Document ID: EPA-HQ-OPP-2002-0325-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-12-12T05:00Z

United
States
Environmental
Protection
Agency
Prevention,
Pesticides
and
Toxic
Substances
(
7101)
EPA
712
 
C
 
02
 
189
December
2002
Health
Effects
Test
Guidelines
OPPTS
870.1000
Acute
Toxicity
Testing
 
Background
i
INTRODUCTION
This
guideline
is
one
of
a
series
of
test
guidelines
that
have
been
developed
by
the
Office
of
Prevention,
Pesticides
and
Toxic
Substances,
United
States
Environmental
Protection
Agency
for
use
in
the
testing
of
pesticides
and
toxic
substances,
and
the
development
of
test
data
that
must
be
submitted
to
the
Agency
for
review
under
Federal
regulations.

The
Office
of
Prevention,
Pesticides
and
Toxic
Substances
(
OPPTS)
has
developed
this
guideline
through
a
process
of
harmonization
that
blended
the
testing
guidance
and
requirements
that
existed
in
the
Office
of
Pollution
Prevention
and
Toxics
(
OPPT)
and
appeared
in
Title
40,
Chapter
I,
Subchapter
R
of
the
Code
of
Federal
Regulations
(
CFR),
the
Office
of
Pesticide
Programs
(
OPP)
which
appeared
in
publications
of
the
National
Technical
Information
Service
(
NTIS)
and
the
guidelines
published
by
the
Organization
for
Economic
Cooperation
and
Development
(
OECD).

The
purpose
of
harmonizing
these
guidelines
into
a
single
set
of
OPPTS
guidelines
is
to
minimize
variations
among
the
testing
procedures
that
must
be
performed
to
meet
the
data
requirements
of
the
U.
S.
Environmental
Protection
Agency
under
the
Toxic
Substances
Control
Act
(
15
U.
S.
C.
2601)
and
the
Federal
Insecticide,
Fungicide
and
Rodenticide
Act
(
7
U.
S.
C.
136,
et
seq.).

Final
Guideline
Release:
This
guideline
is
available
from
the
U.
S.
Government
Printing
Office,
Washington,
DC
20402
on
disks
or
paper
copies:
call
(
202)
512
 
0132.
This
guideline
is
also
available
electronically
in
PDF
(
portable
document
format)
from
EPA's
Internet
Web
site
at
http:/
/
www.
epa.
gov/
opptsfrs/
home/
guidelin.
htm.
1
OPPTS
870.1000
Acute
toxicity
testing
 
background.
(
a)
Scope
 
(
1)
Applicability.
This
guideline
is
intended
to
meet
testing
requirements
of
both
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
(
7
U.
S.
C.
136,
et
seq.)
and
the
Toxic
Substances
Control
Act
(
TSCA)
(
15
U.
S.
C.
2601).

(
2)
Background.
The
source
material
for
this
revised
harmonized
test
guideline
is
OPPTS
870.1000
Acute
Toxicity
Testing
 
Background,
dated
August
1998.

(
b)
Purpose.
The
Agency
considers
the
evaluation
of
toxicity
following
short
term
exposure
to
a
chemical
to
be
an
integral
step
in
the
assessment
of
its
toxic
potential
under
the
regulatory
framework
of
its
pesticide
and
toxic
substances
programs.
In
the
assessment
and
evaluation
of
the
toxic
characteristics
of
a
substance,
acute
toxicity
is
generally
performed
by
the
probable
route
of
exposure
in
order
to
provide
information
on
health
hazards
likely
to
arise
from
short­
term
exposure
by
that
route.
For
pesticides,
the
short­
term
toxicity
testing
battery
consists
of
acute
toxicity
tests
by
the
oral,
dermal,
and
inhalation
routes;
skin
and
eye
irritation
testing;
and
testing
for
dermal
sensitization.
Data
from
an
acute
study
may
serve
as
a
basis
for
hazard
categorization,
labeling,
or
child­
resistant
packaging
and
may
also
serve
to
designate
pesticides
which
may
be
applied
only
by
certified
applicators.
It
may
also
be
an
initial
step
in
establishing
a
dosage
regimen
in
subchronic
and
other
studies
and
may
provide
information
on
absorption
and
the
mode
of
toxic
action
of
a
substance.
An
evaluation
of
acute
toxicity
data
should
include
the
relationship,
if
any,
between
the
exposure
of
animals
to
the
test
substance
and
the
incidence
and
severity
of
all
abnormalities,
including
behavioral
and
clinical
abnormalities
the
reversibility
of
observed
abnormalities,
gross
lesions,
body
weight
changes,
effects
on
mortality,
and
any
other
toxic
effects.

