Document ID: EPA-HQ-OPP-2002-0033-0020
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-01-08T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
October
24,
2002
MEMORANDUM
SUBJECT:
Propanil:
HED
Response
to
Data
Waiver
Requests
and
Comments
to
the
Risk
Assessment.

PC
Code
028201
Case
No.
0226
DP
Barcodes
D285043,
D285044
FROM:
Richard
Griffin,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
Carmen
Rodia
Reregistration
Branch
II
Special
Review
and
Reregistration
Division
(
7508W)

This
memo
has
been
prepared
in
response
to
comments
from
the
National
Agricultural
Aviation
Association
(
NAAA)
and
the
Propanil
Task
Force
(
PTF).
Comments
concern
the
Agency's
risk
assessment
for
propanil,
toxicology
data
requirements,
and
residue
chemistry
data
requirements.
2
NAAA
Comment:

In
brief,
the
NAAA
contends
that
restrictive
label
language
is
not
needed
for
propanil
since
current
Agency
risk
assessment
is
based
on
the
"
overly
conservative"
and
"
antiquated"
occupational
exposure
data
of
the
Pesticide
Handlers
Exposure
Database
(
PHED).
The
NAAA
comments
that
PHED
data
has
not
been
updated
subsequent
to
1992
and
does
not
reflect
new
safety
regulations
and
technological
advances
(
namely
GPS
systems,
personal
protective
equipment,
and
closed
mixingloading
Other
new
technologies
are
listed
to
demonstrate
reduced
worker
exposure
and
reduced
"
bystander"
exposure,
as
well
as
a
higher
level
of
efficacy
associated
with
aerial
application.
The
NAAA
comment
document
also
urges
the
Agency
to
consider
the
benefits
of
NAAA
sponsored
education
and
training
programs
(
such
as
PAASS),
and
concludes
by
pointing
out
the
general
advantages
of
aerial
pesticide
application.

Agency
Response:
The
Agency
acknowledges
and
supports
the
NAAA
in
their
efforts
to
advance
aerial
pesticide
application
in
the
areas
mentioned
in
their
comment
document.
The
Agency
also
acknowledges
that
there
is
a
degree
of
uncertainty
associated
with
the
propanil
occupational
risk
assessment,
as
with
every
occupational
risk
assessment.
However,
the
Agency
takes
exception
to
the
assertion
that
the
uncertainty
associated
with
PHED
data
always
favors
an
overestimation
of
exposure.
As
noted
by
the
NAAA,
the
PHED
dataset
is
not
adequately
robust
for
all
occupational
scenarios,
and
this
may
in
fact
lead
to
the
underestimation
of
(
unit)
exposure
for
certain
activities.
It
should
also
be
noted
that
PHED
exposure
estimates
for
specific
activities
are
pooled
for
a
central
tendency
estimate,
and
may
not
be
representative
of
a
possible
high­
end
exposure.

However,
occupational
exposure
estimates
are
not
determined
solely
by
the
PHED
estimates.
Exposure
estimates
are
also
determined
by
other
input
parameters
such
as
acres
treated
per
day,
application
rates,
and
data
concerning
the
seasonal
duration
of
exposure.
Uncertainty
is
also
associated
with
each
of
these
input
paramenters
and
for
this
reason
a
range
of
exposure
is
estimated
for
the
initial
risk
assessment.
The
range
of
the
estimate
intends
to
represent
a
typical,
or
average
exposure,
to
a
theoretical
high­
end.
The
initial
risk
assessment
is
often
refined
based
on
comments
received,
new
data,
and
refined
analysis.
The
Agency's
objective
is
to
be
adequately
protective
without
overestimating
exposure.

In
the
case
of
propanil
the
aerial
application
high­
end
exposure
estimate
is
based
on
an
acres
treated/
day
estimate
(
provided
by
the
task
force)
of
3,200
acres
(
on
rice)
and
the
maximum
a.
i./
acre
rate
of
6
lbs.
The
lower
end
of
the
exposure
range
is
based
on
350
acres/
day
and
a
rate
of
3
lbs
a.
i./
acre.
This
combination
of
high
acres
treatment/
day
and
a
relatively
high
usage
rate
has
resulted
in
risk
issues
for
workers
mixing/
loading
for
aerial
treatment
and
for
aerial
applicators
(
pilots).
It
should
be
noted
that
the
mixing/
loading
estimates
for
liquids
and
a
dry
flowable
type
formulation
are
3
based
on
the
engineering
controls
of
a
closed
system
or
a
water
soluble
packet.

