79918
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
0
estimate,
1.86
parts
per
billion
(
ppb),
was
used
in
the
acute
exposure
analysis
and
the
corrected
56
 
day
drinking
water
concentration
of
0.4667
ppb
was
used
in
the
chronic
exposure
analysis.
The
SCIGROW
estimated
ground
water
concentration
for
the
prosulfuron
uses
of
0.406585
ppb
contributed
little
to
the
overall
exposure.
The
acute
drinking
water
levels
of
concern
(
DWLOC)
for
prosulfuron
were
based
on
the
acute
RfD,
a
margin
of
exposure
(
MOE),
the
99.9th
percentile
of
the
acute
dietary
exposure
for
U.
S.
population
subgroups
and
the
body
weight
­
daily
water
consumption
of
each
respective
subgroup.
The
calculated
acute
DWLOC
values
for
the
population
subgroups
ranged
from
978
 
3447
ppb.
The
estimated
ground
water
concentration
(
0.406585
ppb)
and
the
peak
day
 
0
surface
water
concentration
(
1.86
ppb)
of
prosulfuron
did
not
exceed
the
acute
DWLOC
values.
The
chronic
(
noncancer
DWLOC
for
prosulfuron
were
based
on
the
chronic
RfD,
any
estimated
residential
exposure,
the
chronic
dietary
exposure
for
select
U.
S.
population
subgroups
and
the
body
weight
­
daily
water
consumption
of
each
respective
subgroup.
The
calculated
chronic
DWLOC
values
for
the
population
subgroups
ranged
from
197
 
694.
The
estimated
ground
water
concentration
(
0.406585
ppb)
and
the
corrected
average
56
 
day
surface
water
concentration
(
0.4667
ppb)
of
prosulfuron
did
not
exceed
the
chronic
DWLOC
values.
Therefore,
there
is
reasonable
certainty
that
the
residues
of
prosulfuron
in
the
drinking
water
would
not
result
in
unacceptable
levels
of
acute
or
chronic
aggregate
human
health
risk,
and
that
such
exposure
would
not
exceed
the
exposure
allowable
by
the
risk
cup.
Nondietary
exposure.
Nondietary
exposure
to
prosulfuron
is
considered
negligible
as
the
chemical
is
registered
for
agricultural
use
only.
For
workers
handling
this
chemical,
acceptable
MOE
(
in
the
range
of
thousands)
have
been
obtained
for
both
acute
and
chronic
scenarios.

D.
Cumulative
Effects
Consideration
of
a
common
mechanism
of
toxicity
is
not
appropriate
at
this
time
since
there
is
no
information
to
indicate
that
toxic
effects
produced
by
prosulfuron
would
be
cumulative
with
those
of
any
other
types
of
chemicals.

E.
Safety
Determination
1.
U.
S.
population.
The
calculation
shows
that
less
than
1%
of
the
RfD
will
be
utilized
for
the
U.
S.
population
based
on
chronic
toxicity
endpoints.
EPA
generally
has
no
concern
for
exposures
below
100%
of
the
RfD
because
the
RfD
represents
the
level
at
or
below
which
daily
aggregate
dietary
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
It
is
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
prosulfuron
residue.
2.
Infants
and
children.
The
calculated
percent
of
the
RfD
that
will
be
utilized
by
aggregate
exposure
to
residues
of
prosulfuron
is
only
2.4%
for
children
(
1
to
6
years
old),
the
most
impacted
subpopulation.
There
were
no
adverse
reproductive
or
developmental
effects
indicated
in
the
prosulfuron
toxicity
data
base,
which
is
considered
to
be
essentially
complete
with
no
data
gaps.
It
is
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate
exposure
to
prosulfuron
residues.

F.
International
Tolerances
No
codex
MRLs
have
been
established
for
residues
of
prosulfuron.
[
FR
Doc.
02
 
32988
Filed
12
 
30
 
02;
8:
45
am]

BILLING
CODE
6560
 
50
 
S
ENVIRONMENTAL
PROTECTION
AGENCY
[
OPP
 
2002
 
0349;
FRL
 
7285
 
6]

Flumioxazin;
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
pesticide
petitions
proposing
the
establishment
of
regulations
for
residues
of
a
certain
pesticide
chemical
in
or
on
various
food
commodities.
DATES:
Comments,
identified
by
docket
ID
number
OPP
 
2002
 
0349,
must
be
received
on
or
before
January
30,
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:
Joanne
I.
Miller,
Registration
Division
(
7505C),
Office
of
Pesticide
Programs,
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460
 
0001;
telephone
number:
(
703)
305
 
6224;
e­
mail
address:
Miller.
Joanne@
epamail.
epa.
gov.
SUPPLEMENTARY
INFORMATION:

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

You
may
be
affected
by
this
action
if
you
are
an
agricultural
producer,
food
manufacturer,
or
pesticide
manufacturer.
Potentially
affected
categories
and
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
the
table
could
also
be
affected.
The
North
American
Industrial
Classification
System
(
NAICS)
codes
have
been
provided
to
assist
you
and
others
in
determining
whether
or
not
this
action
might
apply
to
certain
entities.
If
you
have
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
 
2002
 
0349.
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,

VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00018
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79919
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
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.
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
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
 
2002
 
0349.
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
 
2002
 
0349.
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
 
2002
 
0349.
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
 
2002
 
0349.
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.

VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00019
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79920
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
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:
December
20,
2002.
Debra
Edwards,
Acting
Director,
Registration
Division,
Office
of
Pesticide
Programs.

Summary
of
Petition
The
petitioner
summary
of
the
pesticide
petitions
is
printed
below
as
required
by
FFDCA
section
408(
d)(
3).
The
summary
of
the
petitions
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.

Valent
U.
S.
A.
Corporation
1F6296
and
0F6171
EPA
has
received
pesticide
petitions
(
PP
1F6296,
0F6171)
from
Valent
U.
S.
A.
Corporation,
1333
North
California
Boulevard,
Suite
600,
Walnut
Creek,
California
94596­
8025
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
by
establishing
a
tolerance
for
residues
of
the
herbicide
chemical
flumioxazin,
2­[
7­
fluoro­
3,4­
dihydro­
3­
oxo­
4­(
2­
propynyl)­
2H­
1,4­
benzoxazin­
6­
yl]­
4,5,6,7­
tetrahydro­
1H­
isoindole­
1,3(
2H)­
dione,
in
or
on
the
raw
agricultural
commodities
cotton
at
0.02
parts
per
million
(
ppm),
cotton,
gin
byproducts
at
0.60
ppm,
grape
at
0.02
ppm,
almonds
at
0.02
ppm,
almond,
hulls
at
0.70
ppm
and
sugarcane
at
0.20
ppm.
EPA
has
determined
that
the
petitions
contain
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
Metabolism
of
14C­
flumioxazin
labeled
in
the
phenyl­
or
tetrahydrophthalimido­
rings
has
been
studied
in
soybeans,
peanuts,
grapes
and
corn.
Flumioxazin
was
rapidly
and
extensively
metabolized
to
many
metabolites
in
all
plants.
Even
with
exaggerated
treatment,
individual
metabolites
and
parent
were
only
found
at
very
low
concentrations.
Comparisons
of
metabolites
detected
and
quantified
from
plants
and
animals
show
that
there
are
no
significant
aglycones
in
plants
which
are
not
also
present
in
the
excreta
or
tissues
of
animals.
The
residue
of
concern
is
best
defined
as
the
parent.
2.
Analytical
method.
Practical
analytical
methods
for
detecting
and
measuring
levels
of
flumioxazin
have
been
developed
and
validated
in/
on
all
appropriate
agricultural
commodities
and
respective
processing
fractions.
The
extraction
methodology
has
been
validated
using
aged
radiochemical
residue
samples
from
14C­
metabolism
studies.
The
enforcement
method
has
been
validated
in
soybean
at
an
independent
laboratory
and
by
EPA.
The
limit
of
quantitation
(
LOQ)
of
flumioxazin
in
the
method
is
0.02
ppm
which
will
allow
monitoring
of
food
with
residues
at
the
levels
proposed
for
the
tolerances.
3.
Magnitude
of
residues
 