(
c)
History
 
(
1)
Acute
toxicity
test
guidelines.
Test
guidelines
for
acute
toxicity
were
first
published
by
the
Agency
in
October
1982
as
part
of
Subdivision
F
of
the
Pesticide
Assessment
Guidelines
for
the
Office
of
Pesticide
Programs
(
OPP)
(
see
paragraph
(
g)(
1)
of
this
guideline)
and
in
40
CFR
part
797
in
September
1985
for
the
Office
of
Pollution
Prevention
and
Toxics
(
OPPT).

(
2)
Rejection
rate
analysis.
In
1993,
as
part
of
its
Pesticide
Rejection
Rate
Analysis,
Agency
and
industry
scientists
met
to
perform
a
guidelineby
guideline
review
of
toxicology
studies
including
acute
toxicity
studies.
The
purpose
of
this
guideline­
by­
guideline
review
was
to
identify
those
factors
that
most
frequently
cause
toxicology
studies
required
for
pesticide
reregistration
to
be
rejected.
The
results
were
published
as
the
Pesticide
Reregistration
Rejection
Rate
Analysis:
Toxicology
(
see
paragraph
(
g)(
2)
of
this
guideline).
In
1995,
representatives
from
the
Agency
met
with
the
American
Crop
Protection
Association
(
ACPA),
the
Chemical
Producers
and
Distributors
Association
(
CPDA),
the
Chemical
Manufacturers
Asso­
2
ciation
(
CMA),
Health
Canada,
and
the
California
Department
of
Pesticide
Regulation
(
CDPR)
to
discuss
acceptable
methods
for
the
conduct
of
acute
toxicity
studies.
The
discussions
of
this
meeting
were
incorporated
into
a
preliminary
Registration
Division
document
titled
Conduct
of
Acute
Toxicity
Studies
(
see
paragraph
(
g)(
3)
of
this
guideline).
These
documents
supplement
the
acute
toxicology
guidelines
in
Subdivision
F.

(
3)
Guideline
harmonization.
The
Series
870
Health
Effects
test
guidelines
have
been
harmonized
between
OPP
and
OPPT
and,
where
possible
with
the
Organization
for
Economic
Cooperation
and
Development
(
OECD)
test
guidelines.
Scientific
considerations
from
both
of
the
analyses
described
in
paragraph
(
c)(
2)
of
this
guideline
have
been
incorporated
into
the
revised
test
guidelines.

(
d)
Approaches
to
the
determination
of
acute
toxicity.
(
1)
At
present,
the
evaluation
of
chemicals
for
acute
toxicity
is
necessary
for
the
protection
of
public
health
and
the
environment.
The
Agency
supports
measures
dedicated
to
reducing
the
use
of
animals
in
toxicity
testing.
When
animal
testing
is
required
for
this
purpose,
testing
should
be
done
in
ways
that
minimize
numbers
of
animals
used
and
that
take
full
account
of
their
welfare.
To
this
end,
when
conducting
a
test,
the
Agency
stresses
the
simultaneous
monitoring
of
several
endpoints
of
toxicity
in
animals
in
a
single
acute
study
including
sublethal
effects
as
well
as
lethality.
Dosed
animals
are
observed
for
abnormal
behavioral
manifestations
such
as
increased
salivation
or
muscular
incoordination,
in
addition
to
the
recovery
from
these
effects
during
the
observation
period.
Both
dead
and
surviving
animals
are
necropsied
to
evaluate
gross
anatomical
evidence
of
organ
toxicity.
In
selected
cases,
additional
testing
may
be
justified
to
better
characterize
the
kinds
of
abnormalities
that
have
been
found
in
the
organs
of
the
necropsied
animals.
These
sound,
scientific
practices
represent
some
of
the
means
which
maximize
the
utility
of
the
data
obtained
from
a
limited
number
of
test
animals
to
achieve
a
balance
between
protecting
humans
and
the
environment,
and
the
welfare
and
utilization
of
laboratory
animals.

