Document ID: EPA-HQ-OPP-2003-0165-0001
Agency: epa
Document Type: Notice
Title: Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food
Posted Date: 2003-06-11T04:00Z

34959
Federal
Register
/
Vol.
68,
No.
112
/
Wednesday,
June
11,
2003
/
Notices
ENVIRONMENTAL
PROTECTION
AGENCY
[
OPP
 
2003
 
0165;
FRL
 
7306
 
4]

Notice
of
Filing
a
Pesticide
Petition
to
Establish
a
Tolerance
for
a
Certain
Pesticide
Chemical
in
or
on
Food
AGENCY:
Environmental
Protection
Agency
(
EPA).
ACTION:
Notice.

SUMMARY:
This
notice
announces
the
initial
filing
of
a
pesticide
petition
proposing
the
establishment
of
regulations
for
residues
of
an
inert
ingredient
hygromycin
B
phosphotransferase
(
APH4)
marker
protein
and
the
genetic
material
necessary
for
its
production
in
or
on
various
food
commodities.
DATES:
Comments,
identified
by
docket
ID
number
OPP
 
2003
 
0165,
must
be
received
on
or
before
July
11,
2003.
ADDRESSES:
Comments
may
be
submitted
electronically,
by
mail,
or
through
hand
delivery/
courier.
Follow
the
detailed
instructions
as
provided
in
Unit
I.
of
the
SUPPLEMENTARY
INFORMATION.

FOR
FURTHER
INFORMATION
CONTACT:
Leonard
Cole,
Biopesticides
and
Pollution
Prevention
Division
(
7511C),
Office
of
Pesticide
Programs,
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460
 
0001;
telephone
number:
(
703)
305
 
5412;
e­
mail
address:
cole.
leonard@
epa.
gov.

SUPPLEMENTARY
INFORMATION:

I.
General
Information
A.
Does
this
Action
Apply
to
Me?

You
may
be
potentially
affected
by
this
action
if
you
are
an
agricultural
producer,
food
manufacturer,
or
pesticide
manufacturer.
Potentially
affected
entities
may
include,
but
are
not
limited
to:
 
Crop
production
(
NAICS
111)
 
Animal
production
(
NAICS
112)
 
Food
manufacturing
(
NAICS
311)
 
Pesticide
manufacturing
(
NAICS
32532)
This
listing
is
not
intended
to
be
exhaustive,
but
rather
provides
a
guide
for
readers
regarding
entities
likely
to
be
affected
by
this
action.
Other
types
of
entities
not
listed
in
this
unit
could
also
be
affected.
The
North
American
Industrial
Classification
System
(
NAICS)
codes
have
been
provided
to
assist
you
and
others
in
determining
whether
this
action
might
apply
to
certain
entities.
If
you
have
any
questions
regarding
the
applicability
of
this
action
to
a
particular
entity,
consult
the
person
listed
under
FOR
FURTHER
INFORMATION
CONTACT.

B.
How
Can
I
Get
Copies
of
this
Document
and
Other
Related
Information?
1.
Docket.
EPA
has
established
an
official
public
docket
for
this
action
under
docket
identification
(
ID)
number
OPP
 
2003
 
0165.
The
official
public
docket
consists
of
the
documents
specifically
referenced
in
this
action,
any
public
comments
received,
and
other
information
related
to
this
action.
Although
a
part
of
the
official
docket,
the
public
docket
does
not
include
Confidential
Business
Information
(
CBI)
or
other
information
whose
disclosure
is
restricted
by
statute.
The
official
public
docket
is
the
collection
of
materials
that
is
available
for
public
viewing
at
the
Public
Information
and
Records
Integrity
Branch
(
PIRIB),
Rm.
119,
Crystal
Mall
#
2,
1921
Jefferson
Davis
Hwy.,
Arlington,
VA.
This
docket
facility
is
open
from
8:
30
a.
m.
to
4
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
The
docket
telephone
number
is
(
703)
305
 