i.
Cotton.
Thirteen
field
trials
in
cotton
were
conducted
in
1999
in
EPA
Regions
II
(
1
trial),
IV
(
4
trials),
VI
(
1
trial),
VIII
(
4
trials),
and
X
(
3
trials),
representing
approximately
97%
of
the
U.
S.
cotton
growing
regions.
Seasonal
treatment
ranged
from
0.190
to
0.375
pounds
active
ingredient
per
acre
[
two
applications
of
0.095
lb.
a.
i./
A
each
or
two
applications
of
0.187
lb.
a.
i./
A
each],
1.5­
to
3­
times
the
proposed
application
rate
for
high
organic
soils.
Application
of
VALOR
was
done
lay­
by
and
post
direct
to
the
soil
and
not
over
the
top.
Finite
residues
of
flumioxazin
were
detected
in
7
of
26
duplicate
samples
cottonseed
and
in
14
of
the
16
duplicate
samples
of
gin
trash.
The
LOQ
of
the
residue
method
was
0.01
ppm,
and
the
limit
of
detection
(
LOD)
was
0.005
ppm.
No
residues
of
1­
OH­
HPA
were
detected
(<
0.005
ppm)
in
any
cottonseed
or
gin
trash
sample,
including
samples
from
trial
treated
at
the
2X
rate.
The
data
demonstrate
that
1­
OH­
HPA
is
not
a
residue
of
concern
in
cottonseed
or
cotton
gin
trash.
No
residues
of
flumioxazin
or
its
degradate
were
found
in
the
processed
commodities
treated
ginned
seed,
hulls,
solvent
extracted
meal
and
refined
oil.
All
these
data
support
proposed
tolerance
for
flumioxazin
in/
on
cotton
at
0.02
ppm,
and
in/
on
cotton,
gin
byproducts
at
0.60
ppm.
No
separate
tolerances
are
needed
for
cotton
processed
commodities.
ii.
Grapes.
Twelve
field
trials
in
grapes
were
conducted
in
1999
in
EPA
Regions
I
(
2
trials)
Region
X
(
9
trials)
and
Region
XI
(
1
trial),
representing
approximately
96%
of
the
U.
S.
grapes
growing
regions.
Seasonal
treatment
ranged
from
0.75
to
3.75
pounds
active
ingredient
per
acre
[
two
applications
of
0.375
lb.
a.
i./
A
each
or
two
applications
of
1.87
lb.
a.
i./
A
each]
1
to
5­
times
the
proposed
application
rate.
Application
on
grapes
was
post
direct
and
not
over
the
top.
At
the
proposed
maximum
seasonal
rate
of
0.75
lb.
a.
i./
A,
no
residues
of
flumioxazin
were
found
in/
on
grapes
from
all
12
trials.
Residues
of
flumioxazin
were
detected
in
only
one
of
six
samples
treated
at
2X
application
rate
(
seasonal
total
of
1.5
lb.
a.
i./
A).
The
residue
found,
0.005
ppm,
was
below
the
LOQ
of
0.01
ppm.

VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00020
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79921
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
Grapes
treated
at
5X
(
seasonal
total
of
3.75
lb.
a.
i./
A)
the
proposed
use
rate
were
processed
into
grape
juice
and
raisins.
The
RAC
grapes
contained
0.006
ppm
flumioxazin.
No
residues
(<
0.005
ppm)
of
flumioxazin
were
found
in
grape
juice.
In
raisins
0.007
ppm
flumioxazin
was
detected.
These
residues
were
below
the
LOQ
of
0.01
ppm.
The
data
demonstrate
no
concentration
of
flumioxazin
residues
in
juice
and
raisins.
All
these
data
support
a
proposed
tolerance
for
flumioxazin
in/
on
grapes
of
0.02
ppm.
No
separate
tolerances
are
needed
for
grapes
processed
commodities.
iii.
Almond.
Five
field
trials
in
almonds
were
conducted
in
1999
in
EPA
Regions
X,
representative
of
all
U.
S.
almond
growing
regions.
Seasonal
treatment
ranged
from
0.75
to
1.5
pounds
active
ingredient
per
acre
[
two
applications
of
0.375
lb.
a.
i./
A
each
or
two
applications
of
0.75
lb.
a.
i./
A
each]
1
to
2­
times
the
proposed
application
rate.
Application
on
almonds
was
done
post
direct
and
not
over
the
top.
At
the
proposed
maximum
seasonal
rate
of
0.75
lb.
a.
i./
A,
no
residues
of
flumioxazin
were
found
in/
on
almond
nutmeat
greater
than
the
LOQ
(
0.01
ppm).
The
highest
average
field
Trial
for
residues
of
flumioxazin
in/
on
almond
hulls
was
0.552
ppm.
Residues
of
1­
OHHPA
were
not
detected
in
any
sample
of
almond
hulls
(<
0.05
ppm).
The
LOQ
and
LOD
of
the
residue
method
for
1­
OHHPA
in/
on
almond
hulls
were
0.1
ppm
and
0.05
ppm,
respectively.
All
these
data
support
a
proposed
tolerance
for
flumioxazin
in/
on
almond
of
0.02
ppm,
and
in/
on
almond
hulls
of
0.6
ppm.
iv.
Sugarcane.
Nine
field
trials
in
sugarcane
were
conducted
in
1998
in
EPA
Regions
III
(
4
trials),
IV
(
3
trials),
VI
(
1
trial),
and
XIII
(
1
trial),
representative
of
all
of
the
U.
S.
sugarcane
growing
regions.
Treatments
ranged
from
0.37
to
1.12
pounds
active
ingredient
per
acre,
1­
to
3­
times
the
proposed
application
rate
for
high
organic
soils.
Finite
residues
of
flumioxazin
were
detected
in
14
of
18
duplicate
samples.
Residues
of
flumioxazin
averaged
0.039
ppm
(
standard
deviation
=
0.033
ppm)
from
the
trials
conducted
at
the
proposed
maximum
application
rate.
Analysis
for
the
major
plant
metabolite,
1­
OH­
HPA,
was
conducted
on
all
cane
samples
including
those
from
the
two
3X
processing
trials.
No
residues
of
the
degradate
were
found
in
any
cane
sample.
No
residues
of
flumioxazin
or
its
degradate
were
found
in
the
processed
commodity
refined
sugar.
In
molasses,
produced
from
cane
treated
at
three
times
the
proposed
label
rate,
flumioxazin
was
detected
(
0.055
ppm)
at
approximately
half
of
the
concentration
in
the
starting
sugarcane.
The
degradate,
1­
OH­
HPA,
was
also
detected
in
molasses
(
0.036
ppm).
Because
these
detections
were
in
a
processed
sample
from
cane
treated
at
3X,
and
are
still
less
than
the
proposed
RAC
tolerance,
no
separate
processed
product
tolerances
are
necessary.
All
these
data
support
a
proposed
tolerance
for
flumioxazin
in/
on
sugarcane
at
0.20
ppm.
No
separate
tolerances
for
parent
or
degradate
are
needed
for
processed
commodities.

