Document ID: EPA-HQ-ORD-2006-0187-0035
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-28T05:00Z

­

1
­
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides,
and
Toxic
Substances
TXR
No.
0053509
MEMORANDUM
DATE:
March
20,
2006
SUBJECT:
Human
Studies
Review
Board:
Final
Weight
of
Evidence
Comparison
of
Human
and
Animal
Toxicology
Studies
and
Endpoints
for
Ethephon
Human
Health
Risk
Assessment.

DP
Barcode:
314342
Reregistration
Case#:
0382
PC
Code:
099801
MRID
No.:
several
FROM:
Ray
Kent,
Chief
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

TO:
Tina
E.
Levine,
Ph.
D.,
Director
Health
Effects
Division
(
7509C)

This
document
presents
the
rationale
for
the
selection
of
an
acute
and
chronic
dietary
endpoint
and
point
of
departure
for
ethephon
based
on
data
in
two
human
studies
(
MRIDs
00036510
and
00066931).

Background.
Ethephon
is
a
plant
growth
regulator
used
to
promote
fruit
ripening,
abscission,
flower
induction,
breaking
of
apical
dominance
(
inhibition
of
the
growth
of
lateral
buds
by
the
terminal
bud
of
a
shoot),
and
other
plant
responses.
Ethephon
registrants
have
submitted
many
toxicity
studies
to
support
the
continued
pesticidal
use
of
the
chemical,
and
among
these
studies
are
two
involving
direct
dosing
of
human
subjects
that
OPP
is
considering
using
to
establish
endpoints
to
assess
risk
from
exposure
to
ethephon.
OPP
management
has
requested
that,
whenever
human
studies
support
a
risk
assessment,
HED
compare
the
strengths
and
weaknesses
of
the
human
and
animal
toxicity
studies
and
to
discuss
how
the
human
studies
fit
in
with
the
animal
studies,
i.
e.,
are
the
human
data
consistent
with
animal
data
in
terms
of
types
of
effects
and
effect
levels
or
are
there
notable
differences
between
animals
and
humans.

Both
studies
involving
direct
dosing
of
human
subjects
are
repeated
dose
oral
studies,
one
for
28
days
duration
(
MRID
00036510)
and
the
other
for
16
days
(
MRID
00066931).
The
ethephon
risk
assessment
team
has
compared
human
data
with
animal
data
from
similar
types
of
toxicity
­

2
­
studies,
and
have
made
recommendations
for
endpoint
selection
based
on
the
most
appropriate
studies
and
uncertainty
factors.
All
of
the
studies
considered
in
this
analysis
are
listed
in
summary
form
and
then
the
weight
of
evidence
discussion
of
endpoint
selection
follows.

Chemical
and
Hazard
Characterization.
Ethephon
is
an
organophosphorus
compound
that,
upon
absorption
into
plants,
forms
ethylene
gas
which
is
an
important
component
of
the
plant
hormone
complex.
The
production
of
ethylene
by
plants
occurs
naturally
as
crops
mature
but
it
can
be
slow
during
periods
of
unfavorable
weather.
Ethylene
generated
from
ethephon
is
absorbed
by
the
plant
tissues
and
moderates
the
growth
process.

Although
ethephon
is
an
organophosphorus
compound,
it
is
not
similar
in
structure
to
the
organophosphate
pesticides
currently
under
consideration
in
the
Agency
=

s
Organophosphate
Cumulative
Assessment.
Chemically,
ethephon
does
not
contain
a
good
A
leaving
group
@

which
confers
on
the
insecticidal
organophosphates
the
ability
to
easily
react
with
acetylcholinesterase
of
the
nervous
system,
the
basis
for
their
toxicity
at
relatively
low
doses.
A
second
important
difference
between
the
neurotoxic
organophosphate
insecticides
and
ethephon
is
the
presence
of
free
­
OH
groups
in
ethephon.
In
the
neurotoxic
organophosphates,
the
­
OH
groups
are
esterified
with
alkyl
groups,
typically
methyl­
or
ethyl­.
One
consequence
of
this
is
that
the
insecticidal
organophosphates
are
better
able
to
pass
through
lipid
membranes.
The
acid
dissociation
constants
for
ethephon
are:
K1
=
3.16
X
10­
3
and
K2
=
6.31
X
10­
8
at
25
C.
which
means
that
in
the
blood
at
pH
7.4,
ethephon
exists
in
ionic
form,
primarily
as
the
dianion.

Toxicity.
As
a
strong
acid,
ethephon
is
corrosive
to
the
skin
and
eyes
(
Category
I).
In
acute
and
subchronic
neurotoxicity
studies
in
rats,
there
were
signs
of
neurotoxicity
at
doses
of
500
mg/
kg
and
above
(
acute)
and
300
mg/
kg
(
subchronic).
In
dogs
there
were
no
clinical
signs
of
neurotoxicity
evident
at
75
mg/
kg/
day
although
plasma
and
RBC
cholinesterase
were
inhibited
in
animals
at
doses
as
low
as
7.5
mg/
kg/
day.
In
humans
there
are
clinical
signs
at
1.8
mg/
kg/
day
and
plasma
cholinesterase
is
inhibited
at
0.5
mg/
kg/
day.
Some
of
the
animal
and
human
studies
critical
to
the
discussion
of
endpoint
selection
are
presented
in
this
section.
Appended
to
this
discussion
is
a
summary
table
of
the
human
studies
and
those
animal
studies
where
cholinesterase
was
measured
in
at
least
one
compartment.

Animal
studies
Acute
Neurotoxicity
Study
­
Rat.
In
an
acute
neurotoxicity
study
(
MRID
44000802),
ethephon
technical
grade
was
administered
by
gavage
to
Sprague­
Dawley
rats
(
12/
sex/
group)
at
single
dose
levels
of
0,
500,
1000,
or
2000
mg/
kg/
day
in
deionized
water.
No
cholinesterase
activity
measurements
were
conducted
in
this
study.
All
rats
were
evaluated
for
behavioral
effects
using
functional
observational
battery
(
FOB)
and
motor
activity
prior
to
treatment,
and
on
Day
0
(
5­
5.5
hours
post
treatment
for
FOB
and
5.5­
6
hours
post
treatment
for
motor
activity
measurements),
Day
7
&
Day
14.
The
Day
0
post
treatment
measurements
were
selected
on
the
basis
of
peak
inhibition
of
plasma
cholinesterase
activity
seen
in
a
separate
ancillary
study
(
MRID
44000801).
­

3
­
Animals
that
were
found
dead
and
animals
sacrificed
at
study
completion
(
Day
15)
were
subjected
to
a
complete
necropsy.
Six
rats/
sex/
group
were
perfused
and
animals
in
the
control
and
high
dose
group
underwent
a
histopathological
examination
of
central
and
peripheral
nervous
system
tissues.

Three
females
died
during
the
study.
One
female
in
the
1000
mg/
kg
group
was
found
dead
on
Day
5
and
two
females
in
the
2000
mg/
kg
group
were
found
dead
on
Days
1
and
2
following
treatment.
No
other
mortalities
were
reported.
Red
or
brown
muzzle
fur
staining,
gasping,
labored
breathing,
pallor,
cold
to
touch
and
decreased
activity
were
seen
prior
to
death.
Surviving
rats
in
the
2000
mg/
kg
group
continued
to
exhibit
abnormal
signs.
Body
weight
and
food
consumption
were
significantly
reduced
(
p
<
0.01
­
p
<
0.05)
in
the
high
dose
animals
and
mid
dose
animals
(
food
consumption
only).

