TXR
NO.
0051051
August
13,
2002
MEMORANDUM
SUBJECT:
FENARIMOL
­
2nd
Report
of
the
FQPA
Safety
Factor
Committee.

NOTE:
THIS
REPORT
REPLACES
THE
PREVIOUS
REPORT
OF
THE
FQPA
SAFETY
FACTOR
COMMITTEE
DATED
SEPT.
28,
2001
(
HED
DOC.
NO.
014688).

FROM:
Brenda
Tarplee,
Executive
Secretary
FQPA
Safety
Factor
Committee
Health
Effects
Division
(
7509C)

THROUGH:
Ed
Zager,
Chairman
FQPA
Safety
Factor
Committee
Health
Effects
Division
(
7509C)

TO:
Barry
O'Keefe,
Risk
Assessor
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

PC
Code:
206600
The
Health
Effects
Division
(
HED)
FQPA
Safety
Factor
Committee
(
SFC)
met
on
July
29,
2002
to
evaluate
the
hazard
and
exposure
data
for
Fenarimol
with
regard
to
making
a
decision
on
the
additional
safety
factor
for
the
protection
of
infants
and
children.
The
SFC
concluded
that,
based
on
reliable
data,
an
additional
safety
factor
of
3X
is
necessary
to
protect
the
safety
of
infants
and
children
in
assessing
Fenarimol
exposures
and
risks.
This
report
replaces
the
previous
report
of
the
FQPA
Safety
Factor
Committee
dated
Sept.
28,
2001
(
HED
Doc.
No.
014688
).
2
I.
HAZARD
ASSESSMENT
(
Extracted
from
the
THIRD
Report
of
the
Hazard
Identification
Assessment
Review
Committee
for
Fenarimol
dated
July
29,
2002;
HED
DOC
No.
0050977
)

1.
Adequacy
of
the
Toxicology
Database
The
HED
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
concluded
that
the
Fenarimol
toxicology
database
is
complete
with
respect
to
FQPA
with
the
exception
of
a
special
developmental
toxicity
study
to
assess
for
potential
hormonal
effects.

At
the
July
10,
2001
HIARC
meeting,
it
was
determined
that
a
developmental
neurotoxicity
(
DNT)
study
in
rat
that
incorporated
a
special
provision
to
assess
for
hormonal
effects
is
required
(
TXR.
No.
014662).
The
Registrant
responded
with
a
request
"
that
the
Agency
rescind
the
requirement
for
a
developmental
neurotoxicity
study
of
unproven
design"
since
the
DNT
is
not
designed
to
investigate
the
endpoints
mentioned
(
mating
behavior
in
male
and
difficult
labor
in
females)
(
Letter
from
Gowan,
dated
April
10,
2002).
On
May
23,
2002,
the
HIARC
concurred
with
the
Registrant's
rationale
and
rescinded
their
previous
request
for
the
DNT.
The
HIARC,
instead
is
requesting
a
special
developmental
toxicity
study
that
assesses
the
hormonal
effects
in
rats
especially
related
to
inhibition
of
aromatase.
The
protocol
for
this
study
should
be
submitted
to
HED
for
review
prior
to
initiating
the
study.
The
HIARC
concluded
that
a
3X
database
uncertainty
factor
(
UF
DB)
is
needed
in
the
absence
of
this
study.
The
committee
considered
3X
(
as
opposed
to10X)
to
be
adequate
since
there
is
a
2­
fold
difference
between
the
NOAEL/
LOAEL
for
the
most
sensitive
indicator
and
it
is
considered
unlikely
that
the
results
of
the
special
developmental
toxicity
study
(
tested
at
comparable
doses
of
the
twogeneration
reproduction
study)
will
demonstrate
a
NOAEL
three
times
lower
than
the
current
NOAEL
of
0.6
mg/
kg/
day
from
the
two­
generation
reproduction
study
used
for
establishing
the
chronic
RfD
(
HED
DOC
No.
0050977).

2.
Determination
of
Susceptibility
The
data
provided
no
indication
of
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
Fenarimol.

3.
Degree
of
Concern
and
Residual
Uncertainties
The
HIARC
concluded
that
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
in
any
of
the
available
studies
with
Fenarimol.

4.
Other
Studies
There
are
several
studies
conducted
as
both
non­
guideline
studies
by
the
registrant
as
well
as
reports
in
the
published
literature
that
investigate
the
mechanism
of
the
reduced
fertility
3
in
males
and
dystocia
in
females
caused
by
Fenarimol.
These
studies
indicate
that
Fenarimol
inhibits
aromatase
the
enzyme
that
converts
androgens
to
estrogens.
Thus,
Fenarimol
is
regarded
as
affecting
hormonal
balance
in
mammals.
Fenarimol
also
acts
as
a
fungicide
by
adversely
affecting
the
formation
of
the
fungal
sterol,
ergosterol.
The
HED
Mechanism
of
Toxicity
Assessment
Review
Committee
concluded
that
inhibition
of
aromatase
activity
and
its
expression
(
i.
e.
reduced
fertility
and
dystocia
in
rats)
should
be
regarded
as
endpoints
for
human
risk
assessment
(
June
21,
2001).

