1
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
07/
08/
03
MEMORANDUM
Subject:
EPA
Id
#
059102.
Chlorpyrifos
methyl:
Current
status
of
toxicity
data
gaps
and
bridging
studies
from
chlorpyrifos.

TXR
#
0051734
DP
Barcode
No.:
D289974
Submission
No.:
S634988
PC
Code:
059102
From:
John
Doherty
Reregistration
Branch
III
Health
Effects
Division
7509C
To:
Jackie
Mosby
and
Margaret
Rice
Reregistration
Branch
II/
SRRD
7508C
Through:
Jess
Rowland
Chairperson
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
Health
Effects
Division
7509C
and
Donna
Davis
Reregistration
Branch
III
Health
Effects
Division
7509C
and
Catherine
Eiden
Branch
Senior
Scientist
Reregistration
Branch
III
Health
Effects
Division
7509C
The
Health
Effects
Division
(
HED)
has
reconsidered
the
available
toxicology
data
base
for
chlorpyrifos
methyl
(
CPM)
to
see
if
studies
submitted
for
the
active
ingredient,
chlorpyrifos
(
CPY),
can
be
used
to
address
the
data
gaps
identified
in
the
CPM
Toxicology
Chapter
for
the
RED
dated
April
19,
2000.

The
Reregistration
Branch
III
(
RRBIII)
met
on
April
14,
2003
with
the
Co­
Chairs
of
Health
Chlorpyrifos
methyl/
bridging/
D289974/
2003
2
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee,
Jess
Rowland
and
Elizabeth
Doyle,
to
discuss
and
compare
the
relative
toxicity
to
laboratory
animals
of
CPY
versus
CPM.
Of
these
two
chemicals,
CPY
has
a
more
extensive
and
for
many
studies
a
more
current
toxicity
data
base
than
the
structurally,
closely
related
chemical
CPM.
It
was
concluded
that
if
anything,
CPM
would
be
less
toxic
than
CPY
based
on
comparison
of
cholinesterase
inhibition
particularly
in
rats
and
as
would
be
predicted
based
on
structure
activity
relationships.
Thus,
the
extensive
data
base
for
CPY
may
serve
as
a
surrogate
for
CPM.
Only
data
gaps
for
CPY
should
now
be
considered
as
data
gaps
for
CPM.
As
additional
studies
are
submitted
for
CPY,
they
will
also
serve
to
address
CPM
data
gaps,
with
the
exception
of
the
acute
studies.

For
risk
assessment
purposes,
it
was
recommended
that
CPM
continue
to
be
regulated
based
on
its
current
selection
of
endpoints
and
continued
use
of
the
10
X
uncertainty
factor.
It
is
noted
that
CPY
currently
has
a
10
X
FQPA
uncertainty
factor
based
on
potential
increased
susceptibility
to
infants
and
children.

Comments.

1.
The
decision
that
CPM
is
regarded
as
less
toxic
than
CPY
is
illustrated
in
Table
I
which
shows
the
doses
selected
for
the
acute
and
chronic
dietary
endpoints.

Table
1.
Comparison
of
selected
studies
in
the
toxicity
data
bases
and
other
factors
to
support
bridging
of
data
from
CPY
to
CPM.

Parameter
Chlorpyrifos
(
CPY)
Chlorpyrifos
Methyl
(
CPM)
Comments
Completeness
of
the
data
base.
Essentially
complete.
Most
studies
are
modern.
17
data
gaps
and
many
studies
are
older.

Structure
No
electronic
structure
available
in
files.

CPM
has
methyl
groups
in
place
of
the
ethyl
groups
on
the
phosphorous.
Replacement
of
methyl
groups
may
alter
the
metabolism
and
stability
and
make
one
chemical
a
more
potent
inhibitor
of
ChE
than
the
other.

