Document ID: EPA-HQ-OPP-2005-0265-0025
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-19T04:00Z

Page
1
of
3
January
9,
2006
Patrick
Dobak
Chemical
Review
Manager
Reregistration
Branch
I
Special
Review
and
Reregistration
Division
(
7508C)
Office
of
Pesticide
Programs
Environmental
Protection
Agency
Ariel
Rios
Building
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
Dear
Mr.
Dobak:

Subject:
Dicloran
(
DCNA)
RED:
Docket
Identification
No.
OPP­
2005­
0265
Gowan
Company
appreciates
the
opportunity
to
comment
on
the
Agency's
preliminary
assessments.

Developmental
Neurotoxicity
Study
The
Dicloran
October
27,
2005
Revised
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED)
dated
August
12,
2005
[
PC
Code
031301,
Case
#
0113,
DP
Barcode
D29440]
summarized
the
human
health
risk
assessment
for
dicloran.
We
were
pleased
to
see
that
on
pages
32­
33
of
that
document,
the
Agency
objectively
presented
arguments
both
for
and
against
requiring
a
developmental
neurotoxicity
study.
Gowan
Company
offers
the
following
comments
regarding
the
Agency's
presentation.

Reasons
to
Require
a
DNT
Study
1.
HED
noted
that
single
high
doses
of
aniline,
a
structural
analog
of
dicloran,
produced
"
similar
neuropathology."
The
neuropathological
effects
with
aniline
were
greater
in
four­
week­
old
rats
than
in
seven­
week­
old
rats,
suggesting
that
age
could
be
an
important
variable
in
this
neurotoxicity.

Gowan
Company,
however,
believes
that
the
Agency's
structure­
activity
correlation
with
aniline
was
stretched
beyond
the
breaking
point.
In
the
study
to
which
the
Agency
refers
[
Okazaki
et
al.,
J.
Vet.
Med.
Sci.
63
(
5)
539­
546
(
2001)],
paralytic
gait
and
hindlimb
paralysis
were
observed,
and
then
only
after
a
minimum
of
eight
days
posttreatment
To
us
this
is
suggestive
of
an
effect
on
neurotoxic
esterase.
In
fact,
the
Page
2
of
3
neurotoxicity
of
aniline
has
been
recognized
for
many
years.
In
August
1988
the
Agency
obtained
an
enforceable
consent
agreement
regarding
neurotoxicity
evaluation
of
aniline
under
Section
4
of
TSCA
[
53
FR
31
804].

By
contrast,
with
the
vacuolation
observed
with
dicloran
there
were
no
associative
clinical
signs,
no
neurological
signs,
no
behavioral
signs,
no
effect
on
sciatic
nerves
and
no
effect
on
organ
development
(
hypoplasia
or
aplasia).
In
short,
there
is
no
objective
reason
to
identify
this
histological
observation
as
an
adverse
effect.
Therefore
the
term
"
similar
neuropathology"
is
misleading
if
it
is
also
intended
to
imply
similar
clinical
or
behavioral
effects.

2.
The
Agency's
second
justification
for
requiring
a
developmental
neurotoxicity
study
is
that
dicloran
did
induce
vacuolation
of
the
brain
at
doses
of
25
mg/
kg/
day
in
the
dog
and
71­
94
mg/
kg/
day
in
the
rat
following
exposures
greater
than
90
days.

Gowan
Company
wishes
to
make
three
observations
in
response
to
this
point.

First,
in
a
developmental
neurotoxicity
study
the
total
exposure
time
of
fetuses
and
pups
until
sacrifice
is
less
than
90
days.
From
90­
day
studies
with
rats
and
from
the
rat
developmental
study
it
is
already
known
that
vacuolation
does
not
appear
within
this
time
frame.
Gowan
Company
believes
there
is
no
reasonable
expectation
of
observing
"
neuropathology"
in
a
DNT
study.

Secondly,
we
reiterate
that
vacuolation
was
not
associated
with
any
clinical
or
behavioral
effects.
Neurotoxicity
was
not
observed
in
the
adults
of
either
species.