5805.
2.
Electronic
access.
You
may
access
this
Federal
Register
document
electronically
through
the
EPA
Internet
under
the
``
Federal
Register''
listings
at
http://
www.
epa.
gov/
fedrgstr/.
An
electronic
version
of
the
public
docket
is
available
through
EPA's
electronic
public
docket
and
comment
system,
EPA
Dockets.
You
may
use
EPA
Dockets
at
http://
www.
epa.
gov/
edocket/
to
submit
or
view
public
comments,
access
the
index
listing
of
the
contents
of
the
official
public
docket,
and
to
access
those
documents
in
the
public
docket
that
are
available
electronically.
Although
not
all
docket
materials
may
be
available
electronically,
you
may
still
access
any
of
the
publicly
available
docket
materials
through
the
docket
facility
identified
in
Unit
I.
B.
1.
Once
in
the
system,
select
``
search,''
then
key
in
the
appropriate
docket
ID
number.
Certain
types
of
information
will
not
be
placed
in
the
EPA
Dockets.
Information
claimed
as
CBI
and
other
information
whose
disclosure
is
restricted
by
statute,
which
is
not
included
in
the
official
public
docket,
will
not
be
available
for
public
viewing
in
EPA's
electronic
public
docket.
EPA's
policy
is
that
copyrighted
material
will
not
be
placed
in
EPA's
electronic
public
docket
but
will
be
available
only
in
printed,
paper
form
in
the
official
public
docket.
To
the
extent
feasible,
publicly
available
docket
materials
will
be
made
available
in
EPA's
electronic
public
docket.
When
a
document
is
selected
from
the
index
list
in
EPA
Dockets,
the
system
will
identify
whether
the
document
is
available
for
viewing
in
EPA's
electronic
public
docket.
Although
not
all
docket
materials
may
be
available
electronically,
you
may
still
access
any
of
the
publicly
available
docket
materials
through
the
docket
facility
identified
in
Unit
I.
B.
1.
EPA
intends
to
work
towards
providing
electronic
access
to
all
of
the
publicly
available
docket
materials
through
EPA's
electronic
public
docket.
For
public
commenters,
it
is
important
to
note
that
EPA's
policy
is
that
public
comments,
whether
submitted
electronically
or
in
paper,
will
be
made
available
for
public
viewing
in
EPA's
electronic
public
docket
as
EPA
receives
them
and
without
change,
unless
the
comment
contains
copyrighted
material,
CBI,
or
other
information
whose
disclosure
is
restricted
by
statute.
When
EPA
identifies
a
comment
containing
copyrighted
material,
EPA
will
provide
a
reference
to
that
material
in
the
version
of
the
comment
that
is
placed
in
EPA's
electronic
public
docket.
The
entire
printed
comment,
including
the
copyrighted
material,
will
be
available
in
the
public
docket.
Public
comments
submitted
on
computer
disks
that
are
mailed
or
delivered
to
the
docket
will
be
transferred
to
EPA's
electronic
public
docket.
Public
comments
that
are
mailed
or
delivered
to
the
docket
will
be
scanned
and
placed
in
EPA's
electronic
public
docket.
Where
practical,
physical
objects
will
be
photographed,
and
the
photograph
will
be
placed
in
EPA's
electronic
public
docket
along
with
a
brief
description
written
by
the
docket
staff.

C.
How
and
to
Whom
Do
I
Submit
Comments?
You
may
submit
comments
electronically,
by
mail,
or
through
hand
delivery/
courier.
To
ensure
proper
receipt
by
EPA,
identify
the
appropriate
docket
ID
number
in
the
subject
line
on
the
first
page
of
your
comment.
Please
ensure
that
your
comments
are
submitted
within
the
specified
comment
period.
Comments
received
after
the
close
of
the
comment
period
will
be
marked
``
late.''
EPA
is
not
required
to
consider
these
late
comments.
If
you
wish
to
submit
CBI
or
information
that
is
otherwise
protected
by
statute,
please
follow
the
instructions
in
Unit
I.
D.
Do
not
use
EPA
Dockets
or
e­
mail
to
submit
CBI
or
information
protected
by
statute.
1.
Electronically.
If
you
submit
an
electronic
comment
as
prescribed
in
this
unit,
EPA
recommends
that
you
include
your
name,
mailing
address,
and
an
email
address
or
other
contact
information
in
the
body
of
your
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/
Vol.
68,
No.
112
/
Wednesday,
June
11,
2003
/
Notices
comment.
Also
include
this
contact
information
on
the
outside
of
any
disk
or
CD
ROM
you
submit,
and
in
any
cover
letter
accompanying
the
disk
or
CD
ROM.
This
ensures
that
you
can
be
identified
as
the
submitter
of
the
comment
and
allows
EPA
to
contact
you
in
case
EPA
cannot
read
your
comment
due
to
technical
difficulties
or
needs
further
information
on
the
substance
of
your
comment.
EPA's
policy
is
that
EPA
will
not
edit
your
comment,
and
any
identifying
or
contact
information
provided
in
the
body
of
a
comment
will
be
included
as
part
of
the
comment
that
is
placed
in
the
official
public
docket,
and
made
available
in
EPA's
electronic
public
docket.
If
EPA
cannot
read
your
comment
due
to
technical
difficulties
and
cannot
contact
you
for
clarification,
EPA
may
not
be
able
to
consider
your
comment.
i.
EPA
Dockets.
Your
use
of
EPA's
electronic
public
docket
to
submit
comments
to
EPA
electronically
is
EPA's
preferred
method
for
receiving
comments.
Go
directly
to
EPA
Dockets
at
http://
www.
epa.
gov/
edocket,
and
follow
the
online
instructions
for
submitting
comments.
Once
in
the
system,
select
``
search,''
and
then
key
in
docket
ID
number
OPP
 
