Document ID: EPA-HQ-OPP-2005-0045-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-04-08T04:00Z

Page
1
of
46
A
Comparison
of
the
Results
of
Studies
on
Pesticides
from
12­
or
24­
Month
Dog
Studies
with
Dog
Studies
of
Shorter
Duration
Karl
P.
Baetcke,
Whang
Phang,
and
Vicki
Dellarco*

Health
Effects
Division,
Office
of
Pesticide
Programs,

U.
S.
Environmental
Protection
Agency,
Washington,
D.
C.
20460
4/
7/
05
This
document
is
for
review
by
the
U.
S.
EPA
FIFRA
Scientific
Advisory
Panel
Meeting
May
5­
6,
2005
Page
2
of
46
Table
of
Contents
Executive
Summary
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1.
Introduction
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2.
Methods
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3.
Results
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4.
Discussion
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References
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Appendix
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Page
18
of
45
List
of
Tables
Table
1.
Pesticides
with
lower
NOAELs
in
>
1year
dog
studies
than
in
13­
week
dog
studies.
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Page
9
of
45
Table
2.
Chemicals
with
Data
Base
Uncertainty
Factors
(
UFs)
Applied
to
Derivations
of
RfDs
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Page
13
of
45
Table
A1.
NOAELs
&
LOAELs
(
mg/
kg/
day)
in
13­
Week
and
1­
or
2­
Year
Dog
Studies
(
42
Chemicals)
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19
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45
Table
A2.
NOAELs
&
LOAELs
from
1­
or
2­
yr
dog
studies
with
interim
data
(
1
day
to
3
months)
(
35
chemicals)
.
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Page
24
of
45
Table
A3.
Pesticides
with
Lower
NOAELs
or
LOAELs
(>
1.5)
in
1­
year
than
in
13­
Week
Dog
Studies
(
19
Chemicals)
.
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Page
28
of
45
Page
3
of
46
Executive
Summary
The
Office
of
Pesticide
Programs
has
established
chronic
RfDs
for
304
pesticides
as
of
October
2004.
One
hundred
and
sixteen
(
116
or
38%)
of
the
chronic
RfDs
are
based
on
results
from
dog
studies.
A
retrospective
analysis
of
the
results
of
dog
studies
of
different
duration
conducted
with
77
of
these
116
pesticides
was
undertaken
to
ascertain
whether
data
from
13­
week
dog
studies
alone
would
suffice,
in
the
absence
of
chronic
dog
studies
(
1
year
or
more),
for
the
identification
of
NOAELs
and
LOAELs
for
the
derivation
of
chronic
reference
doses
(
RfDs).
Interim
data
(
13­
weeks
or
less)
from
chronic
dog
studies
and
data
from
subchronic
dog
studies
(
e.
g.,
28­
day)
were
also
compared
with
the
data
from
terminal
sacrifices
in
the
chronic
studies.
The
analysis
showed
that
for
58
of
the
77
pesticides
(
75%),
the
results
of
the
chronic
studies
and
studies
of
lesser
duration
provide
comparable
NOAELs
and
LOAELs.
For
the
remaining
19
pesticides,
where
the
doses
administered
in
the
13­
week
and
chronic
dog
studies
differed,
the
apparent
NOAELs
and/
or
LOAELs
were
lower
in
the
chronic
study
than
in
the
13­
week
study.
Evaluations
of
dose
response
data
and
consideration
of
interim
data
from
1­
to
2­
year
studies
or
results
from
studies
of
other
than
13­
weeks
duration
showed
that
NOAELs
and
LOAELs
would
likely
be
equivalent
for
11
of
the
19
pesticides
if
the
13­
week
studies
had
employed
the
same
dose
levels
as
the
1­
or
2­
year
study.
For
another
2
pesticides,
the
database
contained
a
study
that
would
provide
NOAELs/
LOAELs
comparable
to
the
NOAELs/
LOAELs
identified
in
the
chronic
dog
study.
For
an
additional
pesticide,
the
lack
of
sufficient
clinical
chemistry,
hematologic,
and
histopatholgy
data
limits
meaningful
comparisons
of
the
results
of
the
13­
week
and
chronic
dog
studies.
For
an
additional
2
pesticides,
there
is
a
lack
of
detection
of
effects
in
the
13­
week
study
that
would
be
expected
to
occur
early
on
(
cholinesterase
inhibition
and
effects
on
thyroid
hormones
that
normally
are
observed
at
<
13­
weeks),
which
suggests
that
the
finding
of
different
NOAELs/
LOAELs
is
not
related
to
the
different
duration
of
the
13­
week
and
chronic
studies
but
rather
due
to
variability
in
the
measurement
of
cholinesterase
and
hormone
activity.
There
are
only
3
pesticides
where
there
are
indications
that
a
chronic
dog
study
would
potentially
be
more
appropriate
than
a
13­
week
study
for
the
selection
of
NOAELs
and
LOAELs.
Thus,
the
present
analysis
indicates
that
a
13­
week
dog
study
would
be
adequate
for
identification
of
a
NOAEL
or
LOAEL
that
would
be
similar
to
that
established
from
a
chronic
dog
study
for
all
except
3
pesticides
(
3/
77
or
4%)
of
the
cases
evaluated.
Page
4
of
46
1.
Introduction
The
need
for
multiple
dog
studies
of
different
duration
has
long
been
a
subject
of
debate
among
regulatory
agencies.
Currently,
there
is
no
international
standard
regarding
the
duration
of
dog
studies.
The
Office
of
Pesticide
Programs
(
OPP),
US
Environmental
Protection
Agency
(
USEPA)
requires
that
the
results
of
a
rodent
and
nonrodent
(
i.
e.,
dog)
subchronic
(
13­
week)
study
and
a
chronic
(
2­
year
rat
and
a
1­
year
dog)
study
be
submitted
to
support
the
registration
of
a
food
use
pesticide
or
for
nonfood
use
pesticides
if
exposure
is
likely
to
result
in
repeated
exposure
over
a
significant
time.
The
U.
S.
Food
and
Drug
Administration
has
an
established
standard
duration
of
1­
year
for
dog
studies
although
exceptions
are
made
to
allow
a
6­
month
study
for
pharmaceutical.
The
European
Union
(
EU)
requires
a
6­
month
non­
rodent
study
for
approval
of
pharmaceuticals
and
a
6­
month
dog
study
is
considered
sufficient
for
the
registration
of
most
compounds
in
Japan
(
Spielmann
and
Gerbracht,
2001;
DeGeorge
et
al.,
1999;
Contrera
et
al.,
1993).
For
plant
protection
products,
the
EU
always
requires
a
90­
day
dog
study
and
a
1­
year
dog
study
may
be
required
if
the
dog
is
shown
to
be
more
sensitive
than
the
rat
in
a
90­
day
study;
a
proposal
under
consideration
by
the
EU
is
to
require
only
1
dog
study.
Canada
requires
a
1
year
dog
study
for
pesticides.

The
value
of
testing
pharmaceuticals
in
rodent
and
non­
rodent
species
for
longer
than
13
weeks
or
6
months
has
been
addressed
in
a
number
of
reports.
Lumley
et
al.
(
1992)
evaluated
the
minimum
duration
of
chronic
animal
toxicity
studies
needed
to
detect
adverse
responses
and
to
define
safety
margins
between
the
proposed
use
levels
and
adverse
responses
for
pharmaceutical
compounds.
The
analyses
were
based
on
results
primarily
from
rat,
dog,
and
primate
studies,
but
also
from
other
species.
Additional
toxicities
were
identified
in
longer
than
6
months
for
9
of
75
case
studies
with
6­
month
study
results;
additional
toxicities
were
also
identified
in
12­
month
studies
from
21
of
80
case
studies
that
were
not
observed
in
1
or
3
month
studies.
There
were
no
cases
where
data
from
12­
month
studies
or
longer
had
an
effect
on
development
of
a
pharmaceutical
for
clinical
use.
As
to
the
results
of
toxicity
studies
conducted
specifically
with
dogs,
all
significant
effects
were
identified
within
6
months
for
98%
of
the
pharmaceuticals
(
55
of
56
case
studies).
Based
on
the
results
of
this
retrospective
analysis,
it
was
suggested
that
animal
toxicity
studies
lasting
6
months
would
be
sufficient
for
routine
toxicity
testing
of
therapeutic
agents.

Contrera
et
al.
(
1993)
conducted
a
retrospective
analysis
on
the
results
of
thirty
6­
and
12­
month
duration
non­
rodent
toxicity
studies
on
pharmaceutical
compounds.
Ten
of
the
30
studies
were
1­
year
dog
studies
with
6­
month
interim
sacrifices.
New
toxicological
findings
(
i.
e.,
an
effect
observed
at
12
months
that
was
not
seen
or
recognized
as
significant
at
6
months)
were
identified
in
3
of
the
10
studies.
Both
6­
month
and
1­
year
studies
were
compared
for
27
dog
studies;
new
findings
were
identified
in
5
of
the
27
study
pairs.
Based
on
these
comparisons,
they
concluded
that
the
requirement
for
a
12­
month
non­
rodent
study
be
maintained
because
12­
month
dog
studies
provided
information
of
regulatory
significance
that
was
not
generally
detected
in
6­
month
studies.
They
recommended,
however,
that
the
issue
be
Page
5
of
46
reconsidered
when
additional
data
on
6­
month
and
12­
month
dog
studies
became
available.
Page
6
of
46
The
same
group
analyzed
117
pharmaceuticals
in
the
Center
for
Medicines
Research
toxicology
data
base
and
determined
that
dog
studies
>
6
months
demonstrated
additional
effects
in
only
13
of
the
117
(
11%)
compounds
(
Parkinson
et
al.,
1995).
For
most
of
the
chemicals,
the
significant
effects
were
seen
within
3
months.
In
cases
where
additional
toxicities
were
identified
after
3
months,
similar
responses
were
seen
in
the
rat
studies.
While
these
authors
suggested
that
dog
studies
longer
than
3
months
provide
relatively
little
new
toxicological
information,
they
concluded
that
a
six
month
dosing
period
in
the
dog
should
be
the
only
non­
rodent
bioassay
that
is
routinely
required
for
evaluating
chronic
toxicity.

Participants
at
an
International
Conference
on
Harmonization
(
ICH)
workgroup
reviewed
data
on
dog
studies
(
17
case
studies)
to
arrive
at
a
consensus
on
the
best
duration
time
for
non­
rodent
toxicity
studies
(
DeGeorge
et
al.,
1999).
Members
of
the
workgroup
from
the
European
Union,
the
United
States,
and
Japan
evaluated
results
only
from
dog
studies
with
data
showing
significant
new
findings
that
occurred
beyond
a
6­
month
dosing
period.
For
only
a
small
number
of
cases
(
3
of
the18)
was
there
agreement
that
no
new
findings
were
detected
beyond
6
months
of
treatment.
This
workgroup
concluded
that
the
results
of
their
analysis
supported
a
9­
month
duration
for
non­
rodent
toxicity
studies
because
most
of
the
toxicities
observed
in
the
case
studies
could
have
been
detected
by
9
months.

Gerbracht
and
Spielman
(
1998)
conducted
a
retrospective
analysis
of
studies
on
216
pesticides.
The
data
examined
was
from
studies
submitted
for
regulatory
purposes
to
the
Federal
Institute
of
Health
Protection
of
Consumers
and
Veterinary
Medicine,
Germany.
The
analysis
was
designed
to
examine
the
relevance
of
studies
in
dogs
on
regulatory
testing
of
pesticides.
The
authors
reported
no
significant
differences
in
species­
specific
organ
toxicities
among
rats,
mice
and
dogs
in
13­
week
and
52­
or
104­
week
studies.
However,
haematoxic
effects
were
more
often
detected
in
dogs.
They
reported
that
the
dog
was
generally
more
sensitive
to
the
toxic
effects
of
insecticides
than
rats
or
mice
and
but
that
the
rat
appeared
to
be
more
sensitive
than
the
dog
to
the
toxic
effects
of
herbicides.
Overall,
they
concluded
that
studies
in
both
rats
and
dogs
are
important
for
the
safety
assessment
of
pesticides.

More
recently,
Spielmann
and
Gerbracht
(
2001)
performed
a
comprehensive
analysis
of
data,
also
submitted
to
the
Federal
Institute
of
Health
Protection
of
Consumers
and
Veterinary
Medicine,
Germany,
from
dog
studies
on
172
pesticides.
The
focus
of
this
analysis
was
on
whether
dog
studies
>
13
weeks
provided
important
additional
information
provided
by
studies
of
shorter
duration.
They
reported
that
"
analysis
of
the
severity
of
organ­
specific
toxic
effects
of
pesticides
revealed
that
chronic
long­
term
studies
(
52/
104
weeks)
in
dogs
do
not
provide
specific
additional
information
to
26­
week
studies
in
the
same
species."
They
further
stated
that
"
safety
testing
of
pesticides
in
dogs
should
be
limited
to
subchronic
(
13­
week)
studies
since
an
extension
of
the
duration
of
the
studies
does
not
provide
additional
essential
information."
The
recommendation
for
a
study
of
13­
weeks
duration
was
supported
by
the
finding
that
in
only
7
of
141
pesticide
studies
was
new
and
relevant
information
on
the
toxic
properties
of
the
pesticide
provided
by
chronic
dog
studies
that
was
not
seen
1DER
­
Data
Evaluation
Record
is
the
record
of
the
Office
of
Pesticide
Programs
review
and
conclusions
for
a
submitted
study.
The
DER
includes
data
on
clinical
chemistry,
hemotologic,
and
urinalysis
measurements
and
tabulations
of
histopathologic
findings.
The
HIARC
report
is
the
record
of
toxicological
peer
review
for
the
chemical.
It
summarizes
the
conclusions
of
the
committee
about
the
toxicological
aspects
of
the
risk
assessment
(
e.
g.,
doses,
endpoints,
and
uncertainty
factors
for
use
in
the
Page
7
of
46
in
dog
studies
of
shorter
duration
or
in
studies
with
rats
or
mice.

