Page
1
of
3
EPA/
FDA
Joint
Teleconference
on
July
11,
2006
to
Discuss
1,2,4­
Triazole
(
Free
Triazole)
as
a
Common
Metabolite
of
Triazole
Derivative
Fungicides
and
Anastrozole,
a
Drug
July
18,
2006,
Meeting
Summary
Purpose
of
Teleconference:

For
EPA
to
obtain
input
from
FDA
on
EPA's
assessment
and
assumptions
used
to
consider
the
contribution
of
free
triazole
from
the
pharmaceutical
use
of
anastrozole,
summarized
below.

Attendees:

US
FDA/
CDER
US
EPA/
OPP
Thushi
Amini
Eric
Duffy
John
Lazor
Lee
Lemley
Nam
Atiqur
Rahman
Hasmukh
B.
Patel
John
Strong
Arzu
Selen
Liang
Zhou
Michael
Doherty
HED
Tamue
Gibson
RD
Michael
Goodis
SRRD
Kimberly
Nesci
SRRD
 
prepared
the
meeting
summary
Christina
Scheltema
SRRD
Summary
of
the
Call:

Following
introductions,
EPA
and
FDA
discussed
EPA's
request
for
input
from
FDA
on
the
EPA
approach
to
considering
1,2,4­
triazole
from
the
use
of
anastrozole
(
described
below,
for
the
record).
EPA
explained
its
approach,
discussed
the
assumptions
used,
and
presented
the
conclusion
that
the
estimated
aggregate
risk
is
below
the
EPA's
level
of
concern.
EPA
understands
that
FDA
agrees
with
the
assumptions
that
EPA
used
to
estimate
exposure
to
1,2,4­
triazole
resulting
from
the
use
of
anastrozole
as
a
human
drug,
and
considers
the
assumptions
to
be
conservative.
FDA
explained
that
a
more
refined
estimate
of
exposure
could
be
provided,
but
EPA
stated
that,
because
risks
are
currently
below
our
level
of
concern,
additional
refinements
are
not
necessary
at
this
time.

EPA
understands
that
FDA
will
be
providing
a
memorandum
to
EPA
regarding
this
approach
in
the
future.
Page
2
of
3
EPA's
Approach
for
Considering
1,2,4­
Triazole
from
All
Sources:

Upper­
Bound
Estimate
of
Exposure
to
1,2,4­
Triazole
From
Anatrozole:

Givens:
 
Of
the
administered
dose,
o
Approximately
10%
remains
as
parent
o
There
are
a
number
of
"
minor"
metabolites
(
FDA's
letter
defines
this
as
<
5%)
o
There
are
two
other
"
major"
metabolites
in
addition
to
free
triazole
(
presumably
5%
or
greater)
o
Free
triazole
is
the
major
metabolite
in
plasma
 
Dose
is
1
mg/
day
 
Target
population
is
primarily
adult
women;
therefore,
our
body
weight
for
calculations
is
60
kg.

Estimate
for
conversion
to
free
triazole:
 
100%
of
administered
dose
­
5%
(
all
minor
metabolites)
­
5%
(
major
metabolite
1)
­
5%
(
major
metabolite
2)
­
10%
(
unchanged
parent
compound)
=
75%
(*
Note
that
this
puts
us
in
the
ballpark
of
free
triazole
formation
in
rats
for
the
most
highly
metabolized
triazole
fungicide
[
tetraconazole
@
77%])

Therefore:

1
mg
anastrozole/
day
/
60
kg
=
0.016
mg
anastrozole/
kg/
day
0.016
mg
anastrozole/
kg/
day
/
293.36
mg/
mmol
=
0.0000545
mmol
anastrozole/
kg/
day
0.0000545
mmol
anastrozole/
kg/
day
*
0.75
conversion
to
free
triazole
=
0.000041
mmol
triazole/
mg/
day
0.000041
mmol
triazole/
mg/
day
*
69.07
mg/
mmol
=
0.003
mg
triazole/
kg/
day
Lower­
Bound
Estimate
of
Exposure
to
1,2,4­
Triazole
From
Anatrozole:

The
assumption
for
the
lower­
bound
estimate
is
that
free
triazole
is
"
just
barely"
a
major
metabolite.
Therefore,
the
Agency
assigned
a
conversion
value
of
5%.
Using
the
same
math
as
above,
except
substituting
0.05
in
as
the
conversion
factor,
gives
the
Agency
a
lower­
bound
estimate
of
0.0002
mg
triazole/
kg/
day.
Page
3
of
3
Conclusions
of
EPA's
Approach:

This
is
a
chronic
exposure
scenario.
The
cPAD
for
free
triazole
is
currently
0.005
mg/
kg
day.
Based
on
the
assumptions
above,
both
of
the
bounding­
level
estimates
for
triazole
exposure
from
the
pharmaceutical
use
of
anastrozole
fall
below
EPA's
level
of
concern.

The
chronic
aggregate
exposure
estimate
for
free
triazole
coming
from
the
triazole
fungicides
is
0.00055
mg/
kg/
day
for
females
13­
49.
Therefore,
the
new
aggregate
estimate
(
including
pharmaceutical
exposure)
would
be
somewhere
between
0.00075
and
0.00355
mg/
kg/
day
(
15
and
71%
cPAD,
respectively)
and
would
remain
below
our
level
of
concern.
Note:
we
only
need
to
consider
females
13­
49
since
their
exposure
estimate
is
greater
than
(
and
therefore
covers)
the
adults
50+
group.

Based
on
the
upper­
bound
estimate,
the
pharmaceutical
exposure
to
1,2,4­
triazole
is
an
order
of
magnitude
greater
than
that
resulting
from
agricultural
uses
of
triazole
fungicides.
Based
on
the
lower­
bound
estimate,
the
pharmacuetical
exposure
to
1,2,4­
triazole
is
about
half
of
that
resulting
from
agricultural
uses
of
triazole
fungicides.

Considering
both
pesticidal
and
pharmacological
sources
of
free
triazole,
and
based
on
conservative
assumptions,
there
is
reasonable
certainty
of
no
harm
to
the
U.
S.
population
and
representative
population
subgroups
from
all
exposure
to
free
triazole.
Because
EPA
is
able
to
reach
this
conclusion
with
a
screening­
level
assessment,
the
Agency
has
not
conducted
a
more
refined
co­
exposure
assessment
for
pharmaceutical
uses
to
determine
whether
exposures
from
pesticide
uses
would
adversely
impact
the
pharmaceutical
user.
