OPP,
2003
1
Derivation
of
"
Equivalent"
Reference
Concentrations
for
Azinphos
Methyl,
Chlorpyrifos,
Diazinon
and
Naled
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Washington,
D.
C.

October
20,
2003
OPP,
2003
2
AZINPHOS
METHYL
Principal
Study:
Subchronic
Inhalation
Toxicity
Study
in
Rat
Kimmerle,
G.
(
1976):
Subchronic
Inhalation
Toxicity
Study
of
Azinphos­
methyl
in
Rats.
Arch.
Toxicol.
35:
83­
89.
MRID.
No.
00155011.

In
a
subchronic
inhalation
toxicity
study,
male
and
female
Wistar
rats
were
exposed
to
azinphos­
methyl
aerosol
at
concentrations
of
0.195,
1.24,
or
4.72
mg/
m3
,
6
hr/
day,
5
days/
week
for
90
days.
Plasma
and
RBC
cholinesterase
activity
was
determined
after
2,
4,
6,
8
and
12
weeks
of
treatment.
Plasma
and
red
blood
cell
cholinesterase
inhibition
(
30­
40%)
was
observed
in
both
sexes
at
a
concentration
of
4.72
mg/
m3.
The
NOAEL
was
1.24
mg/
m3,
and
the
LOAEL
was
4.72
mg/
m3.

Critical
Effect
Experimental
Concentration
UF
Equivalent
RfC
Plasma
and
RBC
NOAEL
=
1.24
mg/
m3
100
0.0022
mg/
m3
ChE
inhibition
in
LOAEL
=
4.72
mg/
m3
(
See
below)
both
sexes
Uncertainty
Factor
UF
=
100;
The
uncertainty
factor
of
100
includes
the
10X
for
intra­
species
extrapolation
and
10X
for
inter­
species
variation.

Confidence
in
the
Data
Although
the
study
is
only
90
days
in
duration,
rather
than
a
chronic
exposure,
there
is
high
confidence
in
the
quality
of
the
data
derived.
The
principal
toxicological
effect
of
concern
(
i.
e.,
cholinesterase
inhibition)
observed
via
inhalation
exposure
in
this
study
is
similar
to
that
observed
in
oral
studies.

Calculation
of
Equivalent
RfC
Although
an
RfC
was
not
specifically
established
by
OPP,
a
dose,
endpoint
and
uncertainty
factor
were
selected
for
use
in
risk
assessment
[
using
the
Margin
of
Exposure
(
MOE)],
due
to
concern
for
exposure
via
the
inhalation
route.
However,
for
this
exercise,
an
equivalent
RfC
is
calculated,
using
the
NOAEL
(
adjusted
for
duration
of
experimental
regimen)
and
the
uncertainty
factors.

NOAEL
[
ADJ]
(
mg/
m3)
=
E
(
mg/
m3)
x
D
(
h/
24
h)
x
W
(
days/
7
days)

1.24
mg/
m3
x
6hr/
24hr
x
5days/
7days
=
0.22
mg/
m3
OPP,
2003
3
Equivalent
RfC
=
NOAEL
[
ADJ]
(
mg/
m3)
=
0.0022
mg/
m3
100
(
UF)

Where:
NOAEL
[
ADJ]
(
mg/
m3)
=
Adjusted
for
duration
of
experimental
regimen.
E
=
Experimental
NOAEL
D
=
Number
of
hours
exposed/
24
hr;
and
W
=
Number
of
days
of
exposure/
7
days.
OPP,
2003
4
CHLORPYRIFOS
Principal
Studies:
Subchronic
Inhalation
Toxicity
Study
in
Rat
Newton,
P.
E.,
1988.
A
Thirteen
Week
Nose­
Only
Study
of
Chlorpyrifos
Technical
(
Pyrinex)
in
the
Rat.
Bio/
dynamics,
Inc,
East
Millstone,
New
Jersey
Study
No.
88­
8058.
November
14,
1988.
Unpublished.
MRID
Nos.
40908401;
40908401.

