Document ID: EPA-HQ-OPP-2003-0101-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-03-17T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides
and
Toxic
Substances
March
11,
2003
SUBJECT:
Carbaryl:
Agency
Response
To
Comments
On
Phase
5
Risk
Assessment;
DP
Barcodes:
D286511,
D286777,
D286506,
D286775,
D286771,
D286478,
D286920&
D286510,
and
D286456;
PC
Code:
056801
FROM:
Jeffrey
L.
Dawson,
Chemist/
Risk
Assessor
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

Felicia
Fort,
Chemist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

Kit
Farwell,
DVM/
Toxicologist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THRU:
Whang
Phang,
PhD,
Branch
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

TO:
Anthony
Britten,
Chemical
Review
Manager
Reregistration
Branch
3
Special
Review
&
Reregistration
Division
(
7508C)

Attached
is
the
Agency's
response
to
Phase
5
error
correction
comments
provided
by
several
organizations
on
the
previous
version
of
the
human
health
effects
risk
assessment
(
D284580/
July
30,
2002).
The
intent
of
this
document
is
to
illustrate
how
the
comments
were
considered
in
the
revisions
to
the
risk
assessment.
Each
comment
is
summarized
below
along
with
the
Agency
response
and
any
associated
changes
in
the
risk
assessment.
Appropriate
identifying
information
is
also
included
(
e.
g.,
submitter,
DP
Barcode,
document
cited,
etc.).
Many
of
the
comments
included
issues
related
to
both
the
human
health
risk
assessment
and
the
eco­
risk
assessment.
Only
those
comments
that
pertain
to
the
human
health
risk
assessment
are
addressed
herein.
All
comments
related
to
the
development
of
EECs
used
for
drinking
water
assessments
have
been
addressed
separately
by
the
Environmental
Fate
and
Effects
Division.
2
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
D286511:
ORGANIZATION
=
BEYOND
PESTICIDES,
AUTHOR
=
JESSICA
LUNSFORD,
DATE
=
10/
23/
02
1
Docketing
error.
Comments
have
been
included
in
the
process
despite
any
error.
None
2
Assessment
fails
to
implement
the
10x
safety
factor
based
on
several
issues
including:
dietary
data;

market
share
changes;
3x
and
lack
of
a
true
NOAEL
for
the
chronic
assessment;
and
maximum
versus
typical
application
rates.
The
Agency
has
considered
these
issues
including:
the
CMBS
data
have
been
characterized;
potential
market
share
changes
are
being
evaluated;
the
3x
safety
factor
for
the
chronic
assessment
is
based
on
current
Agency
policy;
and
the
rates
are
based
on
the
best
use
information
available
(
see
Appendix
A).
None,
unless
there
are
additional
changes
with
the
interpretation
and
characterization
of
the
CMBS
and
the
market
share
analysis
will
be
considered
in
the
development
of
the
risk
management
package
for
carbaryl.

3
Selective
use
of
the
CMBS
(
carbamate
market
basket
survey)

and
other
residue
data
for
analysis.
The
Agency
has
presented
the
dietary
risks
in
a
way
that
considers
the
results
of
the
CMBS
with
the
appropriate
characterization.
None,
unless
there
are
additional
changes
with
the
interpretation
and
characterization
of
the
CMBS.

4
Residential
product
market
share
changes
should
be
considered.
The
Agency
is
evaluating
the
potential
impacts
of
such
market
share
changes.
None,
the
market
share
analysis
will
be
considered
in
the
development
of
the
risk
management
package
for
carbaryl.

5
Intermediate­
term
risks
should
be
considered
in
the
residential
assessment.
Intermediate­
term
risks,
where
appropriate
(
i.
e.,
in
post­
application
situations),
were
considered
by
the
Agency.
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
3
6
Actual
rates
exceed
maximum
labeled
rates
by
up
to
a
factor
of
2.
The
Agency
does
not
consider
misuse
scenarios
in
its
assessments.

Additionally,
the
claims
made
were
unsubstantiated.
None,
the
referenced
scenarios
were
unsubstantiated.

7
Several
risk
management
recommendations
were
made.
The
Agency
will
consider
these
during
the
risk
management
phase.
None.

D286511:
ORGANIZATION
=
WA
TOXICS
COALITION
&
NW
COALITION
FOR
ALTERNATIVES
TO
PESTICIDES,
AUTHORS
=
E.
SCHREDER
&
P.
LIND,
DATE
=
10/
28/
02
1
Several
comments
were
made
on
ecological
effects.
WA
state
water
and
sediment
data
were
cited.
The
Agency
used
water
data
from
several
sources
in
WA
state
in
its
oyster
bed
use
assessment.
EFED
will
address
the
remaining
comments.
None
related
to
the
oyster
bed
assessment.

EFED
will
address
the
remaining
comments.

2
A
concern
for
market
share
changes
was
expressed.
The
Agency
is
evaluating
the
potential
impacts
of
such
market
share
changes.
None,
the
market
share
analysis
will
be
considered
in
the
development
of
the
risk
management
package
for
carbaryl.

D286511:
ORGANIZATION
=
NRDC,
AUTHOR
=
JENNIFER
SASS,
DATE
=
10/
28/
02
1
Several
recommendations
were
made
including:
cancellation
of
all
granular
formulations,
cancellation
of
all
pet
uses,
and
use
a
10x
FQPA
safety
factor.
The
Agency
will
consider
these
during
the
risk
management
phase.

The
Agency
has
also
evaluated
the
application
of
the
FQPA
factor
under
the
most
current
policy.
[
See
Appendix
A
for
further
explanation
regarding
the
FQPA
factor.]
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
4
2
Carbaryl
is
an
n­
methyl
carbamate
and
should
be
included
with
the
OPs
for
cumulative
assessment
since
"
they
clearly
share
a
mode
of
action."
There
are
differences
in
pharmacokinetics
and
pharmacodynamics
between
OPs
and
carbamates,
cholinesterase
inhibition
is
by
different
biochemical
mechanisms,
resulting
in
different
time
course
of
events:
time
to
peak
effect,
t1/
2,
duration
of
action,
and
recovery
time
after
exposure.
EPA
is
investigating
the
pharmacokinetics
and
pharmacodynamics
of
N­
methyl
carbamates
for
the
cumulative
assessment
of
these
pesticides.
None.

3
The
Agency
has
"
disregarded
adverse
effects
on
developing
brain
structure
and
function."
Several
Agency
documents
were
cited
to
support
this
claim.
Please
refer
to
Appendix
A.
See
the
response
to
D286511/
comment
1
above.
[
Also,
please
refer
to
Appendix
A.]

4
"
Farm
children
are
especially
vulnerable
to
pesticide
exposure
and
are
not
adequately
considered."

Work
from
several
researchers
has
been
cited
to
support
this
claim
(
e.
g.,
Fenske
and
Hill).
The
Agency
is
currently
evaluating
its
position
on
the
exposures
of
farmchildren.
Preliminary
analysis
of
available
information
does
not
indicate
significant
differences
in
exposures
for
farmchildren
compared
to
the
general
population.
None
at
this
time
outside
of
appropriate
characterization
will
be
added
to
the
assessment
to
address
this
issue
that
reflects
the
most
currently
available
information.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
5
5
Water
issues
were
addressed
including:
non­
agricultural
run­
off
(
e.
g.,
landscape
and
golf
course
use)
and
DWLOCs.
NRDC
indicates
they
anticipate
EECs
would
be
worse
if
non­
agricultural
run­
off
was
considered.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

6
Dietary
(
food)
issues
were
addressed
including:
composite
PDP
samples
were
used
to
estimate
single
servings
consumed,

farmstand/
UPIK
sources
of
commodities
were
not
considered,

and
percent
crop
treated
values
were
"
wrongly"
used
to
adjust
acute
dietary
risk
estimates.
The
dietary
risk
assessment
was
conducted
in
accordance
with
Agency
policy.
The
Agency
is
currently
evaluating
its
position
on
UPIK
sources
of
commodities.
None
at
this
time
outside
of
appropriate
characterization
will
be
added
to
the
assessment
to
address
this
issue
that
reflects
the
most
currently
available
information.

