Document ID: EPA-HQ-OPP-2002-0262-0049
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-04-08T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
May
30,
2002
MEMORANDUM
SUBJECT:
Endosulfan:
Reevaluation
of
the
HED
Risk
Assessment
for
the
Endosulfan
Reregistration
Eligibility
Decision
(
RED)
Document.
Chemical
No.
079401.
Case
No.
0014.
Barcode
D250471.

FROM:
Diana
Locke,
Ph.
D.
Reregistration
Branch
II,
Health
Effects
Division
(
7509C)

THRU:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
Robert
McNally,
Chief
Special
Review
Branch
Special
Review
and
Reregistration
Division
(
7508W)

The
attached
reevaluation
of
the
Human
Health
Assessment
for
the
endosulfan
Reregistration
Eligibility
Decision
(
RED)
document
was
generated
as
part
of
Phase
4/
5/
6
of
the
Proposed
Public
Participation
Process.
The
Health
Effects
Division's
(
HED)
chapter
reflects
revisions
made
in
keeping
with
Agency
responses
to
public
comments,
reviews
of
new
data/
information,
the
Agency's
current
guidelines
concerning
the
retention
of
the
Food
Quality
Protection
Act
(
FQPA)
factor
and
the
risk
assessment,
and
includes
the
results
of
a
dietary
risk
evaluation
using
United
States
Department
of
Agriculture's
(
USDA)
1989­
1992
consumption
data
and
Dietary
Exposure
Evaluation
Model
(
DEEM
 
)
software.
This
chapter
includes
a
summary
of
the
product
chemistry
from
Ken
Dockter,
residue
chemistry
from
John
Punzi,
acute
and
chronic
DEEM
calculations
and
dietary
risk
characterization
from
Sherrie
Kinard,
toxicology
review
from
Robert
Fricke/
Elizabeth
Mendez,
occupational
exposure
from
Renee
2
Sandvig,
incidence
report
from
Jerry
Blondell
&
Monica
Spann,
drinking
water
exposures
from
Nelson
Thurman,
et
al.
[
Environmental
Fate
and
Effects
Division
(
EFED)],
as
well
as
risk
assessment
and
risk
characterization
from
Diana
Locke.

cc:
Stacey
Milan
Margaret
Stasikowski
Lois
Rossi
Pauline
Wagner
3
TABLE
OF
CONTENTS
1.0
EXECUTIVE
SUMMARY
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5
2.0
PHYSICOCHEMICAL
PROPERTIES
CHARACTERIZATION
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9
3.0
HAZARD
CHARACTERIZATION
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11
3.1
Hazard
Profile
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3.2
Pharmacokinetics
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14
3.3
Acute
Toxicity
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14
3.4
Subchronic
and
Chronic
Toxicity
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15
3.5
FQPA
Considerations
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20
3.6
Endocrine
Disruption
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21
3.7
Rationale
for
Retention
of
the
10X
FQPA
Factor
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24
3.7.1
Weight
of
Evidence
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24
3.7.2
Residual
Uncertainties
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28
3.7.3
Other
Considerations
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29
3.8
Dose
Selection
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30
3.8.1
Acute
Reference
Dose
(
RfD)
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30
3.8.2
Chronic
RfD
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32
3.8.3
Dermal
Absorption
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33
3.8.4
Short­
term
(
1­
30
days)
Dermal
Occupational
Exposures
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34
3.8.5
Intermediate­
term
(
one
to
several
months)
Dermal
Occupational
Exposures
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36
3.8.6
Short­
term
(
1­
30
days)
Inhalation
Occupational
Exposures
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36
3.8.7
Intermediate­
Term
(
one
to
several
months)
Inhalation
Occupational
Exposures
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38
3.8.8
Carcinogenic
Potential
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38
4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
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39
4.1
Summary
of
Registered
Uses
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39
4.2
Dietary
Exposure/
Risk
Pathway
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41
4.2.1
Residue
Profile
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41
4.2.2
Acute
Dietary
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43
4.2.3
Chronic
Dietary
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45
4.2.4
Cancer
Dietary
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46
4.3
Drinking
Water
Exposure/
Risk
Pathway
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46
4.3.1
Ground
Water
Resources
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48
4.3.2
Surface
Water
Resources
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48
4.3.3
Estimated
Environmental
Concentrations
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49
4.3.4
Drinking
Water
Levels
of
Comparison
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50
4.4
Residential
Exposure/
Risk
Pathway
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52
4.4.1
Home
and
Recreational
Uses
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52
4.4.2
Other
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52
4
5.0
AGGREGATE
RISK
ASSESSMENT
AND
RISK
CHARACTERIZATION
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52
5.1
Overview
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52
5.2
Acute
Risk
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54
5.2.1
Aggregate
Acute
Risk
Assessment
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54
5.2.2
Acute
DWLOC
Calculations
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54
5.3
Short­
and
Intermediate­
term
Aggregate
Risk
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55
5.4
Chronic
Risk
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55
5.4.1
Aggregate
Chronic
Risk
Assessment
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55
5.4.2
Chronic
DWLOC
Calculations
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56
6.0
CUMULATIVE
RISK
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56
7.0
OCCUPATIONAL
EXPOSURE
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56
7.1
Handler
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56
7.2
Postapplication
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59
7.3
Incident
Data
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61
8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
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62
8.1
Toxicology
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62
8.2
Product
Chemistry
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62
8.3
Residue
Chemistry
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63
8.4
Occupational
Exposure
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63
9.0
ATTACHMENTS
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63
5
1.0
EXECUTIVE
SUMMARY
Endosulfan
(
6,7,8,9,10,10­
hexachloro­
1,5,5a,
6,9,9a­
hexahydro­
6,9­
methano­
2,4,3­
benzodioxathiepin­
3­
oxide)
a
dioxathiepin
(
broadly
classified
as
an
organochlorine),
is
a
broad
spectrum
contact
insecticide
and
acaricide
that
is
used
on
a
wide
variety
of
vegetables,
fruits,
cereal
grains,
and
cotton,
as
well
as
ornamental
shrubs,
trees,
vines,
and
ornamental
herbaceous
plants
in
commercial
agricultural
settings.
Technical
grade
endosulfan
is
composed
of
two
stereochemical
isomers:
"­
endosulfan
and
$­
endosulfan,
in
concentrations
of
approximately
70%
and
30%,
respectively.

Endosulfan
is
formulated
for
occupational
use
as
a
technical
grade
manufacturing
product
(
95%
active
ingredient
[
ai]),
emulsifiable
concentrate
(
9
­
34%
ai),
and
a
wettable
powder
(
1
­
50%
ai).
The
wettable
powder
is
frequently
packaged
in
water
soluble
bags.
It
should
be
noted
that
the
Endosulfan
Task
Force
(
Aventis
Crop
Science
USA
LP,
FMC
Corporation,
and
Makhteshim­
Agan
of
North
America,
Inc.),
who
are
the
primary
data­
submitters
but
not
the
sole
registrants,
are
not
supporting
several
crop,
residential,
and
smoke
canister
uses,
as
well
as
dusts
and
aerosols.
Based
on
the
outcome
of
the
four
6F
Notices
(
02/
05/
97,
02/
13/
97,
03/
18/
98,
and
07/
19/
00)
issued
by
the
Agency,
which
received
no
dissenting
comments
and
have
been
finalized,
the
risk
assessment
was
revised
to
exclude
the
uses
subject
to
those
Notices.
Since
issuance
of
the
preliminary
HED
chapter
(
01/
31/
01),
some
registrants
have
requested
that
new
uses
be
included
but
no
supporting
data
were
provided
and
therefore,
those
uses
have
not
been
included
in
the
risk
assessment.
Depending
on
the
crop
to
be
treated
and
the
formulation
to
be
used,
formulations
containing
endosulfan
may
be
applied
by
groundboom
sprayer,
fixed­
wing
aircraft,
chemigation
(
potatoes
only),
airblast
sprayer,
rights
of
way
sprayer,
low
pressure
handwand,
high
pressure
handwand,
backpack
sprayer,
and
dip
treatment.
The
number
of
allowable
applications
varies,
depending
upon
use.
On
the
majority
of
product
labels,
the
number
of
maximum
allowable
applications
ranges
between
1
and
3
per
season
or
year,
and
does
not
exceed
5.
Over
50
food
tolerances
have
been
established
for
residues
of
endosulfan
in
or
on
various
plant
and
animal
commodities,
and
range
from
0.1
ppm
to
24
ppm.
The
current
tolerance
expression
includes
endosulfan
("­
and
$­
isomers)
and
endosulfan
sulfate
(
a
plant,
animal,
and
environmental
metabolite
of
toxicological
concern).

Due
to
the
availability/
submission
of
acceptable/
guideline
oral,
dermal,
and
inhalation
studies
using
endosulfan,
the
dietary
and
occupational
risk
assessments
were
conducted
using
route­
specific
endpoints.
The
acute
dietary
endpoint
is
based
primarily
on
neurotoxicity.
The
neurotoxicity
is
believed
to
result
from
over­
stimulation
of
the
central
nervous
system
(
CNS).
Characteristic
clinical
signs
of
endosulfan­
induced
neurotoxicity
include,
in
part:
hyperactivity,
tonic
contractions,
involuntary
muscle
movements,
pronounced
sensitivity
to
noise
and
light,
incoordination,
seizures,
and
convulsions.
These
clinical
signs
are
observed
in
humans
accidentally
exposed
to
endosulfan,
and
in
animal
studies
of
varying
treatment
durations
following
different
routes
of
exposure
and
in
different
animal
species.
The
chronic
dietary,
and
short­,
and
intermediate­
term
dermal
and
inhalation
endpoints
are
based
on
the
toxic
effects
observed
in
animals
following
subchronic
or
chronic
exposure,
and
include:
neurotoxicity,
hematological
effects,
and
nephrotoxicity.
In
some
rodent
studies,
endosulfan
inhibited
plasma
cholinesterase
at
the
highest
doses
tested.
Endosulfan
is
not
a
dermal
sensitizer,
nor
is
it
6
mutagenic
or
carcinogenic
("
not
likely"
a
human
carcinogen).

The
endosulfan
residues
of
toxicological
concern
are:
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate
(
6,7,8,9,10,10­
hexachloro­
1,5,5a,
6,9,9a­
hexahydro­
6,9­
methano­
2,4,3­
benzodioxathiepin­
3,3­
oxide).
For
purposes
of
conducting
the
endosulfan
risk
assessment,
the
Agency
assumed
that
the
3
residues
of
toxicological
concern
are
approximately
equal
in
toxicity.
To
fully
characterize
the
hazard
and
subsequent
potential
risk
from
exposures
to
endosulfan,
subchronic
neurotoxicity
and
developmental
neurotoxicity
studies
are
needed.
The
Food
Quality
Protection
Act
Safety
Factor
Committee
(
FQPA
SFC)
concluded
that
a
developmental
neurotoxicity
(
DNT)
study
in
rats
should
be
requested
due
to
concern
by
the
Committee
for:
1)
fetal
effects
reported
in
the
open
literature;
2)
the
severity
of
effects
seen
in
female
offspring
of
the
F
0
generation
(
increased
pituitary)
and
F
1
b
generation
(
increased
uterine
weights)
at
the
highdose
when
compared
to
the
toxicity
observed
in
parental
animals
at
this
dose
in
the
twogeneration
reproduction
study
in
rats;
and
3)
the
subchronic
neurotoxicity
study
will
only
address
the
neuropathological
concerns
resulting
from
exposure
to
endosulfan.
The
potential
for
endosulfan
to
cause
changes
in
endocrine
function
that
lead
to
adverse
effects
was
evaluated
from
the
results
of
the
submitted
guideline
studies
and
available
published
studies.
In
the
process
of
this
evaluation,
endosulfan
was
identified
as
affecting
normal
hormone
metabolism
and
endocrine
function.