In
a
subchronic
nose­
only
inhalation
study,
Fischer
344
rats
(
10/
sex/
concentration)
were
exposed
nose
only
to
Chlorpyrifos
(
95%
a.
i.)
at
vapor
concentrations
of
0,
0.072,
0.143
or
0.287
mg/
m3,
6
hours/
day,
5
days/
week
for13
weeks.
The
study
author
stated
that
the
saturation
or
near
saturation
level
was
0.287
mg/
m3.
There
were
no
treatment­
related
effects
on
mortality,
body
weight,
clinical
signs,
ophthalmoscopy,
hematology,
gross
pathology
or
histopathology.
In
females,
food
consumption
was
slightly
depressed
throughout
the
study
in
all
dose
groups
without
correlation
to
the
dose
level,
although
this
observation
was
not
considered
of
toxicological
significance
due
to
only
slight
decreases
in
corresponding
body
weights.
There
were
some
sporadic
differences
in
clinical
chemistry
parameters,
although
these
were
not
considered
treatment­
related
due
to
a
lack
of
dose­
response
and
inconsistency
between
interim
and
terminal
values.
Sporadic
differences
in
organ
weights
also
were
not
considered
treatment­
related
and
appeared
to
be
attributed
to
the
increase
mean
body
weights.

Significant
plasma
cholinesterase
(
ChE)
inhibition
was
observed
in
the
high
dose
males
(
23%)
and
females
(
25%)
at
the
terminal
sacrifice.
Significant
plasma
ChE
inhibition
was
also
noted
in
females
of
0.072
and
0.143
mg/
m3
the
(
26
and
40%,
respectively),
although
a
dose­
response
relationship
was
not
apparent.
Interim
(
8
week)
measurements
were
similar
or
slightly
greater
than
controls.
Red
blood
cell
(
RBC)
(
interim
and
terminal)
and
brain
(
terminal)
ChE
activities
were
not
significantly
inhibited
at
any
dose
level.
The
plasma
ChE
inhibition
was
not
considered
of
toxicological
significance
because
of
the
minimal
inhibition
(
23­
25%)
at
the
high
dose,
lack
of
dose­
response,
and
an
absence
of
inhibition
in
the
8
week
interval.
The
NOAEL
for
systemic
effects
and
plasma
cholinesterase
inhibition
was
0.287
mg/
m3
(
highest
concentration
tested);
a
LOAEL
was
not
established.

Critical
Effect
Experimental
Concentration
UF
Equivalent
RfC
Lack
of
ChE
NOAEL
=
0.287
mg/
m3
100
0.0005
mg/
m3
(
Occupational)
ChE
inhibition
in
LOAEL
=
Not
established
both
sexes
1000
0.00005
mg/
m3
(
Residential)
(
See
below)
OPP,
2003
5
Uncertainty
Factor
UF
=
100
for
occupational
exposure;
The
uncertainty
factor
of
100
includes
the10X
for
intraspecies
extrapolation
and
10X
for
inter­
species
variation.

UF
=
1000
for
residential
exposure;
The
uncertainty
factor
of
1000
includes
the
10X
for
intraspecies
extrapolation
and
10X
for
inter­
species
variation
and
an
additional
10X
FQPA
Safety
Factor
for
protection
of
infants
and
children
from
residential
uses
(
non­
occupational)
of
chlorpyrifos.
OPP,
2003
6
DIAZINON
Principal
Study:
Subchronic
Inhalation
Toxicity
Study
in
Rat
In
a
21­
day
inhalation
study,
Sprague­
Dawley
rats
(
15/
sex/
concentration)
were
exposed
to
0,
0.1,
1,
10
and
100
mg/
m3
of
Diazinon
(
87%
purity)
for
6
hour/
day
for
a
total
of
21
or
22
consecutive
days.
No
systemic
toxicity
was
seen
at
any
concentration.
The
NOAEL
for
systemic
toxicity
is
>
100
mg/
m3,
the
LOAEL
is
not
established.
The
following
table
illustrates
the
plasma,
RBC
and
brain
cholinesterase
inhibition
data.

