Document ID: EPA-HQ-OPP-2004-0043-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-05-04T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
July
8,
2003
MEMORANDUM
SUBJECT:
Chlorpyrifos
Methyl:
Status
of
Toxicity
Data
Gaps,
Impact
of
New
Data
on
the
Risk
Assessment
and
Impact
on
Cumulative
Risk
Assessment.
DP
Barcode:
D291405
PC
Code:
059102
TO:
Jackie
Mosby/
Margaret
Rice
Special
Review
and
Reregistration
Division
(
7508C)

FROM:
Donna
Davis,
Chief
Reregistration
Branch
3/
HED
(
7509C)

THROUGH:
Catherine
Eiden,
Senior
Scientist
Reregistration
Branch
3/
HED
(
7509C)

At
the
request
of
the
Special
Review
and
Reregistration
Division
(
SRRD),
the
Health
Effects
Division
(
HED)
has
reconsidered
the
toxicity
data
gaps
identified
in
the
chlorpyrifos
methyl
(
CPM)
Toxicology
Chapter
of
the
RED
dated
April
19,
2000
to
support
the
continued
use
of
chlorpyrifos
methyl
on
stored
grain.
Additionally,
SRRD
has
asked
HED
to
comment
on
the
impact
of
the
chlorpyrifos
DNT
on
endpoint
selection
and
safety
factors
for
chlorpyrifos
methyl.
Finally,
HED
has
been
requested
to
comment
on
the
impact
of
retaining
the
use
of
chlorpyrifos
methyl
at
6
ppm
in
stored
grain
on
the
Organophosphate
Cumulative
Risk
Assessment.

Data
Gaps
HED
has
addressed
the
issue
of
toxicity
data
gaps
in
detail
in
our
memorandum
entitled
"
Chlorpryrifos
methyl:
Current
status
of
toxicity
data
gaps
and
bridging
studies
from
chlorpyrifos."
(
John
Doherty,
7/
08/
03,
TXR
#
0051734).
The
findings
in
that
memorandum
are
summarized
briefly
here.
At
the
request
of
SRRD,
HED
considered
if
it
were
possible
to
use
toxicity
data
generated
on
the
closely
related
structural
analog,
chlorpyrifos
(
CPY)
to
address
data
gaps
for
CPM.
Based
on
a
side­
by­
side
comparison
of
critical
endpoints
and
available
data,
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
Co­
Chairs
concluded
that
CPM
was
likely
to
be
less
toxic
than
CPY
based
on
comparison
of
cholinesterase
inhibition,
particularly
in
rats.
Given
the
structural
similarity
between
the
two
chemicals,
toxicity
data
generated
using
CPY
could
be
used
2
to
address
data
gaps
for
CPM
with
the
exception
of
the
acute
toxicity
test
requirements.
Therefore,
the
only
remaining
data
gaps
for
CPM
are
those
that
remain
for
CPY
and
the
CPM
specific
acute
toxicity
testing
data
gaps.
As
CPY
toxicity
studies
are
submitted
to
address
remaining
CPY
data
gaps,
they
can
be
bridged
to
CPM.
Additionally,
the
HIARC
Co­
Chairs
recommended
that
for
risk
assessment
purposes
CPM
continue
to
be
regulated
using
CPM
specific
endpoints
and
that
the
10X
database
uncertainty
factor
for
CPM
continue
to
be
retained.

CPY
DNT
Impacts
on
CPM
Regulatory
Endpoints
and
Uncertainty
Factors
Endpoint
Impacts
As
a
result
of
the
HIARC's
determination
that
toxicity
data
for
CPY
can
be
used
to
satisfy
data
gaps
for
CPM,
SRRD
has
asked
HED
to
comment
on
the
impact
that
the
CPY
developmental
neurotoxicity
study
would
have
on
the
risk
assessment
endpoints
and
safety
factor
for
CPM.

Regulatory
endpoints
currently
established
for
chlorpyrifos
methyl
are
based
on
chemical
specific
toxicity
studies.
A
summary
of
regulatory
endpoints
is
contained
in
Table
1,
below.