Pupillary
constriction
was
observed
in
all
animals
on
Day
0,
particularly
showing
significant
increase
(
p
<
0.001)
in
the
2000
mg/
kg
females.
Urination
was
significantly
increased
(
p
<
0.001)
in
males
in
the
2000
mg/
kg
males
while
body
temperature
was
decreased
in
the
2000
mg/
kg
females,
also
on
Day
0.
Motor
activity
counts
were
significantly
decreased
(
p
<
0.001
­
p
<
0.01)
in
the
2000
mg/
kg
males
and
females
and
for
males
in
the
1000
mg/
kg
males
on
Day
0.
These
were
not
seen
in
subsequent
FOB
or
motor
evaluations
on
Days
7
or
14.
Several
females
in
the
500
(
5/
12)
and
1000
mg/
kg
(
5/
12)
and
several
males
in
the
2000
mg/
kg
group
(
6/
12)
and
some
males
in
the
500
(
3/
12)
and
1000
mg/
kg
(
3/
12)
groups
showed
pinpoint
pupils
on
Day
0.
It
was
also
seen
in
one
control
group
male
and
one
control
female.
For
a
few
animals,
this
condition
was
seen
on
Day
7
(
2,
1,
2
males
in
the
low,
mid
and
high
dose
groups,
respectively
and
one
female
in
each
ethephon
group)
and
Day
14
(
3,
0,
2
males
in
the
low,
mid
and
high
dose
groups,
respectively,
and
2,
0,
1
females
in
the
low,
mid
and
high
dose
groups,
respectively).
There
were
no
treatment
related
gross
pathological
or
neuropathological
lesions.
Brain
weight,
length
and
width
measurements
were
comparable
in
the
treated
and
control
groups.

Female
mortalities
(
1­
5
days
after
treatment)
at
the
two
highest
dose
groups,
various
cholinergic
signs
of
toxicity
and
FOB
findings
among
all
treatment
groups
that
persisted
throughout
the
observation
period
are
all
neurotoxicological
and
are
treatment
related.
Therefore
the
LOAEL
is
500
mg/
kg
bw
(
lowest
dose
tested)
based
on
FOB
findings
(
pinpoint
pupils
that
persisted
throughout
the
14
days
observation
period).
A
NOAEL
was
not
determined.

2­
Week
Range
Finding
Study
(
for
neurotoxicity
dose
selection)
­
Rat.
In
a
2­
week
range­
finding
study
(
MRID
44283001),
to
assess
its
potential
toxicity
and
to
provide
information
on
dose
levels
for
use
on
a
subsequent
13­
week
neurotoxicity
study,
ethephon
technical
grade
Base
20
(
Lot
No.
4051511;
72.5%
a.
i.)
was
administered
by
gavage
to
Sprague­
Dawley
Crl:
CDR(
SD)
BR
rats
(
6/
sex/
group)
at
dose
levels
of
0,
100,
300,
600,
or
1000
mg/
kg/
day.
The
rats
were
evaluated
for
reactions
in
functional
observations
and
motor
activity
measurements
at
2
days
prior
to
study
initiation,
and
prior
to
dosing
on
Days
2
and
8,
and
on
Day
15.

Many
rats
in
the
1000
mg/
kg/
day
(
6/
6
males,
5/
6
females
died
between
Days
3
and
10
of
treatment),
and
600
mg/
kg/
day
(
2/
6
males,
4/
7
females
died
between
Days
2
and
9
of
treatment)
treatment
groups
died
prematurely.
No
particular
gross
histopathological
abnormalities
were
associated
with
treatment.
The
most
common
treatment­
related
observations
in
the
1000
and
600
mg/
kg/
day
treatment
groups
were
abnormal
respiratory
sound
and
respiration
rates.
Rats
in
the
­

4
­
1000
and
600
mg/
kg/
day
treatment
groups
had
mean
body
weights
27­
34
and
13­
19%
lower,
respectively,
than
the
controls
(
days
8­
12),
and
a
mean
food
consumption
23­
48%
lower
than
the
controls
during
the
first
week
of
the
study.

Mean
RBC
Cholinesterase
(
ChE)
activity
levels
were
not
affected
at
any
level.
Mean
plasma
ChE
activity
levels
were
reduced
in
rats
in
all
treatment
groups
on
all
sampling
dates
during
treatment
(
Days
2,
8
and
15)
compared
to
the
controls.
In
male
rats
at
15
days
(
8
days
for
the
1000
mg/
kg/
day
group),
plasma
ChE
activity
levels
in
the
1000,
600,
300,
and
100
mg/
kg/
day
treatment
groups
were
57,
28,
26,
and
16%
lower,
respectively,
than
the
controls.
In
female
rats
at
15
days,
plasma
ChE
activity
levels
in
the
1000,
600,
300,
and
100
mg/
kg/
day
treatment
groups
were
76,
70,
56,
and
32%
lower,
respectively,
than
the
controls.
With
the
exception
of
reduced
plasma
ChE
activity
levels,
rats
in
the
300
and
100
mg/
kg/
day
treatment
groups
exhibited
no
response
to
treatment.

The
LOAEL
for
systemic
toxicity
is
600
mg/
kg/
day
based
on
mortality
and
cholinergic
signs
(
abnormal
respiratory
sounds
and
breathing)
and
body
weight
loss.
The
NOAEL
for
systemic
toxicity
is
300
mg/
kg/
day.
Plasma
ChE
activity
was
inhibited
at
all
dose
levels
but
not
RBC
ChE
activity.
Brain
ChE
activity
was
not
evaluated.

Subchronic
Neurotoxicity
Study
­
Rat.
In
a
subchronic
neurotoxicity
study
(
MRID
44283002),
ethephon
technical
grade
(
72.5%
a.
i.)
was
administered
by
gavage
to
Sprague­
Dawley
rats
(
22/
sex/
group)
at
dose
levels
of
0,
75
or
150
mg/
kg/
day
for
13
weeks.
Additional
rats
(
22/
sex)
were
administered
ethephon
technical
grade
at
400
mg/
kg/
day
for
10
weeks,
then
due
to
mortality
the
dose
was
reduced
to
300
mg/
kg/
day
for
the
remaining
3
weeks
of
the
study.
The
rats
were
evaluated
by
functional
observation
battery
(
FOB)
and
motor
activity
testing
prior
to
treatment
and
during
weeks
4,
8,
and
13
of
treatment.
All
animals
were
examined
twice
daily
for
mortality
and
clinical
signs.
Body
weights
were
recorded
at
least
once
during
the
acclimation
period,
weekly
during
the
study
and
prior
to
sacrifice.