II.
EXPOSURE
ASSESSMENT
1.
Dietary
(
Food)
Exposure
Considerations
(
Correspondence:
S.
Knizner
to
B.
Tarplee
dated
08/
13/
01)
No
changes
since
the
last
review
per
Fenarimol
Team.

Fenarimol
is
a
fungicide
registered
for
use
on
many
foods
considered
to
be
highly
consumed
by
infants
and
children
including
apples,
bananas,
and
pears.
The
HED
Metabolism
Assessment
Review
Committee
(
MARC)
concluded
that
the
tolerance
expression
for
Fenarimol
should
be
expressed
as
Fenarimol
per
se.
For
risk
assessment
purposes,
residues
of
parent
and
two
metabolites
[
alpha­(
2­
chlorophenyl)­
alpha­(
4­
chlorophenyl
1,4­
dihydro­
5­
pyrimidinemethanol
and
5­[(
2­
chlorophenyl­(
4­
chlorophenyl)
methyl
3,4­
dihydro­
4­
pyrimidinol
measured
as
the
total
of
5­[(
2­
chlorophenyl)­(
4­
chlorophenyl
methyl]
pyrimidine]
should
be
included
for
bananas
and
grapes.
Current
tolerances
are
established
at
levels
ranging
from
0.01
ppm
to
3.0
ppm
(
40CFR
§
180.421).
There
are
established
Codex
MRLs
for
Fenarimol
per
se.

The
available
data
bases
for
Fenarimol
consist
of
crop
field
trial
data,
FDA
monitoring
data,
and
Total
Diet
Survey
data.
FDA
monitoring
data
(
1997
through
1999;
LOD
=
0.003
ppm,
parent
only)
include:
more
than
300
apple
samples
with
no
detects;
more
than
500
grape
samples
with
no
detects;
more
than
300
pear
samples
with
no
detects;
more
than
600
banana
samples
with
no
detects;
and
more
than
100
cherry
samples
with
6
detects
and
a
maximum
detection
of
0.214
ppm.

A
Quantitative
Usage
Analysis
for
Fenarimol
was
prepared
by
BEAD
(
J.
Alsadek;
dated
05/
01/
01).
The
sources
cited
in
this
analysis
include
EPA
data
(
90­
99),
USDA/
NASS
(
90­
99),
Cal
DPR
(
93­
95)
and
National
Center
for
Food
and
Agricultural
Policy
(
c.
92).

The
HED
Dietary
Exposure
Evaluation
Model
(
DEEM)
is
used
to
assess
the
risk
from
dietary
exposure
to
Fenarimol
residues
in
food
(
no
acute
RfD
is
established).
The
chronic
DEEM
analysis
will
be
refined
using
FDA
data
and
anticipated
residues
from
field
trial
data
with
the
available
percent
of
crop
treated
estimates
and
processing
data.

The
Committee
recognizes
that
further
refinement
to
the
dietary
food
exposure
analyses
may
be
required
as
the
risk
assessment
is
developed.
Therefore,
provided
the
final
dietary
food
exposure
assessment
includes
all
metabolic
residues
of
concern
and
does
not
4
underestimate
the
potential
risk
for
infants
and
children,
the
safety
factor
recommendations
of
this
Committee
stand.

2.
Dietary
(
Drinking
Water)
Exposure
Considerations
(
Correspondence:
N.
Birchfield
to
B.
Tarplee
dated
July
24,
2002)

The
environmental
fate
database
is
complete
enough
to
provide
a
Tier
1
assessment
of
drinking
water
exposure.
The
data
are
based
on
studies
done
in
the
late
1970s
and
early
1980s
so
are
somewhat
uncertain.
Based
on
current
standards
most
of
the
studies
would
be
judged
to
be
unacceptable
but
they
appear
to
provide
useable
information.
If
a
higher
tier
assessment
is
required
new
studies
must
be
done.
The
data
indicate
that
parent
Fenarimol
is
stable
and
moderately
mobile
in
the
environment.
It
has
been
shown
to
persist
in
treated
field
for
several
years,
and
accumulation
in
soil
and
groundwater
over
time
is
possible.
EFED
concluded
that
the
only
significant
degradation
pathway
appears
to
be
aqueous
photolysis
and
one
significant
degradate
has
been
identified,
4­
chloro­
2­(
5­
pyrimidyl)­
2'­
clorobenzophenone.
Because
of
limitations
in
analytical
methodology
in
the
1970s
and
early
1980s
when
the
fate
studies
were
conducted,
the
identification
and
quantification
of
degradation
products
is
limited.
No
information
is
available
on
the
fate
and
transport
properties
of
this
or
other
possible
degradates.