Concentration
Plasma
ChE
Males
Females
RBC
AChE
Males
Females
Brain
AChE
Males
Females
0.1
mg/
m3
30%*

56%*

18%*

NOAEL
4%

ns
NOAEL
4%

ns
NOAEL
6%

ns
1.0
mg/
m3
50%*

71%*

53%*

LOAEL
45%*

LOAEL
13%*

LOAEL
15%*

10
mg/
m3
60%*

76%*

75%*

75%*

37%*

44%*

100
mg/
m3
80%*

88%*

91%*

93%*

62%*

80%*

*
Statistically
significant
p
<
0.05.
ns
=
not
statistically
significant.

There
is
statistically
significant
inhibition
for
plasma
ChE
in
both
sexes
and
for
RBC
AChE
for
males
at
the
lowest
dose
of
0.1
mg/
m3.
The
LOAEL
for
plasma
ChE
in
both
sexes
and
for
RBC
ChE
in
males
is
<
0.1
mg/
m3;
a
NOAEL
was
not
established.

Critical
Effect
Experimental
Concentration
UF
Equivalent
RfC
Plasma
and
RBC
NOAEL
=
Not
established
300
0.
00006
mg/
m3
ChE
inhibition
in
LOAEL
=
0.1
mg/
m3
(
See
below)
both
sexes.

Uncertainty
Factor
UF
=
300;
The
uncertainty
factor
of
300
includes
the
10X
for
intra­
species
extrapolation,
10X
for
inter­
species
variation
and
an
additional
3X
for
the
use
of
a
LOAEL
(
i.
e.,
lack
of
NOAEL
in
the
critical
study).

Confidence
in
the
Data
OPP,
2003
7
Although
it
is
only
22
days
in
duration,
rather
than
a
chronic
exposure,
there
is
high
confidence
in
the
quality
of
the
data
derived.
The
principal
toxicological
effect
of
concern
(
i.
e.,
cholinesterase
inhibition)
was
measured
in
this
study
which
was
also
the
effect
of
concern
in
oral
studies.
Since
a
NOAEL
was
not
established,
an
additional
3x
uncertainty
factor
is
applied.
Calculation
of
Equivalent
RfC
Although
an
RfC
was
not
specifically
established
by
OPP,
a
dose,
endpoint
and
uncertainty
factor
were
selected
for
use
in
risk
assessments
[
using
the
Margin
of
Exposure
(
MOE)]
due
to
concern
for
exposure
via
the
inhalation
route.
However,
for
this
exercise,
an
equivalent
RfC
is
calculated.
using
the
LOAEL
(
adjusted
for
duration
of
experimental
regimen)
and
the
uncertainty
factors.

LOAEL
[
ADJ]
(
mg/
m3)
=
E
(
mg/
m3)
x
D
(
h/
24
h)
x
W
(
days/
7
days)

0.1
mg/
m3
x
6hr/
24hr
x
5days/
7days
=
0.
018
mg/
m3
Equivalent
RfC
=
LOAEL
[
ADJ]
(
mg/
m3)
=
0.
00006
mg/
m3
300
(
UF)