Key
Endpoint
Selection
Acute
Dietary
RfD
(
endpoint
dose).
NOAEL
=
0.5
mg/
kg
LOAEL
=
1
mg/
kg
based
on
ChE
inhibition
in
a
special
rat
ChE
study
to
determine
the
time
to
peak
effect
of
inhibition.
(
1998,
44648101)
NOAEL
=
1
mg/
kg
LOAEL
=
12.5
mg/
kg
based
on
ChE
inhibition
in
the
dams
in
a
development
toxicity
study.

(
1992
,44680603)
The
selected
dose
levels
are
based
on
different
types
of
studies
but
still
supports
implication
that
CPY
is
more
potent
a
ChE
inhibitor
than
CPM.
Chlorpyrifos
methyl/
bridging/
D289974/
2003
Parameter
Chlorpyrifos
(
CPY)
Chlorpyrifos
Methyl
(
CPM)
Comments
3
Chronic
Dietary
RfD
(
endpoint
dose)
NOAEL
=
0.03
mg/
kg/
day
Based
on
the
comparison
of
several
studies
and
no
single
LOAEL
is
assigned.
Refer
to
HIARC
report
for
list
of
studies
used.
NOAEL
=
0.1
mg/
kg/
day.
LOAEL
=
1.0
mg/
kg/
day
based
on
ChE
inhibition.
(
1991,
42269001)
Doses
are
not
that
different
and
still
supports
implication
that
CPY
is
more
potent
a
ChE
inhibitor
than
CPM.

Total
uncertainty
factor.
1000
10
X
FQPA
for
increased
susceptibility
1000
10
X
for
data
base
uncertainty
factor
Also
includes
10
X
intraspecies
and
10
X
for
interspecies.

Acute
Toxicity
­
Caution
­
studies
for
both
chemicals
are
very
old.

Acute
Oral
LD50
=
163
mg/
kg

137
mg/
kg

Vehicle
not
specified.
(
1963,
Acc
#
112115)
LD50
=
2140
(
1530­
2900)
mg/
kg

1090
(
694­
1710)
mg/
kg

Corn
oil
(
1969,
Acc
#
242152)
Caution­
large
difference
may
be
deceiving
since
strain
of
rat
and
other
conditions
may
not
be
similar.

Acute
Dermal
LD50
=
202
mg/
kg
(
rat)
(
not
identified
in
one
liners)
LD50
>
2000
mg/
kg
(
1964,
Acc
#
242152)
Indicates
CPY
is
more
toxic
then
CPM
Neurotoxicity
Testing
Delayed
type
neurotoxicity
­
hens
Not
neurotox
at
50,
100
or
110
mg/
kg/
day
in
hens
(
00097144,
00405106)
Acute
study
(
1979,
00029503)
is
considered
equivocal
at
higher
doses
but
13
week
study
(
1984,
00145060)
did
not
show
delayed
type
neuro­
toxicity
at
500
mg/
kg/
day.
Toxicity
to
hens
is
greater
for
CPY
than
for
CPM.

Subchronic
and
Chronic
Toxicity
in
Rats
Subchronic
­
rat
LOAEL
<
0.025
mg/
kg/
day
for
ChE.

(
1985,
40436406)
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
1
mg/
kg/
day
based
on
ChE
inhibition
by
dietary
route.
(
1990,
44906902,
45048301)
Supports
implication
that
CPY
is
a
more
potent
ChE
inhibitor
than
CPM.

Chronic
­
rat
NOAEL
=
0.132
mg/
kg/
day
LOAEL
=
0.33
mg/
kg/
day
based
on
plasma
ChE.

(
1990,
42172802)
NOAEL
=
0.1
mg/
kg/
day
LAOEL
=
1
mg/
kg/
day
based
on
both
plasma
and
RBC
ChE
(
1975,
00028752)

Developmental
and
Reproductive
Studies.

Developmental
­
rat
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
3
mg/
kg/
day
based
on
ChE
inhibition
in
dams.

(
1983,
00130400)
NOAEL
=
1
mg/
kg
LOAEL
=
12.5
mg/
kg
based
on
ChE
inhibition
in
the
dams.