The
Agency
welcomes
any
comments
that
may
be
made
by
NAAA
members
concerning
propanil
treatment
on
rice,
especially
comment
concerning
acres
treated
and
the
duration
of
exposure.

Task
Force
Comment
Concerning
Toxicology
Data
Requirements:

28­
day
inhalation
toxicity
study
in
rats
Comment:
The
registrant
argues
that
conducting
a
28­
day
inhalation
study
with
propanil
is
not
warranted.
It
is
proposed
that
a
30­
day
oral
toxicity
study
with
assessment
of
methemoglobinemia
(
as
requested
by
the
HIARC)
should
be
used
for
any
inhalation
risk
assessment,
assuming100%
inhalation
absorption.
Further,
it
is
suggested
that
this
will
provide
a
conservative
estimate
of
inhalation
exposure
under
the
conditions
of
use.

EPA
response:
A
direct
assessment
of
inhalation
toxicity
is
required
in
order
to
fully
characterize
the
hazard
and
dose­
response
for
inhalation
exposures.
Arguments
in
support
of
this
position
follow.
1)
It
is
known
that,
for
some
chemicals,
inhalation
exposure
can
result
in
remarkably
different
toxicological
outcomes
than
oral
exposures.
In
some
situations,
the
respiratory
tract
is
found
to
be
an
unexpected
target.
2)
Alveolar
absorption
often
exceeds
that
of
the
gastrointestinal
tract.
It
is
also
noted
that
no
pharmacokinetic
data
are
available
with
propanil
to
use
in
determining
whether
or
not
absorption
is
equivalent
for
oral
and
inhalation
exposures.
If
absorption
is
less
than
100%
via
the
GI
tract
but
is
found
to
be
100%
via
inhalation,
then
the
use
of
oral
toxicity
data
will
underestimate
risk
associated
with
inhalation
exposures.

Comment:
The
registrant
also
states
that
propanil
will
be
applied
by
both
aerial
and
ground­
boom
applications,
and
that
under
these
conditions
the
particles
produced
are
outside
of
the
inhalable
range.
Therefore,
it
is
the
opinion
of
the
registrant
that
the
majority
of
the
exposure
under
these
conditions
is
expected
to
be
incidental
oral
(
via
the
ingestion
of
respiratory
mucus)
rather
than
inhalation.

EPA
response:
The
use
of
aerial
and
ground­
boom
applications
could
result
in
inhalation
exposure.
The
reason
that
HED
requires
particles
with
a
Mass
Median
Atmospheric
Diameter
(
MMAD)
of
1­
3
µ
m
in
rodent
inhalation
studies
is
so
that
a
portion
of
the
test
article
will
reach
the
lungs.
If
rats
were
exposed
to
slightly
larger
particles,
e.
g.,
an
MMAD
of
10
µ
m,
the
lungs
would
be
virtually
untouched.
While
it
is
important
to
expose
the
lungs,
it
is
also
recognized
that
inhalation
exposure
includes
the
entire
respiratory
tract,
and
it
must
be
assumed
that
absorption
can
occur
anywhere
from
the
nose
to
the
alveoli.
It
cannot
be
assumed
that
all
particles
deposited
in
the
respiratory
mucus
are
ultimately
swallowed
For
some
chemicals
this
is
the
case,
but
4
for
others
it
is
not.
This
position
is
consistent
with
the
HED
Interim
Policy
for
Particle
Size
and
Limit
Concentration,
which
was
reviewed
and
endorsed
by
the
FIFRA
SAP
in
December,
1991.

In
conclusion,
EPA
believes
that
a
28­
day
inhalation
study
with
propanil
is
justified,
based
upon
both
the
toxicological
and
exposure
profiles.