Table
1.
Endpoint
Selection
Summary
for
CPM
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
General
Population
Including
Infants
and
Children
NOAEL=
1
mg/
kg/
day
Inhibition
of
red
blood
cell
cholinesterase.
CPM
Rat
developmental
toxicity
(
MRID
No.:
44680603)

UF
=
100
Acute
RfD
=
0.01
mg/
kg/
day
aPAD
=
Acute
RfD/
10X
DB
UF
=
0.001
mg/
kg/
day
Chronic
Dietary
NOAEL=
0.1
mg/
kg/
day
Inhibition
of
plasma
cholinesterase.
CPM
Chronic/
Carcinogenicity
feeding
study
in
rats
(
MRID
No.:
42269001)

UF
=
100
Chronic
RfD
=
0.001
mg/
kg/
day
cPAD
=
Chronic
RfD/
10X
DB
UF
=
0.0001
mg/
kg/
day
Dermal
Absorption
3%
based
on
comparison
of
the
oral
and
dermal
toxicity
studies
with
chlorpyrifos
using
a
common
species
and
endpoint.

Short­
Term
(
Dermal/
Inhalation)
Oral
NOAEL=
1
mg/
kg/
day
Inhibition
of
red
blood
cell
cholinesterase.
See
Acute
Dietary
Intermediate­
Term
(
Dermal/
Inhalation)
Oral
NOAEL
=
0.1
mg/
kg/
day
Inhibition
of
plasma
cholinesterase
noted
at
the
90­
day
measurement.
See
Chronic
Dietary
Long
Term
(
Dermal/
Inhalation)
Oral
NOAEL
=
0.1
mg/
kg/
day
Inhibition
of
plasma
cholinesterase.
CPM
Chronic/
Carcinogenicity
feeding
study
in
rats
(
MRID
No.:
42269001)
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
3
Carcinogenicity
Classified
as
"
not
likely
a
human
carcinogen."
Carcinogenicity
risk
assessment
is
not
appropriate.

HED
has
completed
the
review
of
the
chlorpyrifos
developmental
neurotoxicity
study
in
rats
as
well
as
supplemental
data
submitted
(
Sue
Makris,
Barcodes:
D254907,
D247891
and
D250250).
The
developmental
neurotoxicity
study
(
DNT)
in
rats
is
currently
classified
as
guideline­
unacceptable
pending
submission
and
review
of
additional
morphometric
data.
In
the
DNT,
a
maternal
NOAEL
was
not
observed,
the
maternal
LOAEL
was
<
0.3
mg/
kg/
day
(
the
lowest
dose
tested)
based
on
plasma
and
RBC
cholinesterase
inhibition.
Due
to
lack
of
morphometric
data,
an
offspring
NOAEL
and
LOAEL
could
not
be
determined.

Based
on
the
available
comparative
toxicological
data,
the
HIARC
Co­
Chairs
(
meeting
dated
...)
determined
that
CPY
is
likely
a
more
potent
cholinesterase
(
ChE)
inhibitor
than
CPM.
Additionally,
work
done
for
the
Revised
(
6/
11/
2002)
Organophosphate
Cumulative
Risk
Assessment
(
OPCRA)
supports
these
comparative
findings.
In
the
cumulative
risk
assessment
CPY
was
assigned
a
relative
potency
factor
of
0.06
relative
to
the
index
chemical
methamidophos,
where
CPM
was
assigned
a
relative
potency
factor
of
0.005
with
respect
to
ChE
inhibition.
Based
on
the
endpoint
(
female
brain
ChE
inhibition)
used
in
the
Revised
OPCRA,
CPY
is
ten
times
more
potent
than
CPM.
Since
the
regulatory
endpoint
of
concern
for
CPM
is
ChE
inhibition,
based
on
both
the
side­
by­
side
comparison
of
available
CPM
and
CPY
toxicity
studies
with
respect
to
plasma
and
red
blood
cell
ChE
inhibition
and
on
the
work
on
brain
cholinesterase
inhibition
in
the
OPCRA,
it
is
clear
that
CPM
is
a
less
potent
ChE
inhibitor,
therefore,
it
is
more
appropriate
to
select
endpoints
from
the
CPM
toxicity
studies
where
ChE
inhibition
was
measured
and
clear
NOAELs
were
established
than
to
look
to
the
ChE
inhibition
response
in
the
chlorpyrifos
DNT
in
which
clear
endpoints
for
ChE
inhibition
(
NOAELs/
LOAELs)
were
not
established.

Therefore,
HED
concludes
that
the
results
of
the
chlorpyrifos
DNT
study
does
not
impact
the
regulatory
endpoints
of
concern
for
chlorpyrifos
methyl.

Safety
Factor
Impacts
For
the
purpose
of
the
2000
CPM
RED
risk
assessment,
in
the
absence
of
a
complete
toxicity
database
with
respect
to
infants
and
children
sensitivity
issues,
a
10X
uncertainty
factor
was
retained
for
CPM.
SRRD
has
asked
HED
to
revisit
this
uncertainty
factor
in
light
of
findings
in
the
CPY
DNT
and
taking
into
consideration
decisions
made
for
CPY.