2.
Methods
The
Science
Information
Branch,
Health
Effects
Division,
Office
of
Pesticide
Programs,
U.
S.
EPA
periodically
prepares
a
tabulation
of
acute
and
chronic
reference
doses
(
RfDs)
that
have
been
established
for
risk
assessments.
The
RfD
is
defined
as
an
estimate,
within
an
order
of
magnitude,
of
exposure
assumed
to
be
without
appreciable
risk
for
adverse
noncancer
health
effects.
In
the
risk
characterization
step,
the
RfD
values
are
compared
to
potential
or
known
environmental
exposure
levels.
RfDs
for
noncancer
effects
are
generally
based
on
identifying
a
no­
observed­
adverseeffect
level
(
NOAEL)
for
a
critical
effect
which
is
usually
determined
from
laboratory
animal
studies.
The
NOAEL
is
typically
divided
by
two
uncertainty
factors
(
UF)
to
account
for
uncertainties
inherent
in
the
extrapolation
from
laboratory
animal
species
to
humans
(
the
interspecies
UF)
and
for
potential
variations
in
sensitivity
among
members
of
the
human
population
(
the
intraspecies
UF).
Additional
uncertainty
factors
may
be
applied
to
the
NOAEL
to
address
the
comprehensiveness
and
quality
of
the
database
available
(
i.
e.,
database
UFs).
The
tabulations
of
RfDs
includes
the
species
and
study
used
for
selection
of
an
RfD,
the
NOAEL
and
LOAEL
from
the
key
study,
a
description
of
the
endpoint
used
to
establish
an
RfD,
as
well
as
other
pertinent
information
(
e.
g.,
uncertainty
factors
applied
to
the
NOAEL
to
establish
an
RfD
and
the
exposure
duration
and
relevant
population
to
which
the
RfD
should
be
applied
for
a
risk
assessment).

The
current
retrospective
analysis
began
with
a
review
of
an
internal
data
base
of
RfDs
established
by
the
Health
Effects
Division,
Office
of
Pesticide
Programs
through
October
2004.
The
species
identified
in
this
data
base
used
to
derive
304
chronic
RfDs
was
considered
as
the
initial
source
of
information.
Of
the
304
chronic
RfDs,
116
(
38%)
were
based
on
data
from
a
dog
study.
The
data
base
on
these
116
pesticides
was
subjected
to
an
initial
analysis
to
determine
whether
the
available
data
were
sufficient
to
compare
the
results
of
>
1
year
dog
studies
with
dog
studies
of
shorter
duration.
Final
selection
of
pesticides
to
be
included
in
the
retrospective
analysis
was
made
after
considering
the
following
criteria:
(
1)
availability
of
a
dog
study
with
a
duration
of
>
1
year
and
a
dog
study
with
a
duration
of
13­
weeks
or
(
2)
availability
of
results
from
a
dog
study
of
>
1year
duration
that
included
clinical
or
hematology
measurements
at
13­
weeks
or
less.
New
pesticides
not
yet
registered
or
pesticides
that
have
had
their
registrations
cancelled
were
not
included
in
this
analysis.
Data
Evaluation
Reports
(
DER's)
and
reports
of
the
Hazard
Identification,
Assessment,
and
Review
Committee
(
HIARC)
were
evaluated
for
additional
information
on
these
inclusion
factors
and
for
additional
details
on
dose­
response
and
effects
data.
1
risk
assessment
and
rationale
to
support
them
as
well
as
the
overall
toxicity
profile
and
hazard
characterization
for
the
chemical).

Page
8
of
46
After
consideration
of
these
factors
for
inclusion
of
a
pesticide
in
the
retrospective
analysis,
EPA
identified
77
pesticides
for
inclusion
in
this
retrospective
analysis.
42
pesticides
were
identified
as
being
amenable
to
comparisons
of
results
from
1
year
or
longer
and
dog
studies
of
13­
weeks
or
less
duration.
An
additional
35
pesticides
for
which
no
13­
week
studies
are
available
but
shorter­
term
and
interim
term
clinical
chemistry
or
hematologic
measurements
are
available
were
also
included
for
comparison
with
terminal
data
from
chronic
studies.
For
most
of
these
35
pesticides,
no
interim
histopathologic
data
are
available.
In
these
cases,
comparisons
of
LOAELs
were
confined
to
effects
on
hematologic
or
clinical
chemistry
parameters.
Also,
for
those
chemicals
that
are
inhibitors
of
cholinesterase
activity,
the
percentage
decreases
in
brain
cholinesterase
activity
are
not
provided
because
brain
cholinesterase
activity
cannot
be
measured
at
interim
time
points.

Results
of
studies
with
dogs
provide
data
that
are
used
for
hazard
identification
as
well
as
hazard
characterization.
Consideration
is
given
to
effects
across
all
doselevels
that
may
be
relevant
to
the
uncertainty
factors
applied
to
a
NOAEL
during
the
derivation
of
a
RfD
and
that
are
in
addition
to
the
standard
interspecies
and
intraspecies
uncertainty
factors.
The
rationale
for
application
of
additional
uncertainty
factors
to
the
NOAEL
derived
from
a
chronic
dog
study
was
also
evaluated,
in
order
to
ascertain
whether
additional
findings
observed
in
a
chronic
dog
study
were
the
sole
bases
for
applying
an
additional
uncertainty
factor.

3.
Results
Table
A1
(
in
Appendix)
shows
the
NOAELs
and
LOAELs
from
42
pesticides
for
which
long­
term
and
13­
week
studies
were
available.
For
23
of
these
(
bolded
in
Table
A1,
in
Appendix),
NOAELs
and
LOAELs
were
comparable
(
i.
e.,
no
more
than
>
1.5­
fold
differences)
at
the
13­
week
and
1­
2
year
time
points.
For
all
35
pesticides
for
which
13­
week
studies
were
not
available,
the
same
NOAELs
and
LOAELs
were
found
at
13­
weeks
(
or
less)
in
1­
year
studies
and
at
1­
year
(
Table
A2,
in
Appendix).
Thus,
58/
77
(
75%)
of
the
dog
studies
evaluated
had
comparable
NOAELs/
LOAELs
at
both
timepoints.
The
initial
evaluation
in
Table
A1,
in
the
Appendix,
indicated
that
19
of
the
77
pesticides
where
chronic
RfDs
were
based
on
a
dog
study
have
NOAELs
or
LOAELs
in
13­
week
studies
higher
(
>
1.5­
fold)
than
NOAELs
or
LOAELs
established
from
chronic
dog
studies.
Because
the
different
NOAELs
or
LOAELs
in
the
chronic
and
13­
week
studies
of
these
19
pesticides
may
be
associated
with
differences
in
the
treatment
doses
selected
in
the
chronic
and
13­
week
studies,
additional
analyses
using
dose­
response
data
were
performed
on
results
of
studies
on
these
pesticides.

Table
A3
(
in
Appendix)
presents
dose­
response
data
for
the
19
pesticides
and
comments
regarding
comparisons
of
the
results
of
dose­
response
data
from
chronic
dogs
studies
and
13­
week
or
shorter
dog
studies
or
from
interim
results
from
1­
year
dog
studies.
The
analysis
of
the
dose­
effect
data
indicated
that
for
11
of
the
19
Page
9
of
46
pesticides,
it
was
likely
that
comparable
NOAELs/
LOAELs
would
be
identified
if
these
pesticides
were
evaluated
in
well
conducted
13­
week
and
chronic
dog
studies.
The
observed
differences
in
NOAELs
or
LOAELs
between
13­
week
and
chronic
studies
for
these
11
pesticides
were
judged
to
be
associated
with
differences
in
dose
selection
and
dose
spacing,
inter­
experimental
variability
(
interim
data
in
the
chronic
study
indicates
the
same
NOAEL/
LOAEL
should
be
observed
in
a
13­
week
study)
or
sensitivity
of
the
study
(
i.
e.,
the
effects
were
of
low
incidence
or
magnitude
and
the
power
of
the
dog
studies
were
limited
because
of
the
use
of
4
dogs/
sex/
dose).

Table
1,
below,
provides
a
summary
of
effects
data
and
further
evaluation
of
8
of
the
remaining
19
pesticides
for
which
a
1­
year
dog
study
appeared
to
be
the
critical
study.
The
lack
of
sufficient
clinical
chemistry,
hematologic,
and
histopatholgy
data
on
Fosetyl
Al
limits
meaningful
comparisons
of
the
results
of
the
13­
week
and
chronic
dog
studies.
A
study
performed
on
2
of
the
8
pesticides
with
rats
would
provide
NOAELs/
LOAELs
comparable
to
the
NOAELs/
LOAELs
identified
in
the
chronic
dog
study
(
Cypermethrin
and
Diflufenzopyr).
In
the
13­
week
study
for
2
additional
pesticides,
there
is
a
lack
of
detection
of
effects
in
the
13­
week
study
that
would
be
expected
to
occur
early
on
(
Triazamate
­
cholinesterase
inhibition;
Ethylene
thiourea
­
effects
on
thyroid
hormones,
both
effects
that
normally
are
observed
at
<
13­
weeks),
which
suggests
that
the
finding
of
different
NOAELs/
LOAELs
is
not
related
to
the
different
duration
of
the
13­
week
and
chronic
studies
but
to
a
lack
of
sensitivity
of
the
study.
Further,
application
of
an
additional
uncertainty
factor
to
the
point
of
departure
for
the
13­
week
study
with
Triazamate,
for
lack
of
a
NOAEL,
would
yield
a
point
of
departure
as
protective
as
the
1­
year
dog
study.

Thus,
there
are
only
3
pesticides
(
Etoxazole,
Hexazinone,
and
Tebuconazole)
where
there
are
indications
that
a
chronic
dog
study,
and
not
a
13­
week
dog
study,
would
result
in
the
selection
of
a
lower
NOAEL
for
the
derivation
of
an
RfD.
Overall,
the
present
analysis
indicates
that
a
13­
week
dog
study
would
be
adequate
for
identification
of
a
NOAEL
that
would
be
similar
to
that
established
from
a
chronic
dog
study
with
the
possible
exception
of
3
of
the
77
pesticides
evaluated.
Page
10
of
46
Table
1.
Pesticides
with
lower
NOAELs
in
>
1year
dog
studies
than
in
13­
week
dog
studies.

Chemical
Differences
in
NOAELs
and
LOAELs
(
13­
week
study
versus
1­
year
study)
Primary
basis
for
selection
of
1­
year
study
Comments
Cypermethrin
4X
and
2X
At
the
LOAEL,
tremors
observed
at
low
incidence
Low
incidence
of
effects
at
LOAEL
in
1­
year
study
and
observation
of
effects
in
1
male
at
NOAEL
in
13­
week
study,
although
considered
transitory,

suggests
sample
size
(
sensitivity)
of
the
study
may
account
for
selection
of
different
NOAELs
and
LOAELs
In
the
absence
of
the
1­
year
study,
a
90­
day
rat
neurotoxicity
study
would
be
used
for
a
chronic
risk
assessment.
An
additional
3X
uncertainty
factor
would
currently
be
applied
to
the
rat
study
to
account
for
lack
of
a
chronic
study.
In
the
rat
90­
day
neurotoxicity
study,
decreased
motor
activity,
increased
foot
splay,
and
decreased
body
weights
were
observed
at
the
LOAEL
of
26.3
mg/
kg/
day;
the
NOAEL
for
the
study
is
5
mg/
kg/
day;
these
NOAELs/
LOAELs
are
not
biologically
significantly
different
than
the
NOAELs/
LOAELs
reported
for
the
1­
year
dog
study
(
6.0/
18.1)

Diflufenzopyr
2.2X
and
1.34X
Effects
on
hematopoietic
system
of
higher
incidence
in
1
year
study
Increased
incidences
of
effects
at
the
LOAEL
in
1
year
study
compared
to
incidences
in
13
wk
study.

The
other
most
appropriate
study
in
the
data
base
is
a
rat
reproduction
study
with
a
NOAEL
of
27.3
and
a
LOAEL
of
113.1
based
on
reduced
body
weight
gain
and
increased
seminal
vesicle
weights
(
1­
year
dog
study
NOAEL,
26
and
LOAEL
299).
Thus,
use
of
the
rat
reproduction
study
to
derive
a
chronic
RfD
would
be
as
protective
as
the
1­
year
dog
study.

Ethylene
thiourea
33.4X
and
33.2X
Thyroid
effects
(
hypertrophy
and
decreased
hormone
levels)
Dose
spacing
differences
between
two
studies
make
comparisons
difficult.

Because
decreases
in
thyroid
hormones
are
typically
seen
early
(
as
early
as
14­
days)
unclear
why
13­
week
study
would
not
be
sufficient
for
selection
of
a
NOAEL/
LOAEL.

No
acceptable
2­
year
rat
study
available;
no
other
study
with
NOAELs/
LOAELs
comparable
or
lower
than
that
from
1­
year
dog
study
Etoxazole
1X
and
2.3X
Hepatocellular
toxicity
It
is
likely
that
actual
NOAEL
would
be
lower
in
1­
year
study
than
in
13­
week
study
based
on
increased
incidence
of
liver
toxicity
or
increases
in
liver
enzymes.
However,
if
the
13­
week
dog
study
was
used
for
the
chronic
RfD,

NOAEL
would
be
the
same
as
in
the
1­
year
dog
study.

The
most
sensitive
study
in
the
data
base
other
than
the
chronic
dog
study
is
the
13­
week
dog
study.
Chemical
Differences
in
NOAELs
and
LOAELs
(
13­
week
study
versus
1­
year
study)
Primary
basis
for
selection
of
1­
year
study
Comments
Page
11
of
46
Fosetyl
Al
1.1X
and
2.6X
Focal/
trace
spermatocytic
and/
or
spermatidic
giant
cells
Limited
details
on
clinical
chemistry,
hematology,
or
histopathology
limit
meaningful
comparions
with
13­
week
study.

In
a
2­
year
rat
study,
the
only
effect
reported
(
non­
neoplastic)
was
an
increase
in
urinary
protein
at
a
LOAEL
of
1500
mg/
kg/
day;
the
NOAEL
is
400
mg/
kg/
day
versus
NOAEL/
LOAEL
250/
500
in
the
1­
year
dog
study.
The
2­

year
rat
study
is
the
only
other
study
in
the
data
base
that
would
be
suitable
for
derivation
of
an
RfD.