No
treatment­
related
changes
in
motor
and
locomotor
activity
were
observed
during
the
study.
Male
rats
in
the
400/
300
mg/
kg/
day
treatment
group
were
more
difficult
to
remove
from
the
home
cage
(
p<
0.05
at
Week
13)
and
more
vocal
during
removal
(
p<
0.01
at
Week
8)
compared
to
the
controls
and
other
treatment
groups.
These
males
also
had
a
slightly
higher
incidence
of
abnormal
respiratory
sounds
(
13/
22
males,
11/
22
females)
during
the
FOB
battery.
In
addition,
males
(
6/
22)
were
cold
to
the
touch
and
exhibited
a
2x­
3x
higher
incidence
of
fur
staining
around
the
head.
No
other
differences
between
the
male
400/
300
mg/
kg/
day
treatment
group
and
the
controls
were
noted.
No
differences
in
the
FOB
battery
results
were
observed
between
the
male
150
or
75
mg/
kg/
day
treatment
groups
and
the
controls,
or
between
any
female
treatment
group
and
the
controls.

Six
rats
(
3/
22
males,
3/
22
females)
died
during
weeks
5
and
10
of
treatment
at
the
400
mg/
kg/
day.
Rats
in
the
400/
300
mg/
kg/
day
treatment
group
had
body
weights
up
to
9%
lower
than
the
controls,
and
exhibited
a
poor
general
physical
condition
(
5/
22
males,
1/
22
females)
compared
to
the
other
test
groups.
Food
consumption
was
comparable
in
all
groups.
Absolute
brain
weights
of
males
in
the
400/
300
mg/
kg/
day
treatment
groups
were
9%
lower
(
0.18
g)
than
the
controls;
relative
weights
were
unaffected,
and
the
difference
could
be
attributed
to
the
depressed
body
weights.
There
were
no
treatment­
related
differences
in
mean
brain
length
and
­

5
­
width
measurements.
No
mortality
or
clinical
signs
of
toxicity
occurred
in
the
75
and
150
mg/
kg/
day
groups.
The
mean
body
weights
of
animals
in
these
two
groups
were
slightly
(#
3%)
but
not
significantly
lower
than
the
controls
at
most
study
intervals.
Brain
cholinesterase
(
ChE)
activity
levels
were
not
affected
by
treatment.
Mean
RBC
and
plasma
ChE
activity
levels
were
significantly
(
p<
0.01
or
0.001)
reduced
in
rats
in
the
400/
300
mg/
kg/
day
treatment
groups
on
all
sampling
dates
during
treatment
compared
to
the
controls.
Mean
RBC
and
plasma
ChE
activity
levels
were
also
reduced
in
rats
in
the
150
and
75
mg/
kg/
day
treatment
groups;
the
difference
was
not
significant
at
all
intervals.
Thus
at
4
weeks,
the
RBC
ChE
activity
was
significantly
reduced
in
females
but
not
in
males
at
the
75
and
150
mg/
kg/
day
dose
levels
(
p<
0.01­
p<
0.001).
At
14
weeks,
RBC
ChE
activity
levels
in
the
400/
300,
150,
and
75
mg/
kg/
day
treatment
groups
(
males
and
females)
were
19­
22,
9­
12,
and
8­
10%
lower,
respectively,
than
the
controls.
At
14
weeks,
plasma
ChE
activity
levels
in
the
male
and
female
treatment
groups
were
20­
25
and
43­
64%
lower,
respectively,
than
the
controls.
With
the
exception
of
reduced
RBC
and
plasma
ChE
activity
levels,
rats
in
the
150
and
75
mg/
kg/
day
treatment
groups
exhibited
no
response
to
treatment.
No
treatment­
related
gross
pathological
abnormalities
were
observed
in
any
treatment
group.
No
macroscopic
or
microscopic
abnormalities
were
observed
in
any
of
the
nervous
system
tissues
in
the
treated
rats.

The
LOAEL
for
neurotoxicological
effects
(
abnormal
respiratory
sounds
in
males
and
females,
vocal
males,
cold
to
touch
in
males
and
mortality)
is
400/
300
mg/
kg/
day
and
the
NOAEL
is
150
mg/
kg/
day.
Brain
ChE
activity
was
not
inhibited
at
any
of
the
dose
levels.

In
separate
studies
conducted
by
the
same
laboratory,
reliability
of
functional
observations
by
several
observers
were
reported
in
a
study
using
acute
doses
of
DDT
or
carbaryl
or
subacutely
with
acrylamide
in
the
same
strain
of
rats
(
MRID
43495514).
The
validity
of
the
laboratory
testing
procedures
was
also
demonstrated
in
two
separate
subchronic
studies
using
the
positive
control
agent
acrylamide
(
MRID
44892202
&
MRID
43495515)
where
full
functional
observation
battery
as
well
as
motor
activity
assessments
and
neuropathological
evaluations
were
conducted.

Sub­
Chronic
Toxicity
Study
­
Mice.
In
a
30­
day
feeding
study
(
MRID
00087920)
to
determine
maximum
tolerated
dose,
ethephon
(
Lot
#
and
purity
not
given)
was
administered
to
albino
mice
Blu:
Ha
(
ICR)
(
10/
sex/
dose)
at
dietary
levels
of
0,
225,
450,
900
,
1800
or
3600
ppm
(
0,
34,
68,
135,
270
or
540
mg/
kg/
day
using
standard
conversion
factor)
for
30
days.
Body
weights
were
recorded
at
initiation
of
the
study
and
weekly
afterwards.
Food
consumption
was
recorded
weekly.
Plasma
and
RBC
ChE
activity
was
determined
days
6,
13,
20
and
28.
At
termination,
gross
autopsies
were
performed
and
brain,
liver,
kidney
and
spleen
weights
were
recorded.
Histopathological
examinations
were
not
performed.

There
were
no
mortalities
and
the
mice
appeared
normal
with
no
effect
on
food
consumption
or
body
weight.
Gross
autopsy
did
not
reveal
any
effects.
A
treatment­
related
significant
depression
in
male
relative
liver
weight
was
observed
at
1800
and
3600
ppm.

RBC
ChE
activity
was
significantly
depressed
in
males
of
the
450
ppm
group
by
the
end
of
the
fourth
week,
and
in
females
by
the
end
of
the
second
week.
In
the
900
ppm
group,
RBC
ChE
activity
became
significantly
depressed
in
males
and
females
by
the
end
of
the
second
week.
In
the
1800
ppm
group,
RBC
ChE
activity
became
significantly
depressed
in
females
by
the
end
of
­

6
­
the
first
week
and
in
the
males
by
the
end
of
the
second
week.
In
the
3600
ppm
group
it
was
significantly
depressed
in
both
males
and
females
by
the
end
of
the
first
week.
Plasma
ChE
activity
was
significantly
depressed
in
both
sexes
by
the
end
of
the
first
week
at
doses
of
900
ppm
and
higher.
By
the
end
of
the
study
significant
and
dose
related
depression
was
observed
in
both
sexes
at
dose
level
of
450
ppm
and
greater.
Brain
ChE
activity
was
not
determined.

The
LOAEL
for
systemic
toxicity
is
1800
ppm
(
270
mg/
kg/
day)
based
on
a
significant
depressed
male
relative
liver
weight
and
the
NOAEL
is
135
mg/
kg/
day.