B.
Toxicological
Profile
1.
Acute
toxicity.
The
acute
toxicity
of
technical
grade
flumioxazin
is
low
by
all
routes.
The
battery
of
acute
toxicity
studies
place
flumioxazin
in
Toxicity
Category
III.
i.
No
abnormal
clinical
signs,
body
weight
changes,
or
gross
pathological
findings
were
observed
and
no
rats
died
following
administration
of
an
oral
dose
of
5
g/
kg
of
flumioxazin
technical.
The
LD50
was
greater
than
5
g/
kg.
ii.
No
deaths,
abnormal
clinical
signs,
body
weight
changes,
or
gross
pathological
findings
were
observed
in
rats
exposed
to
a
2.0
g/
kg
dermal
dose
of
flumioxazin
technical.
The
LD50
was
greater
than
2.0
g/
kg.
iii.
Rats
were
exposed
to
a
dust
aerosol
of
flumioxazin
technical
for
4
hours
at
measured
concentrations
of
1.55
or
3.93
mg/
l,
the
maximum
attainable
concentration.
Irregular
respiration,
bradypnea
and
a
decrease
in
spontaneous
activity
were
observed
in
many
of
the
rats,
but
these
effects
disappeared
within
2
hours
after
termination
of
the
exposure.
No
deaths,
body
weight
changes,
gross
pathological
findings
or
histopathological
changes
in
the
respiratory
organs
were
observed.
The
LC50
for
flumioxazin
technical
was
determined
to
be
greater
than
3.93
mg/
l.
iv.
Flumioxazin
technical
produced
minimal
eye
irritation
in
rabbits
which
cleared
within
48
hours.
v.
Flumioxazin
technical
did
not
produce
any
signs
of
skin
irritation
in
abraded
or
intact
skin
of
rabbits.
vi.
Flumioxazin
technical
was
not
a
skin
sensitizer
when
tested
in
guinea
pigs
using
the
Magnussen
and
Kligman
maximization
test
methodology.
2.
Genotoxicty.
Flumioxazin
does
not
present
a
genetic
hazard.
Flumioxazin
was
evaluated
in
the
following
tests
for
mutagenicity:
i.
A
reverse
gene
mutation
assay
in
Salmonella
typhimurium
and
Escherichia
coli
was
negative
with
or
without
metabolic
activation.
ii.
An
in
vitro
chromosome
aberration
assay
using
Chinese
hamster
ovary
(
CHO)
cells
was
negative
in
the
absence
of
metabolic
activation.
However,
an
increase
in
cells
with
aberrations
was
observed
at
doses
of
1
x
10­
4
M
and
higher
in
the
presence
of
S9.
iii.
An
in
vivo
chromosomal
aberration
study
in
the
rat
was
negative.
No
significant
increase
in
the
incidence
of
chromosomal
aberrations
in
bone
marrow
cells
was
observed
following
treatments
as
high
as
5,000
mg/
kg.
iv.
An
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assay
with
rat
hepatocytes
was
negative.
v.
A
mouse
micronucleus
assay
was
negative
following
intraperitoneal
injection
of
5,000
mg/
kg.
3.
Reproductive
and
developmental
toxicity.
Flumioxazin
shows
developmental
toxicity
in
the
absence
of
maternal
toxicity
in
rats.
Mechanistic
studies
demonstrate
that
the
effect
is
specifically
related
to
the
inhibition
of
heme
synthesis,
that
the
effect
shows
considerable
species
specificity,
and
that
the
rat
is
a
conservative
surrogate
species
for
the
potential
for
developmental
toxicity
in
man.
No
developmental
toxicity
was
observed
in
rabbits.
Developmental
toxicity
to
the
pups
was
seen
in
the
rat
reproduction
study
at
doses
that
were
not
toxic
to
the
parental
animals.
i.
Rat­­
developmental
toxicity.
A
pilot
dose
range­
finding
study
was
conducted
to
determine
appropriate
doses
for
the
definitive
oral
developmental
toxicity
study.
Flumioxazin
technical
was
administered
by
oral
gavage
at
dosages
of
0,
30,
100,
200
and
500
mg/
kg/
day
to
pregnant
rats
on
days
6
through
15
of
gestation.
No
animals
died
during
the
course
of
this
study
and
maternal
toxicity
was
limited
to
decreased
weight
gain
associated
with
high
embryolethality
observed
in
all
dose
groups.
Fetuses
obtained
from
the
30
mg/
kg/
day
dams
had
significantly
reduced
body
weights
and
were
found
to
have
both
skeletal
and
visceral
abnormalities­­
primarily
wavy
ribs
and
ventricular
septal
defects
(
VSD).
Because
of
the
high
degree
of
embryolethality
at
doses
of
100
mg/
kg/
day
and
greater,
the
highest
dose
selected
for
the
definitive
study
was
30
mg/
kg/
day.
In
the
definitive
study,
pregnant
rats
were
administered
oral
doses
of
0,
1,
3,
10
or
30
mg/
kg/
day
of
flumioxazin
technical
on
days
6
through
15
of
gestation.
No
maternal
deaths
were
observed
at
any
dosage
and
no
treatment­
related
effects
on
clinical
signs
or
food
consumption
were
noted.

VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00021
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79922
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
A
decrease
in
maternal
body
weight
gain
was
found
at
30
mg/
kg/
day.
The
number
of
live
fetuses
and
fetal
body
weights
were
decreased
in
the
30
mg/
kg/
day
group
and
the
incidence
of
embryo
mortality
tended
to
be
higher
but
was
not
statistically
significant.
No
effects
on
the
number
of
implantations,
sex
ratios,
or
external
abnormalities
were
found.
The
incidence
of
fetuses
with
cardiovascular
abnormalities,
primarily
VSD,
was
increased
in
the
30
mg/
kg/
day
group.
Other
developmental
effects
observed
at
30
mg/
kg/
day
included
an
increase
in
the
incidence
of
wavy
ribs
and
curvature
of
the
scapula,
and
a
decrease
in
the
number
of
ossified
sacrococcygeal
vertebral
bodies.
Based
on
these
findings,
a
maternal
NOEL
of
30
mg/
kg/
day
and
a
developmental
NOEL
of
3
mg/
kg/
day
are
proposed.
In
a
range­
finding
dermal
developmental
toxicity
study
flumioxazin
technical
was
administered
dermally
at
levels
of
100,
200,
400
and
800
mg/
kg/
day
in
corn
oil.
No
adverse
effects
on
the
dams
were
observed
at
doses
up
to
800
mg/
kg/
day.
Because
of
the
high
degree
of
embryolethality
at
doses
of
400
mg/
kg/
day
and
greater,
the
highest
dose
selected
for
the
definitive
study
was
300
mg/
kg/
day.
On
days
6­
15
of
gestation,
pregnant
rats
were
exposed
dermally
to
dose
levels
of
30,
100,
or
300
mg/
kg/
day
of
flumioxazin
technical
in
corn
oil.
No
adverse
effects
were
observed
in
the
dams
throughout
the
study.
Increased
fetal
mortality
was
accompanied
by
decreases
in
the
number
of
live
fetuses
and
fetal
body
weights
at
doses
of
300
mg/
kg/
day.
No
external
abnormalities
were
observed
at
any
dose
level.
An
increase
in
cardiovascular
abnormalities,
primarily
VSD,
an
increase
in
wavy
ribs
and
a
decrease
in
the
number
of
ossified
sacrococcygeal
vertebral
bodies
was
observed
at
300
mg/
kg/
day.
Based
on
these
results,
a
maternal
NOEL
of
300
mg/
kg/
day
and
a
developmental
NOEL
of
30
mg/
kg/
day
are
proposed.
To
measure
the
dermal
penetration
of
flumioxazin
under
the
conditions
of
the
dermal
teratology
study,
13­
day
pregnant
rats
were
dermally
exposed
to
[
phenyl­
14C]
flumioxazin.
The
systemic
absorption
ranged
from
3.8%
at
2
hours
to
6.9%
of
the
recovered
14C
at
48
hours.
ii.
Mechanistic
studies.
A
series
of
scientific
studies
were
conducted
to
examine
the
mechanism
and
species
differences
in
the
production
of
developmental
toxicity
by
flumioxazin.
This
research
demonstrates
clear
species
differences
between
rats,
rabbits,
mice,
and
(
in
vitro)
humans
and
indicates
a
high
degree
of
correlation
between
the
interruption
of
heme
synthesis
and
the
production
of
developmental
toxicity
in
rats.
The
data
support
that
the
rat
is
a
conservative
model
for
use
in
the
risk
assessment
for
humans.
Specifically
the
studies
demonstrate
that:
 
Flumioxazin
interferes
with
normal
heme
biosynthesis
resulting
in
sidroblastic
anemia
and
porphyria
in
adult
rats.
 
14C­
Flumioxazin
administered
to
pregnant
rats
on
day
12
of
gestation
crosses
the
placenta
and
reaches
the
rat
fetus
at
maximum
levels
of
radiocarbon
(
and
flumioxazin),
4
hours
later.
 
No
clear
pattern
of
adsorption,
distribution,
metabolism,
or
excretion
was
evident
which
could
account
for
the
species­
specific
development
toxicity
in
rats.
 
The
critical
period
of
sensitivity
to
the
developmental
effects
of
flumioxazin
in
rats
is
day
12
of
gestation.
This
correlates
with
the
peak
period
of
protoporphyrin
IX
(
PPIX)
accumulation
in
maternal
rat
liver
and
the
rat
fetus.
 
A
histological
examination
of
rat
fetus
indicated
signs
of
fetal
anemia
within
6
hours
after
dosing,
but
no
histological
changes
in
the
fetal
rat
heart
were
observed
until
36
or
48
hour
after
treatment.
No
effects
were
observed
in
rabbit
fetus
treated
in
the
same
manner
as
the
rats.
 
Other
observations
in
the
pathogenesis
of
the
developmental
effects
of
flumioxazin
in
rat
fetuses
included:
enlarged
heart,
edema,
anemia
(
decreased
red
blood
cell
count
and
hemoglobin),
delayed
closure
of
the
interventricular
foramen,
reduced
serum
protein
and
incomplete/
delayed
ossification
of
the
ribs.
 
The
observation
of
enlarged
heart,
edema
and
anemia
preceding
the
occurrence
of
fetal
mortality
suggest
these
effects
may
be
instrumental
in
the
cause
of
fetal
deaths.
 