For
ease
of
discussion,
unless
specifically
indicated,
the
exposure
and
risk
assessment
review
will
refer
to
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate,
collectively
as
"
endosulfan."

The
FQPA
SFC
recommended
that
the
10x
FQPA
Safety
Factor
be
retained
because
there
were
not
reliable
data
available
to
address
the
following
concerns
or
uncertainties
raised
by
the
following
matters:
1)
evidence
for
increased
susceptibility
of
young
rats,
2)
additional
evidence
for
endocrine
disruption,
3)
uncertainty
regarding
the
neuroendocrine
effects
in
the
young,
and
4)
the
need
for
a
DNT.
The
Committee
determined
that
the
FQPA
safety
factor
(
10x)
is
applicable
for
all
populations
when
assessing
acute
and
chronic
dietary
exposure.
There
are
no
longer
any
supported
residential
uses
of
endosulfan.

Exposure
to
endosulfan
residues
of
toxicological
concern
that
may
occur
from
consumption
of
foods
was
estimated
for
dietary
exposures
that
can
occur
over
a
single­
day
(
i.
e.,
acute)
or
longer
(
chronic),
up
to
a
lifetime.
These
analyses
were
conducted
using
Dietary
Exposure
Evaluation
Model
(
DEEMTM)
version
7.76
software
for
the
general
U.
S.
population
and
for
numerous
population
subgroups,
including
infants,
children,
and
females
of
child­
bearing
age
(
i.
e.,
females
between
13
to
50
years
of
age).
The
acute
dietary
exposure
assessments
were
conducted
using
probabilistic
(
Monte
Carlo)
methodologies.
The
probabilistic
dietary
exposure
analyses
incorporated
residue
estimates
based
largely
on:
percent
crop
treated
(%
CT)
estimates
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD);
data
obtained
from
the
Food
and
Drug
Administration's
(
FDA)
monitoring
program
for
the
years
1994­
1998,
the
United
States
Department
of
Agriculture's
(
USDA)
Pesticide
Data
Program
(
PDP)
for
the
years
1994­
2000;
and,
to
a
lesser
extent,
field
trial
data.
The
residue
estimates,
along
with
data
from
the
USDA's
1989­
1992
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII)
food
consumption
7
survey,
were
used
to
determine
the
exposure
to
food
of
the
various
population
subgroups.
To
assess
risks
from
consumption
of
foods
containing
endosulfan
residues,
the
estimated
acute
and
chronic
dietary
food
exposures
for
all
populations
were
compared
to
the
acute
and
chronic
population
adjusted
doses
(
PADs)
of
0.0015
mg/
kg/
day
(
aPAD)
and
0.0006
mg/
kg/
day
(
cPAD),
respectively.

The
acute
and
chronic
dietary
risk
assessments
were
conducted
for
all
supported
endosulfan
food
uses.
These
assessments
concluded
that
the
acute
risk
estimates
are
above
the
Agency's
level
of
concern
(>
100%
aPAD)
at
the
99.9th
exposure
percentile
for
infants
less
than
1
year
of
age
(
113%
aPAD)
and
children
1­
6
years
of
age
(
146%
aPAD).
The
chronic
risk
estimates
are
below
the
Agency's
level
of
concern
(<
100%
cPAD)
for
the
U.
S.
population
(<
1%
of
the
cPAD)
and
all
population
subgroups,
including
the
highest
exposed
population
subgroup,
children
1­
6
years
of
age
(
17%
cPAD).

Taking
into
account
the
supported
uses
proposed
in
this
action,
the
Agency
concluded
with
reasonable
certainty
that
residues
of
endosulfan
in
drinking
water
would
likely
result
in
a
total
(
food
+
water)
dietary
risk
above
the
Agency's
level
of
concern.
More
specifically,
since
acute
exposures
to
food
alone
result
in
risks
of
concern
for
infants
and
children
1­
6
years
of
age,
any
additional
exposures
to
endosulfan
through
drinking
water
would
increase
the
risks.
However,
modeled
Tier
2
(
PRZM/
EXAMS)
estimates
of
endosulfan
and
endosulfan
sulfate
concentrations
in
surface
water,
combined,
were
below
the
chronic
drinking
water
levels
of
comparison
(
DWLOCs)
for
the
U.
S.
general
population
and
all
population
subgroups
and
therefore,
are
not
of
concern.
The
estimated
ground
water
concentrations
were
also
below
the
chronic
DWLOCs
for
all
population
subgroups
and
are
not
of
concern.
The
Agency
based
this
determination
on
a
comparison
of
estimated
concentrations
of
endosulfan
in
surface
waters
and
ground
waters
to
back­
calculated
"
levels
of
comparison"
for
endosulfan
in
drinking
water.
The
estimates
of
endosulfan
in
surface
and
ground
waters
were
derived
from
water
quality
models
that
used
conservative
assumptions
(
health­
protective)
regarding
the
pesticide
transport
from
the
point
of
application
to
surface
and
ground
water,
and
were
supplemented
with
limited
monitoring
data.
EFED
estimated
acute
(
peak)
and
chronic
(
average)
surface
water
environmental
effect
concentrations
(
EECs)
and
a
ground
water
EEC
for
endosulfan
residues
using
screening­
level
models
and
limited
monitoring
data.
Peak
and
chronic
surface
water
EECs
for
the
combined
residues
of
"­
endosulfan,
$­
endosulfan
and
endosulfan
sulfate
are
8.1
:
g/
L
and
1.3
:
g/
L,
respectively.
The
ground
water
EEC
for
the
combined
residues
is
estimated
to
be
0.012
:
g/
L.
The
available
monitoring
data
indicate
that
90th
percentile
values
would
not
be
expected
to
exceed
peak
EEC
values.
The
Agency's
Office
of
Water
has
not
established
a
Maximum
Contaminant
Level
(
MCL)
for
endosulfan
in
water.

As
mentioned
above,
the
ETF
is
not
supporting
dust
or
smoke
canister
uses,
or
any
uses
of
endosulfan
in
or
around
the
home,
around
public
buildings
or
recreational
areas;
therefore,
the
Agency
did
not
include
the
affected
non­
agricultural
and
residential
uses
in
its
revised
risk
assessment.
However,
the
Agency
is
currently
in
the
process
of
expanding
the
scope
of
the
residential
exposure
assessments
by
developing
guidance
for
characterizing
exposures
from
sources
other
than
residential
uses,
such
as
from
spray
drift;
residential
residue
track­
in;
exposures
to
farm
worker
children;
and
exposures
to
children
in
schools.
Modifications
to
this
8
assessment
shall
be
incorporated
as
updated
guidance
becomes
available.

The
occupational
exposure
assessment
consisted
of
an
analysis
of
the
potential
for
dermal
and
inhalation
exposure
to
occur
in:
1)
occupational
pesticide
handlers
(
includes
mixers,
loaders,
and
applicators);
and
2)
postapplication
workers
during
harvesting
or
other
activities.
Surrogatebased
exposure
assessments
for
each
scenario
were
developed
where
appropriate
data
were
available
using
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1,
and
standard
values.
Submitted
dislodgeable
foliar
residue
(
DFR)
data
on
peaches,
grapes
and
melons
were
used
for
assessing
exposures
during
postapplication
activities
associated
with
fruit
trees
and
lowgrowing
fruit
crops.

There
are
agricultural
and
non­
agricultural
(
e.
g.
ornamentals,
rights­
of­
way)
short­
term
dermal
and
inhalation
occupational
exposures
to
handlers
that
pose
potential
risks
(
Margins
of
Exposure
<
100),
even
with
maximum
feasible
mitigation
measures.
It
is
desirable
that
shortterm
occupational
risks,
expressed
as
MOEs,
be
above
100.
MOEs
below
100
are
of
concern.
Dermal
and
inhalation
risks
for
handlers
were
assessed
separately
since
the
end
effects
for
the
toxicological
endpoints
chosen
for
these
exposures
are
dissimilar
and
Agency
policy
prevents
aggregation
of
the
risks
(
inhalation
plus
dermal)
if
the
toxicological
effects
are
not
the
same.
Handler
exposures
to
endosulfan
are
expected
to
be
short­
term
only
(
1
­
30
days).
Of
the
21
identified
occupational
handler
exposure
scenarios,
5
of
them
are
a
risk
of
concern,
at
the
highest
level
of
mitigation
for
short­
term
dermal
exposure.
For
short­
term
inhalation
exposure,
4
of
the
21
identified
occupational
handler
exposure
scenarios
are
a
risk
of
concern,
at
the
highest
level
of
mitigation.

The
Agency
determined
that
there
are
several
scenarios
in
which
postapplication
occupational
exposure
to
endosulfan
may
occur.
Most
of
these
scenarios
lead
to
dermal
exposure
of
short­
or
intermediate­
term
(
1­
6
months)
duration.
Postapplication
exposures
of
long­
term
duration
are
not
expected.
Short­
and
intermediate­
term
occupational
MOEs
>
100
are
not
of
concern.
For
the
purpose
of
conducting
the
occupational
postapplication
dermal
exposure
assessments,
representative
crop
groups,
and
information
regarding
application
rates
and
dermal
transfer
coefficients
were
used.
Many
of
the
postapplication
exposure
scenarios
lead
to
potential
risks
that
are
of
concern.
Current
endosulfan
labels
list
restricted­
entry
interval
(
REI)
requirements
that
range
from
minimal
reentry
restrictions
(
sprays
have
dried,
etc.),
to
a
24­
hour
REI
with
the
following
early
entry
personal
protective
equipment
(
PPE)
required:
coveralls,
chemical
resistant
gloves,
shoes,
socks,
and
chemical
resistant
headgear
for
overhead
exposures.
For
short­
and
intermediate­
term
postapplication
exposures,
the
day
after
treatment
with
the
emulsifiable
concentrate
(
EC)
formulation
when
the
calculated
MOE
equals
or
exceeds
the
target
MOE
of
100
ranges
from
0
days
(
day
of
application
for
pruning
pecan
trees
to
17
days
for
detasseling
corn
at
an
application
rate
of
1.5
lbs.
ai/
acre.
For
the
wettable
powder
(
WP)
formulation,
the
day
after
treatment
when
the
calculated
MOE
>
100
ranges
from
0
days
for
pruning
pecan
trees
to
30
days
for
girdling
grapes
at
an
application
rate
of
1.5
lbs
ai/
acre.
Thus,
the
current
REI
requirements
do
not
appear
to
be
sufficiently
protective.

Available
incidence
data
clearly
show
that
flagrant
misuse
of
concentrated
formulations
of
endosulfan
could
result
in
exposures
that
cause
serious,
life­
threatening
poisoning,
or
9
permanent
neurological
toxicity.
Both
handler
and
postapplication
workers
have
experienced
moderate
systemic
poisoning
as
a
result
of
exposure
to
endosulfan.
In
addition,
there
appears
to
be
a
consistent
risk
of
skin
rash
or
irritation
among
field
workers
who
have
substantial
contact
with
treated
foliage.
A
number
of
incidents
of
acute
accidental
human
exposure
to
endosulfan
have
been
reported.
The
clinical
signs
and
symptoms
observed
in
humans
following
acute
accidental
exposure
to
endosulfan
are
similar
to
those
observed
in
acute
toxicity
studies
in
animals.
In
humans,
acute
toxicity
caused
by
endosulfan
is
characterized
by
nervousness,
agitation,
tremors,
convulsions,
and
death.
Endosulfan
does
not
appear
to
pose
a
significant
risk
from
spray
drift
exposure.

