Document ID: EPA-HQ-OPP-2005-0297-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-06-07T04:00Z

1
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
April
6,
2006
SUBJECT:
Fenarimol:
Re­
evaluation
of
the
FQPA
Safety
Factor
FROM:
Vicki
Dellarco,
PhD,
Senior
Science
Advisor
William
Burnam,
Senior
Scientist
Health
Effects
Division
(
7509C),
Office
of
Pesticide
Programs
TO:
Christina
Swartz,
Branch
Chief,
Registration
Action
Branch
2
Health
Effects
Division
(
7509C),
Office
of
Pesticide
Programs
In
a
July
29,
2002
HIARC
report
on
fenarimol,
it
was
concluded
that
a
3X
FQPA
Safety
Factor
be
retained
because
of
the
potential
of
fenarimol
to
affect
the
hormone
system
during
reproductive
development
and
the
need
to
better
characterize
its
endocrine
effects.
This
concern
was
based
on
the
observation
from
an
in
vitro
study
that
fenarimol
inhibited
aromatase
(
an
enzyme
complex
responsible
for
estrogen
biosynthesis
that
converts
androgens
into
estrogens,
and
thus
aromatase
inhibition
would
result
in
attenuate
estradiol
levels)
and
its
affect
on
fertility
in
males
(
which
occurred
at
the
mid
and
high
treatment
doses,
8
and
20
mg/
kg
per
day,
respectively)
and
dystocia
in
females
(
which
occurred
at
35
mg/
kg
per
day,
the
only
dose
tested).

Since
this
HIARC
memorandum,
fenarimol
has
been
evaluated
in
studies
considered
in
EPA's
Endocrine
Disruptor
Screening
Program
including
the
Pubertal
Female
and
Uterotrophic
Assays.
The
Pubertal
Female
Assay
involves
the
use
of
rats
to
screen
for
estrogenic
and
thyroid
activity
in
females
during
sexual
maturation,
and
examines
abnormalities
associated
with
sex
organs
and
puberty
markers,
as
well
as
thyroid
tissue.
This
assay
examines
abnormalities
associated
with
sex
organs
and
puberty
markers,
as
well
as
thyroid
tissue.
The
Uterotrophic
assay
involves
the
use
of
female
rats
to
screen
for
estrogenic
effects.
In
this
in
vivo
assay,
uterine
weight
changes
are
measured
in
ovariectomised
or
immature
female
rats.

No
adverse
effects
were
found
in
the
female
pubertal
assay
when
SD
rats
were
treated
at
50
and
250
mg/
kg
day
for
21
days,
except
for
a
decrease
in
T4
and
an
increase
in
circulating
TSH
levels
(
George
et
al.,
2002).
In
the
Uterotrophic
assay,
a
dose
of
200
mg/
kg
day
results
in
a
significant
increase
of
uterine
2
weights
which
were
accompanied
by
an
increase
in
serum
FSH
levels
and
a
decrease
in
serum
T3
levels
(
Anderson
et
al,
2006).
The
uterotrophic
response
and
the
effects
found
on
thyroid
hormone
levels
are
found
at
much
higher
doses
than
the
regulatory
endpoints
based
on
the
rat
multi­
generation
study
where
fenarimol
reduced
fertility
of
males
at
1.2
mg/
kg
per
day
with
a
NOAEL
of
0.6
mg/
kg
per
day.
The
0.6
mg/
kg
NOAEL
is
over
300­
fold
lower
than
the
uterotrophic
response
found
in
rats
at
200
mg/
kg.

In
conclusion,
no
additional
studies
are
needed
on
fenarimol.
This
is
because
of
the
new
special
studies
(
the
pubertal
and
uterotrophic
assays)
along
with
the
existing
standard
2­
generation
rat
reproductive
study
provides
an
adequate
characterization
of
the
reproductive,
developmental
and
endocrine
effects
of
fenarimol,.
In
particular,
the
new
rat
pubertal
study
by
George
et
al.,
provides
a
sensitive
indicator
(
i.
e.,
delay
in
vaginal
opening)
of
potential
adverse
effects
on
the
young
that
may
arise
because
of
aromatase
inhibition.
With
these
new
data,
there
is
greater
confidence
in
the
current
NOAEL
of
0.6
mg/
kg
per
day,
and
thus
the
3X
FQPA
safety
factor
be
reduced
to
1X
because
there
are
adequate
data
evaluating
the
potential
endocrine
effects
of
fenarimol
during
reproduction
and
development
in
the
young
animal.

References:

George
JD,
Tyl
R,
Hamby
BT,
Myers
C,
and
MC
Marr
(
May
20,
2002).
Assessment
of
Pubertal
Developmental
and
Thyroid
Function
in
Juvenile
Female
CD
(
Sprague­
Dawley)
Rats
after
exposure
to
Selected
Chemicals
administered
by
Gavage
on
Postantal
days
22
to
42/
43.
Final
Report
Date
August
22,
2002.
PDF
FILE
ATTACHED
Anderson
et.
al.,
(
2006)
Estrogenic
effects
in
vitro
and
in
vivo
of
the
fungicide
fenarimol.
Tox
Lettters
163:
142­
152.
PDF
FILE
ATTACHED
CC:
TINA
LEVINE