The
occurrence
of
an
enlarged
heart
preceding
the
failure
of
interventricular
foramen
closure
could
be
related
to
the
pathogenesis
rather
than
a
direct
toxic
effect
of
flumioxazin
on
cardiac
tissue.
 
A
strong
correlation
exists
between
PPIX
accumulation,
an
indicator
of
disrupted
heme
synthesis,
and
developmental
toxicity.
Evidence
of
this
correlation
exists
on
the
basis
of
species
differences
between
rats
and
rabbits;
the
critical
period
of
sensitivity
in
the
rat;
and
compound­
specific
differences
with
two
chemicals
structurally
related
to
flumioxazin,
one
which
produces
developmental
effects
in
rats
and
one
which
does
not.
iii.
Rabbits.
In
a
pilot
dose
rangefinding
study
in
rabbits,
flumioxazin
technical
was
administered
to
rabbits
on
days
7
through
19
of
gestation
via
oral
intubation
at
dosages
of
0,
300,
500,
1,000
and
1,500
mg/
kg/
day.
Clinical
observations
were
recorded
and
on
day
29
of
gestation,
all
does
were
sacrificed,
caesarean
sectioned,
and
examined
for
gross
lesions,
number
of
corpora
lutea,
and
number
and
placement
of
implantation
sites,
early
and
late
resorptions
and
live
and
dead
fetuses.
No
deaths,
abortions
or
premature
deliveries
occurred
during
this
study.
Dosages
of
flumioxazin
technical
as
high
as
1,500
mg/
kg/
day
did
not
result
in
significant
clinical
or
necropsy
observations
nor
affect
maternal
body
weight
gains
or
feed
consumption
values.
Similarly,
there
were
no
adverse
effects
of
dosages
of
flumioxazin
technical
up
to
1,500
mg/
kg/
day
on
embryo­
fetal
viability,
sex
ratios,
body
weights
or
external
morphology.
Based
on
these
results,
pregnant
rabbits
were
administered
0,
300,
1,000,
or
3,000
mg/
kg/
day
of
flumioxazin
technical
on
days
7
­
19
of
gestation
by
oral
gavage.
The
highest
dose
was
well
in
excess
of
the
1,000
mg/
kg/
day
limit
dose
for
developmental
toxicity
studies.
The
3,000
mg/
kg/
day
dosage
tended
to
reduce
maternal
body
weight
gains
and
relative
and
absolute
feed
consumption
values.
No
gross
lesions
were
produced
at
any
dose
level.
The
3,000
mg/
kg/
day
dosage
group
litters
tended
to
have
reduced
fetal
body
weights
but
these
differences
were
not
statistically
different.
No
fetal
external,
soft
tissue,
or
skeletal
malformations
or
variants
were
attributable
to
the
test
substance.
Based
on
these
data,
the
maternal
NOEL
was
1,000
mg/
kg/
day
and
the
developmental
NOEL
was
3,000
mg/
kg/
day.
iv.
Reproduction.
Two
pilot
rangefinding
rat
reproduction
studies
were
conducted
with
flumioxazin
technical
at
dosages
from
100
to
5,000
ppm
in
the
diet.
In
the
definitive
two­
generation
reproduction
study
in
the
rat
dietary
levels
of
0,
50,
100,
200
and
300
ppm
established
a
systemic
NOEL
of
200
ppm
based
on
increased
clinical
signs
(
both
sexes
and
generations);
mortality,
gross
and
histopathology
findings
in
the
liver
(
F1
females);
decreased
body
weight/
weight
gain
(
F0
and
F1
females
during
gestation,
F1
males
during
premating)
and
decreased
food
consumption
(
F0
and
F1
females
during
lactation).
The
reproductive
NOEL
of
100
ppm
was
mainly
based
on
developmental
toxicity
at
200
ppm.
Observed
at
200
ppm
were
a
decreased
number
of
live­
born
pups
and
reduced
pup
body
weights.
At
300
ppm
the
following
effects
were
observed:
decreased
pup
body
weight
(
both
generations);
decreased
number
of
live
pups/
litter
and
viability
index
(
both
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00022
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79923
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
generations);
increased
incidence
of
abnormalities
of
the
reproductive
organs
(
predominately
atrophied
or
hypoplastic
testes
and/
or
epididymides
in
F1
males);
decreased
gestation
index
(
F0
females);
decreased
mating
and
fertility
indices
(
F1
males)
and
increased
clinical
signs
(
F1
pups).
4.
Subchronic
toxicity.
Subchronic
toxicity
studies
conducted
with
flumioxazin
technical
in
the
rat
(
oral
and
dermal),
mouse
and
dog
indicate
a
low
level
of
toxicity.
Effects
observed
at
high
dose
levels
consisted
primarily
of
anemia
and
histological
changes
in
the
spleen,
liver
and
bone
marrow
related
to
the
anemia.
i.
Rats.
A
90­
day
subchronic
toxicity
study
was
conducted
in
rats,
with
dietary
intake
levels
of
0,
30,
300,
1,000
and
3,000
ppm
flumioxazin
technical
(
98.4%
purity).
The
no­
observed­
effectlevel
(
NOEL)
of
300
ppm
was
based
on
decreased
body
weights;
anemia;
increases
in
absolute
and/
or
relative
liver,
kidney,
brain
heart
and
thyroid
weights;
and
histological
changes
in
the
spleen,
liver
and
bone
marrow
related
to
the
anemia.
A
second
90
 
day
subchronic
toxicity
study
was
conducted
with
a
sample
of
Flumioxazin
Technical
of
typical
purity
(
94.8%)
at
dietary
concentrations
of
0,
30,
300,
1,000
and
3,000
ppm.
The
NOEL
was
30
ppm
based
on
anemia
and
related
hematological
changes;
increases
in
liver,
heart,
kidney
and
thyroid
weights;
and
histological
changes
in
the
spleen,
liver
and
bone
marrow
related
to
the
anemia.
ii.
Mice.
Dose
levels
for
the
mouse
oncogenicity
study
were
selected
on
the
basis
of
results
from
a
4
 
week
study
of
flumioxazin
in
the
diets
of
mice
at
levels
of
0,
1,000,
3,000
and
10,000
ppm.
In
this
range­
finding
study,
increases
in
absolute
and/
or
relative
liver
weights
were
noted
for
males
at
10,000
ppm
and
at
3,000
and
10,000
ppm
for
females.
iii.
Dogs.
A
90
 
day
study
was
conducted
in
dogs
given
gelatin
capsules
containing
0,
10,
100
or
1,000
mg/
kg/
day.
The
NOEL
of
10
mg/
kg/
day
for
this
study
was
based
on
a
slight
prolongation
of
activated
partial
thromboplastin
time;
increased
total
cholesterol
and
phospholipid
and
elevated
alkaline
phosphatase
activity;
increased
absolute
and
relative
liver
weights;
and
histological
changes
in
the
liver.
iv.
Rats.
A
21
 
day
dermal
toxicity
study
was
conducted
in
rats
at
dose
levels
of
0,
100,
200
or
1,000
mg/
kg/
day.
The
NOEL
was
determined
to
be
300
mg/
kg/
day
based
on
significantly
decreased
hemoglobin
and
hematocrit
values
for
females.
5.
Chronic
toxicity.
Flumioxazin
technical
has
been
tested
in
chronic
studies
with
dogs,
rats
and
mice.
Valent
proposes
a
chronic
oral
endpoint
of
1.8
mg/
kg
bw/
day,
based
on
the
NOEL
for
male
rats
in
the
two­
year
chronic
toxicity
oncogenicity
feeding
study.
i.
Rats.
In
a
2
 