The
HED
MARC
concluded
that
the
aqueous
photolysis
degradate
of
Fenarimol
[
4­
chloro­
2­(
5­
pyrimidyl)­
2'­
chlorobenzophenone]
should
be
included
in
the
drinking
water
risk
assessment.

Only
very
limited
monitoring
data
are
available
and
the
studies
have
not
been
reviewed.
Therefore,
Tier
1
screening
models
were
used
to
determine
estimated
environmental
concentrations
(
EECs)
for
use
in
drinking
water
risk
assessment:
FIRST
for
surface
water
and
SCIGROW
for
groundwater.
For
surface
water,
combined
EECs
for
Fenarimol
and
all
aqueous
photolysis
degradates
(
major
and
minor)
were
included
in
the
most
recent
drinking
water
assessment
by
modeling
Fenarimol
as
being
stable
in
surface
water.
The
SCIGROW
modeling
did
not
include
degradates
but
the
aqueous
photoproduct
is
expected
to
occur
predominately
in
surface
water.

3.
Residential
Exposure
Considerations
(
Correspondence:
B.
O'Keefe
to
B.
Tarplee
dated
July
25,
2002)

Fenarimol
is
currently
registered
for
use
on
ornamental
trees,
shrubs,
lawns,
and
turf
including
golf
courses.
Postapplication
dermal
and
incidential
oral
exposures
to
children
and
infants
are
possible;
mainly
from
exposure
to
treated
turf.
It
is
possible
that
Fenarimol
could
be
applied
twice
in
a
season
to
residential
turf
by
resident
or
professional
applicators;
i.
e.
once
or
twice
at
the
maximum
application
rate
(
2.73
lb
ai/
acre)
or
twice
as
a
split
application
(
half
max.
rate).
Additionally,
Fenarimol
could
be
applied
to
residential
turf
as
many
as
12
times
per
season
at
significantly
lower
rates;
i.
e.

0.51
lb
ai/
acre.
However,
based
upon
conversations
with
the
registrants,
only
one
to
two
applications
per
season
are
anticipated
to
turf,
since
users
rotate
and
switch
between
different
systemic
and
5
contact
fungicides,
and
applications
are
only
anticipated
when
conditions
are
suitable
for
fungal
growth.
It
is
also
possible
that
Fenarimol
could
be
applied
up
to
seven
times
per
season
to
residential
ornamentals
(
0.04875
lb
ai/
acre)
and
backyard
orchards
(
0.09375
lb
ai/
acre);
although
these
scenarios
are
considered
unlikely
based
upon
label
language.

Only
short­
term
non­
cancer
risks
to
residential
handlers
were
anticipated.
The
assessment
uses
the
revised
draft
Standard
Operating
Procedures
(
SOPs)
for
Residential
Exposure
Assessment,
and
includes
surrogate
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
for
loading/
applying
with
a
belly
grinder
type
granular
spreader
and
applying
by
hand,
and
the
Outdoor
Residential
Exposure
Task
Force
(
ORETF)
for
loading/
applying
with
a
push­
type
granular
spreader.

Short­
term
non­
cancer
risks
from
residential
postapplication
exposures
were
estimated
for
Fenarimol.
The
scenarios
assessed
for
the
purpose
of
screening­
level
risk
estimates
included
adults
and
children
performing
high­
contact
play
or
work
activities
on
treated
lawns,
and
adults
mowing
lawns
or
golfing.
Small
children
were
also
assessed
for
incidental
oral
exposure
from
hand­
to­
mouth
activities
while
playing
on
a
treated
lawn.
Some
of
these
exposures
were
combined,
where
it
was
deemed
reasonably
likely
activities
would
co­
occur.
Residential
risk
estimates
utilized
dissipation
rate
data
from
a
turf
transferable
residue
(
TTR)
study,
as
well
as
the
EPA's
original
and
revised
Draft
SOPs
for
Residential
Exposure
Assessment.
The
TTR
data
from
the
submitted
turf
study
had
several
limitations
and
were
considered
unacceptable.
However,
a
dissipation
rate
(
8%
daily)
derived
from
these
data
was
used
to
calculate
exposure
after
day
zero.
This
is
a
slower
dissipation
rate
than
the
10%
rate
listed
in
HED's
SOP.
Also,
the
data
showed
that
6.1%,
0.85%,
and
0.59%
(
for
CA,
IN
&
MS,
respectively)
of
the
applied
Fenarimol
was
detected
on
DAT
0.
By
comparison,
the
Agency's
SOP
uses
a
transfer
efficiency
(
percent
of
application
rate)
of
5%.
The
more
conservative
data
will
be
used
in
the
assessment.