7
Recommendations
were
made
based
on
the
residential
risk
estimates
including:
MOEs
for
residential
handlers,
MOEs
for
children
on
lawns,
and
MOEs
for
children
after
contact
with
treated
pets.
NRDC
also
cited
the
lack
of
a
transferable
residue
study
on
pets.
The
Agency
will
consider
these
during
the
risk
management
phase.
None.
It
should
also
be
noted
a
recently
submitted
transferable
residue
study
for
dog
collars
was
integrated
into
the
current
assessment.

8
Comments
were
made
regarding
the
magnitude
of
occupational
MOEs.
The
Agency
will
consider
these
during
risk
management.
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
6
9
Comments
were
made
regarding
a
lack
of
exposure
data
for
some
occupational
scenarios.
NRDC
indicated
that
a
10x
FQPA
factor
should
be
applied
in
these
cases.
The
Agency
does
not,
under
the
FQPA
statute,
apply
the
FQPA
factor
to
occupational
exposure
scenarios.
None,
the
scenarios
in
question
will
be
further
investigated
during
the
risk
management
phase
to
develop
a
better
understanding
of
their
use
to
allow
for
a
more
informed
risk
management
decision.

D286777:
ORGANIZATION
=
CHERRY
MARKETING
INST.,
AUTHOR
=
PHIL
KORSON,
DATE
=
10/
22/
02
1
Efficacy,
use,
and
information
on
alternatives
were
presented.
In
tart
cherries,
carbaryl
is
used
on
~
9%
of
the
acres
with
an
average
of
1.3
applications
annually.
In
sweet
cherries,
~
31%
of
acres
with
an
average
of
1.6
applications
annually
are
completed.
Mechanical
harvest
was
indicated
as
the
predominant
method.
The
FDA
mandated
zero
tolerance
for
cherry
fruit
fly
larva
was
also
described.
The
Agency
will
consider
this
information
in
the
development
of
the
updated
risk
assessment
and
during
risk
management.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.

D286506:
ORGANIZATION
=
CA
STRAWBERRY
COMMISSION,
AUTHOR
=
JAN
SHARP,
DATE
=
10/
23/
02
1
Efficacy
of
bait
products
was
discussed
and
the
need
for
a
3
day
PHI
versus
the
current
7
day
PHI.

Harvest
intervals
of
3
days
were
presented
as
normal
practice
in
strawberry
cultivation.
No
additional
data
were
presented,

but
additional
work
by
IR­
4
was
discussed
that
would
not
be
available
for
this
process.
The
Agency
will
consider
this
information
in
the
risk
management
process.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
7
D286506:
ORGANIZATION
=
MI
STATE
UNIV/
OCEANA
CTY,
AUTHOR
=
KIMBERLY
SMITH,
DATE
=
10/
29/
02
1
The
lack
of
alternatives,
the
impact
of
a
5
day
REI
(
based
on
previous
assessment),
and
zero
tolerance
criteria
for
asparagus
beetle
were
discussed.
The
Agency
will
consider
this
information
in
the
risk
management
process.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.

D286506:
ORGANIZATION
=
US
ASPARAGUS
INDUSTRY,
AUTHOR
=
SCHREIBER
&
BAKKER,
DATE
=

10/
28/
02
1
The
lack
of
alternatives,
the
impact
of
a
5
day
REI
(
based
on
previous
assessment),
zero
tolerance
criteria
for
beetle
damage,
and
the
unique
need
for
carbaryl
at
harvest
time
because
it
controls
adult
asparagus
beetles
were
discussed.
Use
information
was
also
presented
including:
NASS
information
about
MI
that
indicates
growers
apply
carbaryl
to
~
90%
of
acres
­
4x/
year
and
at
about
½
that
frequency
in
the
east.
The
Agency
will
consider
this
information
in
the
risk
management
process.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
8
D286506:
ORGANIZATION
=
US
APPLE
ASSOC.,
AUTHOR
=
JIM
CRANNEY,
DATE
=
10/
28/
02
1
The
critical
biological
and
economic
needs
for
carbaryl
when
used
for
thinning
apples
was
discussed
along
with
issues
associated
with
alternatives
(
they
are
not
as
favorable
because
they
are
dose
and
climate
dependent).
The
Agency
will
consider
this
information
in
the
risk
management
process.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
9
D286775:
ORGANIZATION
=
NAT.
AG.
APPL.
ASSOC.,
AUTHOR
=
ANDREW
MOORE,
DATE
=
10/
25/
02
1
The
use
of
"
antiquated"
PHED
data,
numerous
educational
efforts,

the
use
of
GPS
instead
of
flaggers,

and
the
need
for
additional
exposure
data
were
discussed.
The
Agency
concurs
with
NAAA
that
the
PHED
data
used
in
this
assessment
may
not
accurately
reflect
exposures
associated
with
the
most
cutting
edge
technologies.

However,
more
recent
data
have
not
been
produced
to
date
than
those
used
in
the
assessment.
It
is
also
not
clear
what
portion
of
the
industry
uses
older
technology
versus
the
more
updated
nozzle
technology
described
in
NAAA's
submission.

The
Agency
still
includes
flaggers
in
its
assessments
because
NAAA's
own
use
survey
indicates
they
are
still
used
in
a
small
percentage
of
applications
(~
15%).
The
Agency
characterizes
this
as
such
in
its
assessments
for
risk
managers.
None,
outside
of
additional
characterization
of
occupational
risks
will
be
included
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
10
D286771:
ORGANIZATION
=
NW
HORT.
COUNCIL,
AUTHOR
=
MICHAEL
WILLETT,
DATE
=
10/
29/
02
1
The
inability
to
use
closed
cabs
for
applying
carbaryl
in
tree
fruit
because
of
the
tree
canopy
shape
(
apple
and
cherry
examples
were
provided)
was
discussed.
Potential
economic
impacts
were
also
discussed.
No
additional
information
was
provided
to
substantiate
this
comment
(
e.
g.,
a
comparison
of
the
size
of
tree
canopies
versus
tractor
size,
etc.).
However,
the
Agency
will
consider
this
comment
during
risk
management.
None
outside
of
providing
additional
characterization
as
appropriate.
The
Agency
also
considered
open
cab
airblast
applicator
scenarios
with
individuals
wearing
protective
headgear
which
is
related
to
this
issue.

2
The
methodology
used
to
calculate
surface
water
concentrations
for
dietary
risk
and
eco­
risk
assessment
was
criticized.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

3
Use
of
the
CMBS
(
carbamate
market
basket
survey)
was
encouraged
for
calculating
dietary
risk.
The
Agency
has
considered
the
CMBS
in
its
calculations.
In
the
previous
assessment
dietary
risks
were
evaluated
both
with
and
without
the
CMBS
which
is
also
the
case
in
the
current
assessment.
The
only
changes
would
be
related
to
additional
language
related
to
the
interpretation
and
characterization
of
the
CMBS.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
11
D286478:
ORGANIZATION
=
USDA
APHIS,
AUTHOR
=
CARL
BAUSCH,
DATE
=
10/
28/
02
1
Comments
described
the
Grasshopper
and
Mormon
Cricket
Suppression
program
mandated
by
the
Plant
Protection
Act
(
7USC7717).
ULV
and
bait
applications
(
aerial
&
ground)
are
used
up
to
a
maximum
application
rate
of
0.50
lb
ai/
acre.
A
NEPA
EIS
has
been
completed.
It
was
also
indicated
that
site­
specific
environmental
assessments
"
will
be
developed
as
specific
areas
are
targeted
for
treatment;
these
EA's
will
address
sensitive
areas,

Statelisted
endangered
and
threatened
species
as
well
as
Federal
candidate
species."