Chronic
Toxicity
Study
­
Dogs.
In
a
two
year
chronic
feeding
study
(
MRID
00060359
&
00147357),
ethephon
AL
(
Source
A:
1030­
42;
75.6%
a.
i.)
was
administered
to
young
adult
Beagle
dogs
(
6/
sex/
dose)
at
dietary
dose
levels
of
0,
30,
300
or
3000
ppm
(
0,
0.75,
7.5,
75
mg/
kg/
day)
for
104
weeks.
A
second
group
(
6/
sex)
was
administered
300
ppm
(
7.5
mg/
kg/
day)
of
ethephon
from
a
different
Source
(
Source
B:
AL­
3096;
73.6%).
In
the
3000
ppm
group,
ethephon
dietary
levels
were
reduced
to
2000
ppm
during
weeks
4­
5
and
to
1000
ppm
during
weeks
6­
24
and
increased
afterward
to
1500
ppm
(
37.5
mg/
kg/
day)
during
weeks
25­
104.
Diets
were
prepared
weekly
and
no
stability
data
were
reported.
Dogs
were
observed
daily
for
clinical
signs.
Body
weights
and
food
consumption
were
recorded
weekly
for
the
first
4
weeks
and
every
4
weeks
afterwards.
Various
clinical
chemistry
measurements
including
ChE
enzyme
activities
were
conducted.
Dogs
were
sacrificed
and
various
organs
examined
macroscopically
and
microscopically.

There
was
no
mortality
in
any
of
the
groups.
There
were
no
remarkable
treatment­
related
signs
of
toxicity.
Minimal
body
weight
losses
and
decreased
food
consumption
were
noted
only
in
the
3000
ppm
group
dogs
during
the
first
3
weeks
of
the
study.
Following
reduction
in
the
dietary
levels
to
2000
ppm,
1000
ppm
and
eventually
to
1500
ppm,
body
weights
and
food
consumption
recovered
in
this
group.
A
slight
decrease
in
the
hematocrit,
hemoglobin
and
RBC
values
of
the
high
dose
females
at
26
weeks
was
reported.
Plasma
ChE
activity
was
significantly
(
statistically,
P<
0.05)
reduced
in
all
test
animals
at
all
sampling
intervals
of
6,
13,
26,
52,
78
and
104
weeks
(
21.64­
66.72%
reduction
in
males
and
23.95­
65.11%
in
females).
RBC
ChE
values
were
also
reduced
significantly
(
statistically)
at
all
sampling
intervals
in
the
300
and
3000
ppm
groups
(
42.19­
79.48%
reduction
in
the
males
and
36.45­
79.02%
in
the
females)
but
not
in
the
30
ppm
group.
Brain
ChE
activity
was
not
inhibited
in
any
of
the
test
groups
and
was
higher
than
the
control
value
(
20.6­
52.9%
above
the
mean
control
value
in
the
females
and
3.68­
38.95%
in
the
males).
Glucose
levels
and
SGPT
were
elevated
in
an
inconsistent
way
in
some
high
dose
animals
while
alkaline
phosphatase
(
SAP)
was
decreased
in
some
high
and
mid­
dose
animals.
These
changes
were
not
considered
to
be
treatment
related.
There
was
no
consistent
pattern
of
organ
weights
and
organ/
body
weight
ratios
when
compared
to
controls.
Occasional
necrotic
thickening
of
the
walls
of
the
stomach
and
duodenum
were
noted
in
all
test
groups
treated
with
Source
A
of
ethephon.
Histopathogical
findings
were
noted
in
the
gastrointestinal
tract
of
dogs
such
as
smooth
muscle
hypertrophy
in
the
stomach/
or
small
intestine
(
4
in
the
high
dose
dogs
and
2
in
the
mid
dose
females).
These
lesions
were
considered
A
incidental
and
not
of
toxicological
concern
@

(
HED
001407).
This
hypertrophy
may
have
also
been
A
secondary
to
the
soft
stool
and
emesis
which
occurred
in
animals
at
the
high
dose
level,
and
infrequently
at
the
next
lower
dose
level
@

(
HED
007214).
Furthermore,
these
lesions
were
not
seen
in
a
later
one
year
study
in
dogs
administered
ethephon
at
doses
up
to
2000
ppm
(
MRID
41135001).
No
compound
related
alterations
were
noted
in
the
low
dose
group
or
in
the
mid
dose
group
treated
with
Source
B
of
­

7
­
the
test
material.
A
study
addendum
with
additional
histopathology
data
on
pancreatic
sections
from
these
dogs
revealed
no
changes
to
the
pancreas
(
MRID
00147357,
HED
004773).

The
LOAEL
for
systemic
toxicity
is
>
1500
ppm
(>
37.5
mg/
kg/
day)
based
on
lack
of
toxicity
at
this
dose.
The
NOAEL
is
1500
ppm
(
37.5
mg/
kg/
day).

Human
studies
Oral
Toxicity
Study
­
Humans.
In
a
non­
guideline
special
human
study
(
MRID
00036510),
ethephon
was
administered
by
capsule
in
a
powdered
formulation
(
10%
a.
i.
weight/
weight)
of
hydrated
silica
and
starch
to
human
adults
(
5/
sex)
at
an
average
dose
of
1.8
mg
a.
i./
kg/
day
or
placebo
0
mg/
kg/
day
(
3/
sex)
for
28
consecutive
days.
Administration
of
the
test
material
or
the
placebo
was
given
orally
by
capsule
divided
into
three
daily
doses.
Each
subject
received
2
capsules
postprandially
for
the
first
two
dosing
periods;
the
third
dose
was
given
at
the
end
of
the
work
day
in
order
to
simulate
as
closely
as
possible
ingestion
of
the
material
as
a
crop
residue.
The
capsules
were
dispensed
daily
(
5
days/
week)
by
an
assistant
who
observed
the
subjects
while
they
took
each
capsule
and
recorded
solicited
comments
related
to
the
ingestion
of
the
material
during
the
first
8
hours.
The
subjects
and
the
assistant
did
not
know
which
capsules
were
placebo
or
the
test
material.
Each
Friday,
the
subjects
received
a
supply
of
capsules
to
be
taken
during
the
two
day
weekend.
All
subjects
were
monitored
regularly
for
adverse
effects.
Hematology
measurements,
clinical
chemistry
and
urinalysis
were
conducted
initially
and
on
Days
7,
14,
21,
28
and
2
weeks
following
the
last
administration.
ChE
(
plasma
and
RBC)
determinations
were
conducted
using
the
 
pH/
hr
method
(
modified
Michel
method)
initially,
and
on
Days
1,
2,
7,
14,
28
and
2
weeks
after
the
last
administration.

The
ethephon
subjects,
though
exhibiting
normal
physical
appearance
and
behavior,
developed
symptoms
consistent
with
exposure
to
a
cholinesterase
inhibitor
such
as
diarrhea,
increased
urination
and
bowel
movement.
Thus
3
females
and
one
male
experienced
a
sudden
A
onset
of
diarrhea
@

or
an
urgency
of
bowel
movement
of
1­
4
days
duration
during
the
first
week
of
the
compound
administration;
the
one
male
experienced
also
loose
stools
for
2
weeks.
Another
male
complained
of
stomach
cramps
or
gas
for
the
duration
of
the
study.
One
subject
in
the
ethephon
group
was
asymptotic.
Five
subjects
experienced
increased
urgency
and
frequency
of
urination,
4
of
whom
experienced
this
symptom
throughout
the
study.
Two
subjects
experienced
decreased
appetite
while
a
third
one
(
experiencing
diarrhea)
experienced
increased
appetite
during
the
first
2
days
of
the
study.
None
of
the
placebo
subjects
had
similar
complaints.

