Document ID: EPA-HQ-OAR-2004-0074-0038
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-01-13T05:00Z

July
2,
2001
Donald
R.
Lynam
Vice
President,
Air
Conservation
Ethyl
Corporation
330
South
Fourth
Street
Richmond,
VA
23219­
4304
Dear
Dr.
Lynam,

On
April
27,
2001,
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.
This
submission
deals
with
protocols
associated
with
the
developmental
physiologically­
based
pharmacokinetic
health
study
(
the
PBPK
study).
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
fulfills
EPA's
study
requirements.

In
an
attachment
to
your
submission,
the
Technical
Advisory
Panel
(
TAP)
commented
on
the
possibility
of
including
neurobehavioral
testing
at
the
end
of
the
PBPK
study.
However
the
TAP
decided
against
inclusion
of
neurobehavioral
testing
since
it
would
involve
significant
expansion
of
the
PBPK
study
and
result
in
little
gain.
The
TAP
acknowledged
that
putative
neurobehavioral
toxicity
needs
to
be
addressed
in
a
future
study
and
acknowledged
EPA's
position
that
neurobehavioral
endpoints
will
need
to
be
addressed
in
a
non­
human
primate.
Additionally,
the
TAP
recommended
that
the
Chemical
Industry
Institute
of
Toxicology
(
CIIT)
should
consider
consulting
EPA
on
this
issue.

In
a
separate
attachment,
CIIT
pointed
out
that
group
sizes
used
in
the
PBPK
study
are
much
smaller
than
those
used
in
most
developmental
neurotoxicity
studies
and
are
unlikely
to
have
sufficient
statistical
power
for
most
behavioral
endpoints.
CIIT
also
concurred
with
the
TAP
opinion
that
neurobehavioral
endpoints
are
beyond
the
scope
of
the
current
experiment.
­
2­

We
agree
with
the
TAP
that
the
inclusion
of
neurobehavioral
endpoints
at
the
end
of
the
PBPK
study
would
be
a
significant
expansion
of
the
PBPK
study
and
result
in
little
gain.
We
also
agree
with
CIIT
that
the
sample
sizes
of
the
PBPK
study
are
too
small
to
yield
sufficient
statistical
power
needed
for
neurobehavioral
testing.
Finally,
in
EPA's
May
11,
2000,
MMT
Alternative
Tier
2
Health
Effects
Testing
Requirements
Notification,
EPA
stated
that
additional
testing
should
"
not
interfere
with
any
of
the
testing
requirements
adopted
today
or
delay
any
additional
Alternative
Tier
2
testing
requirements
which
may
be
adopted
in
the
future."

Finally,
we
agree
with
the
Technical
Advisory
Panel
and
CIIT
comments
that
the
exposure
concentrations
for
the
PBPK
study
should
be
made
dependent
on
the
outcome
of
the
ongoing
subchronic
manganese
sulfate
pharmacokinetic
study.
However,
this
may
be
difficult
given
the
testing
schedule.
We
recommend
that
any
significant
information
emerging
from
the
current
study
be
taken
into
account
in
the
PBPK
study,
regardless
of
the
latter's
progress.
We
also
acknowledge
CIIT's
concern
that
a
stable
concentration
of
1
milligram
of
manganese
per
cubic
meter
(
mg
Mn/
m3)
atmosphere
in
a
8
cubic
meter
inhalation
chamber
may
be
difficult
to
achieve.
We
encourage
CIIT
to
conduct
the
feasibility
studies
proposed
to
determine
an
effective
maximal
concentration.
EPA
requests
that
Ethyl
notify
the
Agency
if
it
encounters
any
difficulty
in
reliably
generating
the
highest
exposure
concentration
of
1
mg
Mn/
m3
during
the
feasibility
studies.

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/

Robert
E.
Larson,
Acting
Director
Transportation
and
Regional
Programs
Division
cc:
Monica
Alvarez,
ORD/
OSP
J.
Michael
Davis,
ORD/
NCEA
Stan
Durkee,
ORD/
OSP
Hal
Zenick,
ORD/
NHEERL
William
Russo,
ORD/
NHEERL
Tim
Backstrom,
OGC
Kevin
Fast,
Hunton
&
Williams