[
NEPA]
=
National
Environmental
Protection
Act
[
EIS]=
Environmental
Impact
Statement
[
EA]
=
Environmental
Assessment
The
Agency
will
consider
this
program
as
appropriate
in
the
risk
assessment.
As
such,
the
Agency
obtained
information
directly
from
USDA/
APHIS
on
the
details
of
how
this
program
is
conducted
and
used
this
information
to
update
the
risk
assessment.
The
Agency
added
occupational
scenarios
that
reflect
USDA/
APHIS
use
patterns.

Residential
scenarios
were
not
added
to
address
this
use
since
it
is
analogous
to
any
drift
situation
where
current
Agency
policy
applies.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
12
D286920
&
D286510:
ORGANIZATION
=
WELLMARK,
AUTHORS
=
CRAWFORD
&
SANDBERG,
DATE
=

10/
25/
02
1
A
study
conducted
by
Mississippi
State
University
(
Boone
et
al)
was
referenced.
The
biological
monitoring
component
of
the
study
was
discussed
and
the
argument
made
that
a
lack
of
TCP
(
a
urinary
metabolite
from
exposure
to
chlorpyrifos
collars)
increase
in
urine
over
time
for
children
living
with
treated
pets
is
an
indication
of
little
or
no
exposure
from
collar
use.
The
Agency
has
considered
the
referenced
biological
monitoring
data
but
has
rejected
it
for
use
in
risk
assessment.
This
decision
was
made
predominantly
because
the
data
are
inconclusive.
In
this
study,

children's
activities
were
not
correlated
with
the
time
or
their
contact
with
treated
animals.
None
outside
of
providing
additional
characterization
language
as
appropriate.

2
The
Agency
used
an
emission
term
developed
based
on
data
from
MSU
(
Boone
et
al)
for
collars
of
0.00029mg/
cm2/
gram
ai/
day.
This
was
said
to
be
too
conservative
because
it
is
the
value
measured
closest
to
the
collar
area
and
"
a
toddler
will
also
have
contact
with
other
regions
of
the
animal."

Boone
measured
residues
on
different
sections
of
the
animals
and
the
Agency
used
the
results
from
near
the
head/
neck
for
assessments.
The
value
cited
from
Boone
et
al
actually
represents
the
average
concentration
over
all
areas
of
the
treated
dogs.
None,
outside
of
additional
characterization
language
as
appropriate.
Also
see
response
to
comment
3
below
as
the
Agency
also
used
data
from
a
recently
submitted
collar
residue
study
to
evaluate
exposures
in
context
with
the
Boone
et
al
data.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
13
3
A
study
(
MRID
45792201)
that
determined
the
amount
of
residues
that
transferred
from
10
dogs
wearing
carbaryl
collars
(
16%
ai)

was
conducted.
Measurements
of
transferability
by
people
petting
dogs
for
20
minutes
over
all
regions
of
the
animals
were
taken
at
24
hours,
96
hours
and
1
week
after
placement
of
the
collars.
A
separate
study
(
report
not
provided)

was
also
conducted
that
measured
residue
release
from
collars.
The
Agency
used
these
data
to
calculate
a
residue
transferability
rate
of
2.6%
to
evaluate
non­
collar
products.
The
Agency
also
evaluated
collar
use
with
the
data
from
this
study
both
distibuting
residues
locally
around
the
collar
and
over
the
entire
dog
for
comparative
purposes.
The
Agency
revised
its
assessment
to
use
these
data
to
provide
companion
risk
assessments
for
non­
collar
pet
products
(
basically
for
comparative
purposes).
The
data
were
also
used
directly
to
assess
pet
collar
use.

4
The
percent
of
transferable
residue
that
was
used
by
the
Agency
in
its
calculations
(
20%)
is
an
overestimate.
Additionally,
the
50%
saliva
extraction
factor
was
said
to
overestimate
exposure
since
the
solubility
of
carbaryl
is
very
low
in
water.
With
regard
to
the
transferability
issue,
the
Agency
calculated
risks
in
several
different
ways
as
indicated
above
in
the
response
to
comment
3
and
there
were
no
changes
in
the
trend
of
the
results.
The
comment
on
saliva
extraction
fails
to
account
for
the
mechanical
agitation
that
would
be
expected
in
a
toddler's
mouth.

This
factor
has
also
been
taken
for
review
to
the
FIFRA
SAP.
Additional
characterization
language
will
be
provided
and
the
results
based
on
the
study
will
be
incorporated
into
the
assessment
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
14
5
It
was
indicated
that
the
suburban
resident
biomonitoring
study
supported
the
continued
use
of
carbaryl
pet
products.
Also,
it
was
reported
"
the
results
of
this
study,

which
contains
biological
monitoring
of
all
age
groups,

indicate
that
the
Agency
has
overestimated
the
exposure
of
users
of
carbaryl
products."
The
Agency
does
not
concur
with
this
statement
because
(
1)
no
reliable
biological
monitoring
data
are
available
for
defining
absorbed
dose
estimates
from
pet
uses
and
(
2)
the
interpretation
of
the
results
of
the
biological
monitoring
estimate
is
inappropriate
because
the
use
patterns
are
so
dissimilar.
The
results
of
the
biological
monitoring
study
actually
agree
quite
closely
with
the
calculations
from
the
risk
assessment
on
residential
turf.
The
Agency
has
never
indicated
that
similarities
between
lawn
and
pet
care
uses.
None
outside
of
additional
characterization
language
to
address
this
comment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
15
D286456:
ORGANIZATION
=
BAYER
CROP
SCIENCE,
AUTHORS
=
NOT
LISTED,
DATE
=
10/
28/
02
D286456:
GENERAL
COMMENTS,
PART
1
(
starts
pg
4)

1
The
application
of
a
3x
factor
for
the
lack
of
a
NOAEL
in
the
chronic
dog
study
was
discussed.
A
5­
week
study
in
dogs
supports
a
NOAEL
of
3.1
mg/
kg/
day
rather
than
it
being
a
LOAEL.
The
3x
factor
should
be
removed.
Brain
ChE
inhibition
of
20%
in
the
chronic
dog
study
is
considered
toxicologically
significant.
None.

2
Label
changes
need
to
be
made
to
reflect
the
results
of
the
confined
rotational
crop
(
CRC)
study.
The
CRC
study
demonstrates
"
that
no
plant­
back
restriction
is
needed
and
no
tolerances
for
rotational
crops
are
required."
The
Agency
concluded
that
the
rotational
crop
study
was
adequate
and
that
the
current
label
restriction
against
rotating
crops
for
which
carbaryl
is
not
registered
is
adequate.

No
changes
should
be
made
to
the
label.
None
3
Inconsistencies
in
the
EFED
review
and
revised
HED
risk
assessment
should
be
corrected.
Monitoring
data
should
be
considered.
The
Agency
will
correct
any
inconsistencies.
Monitoring
data
will
be
considered
and
used
as
appropriate.
Inconsistencies
will
be
corrected
and
monitoring
data
will
be
incorporated
as
determined
to
be
appropriate.

D286456:
LINE
BY
LINE
COMMENTS
ON
TOXICOLOGY
DATABASE,
PART
2
(
starts
pg
6)

1
(
Pg6/
¶
2/
L1­
16)
Bayer
concurs
with
the
Agency's
interpretation
of
the
data
supporting
the
FQPA
factor
of
1.
None.
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
16
2
(
Pg6/
¶
3/
L1­
10)
Carbaryl
presents
no
imminent
carcinogenic
risk
because:

(
1)
high
doses
produce
tumors
via
a
non­
genotoxic
mechanism,
possibly
related
to
altered
metabolism,
(
2)
at
doses
<
MTD
there
was
increased
tumor
incidence
in
only
1
site
of
1
sex
of
1
species,
(
3)
the
p53
knockout
model
was
negative
(
its
been
demonstrated
to
be
sensitive
to
vascular
tumor
induction
by
reference
chemicals),
(
4)
weight
of
evidence
shows
no
potential
for
genotoxicity,
and
(
5)

epidemiological
data
in
production
workers
shows
no
increase
in
tumors.
(
1)
Non­
genotoxic
mechanism
has
not
been
demonstrated;
(
2)
in
addition
to
vascular
tumors,

preneoplastic
lesions
were
seen
at
inadequate
dose
in
mice,
if
mice
had
been
tested
at
an
adequate
dose,

tumors
may
have
developed;
(
3)
p53
mouse
has
not
been
validated
by
EPA;
(
4)
DNA
reactivity
is
manifested
as
chromosomal
aberrations
in
cultured
mammalian
cells,
are
effects
on
karyokinesis
and
cytokinesis,
as
well
as
stress
genes
associated
with
oxidative
damage.