(
2)
EPA
recommends
the
following
means
to
reduce
the
number
of
animals
used
to
evaluate
acute
effects
of
chemical
exposure
while
preserving
its
ability
to
make
reasonable
judgements
about
safety:

(
i)
Use
of
data
from
structurally
related
substances
or
mixtures.
In
order
to
minimize
the
need
for
animal
testing
for
acute
effects,
the
Agency
encourages
the
review
of
existing
acute
toxicity
information
on
chemical
substances
that
are
structurally
related
to
the
agent
under
investigation.
In
certain
cases,
it
may
be
possible
to
obtain
enough
information
to
make
preliminary
hazard
evaluations
that
may
reduce
the
need
for
further
animal
testing
for
acute
effects.
Similarly,
mixtures
or
formulated
products
that
are
substantially
similar
to
well­
characterized
mixtures
or
products
may
not
need
additional
testing
if
there
are
sufficient
bridging
data
available
3
for
meaningful
extrapolation.
In
those
cases,
classification
would
be
extrapolated
from
the
mixture
already
tested.

(
ii)
EPA
recommends
the
Up­
and­
Down
Procedure
(
UDP),
as
detailed
in
this
guideline
and
adopted
by
OECD
as
test
Guideline
425
(
see
paragraph
(
g)(
4)
of
this
guideline),
to
access
acute
oral
toxicity.
This
method
provides
a
point
estimate
of
lethality
and
confidence
interval.
A
dedicated
program
(
AOT425StatPgm)
has
been
developed
by
EPA
to
assist
laboratories
in
the
conduct
of
this
protocol.
The
Agency
strongly
recommends
the
use
of
this
software
package
which
is
available
on
EPA's
Internet
Web
site
at
http://
www.
epa.
gov/
oppfead1/
harmonization.
Acute
oral
toxicity
testing
may
also
be
performed
using
the
Fixed
Dose
Method
of
OECD
Guideline
420
(
see
paragraph
(
g)(
5)
of
this
guideline)
or
the
Acute
Toxic
Class
Method
of
OECD
Guideline
423
(
see
paragraph
(
g)(
6)
of
this
guideline
These
methods
assess
lethality
within
a
dose
range.

(
iii)
Weight
of
evidence
approaches
to
dermal
and
ocular
irritation.
Several
factors
should
be
considered
in
determining
the
corrosion
and
irritation
potential
of
chemicals
before
testing
is
undertaken.
Existing
human
experience
and
data
and
animal
observations
and
data
should
be
the
first
line
of
analysis,
as
it
gives
information
directly
referable
to
effects
on
the
skin.
In
some
cases,
enough
information
may
be
available
from
structurally
related
compounds
to
make
classification
decisions.
Likewise,
pH
extremes
(
pH
<
2
or
>
11.5)
may
indicate
dermal
effects,
especially
when
buffering
capacity
is
known,
although
the
correlation
is
not
perfect.
Generally
such
agents
are
expected
to
produce
significant
effects
on
the
skin.
It
also
stands
to
reason
that
if
a
chemical
is
extremely
toxic
by
the
dermal
route,
a
dermal
irritation/
corrosion
study
may
not
be
needed.
Likewise,
if
there
is
a
lack
of
any
dermal
reaction
at
the
limit
dose
(
2,000
mg/
kg)
in
an
acute
toxicity
study
(
for
which
observations
of
dermal
reactions
were
made),
a
dermal
irritation/
corrosion
study
again
may
not
be
needed
for
labeling
purposes.
It
should
be
noted,
however,
that
often
acute
dermal
toxicity
and
dermal
irritation/
corrosion
testing
are
performed
in
different
species
that
may
differ
in
sensitivity.
In
vitro
alternatives
that
have
been
validated
and
accepted
may
also
be
used
to
help
make
classification
decisions

(
iv)
All
of
the
available
information
on
a
chemical
should
be
used
in
determining
the
need
for
in
vivo
dermal
irritation
testing.
Although
information
might
be
gained
from
the
evaluation
of
single
parameters
within
a
tier
(
e.
g.,
caustic
alkalies
and
acids
with
extreme
pH
(
pH
<
2
or
>
11.5)
should
be
considered
as
dermal
corrosives),
there
is
merit
in
considering
the
totality
of
existing
information
and
making
an
overall
weight
of
evidence
determination.
This
is
especially
true
when
there
is
information
available
on
some
but
not
all
parameters.

(
v)
Use
of
limit
testing.
For
chemicals
judged
to
be
relatively
nontoxic
a
single
group
of
animals
is
given
a
large
dose
of
the
agent.
If
4
no
lethality
is
demonstrated,
no
further
testing
is
pursued.
The
substance
is
classified
in
hazard
categories
according
to
the
limit
dose
used.
(
See
the
following
paragraph
for
a
discussion
of
toxicity
categories
under
FIFRA).