2003
 
0165.
The
system
is
an
``
anonymous
access''
system,
which
means
EPA
will
not
know
your
identity,
e­
mail
address,
or
other
contact
information
unless
you
provide
it
in
the
body
of
your
comment.
ii.
E­
mail.
Comments
may
be
sent
by
e­
mail
to
opp­
docket@
epa.
gov,
Attention:
Docket
ID
Number
OPP
 
2003
 
0165.
In
contrast
to
EPA's
electronic
public
docket,
EPA's
e­
mail
system
is
not
an
``
anonymous
access''
system.
If
you
send
an
e­
mail
comment
directly
to
the
docket
without
going
through
EPA's
electronic
public
docket,
EPA's
e­
mail
system
automatically
captures
your
e­
mail
address.
E­
mail
addresses
that
are
automatically
captured
by
EPA's
e­
mail
system
are
included
as
part
of
the
comment
that
is
placed
in
the
official
public
docket,
and
made
available
in
EPA's
electronic
public
docket.
iii.
Disk
or
CD
ROM.
You
may
submit
comments
on
a
disk
or
CD
ROM
that
you
mail
to
the
mailing
address
identified
in
Unit
I.
C.
2.
These
electronic
submissions
will
be
accepted
in
WordPerfect
or
ASCII
file
format.
Avoid
the
use
of
special
characters
and
any
form
of
encryption.
2.
By
mail.
Send
your
comments
to:
Public
Information
and
Records
Integrity
Branch
(
PIRIB)
(
7502C),
Office
of
Pesticide
Programs
(
OPP),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460
 
0001,
Attention:
Docket
ID
Number
OPP
 
2003
 
0165.
3.
By
hand
delivery
or
courier.
Deliver
your
comments
to:
Public
Information
and
Records
Integrity
Branch
(
PIRIB),
Office
of
Pesticide
Programs
(
OPP),
Environmental
Protection
Agency,
Rm.
119,
Crystal
Mall
#
2,
1921
Jefferson
Davis
Hwy.,
Arlington,
VA,
Attention:
Docket
ID
Number
OPP
 