NOTE:
Since
the
time
of
this
meeting,
the
FQPA
SFC
has
been
informed
that
the
registrant
has
agreed
to
drop
all
residential
uses
from
the
label.

III.
SAFETY
FACTOR
RECOMMENDATION
AND
RATIONALE
1.
FQPA
Safety
Factor
Recommendations
The
FQPA
SFC
recommends
that
OPP
depart
from
the
default
10X
additional
safety
factor
and
instead
use
a
different
additional
safety
factor
of
3X.
This
recommendation
is
based
on
reliable
data
supporting
the
findings
set
forth
below.

A.
Traditional
Additional
Safety
Factor
(
Addressing
Data
Deficiencies)

The
HIARC
concluded,
and
the
FQPA
SFC
concurred,
that
a
3X
additional
traditional
database
uncertainty
factor
to
address
the
data
deficiency
for
the
developmental
6
neurotoxicity
study.
The
rationale
for
why
reliable
data
support
the
safety
of
using
a
3X
to
address
this
data
deficiency
is
discussed
above
in
§
I.
1.

B.
Special
FQPA
Safety
Factors
Taking
into
account
the
recommendation
regarding
the
data
deficiency,
the
FQPA
SFC
recommends
that
no
Special
FQPA
Safety
Factor
is
necessary
to
protect
the
safety
of
infants
and
children
in
assessing
Fenarimol
exposure
and
risks.

2.
Rationale
and
Findings
Regarding
Recommendation
on
Special
FQPA
Safety
Factor
No
special
FQPA
safety
factor
was
needed
because:

There
is
no
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
following
in
utero
exposure
in
the
developmental
studies
with
Fenarimol.
There
is
no
evidence
of
increased
susceptibility
of
young
rats
in
the
reproduction
study
with
Fenarimol.
HIARC
concluded
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
exposure.

There
are
no
residual
uncertainties
identified
in
the
exposure
databases.
The
dietary
food
exposure
assessment
(
chronic
only;
no
acute
endpoint
was
identified)
is
refined
using
FDA
data
and
anticipated
residues
from
field
trial
data
with
the
available
percent
of
crop
treated
estimates
and
processing
data.
EFED
has
provided
conservative
surface
water
modeling
estimates
which
include
Fenarimol
and
all
aqueous
photolysis
degradates
(
which
are
expected
to
occur
predominately
in
surface
water).
The
HED
Residential
SOPs
and
dissipation
rate
data
from
a
TTR
study
will
be
used
to
assess
post­
application
exposure
to
children
as
well
as
incidental
oral
exposure
of
toddlers.
These
assessments
will
not
underestimate
the
exposure
and
risks
posed
by
Fenarimol.

NOTE:
Since
the
time
of
this
meeting,
the
FQPA
SFC
has
been
informed
that
the
registrant
has
agreed
to
drop
all
residential
uses
from
the
label.

3.
Application
of
the
FQPA
Safety
Factors
(
Population
Subgroups
/
Risk
Assessment
Scenarios)

The
FQPA
safety
factor
recommendation
is
for
a
3X
traditional
database
uncertainty
factor
to
address
data
deficiencies
and
no
additional
Special
FQPA
safety
factor.
The
3X
safety
factor
should
be
applied
to
all
dietary
and
residential
non­
dietary
exposure
scenarios.
No
other
FQPA
safety
factor
would
be
appropriate
for
Fenarimol.

4.
Summary
of
FQPA
Safety
Factors
Summary
of
FQPA
Safety
Factors
for
Fenarimol
7
LOAEL
to
NOAEL
(
UF
L)
Subchronic
to
Chronic
(
UFS)
Incomplete
Database
(
UFDB)
Special
FQPA
Safety
Factor
(
Hazard
and
Exposure)

Magnitude
of
Factor
1X
1X
3X
1X
Rationale
for
the
Factor
No
LOAEL
to
NOAEL
extrapolations
performed
No
subchronic
to
Chronic
extrapolations
performed
For
the
lack
of
a
special
developmental
toxicity
study
to
assess
for
potential
hormonal
effects
No
residual
concerns
regarding
preor
post­
natal
toxicity
or
completeness
of
the
toxicity
or
exposure
databases
Endpoints
to
which
the
Factor
is
Applied
Not
Applicable
Not
Applicable
All
Dietary
and
Residential
Non­
Dietary
exposure
assessments.
Not
Applicable