The
aggregate
risk
assessment
for
endosulfan
considers
exposure
from
food,
drinking
water,
and
residential
uses.
Exposures
to
endosulfan
from
food
sources
alone
are
of
concern
for
infants
and
children
1­
6
years
of
age.
Therefore,
the
Agency
could
not
conclude
with
reasonable
certainty
that
no
harm
would
result
from
acute
dietary
(
food
and
water)
exposure
to
endosulfan
residues.
Chronic
aggregate
risks
are
not
of
concern.
As
mentioned
above,
residential
uses
are
not
being
supported
for
reregistration
and
were
not
included
in
this
assessment.

In
conclusion,
there
are
some
dietary
risk
concerns
for
endosulfan,
especially
for
infants
and
children
1­
6
years
of
age.
In
addition,
there
are
occupational
risk
concerns,
even
with
the
highest
feasible
level
of
mitigation
(
PPE,
engineering
controls).

2.0
PHYSICOCHEMICAL
PROPERTIES
CHARACTERIZATION
Endosulfan
is
a
polychlorinated,
non­
ionic
tricylic
hydrocarbon
that
contains
a
cyclic
sulfite
ester
moiety.
The
fused
tricylic
ring
structure
makes
possible
the
two
isomers,
"­
endosulfan
and
$­
endosulfan.
[
In
some
reference
sources
(
e.
g.
USDA's
Pesticide
Data
Program
database)
"­
endosulfan
is
called
"
endosulfan
I",
and
$­
endosulfan
is
called
"
endosulfan
II".]
The
general
structure
of
endosulfan
and
the
specific
structures
of
its
"­
and
$­
isomers
are
shown
below.
Also
shown
is
endosulfan
sulfate,
a
plant,
animal,
and
environmental
metabolite
of
toxicological
concern.
The
numbers
in
parentheses
are
the
Chemical
Abstracts
Service
registry
numbers.

While
often
referred
to
generically
as
a
"
cyclodiene­
type"
insecticide,
endosulfan
contains
only
one
double
bond.
Technical
endosulfan
(
70%
"­
and
30%
$­
endosulfan)
is
a
light
10
O
O
S
O
Cl
Cl
Cl
Cl
Cl
Cl
endosulfan
(
115­
29­
7
)

Cl
Cl
Cl
Cl
Cl
Cl
H
H
O
O
S
O
alpha­
endosulfan
(
959­
98­
8
)
Cl
Cl
Cl
Cl
Cl
Cl
beta­
endosulfan
(
33213­
65­
9)
H
H
O
O
S
O
O
O
S
O
Cl
Cl
Cl
Cl
Cl
Cl
endosulfan
sulfate
(
1031­
07­
8
)
O
(
stereochemistry
unspecified)

Figure
1.
Structures
of:
endosulfan
(
stereochemistry
unspecified);
a
lpha­
endosulfan;
b
e
ta­
endosulfan;
and
endosulfan
sulfate.

to
dark
brown
crystalline
solid.
Compared
to
most
other
discrete
organic
pesticides,
endosulfan
is
11
relatively
large
in
mass
(
molecular
weight
is
406.95
daltons).
The
melting
point
of
the
"­
isomer
ranges
from
108­
1100
C
and
the
melting
point
of
the
$­
isomer
is
208­
2100
C.
The
melting
point
of
technical
endosulfan
ranges
from
70
to
1000
C.
The
vapor
pressure
of
"­
endosulfan
is
3.0
x
10­
6
mm
Hg,
$­
endosulfan
7.2
x
10­
7
mm
Hg,
and
technical
endosulfan
1
x
10­
5
mm
Hg
at
25
0C.
Technical
endosulfan
has
a
water
solubility
that
varies
from
insoluble
to
~
0.33
mg/
L
at
25
0C,
but
has
appreciable
lipophilicity
(
log
K
ow
4.445
to
5.689).
See
Endosulfan,
Product
Chemistry
Chapter
for
Reregistration
Eligibility
Decision.
Ken
Dockter.
December
18,
1998.

Hexachlorobenzene
and
pentachlorobenzene
are
present
in
technical
endosulfan
in
very
low
concentrations.
These
substances
are
not
formed
during
the
manufacture
of
endosulfan,
but
are
contaminants
of
the
feedstocks
used
for
the
manufacture
of
endosulfan.
The
concentration
of
hexachlorobenzene
in
technical
endosulfan
ranges
from
<
75
to
290
µ
g/
kg
and
the
concentration
of
pentachlorobenzene
ranges
from
1000
to
4900
µ
g/
kg.
The
reaction
conditions
of
the
synthesis
used
to
manufacture
endosulfan
are
such
that
formation
of
chlorinated
dioxins
or
dibenzofurans
are
not
expected.

3.0
HAZARD
CHARACTERIZATION
3.1
Hazard
Profile
Except
for
the
absence
of
subchronic
neurotoxicity
and
developmental
neurotoxicity
studies,
the
toxicology
database
is
sufficiently
complete
for
risk
assessment
purposes.
Endosulfan
is
a
chlorinated
cyclodiene
pesticide,
and
like
other
members
of
this
chemical
group,
the
predominant
toxicological
effect
is
over
stimulation
of
the
CNS
[
by
inhibiting
Ca2+,
Mg2+
­
ATPase
and
antagonizing
chloride
ion
transport
in
gamma­
aminobutyric
acid
(
GABA)
receptors]
with
little
or
no
peripheral
component.
Convulsions
(
seizures)
are
typical
symptoms
of
endosulfan
toxicity.
Characteristic
clinical
signs
following
acute
exposure
are
indicative
of
CNS
disturbances
or
over
stimulation
and
include
hyperactivity,
incoordination,
seizures,
convulsions,
and
death.
Although
these
effects
were
not
generally
observed
at
the
Lowest
Observable
Adverse
Effect
Level
(
LOAEL),
at
higher
doses,
they
were
observed
in
the
acute
and
subchronic
toxicity
studies
and
developmental
studies
in
the
rat
and
rabbit.
In
a
chronic
feeding
study,
dogs
also
exhibited
CNS
disturbances
such
as
abnormal
righting
reflexes,
tonic
contractions,
involuntary
muscle
movements,
and
pronounced
sensitivity
to
noise
and
light
(
ENDOSULFAN
(
PC
Code:
079401)
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Document.
Robert
F.
Fricke.
May
9,
2002).

Endosulfan
is
highly
acutely
toxic
via
the
oral
and
inhalation
routes
of
exposure,
with
LD
50
and
LC
50
values
of
30
mg/
kg
bw
and
<
0.5
mg/
L,
respectively,
placing
it
in
Toxicity
Category
I.
By
the
dermal
route,
however,
endosulfan
was
less
toxic,
with
an
LD
50
of
2000
mg/
kg,
(
Toxicity
Category
III).
Further,
endosulfan
is
an
eye
irritant
in
rabbits
(
Toxicity
Category
I),
but
is
not
a
dermal
irritant
or
sensitizer.

The
subchronic
toxicity
of
endosulfan
was
evaluated
in
two
13­
week
feeding
studies
in
the
rat
and
mouse,
two
21­
day
dermal
toxicity
studies
in
the
rat,
and
one
21­
day
inhalation
study,
12
also
in
the
rat.
In
general,
females
are
more
sensitive
to
the
toxic
effects
than
males.
In
the
13­
week
feeding
studies,
anemia
occurs
[
consisting
of
decreased
hemoglobin
and/
or
decreased
mean
red
blood
cell
(
RBC)
hemoglobin
concentration]
at
the
LOAEL
and
higher
doses
in
both
rats
and
mice.
Treatment­
related
anemia,
however,
was
not
observed
in
any
of
the
21­
day
dermal
or
inhalation
studies.
In
the
dermal
studies
in
rats
increased
mortality
was
observed
at
the
LOAEL.
In
one
of
the
dermal
studies,
other
toxic
effects
at
the
LOAEL
included
increased
incidence
of
liver
abnormalities
in
males
and
females
and
increased
absolute
spleen
weight
in
females.
In
the
other
21­
day
dermal
toxicity
study,
females
exhibited
hypersalivation
(
CNS
effect)
at
the
LOAEL.
In
the
21­
day
inhalation
toxicity
study,
the
LOAEL
was
based
on
decreased
body­
weight
gain
and
decreased
leukocyte
counts
in
the
males
and
increased
creatinine
values
in
the
females.

The
chronic
toxicity
of
endosulfan
was
evaluated
in
a
combined
two­
year
feeding/
carcinogenicity
study
in
rats,
a
one­
year
feeding
study
in
dogs,
and
a
carcinogenicity
study
in
mice.
Chronic
toxicological
endpoints
at
the
LOAEL
included,
in
part,
decreased
body
weight
gain
in
male
and
female
rats
(%
2.9
&
&
3.8
mg/
kg/
d)
and
decreased
body
weight
in
male
dogs
(.
1.75
mg/
kg/
d).
Additional
effects
at
the
LOAEL
included
neurological
effects
in
female
dogs,
marked
progressive
glomerulonephrosis
(
kidney
toxicity)
in
male
and
female
rats
and
blood
vessel
aneurysms
in
males
rats.
Endosulfan
did
not
exhibit
any
carcinogenicity
in
rats
or
mice.

The
developmental
toxicity
of
endosulfan
was
evaluated
in
rats
and
rabbits.
Maternal
toxicity
at
the
LOAEL
included
decreased
body
weights
in
rats
and
rabbits
and
increased
incidence
of
clinical
signs
in
rats
(
tonoclonic
convulsions,
increased
salivation,
mortality)
and
rabbits
(
convulsions,
rapid
breathing,
salivation,
hyperactivity,
mortality).
Developmental
toxicity
in
the
rat
included
a
slight
increase
in
the
incidence
of
fragmented
thoracic
vertebral
centra
and
a
slight
increase
in
the
occurrence
of
microsomic
fetuses.
No
developmental
toxicity
was
observed
in
rabbits.
There
are
no
indicators
of
an
increased
quantitative
sensitivity
to
the
fetus
in
either
of
the
submitted
rat
or
rabbit
studies;
the
LOAELs
for
developmental
toxicity
were
equal
to
or
greater
than
the
LOAELs
for
systemic
maternal
toxicity.

The
reproductive
toxicity
of
endosulfan
was
evaluated
in
a
two­
generation
study
in
the
rat.
LOAELs
for
parental
systemic
and
developmental
toxicity
were
established
at
the
highest
dose
tested.
The
LOAEL
for
parental
systemic
toxicity
was
based
on
decreased
body
weight
and
for
developmental
toxicity,
increased
pituitary
and
uterine
weights.
The
increases
in
pituitary
gland
and
uterine
weights
indicate
possible
effects
on
hormonal
metabolism
and
endocrine
function.
These
effects
also
suggest
a
potential
qualitative
sensitivity
of
offspring
to
endosulfan
exposure
either
in
utero
or
during
early
development.
The
increased
incidence
of
parathyroid
hyperplasia
in
male
rats
in
the
carcinogenicity
study
and
several
open
literature
publications
also
show
that
endosulfan
induces
hormonal
effects.

Endosulfan
was
evaluated
in
an
acute
neurotoxicity
screening
battery
in
the
rat
and
an
acute
delayed
neurotoxicity
study
in
the
hen.
The
LOAEL
in
the
rat
study
was
based
on
behavioral
disturbances
such
as
increased
incidences
of
stilted
gait,
hunched
posture,
irregular
respiration,
and
decreased
spontaneous
activity
in
males
and
females;
females
also
had
increased
incidence
of
straddled
hindlimbs,
panting,
and
bristled
coat.
The
acute
delayed
neurotoxicity
13
study
in
the
hen
showed
no
evidence
of
progressive
nerve
damage
in
the
brain,
spinal
cord
and
peripheral
nerve.