(
1992
,44680603)
Supports
implication
that
CPY
is
a
more
potent
ChE
inhibitor
than
CPM.
Chlorpyrifos
methyl/
bridging/
D289974/
2003
Parameter
Chlorpyrifos
(
CPY)
Chlorpyrifos
Methyl
(
CPM)
Comments
4
Mutagenicity
Testing
and
Concern
(
if
any)

Data
base
Apparently
complete
and
without
a
mutagenicity
concern.
Data
base
considered
adequate
­
one
study
positive
with
metabolic
activation.
Neither
chemical
has
a
mutagenicity
concern.

2.
The
current
status
of
the
data
gaps
for
CPM
is
shown
in
Table
2.
The
following
comments
should
be
noted.

(
a).
Acute
toxicity.
The
acute
toxicity
data
bases
for
both
CPY
and
CPM
are
based
on
studies
conducted
in
the
1960s
and
early
1970s.
Thus,
the
acute
oral,
dermal,
inhalation
and
irritation
studies
should
be
repeated
for
both
chemicals
and
cannot
be
bridged.
It
is
strongly
advised
that
these
acute
toxicity
studies
(
except
for
the
irritation
studies)
be
conducted
concurrently
using
all
the
same
parameters.

(
b).
Subchronic
inhalation.
The
subchronic
inhalation
study
with
CPY
(
1988,
40908401)
did
not
demonstrate
a
NOAEL.
Thus
this
study
should
not
be
bridged
to
support
CPM.

(
c)
Rabbit
developmental
toxicity
study.
The
rabbit
developmental
toxicity
study
(
1987,
404354408)
is
considered
a
data
gap
for
CPY
and
therefore
cannot
be
bridged
to
support
the
uses
of
CPM.

(
d)
Dermal
absorption.
The
dermal
absorption
factor
for
CPY
is
set
at
3%
based
on
the
weight
of
evidence
of
the
toxicity
data
for
CPY.
The
HIARC
report
(
May
17,
1999)
also
assigned
3%
as
the
dermal
absorption
factor
for
CPY
using
CPY
as
a
comparative
model.

Table
2.
Status
of
Data
Gaps
for
CPM.

Study
Type
Reason
for
Chlorpyrifos
Methyl
Data
Gap
Bridge
#

870.1100.
Acute
oral
toxicity.
1969
study.
Old
technical
preparation
used.
Newer
methods
of
synthesis
may
change
toxicity.
No
(
a)

870.1200.
Acute
dermal
toxicity
1964
study.
Old
technical
preparation
used.
Newer
methods
of
synthesis
may
change
toxicity.
No
(
a)

870.1300.
Acute
inhalation
toxicity
No
valid
study
with
current
technical
grade.

870.2400.
Primary
ocular
irritation
1974
study.
Old
technical
preparation
used.
Newer
methods
of
synthesis
may
change
toxicity.
No
(
a)

870.2500.
Primary
dermal
irritation
1964
study.
Old
technical
preparation
used.
Newer
methods
of
synthesis
may
change
toxicity.
No
(
a)

870.2600.
Dermal
sensitization.
1985
Study
(
44906901
and
4498001)
is
classified
as
unacceptable.
No
(
a)
Chlorpyrifos
methyl/
bridging/
D289974/
2003
Study
Type
Reason
for
Chlorpyrifos
Methyl
Data
Gap
Bridge
#

5
870.6100.
Acute
delayed
type
neurotoxicity
­
hens
1979
acute
study
is
"
equivocal"
with
some
evidence
of
sciatic
nerve
at
higher
doses.
A
1984
13
week
study
with
CPM
does
not
show
effect
at
500
mg/
kg/
day
(
classified
as
Acceptable).
Yes
00097144
and
00405106
870.6200.
Acute
neurotoxicity
screen.
No
CPM
study.
CPY
study
has
time
to
peak
effect.
Yes
(
1992,
42669101)