Hexazinone
5X
and
3.3X
Hepatocellular
toxicity
Effects
on
ALP
at
37.6
mg/
kg/
day
in
the
1­
year
study
greater
(
males)
or
comparable
(
females)
to
the
effects
on
ALP
at
122.5
mg/
kg/
day
in
the
13
week
study
(
NOAEL
25.9).
1
year
study
provides
data
that
would
lead
to
selection
of
a
lower
NOAEL
(
5.0
mg/
kg/
day)
for
derivation
of
a
chronic
RfD
2­
year
chronic
study
performed
with
rats
has
a
NOAEL
of
10.2
versus
a
NOAEL
of
5.0
in
the
chronic
dog
study.
The
LOAEL
in
the
chronic
rat
study
of
53.3
is
based
on
decreased
body
weights
and
food
efficiency;
the
LOAELs
in
the
rat
and
dog
studies
are
comparable
(
53.3
and
37.6,
respectively),
but
the
effects
were
more
extensive
and
severe
in
the
1­
year
dog
study.
Thus,
use
of
the
chronic
rat
study
would
not
provide
as
protective
a
point
of
departure
for
derivation
of
a
chronic
RfD
Tebuconazole
2.6X
and
8.8X
Adrenal
toxicity
Higher
incidence
of
adrenal
hypertrophy
at
4.4
mg/
kg/
day
(
LOAEL)
in
the
1­

year
study
than
at
38.8
mg/
kg/
day
(
LOAEL)
in
the
13­
week
study.
The
NOAEL
in
the
1­
year
study
is
2.94
mg/
kg/
day.

In
a
2­
year
rat
study,
the
NOAEL
is
7.4
mg/
kg/
day
(
lowest
dose
tested)
and
the
LOAEL
is
22.8
mg/
kg/
day
based
on
body
weight
depression,
decreased
hemoglobin,
hematocrit,
MCV,
and
MCHC,
and
increased
liver
enzymes
in
females;
dose­
related
depressions
in
female
adrenal
weights
were
noted
at
all
dose
levels
in
association
with
dose­
related
decreases
in
adrenal
cortical
degeneration.

The
rat
chronic
study
would
yield
significantly
higher
values
for
the
NOAEL
(>
2­
fold)
and
LOAEL
(>
5­
fold)
if
used
to
establish
a
chronic
RfD.
No
other
study
in
the
data
base
has
a
lower
NOAEL/
LOAEL
than
the
chronic
rat
study.

Thus,
the
1­
year
dog
study
is
more
appropriate
for
selection
of
a
chronic
RfD.
Chemical
Differences
in
NOAELs
and
LOAELs
(
13­
week
study
versus
1­
year
study)
Primary
basis
for
selection
of
1­
year
study
Comments
Page
12
of
46
Triazamate
No
NOAEL
in
13­
week
study/
1.3X
Brain
and
plasma
cholinesterase
inhibition
No
inhibition
of
the
more
critical
effect
(
brain
cholinesterase
inhibition)
in
the
13­
week
study.
However,
use
of
the
13­
week
dog
study
with
the
application
of
an
additional
uncertainty
factor
(
for
lack
of
a
NOAEL)
would
yield
a
lower
point
of
departure
than
the
chronic
dog
study
(
0.01
versus
0.164
mg/
kg/
day).

The
NOAEL/
LOAEL
in
a
2­
year
rat
study
is
0.45/
11.5
mg/
kg/
day
based
on
plasma
cholinesterase
inhibition
(
31­
65%)
and
RBC
cholinesterase
inhibition
(
16­
29%).
Thus,
2­
year
rat
study
would
not
provide
as
sensitive
an
endpoint
as
the
1­
year
or
13­
week
dog
study
for
establishing
a
chronic
RfD.
Page
13
of
46
The
identification
of
new
effects
observed
in
1­
or
2­
year
dog
studies
that
were
not
seen
in
13­
week
dog
studies
or
in
chronic
studies
performed
with
rats
or
mice
was
not
undertaken
in
the
current
retrospective
analysis
because
this
aspect
of
toxicity
studies
in
dogs
was
extensively
evaluated
previously
(
Spielmann
and
Gerbracht,
2001).
However,
consideration
of
the
severity
of
effects
noted
at
any
dose
in
a
rodent
or
non­
rodent
(
dog)
study
may
also
bear
on
the
uncertainty
factors
that
are
applied
to
a
NOAEL
prior
to
assignment
of
a
chronic
RfD.
Thus,
although
the
focus
of
this
retrospective
analysis
was
primarily
on
comparing
NOAELs
and
LOAELs
from
the
results
of
13­
week
and
chronic
dog
studies,
an
additional
analysis
was
undertaken
to
determine
whether
the
characterization
of
effects
noted
in
a
chronic
dog
study
would
lead
to
the
application
of
an
additional
uncertainty
factor
during
the
derivation
of
a
RfD.
Among
the
77
chronic
dog
studies
evaluated,
extra
uncertainty
factors
have
been
applied
to
11
pesticides
during
the
derivation
of
RfDs.
Table
2
(
below)
provides
information
on
the
magnitude
of
the
uncertainty
factors
applied
and
comments
regarding
the
bases
for
application
of
additional
factors
and
whether,
in
the
absence
of
a
chronic
dog
study,
an
additional
uncertainty
factor
would
still
have
been
applied
when
deriving
an
RfD.
As
shown
in
Table
2,
in
no
case
was
an
additional
uncertainty
factor
applied
based
on
effects
seen
in
a
chronic
dog
study
that
was
not
seen
in
other
rodent
or
13­
week
dog
studies.
Thus,
it
is
apparent
from
the
information
provided
in
Table
2
that
the
presence
or
absence
of
the
chronic
dog
study
would
not
affect
uncertainty
factors.
Note
that
the
extra
uncertainty
factors
applied
to
carbofuran
and
carbaryl
reflect
the
absence
of
the
establishment
of
a
NOAEL
in
the
chronic
dog
study,
which
is
a
function
of
dose
selection
and
not
identification
of
additional
toxicities
of
concern.
Page
14
of
46
Table
2.
Chemicals
with
Data
Base
Uncertainty
Factors
(
UFs)
Applied
to
Derivations
of
RfDs
Chemical
Uncertainty
Factor
Comment
Amitraz
1000
Extra
10X
applied
for
data
gap
for
lack
of
Developmental
Neurotoxicity
Toxicity
study;
concern
raised
in
13
week
dog
study
for
signs
of
CNS
depression
observed
in
13­
week
dog
study
and
in
in
rat
and
rabbit
studies;

Bifenthrin
300
Extra
3X
applied
for
lack
of
Developmental
Neurotoxicity
study;
neurotoxicity
also
observed
in
13­
week
dog
study
(
tremors)
and
in
acute,
subchronic
and
reproductive
studies
performed
with
rats
Ethylene
thiourea
1000
Extra
10X
applied
for
lack
of
comparative
thyroid
hormone
study
in
immature
animals;
severe
thyroid
hypertrophy
and
reduced
T3
and
T4
also
observed
in
13­
week
study
Mepiquat
chloride
300
Extra
3X
applied
for
lack
of
Developmental
Neurotoxicity
study;
tonic/
clonic
convulsions
also
seen
in
13­
week
study
Carbaryl
300
Extra
3X
applied
for
lack
of
a
NOAEL
Carbofuran
1000
Extra
10X
applied
for
lack
of
NOAEL
and
for
data
gap
for
reproduction
study
Cypermethrin
1000
Extra
10X
applied
for
lack
of
Developmental
Neurotoxicity
study;
neurotoxicity
also
observed
in
acute
and
subchronic
neurotoxicity
studies;
tremors
and
irregular
gait
observed
at
11
weeks
in
1­
year
dog
study
at
33.9
mg/
kg/
day,
which
is
about
2X
the
LOAEL
Fenpropathrin
1000
Extra
10X
applied
for
lack
Developmental
Neurotoxicity
study;
tremors
seen
over
entire
duration
of
1­
year
dog
study
and
signs
of
neurotoxicity
also
observed
in
studies
performed
with
rats,
mice,
and
rabbits
Halosulfuron
methyl
300
Extra
3X
applied
for
lack
of
Developmental
Neurotoxicity
study;
study
required
because
of
effects
observed
in
a
developmental
toxicity
study,
not
in
the
dog
study
Parathion
300
Extra
3X
applied
for
lack
of
a
NOAEL
Pentachlorophenol
300
Extra
3X
applied
for
lack
of
a
NOAEL
Page
15
of
46
4.
Discussion
The
purpose
of
the
current
retrospective
analysis
of
the
results
of
subchronic
and
chronic
studies
conducted
with
dogs
was
to
ascertain
whether
data
obtained
from
13­
week
dog
studies
would
be
adequate,
in
the
absence
of
a
chronic
dog
study,
for
identifying
NOAELs
and
LOAELs
that
would
be
used
to
derive
chronic
reference
doses
(
RfDs)
in
support
of
pesticide
registrations.
Given
that
RfDs
are
used
for
risk
assessments
on
environmental
chemicals
that
are
intended
to
protect
human
health,
this
retrospective
analysis
focused
on
a
comparison
of
NOAELs
and
LOAELs
that
were
identified
from
subchronic
and
chronic
dog
studies
for
each
of
the
77
pesticides.
A
second
objective
of
this
retrospective
analysis
was
to
evaluate
whether
effects
found
at
any
dose
in
a
chronic
dog
study
would
impact
the
uncertainty
factors
that
would
be
applied
to
a
NOAEL
before
deriving
a
chronic
RfD.

NOAELs
or
LOAELs
established
from
1­
year
dog
studies
were
found
to
be
lower
than
NOAELs
or
LOAELs
established
from
13­
week
or
6­
month
studies
for
19
of
77
pesticides
for
which
dog
studies
were
used
to
derive
chronic
RfDs
by
the
Health
Effects
Division,
Office
of
Pesticide
Programs.
However,
a
comparison
of
dose­
effect
data,
evaluations
of
interim
data
from
1­
year
studies,
or
data
from
shorter
term
studies
indicates
that
for
only
3
of
the
19
pesticides
do
the
data
raise
the
issue
that
the
chronic
dog
study
would
lead
to
a
lower
RfD
than
the
toxicity
data
base
would
lead
to
without
the
availability
of
that
study.

This
current
analysis
also
evaluated
and
compared
the
effects
of
a
13­
week
and
a
1­
year
dog
study
on
the
characterization
of
effects
at
any
dose
that
might
lead
to
the
application
of
additional
uncertainty
factors
that
would
be
incorporated
in
the
derivation
of
an
RfD.
In
no
case
was
an
effect
identified
in
a
chronic
dog
study
that
would
not
be
seen
in
a
shorter
duration
dog
study
or
in
rodent
studies
and
that
would
also
support
the
application
of
additional
uncertainty
factors.
Thus,
this
retrospective
analysis
of
short­
and
long­
term
dog
studies
indicates
that
reliance
on
dog
studies
with
a
13­
week
duration
is
not
likely
to
alter
EPA's
estimates
of
chronic
RfDs.

The
conclusions
drawn
from
this
analysis
of
EPA's
pesticide
data
base
on
dog
studies
regarding
the
adequacy
of
NOAEL's
established
from
13­
week
dog
studies
are
consistent
with
the
findings
reported
by
Spielmann
and
Gerbracht
(
2001).
They
compared
subchronic
and
chronic
dog
studies
with
172
pesticides
and
found
no
significant
differences
in
the
LOAELs
between
the
two
study
types
(
correlation
r
=
0.78­
0.84).
Their
initial
analyses
revealed
organ
specific
effects
that
were
observed
in
chronic
dog
studies
but
not
in
subchronic
dog
studies
(
30
of
50
fungicides,
25
of
44
herbicides,
17
of
38
insecticides,
and
10
of
16
other
pesticides).
Further
analyses
indicated
that
in
only
7
of
141
studies
with
dogs
there
was
significant,
additional
information
provided
by
chronic
dog
studies
that
was
not
provided
in
13­
week
dog
studies
or
in
studies
with
rats
or
mice.
These
authors,
who
conducted
an
in­
depth
review
of
studies
on
the
7
pesticides,
found
that
differences
in
subchronic
and
chronic
studies
with
these
pesticides
could
be
accounted
for
by
a
number
of
factors
(
e.
g.,
differences
in
study
design
and
interpretation
of
results,
and
differences
in
the
extent
of
Page
16
of
46
histopathological
examinations
in
subchronic
and
chronic
studies).
They
concluded
that
extension
of
a
dog
study
beyond
13
weeks
does
not
provide
additional,
essential
information.

