UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
August
21,
2002
MEMORANDUM
SUBJECT:
Acifluorfen:
Response
to
BASF's
Phase
5
Comments
on
the
Risk
Assessment
Document
for
Sodium
Acifluorfen.

DP
Barcode:
D283517
Submission
Code:
S616937
PC
Code:
114402
TXR
No:
0051047
FROM:
Paul
Chin,
Ph.
D.
Reregistration
Branch
I
Health
Effects
Division
(
7509C)
and
Kit
Farwell,
DVM,
Risk
Assessor
Reregistration
Branch
I
Health
Effects
Division
(
7509C)

THROUGH:
Wang
Phang,
Ph.
D.,
Senior
Scientist
Reregistration
Branch
I
Health
Effects
Division
(
7509C)

TO:
Christina
Scheltema
Review
Branch
3
Special
Review
and
Reregistration
Division
(
7508W)

INTRODUCTION:

The
registrant,
BASF,
submitted
a
Phase
5
response
to
the
Risk
Assessment
Document
for
Sodium
Acifluorfen
(
from
BASF
to
Ms.
Christina
Scheltema,
SRRD
dated
May
24,
2002).
The
registrant's
comments
have
been
reviewed
and
addressed
in
detail
below.

DISCUSSION:
­
2­
Preliminary
Human
Health
Risk
Assessment
COMMENT
1
Reassessment
of
Current
Cancer
Classification
Considering
Peroxisome
Proliferation
Associated
Mode
of
Action
BASF
Comment:

BASF
is
submitting
4
week
dietary
study
in
mice
with
TEM
analysis
and
positive
control
data
showing
peroxisome
proliferation
with
a
phthalate
ester.

HED
Response:

We
have
received
4
week
dietary
study
in
mice
with
TEM
analysis
(
MRID
45693401)
and
positive
control
data
(
MRID
45693402,
45686501,
and
45686502).
These
studies
are
being
reviewed
currently.
Upon
completion
of
the
review,
the
possible
mode
of
action
of
acifluorfen
relative
to
its
carcinogenic
potential
will
be
evaluated.

COMMENT
2
Rat
Developmental
Toxicity
Study
and
Recommendation
for
Developmental
Neurotoxicity
Study
BASF
Comment:

BASF
maintains
that
there
is
not
sufficient
evidence
of
neurotoxicity
with
acifluorfen
to
justify
a
DNT
study.
...
It
was
clearly
demonstrated
that
dilated
ventricles
of
brains
were
noted
in
small
pups,
and
there
is
a
direct
correlation
with
pup
size
and
the
dilated
ventricles.

HED
Response:

Please
see
the
following
citation
from
the
previous
HED's
Response
to
BASF's
Phase
3
Comments
on
the
Preliminary
Risk
Assessment
Document
for
Sodium
Acifluorfen
(
Chin,
P.
and
Farwell,
K.
November
29,
2001).

It
is
not
clear
whether
there
is
a
relationship
between
decreased
fetal
weight
and
slightly
dilated
ventricles
of
the
brain.
However,
neurotoxicity
in
the
form
of
clinical
signs
(
such
as
decreased
motor
activity)
and
slightly
dilated
lateral
ventricles
of
the
brain
was
observed
in
the
developmental
toxicity
study
in
rats.
Therefore,
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
recommended
a
developmental
neurotoxicity
study
in
order
to
further
define
the
neurotoxic
potential
in
the
developing
fetus.
­
3­
COMMENT
3
FQPA
Safety
Factor
BASF
Comment:

There
was
no
"
increased
susceptibility"
seen
in
rat
developmental
toxicity
study
 
effects
were
associated
with
underweight
pups
and
maternal
effects
 
therefore,
10X
FQPA
safety
factor
is
not
necessary.

HED
Response:

Please
see
the
following
citation
from
the
previous
HED's
Response
to
BASF's
Phase
3
Comments
on
the
Preliminary
Risk
Assessment
Document
for
Sodium
Acifluorfen
(
Chin,
P.
and
Farwell,
K.
November
29,
2001).

The
current
thinking
is
that
when
adverse
effects
are
seen
at
the
same
dose
level
in
the
fetuses/
offspring
as
in
the
parental
animals
and
the
effects
in
the
fetuses/
offspring
are
different
from
those
seen
in
the
parental
animals
and/
or
considered
to
be
more
severe,
the
result
is
described
as
qualitatively
increased
susceptibility
(
Current
Approach
to
Recommending
the
FQPA
Safety
Factor
for
Use
in
Human
Health
Risk
Assessment;
Brenda
S.
Tarplee
and
Edward
Zager;
HED,
OPP,
US
EPA;
Presented
at
the
California
Pesticide
Residue
Workshop,
March
2000).
In
this
study,
the
developmental
toxicity
(
decreased
fetal
body
weight
and
increase
in
anatomical
variations
including
dilated
lateral
ventricles
of
the
brain)
was
seen
in
the
presence
of
minimal
maternal
toxicity
(
clinical
signs
including
excessive
salivation
and
piloerection)
at
the
same
dose.
According
to
the
current
policy,
HIARC
concluded
that
there
is
qualitative
evidence
of
increased
susceptibility
following
in
utero
exposure
to
acifluorfen
in
the
prenatal
developmental
toxicity
study
in
rats.
The
HIARC
can
not
discount
the
increased
incidence
of
dilated
lateral
ventricles
of
the
brain
because
historical
data
for
the
incidence
were
not
available.

Subsequently,
the
FQPA
Safety
Factor
committee
recommended
a
10X
safety
factor
be
retained
when
assessing
acute
dietary
and
short/
intermediate­
term
residential
(
nonoccupational
exposures
for
females
13­
50.
Since
there
was
a
datagap
for
a
developmental
neurotoxicity
study,
the
FQPA
safety
factor
was
reduced
to
3X
when
assessing
chronic
dietary
and
long­
term
residential
(
non­
occupational)
exposures
for
females
13­
50
and
infants
and
children
subgroups.
­
4­
COMMENT
4
Mouse
Oncogenicity
Study
(
MRID
No.
00122732)

BASF
Comment:

High
dose
in
Mouse
Oncogenicity
Study
(
MRID
No.
00122732)
should
not
be
considered
in
evaluation
of
carcinogenic
potential.
....
Upon
receipt
of
the
additional
study
on
peroxisome
proliferation,
BASF
believes
the
Agency
will
agree
that
a
non­
genotoxic
mode
of
action
has
been
demonstrated
for
the
liver
tumors.

HED
Response:

We
have
received
4
week
dietary
study
in
mice
with
TEM
analysis
(
MRID
45693401)
and
positive
control
data
(
MRID
45693402,
45686501,
and
45686502).
These
studies
are
being
reviewed
currently.
Upon
completion
of
the
review,
the
possible
mode
of
action
of
acifluorfen
relative
to
its
carcinogenic
potential
will
be
evaluated.

COMMENT
5
Mutagenicity
Studies
BASF
Comment:

BASF
maintains
that
the
weight
of
the
evidence
for
acifluorfen
indicates
that
the
compound
is
not
genotoxic.
....
Another
cell
proliferation
test
(
using
a
modern
protocol)
with
acifluorfen
was
conducted.
A
report
from
this
study
will
be
available
in
October
2002.

HED
Response:

This
issue
will
be
considered
when
the
data
from
the
new
cell
proliferation
test
(
using
a
modern
protocol)
with
acifluorfen
become
available.