(
e)
Regulatory
applications
under
FIFRA.
(
1)
Precautionary
labeling
provides
the
pesticide
user
with
a
general
idea
of
the
potential
toxicity,
irritation
and
sensitization
hazard
associated
with
the
use
of
a
pesticide
(
see
EPA
Label
Review
Manual
(
paragraph
(
g)(
7)
of
this
guideline)
and
40
CFR
Part
156
 
Labeling
Requirements
for
Pesticides
and
Devices).
Precautionary
labeling
also
identifies
the
precautions
necessary
to
avoid
exposure
as
well
as
any
personal
protective
equipment
which
should
be
used
when
handling
a
pesticide
and
statements
of
practical
treatment
in
case
of
accidental
exposure.
A
globally
harmonized
system
for
classification
and
labeling
has
been
approved
through
the
United
Nations.
Implementation
will
be
phased
in
by
United
Nations
countries,
with
schedules
to
be
announced.
This
section
describes
the
current
system
in
place
for
pesticides
in
the
United
States
and
will
be
revised
and
updated
when
the
globally
harmonized
system
is
fully
implemented.

(
2)
Precautionary
labeling
which
includes
the
signal
word,
personal
protective
equipment,
hazard
symbol,
and
statements
of
practical
treatment
is
normally
determined
by
six
acute
toxicity
studies
and
product
composition
The
acute
oral,
acute
dermal
and
acute
inhalation
studies
are
used
to
determine
the
LD50
of
a
product
via
the
designated
route
of
exposure.
The
primary
eye
irritation
and
primary
skin
irritation
studies
measure
the
severity
of
irritation
or
corrosivity
caused
by
a
product.
The
dermal
sensitization
study
determines
whether
a
product
is
capable
of
causing
an
allergic
reaction.
With
the
exception
of
the
dermal
sensitization
study,
each
acute
toxicity
study
is
assigned
a
toxicity
category
as
defined
in
the
table
below.
All
products
falling
into
toxicity
categories
I
 
IV
must
bear
a
signal
word
and
in
some
cases
warning
symbols.

(
3)
Personal
Protective
Equipment.
Personal
protective
equipment
which
includes
use
of
protective
clothing,
chemical
resistant
gloves,
protective
eye
gear,
and
respiratory
protective
devices,
is
determined
by
the
results
of
six
acute
toxicity
studies
according
to
toxicity
category
(
see
table).
The
degree
of
protection
required
is
graded
according
to
the
degree
of
acute
toxicity
and
the
hazard
classification
category
of
the
chemical
or
product.
These
requirements
are
set
forth
in
40
CFR
170.240
in
the
Worker
Protection
Standard.

(
4)
Restricted
entry
intervals.
Agricultural
products
must
display
a
restricted
entry
interval.
A
restricted
entry
interval
is
the
time
immediately
following
a
pesticide
application
during
which
entry
into
the
treated
area
is
restricted.
Restricted
entry
intervals
are
based
on
the
most
severe
acute
toxicity
category
assigned
to
the
acute
dermal,
eye
irritation
and
skin
irritation
data
for
all
of
the
active
ingredients
in
a
pesticide
product.
The
dura­
5
tion
of
restricted
entry
intervals
is
based
on
the
severity
of
toxicity,
with
products
classified
in
category
I
requiring
intervals
of
48
hours
or
more
and
products
classified
in
category
III
or
IV
requiring
intervals
of
12
hours.

(
5)
Child­
resistant
packaging.
FIFRA
establishes
standards
with
respect
to
pesticide
packaging
of
products
intended
for
use
in
residential
settings
in
order
to
protect
children
or
adults
from
serious
illness
or
injury
resulting
from
accidental
ingestion
or
contact
with
pesticides.
Criteria
in
40
CFR
part
157
for
which
pesticides
must
be
distributed
or
sold
in
childresistant
packaging
are
based
on
classification
according
to
the
toxicity
categories
set
forth
in
the
table.

(
6)
Restricted
use
pesticide.
The
Agency
determines
whether
a
pesticide
must
be
applied
under
the
direct
supervision
of
a
certified
applicator.
Such
clarification
for
restricted
use
is
based
upon
consideration
of
toxicity
data,
including
acute
toxicity,
exposure,
and
intended
use.