There
have
been
a
number
of
papers
published
on
the
duration
of
dog
studies
for
pharmaceuticals
(
Lumley
et
al.,
1992;
Contrera
et
al
1993;
Parkinson
et
al.,
1995;
DeGeorge
et
al.,
1999).
These
papers
focused
on
retrospective
analyses
of
the
results
of
6
and
12
month
studies.
An
examination
of
these
papers
on
pharmaceuticals
is
supportive
of
the
overall
conclusion
that
long
term
toxicity
studies
in
the
dog
rarely
provide
either
qualitatively
new
toxicological
information
or
quantitative
information
not
already
gained
from
other
required
studies,
i.
e.
a
short
term
study
in
the
dog
in
conjunction
with
short
and
long
term
studies
in
the
rat
but
there
are
important
exceptions.
For
example,
an
International
Conference
on
Harmonization
workgroup,
based
on
a
retrospective
analyses
of
dog
studies
performed
with
pharmaceuticals,
recommended
a
9­
month
duration
for
non­
rodent
(
dog)
toxicity
studies
(
DeGeorge
et
al.,
1999).
This
recommendation
was
based
on
the
finding
that
in
11
of
17
case
studies,
data
from
studies
of
9­
12
months
were
needed
in
order
to
identify
additional
effects
(
e.
g.,
death,
morbidity,
kidney
toxicity,
gingival
hyperplasia,
gastric
irritation)
not
seen
at
6­
months
or
the
9­
to
12­
month
studies
indicated
a
shift
in
the
dose­
response
for
toxic
effects
(
whether
or
not
margins
of
safety
would
be
different
using
the
results
6­
month
and
1­
year
dog
studies
was
not
specifically
addressed
but
a
shift
in
the
doseresponse
was
noted
for
2
of
the
17
case
studies).
Also,
Contrera
et
al.
(
1993)
reported
an
exacerbation
and/
or
extension
of
6
month
observations
in
12­
month
observations
for
8
dog
studies
conducted
with
30
pharmaceuticals;
5
of
the
30
case
studies
were
judged
to
provide
significant
new
information
that
supported
extension
of
dog
studies
from
6
to
12
months;
1
of
the
5
and
1
additional
case
study
showed
that
extension
of
the
dog
study
beyond
6­
months
resulted
in
a
lowering
of
the
margin
of
safety.
Caution
should
be
exercised,
however,
before
comparing
results
of
these
analysis
of
toxicity
tests
performed
in
dogs
with
pharmaceuticals
with
results
of
dog
studies
conducted
with
pesticides.
In
the
case
of
pharmaceuticals,
it
is
important
to
characterize
all
possible
adverse
effects
that
may
occur
in
humans
treated
with
pharmacological
doses.
Thus,
the
recommendations
to
extend
dog
studies
on
pharmaceuticals
beyond
6­
months
appears
to
be
based
largely
on
additional
effects
that
were
observed
at
any
dose
in
chronic
dog
studies
but
not
in
6­
or
9­
month
dog
studies;
there
appear
to
be
few
examples
in
the
literature
reports
where
"
new
findings"
affected
the
margins
of
safety.
In
contrast,
results
of
dog
studies
with
pesticides
are
used
primarily
to
identify
dose­
levels
below
which
no
adverse
health
effects
are
likely
to
occur
in
humans
exposed
to
environmental
levels
of
a
pesticide.
Although
additional
effects
observed
above
a
LOAEL
may
support
the
application
of
additional
uncertainty
factors
when
RfDs
are
derived,
the
current
retrospective
analysis
did
not
identify
a
single
case
where
only
the
results
from
a
dog
study
would
lead
to
the
application
of
an
additional
uncertainty
factor
to
a
NOAEL.
Thus,
the
results
of
this
current
retrospective
analysis
of
studies
on
pesticides,
when
considered
with
the
results
of
the
analysis
by
Spielmann
and
Gerbracht
(
2001),
show,
with
few
exceptions,
that
a
13­
week
dog
study
is
as
adequate
as
a
1­
year
dog
study
for
identification
of
a
NOAEL.
Page
17
of
46
Acknowledgements
We
thank
Doug
Wolf,
National
Health
and
Environmental
Effects
Research
Laboratory,
Nancy
McCarroll,
Office
of
Pesticde
Programs,
U.
S.
Environmental
Protection
Agency,
David
Lai,
Office
of
Pollution
Prevention
and
Toxics,
U.
S.
Environmental
Protection
Agency
and
William
Sette,
Office
of
the
Science
Advisor,
Office
of
Research
and
Development,
U.
S.
Environmental
Protection
Agency
for
their
critical
reviews
of
this
manuscript.
Page
18
of
46
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L.
M.,
and
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(
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Page
19
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46
Appendix
Page
20
of
46
Table
A1.
NOAELs
&
LOAELs
(
mg/
kg/
day)
in
13­
Week
and
1­
or
2­
Year
Dog
Studies
(
42
Chemicals)

Chemical
Duration/
Route
NOAEL
LOAEL
Effects
seen
at
LOAEL
Azafenidan
1­
yr/
diet
0.3
0.87
Hepatocellular
hypertrophy,
multiple
nuclei,
pigment
in
liver
cell,
and
increased
ALP
13­
wk/
diet
0.3
2.0
Hepatocellular
hypertrophy,
increased
ALT
&
ALP
Amitraz
2­
yr/
capsule
0.25
1.0
Increased
blood
sugar
concentration;
slight
hypothermia
13­
wk/
capsule
0.25
1.0
CNS
depression,
hypothermia,
increased
blood
sugar,
neutrophilia
in
bone
marrow,
and
hyperplasia
of
zona
glomerulosa
with
decrease
in
zona
fasiculata
and
reticularis
Baythroid
(
cyfluthrin)
1­
yr/
diet
2.43
10.64
Clinical
signs,
abnormal
gait,
abnormal
postural
reactions
13­
wk/
diet
2.36
13.9
Gait
abnormalities,
vomiting,
decreased
body
weight
gain
Bensulide
1­
yr/
diet
0.5
4
Decreased
body
weight
gain,
brain
and
plasma
cholinesterase
inhibition
13­
wk/
diet
<
1
1
Increased
absolute
liver
weights,
plasma
cholinesterase
inhibition
Bifenazate
1­
yr/
diet
1.01
8.95
Increased
platelets,
leucocytes,
MCV,
reticulocytes,
segmented
neutrophils;

hyperplasia
in
femur,
rib,
and
sternum;
pigment
deposits
in
liver
and
kidney
13­
wk/
diet
0.9
10.4
Decreased
hematocrit,
hemoglobin,
and
RBC's;
increased
MCV,
MCH,
reticulocytes,

and
platelets;
increased
bilirubin;
pigment
deposits
in
Kuppfer
cells
Bifenthrin
1
yr/
capsule
1.3
2.7
Tremors
13
wk/
capsule
2.21
4.42
Tremors
Bispyibac
sodium
1­
yr/
capsule
10
100
Bile
duct
hyperplasia,
hepatocellular
granulation
13­
wk/
capsule
100
600
Clinical
signs,
bile
duct
hyperplasia
(
2/
4
males
versus
0/
4
controls
and
3/
4
females
versus
2/
4
controls)

28­
day/
capsule
<
100
100
Bile
duct
hyperplasia
observed
(
2/
2
males
and
0/
2
females)
(
same
dose­
level
as
1
year
study)

Bromoxynil
phenol
1­
yr/
capsule
1.5
7.5
Decreased
body
weight
gain
13­
wk/
capsule
1.0
5.0
Decreased
body
weight
gain,
liquid
feces
Chemical
Duration/
Route
NOAEL
LOAEL
Effects
seen
at
LOAEL
Page
21
of
46
Cadusafos
1­
yr/
capsule
0.001
0.005
Plasma
cholinesterase
inhibition
13­
wk/
capsule
<
0.01
0.01
Plasma
cholinesterase
inhibition
Chlorethoxyfos
1­
yr/
diet
0.06
0.62
Plasma,
brain,
and
RBC
cholinesterase
inhibition
13­
wk/
diet
0.02
0.19
Plasma
and
brain
cholinesterase
inhibition
Clethodim
1­
yr/
capsule
1.0
75
Increased
absolute
and
relative
liver
weights,
changes
in
hematology
and
clinical
chemistry
(
hematology
and
clinical
chemistry
changes
consistent
only
at
300
mg/
kg/
day
13­
wk/
capsule
25
75
Increased
absolute
and
relative
liver
weights(
Note:
same
LOAEL
as
1­
year)

Cypermethrin
1­
yr/
diet
6.0
18.1
Gait
abnormalities,
tremors,
death
13­
wk/
diet
26.4
34.3
Tremors
and
decreased
body
weights
Dicloran
2­
yr/
diet
2.5
75
Reduced
body
weight
gain,
increased
liver,
kidney,
and
spleen
weights,
changes
in
hematologic
and
clinical
chemistry
parameters,
histopathology
in
the
liver
13­
wk/
diet
2.5
75
Reduced
body
weight
gain,
increased
liver,
kidney
and
spleen
weights,
changes
in
hematologic
and
clinical
chemistry
parameters,
histopathology
in
the
liver
Diflubenzuron
1­
yr/
capsule
2.0
10.0
Increased
methemoglogin
and
sulfhemoglobin
13­
wk/
dietary
2.0
6.24
Increased
methemoglobin
Diflufenzopyr
1­
yr/
diet
26
299
Bone
marrow
hyperplasia,
hemosiderin
deposits
in
liver,
kidney,
and
spleen,

reticulocytosis
13­
wk/
diet
58
403
Erythroid
hyperplasia
in
bone,
extramedullary
hematopoiesis
in
liver
Ethylene
thiourea
1­
yr/
diet
0.18
1.99
Thyroid
follicular
dilation
and
hypertrophy
13­
wk/
diet
6.02
66.23
Mortality,
thyroid
hyperplasia,
increased
thyroid
weights,
and
reduced
T3
and
T4
Etoxazole
1­
year/
diet
4.62
23.5
Increased
ALP
and
liver
weights;
centrolobular
hepatocellular
swelling
13­
wk/
diet
5.33
53.7
Vomiting
and
mucous
stools;
centrolobular
hepatocellur
swelling;
acinar
cell
atrophy
in
the
prostate;
increased
ALP,
triglycerides,
albumin
and
globulin
Fenhexamid
1­
yr/
diet
17
124
Decreased
RBC's
and
hematocrit,
increased
Heinz
bodies,
increased
adrenal
weights
13­
wk/
diet
34
239
Increased
Heinz
bodies,
decreased
RBC's
and
hematocrit
Chemical
Duration/
Route
NOAEL
LOAEL
Effects
seen
at
LOAEL
Page
22
of
46
Flucarbazone
1­
yr/
diet
35.9
183
Decreased
body
weight
gain,
increased
N­
demethylase,
decreased
T4
hormone
13­
wk/
diet
33.8
162
Decreased
T4,
increased
thyroxine
binding,
microsomal
enzyme
induction,

histopathology
in
liver
and
stomach
Fosetyl
Al
2­
yr/
diet
250
(
10,000
ppm)
500
(
20,000
ppm)
Degeneration
of
testes
13­
wk/
diet
274
(
10,000
ppm)
1309
(
50,000
ppm)
Decreased
serum
potassium
Hexaconazole
1­
yr/
capsule
2.0
10.0
Fatty
liver
and
increased
liver
weights
13­
wk/
capsule
5.0
25.0
Decreased
cholesterol
and
triglycerides,
fatty
liver
(
differences
in
NOAELs
between
1­

year
and
13­
week
studies
may
be
accounted
for
by
differences
in
dose
selection;
at
90
days
in
1­
year
study
liver
toxicity
indicated
by
increased
ALP
occurred
at
10
mg/
kg)

Hexazinone
1­
yr/
diet
5.0
37.6
Increased
ALP,
(
increased
AST
decreased
albumin,
increased
globulin
only
seen
at
highest
dose,
167
mg/
kg/
day)

13­
wk/
diet
26
123
Decreased
body
weight
gains
and
increased
ALP
Iodosulfuran
1­
yr/
diet
7.25
43.7
Gross
and
histopatholgy
in
hemopoietic
system
13­
wk/
diet
8.1
49
Hemopoietic
effects
in
bone
and
spleen,
clinical
chemistry
and
hemotologic
changes
Isoxadifen
ethyl
1­
yr/
diet
3.3
24.0
Increased
creatinine,
decreased
specific
gravity,
increased
partial
thromboplastin
time,

renal
tubular
vacuolation
13­
wk/
diet
1.2
6.1
Fat
deposits
in
collecting
ducts
of
kidney,
changes
in
hematologic
parameters,

aspermia,
decreased
body
weight
gain
Mepiquat
chloride
1­
yr/
diet
58.4
95.3
1
year­
sedation,
abdominal
and
lateral
positioning,
tonic/
clonic
convulsions
at
170
mg/
kg/
day
(
13­
week
study
used
to
establish
LOAEL)

13­
wk/
diet
32.4
95.3
Body
weight
loss,
abdominal
and
lateral
positioning,
sedation,
tonic/
clonic
convulsions
hematologic
effects
Metolochlor
1­
yr/
diet
9.7
32.7
Decreased
body
weight
gains
13­
wk/
diet
9.7
29.6
Decreased
body
weight
gains
Paraquat
1
yr/
diet
0.45
0.93
Chronic
pneumonitis
13wk/
diet
0.5
1.5
Increased
lung
weights,
alveolitis,
alveolar
collapse
Chemical
Duration/
Route
NOAEL
LOAEL
Effects
seen
at
LOAEL
Page
23
of
46
Phorate
1­
yr/
capsule
0.05
0.25
RBC
and
brain
cholinesterase
inhibition
105
day/
capsule
0.05
0.25
RBC
cholinesterase
inhibition
Phostebupirim
1­
yr/
diet
0.02
0.13
RBC,
plasma,
and
brain
cholinesterase
inhibition
13­
wk/
diet
0.018
0.15
RBC,
plasma,
and
brain
cholinesterase
inhibition
Prallethrin
1­
yr/
capsule
5.0
10
Increased
cholesterol,
phopholipid,
and
ALP;
subendocardial
red
discoloration
in
the
left
ventricle
of
the
heart
13­
wk/
capsule
3.0
10
Tremors,
mortality,
decreased
albumin/
globulin
ratio,
increased
cholesterol
and
phospholipids
Primisulfuron
methyl
1­
year/
diet
25
250/
125
High
dose
reduced
at
week
10
Decreased
erythrocytes,
hemoglobin,
and
hematocrit;
increased
platelets
(
all
before
week
10);
pale
livers;
hepatocellular
vacuolation;
thyroid
hypeplasia;
high
dose
reduced
at
week
10
because
of
decreases
in
body
weights
13­
wk/
diet
25
250
Decreased
body
weights,
food
consumption,
and
food
efficiency;
decreased
erythrocytes,
hemoglobin,
and
hematocrit;
increased
platelets
and
prothrombin
time;

decreased
thyroid
and
parathyroid
weights;
parafollicular
cell
hyperplasia
Prosulfuron
1­
yr/
diet
1.84
20.2
Decreased
albumin,
decreased
RBCs,,
lipofucsin
accumulation
in
liver
13­
wk/
diet
5.3
57
Decreased
hemoglobin,
hematocrit,
RBC's,
and
albumin;
increased
liver
weights;

hemosiderin
deposits
in
stomach,
spleen,
and
lymph
nodes
Rimsulfuron
1­
yr/
diet
81.8
342.4
Increased
absolute
liver
and
kidney
weights
13­
wk/
diet
9.63
193
Increased
absolute
liver
and
kidney
weights
Spinosad
1­
yr/
diet
2.68
8.22
Increased
aspartate
amino
transferase,
alanine
amino
transferase,
and
triglycerides;

arteritis
and
granular
cell
vacuolation
(
parathyroid)

13­
wk/
diet
4.89
9.73
Vacuolated
cells
in
spleen,
lymph
follicles
of
multiple
tissues,
acinar
cells
of
pancreas,

and
atrophy
of
gastric
mucosa
of
stomach.