Endosulfan
was
not
carcinogenic
and
did
not
show
any
mutagenic
potential.
There
was
no
increase
in
the
frequency
of
tumors
in
either
the
rat
or
mouse
carcinogenicity
studies.
Endosulfan
is
classified
as
having
no
evidence
of
carcinogenicity
for
humans
by
the
Agency.
The
submitted
mutagenicity
studies
have
satisfied
the
data
requirements
for
mutagenicity
testing,
and
there
is
no
concern
for
a
mutagenic
effect
in
somatic
cells.
In
the
in
vitro
or
in
vivo
mutagenicity
studies,
both
the
mouse
lymphoma
forward
mutation
assay
and
the
unscheduled
DNA
synthesis
assay
were
negative.

Both
hexachlorobenzene
and
pentachlorobenzene
are
considered
by
the
Agency
to
be
possible
human
carcinogens
(
B2
carcinogens).
Agricultural
use
of
endosulfan
poses
a
potential
source
of
human
dietary
exposure
to
hexachlorobenzene
and
pentachlorobenzene
and,
therewith,
poses
a
potential
source
of
cancer
risk.
Hexachlorobenzene
itself
was
once
registered
in
the
United
States
as
a
pesticide
active
ingredient.
The
use
of
hexachlorobenzene
in
the
United
States
as
a
pesticide
active
ingredient
was
canceled
in
1984
(
USEPA.
1985).
In
1998
the
Agency
assessed
the
cancer
risks
posed
by
dietary
exposure
to
hexachlorobenzene
and
pentachlorobenzene
from
the
use
of
endosulfan
and
other
pesticide
active
ingredients
(
Assessment
of
the
Dietary
Cancer
Risk
of
Hexachlorobenzene
and
Pentachlorobenzene
as
impurities
in
Chlorothalonil,
PCNB,
Picloram,
and
several
other
pesticides.
William
Smith.
February
26,
1998)
and
concluded
that
the
cancer
risk
to
humans
from
all
pesticidal
sources
of
dietary
exposure
to
the
combined
residues
of
hexachlorobenzene
and
pentachlorobenzene
was
1.81
x
10­
6.
The
Agency
generally
regards
risk
estimates
that
are
greater
than
1
x
10­
6
to
be
risks
of
concern.
While
the
estimated
cancer
risk
posed
by
dietary
exposure
to
hexachlorobenzene
and
pentachlorobenzene
from
use
of
pesticides
that
contain
these
substances
is
slightly
greater
than
1
x
10­
6,
the
Agency
believes
that
its
cancer
risk
estimate
is
an
overestimate
of
actual
cancer
risk.
This
is
largely
because
the
cancer
risk
assessment
was
based
on
several
worst­
case
assumptions
regarding
the
concentrations
of
hexachlorobenzene
and
pentachlorobenzene
in
the
pesticide
active
ingredients
and
in
foods.
Experimental
data
show
that
the
actual
concentrations
of
hexachlorobenzene
and
pentachlorobenzene
in
the
pesticide
active
ingredients
are
much
lower
than
the
concentrations
used
in
the
dietary
exposure
calculations.

Studies
with
radiolabeled
endosulfan
evaluated
the
metabolism
in
the
rat
and
mouse,
and
dermal
absorption
in
the
rat.
Endosulfan
was
found
to
be
rapidly
metabolized
into
mainly
water­
soluble
compounds
and
eliminated
with
very
little
absorption
in
the
gastrointestinal
tract.
The
primary
metabolites
include
endosulfan
sulfate,
endosulfan
diol,
endosulfan
ether,
endosulfan
alpha­
hydroxy
ether,
and
endosulfan
lactone.
The
metabolites
accumulated
in
tissues,
especially
in
the
kidney
and
liver.
Following
dietary
exposure
to
endosulfan,
a
large
amount
of
endosulfan
sulfate
was
recovered
in
the
liver,
small
intestine
and
visceral
fat,
with
a
trace
of
this
metabolite
in
the
muscle.
Dermal
absorption
studies
in
male
and
female
rats
showed
that
endosulfan
is
slowly
absorbed
through
the
skin
and
is
slowly
excreted.
A
dermal
absorption
factor
of
45%
was
used
for
the
assessment
of
occupational
exposure.

3.2
Pharmacokinetics
14
Results
from
toxicity
studies,
metabolism
studies,
and
dermal
absorption
studies
indicate
that
endosulfan
is
absorbed
following
oral,
inhalation,
or
dermal
exposure.
Absorption
from
the
skin
appears
to
be
slow
and
incomplete.
In
a
study
involving
rats,
radiolabeled­
endosulfan
was
applied
dermally
at
doses
of
0.1,
1,
and
10
mg/
kg
for
ten
hours,
after
which
the
skin
was
washed
with
soap
and
rinsed
with
water.
The
percent
of
dose
absorbed
at
24
hours
post­
dosing
was
22.1,
16.1
and
3.8%,
and
at
168
hours
was
44.8,
46.4
and
20.3%
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.
The
percentages
of
the
doses
remaining
on/
in
the
skins
at
168
hours
were
41.4,
56.2
and
72.8%
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.

Following
absorption
from
the
oral
or
dermal
exposure
routes
endosulfan
is
partially
metabolized,
primarily
to
endosulfan
sulfate.
Minor
metabolites
include
endosulfan
diol,
endosulfan
ether,
endosulfan
"­
hydroxy
ether,
and
endosulfan
lactone.
None
of
the
minor
metabolites
of
endosulfan
are
believed
to
be
of
toxicological
concern.
Endosulfan
and
its
metabolites
partition
and
accumulate
predominately
in
the
kidney
and
liver.
Following
dietary
exposure
to
endosulfan,
a
large
amount
of
endosulfan
sulfate
is
recovered
in
the
liver,
small
intestine
and
visceral
fat,
and
only
a
trace
amount
is
recovered
in
muscle
tissue.
Endosulfan
and
its
metabolites
are
excreted
in
both
the
urine
and
feces,
the
latter
being
the
predominant
route
of
excretion.
Most
of
an
absorbed
dose
of
endosulfan
is
excreted
within
a
few
days
to
a
few
weeks,
depending
upon
dose
and
route
of
exposure.

3.3
Acute
Toxicity
Endosulfan
is
highly
toxic
following
acute
oral
exposure
and
moderately
toxic
following
acute
inhalation
exposure.
In
rats,
oral
median
lethal
doses
(
LD
50
values)
are
82
mg/
kg
(
males)
and
30
mg/
kg
(
females).
Medium
lethal
concentrations
(
LC
50
values)
in
rats
following
acute
inhalation
exposure
range
from
0.16
to
0.5
mg/
L.
Endosulfan
is
considerably
less
lethal,
however,
following
acute
dermal
exposure
(
LD
50
is
2
g/
kg).
Endosulfan
is
an
eye
irritant
in
rabbits
(
Toxicity
Category
I)
but
is
not
a
dermal
irritant
or
sensitizer.

Table
1.
Summary
of
Results
from
Acute
Toxicity
Assays
of
Endosulfan.

Guideline#
Study
Type
MRID
Results
Toxicity
Category
870.1100
Acute
Oral
(
50%
wettable
powder)
41183502
LD
50
=
82
mg/
kg
in
%
LD
50
=
30
mg/
kg
in
&
I
870.1200
Acute
Dermal
(
50%
wettable
powder)
41183503
LD
50
=
2000
mg/
kg
III
870.1300
Acute
Inhalation
50%
wettable
powder)
41183504
LC
50
=
0.16­
0.5
mg/
L
II
870.2400
Primary
Eye
Irritation
50%
wettable
powder)
41183505
Eye
irritant
(
Residual
opacity
at
day
13)
I
870.2500
Primary
Skin
Irritation
50%
wettable
powder)
41183506
Non­
irritant
IV
870.2600
Dermal
Sensitization
41183507
Not
a
dermal
sensitizer
NA
15
3.4
Subchronic
and
Chronic
Toxicity
The
potential
for
endosulfan
to
cause
toxicity
following
subchronic
exposure
was
evaluated
in
several
assays
that
included:
two
separate
13­
week
feeding
studies
in
rats
and
mice,
two
21­
day
dermal
toxicity
studies
in
rats,
and
one
21­
day
inhalation
study
in
rats.
In
the
13­
week
feeding
studies,
treatment­
related
hematological
effects
(
consisting
of
decreased
hemoglobin
and/
or
decreased
mean
RBC
hemoglobin
concentration)
were
noted
in
both
species.

Treatment
related
effects
observed
in
the
dermal
toxicity
studies
involving
application
of
endosulfan
technical
to
the
skins
of
rats
included
increased
mortality
in
female
rats,
decreased
body
weights
in
male
rats,
increases
in
reticulocyte
counts
in
both
sexes,
decreased
plasma
cholinesterase
activity
in
both
sexes,
hypersalivation
(
females),
tonic
convulsions
(
females)
and
tonoclonic
convulsions
(
males),
hepatotoxicity
in
males
and
females,
and
increased
absolute
spleen
weight
in
females.
The
treatment­
related
hematological
effects
observed
in
the
subchronic
dietary
studies
were
not
observed
in
the
21­
day
dermal
studies.
In
the
21­
day
inhalation
toxicity
study
conducted
in
male
and
female
rats,
toxicological
effects
believed
to
be
treatment
related
were
decreased
body­
weight
gain
and
leukocyte
counts
(
males)
and
increased
creatinine
values
(
females).

The
potential
for
endosulfan
to
cause
toxicity
following
chronic
exposure
was
evaluated
from
the
results
of
three
separate
studies
that
included:
a
combined
two­
year
feeding/
carcinogenicity
study
in
rats;
a
one­
year
feeding
study
in
dogs;
and
a
carcinogenicity
study
in
mice.
Some
of
the
noteworthy
treatment­
related
effects
observed
in
these
studies
were:
1)
decreased
body
weight
gain
(
observed
in
male
and
female
rats,
and
male
dogs);
2)
neurological
effects
(
observed
in
female
dogs
as
extreme
sensitivity
to
noise
and
optical
stimuli,
tonic
contractions,
and
in
male
dogs
as
a
loss
of
righting
reflex
and
placing
reaction);
3)
marked
progressive
glomerulonephrosis
(
observed
in
male
and
female
rats);
4)
blood
vessel
aneurysms
(
observed
in
male
rats),
and
5)
increased
mortality
(
observed
in
female
mice).

Endosulfan
is
neither
carcinogenic
nor
mutagenic.
The
carcinogenicity
studies
conducted
in
rats
and
mice
do
not
indicate
that
exposure
to
endosulfan
will
result
in
an
increased
incidence
of
neoplastic
lesions.
In
in
vitro
or
in
vivo
mutagenicity
studies,
both
the
mouse
lymphoma
forward
mutation
assay
and
the
unscheduled
DNA
synthesis
assay
were
negative.

The
neurotoxic
properties
of
endosulfan
were
characterized
primarily
from
results
of
two
studies:
a
screening
battery
study
conducted
in
rats
and
a
42­
day
delayed
neurotoxicity
study
conducted
in
hens.
In
the
rat
study,
endosulfan
was
administered
as
a
single
(
acute)
dose,
and
neurotoxic
signs
were
observed
in
both
male
and
female
rats.
For
male
and
female
rats,
clinical
observations
indicative
of
neurotoxicity
included:
increased
incidences
of
stilted
gait;
squatting
posture;
irregular
respiration;
and
decreased
spontaneous
activity.
Female
animals
also
exhibited
an
increased
incidence
of
straddled
hindlimbs,
panting
and
bristled
coat.
In
the
delayed
neurotoxicity
study
no
evidence
of
progressive
nerve
damage
in
the
brains,
spinal
cords,
or
peripheral
nerves
of
treated
Leghorn
hens
was
identified.