year
study
in
rats,
flumioxazin
technical
administered
in
the
diet
at
levels
of
0,
50,
500,
and
1,000
ppm
produced
anemia
and
chronic
nephropathy
in
rats
of
the
500
and
1,000
ppm
groups.
The
anemia
lasted
throughout
the
treatment
period,
however,
it
was
not
progressive
nor
aplastic
in
nature.
No
evidence
of
an
oncogenic
effect
was
observed
in
rats
and
the
NOEL
for
this
study
was
50
ppm
(
1.8
mg/
kg/
day
for
males
and
2.2
mg/
kg/
day
for
females).
ii.
Mice.
Flumioxazin
technical
was
administered
to
mice
at
doses
of
0,
300,
3,000,
and
7,000
ppm
in
diet
for
78
weeks.
An
increased
incidence
of
hypertrophy
of
centrilobular
hepatocytes
was
observed
in
males
of
the
3,000
and
7,000
ppm
groups.
Increases
in
the
incidence
of
diffuse
hypertrophy
and
single
cell
necrosis
of
hepatocytes
were
observed
in
females
of
the
3,000
and
7,000
ppm
groups.
There
was
no
evidence
of
any
treatmentrelated
effect
on
the
incidence
of
tumors.
Flumioxazin
technical
was
not
carcinogenic
to
mice,
and
the
NOEL
for
this
study
was
300
ppm
(
31.1
mg/
kg/
day
for
males
and
36.6
mg/
kg/
day
for
females).
iii.
Dogs.
Flumioxazin
technical
was
administered
to
dogs
in
capsules
at
daily
doses
of
0,
10,
100,
and
1,000
mg/
kg
bw/
day
for
1
year.
Treatment­
related
changes
in
blood
biochemistry
included
increased
total
cholesterol
and
phospholipid
values,
elevated
alpha­
2­
globulin
ratio
at
1,000
mg/
kg/
day
and
increased
alkaline
phosphatase
activity
in
the
100
and
1,000
mg/
kg/
day
groups.
The
absolute
and/
or
relative
liver
weights
were
elevated
in
one
animal
in
the
100
mg/
kg/
day
group
and
four
animals
of
the
1,000
mg/
kg/
day
group.
Minimal
treatment­
related
histological
changes
were
noted
in
the
livers
of
animals
at
the
1,000
mg/
kg/
day
group.
Based
on
these
data
the
NOEL
was
determined
to
be
10
mg/
kg/
day.
iv.
Carcinogenicity.
Flumioxazin
is
not
a
carcinogen.
Adequately
designed
studies
with
both
rats
and
mice
have
shown
that
repeated
high
dose
exposures
produced
anemia,
liver
effects
and
nephropathy,
but
did
not
produce
cancer
in
test
animals.
No
oncogenic
response
was
observed
in
a
rat
2
 
year
chronic
feeding/
oncogenicity
study
or
in
a
78
week
study
on
mice.
Valent
anticipates
that
the
oncogenicity
classification
of
flumioxazin
will
be
``
E''
(
no
evidence
of
carcinogenicity
for
humans).
6.
Animal
metabolism.
The
absorption,
tissue
distribution,
metabolism
and
excretion
of
phenyl­
14Clabeled
flumioxazin
were
studied
in
rats
after
single
oral
doses
of
1
or
100
mg/
kg,
and
after
a
single
oral
dose
of
1
mg/
kg
following
14
daily
oral
doses
at
1
mg/
kg
of
unlabelled
material.
For
all
dose
groups,
most
(
97.9­
102.3%)
of
the
administered
radiolabel
was
excreted
in
the
urine
and
feces
within
7
days
after
radiolabeled
test
material
dosing.
Radiocarbon
tissue
residue
levels
were
generally
low
on
the
seventh
day
postdosing
Radiocarbon
residues
were
higher
in
blood
cells
than
tissues.
Tissue
14C­
residue
levels,
including
those
for
fat,
were
lower
than
blood
levels
which
suggests
little
potential
for
bioaccumulation.
Urinary
radiocarbon
excretion
was
greater
in
females
than
males
in
all
dose
groups.
Flumioxazin
was
extensively
metabolized
by
rats
and
35
metabolites
were
detected
and
quantitated.
The
main
metabolic
reactions
in
rats
were
(
1)
hydroxylation
of
the
tetrahydrophthalimide
moiety;
(
2)
incorporation
of
the
sulfonic
acid
group
into
the
tetrahydrophthalimide
moiety;
(
3)
cleavage
of
the
imide
linkage;
(
4)
cleavage
of
the
benzoxazinoneamide
and;(
5)
acetylation
of
the
aniline
nitrogen
group.
7.
Metabolite
toxicology.
Metabolism
studies
of
flumioxazin
in
rats,
goats,
hens,
soybeans,
and
peanuts,
as
well
as
the
fish
bioaccumulation
study
demonstrate
that
the
parent
is
very
rapidly
metabolized
and,
in
animals,
eliminated.
The
metabolites
detected
and
quantified
from
plants
and
animals
show
that
there
are
no
significant
aglycones
in
plants
which
are
not
also
present
in
the
excreta
or
tissues
of
animals.
Because
parent
and
metabolites
are
not
retained
in
the
body,
the
potential
for
acute
toxicity
from
in
situ
formed
metabolites
is
low.
The
potential
for
chronic
toxicity
is
adequately
tested
by
chronic
exposure
to
the
parent
at
the
MTD
and
consequent
chronic
exposure
to
the
internally
formed
metabolites.
8.
Endocrine
disruption.
No
special
studies
to
investigate
the
potential
for
estrogenic
or
other
endocrine
effects
of
flumioxazin
have
been
performed.
However,
as
summarized
above,
a
large
and
detailed
toxicology
database
exists
for
the
compound
including
studies
in
all
required
categories.
These
studies
include
acute,
sub­
chronic,
chronic,
developmental,
and
reproductive
toxicology
studies
including
detailed
histology
and
histopathology
of
numerous
tissues,
including
endocrine
organs,
following
repeated
or
long
term
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00023
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79924
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
exposures.
These
studies
are
considered
capable
of
revealing
endocrine
effects.
The
results
of
all
of
these
studies
show
no
evidence
of
any
endocrine­
mediated
effects
and
no
pathology
of
the
endocrine
organs.
Consequently,
it
is
concluded
that
flumioxazin
does
not
possess
estrogenic
or
endocrine
disrupting
properties.

C.
Aggregate
Exposure
1.
Dietary
exposure.
A
full
battery
of
toxicology
testing
including
studies
of
acute,
chronic,
oncogenicity,
developmental,
mutagenicity,
and
reproductive
effects
is
available
for
flumioxazin.
In
these
risk
assessments
Valent
has
chosen
as
the
chronic
oral
toxic
endpoint
the
NOEL
for
males
from
the
rat
chronic/
oncogenicity
feeding
study,
1.8
mg/
kg/
day;
and
as
the
acute
oral
toxic
endpoint
the
NOEL
(
proposed
by
EPA)
from
the
rat
oral
developmental
toxicity
study
of
3.0
mg/
kg/
day.
Because
the
acute
oral
endpoint
is
for
fetal
toxicity
to
rats,
Valent
has
chosen
to
use
the
full,
extra
10X
uncertainty
factor
for
appropriate
sub­
groups
of
the
population
as
mandated
by
FQPA.
i.
Food.
a.
Acute
dietary
exposures
to
flumioxazin
residues
were
calculated
for
the
U.
S.
population,
Women
13
years
and
older,
and
five
children
subgroups.
The
calculated
exposure
values
are
very
conservative
because
tolerance­
level
residues
and
100%
of
the
crop
treated
are
assumed.
For
refined
sugar
from
sugarcane
and
juice
from
grapes
for
which
processing
is
required,
concentration
factors
were
considered.
The
calculated
exposures
and
margins
of
exposure
(
MOE)
for
the
higher
exposed
proportions
of
the
subgroups
are
listed
below.
In
all
cases,
margins
of
exposure
relative
to
the
acute
endpoint
from
the
rat
oral
developmental
toxicity
study
exceed
1,000.