2003
 
0165.
Such
deliveries
are
only
accepted
during
the
docket's
normal
hours
of
operation
as
identified
in
Unit
I.
B.
1.

D.
How
Should
I
Submit
CBI
to
the
Agency?

Do
not
submit
information
that
you
consider
to
be
CBI
electronically
through
EPA's
electronic
public
docket
or
by
e­
mail.
You
may
claim
information
that
you
submit
to
EPA
as
CBI
by
marking
any
part
or
all
of
that
information
as
CBI
(
if
you
submit
CBI
on
disk
or
CD
ROM,
mark
the
outside
of
the
disk
or
CD
ROM
as
CBI
and
then
identify
electronically
within
the
disk
or
CD
ROM
the
specific
information
that
is
CBI).
Information
so
marked
will
not
be
disclosed
except
in
accordance
with
procedures
set
forth
in
40
CFR
part
2.
In
addition
to
one
complete
version
of
the
comment
that
includes
any
information
claimed
as
CBI,
a
copy
of
the
comment
that
does
not
contain
the
information
claimed
as
CBI
must
be
submitted
for
inclusion
in
the
public
docket
and
EPA's
electronic
public
docket.
If
you
submit
the
copy
that
does
not
contain
CBI
on
disk
or
CD
ROM,
mark
the
outside
of
the
disk
or
CD
ROM
clearly
that
it
does
not
contain
CBI.
Information
not
marked
as
CBI
will
be
included
in
the
public
docket
and
EPA's
electronic
public
docket
without
prior
notice.
If
you
have
any
questions
about
CBI
or
the
procedures
for
claiming
CBI,
please
consult
the
person
listed
under
FOR
FURTHER
INFORMATION
CONTACT.

E.
What
Should
I
Consider
as
I
Prepare
My
Comments
for
EPA?

You
may
find
the
following
suggestions
helpful
for
preparing
your
comments:
1.
Explain
your
views
as
clearly
as
possible.
2.
Describe
any
assumptions
that
you
used.
3.
Provide
copies
of
any
technical
information
and/
or
data
you
used
that
support
your
views.
4.
If
you
estimate
potential
burden
or
costs,
explain
how
you
arrived
at
the
estimate
that
you
provide.
5.
Provide
specific
examples
to
illustrate
your
concerns.
6.
Make
sure
to
submit
your
comments
by
the
deadline
in
this
notice.
7.
To
ensure
proper
receipt
by
EPA,
be
sure
to
identify
the
docket
ID
number
assigned
to
this
action
in
the
subject
line
on
the
first
page
of
your
response.
You
may
also
provide
the
name,
date,
and
Federal
Register
citation.

II.
What
Action
is
the
Agency
Taking?

EPA
has
received
a
pesticide
petition
as
follows
proposing
the
establishment
and/
or
amendment
of
regulations
for
residues
of
a
certain
pesticide
chemical
in
or
on
various
food
commodities
under
section
408
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a.
EPA
has
determined
that
this
petition
contains
data
or
information
regarding
the
elements
set
forth
in
FFDCA
section
408(
d)(
2);
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
support
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

List
of
Subjects
Environmental
protection,
Agricultural
commodities,
Feed
additives,
Food
additives,
Pesticides
and
pests,
Reporting
and
recordkeeping
requirements.

Dated:
May
29,
2003.
Janet
L.
Andersen,
Director,
Biopesticides
and
Pollution
Prevention
Division,
Office
of
Pesticide
Programs.

Summary
of
Petition
The
petitioner
summary
of
the
pesticide
petition
is
printed
below
as
required
by
FFDCA
section
408(
d)(
3).
The
summary
of
the
petition
was
prepared
by
the
petitioner
and
represents
the
view
of
the
petitioner.
The
petition
summary
announces
the
availability
of
a
description
of
the
analytical
methods
available
to
EPA
for
the
detection
and
measurement
of
the
pesticide
chemical
residues
or
an
explanation
of
why
no
such
method
is
needed.

Syngenta
Seeds,
Inc.

PP
3G6590
EPA
has
received
pesticide
petition
(
PP
3G6590)
from
Syngenta
Seeds,
Inc.,
P.
O.
Box
12257,
3054
Cornwallis
Road,
Research
Triangle
Park,
NC
27709
 
2257,
proposing
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180
to
establish
an
exemption
from
the
requirement
of
a
tolerance
for
the
plant­
pesticide
inert
ingredient
hygromycin
B
phosphotransferase
(
APH4)
marker
protein
and
the
genetic
material
VerDate
Jan<
31>
2003
23:
27
Jun
10,
2003
Jkt
200001
PO
00000
Frm
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Fmt
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4703
E:\
FR\
FM\
11JNN1.
SGM
11JNN1
34961
Federal
Register
/
Vol.
68,
No.
112
/
Wednesday,
June
11,
2003
/
Notices
necessary
for
its
production
in
or
on
cotton.
Pursuant
to
section
408(
d)(
2)(
A)(
i)
of
the
FFDCA,
as
amended,
Syngenta
Seeds,
Inc.
has
submitted
the
following
summary
of
information,
data,
and
arguments
in
support
of
their
pesticide
petition.
This
summary
was
prepared
by
Syngenta
Seeds,
Inc.
and
EPA
has
not
fully
evaluated
the
merits
of
the
pesticide
petition.
The
summary
may
have
been
edited
by
EPA
if
the
terminology
used
was
unclear,
the
summary
contained
extraneous
material,
or
the
summary
unintentionally
made
the
reader
conclude
that
the
findings
reflected
EPA's
position
and
not
the
position
of
the
petitioner.