In
addition
to
the
studies
described
above,
the
neurotoxicity
of
endosulfan
was
evaluated
16
from
results
of
other
toxicity
studies
submitted
under
OPPTS
guidelines.
Results
from
some
of
these
studies
indicate
that
endosulfan
causes
neurotoxicity.
In
a
subchronic
(
13­
week)
feeding
study,
plasma
cholinesterase
activity
was
reduced
by
40%
at
week
13
in
female
rats
administered
endosulfan
at
360
mg/
kg/
day.
In
a
separate
subchronic
toxicity
study
in
which
endosulfan
was
administered
dermally
to
rats,
decreased
plasma
cholinesterase
activity
and
tonoclonic
convulsions
were
seen
in
females.
In
a
chronic
study
in
which
endosulfan
was
administered
to
dogs
via
the
diet,
signs
indicative
of
neurological
effects
were
noted
and
included
loss
or
weakening
of
righting
reactions,
and
tonic
contractions
of
the
abdominal
and
masticatory
muscles.
In
a
developmental
toxicity
study
conducted
in
rats,
dams
dosed
at
6
mg/
kg
exhibited
tonoclonic
seizures,
increased
salivation,
and
hyperactivity.
In
a
developmental
toxicity
study
conducted
in
rabbits,
does
dosed
at
1.8
mg/
kg
exhibited
rapid
breathing,
increased
salivation,
hyperactivity
and
tonoclonic
convulsions.

The
potential
for
endosulfan
to
cause
developmental
toxicity
was
evaluated
from
the
results
of
studies
conducted
in
pregnant
rats
and
rabbits
under
OPPTS
guidelines,
and
from
a
published
study
involving
neonatal
rats
(
Lakshmana
and
Raju,
1994).
In
the
studies
conducted
under
OPPTS
guidelines,
pregnant
animals
were
exposed
to
endosulfan.
Results
from
the
OPPTS
guideline
studies
indicate
that
there
is
no
increased
or
special
fetal
sensitivity
to
the
toxicity
of
endosulfan.
Treatment­
related
developmental
toxicity
was
only
noted
in
the
rat
study,
and
only
occurred
at
the
dose
(
highest
dose
tested)
that
also
caused
maternal
toxicity.
The
developmental
toxicity
was
characterized
by
a
slight
increase
in
the
incidence
of
fragmented
thoracic
vertebral
centra
and
a
slight
increase
in
the
occurrence
of
fetuses
weighing
less
than
3
grams.
Results
from
the
study
published
by
Lakshmana
and
Raju
(
1994)
suggest
that
neonates
could
have
special
or
increased
sensitivity
to
the
effects
of
endosulfan.
In
this
study
rat
pups
of
both
sexes
were
administered
endosulfan
via
gastric
intubation
at
6
mg/
kg/
day
from
post­
natal
days
2­
25.
Levels
of
acetyl
cholinesterase,
noradrenaline,
dopamine
and
serotonin
were
assayed
in
the
olfactory
bulb,
hippocampus,
visual
cortex,
brainstem
and
cerebellum.
Performance
in
operant
conditioning
for
solid
food
reward
was
assessed
in
25­
day­
old
rats.
Compared
to
control
animals,
noradrenaline
levels
in
treated
animals
were
increased
in
the
olfactory
bulb,
brainstem,
hippocampus
and
cerebellum
at
25
days
of
age.
Dopamine
levels
were
decreased
in
the
hippocampus
at
both
10
and
25
days.
Serotonin
levels
were
increased
in
the
olfactory
bulb,
hippocampus,
visual
cortex
and
brainstem
at
10
days
of
age,
but
were
decreased
in
the
brainstem
and
cerebellum
at
25
days
of
age.
The
activity
of
acetyl
cholinesterase
was
not
different
from
the
control
groups
in
any
of
the
regions
studied.
These
changes
in
the
concentrations
of
noradrenaline,
dopamine,
and
serotonin
in
the
brains
of
treated
neonates
were
accompanied
by
deficits
in
acquisition
as
well
as
retention
of
memory.

The
potential
for
endosulfan
to
cause
reproductive
toxicity
was
evaluated
from
results
of
a
two­
generation
guideline
study
conducted
in
rats.
In
this
study,
an
initial
parent
(
F
0)
generation
of
rats
were
exposed
to
endosulfan
(
97%
ai)
via
the
diet
during
premating
and
through
gestation
and
lactation
periods,
at
dose
levels
of:
0,
0.20,
1.00,
and
4.99
mg/
kg/
day
in
males;
and
0,
0.24,
1.23,
and
6.18
mg/
kg/
day
in
females.
No
reproductive
toxicity
was
noted.
Pregnancy
rate,
gestation
times,
the
ability
to
rear
young
to
weaning,
and
pre­
coital
time
were
comparable
among
the
groups
at
both
matings
in
both
the
F
0
and
F
1
generations.
Some
effects
indicative
of
developmental
toxicity
were
noted,
but
only
at
doses
(
the
highest
doses
tested)
that
caused
17
parental
toxicity.
These
effects
include:
increased
pituitary
weights
in
high­
dose
female
pups
of
the
first
mating
of
the
F
0
generation;
and
increased
uterine
weights
in
high­
dose
female
pups
of
the
first
mating
of
the
F
l
b
generation.
The
parental
effects
that
occurred
at
the
same
or
lower
dose
levels
include
the
following:
increased
heart
weight
at
the
mid­
and
high­
dose
levels
and
increased
liver
and
kidney
weights
at
the
high­
dose
level
(
F
0
males);
increased
brain
and
liver
weights
at
the
high­
dose
level
(
F
0
females).

Table
2.
Subchronic,
Chronic,
and
Other
Toxicity
Guideline
#/
Study
Type
MRID
#
/
Year/
Classification/
Doses
Results
870.3100
13­
week
subchronic
feeding
study
in
rats
(
97.2%)
00145668
(
1985)
Acceptable/
Guideline
0,0.5,
1.5,
3.0,
&
18
mg/
kg/
d
LOAEL=
1.5
mg/
kg/
d
based
on
kidney
abnormalities
&
increased
spleen
weight
in
male
rats.
NOAEL=
0.5
mg/
kg/
d
870.3100
13­
week
subchronic
feeding
study
in
mice
(
97.2%)
00147182
(
1984)
Acceptable/
Guideline
0,
0.24,
0.74,
2.13,
&
7.3
mg/
kg/
d
for
males.
0,
0.27,
0.80,
2.39,
&
7.52
mg/
kg/
d
for
females.
LOAEL=
7.3
mg/
kg/
d
based
on
high
incidences
of
mortality
in
both
males
&
females.
NOAEL=
2.1
mg/
kg/
d
in
males.

870.3200
30­
day
subchronic
dermal
toxicity
study
in
rats
(
49.5%)
41048506
(
1987)
Acceptable/
Guideline
0,
160,
&
640
mg/
kg/
d
for
males.
0,
80,
&
160
mg/
kg/
d
in
females.
Systemic
LOAEL=
640
mg/
kg/
d
in
males
based
on
body
weight.
LOAEL=
80
mg/
kg/
d
in
females
based
on
mortality
&
decreased
plasma
ChE
activity.
NOAEL=
160
&
40
mg/
kg/
d
in
males
&
females,
respectively.

870.3200
21­
day
dermal
toxicity
study
in
rats
(
97.2%)
146841
(
1985)
&
147744
(
1985).
Acceptable/
Guideline
0,
12,
48,
96,
&
192
mg/
kg/
d
for
males.
0,3,
6,
12,
&
48
mg/
kg/
d
for
females.
21
applications
over
30
days.
Systemic
NOAEL=
12
mg/
kg/
d
for
females
&
96
mg/
kg/
d
for
males.
LOAEL=
48
mg/
kg/
d
for
females
&
192
mg/
kg/
d
for
males
based
on
increased
mortality
&
increased
serum
ChEI.

870.3200
21­
day
dermal
toxicity
study
in
rats
(
97.2%
w/
w)
257684
&
257685
(
1985)
Acceptable/
Guideline
0,
1,
3,
9,
&
27
mg/
kg/
d
for
males
&
females,
&
6
males
only
at
81
mg/
kg/
d,
for
21
applications
over
30
days.
Systemic
NOAEL=
9
mg/
kg/
d
for
females
&
27
mg/
kg/
d
for
males.
LOAEL=
27
mg/
kg/
d
in
females
&
81
mg/
kg/
d
in
males
based
on
increased
mortality
in
both
sexes.

870.3455
21­
day
inhalation
study
in
rats
(
97.2%)
41667501
(
1990)
supplemental
to
00147183
(
1984)
Acceptable/
Guideline
0,
0.0005,
0.0010,
&
0.0020
mg/
L
air
(
0.097,
0.194,
0.387
mg/
kg/
d)
both
sexes
nose­
only
for
6
hrs/
d
for
21
exposures
over
29
days.
NOAEL=
0.001
ai/
L
(
0.194
mg/
kg/
d)
&
LOAEL=
0.002
ai/
L
(
0.387
mg/
kg/
d)
based
on
decreased
body
weight
gain
&
decreased
leukocyte
counts
in
males
&
increased
creatinine
values
in
females.
18
870.4100
1­
year
chronic
toxicity
feeding
study
in
dogs
(
96.5%)
41099501
(
1989)
Acceptable/
Guideline
0,
3,
10,
30,
&
30/
45/
60
ppm
(
0,
0.65,
1.75,
0.65­
1.30
mg/
kg/
d
for
males
&
0,
0.57,
1.75,
and
0.65­
1.30
mg/
kg/
d
for
females).
NOAEL=
10
ppm
(
0.65
and
0.57
mg/
kg/
d
in
males
&
females,
respectively)
&
LOAEL=
30
ppm
(
1.75
mg/
kg/
d)
based
on
decreased
body
weight
gain
in
males
&
increased
incidences
of
neurologic
findings
in
males
&
females
(
loss
or
weakening
of
placing
&
righting
reactions,
tonic
contractions
of
abdominal
muscle
&
masticatory
muscles
a
few
hours
after
feeding).

870.4300
Chronic/
Carcinogenic
Feeding
Study
in
Rats
(
97.1%)
41099502
(
1989)
Acceptable/
Guideline
0,
3,
7.5,
15,
and
75
ppm
(
0,
0.1,
0.3,
0.6,
2.9
mg/
kg/
d
for
males
and
0,
0.1,
0.4,
0.7,
and
3.8
mg/
kg/
d
for
females)
for
104
weeks
Systemic
NOAEL=
15
ppm
(
0.6
&
0.7
mg/
kg/
d
for
males
&
females,
respectively)
&
LOAEL=
75
ppm
(
2.9
&
3.8
mg/
kg/
d
for
males
&
females,
respectively)
based
on
decreased
body
weight
gain
in
males
&
females,
enlarged
kidneys
in
females,
&
increased
incidences
of
marked
progressive
glomerulonephrosis
in
males
&
females,
&
blood
vessel
aneurysms
in
males.
Dosing
was
considered
adequate.

870.4200
Chronic/
Carcinogenic
Feeding
Study
in
Mice
(
97.9%)
40792401
(
1988)
Acceptable/
Guideline
for
carcinogenicity
but,
not
acceptable
for
a
combined
chronic/
carcinogenicity
study
in
mice
because
some
clinical
chemistry
parameters
were
not
evaluated.
0,
2,
6
&
18
ppm
(
0,
0.3,
0.9
&
2.6
mg/
kg/
day)
for
24
months.
Systemic
NOAEL=
6
ppm
(
0.9
mg/
kg/
day),
&
LOAEL
=
18
ppm
(
2.65
mg/
kg/
day),
based
on
increased
incidences
of
mortality
in
females.
At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate.

870.3700
Developmental
Toxicity
in
Rats
(
97.3%)
43129101
(
1993)
Acceptable/
Guideline
0
(
sesame
oil),
0.7,
2.0,
&
6.0
mg/
kg/
d
from
days
7
through
16
of
gestation
by
gavage.
This
study
was
a
repeat
study
for
an
unacceptable
developmental
toxicity
study
(
ACC#
243707).
Maternal
toxicity
NOAEL=
2.0
mg/
kg/
d
&
LOAEL=
6.0
mg/
kg/
d
based
on
80
%
mortality,
tonoclonic
convulsions,
increased
salivation,
&
decreased
body
weight
gains
&
food
consumption.
Developmental
toxicity
NOAEL=
2.0
mg/
kg/
d
&
LOAEL=
6.0
mg/
kg/
d
based
on
a
slight
increase
in
the
incidence
of
fragmented
thoracic
vertebral
centra
&
a
slight
increase
in
the
occurrence
of
fetuses/
litter
weighing
less
than
3
grams.