TIER
I
CALCULATED
ACUTE
DIETARY
EXPOSURES
TO
THE
TOTAL
U.
S.
POPULATION
AND
SELECTED
SUB­
POPULATIONS
TO
FLUMIOXAZIN
RESIDUES
IN
FOOD
Population
Subgroup
95th
Percentile
99.9th
Percentile
Exposure
(
mg/
kg/
day)
MOE
Exposure
(
mg/
kg/
day)
MOE
Total
U.
S.
Population
0.000063
47,737
0.000287
10,442
Women
13
Years
and
Older
0.000040
74,350
0.000128
23,527
Children
7
to
12
Years
0.000076
39,620
0.000310
9,675
Children
1
to
6
Years
0.000153
19,583
0.000599
5,008
All
Infants
0.000205
14,608
0.000800
3,750
Non­
Nursing
Infants
(<
1
yr
old)
0.000217
13,807
0.000799
3,753
Nursing
Infants
(<
1
yr
old)
0.000106
28,357
0.000283
10,612
b.
Chronic
dietary
exposures
to
flumioxazin
residues
were
calculated
for
the
U.
S.
population
and
25
population
subgroups.
This
modified
Tier
I
analysis
assumes
tolerance­
level
residues,
processing
factors
for
grape
and
cane
sugar,
and
100
percent
of
the
crops
treated.
The
results
from
several
representative
subgroups
are
listed
below.
All
calculated
chronic
dietary
exposures
were
below
5%
of
the
c­
PAD.
The
c­
PAD
was
defined
as
the
NOEL
from
the
rat
oral
two­
year
combined
chronic
toxicity
oncogenicity
study
(
1.8
mg/
kg/
day
for
males)
divided
by
the
100X
uncertainty
factor
for
the
adult
exposures
(
0.018
mg/
kg/
day),
or
divided
by
1,000
to
include
the
extra
10X
uncertainty
factor
for
adult
females
of
child­
bearing
age
and
infant
and
children
population
subgroups
(
0.0018
mg/
kg/
day).
Generally
speaking,
the
Agency
has
no
cause
for
concern
if
total
residue
contribution
for
published
and
proposed
tolerances
is
less
than
100
percent
of
the
c­
PAD.
TIER
I
CALCULATED
CHRONIC
DIETARY
EXPOSURES
TO
THE
TOTAL
U.
S.
POPULATION
AND
SELECTED
SUBPOPULATIONS
TO
FLUMIOXAZIN
RESIDUES
IN
FOOD
Population
Subgroup
Exposure
(
mg/
kg/
day)
Percent
of
c­
PAD
Total
U.
S.
Population
(
total)
(
0.018)*
0.000020
0.11
Females
13+
(
nursing)
(
0.0018)*
0.000016
0.89
Females
13+
(
preg./
not
nursing)
(
0.0018)*
0.000015
0.83
Children
7­
12
yrs
(
0.018)*
0.000030
0.17
Children
1­
6
yrs
(
0.0018)*
0.000052
2.89
All
Infants
(<
1
year)
(
0.0018)*
0.000067
3.72
TIER
I
CALCULATED
CHRONIC
DIETARY
EXPOSURES
TO
THE
TOTAL
U.
S.
POPULATION
AND
SELECTED
SUBPOPULATIONS
TO
FLUMIOXAZIN
RESIDUES
IN
FOOD
 
Continued
Population
Subgroup
Exposure
(
mg/
kg/
day)
Percent
of
c­
PAD
Non­
Nursing
Infants
(
0.0018)*
0.000082
4.56
Nursing
Infants
(
0.0018)*
0.000016
0.89
*
c­
PAD
value
used
to
calculate
percent
of
occupancy.

ii.
Drinking
water.
Since
flumioxazin
is
applied
outdoors
to
growing
agricultural
crops,
the
potential
exists
for
the
parent
or
its
metabolites
to
reach
ground
or
surface
water
that
may
be
used
for
drinking
water.
Because
of
the
physical
properties
of
flumioxazin,
it
is
unlikely
that
flumioxazin
or
its
metabolites
can
leach
to
potable
groundwater.
To
quantify
potential
exposure
from
drinking
water,
surface
water
concentrations
for
flumioxazin
were
estimated
using
GENEEC
1.2.
Because
KOC
could
not
be
measured
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00024
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79925
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
directly
in
adsorption­
desorption
studies
because
of
chemical
stability,
GEEC
values
representative
of
a
range
of
KOC
values
were
modeled.
The
simulation
that
was
selected
for
these
exposure
estimates
used
an
average
KOC
of
385,
indicating
high
mobility.
The
peak
GEEC
concentration
predicted
in
the
simulated
pond
water
was
9.8
ppb.
Using
standard
assumptions
about
body
weight
and
water
consumption,
the
acute
exposure
from
this
drinking
water
would
be
0.00028
and
0.00098
mg/
kg/
day
for
adults
and
children,
respectively.
The
56­
day
GEEC
concentration
predicted
in
the
simulated
pond
water
was
0.34
ppb.
Chronic
exposure
from
this
drinking
water
would
be
0.0000097
and
0.000034
mg/
kg/
day
for
adults
and
children,
respectively;
1.9
percent
of
the
c­
PAD
of
0.0018
mg/
kg/
day
for
children.
Based
on
this
worse
case
analysis,
the
contribution
of
drinking
water
to
the
dietary
exposure
is
comparable
to
that
from
food,
but
the
risk
is
still
negligible.
2.
Non­
dietary
exposure.
Flumioxazin
is
proposed
only
for
agricultural
uses
and
no
homeowner
or
turf
uses.
Thus,
no
non­
dietary
risk
assessment
is
needed.

D.
Cumulative
Effects
Section
408(
b)(
2)(
D)(
v)
requires
that
the
Agency
must
consider
``
available
information''
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
``
other
substances
that
have
a
common
mechanism
of
toxicity.''
Available
information
in
this
context
include
not
only
toxicity,
chemistry,
and
exposure
data,
but
also
scientific
policies
and
methodologies
for
understanding
common
mechanisms
of
toxicity
and
conducting
cumulative
risk
assessments.
For
most
pesticides,
although
the
Agency
has
some
information
in
its
files
that
may
turn
out
to
be
helpful
in
eventually
determining
whether
a
pesticide
shares
a
common
mechanism
of
toxicity
with
any
other
substances,
EPA
does
not
at
this
time
have
the
methodologies
to
resolve
the
complex
scientific
issues
concerning
common
mechanism
of
toxicity
in
a
meaningful
way.
There
are
other
pesticidal
compounds
that
are
structurally
related
to
flumioxazin
and
have
similar
effects
on
animals.
In
consideration
of
potential
cumulative
effects
of
flumioxazin
and
other
substances
that
may
have
a
common
mechanism
of
toxicity,
there
are
currently
no
available
data
or
other
reliable
information
indicating
that
any
toxic
effects
produced
by
flumioxazin
would
be
cumulative
with
those
of
other
chemical
compounds.
Thus,
only
the
potential
risks
of
flumioxazin
have
been
considered
in
this
assessment
of
aggregate
exposure
and
effects.
Valent
will
submit
information
for
EPA
to
consider
concerning
potential
cumulative
effects
of
flumioxazin
consistent
with
the
schedule
established
by
EPA
at
62
FR
42020
(
Aug.
4,
1997)
and
other
subsequent
EPA
publications
pursuant
to
the
Food
Quality
Protection
Act.

E.
Safety
Determination
1.
U.
S.
population
 
i.
Acute
risk.
The
potential
acute
exposure
from
food
to
the
U.
S.
population
and
various
nonchild
infant
population
subgroups
provide
MOE
values
exceeding
1,000.
Addition
of
the
worse
case,
but
small
``
background''
dietary
exposure
from
water
reduces
the
MOE
value
at
the
99.9th
percentile
from
10,442
to
5,291.
In
a
conservative
policy,
the
Agency
has
no
cause
for
concern
if
total
acute
exposure
to
adults
calculated
for
the
95th
percentile
(
for
the
Tier
I
calculated
acute
dietary
exposure
using
tolerance
level
residues
and
100%
crops
treated)
yields
a
MOE
of
100
or
larger.
For
women
of
child
bearing
age
where
an
MOE
of
1,000
or
larger
is
appropriate,
the
addition
of
water
to
the
diet
of
women,
13
years
and
older,
reduces
the
MOE
(
99.9th
percentile)
from
23,527
to
7,353.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
overall
U.
S.
Population
and
many
non­
child/
infant
subgroups
from
aggregate,
acute
exposure
to
flumioxazin
residues.
ii.
Chronic
risk.
Using
the
dietary
exposure
assessment
procedures
described
above
for
flumioxazin,
calculated
chronic
dietary
exposure
resulting
from
residue
exposure
from
proposed
uses
of
flumioxazin
is
minimal.
The
estimated
chronic
dietary
exposure
from
food
for
the
overall
U.
S.
Population
and
many
non­
child/
infant
subgroups
is
0.11
to
0.89%
of
the
appropriate
c­
PAD.
Addition
of
the
small
but
worse
case
potential
exposure
from
drinking
water
(
calculated
above)
increases
exposure
by
0.0000097
mg/
kg
/
day
and
the
maximum
occupancy
of
the
c­
PAD
from
0.89
to
1.43%
(
women
13
+).
Generally,
the
Agency
has
no
cause
for
concern
if
total
residue
contribution
is
less
than
100%
of
the
appropriate
c­
PAD.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
overall
U.
S.
Population
and
many
non­
child/
infant
subgroups
from
aggregate,
chronic
exposure
to
flumioxazin
residues.
2.
Infants
and
children
 