The
HED
Hazard
Identification
Review
Committee
(
HIARC
)
considered
the
implications
of
the
CPY
DNT
results
with
respect
to
children's
sensitivity
and
susceptibility
on
March
28,
2000
(
Chlorpyrifos
Children's
Hazard:
Sensitivity
and
Susceptibility,
3/
28/
2000,
K.
Baetcke,
V.
Dellarco,
S.
Makris
and
D.
Smegal)
for
CPY.
The
HIARC
determined
that
the
10X
uncertainty
factor
(
UF)
would
be
retained
for
CPY
based
on
a
complete
weight
of
the
evidence
approach
to
sensitivity.
Literature
data
as
well
as
the
DNT
identified
potential
brain
effects
at
high
doses
(
well
above
the
doses
where
ChE
inhibition
was
seen).
The
neurobehavioral
ramifications
of
these
brain
effects
were
unclear,
therefore,
the
10X
UF
was
retained
based
on
residual
concern.
4
HED
has
determined
that
it
is
appropriate
to
bridge
the
results
of
the
CPY
DNT
to
CPM.
However,
in
the
absence
of
a
chemical
specific
CPM
DNT
study,
it
is
not
possible
to
either
establish
or
to
rule
out
the
potential
for
susceptibility
after
exposure
to
CPM
based
on
the
weight
of
the
evidence
findings
for
CPY;
therefore,
HED
will
continue
to
apply
a
10X
database
uncertainty
factor
to
the
risk
assessment
for
CPM
as
a
protective
measure
in
the
absence
of
chemical
specific
DNT
data.

Cumulative
Risk
Assessment
Impact
HED
has
been
asked
to
run
a
screening
level
assessment
to
determine
if
the
inclusion
of
CPM
on
stored
grain
at
6.0
ppm
and
at
3.0
ppm
will
have
an
impact
on
the
cumulative
risk
assessment.
Attachment
1
contains
the
detailed
results
of
the
screening
runs.
A
summary
table
comparing
the
findings
are
shown
in
Table
2,
below.

The
conditions
of
the
runs
performed
by
Bill
Smith
(
Chemistry
and
Exposure
Branch,
6/
10/
03)
are
summarized
as
follows:
°
FQPA
factors
for
OPs
were
set
as
in
the
Revised
OPCRA
(
6/
11/
02),
i.
e.,
methamidophos,
dimethoate/
omethoate
&
CPY
=
1;
all
other
chemicals
=
3.
°
CPM
was
assigned
a
factor
of
10
as
a
worst
case
assumption
in
this
screening
level
assessment
°
Residues
of
CPM
were
exclusively
from
the
Pesticide
Data
Program
(
PDP)
monitoring
data,
primarily
on
wheat
which
reflects
the
current
6
ppm
use.
The
PDP
data
included
1562
samples
of
wheat
with
920
detects/
642
non­
detects,
867
samples
of
rice
with
4
detects/
867
non­
detects,
and
332
samples
of
oats
with
1
detect/
331
non­
detects.
°
Two
runs
were
conducted.
The
first
run
duplicated
the
conditions
of
the
6/
11/
02
CRA
and
did
NOT
include
CPM.
The
second
run
reflects
addition
of
CPM.
at
6.0
ppm.
°
The
Point
of
Departure
(
POD)
for
methamidaphos
was
used
to
calculate
MOEs.

Table
2.
Cumulative
Run
Summary
Results
(
per
capita)

Subpopulations
95th
Percentile
99th
Percentile
99.9th
Percentile
Without
CPM
Exposure
MOE
With
CPM
Exposure
MOE
Without
CPM
Exposure
MOE
With
CPM
Exposure
MOE
Without
CPM
Exposure
MOE
With
CPM
Exposure
MOE
Children
1
­
2
years
0.000218
367
0.000221
361
0.000609
131
0.000613
130
0.001758
45
0.001762
45
Children
3
­
5
years
0.000174
459
0.000178
449
0.000492
162
0.000496
161
0.001520
52
0.001524
52
Children
6
­
12
years
0.000095
843
0.000098
817
0.000290
275
0.000293
272
0.000972
82
0.000975
82
Youth
13
­
19
years
0.000049
1618
0.000051
1559
0.000156
511
0.000158
505
0.000510
156
0.000510
156
Adults
20
­
49
years
0.000062
1296
0.000063
1267
0.000186
431
0.000187
427
0.000630
126
0.000631
126
5
Adults
50+
years
0.000070
1150
0.000071
1132
0.000201
398
0.000202
395
0.000670
119
0.000671
119
Results
of
the
screening
level
runs
are
consistent
with
what
would
be
predicted
based
on
the
CPM
relative
potency
factor
at
0.005
relative
to
the
index
chemical,
methamidophos,
and
the
low
CPM
residues
which
are
confined
to
foods
that
are
not
among
the
most
highly
consumed
on
a
mg/
kg/
body
weight
basis.
Based
on
the
results
of
the
runs
above
using
data
reflecting
the
6
ppm
use
rate,
which
showed
no
significant
difference
in
the
OPCRA
with
or
without
CPM,
no
additional
runs
were
completed
to
reflect
lowering
on
the
use
rate.