A.
Product
Name
and
Proposed
Use
Practices
Hygromycin
B
phosphotransferase
(
APH4)
marker
protein
is
proposed
for
use
as
a
plant­
incorporated
protectant
formulation
inert
ingredient.
APH4
protein
is
an
aminocyclitol
phosphotransferase
that
catalyzes
the
phosphorylation
of
hygromycin
and
closely
related
aminoglycoside
antibiotics.
Expression
of
the
APH4
gene
in
plant
cells
allows
for
growth
and
selection
of
transformed
cells
in
the
presence
of
hygromycin
B.
APH4
has
no
insecticidal
activity.

B.
Product
Identity/
Chemistry
1.
Identity
of
the
pesticide
and
corresponding
residues.
The
aph4
gene
in
event
COT102
cotton
plants
was
derived
from
a
plasmid
harbored
by
a
hygromycin­
resistant
isolate
of
E.
coli,
and
encodes
a
341
amino­
acid
enzyme,
hygromycin
B
phosphotransferase
(
APH4).
Hygromycin
B
phosphotransferases
with
significant
homology
to
the
APH4
protein
in
event
COT102
plants
have
also
been
identified
in
other
microbes
including
Streptomyces
hygroscopicus,
the
source
of
hygromycin
B.
APH4
has
a
molecular
weight
of
ca.
42,000
and
catalyzes
the
phosphorylation
of
the
4­
hydroxyl
group
on
the
hyosamine
moiety
of
hygromycin
B,
thereby
inactivating
it.
The
enzyme
has
a
narrow
range
of
substrates,
in
that
it
phosphorylates
hygromycin
B,
hygromycin
B2
and
the
closely
related
antibiotics
destomycin
A
and
destomycin
B,
but
does
not
phosphorylate
other
aminocyclitol
or
aminoglycoside
antibiotics
including
neomycin,
streptomycin,
gentamicin,
kanamycin,
spectinomycin,
tobramycin,
and
amikacin.
Hygromycin
B
is
not
used
in
human
clinical
therapy,
but
is
principally
used
as
an
antihelminthic
agent
in
swine
and
poultry
feeds.
2.
Magnitude
of
residue
at
the
time
of
harvest
and
method
used
to
determine
the
residue.
A
determination
of
the
magnitude
of
residue
at
harvest
is
not
required
for
residues
exempt
from
tolerances.
However,
the
petitioner
has
provided
data
on
the
quantity
of
APH4
protein
measured
in
various
plant
parts
including
seeds
of
VIP3A
cotton,
as
measured
by
enzyme
linked
immunosorbent
assay
(
ELISA).
APH4
was
either
not
detectable
in
most
COT102
plant
tissues
or
the
levels
were
too
low
to
quantify.
Pollen
was
the
only
tissue
in
which
quantifiable
levels
were
measured.
3.
A
statement
of
why
an
analytical
method
for
detecting
and
measuring
the
levels
of
the
pesticide
residue
are
not
needed.
An
analytical
method
is
not
required
because
this
petition
requests
an
exemption
from
tolerances.
However,
the
petitioner
has
submitted
an
analytical
method
for
detection
of
the
APH4
protein
by
ELISA
analysis.