870.3700
Developmental
Toxicity
in
Rabbits
(
97.3%)
00094837
(
1981)
Acceptable/
Guideline
0,
0.3,
0.7,
&
1.8
mg/
kg/
d
from
days
6
through
28
of
gestation
by
gavage
Maternal
NOAEL=
0.7
mg/
kg/
d
&
LOAEL=
1.8
mg/
kg/
d
based
on
decreased
body
weight,
as
well
as
increased
incidences
of
deaths,
convulsions,
rapid
breathing,
salivation
&
hyperactivity.
Developmental
NOAEL=
1.8
mg/
kg/
d,
the
highest
dose
tested
870.3800
2­
Generation
Reproductive
Toxicity
in
Rats
(
97%)
00148264
(
1984)
Acceptable/
Guideline
0,
3,
15,
&
75
ppm
(
0,
0.2,
1.0,
&
5.0
mg/
kg/
d
in
males
&
0,
0.2,
1.2,
&
6.2
mg/
kg/
d
in
females)
in
the
diet
for
two
generations
Parental
toxicity
NOAEL=
15
ppm
(
1.2
mg/
kg/
d)
&
LOAEL=
75
ppm
(
6.2
mg/
kg/
d)
based
on
decreased
body
weight.
Reproductive
NOAEL=
75
ppm
(
6.2
mg/
kg/
d),
the
highest
dose
tested.
Developmental
toxicity
NOAEL=
15
ppm
(
1.2
mg/
kg/
d)
&
LOAEL=
75
ppm
(
6.2
mg/
kg/
d),
based
on
increased
pituitary
&
uterine
weights.
19
870.6200
Acute
Neurotoxicity
screen
in
rats
(
98.6%)
44403101
(
1997)
Acceptable/
Guideline
One
control
group
was
assigned
to
males,
dosed
by
gavage
at
25,
50
&
100
mg/
kg
&
females
dosed
at
3,
6
&
12
mg/
kg.
The
other
control
group
was
assigned
to
males
dosed
at
6.25
&
12.5
mg/
kg
&
females
at
0.75
&
1.5
mg/
kg.
NOAEL=
12.5
mg/
kg
for
males,
1.5
mg/
kg
for
females.
LOAEL=
25
mg/
kg
for
males
based
on
increased
incidences
of
stilted
gait,
squatting
posture,
&
irregular
respiration,
as
well
as
decreased
spontaneous
activity.
LOAEL=
3
mg/
kg
for
females
based
on
an
increased
incidence
of
stilted
gait,
squatting
posture,
straddled
hindlimbs,
irregular
respirations,
panting
&
bristled
coat
&
decreased
spontaneous
activity.

870.5300
Chromosome
Aberrations
in
mice
(
97.2%)
00148266
(
1984)
Acceptable
Six
doses
ranging
from
6.25­
50
:
g/
ml
w/
o
S9
activation,
seven
doses
from
6.25­
100
:
g/
ml
with
S9
activation
induced
a
significant
increase
in
mutations
at
the
thymidine
kinase
(
TK)
locus
in
L5178Y
mouse
lymphoma.
Non­
mutagenic
in
the
mouse
lymphoma
forward
mutation
assay.

870.5550
Unscheduled
DNA
Synthesis
in
rat
(
97.2%)
00148265
(
1984)
Acceptable
Cytotoxicity
&
UDS
assay
were
performed
in
parallel.
Fifteen
test
concentrations
ranging
from
1020­
0.102
:
g/
ml.
Inactive
in
primary
rat
hepatocyte
unscheduled
DNA
synthesis
(
UDS)
assay.

870.7485
Metabolism
in
Rats
050037030
(
1978)
Metabolites
accumulated
in
tissues,
especially
in
the
kidney
&
liver.
Metabolites
include
endosulfan
sulfate,
endosulfan
diol,
endosulfan
ether,
endosulfan
alpha­
hydroxy
ether,
&
endosulfan
lactone.

870.7485
Metabolism
in
Mice
00004257
(
1966)
Large
amount
of
endosulfan
sulfate
was
recovered
in
the
liver,
small
intestine
&
visceral
fat
with
a
trace
of
this
metabolite
in
the
muscle.

870.7600
Dermal
Penetration
in
Rats
(
94.6%)
40223601
(
1986)
Acceptable
Males
treated
topically
with
radiolabeled
suspension
at
nominal
doses
of
0.1,
1.0,
&
10
mg/
kg
&
exposed
for
0.5,
1,
2,
4,
10
&
24
hrs.
%
doses
absorbed
over
24­
hour
period
were
2.2­
21.6,
0.32­
21.52,
&
0.08­
8.38
for
the
0.1,
1.0,
&
10
mg/
kg
dose
groups,
respectively.
%
doses
remaining
in/
on
the
skin
after
soap
&
water
washes
over
a
24­
hour
period
were
62.1­
56.5,
78.1­
57.7,
&
80.2­
66.7
for
the
0.1,
1,
&
10
mg/
kg
dose
groups,
respectively.
Significant
portions
of
the
dose
remained
on
the
skin.

870.7600
Dermal
Absorption
in
Rats
(
94.6%)
41048504
(
1988)
Acceptable
Females
treated
topically
with
radiolabel
at
nominal
doses
of
0.1,
1,
&
10
mg/
kg
(
1.9,
21.9,
&
231.4
mg/
cm2)
%
doses
absorbed
at
24
hours
were
22.1,
16.1
&
3.8%
&
at
168
hours
were
44.8,
46.4
&
20.3%
for
the
0.1,
1,
&
10
mg/
kg
dose
groups,
respectively.
%
doses
remaining
on/
in
skin
at
168
hours
were
41.4,
56.2
&
72.8%
for
the
0.1,
1,
&
10
mg/
kg
dose
groups,
respectively.
Dermal
absorption
factor
of
45
%
at
168
hours
post­
exposure.

3.5
FQPA
Considerations
The
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
toxicology
database
for
indications
of
increased
susceptibility
of
rats
and
rabbits
to
in
utero
and/
or
postnatal
exposure
to
endosulfan.
Although
developmental
toxicity
was
only
seen
at
or
above
parentally
toxic
doses,
there
were
treatment­
related
clinical
signs
of
neurotoxicity
20
following
oral
exposures
in
the
rat,
rabbit,
and
dog,
and
via
the
dermal
route
in
rats.
To
fully
assess
the
neurotoxic
potential
of
endosulfan,
acute
and
subchronic
neurotoxicity
studies
in
the
rat
were
requested
by
the
Agency.
The
acute
neurotoxicity
study
was
reviewed
and
found
to
be
acceptable/
guideline.
The
subchronic
neurotoxicity
study
has
not
been
received
by
the
Agency
and
remains
a
data
gap.
The
FQPA
Safety
Factor
Committee
(
FQPA
SFC)
re­
reviewed
the
hazard
and
exposure
data
for
endosulfan
(
Endosulfan
­
Report
of
the
FQPA
Safety
Factor
Committee,
Carol
Christensen,
February
14,
2002)
and
concluded
that
a
developmental
neurotoxicity
(
DNT)
study
in
rats
should
be
requested
(
as
it
also
was
in
1998)
for
endosulfan
due
to
concern
by
the
Committee
for:
1)
fetal
effects
reported
in
the
open
literature
[
Lakshmana
and
Raju
1994.
Toxicology
91(
2):
139­
150];
2)
the
severity
of
effects
seen
in
female
offspring
of
the
F
0
generation
(
increased
pituitary)
and
F
1
b
generation
(
increased
uterine
weights)
at
the
highdose
when
compared
to
the
toxicity
observed
in
parental
animals
at
this
dose
in
the
twogeneration
reproduction
study
in
rats;
and
3)
the
subchronic
neurotoxicity
study
will
only
address
the
neuropathological
concerns
resulting
from
exposure
to
endosulfan
in
adults.
A
developmental
neurotoxicity
study
will
provide
the
critical
data
needed
to
demonstrate
the
toxic
effects
of
endosulfan
on
the
developing
fetal
nervous
system.

As
mentioned
above,
the
HIARC
determined
that
under
the
conditions
of
the
available
Agency
guideline
studies,
there
is
no
evidence
of
enhanced
susceptibility
of
the
offspring
to
exposure
to
endosulfan.
However,
a
recent
review
by
the
Agency
for
Toxic
Substances
and
Disease
Registry
[
Toxicological
Profile
for
Endosulfan
(
Update).
ATSDR.
September
2000]
reported
the
results
of
non­
guideline
studies
which
demonstrated
that
young
rats
may
be
more
susceptible
than
older
rats
upon
exposure
to
endosulfan.
Studies
conducted
by
Sinha
et
al.
(
1995
&
1997)
and
Zaidi
et
al.
(
1985)
illustrate
effects
to
the
offspring
at
doses
lower
than
those
showing
effects
in
adults.
In
a
study
by
Sinha
et
al.,
both
three
week
and
three
months
old
rats
were
treated
orally;
decreased
intratesticular
spermatid
count
and
increased
percentage
of
abnormal
sperm
were
seen
in
three
week
old
rats
at
doses
lower
than
those
eliciting
similar
effects
in
three
month
old
rats.
In
the
Zaidi
study,
neonatal
rat
pups
were
dosed
for
25
days
intraperitoneally
and
displayed
increased
serotonin
binding
to
the
frontal
cortical
membranes
of
the
brain
and
increased
aggressive
behavior.
Adults
exposed
in
a
similar
manner
did
not
display
these
effects.

There
is
evidence
for
endocrine
disruption
both
in
studies
submitted
to
the
Agency
and
those
published
in
the
open
literature.
In
the
chronic
toxicity/
carcinogenicity
study
in
rats,
endosulfan
induced
testicular
atrophy
and
parathyroid
hyperplasia.
In
the
multi­
generation
reproduction
study,
increased
pituitary
and
uterine
weights
were
seen.
Endosulfan
is
considered
to
be
an
endocrine
disruptor.
Substances
that
act
as
endocrine
disruptors
may
perturb
the
endocrine
system
in
a
variety
of
ways
including,
but
not
limited
to,
interfering
with
the
synthesis,
secretion,
or
transport
of
hormones
in
the
organism.
The
Agency
emphasizes
the
fact
that
the
endocrine
system
integrates
a
variety
of
CNS­
pituitary­
target
organ
pathways
that
not
only
affect
reproductive
or
sexually
regulated
parameters
but
also
regulates
a
wide
array
of
bodily
functions
and
homeostasis.
See
Section
3.6
below.

Previously,
the
FQPA
factor
was
retained
based
on
the
suggestive
special
sensitivity
and
the
uncertainty
associated
with
the
data
gap
(
subchronic
neurotoxicity
and
developmental
21
neurotoxicity
studies
are
requested),
but
was
reduced
from
10x
to
3x
because:
1)
there
is
no
evidence
of
increased
susceptibility
in
any
submitted
guideline
study;
2)
the
severity
of
the
fetal
effects
in
the
reproductive
toxicity
study
were
not
consistent
between
generations
and
the
target
organ
toxicity
seen
in
this
study
was
not
seen
in
any
other
study;
and
3)
reliable
data
and
conservative
assumptions
were
used
to
assess
the
potential
dietary
(
food
and
water)
exposure
to
this
chemical
(
Endosulfan
­
Report
of
the
FQPA
Safety
Factor
Committee.
Brenda
Tarplee.
November
20,
1998).
However,
based
on
the
evidence,
and
the
uncertainties,
discussed
above,
the
FQPA
SFC
reconsidered
its
findings
at
the
February
2002
meeting.