Sulfosate
1­
yr/
gavage
10
50
Salivation,
emesis,
and
hydrocephalus
13­
wk/
gavage
10
50
Salivation,
emesis,
hydrocephalus
Tebuconazole
1­
yr/
diet
2.94
4.39
Hypertrophy
of
adrenal
zona
fasciculata
cells
13­
wk/
diet
73.4
351.8
Decreased
body
weights
and
body
weight
gains,
increased
N­
demethylase
activity
Chemical
Duration/
Route
NOAEL
LOAEL
Effects
seen
at
LOAEL
Page
24
of
46
Tebufenozide
1­
yr/
diet
1.8
8.7
Decreased
body
weight
gain
(
males)
bone
marrow
hyperplasia,
spleen
hematopoiesis
and
sinusoidal
engorgement,
increases
in
absolute
liver
weights,
increased
pigment
in
Kupffer
cells,
decreased
RBC's,
hemoglobin,
hematocrit,
increased
Heinz
bodies,

methemoglobin,
MCV
13­
wk/
diet
2.1
20.1
Decreased
hemoglobin,
RBC,
hematocrit
and
elevated
MCV;
increased
Heinz
bodies,

increased
liver
weights,
increased
pigment
in
Kupffer
cells,
hematopoiesis
in
spleen
and
increased
spleen
weights
Thiophanate
methyl
1­
yr/
capsule
8
40
Decreased
T4
levels
in
males
at
6
months;
increased
TSH;
increased
thyroid
weights
in
males;
follicular
cell
hypertrophy
13­
wk/
capsule
<
50
50
Follicular
cell
hypertrophy;
in
females,
decreased
T3
and
T4;
increased
TSH
Tralkoxydim
1­
yr/
capsule
0.5
5.0
Increased
liver
weights,
increased
ALT,
periportal
fatty
changes
13­
wk/
capsule
0.5
5.0
Increased
liver
weights,
decreased
albumin,
triglycerides,
and
total
protein,
increased
N­
demethylase
activity
Triazamate
1­
yr/
diet
0.0164
0.0236
Brain
cholinesterase
inhibition
13­
wk/
diet
<
0.03
0.03
Plasma
cholinesterase
inhibition
(
brain
and
RBC
cholinesterase
not
affected)

Triadimenol
2­
yr/
diet
3.75
15
Increased
ALP
and
N­
demethylase
activity
13­
wk/
diet
<
3.75
3.75
Decreased
body
weight
gain,
increased
ALP
Zoxamide
1­
yr/
diet
48
255
Decreased
body
weight
gain,
increased
liver
and
thyroid
weights,
increased
ALP;
(
at
6
months
in
1­
year
­
increased
ALP
at
255;
ALP
not
measured
at
earlier
time
points)

13­
wk/
diet
55
322
Increased
liver
weights
(
effects
on
liver
weight
in
the
13­
wk.
study
at
the
same
dietary
level
used
in
the
1­
year
study
­
7500
ppm)
Page
25
of
46
Table
A2.
NOAELs
&
LOAELs
from
1­
or
2­
yr
dog
studies
with
interim
data
(
1
day
to
3
months)
(
35
chemicals)

Chemicals
Duration
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
Effects
seen
at
LOAEL
Acetochlor
1
yr
2.0
10
Increased
ALT
(
70%),
GGT
(
at
13
weeks
only),
OCT
(
122%),
and
triglycerides
(
only
at
12
weeks);

decreased
glucose
(
9%)

12
weeks
2.0
10
Increased
ALT
(
32%),
GGT
(
33%),
OCT
(
48%)
and
triglycerides
(
34%);
decreased
glucose
(
11%)

Azinphos
methyl
1
yr
0.15
0.69
Diarrhea,
RBC
cholinesterase
inhibition
(
RBC
cholinesterase
inhibition
observed
at
4
weeks
used
for
RfD)

4
weeks
0.15
0.69
RBC
cholinesterase
inhibition
Bentazon
1
yr
3.1
13.1
Anticoagulation
effects
(
at
week
13)
and
blood
in
feces
(
1/
6
males
at
week
4)

4­
13
weeks
3.1
13.1
Anticoagulation
effects
and
blood
in
feces
Carbaryl
1
yr
<
3.1
3.1
Plasma
(
23%
in
females)
and
brain
cholinesterase
inhibition
5
weeks
1.43
3.83
Plasma
cholinesterase
inhibition
(
22%
in
females)(
5
week
study
used
to
identify
NOAEL)

Carbofuran
1
yr
<
0.25
0.25
Plasma
cholinesterase
inhibition
(
12%
in
males)

3
days
<
0.25
0.25
Plasma
cholinesterase
inhibition
(
18%
in
males)

Chlorpropham
1
yr
5
50
Increased
thyroid
weight
(
95%),
enlarged
irregular
follicles
with
clear
staining
follicles
(
3
males
and
4
females);
no
T4
decrease
at
1­
year
at
50
mg/
kg/
day
but
T4
decreased
43%
at
350
mg/
kg/
day)

14
weeks
5
50
Decreased
T4
(
33%)

28
day
5
50
Histopathology
in
thyroid
(
1/
1
of
each
sex)

Clofentezine
1
yr
1.25
25
Increased
organ
weights,
histopathology
in
liver,
increased
cholesterol
(
33%)
and
triglycerides
(
44%)

4
weeks
1.25
25
Begining
at
4
weeks
in
1
year­
increased
cholesterol
(
34%)
and
triglycerides
(
27%)

Coumaphos
1
yr
0.025
0.775
RBC
(
47%),
plasma
(
76%),
brain
cholinesterase
inhibition
90
days
0.025
0.775
RBC
(
42%)
and
plasma
(
63%)
cholinesterase
inhibition
Cyhalothrin
1
yr
0.1
0.5
Muscle
tremors
&
convulsions
(
2/
6
males
at
week
52)

2
weeks
0.1
0.5
Muscle
tremors/
ataxia
(
1/
6
males
and
1/
6
females
beginning
at
2
days)

Dichlorvos
1
yr
0.05
0.10
RBC
(
53%),
plasma
(
53%),
and
brain
cholinesterase
inhibition
12
days
0.05
0.10
RBC
(
54%)
and
plasma
(
48%)
cholinesterase
inhibition
Chemicals
Duration
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
Effects
seen
at
LOAEL
Page
26
of
46
Dicofol
1
yr
0.12
0.82
Inhibition
of
ACTH
stimulated
release
of
cortisol
(
21%)

13­
weeks
0.12
0.82
Inhibition
of
ACTH
stimulated
release
of
cortisol
(
30%)

Disulfoton
1
yr
0.013
0.094
RBC
(
38%),
brain,
corneal,
and
retinal
cholinesterase
inhibition
13
weeks
0.013
0.094
RBC
(
49%)
and
plasma
cholinesterase
inhibition
Diquat
dibromide
1
yr
0.5
2.5
Cataracts
,
lens
opacity
(
2/
4
females);
decreased
adrenal
and
epididymis
weights
8
weeks
0.5
2.5
Lens
opacity
(
1/
4
females)

Ethion
1
yr
0.05
0.52
Plasma
cholinesterase
inhibition
(
56%)

3­
weeks
0.05
0.52
Plasma
cholinesterase
inhibition
(
53%)

Ethoprop
1­
yr
0.01
0.025
Plasma
cholinesterase
inhibition
(
males,
6%;
females,
32%)
(
NOAEL
based
on
5
month
study);
at
6
weeks
in
1­
year
study,
plasma
cholinesterase
inhibition
(
males,
15%;
females,
28%)

6­
weeks
0.01
0.025
Plasma
cholinesterase
inhibition
(
males,
15%;
females,
28%);
also,
plasma
cholinesterase
inhibition
at
week
12
in
a
5­
month
study
(
males31%;
females,
29%);
no
plasma
cholinesterase
inhibition
at
0.01)

Fenamiphos
1
yr
0.01
0.03
Plasma
cholinesterase
inhibition
(
males,
26%;
females,
26%)(
NOAEL
established
from
6­
month
study)

3
months
0.01
0.03
Plasma
cholinesterase
inhibition
(
males,
25%;
females,
21%)

Fenitrothion
1­
yr
0.125
0.25
Plasma
cholinesterase
inhibition
(
males,
15%;
females,
26%)

4­
weeks
0.125
0.25
Plasma
cholinesterase
inhibition
(
males,
14%;
females,
22%)

Fenpropathrin
1
yr
2.5
6.25
Tremors
(
4/
4
of
each
sex)

Entire
time
2.5
6.25
Tremors
(
incidences
not
provided)

Fludioxonil
1­
yr
3
35
Decreased
body
weight
gain
(
43%)

3­
months
3
35
Decreased
body
weight
gain
(
31%)

Halosulfuron
methyl
1yr
10
40
Decreased
body
weight
gain
(
16%)

0
to
13
weeks
10
40
Decreased
body
weight
gain
(
7%)

Imazalil
1­
yr
2.5
20
Increased
liver
weights,
increased
ALP
(
80%),
decreased
body
weight
gains
(
60%
during
weeks
0­

12);
vomiting
(
occasional
in
4/
4
of
each
sex
during
week
46
and
later
0­
12
weeks
2.5
20
Decreased
body
weight
gains,
increased
ALP
(
111%);
vomiting
(
4/
4
males
up
to
day
29)
Chemicals
Duration
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
Effects
seen
at
LOAEL
Page
27
of
46
Iprovalicarb
1­
yr
2.6
24.7
Hepatocellular
hypertrophy
(
4/
4
each
sex,
minimal),
increased
absolute
liver
weights
(
24%),

increased
ALP
(
155%)

28
day
study
3.0
31.5
Hepatocellular
hypertrophy
(
2/
2
of
each
sex),
vacuolated
hepatocytes
(
2/
2
of
each
sex),
increased
ALP
(
88%)

Linuron
1­
yr
0.77
3.5
Increased
methemoglobin
(
no
statistically
significant
increases
at
1
year)­
and
sulfhemoglobin
(
0.7%

versus
0.3%
in
contols)

3
months
0.77
3.5
Increased
methemoglobin
(
1.1%
versus
0.1%
in
controls)­
and
sulfhemoglobin
(
0.6%
versus
0.3%
in
controls)

Methidithion
1
yr
0.15
1.33
Increased
ALP
(
132%)
and
SGTP
(
641%);
RBC
(
76%)
cholinesterase
inhibition,
chronic
hepatitis,

distended
bile
canaliculi,
elevated
hepatic
enzymes
3
months
0.15
1.33
Increased
ALP
(
181%)
and
SGTP
(
664%);
(
83%)
cholinesterase
inhibition
Nitrapyrin
1­
year
3.0
15.0
Increased
ALP
(
137%),
cholesterol
(
50%),
and
absolute
liver
weights;
liver
hypertrophy
3
months
3.0
15.0
Increased
ALP
(
30%)
and
cholesterol
(
38%)

Oxydemeton
methyl
1
yr
0.0125
0.125
Brain
cholinesterase
inhibition
(
males,
15%;
females
12%);
RBC
cholinesterase
inhibition
(
males,

11%;
females,
15%);
plasma
cholinesterase
inhibition
(
males,
19%;
females,
15%)

3
months
0.0125
0.125
Plasma
cholinesterase
inhibition
(
16%
in
males
and
10%
in
females)

Parathion
1
yr
<
0.01
0.01
RBC
(
22%),
plasma
(
27%),
and
brain
cholinesterase
inhibition
2
months
<
0.01
0.01
RBC
(
26%)
and
plasma
(
25%)
cholinesterase
inhibition
Pentachlorophenol
1
yr
<
1.5
1.5
Increased
liver
weights,
increased
stomach
lymphocytic
mucosal
inflammation,
increased
ALP
(
85%)

13
weeks
<
1.5
1.5
Increased
ALP
(
49%)

Prohexadion
1
yr
80
200
Renal
pathology,
increased
urinary
volume
(
34%),
sodium
(
69%
at
week
39),
choloride
(
at
week
12),

and
potassium
(
at
week
13)

13
weeks
80
200
Increased
urinary
volume
(
90%),
chloride
62%),
sodium
(
94%),
and
potassium
(
52%)

Pyridiben
1
yr
0.5
1.0
Decreased
body
weight
gains
(
29%)

13
weeks
0.5
1.0
Decreased
body
weight
gains
((
27%)

Sulprofos
2
yr
0.25
2.5
RBC
(
53%),
plasma
(
47%),
and
brain
cholinesterase
inhibition
1
month
0.25
2.5
RBC
(
68%)
and
plasma
(
54%)
cholinesterase
inhibition
Chemicals
Duration
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
Effects
seen
at
LOAEL
Page
28
of
46
TCP
1­
yr
12
48
Increases
in
liver
enzymes
ALP
(
127%)
and
ALT
(
94%)

3
months
12
48
Increases
in
liver
enzymes
ALP
(
55%)
and
ALT
(
85%)

Terbufos
1
yr
0.005
0.015
Plasma
cholinesterase
inhibition
(
28­
day
study
used
for
RfD)

28
day
study
0.005
0.015
Plasma
cholinesterase
inhibition
(
basis
of
RfD)

Triadimefon
2­
yr
11.4
33.7
Increased
ALP
(
25%);
decreased
GPT
(
30%)

13
weeks
11.4
33.7
Increased
ALP
(
17%)
and
decreased
GPT
(
19%)

Tribufos
1
yr
0.1
0.4
Plasma
cholinesterase
inhibition
(
33%)

13­
weeks
0.1
0.4
Plasma
cholinesterase
inhibition
(
28%)
Page
29
of
46
Table
A3.
Pesticides
with
Lower
NOAELs
or
LOAELs
(>
1.5)
in
1­
year
than
in
13­
Week
Dog
Studies
(
19
Chemicals)

Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Azafenidan
1­
year
diet
0
0.16
0.30
(
NOAEL)

0.87
(
LOAEL)
3.53
11.01
12
weeks
in
1­
year
0.30
(
NOAEL)

0.87
(
LOAEL)
3.53
11.01
13­
week/
diet
0
0.34
(
NOAEL)

2.02
(
LOAEL)
4.0
8.64
Hepatocellular
hypertrophy,
pigment
in
liver
cells,
or
multiple
nuclei
in
liver
not
observed
in
any
dogs
Hepatocellular
hypertrophy
(
0/
5);
pigment
in
liver
cells
(
males,
2/
5;
females,
1/
5);
multiple
nuclei
in
liver
(
0/
5
of
each
sex)

Hepatocellular
hypertrophy
(
0/
5
of
each
sex);
pigment
in
liver
cells
(
4/
5
of
each
sex);
multiple
nuclei
in
liver
(
0/
5
of
each
sex)

Hepatocellular
hypertrophy
(
3/
5
of
each
sex);
pigment
in
liver
cells
(
5/
5
of
each
sex);
multiple
nuclei
in
liver
(
males,
5/
5;
females,
3/
5);
increased
ALT
(
males,
175%;
females,
209%);
increased
ALP
(
50%
in
males,
no
increase
in
females)

Hepatocellular
hypertrophy
(
5/
5
of
each
sex);
pigment
in
liver
cells
(
5/
5
of
each
sex);
multiple
nuclei
in
liver
(
5/
5
of
each
sex);
increased
ALT
(
males,
320%;
females
379%);
increased
ALP
(
males,
233%;

females,
84%)

Hepatocelluar
hypertrophy
(
5/
5
of
each
sex);
pigment
in
liver
cells
(
5/
5
of
each
sex);
multiple
nuclei
in
liver
(
5/
5);
increased
ALT(
518%);
increased
ALP
(
302%
and
105%
in
males
and
females)

Increased
ALT
(
males,
230%;
females,
187%);
increased
ALP
in
males
(
34%;
no
increase
in
females))

Increased
ALT
(
males,
557%;
females,
338%);
increased
ALP
(
males,
141%;
females67%)

Increased
ALT
(
males,
722%;
females
587%);
increased
ALP
(
males,
221%
females
137%)

Hepatocellular
hypertrophy,
pigment
in
male
liver
cells
or
multiple
nuclei
in
liver
cells
not
observed
Hepatocellular
hypertrophy
(
0/
4
males
and
0/
4
females);
pigment
in
male
liver
cells
(
1/
4);
increased
ALT
(
31%
in
females,
not
statistically
significant
but
consistent
with
dose
response)

Hepatocellular
hypertrophy
(
1/
4
male
and
2/
4
females);
pigment
in
liver
cells
(
4/
4
in
each
sex);
increased
ALT
(
males,
150%;
females,
344%)

Hepatocellular
hypertrophy
(
3/
4
males
and
1/
4
females);
pigment
in
male
liver
cells
(
4/
4
in
each
sex);

multiple
nuclei
in
liver
(
2/
4
and
0/
4
in
males
and
females);
increased
ALT
(
males,
440%;
females,
278%);

increased
ALP
in
females
(
43%)

Hepatocellular
hypertrophy
(
2/
4
males
and
4/
4
females);
pigment
in
liver
cells
(
4/
4
in
each
sex);
multiple
nuclei
in
liver
cells(
2/
4
and
4/
4
in
males
and
females);
increased
ALT
(
460%
and
678%
in
males
and
females);
increased
ALP
in
females
(
222%)
Liver
histopathology
and
changes
in
enzyme
levels
(
ALT
and
ALP)

somewhat
more
pronounced
in
1
year
versus
13
week
study
at
LOAEL
of
0.87
in
1­
year
study
and
LOAEL
of
2.02
in
13­
week
study.
However,

interim
data
at
12
weeks
in
1­
year
study
indicate
that
same
NOAEL
and
LOAEL
would
be
established
at
12­

weeks
and
1­
year
based
on
changes
in
enzyme
parameters.
If
performed
at
12­
weeks
in
the
1­
year
study,

likely
hepatocellular
hypertrophy
would
have
been
observed
based
on
the
changes
in
enzyme
levels.
Thus,

differences
in
LOAELs
between
1­

year
and
13­
week
studies
may
be
attributed
to
inter­
experimental
variability
or
dose
selection
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
30
of
46
Bifenthrin
1­
year/
capsule
0
0.66
1.3
(
NOAEL)

2..
7
(
LOAEL)
4.4
13­
week/
capsule
0
2.21
(
NOAEL)

4.42
(
LOAEL)
8.84
17.7
Tremors
in
1/
4
males
and
2/
4
females
beginning
at
16
weeks
Tremors
in
all
animals
of
both
sexes
No
tremors
in
any
dogs
Tremors
in
1/
4
male
dogs
(
investigator
claims
due
to
handling
and
not
treatment
related;
seen
occasionally
in
untreated
dogs
in
other
studies;
reviewer
agreed
not
treatment
related)

Tremors
in
3/
4
males
and
3/
4
females
Tremors
in
all
animals
of
both
sexes
Tremors
in
all
animals
of
both
sexes
Increased
incidence
of
tremors
(
only
critical
effect)
observed
at
the
LOAEL
in
the
13­
week
study
compared
to
the
incidence
of
tremors
observed
in
the
1­
year
study
indicates
that
the
actual
NOAELs
and
LOAELs
in
the
two
studies
would
not
be
significantly
different.
Differences
between
NOAELs
and
LOAELs
for
the
two
studies
may
be
attributed
to
differences
in
dose
selection
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
31
of
46
Bispyibac
sodium
1
year/
capsule
0
10
(
NOAEL)

100
(
LOAEL)
750
13
week/
capsule
0
30
100
(
NOAEL)

600
(
LOAEL)

28
day/
capsule
0
100
(
LOAEL)
300
600
Hyperplasia
of
the
intrahepatic
bile
ducts
(
0/
4
in
both
sexes)

Hyperplasia
of
the
intrahepatic
bile
ducts
(
0/
4
in
both
sexes)

Hyperplasia
of
the
intrahepatic
bile
ducts(
1/
4
males
and
1/
4
females)

Hyperplasia
of
the
intrahepatic
bile
ducts(
4/
4
males
and
3/
4
females)

Proliferation
of
the
intrahepatic
bile
ducts
(
0/
4
males
and
2/
4
females)

Proliferation
of
the
intrahepatic
bile
ducts
(
0/
4
males
and
1/
4
females)

Proliferation
of
the
intrahepatic
bile
ducts
(
0/
4
males
and
1/
4
females)

Proliferation
of
the
intrahepatic
bile
ducts
(
2/
4
males
and
3/
4
females)

Bile
duct
hyperplasia
(
2/
2
males)

Bile
duct
hyperplasia
(
2/
2
males
and
2/
2
females)

Bile
duct
hyperplasia
(
2/
2
males
and
2/
2
females)
Bile
duct
hyperplasia
(
2/
2
males)

observed
in
28­
day/
capsule
study
at
same
dose­
level
(
100
mg/
kg/
day)
as
1­
year
study
(
incidence,
1/
4
males
and
1/
4
females);
no
other
significant
observations
at
the
LOAEL
in
the
1­

year,
13­
week
study,
or
28­
day
study;
given
the
background
incidence
(
e.
g.,
2/
4
females
in
control
females
in
the
13­
week
study)
and
the
results
of
the
28­
day
study,
the
difference
in
LOAELs
for
the
13
week
and
1­
year
study
may
be
a
result
of
inter­
experimental
variability.
Page
32
of
46
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Cadusafos
1­
year/
capsule
0
0.0002
0.001(
NOAEL)

0.005
(
LOAEL)
0.020
13
weeks
in
1­
year
0.0002
0.001
0.005
0.020
13­
week
study
0
0.01
(
LOAEL)
0.03
0.09
Plasma
cholinesterase
inhibition
(
8%
in
females)

Plasma
cholinesterase
inhibition
(
23%
in
females
and
13%
in
males)

Plasma
cholinesterase
inhibition
(
26%
in
females
and
39%
in
males)

No
plasma
cholinesterase
inhibition
Plasma
cholinesterase
inhibition
(
22%
in
females
and
5%
in
males)

Plasma
cholinesterase
inhibition
(
23%
in
females
and
25%
in
males)

Plasma
cholinesterase
inhibition
(
22%
in
males
and
22%
in
females)

Plasma
cholinesterase
inhibition
(
29%
in
males
and
24%
in
females)

Plasma
cholinesterase
inhibition
(
56%
in
males
and
54%
in
females)
Plasma
cholinesterase
inhibition
comparable
at
13­
weeks
and
at
termination
of
1­
year
study.
NOAEL
in
13­
week
study
would
likely
equal
or
approach
NOAEL
in
1
year
study
if
dose
selections
were
comparable
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
33
of
46
Clethodium
1
year/
capsule
0
1.0
(
NOAEL)

75.0
(
LOAEL)
300.0
13­
week/
capsule
0
1.0
25.0
(
NOAEL)

75.0
(
LOAEL)
125.0
Increased
absolute
liver
weights
(
16%)

Increased
absolute
liver
weights
(
60%);
hematology
and
clinical
chemistry
changes
consistent
only
at
300
mg/
kg/
day
Increased
absolute
liver
weights
(
16%)

Increased
absolute
liver
weights
(
34%)
Same
LOAEL
and
same
percentage
increase
in
liver
weights
at
the
LOAEL
in
13­
week
study
and
in
1­

year
study;
differences
in
NOAEL's
can
be
accounted
for
by
dose
selection.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
34
of
46
Cypermethrin
1­
year/
diet
0
2.9
6.0
(
NOAEL)

18.1
(
LOAEL)
33.9
13­
week/
diet
0
10.4
20.7
24.6
(
NOAEL)

37.0
LOAEL
No
effects
Tremors
and
irregular
gate
in
1
male
observed
on
2
of
133
days
before
death
beginning
on
week
19;

tremors
and
irregular
gate
in
2nd
dog
on
3
occasions
(
test
weeks
39
and
44)
during
study
(
369
days);
no
tremors
or
irregular
gate
observed
in
females
Tremors
observed
in
males
on
up
to
54
days
of
368
days
beginning
at
week
11;
irregular
gait
observed
in
males
on
up
to
94
days
of
368
days
beginning
at
week
11;
tremors
in
females
(
2
dogs)
observed
on
up
to
132
days
beginning
at
week
33;
irregular
gait
observed
in
females
(
2
dogs)
on
up
to
148
days
beginning
at
week
33;
body
weights
decreased
from
18
to
24%
from
week
36
to
week
52
No
effects
No
effects
1
male
exhibited
tremors
on
days
66
and
67
(
considered
transitory
and
not
related
to
treatment)

Two
females
and
1
male
exhibited
tremors
beginning
on
day
49;
one
male
and
1
female
exhibited
tremor
activity
on
two
occasions
(
male)
or
during
weeks
8,
9,
or
12
during
detailed
physical
of
the
female;

decreases
in
body
weights
in
males
and
females
(
10%
and
18%,
respectively)
Gait
abnormalities,
salivation,
death;

not
observed
at
3
months
at
18.1
in
1­
year
study;
however,
effects
at
33.9
and
37.0
in
1­
year
study
and
13­
week
study
comparable:
tremors
and
irreglar
gait
observed
in
2/
4
males
at
11
or
16
weeks
at
33.9
mg/
kg/
day
in
1
year
study;
2/
4
females
and
1
male
exhibited
tremors
during
course
of
13­
week
study;
low
incidence
of
effects
at
LOAEL
in
1­
year
study
and
observation
of
effects
in
1
male
at
NOAEL
in
13­
week
study,
although
considered
transitory,
suggests
sample
size
(
sensitivity)
of
the
study
may
account
for
selection
of
different
NOAELs
and
LOAELs;
however,
use
of
1­
year
for
selection
of
a
NOAEL
can
not
be
discounted.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
35
of
46
Diflufenzopyr
1
year/
diet
0
26
(
NOAEL)

299
(
LOAEL)
529
13
week/
diet
0
58
(
NOAEL)

403
(
LOAEL)
1131
Incidences
for
hyperplasia,
reticulocytosis,
and
hemosiderin
deposits
not
stated
Incidences
for
hyperplasia,
reticulocytosis,
and
hemosiderin
deposits
not
stated
Bone
marrow
hyperplasia
(
all
animals);
reticulocytosis
(
4/
4
males
and
2/
4
females);
hemosiderin
deposits
in
the
kidney
(
1/
4
males)

Bone
marrow
hyperplasia
(
all
animals);
reticulocytosis
(
all
animals,
statistically
significant
at
13
weeks);

hemosiderin
deposits
in
the
kidney
(
2/
4
females)
and
in
the
liver
(
2/
4
males
and
3/
4
females)

No
effects
reported
No
effects
reported
Bone
marrow
hyperplasia
(
2/
4
males
and
1/
4
females),
hemosiderin
deposits
in
the
liver
(
1/
4
females),

extramedullary
hemopoiesis
in
the
liver
(
2/
4
males
and
1/
4
females)

Bone
marrow
hyperplasia
(
all
animals);
extramedullary
hemopoiesis
in
the
liver
(
all
animals);

reticulolcytosis
(
2/
4
males
and
1/
4
females)
No
interim
pathology
in
1­
year
study.