C.
Mammalian
Toxicological
Profile
Syngenta
Seeds
is
providing
the
results
of
a
mammalian
toxicology
study,
in
vitro
digestibility
study,
and
bioinformatics
evaluations
conducted
on
the
selectable
marker
protein
APH4.
These
studies,
summarized
herein,
demonstrate
the
lack
of
toxicity
of
the
APH4
protein
following
acute
oral
exposure
to
mice,
rapid
degradation
of
APH4
upon
exposure
to
simulated
gastric
and
intestinal
fluids,
and
the
lack
of
amino
acid
sequence
similarity
of
the
APH4
protein
to
proteins
known
to
be
mammalian
toxins
or
human
allergens.
When
proteins
are
toxic,
they
are
known
to
act
via
acute
mechanisms
and
at
very
low
doses
(
Ref.
1).
Therefore,
when
a
protein
demonstrates
no
acute
oral
toxicity
in
high­
dose
testing
using
a
standard
laboratory
mammalian
test
species,
this
supports
the
determination
that
the
protein
will
be
non­
toxic
to
humans
and
other
mammals,
and
will
not
present
a
hazard
under
any
realistic
exposure
scenario,
including
long­
term
exposures.
Because
it
is
not
possible
to
extract
sufficient
APH4
protein
from
transformed
plants
for
toxicology
studies,
APH4
protein
was
produced
in
recombinant
E.
coli
by
over­
expressing
the
same
aph4
gene
that
was
introduced
into
VIP3A
cotton
event
COT102.
The
aph4
gene
was
cloned
into
the
inducible,
over­
expression
pET­
3a
 
vector
(
Novagen,
Madison,
WI)
in
E.
coli
BL21DE3pLysS.
The
APH4
protein,
as
encoded
in
this
vector,
was
identical
in
amino
acid
sequence
to
that
encoded
by
the
plant
transformation
vector,
pCOT1,
except
for
an
additional
11
amino
acids
from
the
T7
TagTM
and
three
amino
acids
from
the
vector
polylinker.
Following
purification
from
E.
coli,
dialysis
and
lyophilization,
the
resulting
sample,
designated
Test
Substance
APH4­
0102,
was
estimated
by
ELISA
to
contain
ca.
42.6%
APH4
protein
by
weight.
The
test
material
was
confirmed
to
be
enzymatically
active.
An
acute
mouse
oral
toxicity
study
was
conducted
at
the
Syngenta
Central
Toxicology
Laboratory
(
Alderley
Park,
Macclesfield,
Cheshire,
UK)
according
to
OPPTS
Harmonized
Guideline
870.1100.
Test
substance
APH4­
0102
(
see
above
description
of
test
substance)
was
administered
to
five
male
and
five
female
mice
strain
Alderley
Park
albino
mouse
(
APfCD­
1);
8
 
9
weeks
old
via
a
gavage
dose
of
1,828
milligrams/
kilogram
(
mg/
kg)
body
weight.
The
test
substance
contained
ca.
42.6%
APH4
protein
by
weight.
Therefore,
the
mice
received
ca.
779
mg
APH4/
kg
body
weight.
A
negative
control
group
(
5
mice/
sex)
concurrently
received
the
dosing
vehicle
alone,
a
suspension
of
1%
methylcellulose,
at
the
same
dosing
volume
as
used
for
the
test
material
mixture.
Food
was
provided
ad
libitum,
except
during
the
ca.
1
 
hour
prior
to
dosing,
when
the
animals
were
fasted.
Water
was
provided
ad
libitum
throughout
the
study.
Observations
for
mortality
and
clinical/
behavioral
signs
of
toxicity
were
made
at
least
twice
on
the
day
of
dosing,
and
at
least
once
daily
thereafter
for
14
days.
Detailed
clinical
observations
were
made
for
each
animal
at
each
observation
time.
Body
weights
were
recorded
daily
and
food
consumption
was
recorded
weekly.
Surviving
animals
were
euthanized
14
days
post
dosing
and
subjected
to
gross
necropsy.
Organ
weights
(
brain,
liver
with
gall
bladder,
kidneys
and
spleen)
were
recorded
and
principal
tissues
were
processed
for
microscopic
examination.
No
mortalities
occurred
during
the
study,
and
no
clinical
signs
of
toxicity
were
observed
in
either
the
test
or
control
groups.
There
were
no
treatment­
related
effects
on
body
weight,
food
consumption,
or
organ
weights,
nor
were
any
treatment­
related
effects
observed
following
macroscopic
or
microscopic
examination.
APH4
 
0102
is
not
acutely
toxic
to
mice.
There
is
no
evidence
of
toxicity
of
the
test
substance
at
1,828
mg
APH4
 