safety
factor
for
infants
and
children.
In
assessing
the
potential
for
additional
sensitivity
of
infants
and
children
to
residues
of
flumioxazin,
FFDCA
section
408
provides
that
EPA
shall
apply
an
additional
margin
of
safety,
up
to
tenfold
for
added
protection
for
infants
and
children
in
the
case
of
threshold
effects
unless
EPA
determines
that
a
different
margin
of
safety
will
be
safe
for
infants
and
children.
i.
Children.
The
toxicological
database
for
evaluating
pre­
and
post­
natal
toxicity
for
flumioxazin
is
complete
with
respect
to
current
data
requirements.
Developmental
toxicity
was
observed
by
both
oral
and
dermal
routes
in
rats.
Therefore,
reliable
data
support
use
of
the
standard
100­
fold
uncertainty
factor
and
an
additional
uncertainty
factor
of
10X
for
flumioxazin
to
be
further
protective
of
infants
and
children.
ii.
Developmental
toxicity
studies.
Flumioxazin
shows
developmental
toxicity
in
the
absence
of
maternal
toxicity
in
rats.
Mechanistic
studies
demonstrate
that
the
effect
is
specifically
related
to
the
inhibition
of
heme
synthesis,
that
the
effect
shows
considerable
species
specificity,
and
that
the
rat
is
a
conservative
surrogate
species
for
the
potential
for
developmental
toxicity
in
man.
No
developmental
toxicity
was
observed
in
rabbits.
Developmental
toxicity
to
the
pups
was
seen
in
the
rat
reproduction
study
at
doses
that
were
not
toxic
to
the
parental
animals.
a.
Rats.
In
the
definitive
rat
oral
developmental
toxicity
study,
pregnant
rats
were
administered
oral
doses
of
0,
1,
3,
10
or
30
mg/
kg/
day
of
flumioxazin
technical
on
days
6
through
15
of
gestation.
No
maternal
deaths
were
observed
at
any
dosage
and
no
treatment­
related
effects
on
clinical
signs
or
food
consumption
were
noted.
A
decrease
in
maternal
body
weight
gain
was
found
at
30
mg/
kg/
day.
The
number
of
live
fetuses
and
fetal
body
weights
were
decreased
in
the
30
mg/
kg/
day
group
and
the
incidence
of
embryo
mortality
tended
to
be
higher
but
was
not
statistically
significant.
No
effects
on
the
number
of
implantations,
sex
ratios,
or
external
abnormalities
were
found.
The
incidence
of
fetuses
with
cardiovascular
abnormalities,
primarily
VSD,
was
increased
in
the
30
mg/
kg/
day
group.
Other
developmental
effects
observed
at
30
mg/
kg/
day
included
an
increase
in
the
incidence
of
wavy
ribs
and
curvature
of
the
scapula,
and
a
decrease
in
the
number
of
ossified
sacrococcygeal
vertebral
bodies.
Based
on
these
findings,
a
maternal
NOEL
of
30
mg/
kg/
day
and
a
developmental
NOEL
of
3
mg/
kg/
day
are
proposed.
On
days
6­
15
of
gestation,
pregnant
rats
were
exposed
dermally
to
dose
levels
of
30,
100,
or
300
mg/
kg/
day
of
flumioxazin
technical
in
corn
oil.
No
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00025
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79926
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
adverse
effects
were
observed
in
the
dams
throughout
the
study.
Increased
fetal
mortality
was
accompanied
by
decreases
in
the
number
of
live
fetuses
and
fetal
body
weights
at
doses
of
300
mg/
kg/
day.
No
external
abnormalities
were
observed
at
any
dose
level.
An
increase
in
cardiovascular
abnormalities,
primarily
VSD,
an
increase
in
wavy
ribs
and
a
decrease
in
the
number
of
ossified
sacrococcygeal
vertebral
bodies
was
observed
at
300
mg/
kg/
day.
Based
on
these
results,
a
maternal
NOEL
of
300
mg/
kg/
day
and
a
developmental
NOEL
of
30
mg/
kg/
day
are
proposed.
To
measure
the
dermal
penetration
of
flumioxazin
under
the
conditions
of
the
dermal
teratology
study,
13­
day
pregnant
rats
were
dermally
exposed
to
[
phenyl­
14C]
flumioxazin.
The
systemic
absorption
ranged
from
3.8%
at
2
hours
to
6.9%
of
the
recovered
14C
at
48
hours.
b.
Mechanistic
studies.
A
series
of
scientific
studies
were
conducted
to
examine
the
mechanism
and
species
differences
in
the
production
of
developmental
toxicity
by
flumioxazin.
This
research
demonstrates
clear
species
differences
between
rats,
rabbits,
mice,
and
(
in
vitro)
humans
and
indicates
a
high
degree
of
correlation
between
the
interruption
of
heme
synthesis
and
the
production
of
developmental
toxicity
in
rats.
The
data
support
that
the
rat
is
a
conservative
model
for
use
in
the
risk
assessment
for
humans.
Specifically
the
studies
demonstrate
that:
 
Flumioxazin
interferes
with
normal
heme
biosynthesis
resulting
in
sidroblastic
anemia
and
porphyria
in
adult
rats.
 
14C­
Flumioxazin
administered
to
pregnant
rats
on
day
12
of
gestation
crosses
the
placenta
and
reaches
the
rat
fetus
at
maximum
levels
of
radiocarbon
(
and
flumioxazin),
4
hours
later.
 
No
clear
pattern
of
adsorption,
distribution,
metabolism,
or
excretion
was
evident
which
could
account
for
the
species­
specific
development
toxicity
in
rats.
 
The
critical
period
of
sensitivity
to
the
developmental
effects
of
flumioxazin
in
rats
is
day
12
of
gestation.
This
correlates
with
the
peak
period
of
protoporphyrin
IX
(
PPIX)
accumulation
in
maternal
rat
liver
and
the
rat
fetus.
 
A
histological
examination
of
rat
fetus
indicated
signs
of
fetal
anemia
within
6
hours
after
dosing,
but
no
histological
changes
in
the
fetal
rat
heart
were
observed
until
36
or
48
hour
after
treatment.
No
effects
were
observed
in
rabbit
fetus
treated
in
the
same
manner
as
the
rats.
 
Other
observations
in
the
pathogenesis
of
the
developmental
effects
of
flumioxazin
in
rat
fetuses
included:
enlarged
heart,
edema,
anemia
(
decreased
red
blood
cell
count
and
hemoglobin),
delayed
closure
of
the
interventricular
foramen,
reduced
serum
protein
and
incomplete/
delayed
ossification
of
the
ribs.
 
The
observation
of
enlarged
heart,
edema
and
anemia
preceding
the
occurrence
of
fetal
mortality
suggest
these
effects
may
be
instrumental
in
the
cause
of
fetal
deaths.
 
The
occurrence
of
an
enlarged
heart
preceding
the
failure
of
interventricular
foramen
closure
could
be
related
to
the
pathogenesis
rather
than
a
direct
toxic
effect
of
flumioxazin
on
cardiac
tissue.
 