Unexpectedly,
plasma
and
RBC
ChE
activities
were
similar
or
slightly
higher
than
initial
values
in
the
test
subjects
(
the
details
of
the
ChE
determinations
were
not
provided).
No
compound
effects
regarding
hematology,
clinical
chemistries
and
urinalysis
were
reported.

It
is
concluded
that
the
daily
dose
of
1.8
mg/
kg/
day
is
the
LOAEL
for
the
oral
ingestion
of
ethephon
in
human
subjects.
The
NOAEL
is
<
1.8
mg/
kg/
day.

Oral
Toxicity
Study
­
Humans.
In
a
non­
guideline
special
human
study
(
MRID
00066931),
ethephon
was
administered
by
capsule
in
a
powdered
formulation
(
2.5%
a.
i.
weight/
weight)
of
hydrated
silica
and
starch
to
human
adults
(
10/
sex)
at
an
average
dose
of
0.5
mg
a.
i./
kg/
day
or
placebo
0
mg/
kg/
day
(
6
males
and
4
females)
for
16
consecutive
days
followed
by
a
29
day
­

8
­
recovery
period
(
phase
3).
The
dosing
phase
(
phase
II)
was
preceded
with
a
6
day
period
(
phase
I)
where
all
subjects
received
daily
placebos.
Administration
of
the
test
material
or
the
placebo
was
given
orally
by
capsule
divided
into
three
daily
doses.
Each
subject
received
2
capsules
postprandially
for
the
first
two
dosing
periods;
the
third
dose
was
given
at
the
end
of
the
work
day
in
order
to
simulate
as
closely
as
possible
ingestion
of
the
material
as
a
crop
residue.
The
capsules
were
dispensed
daily
(
5
days/
week)
by
an
assistant
who
observed
the
subjects
while
they
took
each
capsule
and
recorded
solicited
comments
related
to
the
ingestion
of
the
material
for
8
hours.
The
subjects
and
the
assistant
did
not
know
which
capsules
were
placebo
or
the
test
material
in
of
the
study
phases.
Each
Friday,
the
subjects
received
a
supply
of
capsules
to
be
taken
during
the
two
day
weekend.
All
subjects
were
monitored
regularly
for
adverse
effects.
Hematology
measurements
and
clinical
chemistry
were
conducted
on
blood
samples
collected
during
phases
I,
II
and
III
while
urinalysis
was
conducted
on
samples
collected
during
phase
II.
ChE
(
plasma
and
RBC)
determinations
were
conducted
using
the
 
pH/
hr
method
(
modified
Michel
method)
on
blood
collected
during
phases
I,
II,
and
III.

No
clinical
symptoms
were
reported.
Hematological,
clinical
chemistry
values
and
urinalysis
parameters
were
comparable
to
the
placebo
controls.
Plasma
and
RBC
ChE
activities
were
significantly
inhibited
in
both
placebo
and
test
groups.
­

9
­
Weight
of
Evidence
Discussion
and
Endpoint
selection.
Selection
of
endpoints
for
ethephon
has
been
difficult.
At
times,
ethephon
has
been
regarded
as
an
organophosphate
because
it
is
in
fact
an
organophosphorus
compound
and
because
it
inhibits
plasma
and
RBC
cholinesterase
­
at
levels
as
low
as
7.5
mg/
kg
in
dogs.
On
the
other
hand,
ethephon
as
a
dibasic
phosphonate
is
chemically
unlike
the
organophosphate
triesters
that
are
the
subject
of
the
Agency
=

s
Organophosphate
Cumulative
risk
assessment.
Clinical
signs
of
neurotoxicity
in
animal
studies
are
not
apparent
except
at
high
doses
of
ethephon
­
300
mg/
kg
and
higher.

Both
human
studies
discussed
in
this
paper
have
been
used
to
establish
RfDs.
In
1988,
HED
first
set
an
RfD
for
ethephon
and
it
was
based
on
the
16­
day
human
study
in
which
there
was
plasma
cholinesterase
depression
at
0.5
mg/
kg.
This
RfD
is
in
the
current
version
of
IRIS.
The
1995
Ethephon
RED
discusses
the
chronology
of
RfD
selection
from
1988
to
1995:

A
j.
Reference
Dose/
Other
Toxicological
Considerations
The
RfD
for
this
chemical
was
first
assessed
by
the
Health
Effects
Division
RfD
Committee
on
March
8,
1988
and
subsequently
verified
by
the
Agency
RfD
Work
Group
on
March
23,
1988.
At
that
time
the
RfD
was
based
on
a
16­
day
human
study
(
MRID
00066931)
with
a
LOEL
of
0.5
mg/
kg/
day
(
only
dose
tested)
for
plasma
cholinesterase
inhibition.
An
uncertainty
factor
(
UF)
of
100
was
used
to
account
for
intraspecies
variability
and
the
lack
of
a
NOEL.
On
this
basis,
the
RfD
was
calculated
to
be
0.005
mg/
kg/
day.
Subsequently,
a
new
chronic
feeding
study
in
dogs
and
a
carcinogenicity
study
in
mice
were
submitted.
The
OPP/
HED
RfD
Peer
Review
Committee
determined
on
February
10,
1994
that
the
reference
dose
(
RfD)
should
be
based
on
the
28­
day
study
in
human
subjects
(
MRID
00036510).
Clinical
signs
of
toxicity
were
observed
at
1.8
mg/
kg/
day
(
only
dose
tested)
and
included
diarrhea,
urgency
of
bowel
movements,
urinary
urgency
and
stomach
cramps.
An
uncertainty
factor
(
UF)
of
100
was
used
to
account
for
intraspecies
variability
and
the
lack
of
a
NOEL.
On
this
basis
the
RfD
was
calculated
to
be
0.018
mg/
kg/
day,
the
chronic
dietary
endpoint.@

The
rationale
for
the
switch
in
human
studies
has
not
been
articulated
anywhere.
A
Report
from
HED's
Hazard
Identification
and
Assessment
Review
Committee
(
HIARC)
dated
4/
1/
98
states
in
reference
to
the
28­
day
human
study:
A
This
human
study
is
considered
to
be
of
better
quality
and
the
findings
more
reliable
than
the
16­
day
human
study
previously
used
to
define
the
RfD.@
The
updated
executive
summary
of
the
DER
for
the
16­
day
human
study
states:
A
Plasma
and
RBC
ChE
activities
were
significantly
inhibited
in
both
placebo
and
test
groups.
Therefore,
this
finding
makes
any
conclusions
regarding
the
effects
attributable
to
ethephon
administration
impossible.
This
is
in
contradiction
to
the
study
authors
overall
conclusion
that
a
daily
ethephon
oral
dosage
of
0.5
mg/
kg/
day
produces
significant
plasma
ChE
inhibition,
which
is
reversible
in
15
days.@

Since
1994,
the
HIARC
has
repeatedly
(
8/
9/
94,
4/
1/
98,
7/
15/
02
and
11/
5/
02)
selected
the
28­
day
human
study
to
assess
all
relevant
exposure
scenarios,
and
at
the
last
HIARC
meeting,
a
weight
­
of
­
evidence
comment
regarding
endpoint
selection
was
included:

A
HIARC
had
considered
experimental
animal
studies
on
ethephon
and
concluded
this
human
study
was
most
appropriate
for
selection
of
the
endpoint
of
toxicity
for
risk
assessment.
The
clinical
signs
of
toxicity
in
this
human
study
occurred
at
dose
levels
that
­

10
­
were
much
lower
than
seen
in
experimental
animals.
In
animals,
ethephon
caused
inhibition
of
blood
(
RBC
and
plasma)
ChE
activity
without
concurrent
clinical
signs
of
toxicity.
At
the
same
time,
brain
ChE
was
not
inhibited
at
any
dose
level
of
ethephon
treatment
in
any
of
the
studies
where
measurements
were
made.
Thus
in
a
2­
week
range
finding
study
in
rats
(
MRID
44283001),
the
NOAEL
for
ethephon
toxicity
was
300
mg/
kg/
day
based
on
mortality
and
cholinergic
signs
of
abnormal
respiratory
sounds
and
breathing
at
600
mg/
kg/
day,
while
plasma
ChE
activity
was
inhibited
at
the
lowest
dose
level
used
of
100
mg/
kg/
day.
In
a
subchronic
neurotoxicity
study
in
rats
(
MRID
44283002)
the
NOAEL
was
150
mg/
kg/
day
based
on
neurotoxic
effects
(
abnormal
respiratory
sounds,
vocalization
in
males,
cold
to
touch
in
males
and
mortality)
occurring
at
400/
300
mg/
kg/
day
while
blood
ChE
activity
was
inhibited
at
all
dose
levels
including
the
lowest
dose
tested
of
75
mg/
kg/
day.@

In
the
developmental
studies
in
rats
and
rabbits
...
ChE
measurements
were
not
made,
but
the
maternal
and
developmental
toxicity
occurred
at
much
higher
doses
than
the
clinical
signs
observed
in
the
human
study.
Therefore,
these
studies
were
considered
inappropriate
for
the
dose
and
end
point
selection
for
risk
assessment.@

Conclusions.
A
number
of
conclusions
relevant
to
endpoint
selection
can
be
drawn
from
the
database
of
ethephon
oral
toxicity
studies
in
humans
and
animals:
(
1)
ethephon
is
neurotoxic
in
animal
studies
only
at
high
doses
(
300
mg/
kg
and
above),
(
2)
ethephon
inhibits
blood
cholinesterases,
in
particular
plasma
cholinesterase
in
animals
and
humans
at
relatively
low
doses,
(
3)
brain
acetylcholinesterase
is
insensitive
to
ethephon
in
adult
animals.
Accordingly,
the
ethephon
risk
assessment
team
concluded
that
measures
of
blood
cholinesterase,
either
plasma
or
RBC,
were
not
appropriate
for
endpoint
selection
for
ethephon.
The
team
then
debated
whether
to
use
effects
in
animals
(
LOAEL
approximately
80
mg/
kg/
day)
or
in
humans
(
LOAEL
of
1.8
mg/
kg/
day)
for
endpoint
selection,
and
opted
as
a
matter
of
prudence
to
base
endpoint
selection
on
effects
observed
in
humans.

The
team
recognized
that
there
are
technical
deficiencies
in
the
human
study,
including
1)
inadequate
reporting
of
experimental
details,
2)
the
clinical
signs
observed
in
the
study,
diarrhea
and
increased
frequency
of
urination,
are
consistent
with
a
cholinergic
mode
of
toxicity,
but
other
signs
associated
with
a
cholinesterase
inhibitor
such
as
pinpoint
pupils
(
miosis),
sweating,
runny
nose,
tearing,
salivation,
respiratory
distress
and
muscle
fasciculation
(
twitching),
were
not
seen,
3)
the
test
subjects
reported
symptoms
as
they
considered
appropriate,
and
it
is
difficult
to
interpret
what
the
self­
reported
symptoms
mean
in
terms
of
a
biological
response.
Despite
the
limitations
of
the
study,
and
the
equivocal
nature
of
the
reported
findings,
the
HED
ethephon
risk
assessment
team
believes
that,
in
the
absence
of
data
ruling
out
the
observed
effects
as
inconsequential,
the
28­
day
human
study
is
the
most
appropriate
study
to
use
for
assessing
both
the
acute
and
chronic
dietary
risks
of
ethephon.

The
point
of
departure
for
the
dietary
assessments
was
1.8
mg/
kg/
day.
An
uncertainty
factor
of
10x
for
intraspecies
variability
and
a
3x
factor
for
use
of
a
LOAEL
was
applied
to
the
POD
to
obtain
a
reference
dose
of
0.06
mg/
kg/
day
for
assessment
of
both
acute
and
chronic
dietary
risks.
­

11
­
Bibliography
Reese,
W.
H.,
Jr.
(
1972)
Final
Report­­
Phase
II:
Evaluation
of
Ethrel
in
Human
Volunteers:
BRL
Project
No.
7223.
(
Unpublished
study
received
on
unknown
date
under
4F1490;
prepared
by
Litton
Industries,
submitted
by
Union
Carbide
Agricultural
Products
Co.,
Ambler,
Pa.;
CDL:
093946­
D)
(
MRID
00036510)

Weir,
R.
J.
(
1977)
Final
Report:
Evaluation
of
Ethephon
in
Human
Volunteers:
LBI
Project
No.
2416.
(
Unpublished
study
received
Aug
30,
1978
under
264­
267;
prepared
by
Litton
Bionetics,
Inc.,
submitted
by
Union
Carbide
Agricultural
Products
Co.,
Inc.,
Ambler,
Pa.;
CDL:
235116­
A)
(
MRID
00066931)
­
12
­

Guideline
No./

Study
Type
MRID
No.
(
year)/

Classification
/
Doses
Plasma
ChEI
RBC
ChEI
Brain
ChEI
Systemic
870.3100
90­
Day
oral
toxicity
rats
00029516
(
1979)

Unacceptable/
Guideline
75%
a.
i.

0,
50,
100
or
200
mg/
kg/
day
Plasma
ChE
activity
in
females
was
74%,
63%

and
59%
of
controls
and
in
males
83%,
83%
and
67%

in
the
50,
100
and
200
mg/
kg/
day
groups,

respectively
at
45
days
and
90
days
(
except
that
the
LDT
group
did
not
differ
from
controls
at
90
days).
RBC
ChE
activity
was
not
affected
at
any
dose
Brain
ChE
activity
was
significantly
depressed
(
75%
and
87%
of
controls)
at
90
days
in
males
in
the
100
and
200
mg/
kg/
day
groups,

respectively.
This
is
also
the
only
study
that
reports
brain
ChE
inhibition
following
treatment
with
ethephon
LOAEL
=
200
mg/
kg/
day
for
systemic
toxicity
based
on
decreased
ovary
weight,

ovarian/
body
weight
ratio
and
liver/
body
weight
ratio
in
females
with
a
NOAEL
of
100
mg/
kg/
day.