0102/
kg
body
weight,
representing
ca.
779
mg
APH4
protein/
kg
body
weight.
The
estimated
LD50
value
for
pure
APH4
protein
in
male
and
female
mice
is
>
779
mg/
kg
body
weight,
the
single
dose
tested.
The
APH4
protein
shows
no
homology
to
proteins
known
to
be
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112
/
Wednesday,
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11,
2003
/
Notices
mammalian
toxins
or
human
allergens;
is
not
derived
from
a
source
known
to
produce
allergens;
is
not
targeted
to
a
cellular
pathway
for
glycosylation
in
the
plant;
and
is
rapidly
degraded
upon
exposure
to
simulated
gastric
and
intestinal.
The
genetic
material
necessary
for
the
production
of
APH4
as
an
inert
ingredient
are
the
nucleic
acids
(
DNA)
which
comprise
genetic
material
encoding
this
protein
and
its
regulatory
regions.
``
Regulatory
regions''
are
the
genetic
material
that
control
the
expression
of
the
genetic
material
encoding
the
protein,
such
as
promoters,
terminators,
and
enhancers.
DNA
is
common
to
all
forms
of
plant
and
animal
life
and
the
Agency
has
previously
stated
that
they
are
not
aware
of
an
instance
where
these
nucleic
acids
have
been
associated
with
toxic
effects
related
to
their
consumption
as
a
component
of
food.
These
ubiquitous
nucleic
acids,
as
they
appear
in
the
subject
inert
ingredient,
have
been
adequately
characterized.
Therefore,
no
mammalian
toxicity
is
anticipated
from
dietary
exposure
to
the
genetic
material
necessary
for
the
production
of
the
subject
inert
plant
pesticidal
ingredient.

D.
Aggregate
Exposure
1.
Dietary
exposure
 
i.
Food.
Derivatives
of
cottonseed
(
e.
g.,
refined
cottonseed
oil)
and
fiber
(
e.
g.,
linters,
which
are
essentially
100%
cellulose)
are
used
in
some
food
products.
However,
APH4
was
not
detected
in
most
of
the
samples
of
COT102­
derived
cottonseed
analyzed
or
any
of
the
cotton
fiber
samples
analyzed.
In
the
few
cottonseed
samples
in
which
APH4
was
detectable,
the
quantities
were
below
the
limit
of
quantification
(<
137
ng
APH4/
g
fresh
wt;
<
150
ng
APH4/
g
dry
wt).
It
is
expected
that
any
trace
quantities
of
APH4
in
cottonseed
will
be
eliminated
by
standard
seed
processing
methods.
As
demonstrated
by
the
analysis
of
cottonseed
products
for
VIP3A
protein,
no
VIP3A
was
detected
in
refined
cottonseed
oil
from
COT102­
derived
plants,
despite
the
presence
of
ca.
3
micrograms
VIP3A/
g
seed
(
fresh
or
dry
wt.).
Additionally,
no
protein
of
any
kind
was
detected
in
the
same
sample
of
refined
cottonseed
oil.
It
can
be
concluded
that
APH4,
as
produced
in
COT102­
derived
cotton
plants,
does
not
pose
a
risk
of
becoming
allergenic
via
food,
because
there
will
be
no
exposure
via
food.
Additionally,
the
APH4
protein
shows
no
amino
acid
sequence
homology
to
known
allergens;
is
not
derived
from
a
source
known
to
produce
allergens;
is
not
targeted
to
a
cellular
pathway
for
glycosylation
in
the
plant;
and
is
rapidly
degraded
upon
exposure
to
simulated
gastric
and
intestinal.
ii.
Drinking
water.
No
exposure
to
the
APH4
and
the
genetic
material
necessary
for
its
production
as
an
inert
ingredient
via
drinking
water
are
expected.
The
protein
is
incorporated
into
the
plant
and
will
therefore
not
be
available
to
drinking
water
sources.
2.
Non­
dietary
exposure.
Non­
dietary
exposure
is
not
anticipated,
due
to
the
proposed
use
pattern
of
the
product.
Exposure
via
dermal
or
inhalation
routes
is
unlikely
because
the
inert
ingredient
is
contained
within
plant
cells.
However,
if
exposure
were
to
occur
by
non­
dietary
routes,
no
risk
would
be
expected
because
the
APH4
protein
is
not
toxic
to
mammals.

E.
Cumulative
Exposure
Because
there
is
no
indication
of
mammalian
toxicity
to
the
APH4
protein,
it
is
reasonable
to
conclude
that
there
are
no
cumulative
effects
for
this
inert
ingredient.

