Document ID: EPA-HQ-OPP-2002-0250-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-09-24T04:00Z

1
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
MEMORANDUM
Subject:
EPA
Id
No.:
206600.
Fenarimol:
Tentative
response
to
the
registrant's
comments
on
the
preliminary
human
health
risk
assessment­
Toxicology
issues.

PC
Code
No.:
206600
DP
Barcode
No.:
D282387
Submission
No.:
S614096
From:
Barry
O'Keefe
and
John
Doherty
ReRegistration
Branch
III
Health
Effects
Division
7509C
To:
Tom
Myers
and
Margaret
Rice
Product
Manager
#
52
Special
Review
and
ReRegistration
Division
7507C
Through:
Catherine
Eiden
Branch
Senior
Scientist
ReRegistration
Branch
III
Health
Effects
Division
7509C
Introduction
The
Gowan
Company
submitted
several
comments
and
questions
concerning
the
data
requirements
and
data
interpretation
presented
in
the
toxicology
assessment
portion
of
the
Health
Effects
Division's
(
HED's)
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
document
for
fenarimol.
HED
is
currently
conducting
a
detailed
review
of
these
comments
and
questions.
No
conclusions
can
be
reached
for
some
of
these
issues
until
all
of
the
supporting
data
and
information
provided
to
the
Agency
is
assessed
and
reviewed
by
appropriate
peer
review
committees
in
HED.
This
process
is
currently
underway.
After
review,
some
of
the
issues
raised
by
the
Gowan
Company
may
result
in
changes
in
risk
estimates.
Toxicology
issues
of
concern
to
the
Gowan
Company
and
tentative
comments
on
their
status
are
listed
below.
Other
issues
such
as
those
related
to
exposure
and
chemistry
have
been
addressed
separately.

1.
Requirement
for
the
Primary
Dermal
Irritation
Study.
2
A
primary
dermal
irritation
study
for
technical
fenarimol
was
indicated
as
a
data
gap.
The
registrant
has
agreed
to
conduct
the
Primary
Dermal
Irritation
Study
to
satisfy
the
requirement
and
expects
to
submit
this
study
before
the
end
of
2002.

2.
Requirement
for
a
28­
Day
Inhalation
Toxicity
Study.

The
Gowan
Company
requested
that
the
Agency
rescind
the
data
requirement
for
the
28­
day
inhalation
study.
They
disagree
on
its
need
and
cite
that
this
issue
was
addressed
recently
by
the
CropLife
America
an
industrial
organization.
They
also
state
that
the
sprays
that
will
typically
result
from
fenarimol
use
will
have
droplets
that
will
be
tens
or
thousands
of
micrometers
in
diameter
or
much
larger
than
the
respirable
droplets
of
a
few
micrometers
in
diameter.
There
larger
droplets
will
not
reach
the
alveoli
and
will
become
trapped
in
the
upper
respiratory
tract
and
eventually
swallowed.
Thus,
the
endpoint
from
an
oral
toxicity
study
is
a
more
appropriate
endpoint.

There
have
been
some
recent
changes
in
HED
policy
regarding
the
need
for
subchronic
inhalation
toxicity
studies.
The
comments
of
the
CropLife
America
organization
have
been
taken
into
consideration
at
a
recent
presentation
to
the
Agency.
As
a
result
of
these
recent
changes,
the
Gowan
Company
may
submit
a
waiver
for
the
28­
day
inhalation
study.
This
waiver
must
contain
sufficient
data
on
the
particle
size
of
the
sprays
and
other
preparations
that
may
result
in
inhalation
exposure.
It
also
must
contain
sufficient
other
information
regarding
the
potential
inhalation
exposure
such
as
duration
of
exposure
in
terms
of
hours
per
day,
per
week
etc.
The
completed
waiver
request
will
be
presented
to
a
peer
review
committee
that
will
determine
the
need
for
the
subchronic
inhalation
toxicity
study.
This
peer
review
group
will
consist
of
toxicologists
with
expertise
in
inhalation
toxicology
as
well
as
occupational
and
residential
exposure
representatives.
The
decision
on
the
need
for
the
subchronic
inhalation
toxicity
study
will
be
based
all
relevant
factors.

The
more
complete
the
information
in
the
waiver
request
is,
the
better
chance
for
the
waiver
to
be
granted.
The
limited
information
provided
in
the
April
10,
2002
letter
in
not
sufficient
to
bring
to
a
peer
review
committee
to
consider
a
waiver
for
an
inhalation
toxicity
study.