(
7)
Biochemical
pest
control
agents
are
tested
in
a
special
tiered
progression
The
technical
grade
biochemical
pest
control
agent
is
always
characterized
by
acute
toxicity
tests.
However,
because
of
their
nontoxic
mode
of
action
against
the
target
pest,
further
testing
of
the
biochemical
pest
control
agent
is
normally
not
required.
Microbial
pest
control
agents
are
tested
using
the
OPPTS
Harmonized
Test
Guidelines
Series
885,
Microbial
Pesticide
Test
Guidelines,
for
pathogenicity/
infectivity.
In
addition,
all
formulations
of
microbial
pest
control
agents
are
tested
for
precautionary
labeling
using
acute
toxicity
tests
in
the
OPPTS
Harmonized
Test
Guidelines
Series
870,
Health
Effects
Test
Guidelines.
6
Toxicity
Categories
Study
Category
I
Category
II
Category
III
Category
IV
Acute
Oral
Up
to
and
including
50
mg/
kg
>
50
through
500
mg/
kg
>
500
through
5000
mg/
kg
>
5000
mg/
kg
Acute
Dermal
Up
to
and
including
200
mg/
kg
>
200
through
2000
mg/
kg
>
2000
through
5000
mg/
kg
>
5000
mg/
kg
Acute
Inhalation
Up
to
and
including
0.05
mg/
liter
>
0.05
through
0.5
mg/
liter
>
0.5
through
2
mg/
liter
>
2
mg/
liter
Eye
Irritation
Corrosive
(
irreversible
destruction
of
ocular
tissue)
or
corneal
involvement
or
irritation
persisting
for
more
than
21
days
Corneal
involvement
or
irritation
clearing
in
8­
21
days
Corneal
involvement
or
irritation
clearing
in
7
days
or
less
Minimal
effects
clearing
in
less
than
24
hours
Skin
irritation
Corrosive
(
tissue
destruction
into
the
dermis
and/
or
scarring)
Severe
irritation
at
72
hours
(
severe
erythema
or
edema)
Moderate
irritation
at
72
hours
(
moderate
erythema)
Mild
or
slight
irritation
(
no
irritation
or
slight
erythema)

Study
Study
results
Study
results
Dermal
Sensitization
Product
is
a
sensitizer
or
is
positive
for
sensitization
Product
is
not
a
sensitizer
or
is
negative
for
sensitization
(
f)
Regulatory
applications
under
TSCA.
(
i)
Acute
oral
toxicity
data
are
used
to
provide
a
basic
understanding
of
acute
effects
and
to
serve
as
a
starting
point
for
human
hazard
and
risk
assessments
focused
on
occupational
and
general
population
exposures.

(
ii)
Acute
oral
toxicity
testing
is
included
in
testing
menus
to
obtain
basic
or
``
screening
level''
information
on
certain
chemicals.
These
include
higher
volume/
higher
exposure
new
chemicals
where
TSCA
section
5(
e)
``
exposure­
based''
testing
authorities
are
used
to
obtain
a
basic
level
of
hazard
and
environmental
fate
information;
and
High
Production
Volume
existing
chemicals
(
i.
e.,
those
produced
and/
or
imported
at
or
above
1
million
lbs/
yr)
information
data
set.

(
g)
References.
The
following
references
should
be
consulted
for
additional
background
information
on
this
test
guideline.

(
1)
U.
S.
Environmental
Protection
Agency.
Pesticide
Assessment
Guidelines,
Subdivision
F:
Health
Effects.
EPA
report
540/
09
 
82
 
025,
October
1982.

(
2)
U.
S.
Environmental
Protection
Agency.
Pesticide
Reregistration
Rejection
Rate
Analysis:
Toxicology.
EPA
report
738
 
R
 
93
 
004.
July
1993.

(
3)
U.
S.
Environmental
Protection
Agency.
Conduct
of
Acute
Toxicity
Studies.
EPA
report
737
 
R
 
97
 
002.
September
1997.

(
4)
Organization
for
Economic
Cooperation
and
Development,
OECD
Guidelines
for
Testing
of
Chemicals.
Guideline
425:
Acute
Oral
Toxicity
 
Up­
and­
Down
Method.
Approved:
December
2001.
7
(
5)
Organization
for
Economic
Cooperation
and
Development,
OECD
Guidelines
for
Testing
of
Chemicals.
Guideline
420:
Acute
Oral
Toxicity­
Fixed
Done
Method.
Adopted:
December
2001.

(
6)
Organization
for
Economic
Cooperation
and
Development,
OECD
Guidelines
for
Testing
of
Chemicals.
Guideline
423:
Acute
Oral
Toxicity­
Acute
Toxic
Class
Method.
Adopted:
December
2001.

(
7)
U.
S.
Environmental
Protection
Agency.
Label
Review
Manual
2nd
Edition.
EPA
report
737
 
B
 
96
 
001.
December
1996.