Increased
incidences
of
effects
at
the
LOAEL
in
1
year
study
compared
to
incidences
in
13
wk
study
indicate
1
year
study
more
definitive.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
36
of
46
Ethylene
thiourea
1­
year/
diet
0
0.18
(
NOAEL)

1.99
(
LOAEL)
20.13
13­
weeks
in
1­
year
0.18
1.99
20.13
13­
week/
diet
0
0.39
6.02
(
NOAEL)

66.23
(
LOAEL)
No
apparent
reductions
in
T3
or
T4;
follicular
dilation
and
hypertrophy
(
males
1/
4
and
females
1/
4);

T3
reduced
(
males
9%;
females
24%)
T4
reduced
(
males
27%;
females
no
reduction);
increased
thyroid
weights
(
males,
170%;
females72%);
follicular
dilation
and
hypertrophy
(
males
2/
2
and
females
2/
3);

No
apparent
reductions
in
T3
or
T4
T3
reduced
(
males
21%;
females
10%);
T4
reduced
(
males
46%;
females
10%)

(
Note:
details
on
thyroid
histopathology
observed
at
all
doses
not
provided
in
the
Data
Evaluation
Record)
although
not
statistically
significant,
T4
reduced
8%
and
10%
at
weeks
4
and
8
in
males,
respectively;

see
additional
doses
for
evidence
of
dose­
response
increases
in
effects
No
increase
in
thyroid
weights;
although
not
statistically
significant,
T4
reduced
19%
and
18%
at
weeks
4
and
8
in
males,
respectively
mortality
(
2/
4);
statistically
significant
thyroid
changes:
reduced
T3
(
males,
71%
at
week
8;
females,
66%

at
week
8);
reduced
T4
(
males,
91%
at
week
8;
females,
90%
at
week
8);
increased
thyroid
weights
(
male,
1200%;
females,
1400%);
diffuse
hyperplasia
of
the
thyroid
in
all
dogs
No
apparent
reduction
in
thyroid
hormones
was
observed
at
the
LOAEL
(
1.99
mg/
kg/
day)
in
the
1­

year
study,
whereas,
although
not
statistically
significant,
T4
was
reduced
by
8%
to
10%
at
0.39
mg/
kg/
day
and
by
18­
19%
at
weeks
4
and
8
at
6.02
mg/
kg/
day
in
the
13­

week
study;
the
dose­
response
effects
on
T3
across
dose­
levels
suggest
the
effect
at
1.99
may
be
biologically
significant
and
treatment
related.
Thyroid
weight
were
increased
up
to
170%
at
20
mg/
kg/
day
in
the
1­
year
study
and
by
1500%
at
66
mg/
kg/
day
in
the
13
week
study.

Based
on
(
1)
the
similarities
in
hormone
measurements
at
20.13
mg/
kg/
day
at
1­
year
and
at
13­
weeks
during
the
1­
year
study,
and
(
2)
a
comparison
of
the
effects
on
hormone
levels
at
66.23
and
6.02
mg/
kg/
day
in
the
13­
week
study
versus
effects
on
hormone
levels
at
20.1
mg/
kg/
day
in
the
1­
year
study,
it
appears
differences
between
the
2
studies
may
be
a
consequence
of
dose
selection
or
inter­
experimental
variability
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
37
of
46
Etoxazole
1­
year/
diet
0
4.62
(
NOAEL)

23.5
(
LOAEL)
116.0
13
weeks
in
1­
year
4.62
(
NOAEL)

23.5
(
LOAEL)
116.0
13­
week/
diet
0
5.33
(
NOAEL)

53.7
(
LOAEL)
268
Increased
liver
weights
(
16%
in
males)

Increased
ALP
(
males
262%;
females
75%);
increased
liver
weights
(
males
29%;
females
34%);

centrolobular
hepatocellular
swelling
(
4/
4
each
sex)

Increased
ALP
(
males
586%;
females
955%);
increased
liver
weights
(
males
75%;
females
76%);

centrolobular
hepatocellular
swelling
(
4/
4
each
sex)

Increased
ALP
(
males
155%;
females
107%)

Increased
ALP
(
males
371%;
females
599%)

No
increase
in
liver
weights
Increased
ALP
(
males,
196%;
females,
107
%);
increased
liver
weights
(
21­
23%);
centrolobular
hepatocellular
swelling
(
4/
4,
each
sex)

Increased
ALP
(
males,
196%;
females,
855);
increased
liver
weights
(
33­
51%);
hepatocellular
swelling
(
4/
4
each
sex)
Comparable
severity
or
incidence
of
effects
at
LOAEL
of
23.5
in
1­
year
study
and
LOAEL
of
53.7
in
13­
week
study.
Increases
in
ALP
at
13­
weeks
at
23.5
mg/
kg/
day
less
than
at
1­
year
(
males)
but
more
in
females.

Increases
in
ALP
greater
in
both
males
and
females
at
highest
dose
tested
at
1­
year
compared
to
13­

week
interim
data.
Overall,
data
indicate
actual
LOAEL
would
be
better
defined
using
1­
year
study.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
38
of
46
Fenhexamid
1
year/
diet
0
17.0
(
NOAEL)

124.0
(
LOAEL)
918.0
13
weeks
in
1
year
17
(
NOAEL)

124
(
LOAEL)
918.0
13
week/
diet
0
34
(
NOAEL)

239
(
LOAEL)
1748
Increased
adrenal
weights
in
females
(
8%)

Decreased
RBC's
(
9%
and
17%
in
males
and
females)
and
hematocrit
(
8%
and
15%
in
males
and
females);
increased
Heinz
bodies
(
4
versus
0
control
males
and
30
versus
0
control
females);
increased
adrenal
weights
in
females
(
15%)

Decreased
RBC's
(
males,
22%;
females,
18%)
and
hematocrit
(
males,
18%;
females,
15%);
increased
Heinz
bodies
(
36
versus
0
control
males
and
46
versus
0
control
females);
increased
adrenal
weights
in
females
(
25%)

Decreased
RBC's
(
males,
9%;
females,
16%)
and
hematocrit
(
males,
6%;
females,
14%),
increased
Heinz
bodies
(
3.0
versus
0
control
males
and
8
versus
0
control
females)

Decreased
RBC's
(
males,
19%;
females,
21%)
and
hematocrit
(
males,
16%;
females,
18%);
increased
Heinz
bodies
(
45
versus
0
control
males
and
37
versus
control
females)

Decreased
RBC's
(
males,
10%;
females,
16%)
and
hematocrit
(
males,
9%;
females,
14%);
increased
Heinz
bodies
(
18
versus
0
control
males
and
18
versus
0
control
females);
adrenal
weights
apparently
not
affected
Decreased
RBC's
(
males,
15%;
females,
14%)
and
hematocrit
(
males,
14%;
females,
10%);
increased
Heinz
bodies
(
50
versus
0
control
males
and
94
versus
0
control
females);
adrenal
weights
apparently
not
affected
At
13
weeks
in
1­
year
study,

magnitude
of
effects
of
decreased
RBC's
and
hematocrit,
and
increased
Heinz
bodies
comparable
magnitude
of
changes
in
same
parameters
at
124
mg/
kg/
day
at
termination
of
1­

year
study;
difference
in
NOAELs
between
1­
year
and
13­
week
study
can
be
associated
with
interexperimental
variability
Page
39
of
46
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Fosetyl
Al
1­
year/
diet
0
250
(
NOAEL)

500
(
LOAEL)
1000
13­
week/
diet
0
55
274
(
NOAEL)

1309
(
LOAEL)
spermatocytic
and/
or
spermatidic
giant
cells
(
2/
6,
graded
as
focal/
trace)

spermatocytic
and/
or
spermatidic
giant
cells
(
6/
6,
graded
as
numerous
focal
to
multifocal/
trace)

Decreased
serum
potassium
(
13%
in
males,
and
18%
in
females;
potassium
also
decreased
at
weeks
4
and
8)
1981
and
1982
studies
with
limited
details
on
clinical
chemistry,

hematology,
or
histopathology
observations.
Data
Evaluation
Record
states
testicular
effects
were
slight.
Insufficient
detail
to
make
meaningful
comparisons
Hexaconazole
1
year/
capsule
0
2.0
(
NOAEL)

10.0
(
LOAEL)
50.0
13
week/
capsule
0
5.0
(
NOAEL)

25.0
(
LOAEL)

75
reduced
to
50.0
at
10
days
Fatty
liver
(
3/
4
males);
increased
liver
weights
(
16%)

Fatty
liver
(
4/
4
males
and
4/
4
females);
increased
liver
weights
(
70%)

Decreased
cholesterol
(
males,
38%;
females,
29%)
and
triglycerides
(
males,
14%;
females,
34%);

increased
AAT
(
males,
251%;
females,
163%),
fatty
liver
(
number
of
dogs
affected
not
given)

Decreased
cholesterol
(
males,
68%;
females,
54%)
and
triglycerides
(
males,
49%;
females,
51%);

increased
AAT
(
males,
285%;
females,
229%)
liver
weights
increased
(
males,
34%;
females,
48%)
1­
year
study
classified
as
supplementary:
deficient
in
that
the
colony
of
dogs
used
was
of
questionable
health
(
26
of
the
32
dogs
had
some
degree
of
pnuemonia);
missing
clinical
chemistry
and
hematology
data
make
data
interpretation
difficult;
did
not
satisfy
guideline
requirements.
Thus,

some
doubt
meaningful
comparison
of
2
studies
are
possible.
However,

severity
of
effects
noted
at
LOAEL
in
3­
month
study
suggest
that
effects
would
be
seen
at
or
approaching
10
mg/
kg/
day,
the
same
LOAEL
as
in
the
1­
year
study.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
40
of
46
Hexazinone
1­
year/
diet
0
5.0
(
NOAEL)

37.6
(
LOAEL)
167.0
at
13
weeks
37.6
167.0
13­
week/
diet
0
5.1
25.9
(
NOAEL)

122.5
(
LOAEL)
Increased
ALP
(
males,
3091%;
females,
94%)

Increased
ALP
(
males,
1271%;
females
459%);
increased
AST
(
males,
40%;
females,
41%);
increased
ALT
(
males,
176%;
females,
159%);
single
cell
necrosis
(
liver)
(
3/
5
males
and
3/
5
females);
decreased
body
weights
(
males,
22%,
females,
33%)

Increased
ALP
(
males,
96%;
females,
23%)

Increased
ALP
(
males,
246%;
females,
207%);
no
increases
in
AST;
increased
ALT
(
males,
118%);
body
weights
decreased
(
males,
24%,
females,
28%)

Note:
because
control
animals
weigh
less
than
animals
in
all
treatment
groups,
body
weight
gains
used
for
comparisons
Increased
liver
weights
(
males,
10%)

Increased
liver
weights
(
males,
21%)

Increased
ALP
(
males,
214%;
females,
124%);
no
apparent
increases
in
AST
or
ALT;
increased
liver
weights
(
males,
26%,
females,
33%);
proteinuria
(
1/
4
of
each
sex);
body
weight
gains
decreased
(
0.7
controls
versus
minus
0.9
kg
in
males
and
minus
0.3
kg
in
females)
Effects
on
ALP
at
37.6
mg/
kg/
day
in
the
1­
year
study
greater
(
males)
or
comparable
(
females)
to
the
effects
on
ALP
at
122.5
mg/
kg/
day
in
the
13
week
study.
1
year
study
provides
data
that
would
lead
to
selection
of
a
lower
NOAEL
for
establishment
of
a
chronic
RfD
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
41
of
46
Prosulfuron
1
year/
diet
0
0.31
1.84
(
NOAEL)

20.2
(
LOAEL)
48.8
3
months
in
1
year
1.84
(
NOAEL)

20.2
(
LOAEL)
48.8
13
week/
diet
0
0.59
6.5
(
NOAEL)

54.0
(
LOAEL)
120.0
No
lipofucsin
accumulation
in
the
liver
No
lipofucsin
accumulation
in
the
liver
No
lipofucsin
accumulation
in
the
liver
Decreased
albumin
(
males,
6%;
females,
12%);
decreased
RBC's
(
males,
0%;
females,
11%);
lipofucsin
accumulation
in
the
liver
(
3/
4
males
and
1/
4)
females;
increased
liver
weights
(
females
27%,
not
statistically
significant)

Decreased
albumin
(
males,
16%;
females,
15%);
decreased
RBC's
(
males,
10%;
females,
12%);

hemoglobin
decreased
16%
in
females);
hematocrit
decreased
16%
in
females;
lipofucsin
accumulation
in
the
liver
(
2/
4
males
and
3/
4
females);
increased
liver
weights
(
females
34%,
not
statistically
significant)

Decreased
albumin
(
males,
0%;
females,
12%);
decreased
RBC's
(
males,
8%;
females,
7%);

hemoglobin
decreased
16%
at
1­
month
Decreased
albumin
(
males,
13%;
and
females,
12%);
decreased
RBC's
(
males,
7%;
females
6%);

hemoglobin
decreased
10%
at
1­
month
Decreased
albumin
(
males,
19%;
females,
16%);
decreased
hemoglobin
(
males,
12%;
females,
14%);

decreased
hematocrit
(
males,
8%;
females,
12%);
decreased
RBC's
(
males,
14%;
females,
17%);

increased
liver
weights
(
females
42%,
statistically
significant);
hemosiderin
deposits
in
stomach
(
0/
4
males
and
1/
4
females),
spleen
(
1/
4
males
and
1/
4
females)

Decreased
albumin
(
males,
37%;
females,
23%);
decreased
hemoglobin
(
males,
22%;
females,
16%);

decreased
hematocrit
(
males,
18%;
females,
12%);
decreased
RBC's
(
16%);
increased
liver
weights
(
females
53%,
statistically
significant);
hemosiderin
deposits
in
stomach
(
1/
4
males
and
0/
4
females)
and
spleen
(
1/
4
males
and
1/
4
females)
Comparable
effects
detected
at
3
months
in
1­
year
study
and
at
the
end
of
the
1­
year
study
at
the
same
LOAEL;
effects
at
48.8
mg/
kg/
day
(
1­

year
study)
and
54.0
mg/
kg/
day
(
13­

week
study)
comparable;
thus,

differences
in
NOAELs
between
1­

year
and
13­
week
studies
may
be
accounted
for
by
differences
in
dose
selection.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
42
of
46
Spinosad
1­
year/
diet
0
1.44
2.68
(
NOAEL)

8.46
(
LOAEL)

13­
week/
diet
0
4.89
(
NOAEL)

9.73
(
LOAEL)
33.4
Vacuolated
cell
aggregations
in
lymphoid
tissue
(
spleen,
faucial
tonsil,
lymph
node
or
intestine)(
4/
4
males
and
2/
4
females);
increased
ALT
(
males
only,
140%
at
26
weeks;
no
increase
at
week
52)
and
AST
(
males
only,
56%
at
26
weeks,
no
increase
at
week
52).
Increased
triglycerides
(
males
only,
38%
at
week
26,
no
increase
at
week
52)
arterites
in
the
epididymis
(
1/
4
males)
or
cerebral
meninges
(
1/
4
females);
slight
vacuolation
of
the
parathyroid
(
2/
4
males)

Vacuolated
cell
aggregation
in
lymphoid
tissues
(
cervical,
mesenteric,
faucial
tonsil,
ileum,
colon,
or
rectum
lymph
nodes)(
4/
4
males
and
4/
4
females);
vacuolated
acinar
cells
of
the
pancreas
(
2/
4
males
and
0/
4
females)

Vacuolated
cell
aggregation
in
lymphoid
tissues
(
4/
4males
and
4/
4
females).
Vacuolated
cells
of
the
parathyroid
(
4/
4
males
and
4/
4
females);
vacuolated
nerve
cells
in
the
brain
(
3/
4
males
and
1/
4
females);

increased
ALP
(
males,
34%,
females,
163%);
increased
ALT
(
males,
91%,
females,
405%);
increased
AST
(
males,
49%,
females,
1,025
%).
Kupffer
cell
proliferation
(
3/
4
males
and
3/
4
females);
increased
triglycerides
(
33%
males
and
25%
females);
decreased
albumin
(
22%
males
and
22%
females);

testicular
arteritis
(
2/
4)
The
primary
effects
of
spinsad
are
vacuolated
cell
aggregations
in
lymphoid
tissues.
The
tissues
affected
and
the
incidences
reported
are
equivalent
at
8.46
mg/
kg/
day
in
the
1­
year
study
and
at
9.73
mg/
kg/
day
in
the
13­
week
study.