Lastly,
HED
is
already
using
an
oral
toxicity
endpoint
for
the
inhalation
exposure
scenarios.
However,
the
subchronic
inhalation
toxicity
study
is
considered
more
appropriate
for
risk
assessment.

3.
Requirement
for
a
Special
"
Developmental
Neurotoxicity"
Study.

The
registrant
has
stated
that
the
special
"
developmental
neurotoxicity"
study
(
DNT)
is
not
needed
and
HED's
rationale
is
flawed,
since
DNT
triggers
were
not
met.
They
also
state
that
since
the
DNT
study
is
not
needed,
that
the
Food
Quality
Protection
Act
(
FQPA)
10
x
safety
factor
should
not
be
retained.

HED
agrees
that
there
is
some
confusion
with
regard
to
making
the
request
for
a
Developmental
Neurotoxicity
Study.
In
particular,
this
study
should
not
have
been
called
a
Developmental
Neurotoxicity
Study
but
more
correctly
a
Special
Developmental
Toxicity
Study.
3
To
help
clarify
this
issue,
the
registrant
is
now
being
asked
to
develop
a
protocol
for
a
Special
Developmental
Toxicity
study
that
will
assess
for
possible
effects
of
fenarimol
on
the
rat
hormonal
systems.
This
protocol
will
follow
the
same
dosing
regimen
during
gestation
and
lactation
that
is
normally
used
for
the
developmental
neurotoxicity
study.
The
pups
should
then
be
examined
for
potential
hormonal
effects
such
as
levels
of
circulating
androgens
and
estrogens
and
close
examination
of
target
organs
for
androgens
and
estrogens
as
well
as
behavioral
modifications
related
to
hormonal
imbalance
that
might
result
from
fenarimol.
Should
there
be
any
particular
parameters
in
the
FOB
paradigm
that
might
be
used
to
assess
for
hormonal
disruption,
then
these
parameters
should
remain
in
the
special
developmental
toxicity
study
protocol
for
fenarimol.
Additional
parameters
specific
for
assuring
that
fenarimol
does
not
affect
systems
related
to
development
as
influenced
by
the
hormonal
system
may
also
need
to
be
included.
For
example,
the
rat
pups
may
need
to
be
allowed
to
reach
adulthood
and
be
assessed
for
reproductive
performance
to
assure
that
in
utero
exposure
to
fenarimol
did
not
affect
sexual
development.

HED
acknowledges
that
inclusions
of
hormonal
endpoints
in
a
special
developmental
toxicity
study
protocol
is
a
departure
from
the
current
harmonized
guidelines.
However,
since
the
critical
endpoint
for
risk
assessment
for
fenarimol
is
based
on
the
effects
of
this
chemical
on
aromatase
an
enzyme
critical
to
hormone
metabolism,
HED
believes
it
has
the
responsibility
under
FQPA
to
require
additional
testing
to
demonstrate
potential
toxicity
during
fetal
and
neonatal
development
related
to
hormonal
effects.
The
registrant
is
strongly
advised
to
submit
the
protocol
to
the
Agency
prior
to
initiating
the
study.

The
issue
of
appropriateness
of
retaining
the
10x
FQPA
safety
factor
will
also
be
addressed
by
the
HIARC
in
terms
of
evolving
policies
regarding
incomplete
data
bases.

1.
Dermal
Absorption
Factor.

The
Gowan
Company
disagrees
with
the
Agency's
recommendations
to
use
a
20%
dermal
absorption
factor
in
dermal
exposure
risk
assessments.
The
Gowan
Company
provided
a
rationale
and
supporting
data
to
demonstrate
a
lower
dermal
absorption
factor
of
2.6%
is
appropriate.
It
was
indicated
that
if
this
lower
dermal
absorption
factor
is
formally
approved
by
HED,
then
dermal
MOEs
would
be
increased
approximately
seven
fold.
The
registrant
also
provided
additional
information
that
was
requested
by
HED
for
the
monkey
dermal
absorption
study.

ReRegistration
Branch
III
has
incorporated
the
information
provided
for
the
monkey
study
into
an
updated
DER.
The
issue
of
selecting
the
dermal
absorption
factor
for
fenarimol
will
be
discussed
in
a
special
peer
review
HIARC
meeting
within
the
next
several
weeks.
The
updated
DER
for
the
monkey
study,
the
commentary
by
the
European
Union
and
the
registrant's
other
suggestions
related
to
the
selection
of
the
dermal
absorption
factor
will
be
considered
in
this
peer
review
process.