Also,
see
further
discussion
of
epidemiological
study
of
workers
below.
None.

3
(
Pg6­
7/
¶
4­
1/
L5­
15)
Same
as
comment
1
in
General
Comments
Section
(
Pt
1).
Same
as
comment
1
in
General
Comments
Section
(
Pt
1).
Same
as
comment
1
in
General
Comments
Section
(
Pt
1).
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
17
4
(
Pg11/
¶
3/
L1­
10)
Risks
from
carbaryl
contained
in
cigarette
smoke
are
"
insignificant
and
is
not
calculable."
The
Agency
did
calculate
noncancer
risks
for
carbaryl
contained
in
cigarette
smoke
with
the
acknowledgment
that
both
sidestream
and
main­
stream
smoke
were
included
which
is
a
likely
overestimate
of
exposure.
The
Agency
did
not
attempt
to
calculate
cancer
risks
attributable
from
carbaryl
contained
in
cigarette
smoke
because
it
would
be
indistinguishable
from
other
chronic
health
effects
associated
with
smoking
(
including
cancer).
None.

5
(
Pg16/
¶
2/
L1­
3)
There
is
no
clear
scientific
basis
for
requesting
a
90­

day
inhalation
study
in
rats.
A
submission
from
Crop­
Life
America
on
this
topic
was
included
that
discussed
(
1)
spray
droplet
size
based
on
ASAE
criteria,
(
2)
particle
deposition
in
the
respiratory
tract,

and
(
3)
the
guidelines
for
28­
or
90­

day
inhalation
toxicity
studies.
Spray
droplets
are
large
and
inhalation
MOEs
for
liquid
formulations
are
generally
greater
than
~
50,000.
However,
use
of
dust,

granular,
and
bait
applications
have
MOEs
ranging
from
28
­
714.
An
inhalation
study
is
still
required
to
address
these
concerns.
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
18
D286456:
SUPPORTING
DISCUSSION
COMMENTS
ON
TOXICOLOGY
DATABASE,
PART
2
(
starts
pg
16)

1
Several
topics
pertaining
to
the
combined
oncogenicity/
chronic
toxicity
studies
were
discussed
including:
(
1)
the
data
are
considered
equivocal
since
tumors
occurred
in
1
site
of
1
sex
of
1
species,
(
2)
adequate
historical
control
data
were
not
available
from
the
laboratory
that
conducted
the
studies,
(
3)
the
lack
of
significant
histopathological
findings
at
the
1
year
sacrifice
which
didn't
correlate
well
with
the
detection
of
tumors
in
certain
tissues,
and
another
slide
review
was
completed
by
"
independent
pathologists."
(
1)
Pre­
neoplastic
lesions
seen
at
inadequate
dose
in
mice,
if
tested
at
adequate
dose,
tumors
may
have
developed;
(
2)
tumor
incidence
was
compared
to
concurrent
controls
and
historical
data
submitted
by
registrant;
(
3)
analysis
in
the
CARC
report
is
based
on
a
reevaluation
of
slides
from
the
mouse
carcinogenicity
study
by
an
acceptable
Pathology
Working
Group
which
was
performed
in
accordance
with
PR
Notice
94­
5
(
D233467;
HED
document
012394).
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
19
2
Several
topics
pertaining
to
the
combined
oncogenicity/
chronic
toxicity
studies
were
discussed
including:
those
addressed
above
in
comment
1
and
altered
metabolism
from
"
unrealistically
high"
doses
may
impact
formation
of
tumors,

and
the
significance
of
vascular
tumors.
It
could
not
be
determined
if
there
was
a
change
in
metabolism
in
mice
at
1000
ppm,
a
dose
that
caused
tumors.
The
DNA
binding
study
had
limited
sensitivity.
The
P­
450
study
showed
that
carbaryl
is
a
weak
enzyme
inducer
in
mice
but
there
were
no
studies
to
examine
the
effect
of
increasing
doses.
Alteration
in
metabolism,
by
itself,
is
not
sufficient
evidence
of
a
nonlinear
mode
of
action,
and
there
was
no
correlation
between
the
metabolic
shift
and
increased
toxicity
or
tumor
formation.
None.

3
The
epidemiological/
worker
exposure
information
was
discussed.
"
The
population
of
exposed
persons
with
the
highest
and
most
consistent
carbaryl
exposure,
show
no
indication
of
effects
on
tumor
incidence."
The
sample
of
workers
was
too
small
and
the
period
of
follow
up
to
too
short
to
permit
definitive
conclusions.
None.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
20
D286456:
COMMENTS
ON
DIETARY
EXPOSURE
ANALYSIS,
PART
3
(
starts
pg
24)

1
Bayer
concurs
with
the
Agency's
last
revisions
to
the
dietary
analysis
including:
use
of
processing
factors,

use
of
cooking
and
washing
factors,

removal
of
non­
supported
commodities,
use
of
updated
PAD
and
Q1*
values,
and
use
of
1994
­

1998
CFSII
data.
None.
None.

2
The
utility
of
the
carbamate
market
basket
survey
was
discussed.

Additionally,
the
protocols
for
sample
preparation
in
various
commodities
were
presented
from
the
CMBS
and
PDP
for
comparative
purposes.
It
was
indicated
that
it
was
"
the
professional
judgement
of
the
study
designers"
to
add
"
gentle
rubbing
to
the
protocol
but
not
the
drying
process."
These
comments
have
been
addressed
in
the
revised
dietary
assessment.
These
comments
have
been
addressed
in
the
revised
dietary
assessment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
21
3
The
use
and
surrogation
of
monitoring
residue
data
was
discussed.
This
included
a
ranking
of
types
of
residue
data
(
i.
e.,
closer
to
the
dinner
plate
is
preferable
for
risk
assessment).
The
Agency's
decompositing
approach
was
discussed
and
a
line­
by­
line
examination
for
each
food
and
food
form
was
performed
with
an
accompanying
proposal
for
which
source
of
residue
data
to
use
for
each.
These
comments
have
been
addressed
in
the
revised
dietary
assessment.
These
comments
have
been
addressed
in
the
revised
dietary
assessment.

4
The
need
to
update
the
percent
crop
treated
data
used
in
the
assessment
was
discussed.
The
revised
dietary
assessment
will
include
revised
percent
crop
treated
data.
The
revised
dietary
assessment
will
include
revised
percent
crop
treated
data.

5
A
strategy
was
proposed
for
refining
the
dietary
risk
assessment
that
included:
replacement
of
residue
data
for
leafy
crops,
use
of
1999­
2000
PDP
data
for
newly
sampled
crops,
and
refine
the
data
used
for
squash
and
peaches.
These
comments
have
been
addressed
in
the
revised
dietary
assessment.
These
comments
have
been
addressed
in
the
revised
dietary
assessment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
22
D286456:
LINE
BY
LINE
COMMENTS
ON
ESTIMATED
ENVIRON.
CONC.,
PART
4
(
starts
pg
33)

1
(
Pg9/
¶
3/
L1­
16)
The
use
of
"
the
drinking
water
program
conducted
by
the
registrant
provides
a
real
world
assessment
of
the
potential
for
human
exposure
to
carbaryl
in
drinking
water
derived
from
surface
water."
These
data
were
advocated
over
the
use
of
PRZM/
EXAMS.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

2
(
Section
4.3)
Comments
were
made
concerning
inconsistencies
between
EFED
and
the
HED
risk
assessment
chapter.
The
Agency
will
correct
any
inconsistencies.
Monitoring
data
will
be
considered
and
used
as
appropriate.
Inconsistencies
will
be
corrected
and
monitoring
data
will
be
incorporated
as
determined
to
be
appropriate.