The
increases
in
ALT
and
AST
observed
in
the
1­
year
study
at
the
LOAEL
of
8.46
mg/
kgday
are
transitory,
not
accompanied
by
hepatocellular
histopathology,
and
are
of
questionable
significance.

Also,
as
stated
in
the
Data
Evaluation
Report,
there
was
no
evidence
of
progression
in
severity
of
the
effects
on
lymphoid
tissue
based
on
a
comparison
of
the
1­
year
and
13
week
study.

Given
the
similarity
of
effects
noted
on
lymphoid
tissues
at
the
LOAEL
in
each
of
the
studies,
it
is
likely
the
actual
NOAELs
would
be
comparable.
Page
43
of
46
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Tebuconazole
1
year/
diet
(
1989)
0
2.94
(
NOAEL)

4.39
(
LOAEL)

13
week/
diet
0
7.5
(
NOAEL)

38.8
(
LOAEL)
207.6
Hyertrophy
of
adrenal
zona
fasiculata
(
0/
4
males
and
1/
4
females)

Hyertrophy
of
adrenal
zona
fasiculata
(
0/
4
males
and
0/
4
females)

Hypertrophy
of
adrenal
zona
fasciculata,
minimal
to
mild
(
4/
4
males
and
4/
4
females);
fatty
changes
in
the
zona
glomerulosa
(
3/
4
males
and
2/
4
females)
and
lipid
hyperplasia
in
the
cortex
(
2/
4
males
and
0/
4
females
Vacuolation
of
the
adreanals
zona
fasiculata
(
0/
4
males
and
1/
4
females)

Vacuolation
of
the
adrenal
zona
fasiculata
(
0/
4
males
and
1/
4
females);
increased
N­
demethylase
activity
(
31%)

Decreased
body
weights
(
6%),
increased
N­
demethylase
activity
(
180%);
vacuolation
of
the
adrenal
zona
fasiculata
(
0/
4
males
and
2/
4
females);
Note:
the
increased
incidence
of
vacuole
formation
in
the
adrenals
was
considered
to
be
an
adaptive
response
and
was
not
considered
an
effect
at
the
LOAEL
Decreased
body
weight
(
17%);
vacuolation
of
the
adrenal
zona
fasiculata
(
1/
4
males;
no
information
on
females);
increased
N­
demethylase
activity
(
355%);
increased
ALP
(
males,
160%;
females,
52%);

cataracts
in
0/
4
males
and
3/
4
females
1­
year
study
provides
more
definitive
information
on
effects
on
adrenal
and
there
are
pronounced
differences
in
NOAELs/
LOAELs
between
the
1­

year
and
13­
week
studies.
In
the
1­

year
study,
all
animals
were
observed
to
have
hypertrophy
of
the
adrenal
zona
fasiculata
at
a
dose
level
of
4.39
mg/
kg/
day,
whereas
only
2/
4
females
and
no
males
were
observed
to
have
this
effect
at
a
dose
level
of
38.8
mg/
kg/
day
in
the
13
week
study.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
44
of
46
Tebufenozide
1­
year/
diet
0
0.6
1.8
(
NOAEL)

8.0
(
LOAEL)
53.0
13­
week/
diet
0
2.1
(
NOAEL)

20.1
(
LOAEL)
202.2
Sinusoidal
engorgement
(
2/
4
males
and
1/
4
females);
bone
marrow
hyperplasia
(
1/
4
males
and
4/
4
females);
increased
pigment
in
Kupffer
cells
(
1/
4
males
and
1/
4
females);
decreased
RBC's
(
16%);

decreased
hemoglobin
(
10%,
statistically
significant
only
in
males);
decreased
hematocrit
(
14%);

increased
Heinz
bodies
(
12­
fold)

Sinusoidal
engorgement
(
4/
4
males
and
4/
4
females);
bone
marrow
hyperplasia
(
4/
4
males
and
4/
4
females);
spleen
hematopoiesis
(
3/
4
males
and
4/
4
females);
increased
pigment
in
Kupffer
cells
(
3/
4
males
and
3/
4
females);
decreased
RBC's
(
15%
consistent
over
the
course
of
the
study);
decreased
hemoglobin
(
10%);
decreased
hematocrit
(
12%);
increased
Heinz
bodies
(
66­
fold);
increased
methemoglobin
(
89%
in
males)

Sinusoidal
engorgement
(
4/
4
males
and
4/
4
females);
bone
marrow
hyperplasia
(
0/
4
males
and
0/
4
females);
spleen
hemopoiesis
(
1/
4
males
and
3/
4
females);
increased
pigment
in
Kupffer
cells
(
4/
4
males
and
4/
4
females);
decreased
RBC's
(
8%,
statistically
significant);
decreased
hemoglobin
(
8%);

hematocrit
decreased
<
10%,
not
statistically
significant;
increased
Heinz
bodies
(
65­
fold)

Bone
marrow
hyperplasia
(
4/
4
males
and
4/
4
females);
spleen
hemopoieses
(
4/
4
males
and
4/
4
females);
sinusoidal
engorgement
(
4/
4
males
and
4/
4
females);
increased
pigment
in
Kupffer
cells
(
4/
4
males
and
4/
4
females);
decreased
RBC;
s
(
13%,
statistically
significant);
decreased
hemoglobin
(
7%);

hematocrit
decreased
<
10%,
not
statistically
significant;
increased
Heinz
bodies
(
190­
fold);
increased
methemoglobin
(
171%)
Decreased
hematocrit
(
14%
at
8mg/
kg/
day
and
12%
at
53
mg/
kg/
day)
statistically
significant
during
a
single
of
5
time
periods
during
the
course
of
the
study)
and
MCV
(
115%
at
8
mg/
kg/
day
and116%
at
53
mg/
kg/
day)

statistically
significant
only
at
highest
dose
during
the
course
of
the
study)

Bone
marrow
hyperplasia
observed
at
8.0
mg/
kg/
day
in
1­
year
study
and
at
202.2
mg/
kg/
day
in
13­
week
study.

However,
increased
incidence
of
sinusoidal
engorgement
and
pigment
in
Kuppffer
cells
and
increase
in
Heinz
bodies
at
LOAEL
in
13­
week
study
when
compared
to
incidence
of
these
lesions
in
the
1­
year
study
indicates
that
actual
LOAEL
in
13
week
study
would
approach
that
of
the
1­
year
study.
Page
45
of
46
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Thiophanate
methyl
1­
year/
capsule
0
8
(
NOAEL)

40
(
LOAEL)
200
3­
month/
capsule
0
<
50
(
NOAEL);

50(
LOAEL)
200
800
(
lowered
to
400
at
50
days)
Thyroid
follicular
cell
hypertrophy
(
0/
4
males
and
2/
4
females);
increased
thyroid
weights
(
males,
33%,

not
statistically
significant;
females,
44%,);
decreased
T4
(
at
6
months,
males,
70%;
females,
no
decrease)

Thyroid
follicular
cell
hypertrophy
(
4/
4
males
and
3/
4
females);
thyroid
follicular
cell
hyperplasia
(
1/
4
males
and
1/
4
females);
increased
thyroid
weights
(
males,
41%;
females,
39%,
neither
statistically
significant);
decreased
T4
(
at
6
months,
males,
79%;
females,
no
decrease)

Thyroid
follicular
cell
hypertrophy
(
1/
4
males
and
1/
4
females);
decreased
T3
(
males,
no
decrease;

females,
14%,
not
statistically
significant)

Thyroid
follicular
cell
hypertrophy
(
3/
4
males
and
2/
4
females);
thyroid
follicular
cell
hyperplasia
(
1/
4
males;
0/
4
females);
increased
thyroid
weights
(
males,
31%,
not
statistically
significant;
females,
no
effect);
decreased
T3
(
males,
no
decrease;
females,
26%);
decreased
T4
(
males,
no
decrease;
females,

47%)
Thyroid
follicular
cell
hypertrophy
(
4/
4
,
males
and
4/
4
females);
thyroid
follicular
cell
hyperplasia
(
4/
4
males;
3/
4
females);
increased
thyroid
weights
(
males,
49%,
not
statistically
significant;
females,
no
effect);
decreased
T3
(
males,
22%,
not
statistically
significant;
females,
25%);
decreased
T4
(
males,
no
effect;
females,
31%,
not
statistically
significant)
Incidence
of
thyroid
follicular
cell
hypertrophy
comparable
at
the
LOAELs
in
1­
year
and
3­
month
studies.
Variability
in
T3
and
T4
measurements
limit
quantitative
comparisons
of
2
studies.

Differences
in
LOAELs
not
biologically
significant;

Incidence
of
thyroid
follicular
cell
hypertrophy
comparable
in
1­
year
and
3­
month
studies
at
200
mg/
kg/
day;
incidence
of
thyroid
follicular
cell
hyperplasia
greater
in
3­

month
study
than
in
1­
year
study
at
200
mg/
kg/
day;
increased
thyroid
weights
comparable
in
males
but
not
females
in
1­
year
and
3­
month
studies
.
Unlikely
if
selection
of
same
doses
in
two
studies
would
have
resulted
in
significantly
different
NOAELs
Also,
in
a
2­
year
rat
study,
the
NOAEL/
LOAEL
was
identified
as
8.8
mg/
kg/
day
and
54.4
mg/
kg/
day
based
on
hepatocellular
hypertrophy,

increased
severity
of
nephropathy,

increased
thyroid
weights,
follicular
cell
hypertrophy
and
hyperplasia,
and
decreased
T3
and
T4
hormone
levels.
Given
the
similarities
in
effects
observed
in
the
1­
year
dog
study
and
the
2­
year
rat
study
and
the
comparability
of
the
NOAELs/
LOAELs
in
the
2
studies,

selection
of
the
rat
study
for
establishment
of
a
chronic
RfD,

absent
a
1­
year
dog
study,
would
be
appropriate.
Chemical/

Duration/
Route
Doses
(
mg/
kg/
day)
Effects
Comment
Page
46
of
46
Triazamate
1
year/
diet
0
0.0025
0.0078
0.0164
(
NOAEL)

0.0236
(
LOAEL)
0.39
4.42
13­
weeks
in
1­
year
0.0236
0.39
4.42
13
week/
diet
0.03
(
LOAEL)
0.31
3.1
11.0
Brain
cholinesterase
inhibition
(
males
only
12%,
not
statistically
significant);
no
plasma
or
RBC
cholinesterase
inhibition
Brain
cholinesterase
inhibition
(
males
33%
and
females
20%);
plasma
cholinesterase
inhibition
(
males
39%
and
females
13%
not
statistically
significant);
no
statistically
significant
reductions
in
RBC
cholinesterase
activity
Brain
cholinesterase
inhibition
(
males
39%
and
females
47%);
plasma
cholinesterase
inhibition
(
males
72%
and
females
79%);
RBC
cholinesterase
inhibition
(
males
33%
and
females
18%)

No
cholinesterase
inhibition
Plasma
cholinesterase
inhibition
(
males
31%
and
females
no
inhibition)

Plasma
cholinesterase
inhibition
(
males
67%
and
females
62%);
RBC
cholinesterase
inhibition
(
males
23%
and
females
no
inhibition)

(
No
statistically
significant
reduction
in
RBC
or
brain
cholinesterase
activity
at
any
dose)

Plasma
cholinesterase
inhibition
(
males
none
and
females
26%)

Plasma
cholinesterase
inhbition
(
males
61%
and
females
61%)

Plasma
cholinesterase
inhibition
(
males
81%
and
females
84%)

Plasma
cholinesterase
inhibition
(
males
89%
and
females
90%)
Effect
at
0.39
mg/
kg/
day
on
plasma
cholinesterase
inhibition
and
RBC
cholinesterase
inhibition
in
males
at
13­
weeks
in
1­
year
study
and
at
termination
in
1­
year
study
comparable,
indicating
13­
weeks
duration
sufficient
to
establish
NOAEL/
LOAEL..

NOAEL
not
established
in
13­
week
study
but
may
have
approached
or
equaled
NOAEL
in
1­
year
study
based
on
plasma
cholinesterase
inhibition
(
i.
e.,
plasma
cholinesterase
inhibited
at
0.03
mg/
kg/
day
in
13­

week
study
but
not
at
0.02
mg/
kg/
day
in
1­
year
study.
However,
based
on
inhibition
of
brain
cholinesterase
activity,
1­
year
study
more
definitive.

Unknown
why
no
brain
cholinesterase
inhibition
observed
at
any
dose
in
13­
week
study.