Where:
LOAEL
[
ADJ]
(
mg/
m3)
=
Adjusted
for
duration
of
experimental
regimen.
E
=
Experimental
LOAEL
D
=
Number
of
hours/
exposed/
24
hr;
and
W
=
Number
of
days
of
exposure/
7
days.
OPP,
2003
8
NALED
Principal
Study:
Subchronic
Inhalation
Toxicity
Study
in
Rat
Griffis,
L.
Thirteen­
week
Aerosol
Inhalation
Toxicology
study
of
Chevron
Naled
Technical
(
SX­
1655)
in
Rats:
Project
ID:
SOCAL
2400:
SX­
1665.
Unpublished
study
prepared
by
Chevron
Environmental
Health
Center.
MRID
No.
00164224;
00265678;
00265680
In
a
subchronic
inhalation
toxicity
study,
male
and
female
Fischer­
344
rats
were
exposed
(
whole
body)
to
filtered
air
(
control
group)
or
aerosols
containing
0,
0.23,
1.29
or
5.8
mg/
m3
of
naled
for
6
hours/
day,
5
days/
weeks
for
13
weeks.
Additional
control
and
high
dose
groups
were
allowed
to
recover
for
6
weeks.
Exposure
to
the
highest
concentration
of
5.8
mg/
m3
resulted
in
clinical
signs
of
toxicity
manifest
as
tremors,
salivation,
nasal
discharge,
abnormal
respiration,
and
anogenital
staining.
The
clinical
signs
were
consistent
with
cholinergic
effects
and
the
observed
inhibition
of
cholinesterase
activity.
Brain
cholinesterase
was
inhibited
at
5.8
mg/
m3
.
Plasma
and
RBC
cholinesterases
were
inhibited
at
1.29
and
5.8
mg/
m3.
Only
plasma
cholinesterase
continued
to
be
inhibited
six
weeks
after
exposure
to
the
high
concentration.
No
other
treatment­
related
effects
were
observed.
The
NOAEL
was
0.23
mg/
m3
and
the
LOAEL
was
1.29
mg/
m3
based
on
depression
of
plasma
and
RBC
cholinesterase
activities.

Critical
Effect
Experimental
Concentration
UF
Equivalent
RfC
Plasma
and
RBC
NOAEL
=
0.23
mg/
m3
100
0.0004
mg/
m3
ChE
inhibition.
LOAEL
=
1.29
mg/
m3
(
See
below)

Uncertainty
Factor
UF
=
100;
The
uncertainty
factor
of
100
includes
the
10X
for
intra­
species
extrapolation
and
10X
for
inter­
species
variation.

Confidence
in
the
Data
Although
the
study
is
only
90
days
in
duration,
rather
than
a
chronic
exposure,
there
is
high
confidence
in
the
quality
of
the
data
derived.
Plasma
and
RBC
cholinesterase
were
inhibited
as
early
as
day
15
of
the
study.
The
results
of
the
90­
day
study
are
supported
by
a
21­
day
inhalation
study
where
a
concentration
of
3.4
mg/
m3
caused
plasma
and
RBC
cholinesterase
inhibition
by
day
5
of
treatment
and
decreases
in
food
consumption
and
body
weight
on
day
7
(
MRID
40087201).

Calculation
of
Equivalent
RfC
Although
an
RfC
was
not
specifically
established
by
OPP,
a
dose,
endpoint
and
uncertainty
factor
OPP,
2003
9
were
selected
for
use
in
risk
assessment
[
using
the
Margin
of
Exposure
(
MOE)],
due
to
concern
for
exposure
via
the
inhalation
route.
However,
for
this
exercise,
an
equivalent
RfC
is
calculated
using
the
NOAEL
(
adjusted
for
duration
of
experimental
regimen)
and
the
uncertainty
factors.
NOAEL
[
ADJ]
(
mg/
m3)
=
E
(
mg/
m3)
x
D
(
h/
24
h)
x
W
(
days/
7
days)

0.23
mg/
m3
x
6hr/
24hr
x
5days/
7days
=
0.04
mg/
m3
Equivalent
RfC
=
NOAEL
[
ADJ]
(
mg/
m3)
=
0.0004
mg/
m3
100
(
UF)
Where:
NOAEL
[
ADJ]
(
mg/
m3)
=
Adjusted
for
duration
of
experimental
regimen.
E
=
Experimental
NOAEL
D
=
Number
of
hours
exposed/
24
hr;
and
W
=
Number
of
days
of
exposure/
7
days.