3
(
Pg40/
¶
3/
L1­
16)
Comments
were
related
to
item
1
above.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

4
(
Pg40/
¶
6)
Information
was
provided
about
NAWQA
and
the
recovery
of
carbaryl
residues
in
the
multi­
residue
methods.
This
was
done
in
response
to
general
comments
included
in
the
risk
assessment
pertaining
to
the
referenced
analytical
method.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

5
(
Pg41/
¶
3)
HED
risk
assessment
is
inconsistent
with
EFED
RED
chapter.
The
Agency
will
correct
any
inconsistencies.
Inconsistencies
will
be
corrected
as
determined
to
be
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
23
6
(
Pg41/
¶
3/
L12)
Information
was
provided
concerning
sampling
methods
that
describes
why
NAWQA
and
the
Bayer
drinking
water
study
results
are
different.

Essentially,
differences
were
attributed
to
the
different
types
of
sample
locations
used
in
both
studies.
Results
of
the
drinking
water
study
were
also
compared
to
the
EPA/
USGS
reservoir
study
and
the
USDA
PDP
drinking
water
study.
EFED
will
address
this
comment.
EFED
will
address
this
comment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
24
7
(
Pg41/
¶
3/
Last
line)
Information
was
provided
concerning
the
determination
of
peak
water
concentrations.
The
distributions
can
be
used
to
obtain
up
to
the
99th
%
tile.
The
peak
concentration
was
in
a
small
river
while
most
community
water
systems
are
likely
to
be
on
larger
bodies
of
water.

Therefore,
"
peak
values
are
not
likely
to
be
an
order
of
magnitude
greater
than
the
amounts
present
in
the
collected
samples."

Additionally,
because
the
maximum
observed
concentration
is
more
than
an
order
of
magnitude
less
than
the
DWLOC
for
carbaryl
the
drinking
water
study
should
be
sufficient
to
demonstrate
that
concentrations
of
carbaryl
"
do
not
result
in
an
unacceptable
contribution
to
dietary
exposure."
EFED
will
address
this
comment.
EFED
will
address
this
comment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
25
8
(
Pg41/
¶
4/
L1­
2)
Comments
were
provided
concerning
the
use
of
peak
water
concentrations
for
risk
assessments
rather
than
specific
percentiles
(
e.
g.,
95th
or
99th).
A
more
thorough
discussion
of
the
concentration
distributions
should
be
provided.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

9
(
Pg41­
42/
¶
5)
Additional
comments
were
made
concerning
the
use
of
the
drinking
water
monitoring
study
instead
of
PRZM
EXAMS.
EFED
will
address
this
comment.
EFED
will
address
this
comment.

D286456:
LINE
BY
LINE
COMMENTS
ON
5/
30/
02
RESIDUE
CHEMISTRY
CHAPTER,
PART
5
(
starts
pg
38)

1
(
Pg6/
¶
1&
2)
Comments
were
made
concerning
an
inconsistency
with
¶
4
pertaining
to
the
lack
of
storage
stability
data
on
dried
fruit.

Information
in
¶
4
indicates
there
is
an
adequate
study
on
raisins.
The
Agency
will
correct
any
inconsistencies.
Inconsistencies
will
be
corrected
as
determined
to
be
appropriate.

2
(
Pg9/
¶
16)
Comments
were
made
concerning
the
requirements
for
20
field
trials
on
wheat
hay.
A
comparison
was
made
to
grasses
that
are
another
major
component
in
cattle
diets
that
required
only
12
field
trials.
The
number
of
trials
required
for
a
crop
takes
into
account
not
only
its
production
acreage,
but
also
its
dietary
significance
which
is
why
the
Agency
requires
20
field
trials
on
wheat
hay
and
only
12
for
grasses.
None
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
26
3
(
Pg7/
¶
4)
The
Agency
indicated
tolerances
were
needed
for
citrus
fruit
oil,
raisins,
wet
apple
pomace,

and
rice
hulls.
It
was
indicated
that
tolerances
in
raisins
and
wet
apple
pomace
were
not
needed
because
the
HAFT
for
apples
or
grapes
times
their
respective
concentration
factors
are
below
1.5x
the
reassessed
tolerances
for
apples
and
grapes,
respectively.
The
Agency
will
correct
any
inconsistencies.
Inconsistencies
will
be
corrected
as
determined
to
be
appropriate.

4
(
Pg12/
¶
2)
The
label
restriction
concerning
rotational
crops
requires
updating.
The
Agency
concluded
that
the
rotational
crop
study
was
adequate
and
that
the
current
label
restriction
against
rotating
crops
for
which
carbaryl
is
not
registered
is
adequate.

No
changes
should
be
made
to
the
label.
None
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
27
D286456:
SUPPORTING
DISCUSSION
COMMENTS
ON
RESIDUE
CHEMISTRY
DATABASE,
PART
5
(
starts
pg
40)

1
A
confined
rotational
crop
study
(
MRID
43651701)
was
discussed.

Additionally,
it
was
presented
that
"
the
results
of
the
CRC
study
demonstrate
that
no
plant­
back
restriction
is
needed
and
no
tolerances
for
rotational
crops
are
required."
The
Agency
concluded
that
the
rotational
crop
study
was
adequate
and
that
the
current
label
restriction
against
rotating
crops
for
which
carbaryl
is
not
registered
is
adequate.

No
changes
should
be
made
to
the
label.
None
D286456:
LINE
BY
LINE
COMMENTS
ON
OCC./
RES.
EXPOSURE
ASSESSMENT,
PART
6
(
starts
pg
42)

1
(
Sec
2.1.3)
For
calculations
involving
treatment
to
over
350
acres,
it
was
indicated
that
there
is
poor
correlation
between
exposure
and
the
acres
treated.
This
was
attributed
to
an
"
efficiency
of
application"
associated
with
the
treatment
of
larger
acreages
(
e.
g.,

rather
than
use
a
number
of
small
volume
jugs
a
mechanical
transfer
device
would
be
used).
This
analysis
was
based
on
an
ethoprop
biomonitoring
study
(
MRID
45621501).
The
AHETF
was
identified
as
a
body
that
would
investigate
this
phenomena
further.
The
Agency
has
had
similar
concerns
and
welcomes
the
additional
data
that
could
be
generated
under
the
AHETF
that
could
be
used
to
refine
its
approach.
This
will
not,
however,

occur
in
a
manner
that
will
be
timely
for
the
carbaryl
risk
management
decision.
Analysis
of
the
ethoprop
study
is
inconclusive
with
regard
to
this
issue.
Additional
characterization
language
will
be
provided
and
the
results
based
on
the
study
will
be
incorporated
into
the
assessment
as
appropriate.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
28
2
The
inability
to
use
closed
cabs
for
applying
carbaryl
in
tree
fruit
was
described
because
of
the
tree
canopy
shape.
It
was
also
indicated
that
the
Agency
should
differentiate
between
its
available
tree
and
grape
data
instead
of
combining
them
as
is
now
done
and
that
a
protection
factor
be
applied
for
the
use
of
headgear.
No
information
was
provided
to
substantiate
the
comment
about
cab
entry
into
orchards
(
e.
g.,
a
comparison
of
the
size
of
tree
canopies
versus
tractor
size,
etc.).

However,
the
Agency
will
consider
this
comment
during
risk
management.
Additionally,
headgear
for
open
cab
airblast
applicators
with
high
levels
of
personal
protective
equipment
was
used
in
the
assessment.
Characterization
language
will
be
provided
as
appropriate
to
address
this
issue.