870.6200.
Subchronic
neurotoxicity
screen
No
CPM
study.
CPY
study
did
not
include
ChE
assessments
and
was
acceptable
for
FOB
and
motor
activity
etc
only.
An
acceptable
CPM
subchronic
study
(
1990,
44906902
and
45048301)
established
the
NOAEL
and
LOAELs
for
plasma,
RBC
and
brain
ChE
for
CPM.
Yes
­
for
FOB,
motor
activity
etc.
(
1993,
42929801)

870.3200.
Subchronic
dermal
No
CPM
study.
Yes
(
1988,
40972801)

870.3250.
Subchronic
inhalation
No
CPM
study.
No
(
b)

870.4100.
Chronic
non­
rodent
(
dog)
1974
CPM
study
(
00029477).
Study
is
considered
unacceptable
for
ChE
assessment.
No
(
c)

870.3700.
Developmental
toxicity
­
rabbits
1976
CPM
study
(
00030758).
According
to
the
HIARC
report
(
5/
17/
99),
this
study
is
considered
a
data
gap
because
of
several
deficiencies.
No
(
d)

870.3800.
Multigeneration
reproduction
study.
1975
CPM
study
(
00030757).
According
to
the
HIARC
report
(
5/
17/
99),
this
study
is
considered
a
data
gap
because
of
several
deficiencies
including
that
only
2
doses
were
assessed.
Note:
A
replacement
study
(
MRID
No.:
45826201)
has
been
received
and
is
currently
under
review
by
the
contractor
(
due
9/
30/
03).
Yes
(
1991,
41930301)

870.6300.
Developmental
neurotoxicity
­
rat
No
CPM
study.
Yes
(
1998,
44556901,
44661001,
44787301)

870.7485.
General
metabolism
­
rat
(
1971,
0029484).
Study
classified
as
unacceptable
and
not
upgradeable.
Uses
only
two
males
in
a
preliminary
study.
Yes
(
e)
(
1987,
40458901)

870.7600.
Dermal
absorption.
1995
Study
(
44913001).
In
vitro
studies
are
not
acceptable
for
demonstration
of
dermal
absorption.
Yes
(
f)

#
The
MRID
number
fo
the
study
with
CPY
that
is
considered
acceptable
for
bridging
to
support
CPM
is
identified.
(
a)
The
acute
studies
for
both
CPY
and
CPM
are
based
on
very
old
data
and
should
be
repeated
for
each
chemical.
Note
the
Acc
#
for
all
the
acute
studies
is
242152.
(
b)
The
study
(
1988,
40908401)
with
CPY
did
not
demonstrate
a
NOAEL
and
is
therefore
a
data
gap
for
both
CPY
and
CPM.
Chlorpyrifos
methyl/
bridging/
D289974/
2003
6
(
c)
The
dog
studies
with
both
CPY
and
CPM
were
conducted
at
approximately
the
same
time
(
early
seventies)
and
the
study
with
CPY
demonstrated
much
variability
in
the
ChE
assessments
and
thus
contributing
to
problems
in
bridging
the
study.
This
remains
a
gap
for
both
CPY
and
CPM.
(
d)
The
rabbit
developmental
toxicity
study
(
1987,
404354408)
is
considered
a
data
gap
for
CPY
and
therefore
cannot
be
bridged
to
support
the
uses
of
CPM.
(
e)
The
differences
in
toxicity
between
CPY
and
CPM
may
be
related
to
differences
in
the
pharmacokinetics
for
each
chemical
but
it
is
not
necessary
to
prove
this
difference
at
this
time.
(
f)
The
dermal
absorption
of
3%
for
CPY
was
based
on
a
weight
of
the
evidence
approach
that
includes
a
study
with
humans.
The
HIARC
(
refer
to
report
dated
May
17,
1999)
used
the
CPY
approach
as
a
model
and
also
assigned
3%
as
the
dermal
absorption
factor
for
CPM.