F.
Safety
Determination
1.
U.
S.
population.
The
lack
of
mammalian
toxicity
at
high
levels
of
exposure
to
the
APH4
protein
demonstrates
the
safety
of
the
product
at
levels
well
above
possible
maximum
exposure
levels
anticipated
via
consumption
of
processed
food
products
produced
from
VIP3A
cotton.
Moreover,
little
to
no
human
dietary
exposure
to
APH4
protein
is
expected
to
occur
via
VIP3A
cotton.
Due
to
the
lack
of
toxicity
of
the
APH4
protein
and
its
very
low
potential
for
allergenicity,
dietary
exposure
is
not
anticipated
to
pose
any
harm
for
the
U.
S.
population.
No
special
safety
provisions
are
applicable
for
consumption
patterns
or
for
any
population
sub­
groups.
2.
Infants
and
children.
Syngenta
has
evaluated
the
acute
toxicity
data
generated
on
APH4,
the
lack
of
homology
to
known
allergens
or
toxins,
and
the
limited
exposure
to
this
protein
based
on
the
residue
profile
and
limited
number
of
food/
feed
products
resulting
from
cotton
and
has
determined
that
there
is
ample
evidence
to
indicate
a
reasonable
certainty
of
no
harm
to
infants
and
children
as
a
result
of
the
use
of
this
product.

G.
Effects
on
the
Immune
and
Endocrine
Systems
The
inert
ingredient
APH4
is
a
protein,
derived
from
sources
that
are
not
known
to
exert
an
influence
on
the
endocrine
or
immune
systems.

H.
Existing
Tolerances
The
registrant
is
not
aware
of
any
known
existing
tolerances
or
exemptions
for
APH4
and
the
genetic
material
necessary
for
its
production
as
an
inert
ingredient.

I.
International
Tolerances
The
registrant
is
not
aware
that
any
Codex
maximum
residue
levels
exist
for
the
APH4
protein
and
the
genetic
material
necessary
for
its
production.

J.
Reference
1.
Sjoblad,
R.
D.,
J.
T.
McClintock
and
R.
Engler
(
1992)
Toxicological
considerations
for
protein
components
of
biological
pesticide
products.
Regulatory
Toxicol.
Pharmacol.
15:
3
 
9.

[
FR
Doc
03
 
14327
Filed
6
 
10
 
03;
8:
45
am]

BILLING
CODE
6560
 
50
 
S
ENVIRONMENTAL
PROTECTION
AGENCY
[
OPP
 
2003
 
0187;
FRL
 
7311
 
8]

Experimental
Use
Permit;
Receipt
of
Application
for
Use
of
Aspergillus
Flavus
NRRL
21882
AGENCY:
Environmental
Protection
Agency
(
EPA).
ACTION:
Notice.

SUMMARY:
This
notice
announces
receipt
of
an
application
75624­
EUP­
R
from
Circle
One
Global,
Inc.
requesting
an
experimental
use
permit
(
EUP)
for
the
Aspergillus
flavus
NRRL
21882.
The
Agency
has
determined
that
the
application
may
be
of
regional
and
national
significance.
Therefore,
in
accordance
with
40
CFR
172.11(
a),
the
Agency
is
soliciting
comments
on
this
application.

DATES:
Comments,
identified
by
docket
ID
number
OPP
 
2003
 
0187,
must
be
received
on
or
before
July
11,
2003.
ADDRESSES:
Comments
may
be
submitted
electronically,
by
mail,
or
through
hand
delivery/
courier.
Follow
the
detailed
instructions
as
provided
in
Unit
I.
of
the
SUPPLEMENTARY
INFORMATION.

FOR
FURTHER
INFORMATION
CONTACT:
Shanaz
Bacchus,
Biopesticides
and
Pollution
Prevention
Division
(
7511C),
Office
of
Pesticide
Programs,
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460
 
0001;
telephone
number:
(
703)
308
 
8097;
e­
mail
address:
bacchus.
shanaz@
epa.
gov.

SUPPLEMENTARY
INFORMATION:

I.
General
Information
A.
Does
this
Action
Apply
to
Me?

This
action
is
directed
to
the
public
in
general.
This
action
may,
however,
be
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