Additionally,
the
Agency
incorporated
headgear
into
its
assessment
for
open
cab
airblast
applicators
as
it
is
apparent
based
on
the
comment
that
Bayer
would
be
willing
to
address
this
issue
through
labeling.
The
Agency
applied
a
50
percent
protection
factor
for
headgear
use
only
to
applicators
who
were
also
wearing
maximum
levels
of
personal
protective
equipment
(
e.
g.,
coveralls,
gloves,

respirator).

3
The
use
of
ARTF
proposed
transfer
coefficients
was
discussed.
An
illustration
was
provided
for
tree
crop
activities.
The
transfer
coefficients
that
were
proposed
include
84
cm2/
hr
for
low
exposure
activities
such
as
propping,
493
cm2/
hr
for
low
exposure
activities
such
as
scouting,
pruning
and
pinching
and
1440
cm2/
hr
for
high
exposure
activities
such
as
hand
harvest
and
thinning.
The
Agency
is
currently
evaluating
the
results
of
the
entire
ARTF
project.
Much
of
the
decisions
needed
to
modify
the
Agency's
currently
used
policy
3.1
rest
on
this
review
which
is
still
pending.
The
Agency
did,
however,
modify
TC
values
for
tree
crop
harvesters
(
based
on
ARTF
data)
and
thinners
(
correcting
a
study
error).
It
should
also
be
mentioned
that
Bayer
Crop
Science
conducted
a
biological
monitoring
study
in
tree
harvesters
and
thinners.
Preliminary
results
support
the
Agency's
current
value
for
thinning.
This
study
has
not
yet
been
formally
submitted.
The
Agency
has
used
the
updated
tree
crop
thinner
and
harvester
TCs
in
its
most
recent
assessment.
#
ISSUE
AGENCY
RESPONSE
ACTIONS
NEEDED
FOR
RISK
ASSESSMENT
29
4
A
suburban
resident
biological
monitoring
study
has
been
conducted.
Bayer
urges
the
Agency
to
consider
these
data
in
its
evaluation
of
residential
exposures.
The
Agency
has
reviewed
this
study
and
will
incorporate
it
as
appropriate
in
the
assessment.
The
results
of
this
study
were
incorporated
into
the
assessment
as
appropriate.

D286456:
COMMENTS
ON
AGGREGATE
RISK
ASSESSMENT
&
CHARACTERIZATION,
PART
7
(
starts
pg
46)

1
Comments
were
made
concerning
the
use
of
deterministic
risk
assessment
approaches,
the
use
of
updated
use
information
from
surveys
and
biological
monitoring,

and
the
Bayer
Crop
Science
plans
to
submit
probabilistic
model
analyses
to
support
carbaryl
registrations.
The
Agency
will
consider
the
results
of
the
recently
submitted
probabilistic
assessment
as
appropriate.
It
will
be
considered
in
conjunction
with
the
results
of
the
HED
risk
assessment.
None
to
the
risk
assessment
document
itself.

The
Agency
will
develop
a
separate
review
and
analysis
of
the
submission
as
appropriate.

Both
the
probabilistic
assessment
and
the
HED
risk
assessment
will
be
considered
concurrently
during
risk
management.

D286456:
APPENDICES
­
VARIOUS
APPENDICES
WERE
ATTACHED
THAT
CONTAINED
SPECIFIC
INPUTS
SUGGESTED
BY
BAYER,
THESE
WERE
CONSIDERED
AS
APPROPRIATE
(
starts
pg
47)
30
Appendix
A:
Agency
Response
To
NRDC
Comments
31
D286511:
ORGANIZATION
=
NRDC,
AUTHOR
=
JENNIFER
SASS,
DATE
=
10/
28/
02
The
National
Resource
Defense
Council
(
NRDC)
contends
that
the
Agency
should
retain
the
full
default
10x
Food
Quality
Protection
Act
Safety
Factor
(
FQPA
SF)
for
carbaryl
for
the
protection
of
infants
and
children.

On
August
27,
1998,
the
FQPA
SF
Committee
recommended
the
retention
of
the
10X
FQPA
safety
factor
for
carbaryl
owing
to
the
incompleteness
of
the
toxicology
data
base,
specifically,
the
lack
of
acceptable
studies
of
pre­
natal
developmental
toxicity
in
rats
and
rabbits
and
two
generation
reproduction
toxicity
in
rats
(
Txr.
No.
012834).

The
following
year,
EPA
received
and
reviewed
pre­
natal
developmental
toxicity
studies
in
rats
and
rabbits.
On
December
13,
1999
and
on
April
30,
2001,
the
FQPA
SF
Committee
recommended
the
retention
of
the
of
the
10X
FQPA
safety
factor
due
to
the
lack
of
the
twogeneration
reproduction
study
in
rats,
as
well
as
the
concerns
for
the
results
of
the
developmental
neurotoxicity
study
(
Txr.
No.
013891).

The
registrant
subsequently
submitted
a
two
generation
reproduction
study
in
rats
and
conducted
morphometric
measurements
of
brains
of
rats
in
the
developmental
neurotoxicity
study
(
HIARC
report,
March
5,
2002).
On
April
3,
2002,
the
FQPA
SF
Committee,
based
on
the
weight­
of­
evidence
of
all
available
studies
(
both
submitted
to
the
Health
Effects
Division
[
HED],
as
well
as
those
published
in
the
literature)
determined
that
reliable
data
demonstrated
that
the
safety
of
infants
and
children
will
be
protected
by
the
use
of
a
3x
FQPA
SF
for
chronic
dietary
and
long­
term
dermal
and
inhalation
exposures.
The
3x
FQPA
SF
was
applied
to
extrapolate
a
NOAEL
(
no­
observed­
adverse­
effect­
level)
from
a
LOAEL
(
lowestobserved
adverse­
effect­
level).
For
acute
dietary
and
short­
and
intermediate­
term
exposures,
the
Committee
recommended
that
the
FQPA
SF
be
reduced
to
1x
(
Txr.
No.
0050634).

This
determination
was
based
on
an
analysis
of
the
toxicology
data
which
followed
the
approach
described
in
the
2002
guidance
document,
Determination
of
the
Appropriate
FQPA
Safety
Factor(
s)
in
Tolerance
Assessment
(
February
28,
2002).
This
analysis
entails
1)
determination
of
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
2)
identification
of
any
residual
concerns
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical;
and
3)
if
residual
concerns
are
identified,
a
determination
as
to
whether
these
residual
concerns
can
be
addressed
by
a
special
FQPA
safety
factor.

Following
are
individual
NRDC
comments
on
the
FQPA
factor
and
the
HED
responses.
32
NRDC
Comment:
The
FQPA
memos
of
December
13,
1999
and
April
30,
2001
both
say
that
the
10x
FQPA
safety
factor
was
retained
because
the
developmental
neurotoxicity
study
showed
significant
changes
in
morphometric
measurements.
Decreased
cerebellar
length
in
the
10
mg/
kg/
day
group
is
"
still
regarded
as
a
treatment­
related
effect".

HED
Response:
The
reasons
for
retaining
the
10x
FQPA
safety
factor
in
1999
and
2001
were
not
only
due
to
concerns
about
the
need
for
additional
brain
morphometric
measurements,
but
also
due
to
the
datagap
for
a
reproduction
study.

Since
the
FQPA
documents
of
December
13,
1999
and
April
30,
2001
were
written,
a
twogeneration
reproduction
study
and
new
brain
morphometric
measurements
in
control
and
high­
dose
groups
from
the
developmental
neurotoxicity
study
in
rats
were
received
and
reviewed.
Based
on
these
new
data,
the
FQPA
SF
Committee
reconsidered
the
safety
factor
in
2002.

In
addition
to
these
new
data,
the
Committee
used
a
weight­
of­
the­
evidence
approach
to
determining
the
magnitude
of
the
FQPA
safety
factor
that
differed
slightly
from
the
approach
it
used
in
1999
and
2001.
This
weight­
of­
evidence
approach
included
an
analysis
of
data
from
different
studies
considered
together
and
included
1)
determination
of
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identification
of
any
residual
concerns
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
This
approach
is
described
in
the
guidance
document,
Determination
of
the
Appropriate
FQPA
Safety
Factor(
s)
in
Tolerance
Assessment
(
February
28,
2002).