Non­
guideline
30
day
oral
feeding
study
Mice
00087920
(
1978)

Acceptable/
Non­

Guideline
Purity
not
reported
0,
225,
450,
900
or
3600
ppm
(
0,
34,
68,
135,
or
540
mg/
kg/
day)
LOAEL
=
68
mkd
Plasma
ChE
activity
was
significantly
depressed
in
both
sexes
by
the
end
of
the
first
week
at
doses
of
900
ppm
and
higher.
By
the
end
of
the
study
significant
and
dose
related
depression
was
observed
in
both
sexes
at
dose
level
of
450
ppm
and
greater.
The
NOAEL
is
34
mkd
LOAEL
=
68
mkd
RBC
ChE
activity
was
significantly
depressed
in
males
of
the
450
ppm
group
by
the
end
of
the
fourth
week,
and
in
females
by
the
end
of
the
second
week.

NOAEL
is
34
mkd
Not
evaluated
The
LOAEL
for
systemic
toxicity
is
1800
ppm
(
270
mg/
kg/
day)
based
on
a
significant
depressed
male
relative
liver
weight
and
the
NOAEL
is
135
mg/
kg/
day.

870.4100b
2­
Year
Chronic
toxicity
­
dogs
00060359
(
1977)

Acceptable/
guideline
75.6%
purity
0,
30,
300
or
3000
ppm
(
0,

0.75,
7.5,
75
mg/
kg/
day)
LOAEL
=
0.75
mkd
Plasma
ChE
activity
was
significantly
(
statistically,

P<
0.05)
reduced
in
all
test
animals
at
all
sampling
intervals
of
6,
13,
26,
52,

78
and
104
weeks
(
21.64­

66.72%
reduction
in
males
and
23.95­
65.11%
in
females).
NOAEL
<
0.75
mkd
LOAEL
=
7.5
mkd
RBC
ChE
values
were
also
reduced
significantly
(
statistically)
at
all
sampling
intervals
in
the
300
and
3000
ppm
groups
(
42.19­

79.48%
reduction
in
the
males
and
36.45­
79.02%
in
the
females)
but
not
in
the
30
ppm
group.
NOAEL
=
0.75
mkd
LOAEL
>
37.5
mkd
Brain
ChE
activity
was
not
inhibited
in
any
of
the
test
groups
and
was
higher
than
the
control
value
(
20.6­
52.9%
above
the
mean
control
value
in
the
females
and
3.68­

38.95%
in
the
males).

NOAEL
=
37.5
mkd
LOAEL
for
systemic
toxicity
is
>
1500
ppm
(>
37.5
mg/
kg/
day)
based
on
lack
of
toxicity
at
this
dose.
The
NOAEL
=

1500
ppm
(
37.5
mg/
kg/
day).
[
The
high
dose
was
eventually
adjusted
to
1500
ppm
(
37.5
mg/
kg/
day)
during
weeks
25­
104.]

870.4100b
2­
week
Range
Finding
Study
for
1­
Year
Chronic
41135001
(
1989)

2­
week
Range
Finding
Study:
30,
100,
300,
1000,

3000,
or
10000
ppm
(
0.8,
LOAEL
=
0.8
mkd.

Plasma
ChE
activity
was
inhibited
at
all
dose
levels
(
36­
93%
at
one
week
and
LOAEL
=
8.2
mkd.
RBC
ChE
activity
was
inhibited
at
levels
of
1000
ppm
and
above
(
47­

90%
at
one
week
and
56­
95%
Not
evaluated
Range
Finding
Study
(
ChEI
not
evaluated
in
main
study)

LOAEL
=
85
mkd.
No
mortalities
or
clinical
signs
were
observed.
The
females
­
13
­

Guideline
No./

Study
Type
MRID
No.
(
year)/

Classification
/
Doses
Plasma
ChEI
RBC
ChEI
Brain
ChEI
Systemic
toxicity
dogs
2.7,
8.2,
28.5,
85.5,
285
mg/
kg/
day)

[
1
animal
per
sex
per
dose
in
range­
finding
study]]
41­
94%
at
two
weeks
in
males
and
27­
94%
at
one
week
and
33­
95%
at
two
weeks
in
females).

NOAEL
<
0.8
mkd.
at
two
weeks)
in
males
and
300
ppm
and
above
in
females
(
22­

93%
at
one
week
and
27­
98%

at
two
weeks).
NOAEL
=
2.7
mkd.
receiving
the
3000
and
10000
ppm
and
the
male
receiving
the
10000
ppm
had
weight
losses.
NOAEL
=
28.5
mkd.

870.4200
18­
Month
Carcinogenicity
Mouse
41050801
(
1988)

Acceptable/
guideline
70.6­
72.1%
a.
i.

0,
100,
1000,
10,000
or
50,000
ppm
(
0,
15.5,
156,
1630,
7750
mg/
kg/
day
A
statistically
significant
(
p<
0.01)
dose
related
depression
in
plasma
ChE
activity
in
males
and
females
was
reported
at
156
&
1630
mg/
kg/
day.

At
52
weeks
the
plasma
ChE
activity
was
65%
of
the
control
in
males
and
59%
of
the
control
in
females
at
156
mg/
kg/
day
A
statistically
significant
(
p<
0.01)
dose
related
depression
in
RBC
ChE
activity
in
males
and
females
was
reported
at
,
156
&
1630
mg/
kg/
day.
At
52
weeks
the
RBC
ChE
activity
was
64%
of
the
control
in
both
males
and
females
at
156
mg/
kg/
day.
Brain
ChE
activity
was
not
inhibited
at
any
of
the
dose
levels.
LOAEL
=
10000
ppm
(
1630
mg/
kg/
day)

based
on
body
weight
and
body
weight
gain
depression
in
females.
NOAEL
=

1000
ppm
(
156
mg/
kg/
day).

The
50,000
ppm
group
was
terminated
at
12
days
due
to
excessive
mortality
and
moribundity
and
clinical
signs
of
tremors
and
dehydration.

Negative
for
carcinogenicity
870.4300
24­
Month
Carcinogenicity
Rats
00060358
(
1978)

Acceptable/
guideline
75.6%
purity
0,
30,
300,
or
3,000
ppm
(
0,
1.5,
15,
150
mg/
kg/
day)
There
was
a
dose
related
inhibition
of
plasma
ChE
activity.
Plasma
ChE
inhibition
ranged
form
17.5­
34.7%
for
high­
dose
males
and
15.7­
61.5%
for
high­
dose
females.

Plasma
activity
was
also
inhibited
to
a
lesser
extent
at
the
300
ppm
level.
There
was
dose
related
inhibition
of
RBC
ChE
activity.

RBC
ChE
inhibition
ranged
from
20­
31%
for
the
high
dose
males
and
15.7­
33.6%
for
the
high
dose
females.
RBC
ChE
activities
was
also
inhibited
to
a
lesser
extent
at
the
300
ppm
level.
Brain
ChE
activity
was
not
inhibited
at
any
of
the
dose
levels.
LOAEL
=
>
3,000
ppm
(
150
mg/
kg/
day)

for
systemic
toxicity,
the
highest
dose
tested,
based
on
the
lack
of
clinical
toxicity
and
treatment
related
histopathological
findings.

NOAEL
=
3000
ppm
(
150
mg/
kg/
day).

There
was
a
significant
increase
in
pancreatic
islet
cell
tumors
at
the
3000
ppm
dose
level
that
were
within
the
historical
range.

870.4300
24­
Month
Carcinogenicity
Rats
41139001
(
1989)

Acceptable/
guideline
70.6­
72.1%
a.
i.

