Document ID: EPA-HQ-OAR-2004-0074-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-01-12T05:00Z

July
27,
2000
Donald
R.
Lynam
Vice
President,
Air
Conservation
Ethyl
Corporation
330
South
Fourth
Street
Richmond,
VA
23219­
4304
Dear
Dr.
Lynam,

On
May
26,
2000,
the
Ethyl
Corporation
(
Ethyl)
submitted
to
the
Environmental
Protection
Agency
(
EPA)
a
draft
health
study
protocol
for
MMT,
as
required
under
the
Alternative
Tier
2
Health
Effects
Testing
Requirements.
These
requirements
were
finalized
in
the
notification
received
by
Ethyl
on
May
25,
2000.
As
you
know,
the
notification
requires
EPA
review
and
approval
of
these
protocols.

We
believe
that
the
draft
protocol
generally
fulfills
EPA's
study
requirements.
We
agree
with
Ethyl's
proposal
to
use
manganese
(
Mn)
sulfate
as
the
major
test
species
at
three
exposure
levels
with
0.5
mg
Mn/
m3
being
the
highest
concentration
and
to
use
Mn
phosphate
as
the
second
test
compound
at
a
single
exposure
level
of
0.1
mg
Mn/
m3.
We
also
agree
with
Ethyl's
proposal
to
start
the
exposure
of
aged
rats
at
about
16
months
of
age
rather
than
18
months
of
age.
Finally,
we
do
not
object
to
Ethyl's
proposal
to
amend
the
protocol
to
accommodate
biochemical
measures
at
Wake
Forest
University
and
radio
tracer
work
at
the
Chemical
Industry
Institute
of
Toxicology
(
CIIT),
both
of
which
will
fall
outside
of
the
Good
Laboratory
Practices
(
GLP)
approach
specified
in
the
notification.
While
allowing
this
approach
for
work
not
required
by
the
notification,
we
emphasize
that
this
approval
does
not
allow
any
changes
that
would
confound
the
GLP
conduct
of
the
studies
described
in
EPA's
MMT
study
requirements.

In
addition,
we
have
the
following
technical
comments.
First,
on
June
15,
2000,
in
the
meeting
between
Ethyl,
CIIT
and
EPA,
Dr.
David
Dorman
informed
us
of
the
potential
difficulty
in
consistently
achieving
the
lowest
exposure
level
of
0.01
mg
Mn/
m3
during
inhalation
exposure.
If
it
is
determined
that
the
0.01
mg
Mn/
m3
exposure
level
cannot
be
consistently
achieved
in
practice,
EPA
recommends
that
the
draft
protocol
clearly
provide
the
investigator
the
flexibility
to
increase
the
lowest
exposure
concentration
to
a
level
readily
achievable
with
their
exposure
system.
Second,
the
10
ppm
dietary
Mn
level
and
use
of
AIN­
93G
diet
(
pelleted
semi­
purified
certified
diet),
mentioned
on
page
13
of
the
draft
protocols,
are
justified
based
on
the
results
of
the
14­
day
studies.
Third,
we
recommend
that
the
revised
protocol
include
a
reference
for
­
2­

the
National
Research
Council
recommendation
of
35
ppm
iron
in
the
diet.
Finally,
the
manganese
analysis
in
the
ovary
may
be
affected
by
the
stage
of
folliculogenesis,
for
example,
samples
having
large
antral
follicles
due
to
increased
fluid
volume
may
skew
the
Mn
concentration
data.
Therefore,
we
recommend
that
the
draft
protocol
be
revised
to
ensure
that
ovarian
samples
(
mentioned
on
page
17
of
the
draft
protocol)
be
described
in
sufficient
detail
so
that
the
Mn
analysis
data
can
be
interpreted
appropriately.

Finally,
we
have
the
following
comments
regarding
peer
review.
First,
the
Alternative
Tier
2
requirements
require
individual
peer
review
comments
to
be
submitted
with
the
study
protocol.
Ethyl
provided
consensus
comments
from
the
Technical
Advisory
Panel
(
TAP),
rather
than
individual
peer
review
comments
as
required
by
EPA.
Unedited
comments
from
individual
peer
reviewers
can
be
essential
for
evaluating
whether
there
were
any
important
differences
in
viewpoints
that
are
not
reflected
in
the
consensus
comments.
We
trust
that
for
future
submissions
of
study
protocols,
requirements
of
the
notification
will
be
satisfied
by
submitting
individual
peer
review
comments
along
with
the
appropriate
study
protocol.
Second,
we
recommend
resolution
of
a
potential
conflict
of
interest
situation
for
one
member
of
the
TAP
who
is
performing
some
of
the
toxicology
work
not
covered
by
the
notification.
(
We
understand
that
Ethyl
is
agreeable
to
this
change.)
Finally,
we
ask
that
more
specific
information
on
individual
peer
reviewers
be
included
in
any
future
nominations
of
peer
reviewers
such
as
the
peer
reviewer's
affiliation
or
any
potential
conflicts
of
interest.

We
look
forward
to
Ethyl's
submission
of
the
revised
draft
protocol
as
required
under
the
notification.
If
you
have
any
questions
concerning
our
review,
please
contact
Joe
Sopata
of
my
staff
at
(
202)
564­
9034.

Sincerely,

/
s/

Merrylin
Zaw­
Mon,
Director
Transportation
and
Regional
Programs
Division
cc:
J.
Michael
Davis,
ORD/
NCEA
Stan
Durkee,
ORD/
OSP
Joe
Elder,
ORD/
NHEERL
Hal
Zenick,
ORD/
NHEERL
William
Farland,
ORD/
NHEERL
Tim
Backstrom,
OGC
Kevin
Fast,
Hunton
&
Williams