A
strong
correlation
exists
between
PPIX
accumulation,
an
indicator
of
disrupted
heme
synthesis,
and
developmental
toxicity.
Evidence
of
this
correlation
exists
on
the
basis
of
species
differences
between
rats
and
rabbits;
the
critical
period
of
sensitivity
in
the
rat;
and
compound­
specific
differences
with
two
chemicals
structurally
related
to
flumioxazin,
one
which
produces
developmental
effects
in
rats
and
one
which
does
not.
c.
Rabbits.
Pregnant
rabbits
were
administered
0,
300,
1,000,
or
3,000
mg/
kg/
day
of
flumioxazin
technical
on
days
7
­
19
of
gestation
by
oral
gavage.
The
highest
dose
was
well
in
excess
of
the
1,000
mg/
kg/
day
limit
dose
for
developmental
toxicity
studies.
The
3,000
mg/
kg/
day
dosage
tended
to
reduce
maternal
body
weight
gains
and
relative
and
absolute
feed
consumption
values.
No
gross
lesions
were
produced
at
any
dose
level.
The
3,000
mg/
kg/
day
dosage
group
litters
tended
to
have
reduced
fetal
body
weights
but
these
differences
were
not
statistically
different.
No
fetal
external,
soft
tissue,
or
skeletal
malformations
or
variants
were
attributable
to
the
test
substance.
Based
on
these
data,
the
maternal
NOEL
was
1,000
mg/
kg/
day
and
the
developmental
NOEL
was
3,000
mg/
kg/
day.
iii.
Reproductive
toxicity
study.
In
the
two­
generation
reproduction
study
in
the
rat
dietary
levels
of
0,
50,
100,
200
and
300
ppm
established
a
systemic
NOEL
of
200
ppm
based
on
increased
clinical
signs
(
both
sexes
and
generations);
mortality,
gross
and
histopathology
findings
in
the
liver
(
F1
females);
decreased
body
weight/
weight
gain
(
F0
and
F1
females
during
gestation,
F1
males
during
premating)
and
decreased
food
consumption
(
F0
and
F1
females
during
lactation).
The
reproductive
NOEL
of
100
ppm
was
mainly
based
on
developmental
toxicity
at
200
ppm.
Observed
at
200
ppm
were
a
decreased
number
of
live­
born
pups
and
reduced
pup
body
weights.
At
300
ppm
the
following
effects
were
observed:
decreased
pup
body
weight
(
both
generations);
decreased
number
of
live
pups/
litter
and
viability
index
(
both
generations);
increased
incidence
of
abnormalities
of
the
reproductive
organs
(
predominately
atrophied
or
hypoplastic
testes
and/
or
epididymides
in
F1
males);
decreased
gestation
index
(
F0
females);
decreased
mating
and
fertility
indices
(
F1
males)
and
increased
clinical
signs
(
F1
pups).
iv.
Prenatal
and
postnatal
sensitivity.
Flumioxazin
interferes
with
normal
heme
biosynthesis
resulting
in
sidroblastic
anemia
and
porphyria
in
adult
rats.
Clear
species
differences
between
rats,
rabbits,
mice,
and
(
in
vitro)
humans
were
demonstrated.
There
is
a
high
degree
of
correlation
between
the
interruption
of
heme
synthesis,
consequent
PPIX
accumulation,
and
the
production
of
developmental
toxicity
in
rats.
The
data
support
that
the
rat
is
a
conservative
model
for
use
in
the
risk
assessment
for
humans.
v.
Acute
exposure
and
risk.
The
potential
acute
exposure
from
food
to
the
various
child
and
infant
population
subgroups
all
provide
MOE
values
exceeding
1,000.
Addition
of
the
worse
case,
but
small
``
background''
dietary
exposure
from
water
(
0.00098
mg/
kg/
day)
to
the
99.9th
percentile
food
exposure
for
infants
reduces
the
MOE
value
from
3,753
to
1,686.
In
a
conservative
policy
with
the
addition
of
the
FQPA
extra
10X
uncertainty
factor,
the
Agency
has
no
cause
for
concern
if
total
acute
exposure
to
infants
and
children
calculated
for
the
95th
percentile
for
the
Tier
I
acute
dietary
exposure
yields
a
MOE
of
1,000
or
larger.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate,
acute
exposure
to
flumioxazin
residues.
vi.
Chronic
exposure
and
risk.
Using
the
conservative
exposure
assumptions
described
above,
the
percentage
of
the
c­
PAD
that
will
be
utilized
by
dietary
(
food
only)
exposure
to
residues
of
flumioxazin
ranges
from
0.17%
for
children
7­
12
years,
to
4.6%
for
Non­
Nursing
Infants.
Adding
the
worse
case
potential
incremental
exposure
to
infants
and
children
from
flumioxazin
in
drinking
water
(
0.000034
mg/
kg/
day)
increases
the
aggregate,
chronic
dietary
exposure
by
1.9%.
The
addition
of
the
exposure
attributable
to
drinking
water
increases
the
occupancy
of
the
c­
PAD
for
Non­
Nursing
Infants
to
6.44%.
EPA
generally
has
no
concern
for
exposures
below
100%
of
the
c­
PAD
because
the
c­
PAD,
in
this
case
including
the
extra
10X
FQPA
uncertainty
factor,
represents
the
level
at
or
below
which
daily
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00026
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
79927
Federal
Register
/
Vol.
67,
No.
251
/
Tuesday,
December
31,
2002
/
Notices
aggregate
dietary
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate,
chronic
exposure
to
flumioxazin
residues.
vii.
Determination
of
safety
 
Summary.
Aggregate
acute
or
chronic
dietary
exposure
to
various
subpopulations
of
children
and
adults
demonstrate
acceptable
risk.
Chronic
dietary
exposures
to
flumioxazin
occupy
considerably
less
than
100%
of
the
appropriate
c­
PAD,
and
all
acute
dietary
MOE
values
exceed
1,000.
Chronic
and
acute
dietary
risk
to
children
from
flumioxazin
should
not
be
of
concern.
Further,
flumioxazin
has
only
agricultural
uses
and
no
other
uses,
such
as
indoor
pest
control,
homeowner
or
turf,
that
could
lead
to
unique,
enhanced
exposures
to
vulnerable
subgroups
of
the
population.
It
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
Population
or
to
any
sub­
group
of
the
U.
S.
population,
including
infants
and
children,
from
aggregate
chronic
or
aggregate
acute
exposures
to
flumioxazin
residues
resulting
from
proposed
uses.

F.
International
Tolerances
Flumioxazin
has
not
been
evaluated
by
the
World
Health
Organization,
Joint
Meeting
on
Pesticide
Residues
(
JMPR)
and
there
are
no
Codex
Maximum
Residue
Limits
(
MRL)
for
flumioxazin.
MRL
values
have
been
established
to
allow
the
following
uses
of
flumioxazin
in
the
following
countries.

Country
Crop
MRL
(
ppm)

Brazil
Soybean
0.05
Argentina
Soybean
Sunflower
0.015
0.02
Paraguay
Soybean
0.015
South
Africa
Soybean
Groundnut
0.02
0.02
[
FR
Doc.
02
 
32990
Filed
12
 
30
 
02;
8:
45
am]

BILLING
CODE
6560
 
50
 
S
ENVIRONMENTAL
PROTECTION
AGENCY
[
OPPT
 
2002
 
0077;
FRL
 
7286
 
8]

Certain
New
Chemicals;
Receipt
and
Status
Information
AGENCY:
Environmental
Protection
Agency
(
EPA).
ACTION:
Notice.
SUMMARY:
Section
5
of
the
Toxic
Substances
Control
Act
(
TSCA)
requires
any
person
who
intends
to
manufacture
(
defined
by
statute
to
include
import)
a
new
chemical
(
i.
e.,
a
chemical
not
on
the
TSCA
Inventory)
to
notify
EPA
and
comply
with
the
statutory
provisions
pertaining
to
the
manufacture
of
new
chemicals.
Under
sections
5(
d)(
2)
and
5(
d)(
3)
of
TSCA,
EPA
is
required
to
publish
a
notice
of
receipt
of
a
premanufacture
notice
(
PMN)
or
an
application
for
a
test
marketing
exemption
(
TME),
and
to
publish
periodic
status
reports
on
the
chemicals
under
review
and
the
receipt
of
notices
of
commencement
to
manufacture
those
chemicals.
This
status
report,
which
covers
the
period
from
November
20,
2002
to
December
10,
2002,
consists
of
the
PMNs
pending
or
expired,
and
the
notices
of
commencement
to
manufacture
a
new
chemical
that
the
Agency
has
received
under
TSCA
section
5
during
this
time
period.

DATES:
Comments
identified
by
the
docket
ID
number
OPPT
 
2002
 
0077
and
the
specific
PMN
number
or
TME
number,
must
be
received
on
or
before
January
30,
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:
Barbara
Cunningham,
Acting
Director,
Environmental
Assistance
Division,
Office
of
Pollution
Prevention
and
Toxics
(
7408M),
Environmental
Protection
Agency,
1200
Pennsylvania
Ave.,
NW.,
Washington,
DC
20460
 
0001;
telephone
number:
(
202)
554
 
1404;
e­
mail
address:
TSCAHotline
epa.
gov.

SUPPLEMENTARY
INFORMATION:

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

This
action
is
directed
to
the
public
in
general.
As
such,
the
Agency
has
not
attempted
to
describe
the
specific
entities
that
this
action
may
apply
to.
Although
others
may
be
affected,
this
action
applies
directly
to
the
submitter
of
the
premanufacture
notices
addressed
in
the
action.
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
OPPT
 
2002
 
0077.
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
EPA
Docket
Center,
Rm.
B102­
Reading
Room,
EPA
West,
1301
Constitution
Ave.,
NW.,
Washington,
DC.
The
EPA
Docket
Center
is
open
from
8:
30
a.
m.
to
4:
30
p.
m.,
Monday
through
Friday,
excluding
legal
holidays.
The
EPA
Docket
Center
Reading
Room
telephone
number
is
(
202)
566
 
1744
and
the
telephone
number
for
the
OPPT
Docket,
which
is
located
in
EPA
Docket
Center,
is
(
202)
566
 
0280.
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
VerDate
Dec<
13>
2002
16:
26
Dec
30,
2002
Jkt
200001
PO
00000
Frm
00027
Fmt
4703
Sfmt
4703
E:\
FR\
FM\
31DEN1.
SGM
31DEN1