The
FQPA
SFC
recommended
that
the
10x
FQPA
Safety
Factor
should
be
retained
because
there
were
no
reliable
data
available
to
address
the
following
concerns
or
uncertainties
raised
by
the
following
matters:
1)
evidence
for
increased
susceptibility
of
young
rats,
2)
additional
evidence
for
endocrine
disruption,
3)
uncertainty
regarding
the
neuroendocrine
effects
in
the
young,
and
4)
the
need
for
a
DNT.
This
decision
has
been
challenged
by
the
ETF.
See
discussion
below
in
section
3.7.
The
Committee
determined
that
the
FQPA
safety
factor
(
10x)
is
applicable
for
all
populations
when
assessing
acute
and
chronic
dietary
exposure.
There
are
no
longer
any
residential
uses
for
this
chemical,
so
the
FQPA
Safety
factor
does
not
apply
to
the
short­
term
or
intermediate­
term
exposure
scenarios.
In
accordance
with
current
Agency
guidance,
the
FQPA
Safety
Factor
is
not
applied
for
the
occupational
risk
assessment
(
Memorandum,
Special
Report
of
the
FQPA
Safety
Factor
Committee.
Brenda
Tarplee
&
Jess
Rowland.
April
15,
1998).

3.6
Endocrine
Disruption
The
potential
for
endosulfan
to
cause
changes
in
endocrine
function
was
evaluated
in
an
earlier
review
from
the
results
of
the
OPPTS
guideline
studies
described
above
and
studies
available
in
the
published
literature.
One
of
the
ETF
members,
AgrEvo,
submitted
a
literature
review
(
MRID#
44939102.
December
18,
1998)
in
which
the
registrant
concluded
that
"
endosulfan
does
not
meet
the
criteria
of
an
endocrine
disruptor."
The
registrant
stated
that
in
vitro
studies
show
that
endosulfan
has
a
low
binding
potency
to
the
human
estrogen
receptors
and
that
"
no
effects
were
found
on
endocrine,
reproductive
or
sexually
regulated
systems
in
vivo
at
doses
causing
clear
toxicity."
A
second
literature
review
(
MRID#
45300203.
December
18,
2000)
submitted
by
the
registrants
provided
no
new
information,
with
the
exception
of
a
new
1999
Heusel
study
on
possible
endocrine
effects
in
fish
(
vitellogenin
gene
expression).

The
Agency
identifies
an
environmental
endocrine
disruptor
as
an
exogenous
agent
that
interferes
with
the
synthesis,
secretion,
transport,
binding
action,
or
elimination
of
natural
hormones
in
the
body
that
are
responsible
for
the
maintenance
of
homeostasis,
reproduction,
development,
and/
or
behavior
(
Crisp
et
al.
1998).
Based
on
these
criteria,
the
Agency
disagrees
with
the
conclusion
by
the
registrant
that
endosulfan
does
not
meet
the
definition
of
an
endocrine
disruptor
(
ENDOSULFAN:
Evaluation
of
Registrant
Submission
Endosulfan:
Evaluation
of
Possible
Endocrine
Effects
in
Mammalian
Species.
Elizabeth
Mendez.
December
11,
2000).
Binding
to
the
estrogen
receptor
is
only
one
potential
mode
of
action
for
endocrine
disruptors,
namely
direct
interaction
with
a
receptor
in
the
target
cells.
Substances
that
act
as
endocrine
disruptors
may
perturb
the
endocrine
system
in
a
variety
of
ways,
including
but
not
limited
to,
22
interfering
with
the
synthesis,
secretion,
or
transport
of
hormones
in
the
organism.
Consequently,
the
absence
of
high
binding
affinity
to
the
estrogen
receptor
should
not
be
interpreted
as
lack
of
endocrine
disruption
potential.
The
Agency
notes
that
other
organochlorines
(
i.
e.
DDT,
DDE,
dieldrin,
and
methoxychlor)
have
been
demonstrated
to
interact
with
the
endocrine
system
in
spite
of
differing
binding
affinities
to
the
estrogen
receptor.
Finally,
the
registrant
stated
that
no
effects
were
reported
after
administration
of
endosulfan
on
the
endocrine,
reproductive
or
sexually
regulated
systems
at
doses
causing
clear
toxicity.
However,
it
is
noteworthy
that
testicular
atrophy
was
reported
during
a
chronic
oral
toxicity
study
in
rats
(
MRID#
00004256)
submitted
to
the
Agency.
Additionally,
increased
pituitary
and
uterine
weights
were
also
observed
during
a
multi­
generation
reproduction
study
(
MRID#
00148264).
Furthermore,
an
increase
in
the
incidence
of
parathyroid
hyperplasia
was
also
reported
during
the
chronic
oral
toxicity
study
in
rats.
The
Agency
emphasizes
the
fact
that
the
endocrine
system
integrates
a
variety
of
CNS­
pituitary­
target
organ
pathways
that
not
only
affect
reproductive
or
sexually
regulated
parameters
but
also
regulates
a
wide
array
of
bodily
functions
and
homeostasis
(
Cooper
and
Kavlock,
1997).
Though
this
is
not
the
case
for
endosulfan,
it
is
important
to
note
that
a
lack
of
overt
toxicity
to
the
reproductive
system
should
not
be
interpreted
as
conclusive
evidence
of
a
lack
of
endocrine
disruption.
Given
the
effects
noted
in
the
chronic
oral
toxicity
study
in
rats
and
the
multi­
generation
reproduction
study
submitted
to
the
Agency,
the
evidence
showing
endosulfan
to
act
as
an
endocrine
disruptor
cannot
be
discounted.
The
Agency
has
requested
that
a
Developmental
Neurotoxicity
Study
be
conducted;
the
Agency
believes
that
this
study
will
provide
additional
data
that
may
help
elucidate
this
matter.

In
addition,
the
Agency
for
Toxic
Substances
and
Disease
Registry
(
ATSDR)
reported
[
Toxicological
Profile
for
Endosulfan
(
Update),
September
2000]
a
number
of
studies
that
assessed
endosulfan's
effects
on
the
endocrine
system.
Singh
and
Pandey
(
1989)
dosed
adult
rats
orally
for
7
days
and
observed
decreased
testicular
testosterone
in
conjunction
with
increased
serum
testosterone
which
suggests
sex­
hormone
binding
globulin
(
SHBG)
may
be
affected.
In
a
subsequent
study,
these
researchers
dosed
rats
orally
for
15­
30
days.
Under
the
conditions
of
this
study,
decreases
in
testicular
testosterone,
plasma
testosterone,
LH,
and
FSH
as
well
as
decreased
steroidogenic
enzyme
and
cytochrome
P­
450­
dependent
monooxygenase
were
reported.
These
decreases
in
LH
may
lead
to
decreases
in
the
activity
of
Steroidogenic
Acute
Regulatory
Protein
(
responsible
for
translocation
of
cholesterol
to
the
inner
mitochondria)
and
may
therefore
affect
the
conversion
of
cholesterol
to
testosterone.
Vonier
et
al.
(
1996)
conducted
a
competitive
binding
assay
using
alligator
oviduct
tissue
and
found
endosulfan
exposure
significantly
inhibited
3H­
17­
estradiol
binding
to
the
estrogen
receptor
and
progestin
3H­
R5020
binding
to
the
progesterone
receptor.
Ramamoorthy
et
al.
used
the
yeast
reporter
system
to
discover
endosulfan
induced
human­
ER­
mediated­
gal
activation.
Endosulfan
induced
galactosidase
transcription/
expression
to
about
32%
of
the
induction
seen
after
estradiol
treatment
at
0.01
µ
M.
In
a
study
by
Sinha
et
al.
(
1995)
rats
dosed
orally
with
endosulfan
for
70
days
exhibited
decreases
in
sperm
counts
in
the
cauda
epididymis
as
well
as
decreased
intratesticular
spermatid
counts.
Finally,
Lakshmana
et
al.
(
1994)
showed
endosulfan
induces
small
but
significant
changes
in
the
levels
of
noradrenaline,
dopamine
and
serotonin
in
the
developing
rat
brain
and
deficits
in
the
operant
learning
performance
suggesting
possible
effects
on
the
neuroendocrine
system.
23
The
ETF
submitted
comments
(
February
28,
2002)
on
the
Agency's
Response
to
Comments
(
January
18,
2002)
in
which
the
ETF
did
not
dispute
that
there
is
indirect
evidence
of
endocrine
disruption
in
the
database.
The
ETF
asserted,
however,
that
since
these
effects
occur
at
approximately
the
doses
that
elicit
systemic
toxicity,
that
flagging
the
effects
as
suggestive
of
endocrine
disruption
is
inappropriate.
The
Agency
disagrees.
The
fact
that
there
is
systemic
toxicity
does
not
negate
that
the
effects
seen
may
be
the
result
of
perturbations
of
the
endocrine
system.
In
fact,
it
suggests
that
the
endocrine
system
may
be
one
of
the
many
systems
adversely
affected
by
the
test
compound.
The
ETF
then
suggested
that
the
endocrine
effects
reported
in
the
public
literature
(
and
cited
in
the
Agency's
response)
may
be
due
to
nephro­
and/
or
hepato­
toxicity.
As
pointed
out
by
the
registrant,
however,
kidney
and
liver
toxicity
were
not
evaluated
in
said
studies.
In
the
absence
of
empirical
data,
the
ETF's
assumption
that
these
effects
reflect
liver
and/
or
kidney
toxicity
is
not
warranted.
Furthermore,
even
if
kidney
and
liver
toxicity
had
been
reported
that
still
does
not
negate
the
possibility
of
disruption
of
the
endocrine
system.
The
ETF
stated
that
the
Agency
has
hypothesized
about
the
possible
mechanism
of
endocrine
disruption
of
endosulfan.
That
is
not
accurate.
Since
the
registrants
had
themselves
initially
limited
their
criteria
for
endocrine
disruption
to
receptor
binding,
the
Agency
provided
a
number
of
examples
of
potential
mechanisms
of
endocrine
disruption
(
ENDOSULFAN:
Evaluation
of
Registrant
Submission
Endosulfan:
Evaluation
of
Possible
Endocrine
Effects
in
Mammalian
Species.
Elizabeth
Mendez.
December
11,
2000).
These
are
examples,
not
hypothesis,
theories
or
determination
of
mechanism
of
endocrine
disruption.
In
addition,
the
ETF
disagreed
with
the
Agency's
use
of
the
1978
National
Cancer
Institute
(
NCI)
study
in
which
testicular
atrophy
was
reported.
The
registrant
claimed
that
this
was
a
non­
guideline
study,
and
that
frank
systemic
toxicity
was
seen.
Again,
the
presence
of
systemic
toxicity
does
not
negate
potential
for
endocrine
disruption.
As
for
the
study
being
non­
guideline,
this
did
not
and
does
not
preclude
the
Agency
from
using
it
as
part
of
the
weight­
of­
the­
evidence
analysis.
Finally,
the
ETF
stated
that
the
uterine
and
pituitary
effects
seen
in
the
offspring
during
the
submitted
2­
generation
reproduction
study
are
not
seen
in
the
rest
of
the
database
and
are
therefore,
in
their
opinion,
suspect.
The
Agency
must
point
out
that
in
other
studies
in
the
database
where
uterine
and
pituitary
effects
may
have
been
assessed,
exposure
is
to
adult
animals.
In
the
2­
generation
reproduction
study,
exposure
occurs
during
the
prenatal,
perinatal,
"
childhood",
and
perhaps
more
importantly,
during
the
sexual
maturation
periods,
as
well
as
adulthood.
It
is
possible
that
the
uterine
and
pituitary
effects
were
not
seen
in
the
other
studies
because
exposure
to
the
test
compound
began
after
a
crucial
development
period
in
the
life­
span
of
the
animals.