The
FQPA
SF
Committee
analyzed
the
degree
of
concern
and
uncertainties
present
in
the
developmental
neurotoxicity
study.
The
Committee
reported
that
there
was
no
concern
for
the
lack
of
brain
morphometric
measurements
in
the
offspring
at
the
mid­
dose
because
even
at
the
high
dose,
the
morphometric
changes
were
minimal
and
it
is
unlikely
that
adverse
effects
would
be
seen
at
the
mid­
dose
level.
There
was
no
concern
for
the
lack
of
comparative
data
in
adults
and
offspring
for
cholinesterase
inhibition
because
no
alterations
in
the
functional
observational
battery
(
FOB)
were
seen
in
pups.
Other
studies
have
shown
that
when
cholinesterase
inhibition
was
seen,
it
usually
was
accompanied
by
FOB
alterations.
Additionally,
the
results
of
the
National
Institute
for
Environmental
Health
Sciences
study
indicate
that
there
is
no
difference
in
the
levels
at
which
cholinesterase
inhibition
occurs
in
pups
and
adults.
This
study
showed
that
the
dose­
related
decrease
in
cholinesterase
activity
in
the
brain
and
blood
of
dams
at
gestation
day
19
was
very
similar
to
the
fetal
brain
cholinesterase
levels
taken
at
the
same
time.
Because
limiting
carbaryl
to
levels
which
will
not
cause
cholinesterase
inhibition
in
adults
will
be
equally
protective
of
infants
and
children,
an
acute
RfD
for
Carbaryl,
using
the
NOAEL
of
1
mg/
kg/
day
in
the
developmental
neurotoxicity
study
in
rats,
is
protective
of
single
dose
exposures
to
infants
and
children.
33
NRDC
Comment:
In
referring
to
the
April
3,
2002
FQPA
SF
Committee
report,
the
NRDC
says
that
"
the
FQPA
committee
seems
to
suddenly
alter
their
position
on
the
developmental
neurotoxicity
study
results,
without
any
new
data,
and
in
spite
of
statistically
significant
alterations
in
cerebellar
structure
and
size
in
female
pups.
The
FQPA
committee
indicates
that
the
morphometric
changes
observed
at
the
high
dose
were
minimal,
and
therefore,
'
it
is
unlikely
that
adverse
effects
would
be
seen
at
the
mid­
dose
level
(
1
mg/
kg/
day)'.
This
is
stated
without
any
supportive
data,
and
contrary
to
the
study
results."

"
Moreover,
in
the
April
3,
2002
document,
discussed
above,
the
Agency
erroneously
determines
that
the
high
dose
in
the
rat
developmental
neurotoxicity
study
can
be
accepted
as
a
lowest­
affect­
level
(
LOAEL).
Therefore
the
Agency
erroneously
determines
that
the
middose
of
1
mg/
kg/
day
in
the
developmental
neurotoxicity
study
is
acceptable
for
the
NOAEL,
despite
the
complete
lack
of
morphometric
data
from
the
mid­
dose
group."

HED
Response:
The
developmental
neurotoxicity
study
results
were
re­
evaluated
because
new
data
became
available
for
analysis
by
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC):
the
registrant
conducted
new
brain
morphometric
measurements
in
control
and
high­
dose
groups
in
the
developmental
neurotoxicity
study
(
Txr
No.
0050307).

Toxicity
studies
are
designed
to
determine
the
type
of
toxicity
which
occurs
and
the
doses
at
which
this
occurs.
The
risk
assessment
methodology
used
by
EPA
relies
on
two
key
measures
of
toxicity,
the
lowest
dose
at
which
toxicity
occurs,
the
LOAEL
or
lowestobserved
adverse­
effect­
level,
and
the
next
lower
dose,
the
NOAEL,
or
no­
observed­
adverseeffect
level,
at
which
toxicity
is
not
observed.
An
ideal
study
would
provide
both
a
clear
LOAEL
and
NOAEL.
In
the
carbaryl
developmental
neurotoxicity
study,
morphometric
analysis
was
conducted
in
control
and
high­
dose
groups
(
10
mg/
kg/
day),
but
not
in
low­
dose
(
0.1
mg/
kg/
day)
or
mid­
dose
(
1.0
mg/
kg/
day)
groups.
Upon
review
of
the
data,
HED
requested
that
morphometric
analysis
of
the
low­
dose
and
mid­
dose
groups
be
conducted,
but
this
was
not
possible
due
to
technical
difficulties
because
the
brain
tissues
had
dried
during
the
preservation
process.

Since
effects
on
brain
morphometric
measurements
occurred
in
the
high­
dose
group,
but
measurements
were
not
possible
in
the
low­
dose
and
mid­
dose
groups,
a
NOAEL
was
extrapolated.
HED
considers
extrapolation
reasonable
in
this
case
because
there
is
high
confidence
in
the
adequacy
of
the
doses
tested
and
any
concern
for
the
lack
of
morphometric
analysis
at
the
mid­
dose
was
negated
since
even
at
the
high
dose,
the
changes,
although
statistically
significant,
were
minimal
in
nature
and
were
judged
not
likely
to
be
present
at
the
mid
dose.

As
discussed
in
the
HIARC
reports
(
March
5,
2002
and
May
9,
2002)
and
the
FQPA
SF
Committee
report
(
April
3,
2002),
both
committees
determined
that
it
was
unlikely
that
there
would
be
any
adverse
effects
on
brain
morphometry
at
the
next
lower
dose
of
1
mg/
kg/
day,
which
was
1/
10
the
dose
at
which
the
effects
of
minimal
severity
were
noted.
HED
considers
34
this
conclusion
reasonable
because
effects
were
of
minimal
severity
and
dose
spacing
between
the
mid­
dose
and
high­
dose
groups
was
large.
Had
the
effects
been
more
severe,
or
had
the
dose
for
the
high­
dose
group
been
closer
to
that
for
the
mid­
dose
group,
then
HED
would
be
more
likely
to
require
an
additional
safety
factor
to
compensate
for
the
weakness
in
the
data.

NRDC
Comment:
"
In
the
April
3,
2002
document
discussed
above,
the
Agency
determined
that
the
2­
generation
reproduction
study
demonstrated
quantitative
evidence
of
increased
susceptibility
of
the
young
animals
following
exposure
to
carbaryl.
Results
demonstrated
that
the
NOAEL
for
parents
was
27
mg/
kg/
day
for
males
and
30
mg/
kg/
day
for
females,
based
on
decreases
in
body
weight,
weight
gain,
and
food
consumption.
In
the
offspring
the
NOAEL
was
5
mg/
kg/
day
in
males
and
6
mg/
kg/
day
in
females
(
5­
6X
lower
than
in
adults)
based
on
pup
death.
It
is
obvious
that
pups
are
more
susceptible
to
carbaryl
toxicity
and
that
the
endpoint
measured
in
pups
is
far
more
extreme
than
for
adults,
death
versus
weight
loss.
Therefore,
it
is
likely
that
pups
are
even
more
susceptible
that
the
study
data
indicates."

HED
Response:
Offspring
toxicity
did
occur
at
doses
below
those
causing
parental
toxicity.
However,
the
dose­
response
relationship
for
the
offspring
effects
was
well­
characterized
with
a
clear
NOAEL.
The
dose
used
for
establishing
the
Chronic
Reference
Dose
(
cRfD)
for
chronic
dietary
risk
assessment
is
lower
than
that
NOAEL,
and
well
below
the
dose
at
which
offspring
toxicity
occurred.
The
HIARC
performed
the
analysis
for
any
residual
uncertainties
for
pre­
and
postnatal
toxicity
and
concluded
that
there
were
no
residual
uncertainties
for
preand
postnatal
toxicity
and
the
potential
risk
to
infants
and
children
is
fully
characterized.