0,
300,
3000,
10000,
or
30000
ppm
(
0,
13,
131,
446,
1465
%,

0,
16,
161,
543,
or
1794
&

mg/
kg/
day)
Plasma
ChE
activity
was
statistically
(
p
<
0.05
­

<
0.001)
significantly
inhibited
at
all
dose
levels
at
test
weeks
13,
26,
51
and
78
in
both
sexes.
ChE
activity
remained
inhibited
in
recovery
animals
one
month
after
discontinued
feeding
of
ethephon.
RBC
ChE
activity
was
statistically
(
p
<
0.05
­<
0.001)

significantly
inhibited
at
all
dose
levels
at
test
weeks
13,

26,
51
and
78
in
both
sexes.

ChE
activity
remained
inhibited
in
recovery
animals
one
month
after
discontinued
feeding
of
ethephon.
RBC
ChE
depressions
of
82­
87%

occurred
in
both
sexesat
the
highest
dose.
Brain
ChE
activity
was
not
inhibited
at
any
of
the
dose
levels.
LOAEL
=
10,000
ppm
(
446
mg/
kg/
day)

for
systemic
toxicity
based
on
reduction
in
mean
body
weight
and
mean
body
weight
gain
in
males
and
the
NOAEL
is
3000
ppm
(
131
mg/
kg/
day).

The
test
material
was
not
carcinogenic
at
the
doses
tested.
­
14
­

Guideline
No./

Study
Type
MRID
No.
(
year)/

Classification
/
Doses
Plasma
ChEI
RBC
ChEI
Brain
ChEI
Systemic
870.6200a
Acute
neurotoxicity
screening
battery
in
rats
44000802
(
1996)

Acceptable/
guideline
72.4%
a.
i.

Single
doses
at
0,
500,

1000
or
2000
mg/
kg
sacrificed
on
Day
15
Not
evaluated
Not
evaluated
Not
evaluated
LOAEL
=
500
mg/
kg
bw
(
the
lowest
dose
tested)
based
on
pinpoint
pupils
in
all
ethephon
treated
groups
which
lasted
throughout
the
observation
period.
A
NOAEL
was
not
established.
Pupillary
constriction,
increased
urination
(
males
only),
reduced
food
consumption
and
body
weight,
decreased
body
temperature
(
females
only),
and
reduced
motor
activity
and
mortality
at
the
mid­
and
the
highdose
level.
No
neuropathological
lesions
were
seen
that
were
attribute
to
treatment.

None­
guideline
2­
week
range
finding
neurotoxicity
study
in
rats
44283001
(
1997)

Acceptable/
nonguideline
72.5%
a.
i.

0,
100,
300,
600,
or
1000
mg/
kg/
day,
gavage.
Plasma
ChE
activity
was
inhibited
at
all
dose
levels
[
RBC
ChE
was
not
inhibited
at
any
dose
level]
Not
evaluated
LOAEL
=
600
mg/
kg/
day
based
on
mortality
and
cholinergic
signs
(
abnormal
respiratory
sounds
and
breathing)
and
body
weight
loss.
The
NOAEL
for
systemic
toxicity
is
300
mg/
kg/
day.

Mortality
at
1000
mg/
kg/
day
(
6/
6
males,

5/
6
females
died
between
Days
3
and
10),

and
600
mg/
kg/
day
(
2/
6
males,
4/
7
females
died
between
Days
2
and
9).

Rats
in
the
1000
and
600
mg/
kg/
day
treatment
groups
had
mean
body
weights
27­
34
and
13­
19%
lower,
respectively,

than
the
controls
(
days
8­
12),
and
a
mean
food
consumption
23­
48%
lower
than
the
controls
during
the
first
week
of
the
study.

870.6200b
Subchronic
neurotoxicity
screening
battery
in
rats
44283002
(
1997)

Acceptable/
nonguideline
72.5%
a.
i.

0,
75
,
150
or
400/
300
mg/
kg/
day
for
13
weeks.
Mean
plasma
ChE
levels
were
significantly
(
p<
0.01
or
0.001)
reduced
in
the
400/
300
mg/
kg/
day
treatment
groups
on
all
sampling
dates
during
treatment
compared
to
the
controls.
Mean
plasma
ChE
activity
levels
were
also
reduced
in
rats
in
the
150
and
75
mg/
kg/
day
treatment
groups,
but
the
Mean
RBC
ChE
levels
were
significantly
(
p<
0.01
or
0.001)

reduced
in
rats
in
the
400/
300
mg/
kg/
day
treatment
groups
on
all
sampling
dates
during
treatment
compared
to
the
controls.
Mean
RBC
ChE
activity
levels
were
also
reduced
in
rats
in
the
150
and
75
mg/
kg/
day
treatment
groups;
the
difference
was
not
significant
at
all
intervals.
Brain
ChE
activity
was
not
inhibited
at
any
of
the
dose
levels.
LOAEL
for
neurotoxic
effects
(
abnormal
respiratory
sounds,
vocalization
in
males,

cold
to
touch
in
males
and
mortality)
is
400/
300
mg/
kg/
day,
the
highest
dose
tested.
The
NOAEL
for
neurotoxic
effects
is
150
mg/
kg/
day.
­
15
­

Guideline
No./

Study
Type
MRID
No.
(
year)/

Classification
/
Doses
Plasma
ChEI
RBC
ChEI
Brain
ChEI
Systemic
difference
was
not
significant
at
all
intervals.

At
14
weeks,
plasma
ChE
activity
levels
in
the
male
and
female
treatment
groups
were
20­
25
and
43­
64%
lower,

respectively,
than
the
controls.
Thus
at
4
weeks,
the
RBC
ChE
activity
was
significantly
reduced
in
females
but
not
in
males
at
the
75
and
150
mg/
kg/
day
dose
levels
(
p<
0.01­

p<
0.001).
At
14
weeks,
RBC
ChE
activity
levels
in
the
400/
300,
150,
and
75
mg/
kg/
day
treatment
groups
(
males
and
females)
were
19­

22,
9­
12,
and
8­
10%
lower,

respectively,
than
the
controls.

Special
studies
Human
Oral
Study
00036510
(
1972)

Acceptable/
non­
guideline
0
(
3/
sex)
or
1.8
mg/
kg/
day
(
5/
sex)
for
28
days
Slight
elevation
(
not
significant)
Slight
elevation
(
not
significant)
Not
evaluated
LOAEL
=
1.8
mg/
kg/
day
based
on
diarrhea
and
increased
urgency
and
frequency
of
urination,
loose
stools,

stomach
cramps
or
gas.

NOAEL
=
<
1.8
mg/
kg/
day
Special
studies
Human
Oral
Study
00066931
(
1977)

Unclassifiable
0
(
6
males
and
4
females)

or
0.5
mg/
kg/
day
(
10/
sex)

for
16
days
with
29
day
recovery
period.
Plasma
activity
was
significantly
inhibited
in
both
placebo
and
test
groups.
RBC
activity
was
significantly
inhibited
in
both
placebo
and
test
groups.
Not
evaluated
No
clinical
symptoms
were
reported.

Hematological,
clinical
chemistry
values
and
urinalysis
parameters
were
comparable
to
the
placebo
controls.