneration
reproduction
study
in
guinea
pigs.
C.
Aggregate
Exposure
1.
Dietary
exposure
i.
Food
For
the
purposes
of
assessing
the
potential
dietary
exposure
from
use
on
filbert,
an
estimate
of
aggregate
exposure
is
determined
by
basing
the
TMRC
from
previously
established
tolerances
and
the
proposed
tolerance
on
filbert
for
fenarimol
at
0.02
parts
per
million
(
ppm)
and
assuming
the
100%
of
the
filbert
crop
has
a
residue
of
fenarimol
at
the
tolerance
level.
Exposure
of
humans
to
residues
could
also
result
if
such
residues
are
transferred
to
meat,
milk,
poultry
or
eggs.
Since
there
is
no
livestock
feed
commodity
associated
with
filbert,
there
is
no
reasonable
expectation
that
measurable
secondary
residues
of
fenarimol
will
occur
in
meat,
milk,
poultry
or
eggs
under
the
terms
of
the
proposed
use.
Other
established
tolerances
for
fenarimol
on
food
or
feed
crops
in
the
United
States
are
established
under
40
CFR
part
180.421.
The
use
of
a
tolerance
level
and
100%
of
crop
treated
clearly
results
in
an
overestimate
of
human
exposure
and
a
safety
determination
for
use
on
filbert
that
is
based
on
conservative
exposure
assessment.
ii.
Drinking
water.
Based
upon
the
available
environmental
studies
conducted
with
fenarimol
wherein
its
properties
show
little
potential
for
mobility
in
soil
and
extremely
rapid
photolysis
in
water,
there
is
no
anticipated
exposure
to
residues
of
fenarimol
in
drinking
water.
2.
Non­
dietary
exposure.
The
proposed
use
on
filbert
involves
application
of
fenarimol
to
a
crop
grown
in
an
agricultural
environment.
Thus,
the
potential
for
non­
occupational,
non­
dietary
exposure
to
the
general
population
is
not
expected
to
be
significant.
There
are
no
residential
uses
of
fenarimol.

D.
Cumulative
Effects
There
is
no
evidence
that
there
is
a
common
mechanism
of
toxicity
with
any
other
chemical
compound
or
that
potential
toxic
effects
of
fenarimol
would
be
cumulative
with
those
of
any
other
pesticide
chemical.
Thus
it
is
believed
that
it
is
appropriate
to
consider
only
the
potential
risks
of
fenarimol
in
its
exposure
assessment.
E.
Safety
Determination
1.
U.
S.
population.
It
is
concluded
that
aggregate
exposure
to
fenarimol
will
utilize
less
than
2%
of
the
chronic
RfD
for
the
U.
S.
general
population
and
less
than
14%
of
the
acute
RfD
for
females
13
­
50
at
the
99.9
percentile
level.
EPA
generally
has
no
concern
for
exposures
below
100%
of
the
RfD
because
the
RfD
represents
the
level
at
or
below
which
daily
aggregate
dietary
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
It
is
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
fenarimol
residues
in
or
on
filbert.
2.
Infants
and
children.
In
assessing
the
potential
for
additional
sensitivity
of
infants
and
children
to
residues
of
fenarimol,
data
from
developmental
toxicity
studies
in
rats
and
rabbits
and
a
multigeneration
reproduction
study
in
the
rat
are
considered.
The
developmental
toxicity
studies
are
5
designed
to
evaluate
adverse
effects
on
the
developing
organism
resulting
from
pesticide
exposure
during
prenatal
development
to
one
or
both
parents.
Reproduction
studies
provide
information
relating
to
effects
from
exposure
to
the
pesticide
on
the
reproductive
capability
and
potential
systemic
toxicity
of
mating
animals
and
on
various
parameters
associated
with
the
well­
being
of
offspring.
FFDCA
section
408
provides
that
EPA
may
apply
an
additional
safety
factor
for
infants
and
children
in
the
case
of
threshold
effects
to
account
for
pre­
and
post­
natal
toxicity
and
the
completeness
of
the
data
base.
Based
on
the
current
toxicological
data
requirements,
the
data
base
for
fenarimol
relative
to
pre­
and
post­
natal
effects
for
children
is
complete.
Further,
for
fenarimol,
the
NOEL
in
the
chronic
feeding
study
which
was
used
to
calculate
the
RID
(
6.5
mg/
kg/
day
used
by
EPA
or
1.2
mg/
kg/
day
used
by
The
World
Health
Organization)
is
already
lower
than
the
NOELs
from
the
developmental
studies
in
rats
and
rabbits.
Concerning
the
multi­
generation
reproduction
study,
the
effects
on
reproduction
are
considered
to
be
specific
effect
caused
by
aromatase
inhibition.
The
aromatase
enzyme
promotes
normal
sexual
behavior
in
rats
and
mice,
but
not
in
guinea
pigs
or
primates,
including
humans.
A
NOEL
of
35
mg/
kg/
day
for
reproductive
effects
relevant
to
humans
was
established
based
on
the
NOEL
from
the
multigeneration
reproduction
study
in
guinea
pigs.
In
addition,
a
NOEL
of
13
mg/
kg/
day
for
developmental
effects
was
established
based
upon
the
NOEL
from
the
teratology
study
in
rats.
Therefore,
it
is
concluded
that
an
additional
uncertainty
factor
is
not
needed
and
that
the
RfD
at
0.065
mg/
kg/
day
is
appropriate
for
assessing
risk
to
infants
and
children.
F.
International
Tolerances
There
is
no
Codex
or
national
maximum
residue
level
established
for
fenarimol
on
filbert.