HED
agrees
with
NRDC
that
the
offspring
NOAEL
is
5­
6
fold
lower
than
the
parental
NOAEL.
However,
HED
believes
that
the
chronic
RfD
is
sufficiently
protective
of
infants
and
children
for
potential
adverse
effects
from
exposure
to
carbaryl
based
on
the
following
factors.
1)
The
extrapolated
NOAEL
of
1
mg/
kg/
day
used
for
deriving
the
cRfD
(
LOAEL
of
3
mg/
kg/
day
÷
3x
UF)
is
5­
fold
lower
than
the
NOAEL
of
5
mg/
kg/
day
in
the
two
generation
reproduction
study.
2)
Use
of
the
1
mg/
kg/
day
results
in
a
lower
cRfD
(
0.01
mg/
kg/
day)
rather
than
the
use
of
5
mg/
kg/
day
which
would
have
resulted
in
a
higher
(
less
protective)
cRfD
(
0.05
mg/
kg/
day).
3)
The
cRfD
is
based
on
the
most
sensitive
species
(
dogs)
exhibiting
the
most
sensitive
endpoint
(
cholinesterase
inhibition)
at
the
lowest
administered
dose
(
1
mg/
kg/
day)
and
therefore
provides
additional
protection
for
the
effects
seen
in
rats
(
including
the
reproduction
and
developmental
neurotoxicity
studies).
4)
The
critical
study
selected
for
the
cRfD
is
of
longer
duration
(
1­
year)
and
thus
appropriate
for
the
chronic
dietary
assessments,
rather
than
the
reproduction
study
which
is
of
shorter
duration
(
13
weeks).
5)
The
data
indicate
no
differences
between
rat
pups
and
adults
with
regard
to
cholinesterase
inhibition,
which
is
the
endpoint
of
concern
for
the
cRfD.
Therefore,
the
Agency
believes
that
the
3x
FQPA
safety
factor
is
adequate
for
the
protection
of
infants
and
children
from
long­
term
exposure
to
carbaryl.
35
NRDC
Comment:
The
NRDC
letter
characterizes
the
decision
to
reduce
the
FQPA
SF
from
10x
to
1x
as,
"
an
about
face,
without
supportive
data,
and
in
contradiction
to
the
reported
results
of
the
study".

HED
Response:
The
decision
to
reduce
the
FQPA
SF
to
3x
for
chronic
dietary
and
longterm
dermal
and
inhalation
exposures
and
to
1x
for
acute
dietary
and
short­
and
intermediateterm
exposures,
was
made
following
receipt
and
evaluation
of
new
data.
The
new
data
which
became
available
included
a
new
reproduction
study
and
new
brain
morphometric
measurements
in
control
and
high­
dose
animals
in
the
developmental
neurotoxicity
study.

These
data
were
examined
very
carefully
by
two
separate
committees
(
HIARC
and
FQPA
SF
Committee)
using
the
approach
described
in
Determination
of
the
Appropriate
FQPA
Safety
Factor(
s)
in
Tolerance
Assessment
(
February
28,
2002).
The
committees
used
a
weight­
ofevidence
approach
in
which
data
from
different
studies
are
considered
together
and
entails
1)
determination
of
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identification
of
any
residual
concerns
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.

The
purpose
of
the
FQPA
infant's
and
children's
health
safety
factor
is
"
to
take
into
account
potential
pre­
and
post­
natal
toxicity
and
completeness
of
data
with
respect
to
exposure
and
toxicity
to
infants
and
children"
(
FFDCA
section
408(
b)(
2)(
C)).
Because
these
developmental
effects
are
well
characterized,
and
appropriate
safety
factors
are
applied
to
the
NOAEL
derived
from
the
developmental
neurotoxicity
study,
and
there
are
no
concerns
or
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity,
the
committees
concluded
that
there
is
no
need
for
an
additional
FQPA
safety
factor
to
address
potential
pre­
or
postnatal
toxicity.
36
NRDC
Comment:
"
The
endpoint
of
all
toxicological
studies
used
in
the
carbaryl
assessment
ignores
regional
variability
in
responses
within
different
brain
regions,
and
masks
local
perturbations
that
may
be
very
severe.
NRDC
believes
that
histopathological
examination
may
reveal
regionally
affected
brain
areas.
Also,
behavioral
and
cognitive
testing,
including
learning
and
memory
tests,
reflex
tests,
and
others,
are
key
to
assessing
the
true
toxic
effects
of
any
neurotoxic
and
fetotoxic
chemicals.
Most
importantly,
with
any
developmental
neurotoxic
chemical
such
as
carbaryl,
effects
are
the
result
of
more
than
the
magnitude
of
the
dose.
Rather,
the
effect
is
dependant
on
the
dose,
the
duration
of
the
effect
(
ChEI),
and
the
stage
of
developmental
at
which
the
exposure
takes
place.
Exposures
during
key
windows
of
susceptibility
during
neural
developmental,
even
at
very
low
doses,
are
most
likely
to
have
permanent,
devastating
effects
on
neural
function,
including
behavior
and
cognition.
The
effects
of
carbaryl
exposure
on
fetuses,
infants,
and
children
have
not
been
adequately
described
in
this
assessment."

"
In
addition
to
paying
attention
to
sensitive
biological
endpoints,
it
is
also
essential
to
recognize
the
value
of
these
physiological
systems
to
the
complete
integrity
of
a
person.
For
example,
neurotoxic
damage
resulting
in
the
permanent
loss
of
several
IQ
points
in
a
lab
animal
may
not
even
be
detectable,
but
may
severely
limit
the
potential
of
a
person
or
exposed
population.
For
instance,
inability
to
pay
attention,
mood
changes,
inability
to
predict
consequences
of
actions,
and
explosive
temper
are
all
result
of
fetal
exposure
to
alcohol.
While
these
effects
might
seem
subtle
or
almost
negligible
in
an
animal
study
measuring
crude
endpoints
such
as
BW
changes
or
fetal
death,
they
can
cripple
the
social
and
emotional
potential
of
an
affected
human."

HED
Response:
A
number
of
toxicity
studies
were
evaluated
for
the
carbaryl
risk
assessment.
These
included
guideline
studies
required
by
law
(
40
CFR
Part
158),
nonguideline
studies,
and
studies
from
the
open
literature.
These
toxicity
studies
for
carbaryl
examined
many
sensitive
toxicity
endpoints
in
acute,
subchronic,
and
chronic
toxicity
studies
in
a
variety
of
species,
as
well
as
in
vivo
and
in
vitro
mutagenicity
studies.

Specifically,
these
studies
evaluated
histopathology
of
different
regions
of
the
brain,
cholinesterase
activity
in
different
brain
regions,
cholinesterase
activity
in
blood,
neurobehavior
in
adults
and
offspring,
and
made
observations
for
clinical
signs
of
toxicity.
Cognitive
functions
of
learning
and
memory
were
evaluated
in
the
developmental
neurotoxicity
study.

The
developmental
and
reproduction
studies
evaluated
effects
to
fetuses
after
exposure
during
the
critical
period
during
which
development
of
the
fetus
occurs.
The
reproduction
study
evaluated
toxicity
in
offspring
after
exposure
to
fetuses
throughout
gestation,
and
to
offspring
by
exposure
through
nursing
and
subsequent
diet
during
development
to
adulthood.

In
addition,
postmortem
examinations
were
conducted,
organ
weights
were
determined,
histopathological
examinations
were
conducted
for
all
tissues
and
organs,
and
urinalyses
and
numerous
clinical
chemistry
and
hematological
analyses
were
conducted.
37
This
robust
toxicology
database
indicates
that
the
endpoint
which
is
most
likely
to
show
adverse
effects
at
the
lowest
dose
is
cholinesterase
inhibition.
Therefore,
if
infants
and
children
are
protected
for
cholinesterase
inhibition,
HED
believes
they
are
protected
for
any
other
type
of
adverse
effects
resulting
from
exposure
to
carbaryl.
HED
believes
that
the
risk
assessment
addresses
all
potential
effects
that
may
result
during
the
windows
of
development
for
fetuses,
infants,
and
children.