Ethephon:

WOE
Comparison
Of
Human
And
Animal
Studies
For
Single
Chemical
Assessment
Abdallah
Abdallah
Khasawinah
Khasawinah,
Ph.
D.

,
Ph.
D.

U.
S.
EPA
U.
S.
EPA
Office
of
Pesticide
Programs
Office
of
Pesticide
Programs
April
5,
2006
April
5,
2006
2
What
is
What
is
Ethephon
Ethephon?


Organophosphonate
(
2­
Chloroethylphosphonic
acid)


Plant
growth
regulator

Applied
to
vegetables,
fruit
trees,
and
crops

Mode
of
action

Releases
ethylene
gas
thus
inducing
flowering,

ripening,
abscission
formation,
and
the
breaking
of
apical
dominance
3
Ethephon
Ethephon:
Structure
:
Structure
HO
HO
P
O
CH
2CH
2
Cl
4
Human
Study
Details
:
1972
Study
Human
Study
Details
:
1972
Study

Administered
orally
in
capsules
of
powdered
formulation
(
10%
ai)
in
hydrated
silica
and
starch
for
28
days

Dose
 
0
(
3
adults/
sex)
or
1.8
(
5
adults/
sex)
mg
ai/
kg/
day

Age
 
Males
25­
48,
Females
23­
35
years

Weight
°
Males
167­
204,
Females
105­
141lbs
5
Human
Study
Details
Human
Study
Details

Daily
dose
of
4
capsules:


2
postprandially

2
end
of
work
day

Monitored
constantly
hours
1­
8

Clinical
lab
studies
(
hematology,
chemistry,
urinalysis)


Days
 
5,
0,
7,
14,
21
and
28

2
weeks
after
last
dose
6
Human
Study
Details
Human
Study
Details
Cholinesterase
Determination:


Erythrocytes

Blood
plasma

Modified
Michel
method,
measured
on
Day
­
5,
­
2,
0,
1,
2,
7,
14,
and
28
and
2
weeks
after
last
dose
7
Human
Study
Details
:
1977
Study
Human
Study
Details
:
1977
Study

1977
study
was
conducted
at
0.5
mg/
kg/
day

10/
sex
treated
group

6
males
and
4
females

16
days
followed
by
29
day
recovery

Study
conduct
similar
to
the
1972
study
8
­­

Clinical
evaluations
Timing
of
Blood
Sampling
­­
Modified
Michel
Method
No
details
given
­­

Both
Sexes
Treated
Double
Blind
Study
Strengths
One
Dose
Only
in
both
studies
­­
Weaknesses
Table
1.
Comparison
of
strengths
and
weaknesses
of
the
Ethephon
Human
Studies
9
HS
Results
HS
Results
1972
Study:


Diarrhea,
increased
urination
and
bowel
movement,
stomach
cramps
in
treated
subjects.
None
in
placebo
group

No
changes
in
blood
ChE
activity

No
treatment
effects
on
hematology,

clinical
chemistries
and
urinalysis

LOAEL
=
1.8
mg/
kg/
day
10
HS
Results
HS
Results
1977
Study:


No
Clinical
Symptoms
Reported

No
treatment
effects
on
hematology,

clinical
chemistries
and
urinalysis

Plasma
and
RBC
ChE
activities
inhibited
in
both
placebo
and
test
groups
11
Agency
Approaches
of
Agency
Approaches
of
Ethephon
Ethephon
into
Single
into
Single
Chemical
Assessment
Chemical
Assessment
Table
2.
Human
Study
in
Risk
Assessment
Prameter
Human
Study
LOAEL
1.8
mg/
kg/
d
UF
LOAEL
 
to­
NOAEL
3XL
NOAEL
0.6
UF
(
intrasp)
10X
UF
(
intersp)
1X
FQPA
SF
1X
Acute
RfD
0.06
mg/
kg/
d
Chronic
RfD
0.06
mg/
kg/
d
Endpoint
Cholinergic
toxicity
12
Table
3.
Ethephon
Animal
Toxicity
Study
NOAEL
LOAEL
Toxicity
End
Point
2­
Week
Study
­
Rat
300
600
Cholinergic
­
gavage
90­
d
Rat
100
200
Systemic
Toxicity
­
gavage
90­
d
Neurotox.­
Rat
150
300
Cholinergic
­
gavage
Develop.
Rat
500
600
Cholinergic
­
gavage
Develop.
Rabbit
50
100
Cholinergic
­
gavage
2­
Gen.
Repro.
24
245
Body
wt
and
food
consumption
decrease
2­
year
­
Rat
131
446
Systemic
toxicity
18
month
­
Mice
156
1630
Systemic
toxicity
1­
year
­
Dog
28
52
Systemic
toxicity.
anemia
2­
year
Dog
38
>
38
No
toxicity
at
the
highest
dose
tested
13
WOE
Comparison
of
Human
and
Animal
Studies

Human
Studies:
Clinical
signs
at
much
lower
doses

Animals:
Inhibition
of
blood
ChE
activity
without
concurrent
clinical
toxicity

No
increased
pre­
and/
or
post­
natal
toxicity
in
experimental
animals
14
WOE
Comparison
of
Human
and
Animal
Studies

Human
Studies
effects
not
transient

Reflect
toxicokinetics
of
ethephon

Consistent
with
a
C
max
reaction

Repeated
exposures
do
not
lead
to
cumulative
toxicity
 
progression

Ethephon
is
rapidly
absorbed,
metabolized
and
eliminated
15
Ethephon
Ethephon
Charge
to
the
HSRB
Charge
to
the
HSRB

The
Agency's
WOE
document
and
DERs
for
ethephon
describe
the
study
design
and
results
of
the
ethephon
repeat
dose,
oral,
human
toxicity
studies.
The
Agency
has
concluded
that
the
28­

day
human
study
is
sufficiently
robust
to
establish
a
point
of
departure
for
extrapolating
acute
and
chronic
dietary
risk.


Please
comment
on
the
scientific
evidence
that
supports
this
conclusion.