Thirdly,
the
rat
developmental
toxicity
study
was
reviewed
in
June
2005
(
DP
Barcode
294475).
The
maternal
LOAEL
in
this
study
was
determined
to
be
50
mg/
kg/
day
and
the
developmental
LOAEL
was
determined
to
be
100
mg/
kg/
day.
These
may
be
compared
with
the
vacuolation
LOEL
of
71
­
94
mg/
kg/
day
observed
in
the
rat
chronic/
oncogenicity
study.
From
this
we
infer
that
there
is
no
expectation
of
increased
sensitivity
of
perinatal
rats.

In
summary,
Gowan
Company
does
not
believe
that
the
Agency's
justifications
for
conducting
a
DNT
study
are
in
fact
cogent.

Reasons
Against
Requiring
a
DNT
Study
The
Agency
also
listed
seven
reasons
which
could
be
used
to
support
not
conducting
a
DNT
study.
Gowan
Company
agrees
with
these
arguments,
which
are
summarized
below.

1.
No
neurotoxic
signs
were
seen
in
any
study
with
dicloran,
including
the
two
studies
in
which
significant
neuropathology
were
observed
(
the
rat
chronic/
oncogenicity
study
and
the
dog
chronic
study).
Particular
effort
was
made
to
investigate
this
in
the
rat
study.
A
functional
observational
battery
involving
26
parameters
was
administered
Page
3
of
3
one
year
into
the
study.

2.
Neuropathology
was
reported
only
at
the
highest
dose
levels
tested
in
the
rat
and
dog
chronic
studies.
These
were
71.0
and
94.1
mg/
kg/
day
for
male
and
female
rats
and
25
mg/
kg/
day
for
male
and
female
dogs.

3.
There
was
no
dose­
response.
Pronounced
vacuolation
was
observed
at
the
highest
doses
in
these
studies,
but
none
at
all
was
observed
at
the
next
lowest
dose
levels.

4.
Regulatory
endpoints
are
based
on
the
chronic
NOAEL
(
2.5
mg/
kg/
day)
from
the
dog
chronic
study.
This
level
is
far
lower
than
the
doses
that
produced
vacuolation
(
25
mg/
kg/
day
in
the
dog
and
71­
94
mg/
kg/
day
in
the
rat).

5.
Vacuolation
appears
to
require
either
very
high
doses
or
exposures
greater
than
90
days.
In
the
chronic
studies,
vacuolation
was
observed
in
the
cerebral
cortex,
cerebellar
cortex,
the
medusa/
pons
regions
of
the
brain
and
in
the
cervical,
thoracic
and
lumbar
segments
of
the
spinal
cord
after
12
months
exposure
of
both
species.
It
was
not
observed
in
90­
day
studies
with
either
species.
In
a
single­
dose
study,
neurotoxic
effects
(
paralysis
and
depression)
were
observed
only
at
2500
mg/
kg,
which
is
a
thousand
times
higher
than
the
chronic
NOAEL
upon
which
the
chronic
reference
dose
is
established.

6.
There
was
no
evidence
of
susceptibility
in
the
developmental
and
reproductive
studies.
As
HED
noted
(
pages
29­
30),
there
is
no
qualitative
or
quantitative
evidence
for
increased
susceptibility
in
the
developmental
toxicity
or
reproduction
studies.

7.
A
DNT
study
in
rats
is
unlikely
to
yield
a
NOAEL
lower
than
the
current
NOAEL
of
2.5
mg/
kg/
day
in
the
more
sensitive
species,
dogs.
As
HED
itself
has
said
(
page
31),
a
DNT
study
is
considered
to
simply
be
confirmatory.

For
these
reasons,
Gowan
Company
respectfully
requests
a
waiver
from
the
requirement
of
conducting
a
developmental
neurotoxicity
study
with
dicloran.

Again,
we
thank
the
Agency
for
the
opportunity
to
comment.

Sincerely,

Robert
E.
Hawk
Regulatory
Affairs
Manager
Gowan
Company
tel.
928­
819­
1544
rhawk@
gowanco.
com