Developmental
Neurotoxicity
Study
Comment:
The
Registrant
does
not
agree
with
the
Agency's
arguments
for
requiring
the
developmental
neurotoxicity
(
DNT)
study
for
propanil.
The
registrant
argues
that
the
axonal
degeneration
of
sciatic
nerves
observed
in
the
chronic
rat
study
was
an
age­
related
finding,
and
that
the
increased
incidence
at
the
high­
dose
was
attributable
to
increased
survival
in
female
rats
at
that
dose.
Additionally,
the
registrant
did
not
agree
that
there
was
any
basis
for
the
Agency's
determination
that
alterations
in
delayed
sexual
development,
decreased
testicular
sperm
counts
and
production
rates
in
the
reproduction
study,
and
treatment­
related
Leydig
cell
tumors
in
the
chronic
rat
study
were
indicative
of
effects
on
the
neuroendocrine
system,
since
there
were
no
alterations
in
testosterone,
luteinizing
hormone
or
estradiol
levels
in
P
males
in
the
reproduction
study.

EPA
response:
The
database
for
propanil
was
evaluated
in
accordance
with
procedures
for
determining
the
need
for
a
developmental
neurotoxicity
study,
which
have
been
fully
described
in
OPP
guidance
documents
on
the
determination
of
the
FQPA
factor
(
EPA,
1999;
2002).
These
documents
specify
the
use
of
a
weight
of
evidence
evaluation
of
each
chemical
data
base,
considering
factors
that
include
presence
of
neuropathology
in
the
database,
hormonal
alterations,
and
structure
activity
relationships,
as
indicative
of
the
need
for
a
DNT.
First,
in
the
chronic/
carcinogenicity
study
in
rats
with
propanil,
axonal
degeneration
of
the
sciatic
nerve
was
observed
in
21/
50
(
42%)
of
the
high
dose
female
rats,
as
compared
to
13/
50
(
26%)
of
the
control
females.
While
this
finding
was
observed
primarily
at
terminal
sacrifice,
it
is
nevertheless
indicative
of
an
adverse
effect
of
propanil
on
the
nervous
system.
Although
the
axonal
degeneration
was
expressed
in
aged
animals,
the
initial
insult
to
the
nervous
system
might
have
occurred
in
the
animals
when
they
were
young.
Therefore
this
evidence
of
neuropathology
cannot
be
discounted.

The
second
point
raised
by
the
registrant
is
that
adult
male
hormone
levels
(
testosterone,
luteinizing
hormone,
and
estradiol)
were
not
altered
in
adult
P
generation
males
in
the
two­
generation
reproduction
study
with
propanil.
However,
it
is
noted
that
with
linuron,
a
structurally
related
antiandrogenic
pesticide
that
has
been
examined
extensively
in
the
peer­
reviewed
literature,
exposure
during
the
period
of
late
gestation
has
been
shown
to
alter
sexual
differentiation
in
the
rat,
and
that
the
timing
of
exposure
is
crucial
to
the
expression
of
this
effect.
Since
the
P
generation
rats
of
the
propanil
5
reproduction
study
are
not
exposed
to
test
substance
during
that
critical
late
gestation
time
period,
a
lack
of
treatment­
related
effect
on
these
hormonal
profiles
would
not
be
unexpected;
hormonal
measurements
of
the
F1
adult
males
would
have
been
more
appropriate.
Additionally,
other
aspects
of
propanil
reproductive
system
toxicity
are
similar
to
linuron
for
rats
exposed
during
sexual
differentiation,
i.
e,
delayed
sexual
maturation
and
alterations
in
spermatogenesis,
or
for
male
rats
with
lifetime
exposures,
i.
e.,
a
treatment­
related
increase
in
the
incidence
of
testicular
interstitial
(
Leydig)
cell
tumors.
While
the
available
data
base
for
propanil
does
not
provide
a
detailed
evaluation
of
its
endocrine­
disruptive
potential,
the
evidence
at
hand
is
adequate
to
arrive
at
the
conclusion
that
propanil
likely
has
a
similar
mode
of
action
as
linuron.
The
neurodevelopmental
literature
support
the
Agency
position
that
endocrine
disruptions
can
profoundly
effect
the
structural
and
functional
organization
of
the
nervous
system
during
development.
Consequently,
there
is
sufficient
overall
evidence
to
justify
requiring
a
developmental
neurotoxicity
study
in
rats,
in
order
to
examine
the
potential
for
structural
and
functional
alterations
in
the
nervous
system
that
may
result
from
exposures
during
critical
stages
of
early
nervous
system
development.