HED
concludes
that
there
is
no
significant
impact
on
the
OPCRA
as
a
result
of
retaining
the
use
of
CPM
on
stored
grain
at
6.0
ppm.
6
Attachment
1.
Cumulative
Risk
Assessment
Runs
DEEM­
FDIC
Acute
Analysis
for
Cumulative
without
CPM
U.
S.
Environmental
Protection
Agency
Ver.
1.33
DEEM­
FCID
ACUTE
Analysis
for
CUMULATIVE
OP
EXPOSURE
(
1994­
98
data)
Residue
file:
OPCRA­
R2.
R98
Adjustment
factor
#
2
used.
Analysis
Date:
06­
09­
2003/
10:
12:
57
Residue
file
dated:
12­
17­
2002/
14:
11:
03/
8
NOEL
(
Acute)
=
0.080000
mg/
kg
body­
wt/
day
Daily
totals
for
food
and
foodform
consumption
used.
MC
iterations
=
1000
MC
list
in
residue
file
MC
seed
=
10
Run
Comment:
"
OPCRA­
R2:
Check
sample
using
same
FQPA
factors
as
in
OPCRA­
R1"
===============================================================================

Summary
calculations
(
per
capita):

95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
MOE
Exposure
MOE
Exposure
MOE
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
Children
1­
2
yrs:
0.000218
367
0.000609
131
0.001758
45
Children
3­
5
yrs:
0.000174
459
0.000492
162
0.001520
52
Children
6­
12
yrs:
0.000095
843
0.000290
275
0.000972
82
Youth
13­
19
yrs:
0.000049
1618
0.000156
511
0.000510
156
Adults
20­
49
yrs:
0.000062
1296
0.000186
431
0.000630
126
Adults
50+
yrs:
0.000070
1150
0.000201
398
0.000670
119
DEEM­
FDIC
Acute
Analysis
for
Cumulative
with
CPM
U.
S.
Environmental
Protection
Agency
Ver.
1.33
DEEM­
FCID
ACUTE
Analysis
for
CUMULATIVE
OP
EXPOSURE
(
1994­
98
data)
Residue
file:
OPCRA­
R2.
R98
Adjustment
factor
#
2
used.
Analysis
Date:
06­
09­
2003/
11:
24:
49
Residue
file
dated:
06­
04­
2003/
12:
57:
35/
8
NOEL
(
Acute)
=
0.080000
mg/
kg
body­
wt/
day
Daily
totals
for
food
and
foodform
consumption
used.
MC
iterations
=
1000
MC
list
in
residue
file
MC
seed
=
10
Run
Comment:
"
OPCRA­
R2
Check
sample
using
same
FQPA
factors
as
in
OPCRA­
R1,
but
with
chlorpyrifos
methyl
included
[
RPF=
0.005;
FQPA
factor
=
10X]"
===============================================================================

Summary
calculations
(
per
capita):

95th
Percentile
99th
Percentile
99.9th
Percentile
Exposure
MOE
Exposure
MOE
Exposure
MOE
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
­­­­­­­­­­
­­­­­­­­
Children
1­
2
yrs:
0.000221
361
0.000613
130
0.001762
45
Children
3­
5
yrs:
0.000178
449
0.000496
161
0.001524
52
Children
6­
12
yrs:
0.000098
817
0.000293
272
0.000975
82
Youth
13­
19
yrs:
0.000051
1559
0.000158
505
0.000510
156
Adults
20­
49
yrs:
0.000063
1267
0.000187
427
0.000631
126
Adults
50+
yrs:
0.000071
1132
0.000202
395
0.000671
119
cc:
Donna
Davis,
John
Doherty,
Catherine
Eiden