The
FQPA
(
1996)
requires
that
the
Agency
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticides
and
inerts)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
such
other
endocrine
effect......"
The
Agency
is
developing
criteria
for
characterizing
and
testing
endocrine
disrupting
chemicals
and
plans
to
implement
an
Endocrine
Disruptor
Screening
Program
in
the
future.
Endosulfan
will
be
reevaluated
at
that
time
and
additional
testing
may
be
requested.

3.7
Rationale
for
Retention
of
the
10X
FQPA
Factor
The
ETF
submitted
comments
(
December
18,
1998;
December
18,
2000;
February
28,
2002;
&
April
5,
2002)
and
followed
up
with
a
meetings
with
the
Agency
(
April
10,
2002
&
May
1
The
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
and
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA)
as
Amended
by
the
Food
Quality
Protection
Act
(
FQPA)
of
August
3,
1996
.
Section
408
(
b)(
2)(
C)(
i)
and
Section
408
(
b)(
2)(
D)(
viii).

24
15,
2002),
as
well
as
a
conference
call
with
the
Agency
(
May
2,
2002),
to
present
arguments
against
the
Agency's
endocrine
disruption
call
and/
or
the
retention
of
an
FQPA
factor
for
endosulfan.
The
registrants
presented
their
case
as
to
why
they
felt
that
the
Agency's
concerns
for
susceptibility
of
the
young,
endocrine
disruption,
and
effects
on
sperm
were
not
valid.
The
ETF
places
great
emphasis
on
the
variability
of
response
and
inconsistency
of
occurrence
of
these
effects,
particularly
in
the
literature,
to
dispute
the
Agency's
concerns
and
argue
against
retention
of
the
10X.
It
must
be
said
on
the
onset
that
under
FQPA,
every
chemical
is
given
a
10X
safety
factor
to
protect
infants,
children,
and
women
of
childbearing
age,
and
the
Agency
must
have
just
cause
to
reduce
or
remove
the
10X.
The
weight
of
evidence
supporting
the
Agency's
concerns,
compounded
by
the
multiple
uncertainties,
do
not
give
the
Agency
cause
for
reducing
the
safety
factor.

3.7.1
Weight
of
Evidence
In
compliance
with
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
requirement
for
the
reregistration
of
chemicals,
HED
has
reevaluated
the
toxicological
database
for
endosulfan.
The
statute
in
the
FQPA
states
that
"
an
additional
tenfold
margin
of
safety
for
the
pesticide
chemical
residue
and
other
sources
of
exposure
shall
be
applied
for
infants
and
children
to
take
into
account
potential
pre­
and
post­
natal
toxicity
and
completeness
of
the
data
with
respect
to
exposure
and
toxicity
to
infants
and
children.
Notwithstanding
such
requirement
for
an
additional
margin
of
safety,
the
Administrator
may
use
a
different
margin
of
safety
for
the
pesticide
chemical
residue
only
if,
on
the
basis
of
reliable
data,
such
margin
will
be
safe
for
infants
and
children."
Moreover,
in
the
FQPA
safety
factor
provision
the
Agency
is
required
to
consider,
among
other
relevant
factors,
the
potential
for
a
pesticide
to
have
an
effect
in
humans
that
is
similar
to
effects
caused
by
naturally
occurring
estrogen
or
other
endocrine
effects
when
establishing,
modifying,
leaving
in
effect
or
revoking
a
tolerance
or
exemption
for
a
pesticide
chemical
residue.
1
As
part
of
the
reevaluation
process
for
endosulfan,
the
FQPA
Safety
Factor
Committee
has
evaluated
this
chemical
on
two
occasions.
See
ENDOSULFAN
­
Supporting
documentation
for
findings
of
FQPA
Safety
Committee
on
February
11,
2002.
Elizabeth
Méndez.
May
9,
2002.
On
November
2,
1998
the
committee
evaluated
the
toxicological
database
for
endosulfan
as
well
as
the
potential
for
exposure
to
this
compound
via
the
diet
and/
or
occupational/
residential
uses.
Based
on
the
information
provided
to
the
committee
at
that
time,
the
committee
concluded
that
the
10X
default
FQPA
safety
factor
could
be
reduced
to
3X.
The
rationale
for
the
conclusions
of
the
committee
are
provided
in
the
Report
of
the
FQPA
Safety
Factor
Committee
dated
November
20,
1998.
In
response
to
comments
provided
by
the
ETF,
the
Agency
reconsidered
the
endpoints
used
for
dermal
risk
assessment
purposes.
On
February
11th,
2002
the
FQPA
Safety
Factor
Committee
convened
to
determine
the
impact
these
changes
might
have
on
the
FQPA
safety
factor
determination
as
well
as
reconsider
recent
data
regarding
effects
on
the
25
endocrine/
neuroendocrine
system
pursuant
to
the
Agency
guidance
on
the
evaluation
and
consideration
of
these
endpoints
for
FQPA
safety
factor
determination
purposes.
Based
on
the
submitted
background
material,
the
committee
concluded
that
the
default
10X
FQPA
safety
factor
should
be
retained.
The
committee
based
its
conclusions
on
the
fact
that
there
are
no
reliable
data
to
address
residual
uncertainties
and
concerns
pertaining
to
the
possible
increased
susceptibility
of
young
rats
to
endocrine
and
neurotoxic
effects
in
the
young.
Additionally,
the
subchronic
neurotoxicity
and
developmental
neurotoxicity
studies
requested
by
the
Agency
are
still
outstanding.
The
rationale
for
retaining
the
10X
FQPA
safety
factor
is
explained
in
further
detail
in
the
Report
of
the
FQPA
Safety
Factor
Committee
dated
February
14,
2002.

On
April
10th
2002,
OPP
staff
met
with
members
of
the
ETF
to
discuss
the
impact
of
the
endocrine
disrupting
potential
of
this
chemical
on
the
retention
of
the
default
10X
FQPA
safety
factor.
In
addition,
ETF
submitted
a
response
to
the
FQPA
Safety
Factor
Committee
dated
April
5th,
2002.
This
document
as
well
as
the
comments
provided
by
ETF
during
the
April
10th
meeting
have
been
taken
into
consideration
by
the
Agency.
The
Agency's
response
to
the
most
salient
issues
discussed
with
ETF
are
as
follows:

1)
The
ETF
correctly
pointed
out
that
rats
exposed
to
1
mg/
kg/
day
of
endosulfan
from
postnatal
days
(
PND)
1­
35
exhibit
an
increase
(
p
<
0.05)
in
binding
of
serotonin
in
the
frontal
cortex
of
the
brain
and
an
increase
in
aggressive
behavior.
A
similar
effect
was
not
seen
in
adult
rats
dosed
at
the
1
mg/
kg/
day
dose
level.
However,
adult
rats
exposed
to
a
higher
dose,
3
mg/
kg/
day,
for
15
to
30
days
did
exhibit
the
increase
in
serotonin
and
aggressive
behavior.
These
findings
reaffirm
the
Agency's
current
determination
of
enhanced
susceptibility
on
a
quantitative
basis
(
e.
g.,
effects
at
1
mg/
kg/
day
in
neonates
versus
3
mg/
kg/
day
in
adults).

2)
The
ETF
asserted
that
the
potential
endocrine
disruptor
effects
occur
at
systemically
toxic
doses.
Again,
as
the
Agency
has
stated
in
the
past,
systemic
toxicity
does
not
negate
the
potential
for
endocrine
disruption
effects.
The
effects
seen
in
this
study
may
reflect
a
perturbation
of
the
endocrine
system.

3)
The
ETF
claimed
that
sperm
parameter
effects
are
too
variable
to
make
any
assessments
since
these
endpoints
may
be
affected
by
stress,
circadian
rhythms,
etc.
If
this
were
the
case,
these
same
external
influences
would
affect
control
groups,
which
did
not
exhibit
the
sperm
effects
noted
in
the
treated
groups.
Therefore,
the
Agency
considers
the
sperm
effects
to
be
indicative
of
toxicity
and
potential
endocrine
perturbations.

4)
The
ETF
disagreed
with
the
Agency's
use
of
open
literature
studies
in
its
evaluation
claiming
the
literature
studies
have
not
been
thoroughly
reviewed.
However,
all
of
these
studies
were
peer
reviewed.

5)
In
a
recent
study
(
Sinha
et
al.,
2001),
Druckrey
rats
exposed
in
utero
(
GD12
through
parturition)
only
and
evaluated
on
PND
100
(
i.
e.
as
young
adults)
exhibited
decreases
in
sperm
2
Sinha,
N.,
Adhikari,
N.,
and
Saxena,
D.
K.
Effect
of
Endosulfan
During
Fetal
Gonadal
Differentiation
in
Spermatogenesis
in
Rats.
Environmental
Toxicology
and
Pharmacology
10:
29­
32.
(
2001)

26
parameters,
as
well
as
decreases
in
testes,
seminal
vesicle,
and
epidydimis
weights.
2
The
ETF
argues
that
since
similar
results
were
not
observed
in
another
study
in
which
Wistar
rats
were
dosed
from
gestation
day
(
GD)
15­
PND
21,
the
effects
seen
in
the
Druckrey
rats
are
invalid.
It
is
important
to
note
the
persistence
of
the
effects,
although
exposure
was
exclusively
in
utero,
effects
were
seen
on
PND
100.
Also
noteworthy
is
the
fact
that
Druckrey
rats
are
very
sensitive
to
endocrine
disruption
effects.
Consequently,
lack
of
effects
in
the
study
using
Wistar
rats
is
not
a
valid
point
to
disqualify
the
findings
in
another
study
that
used
a
different
strain
and
protocol.

6)
The
ETF
asserted
that
histopathology
of
testicular
tissue
is
a
more
sensitive
and
reliable
endpoint
than
sperm
parameters.
However,
in
the
absence
of
this
histopathological
data,
the
sperm
effects
observed
in
open
literature
studies
and
found
at
lower
doses
than
effects
observed
in
studies
submitted
by
the
registrant
are
an
indication
that
endocrine
disruption
effects
may
be
occurring.

7)
The
ETF
asserted
that
the
National
Cancer
Institute
(
NCI)
study
demonstrating
testicular
atrophy
should
not
be
used
since
it
was
not
a
guideline
study
and
that
systemic
toxicity
was
seen
at
the
same
doses
as
endocrine
disruption.
The
Agency
can
and
will
use
open
literature
studies
that
have
been
subjected
to
peer
review
as
part
of
their
evaluation.
As
mentioned
above
(#
2),
the
presence
of
systemic
toxicity
does
not
negate
the
potential
for
endocrine
disruption
effects.

8)
The
ETF
argued
that
the
pituitary
and
uterine
weight
effects
in
the
guideline
multi­
generation
reproductive
toxicity
study
were
not
seen
in
the
remainder
of
the
database.
However,
one
should
consider
that
in
other
studies,
where
these
parameters
are
evaluated,
dosing
began
during
adulthood.
While
in
the
2­
generation
reproduction
toxicity
study
animals
were
dosed
in
utero,
perinatally,
during
pubescence
and
perhaps
most
importantly,
during
the
sexual
maturation
phase
of
the
animals
life
span.
Therefore,
there
is
no
basis
for
discounting
the
effects.

9)
To
expand
upon
what
was
said
above
(#
8),
the
ETF
stated
that
the
Agency
should
rely
on
the
results
of
the
guideline
studies
only,
which
did
not
detect
the
effects
discussed
in
the
literature
studies.
However,
the
registrant's
submitted
reproduction
study
did
not
include
the
assessment
of
endpoints
that
are
indicative
of
potential
endocrine
effects
(
such
as
estrous
cyclicity,
sperm
measures,
and
age
at
sexual
maturation)
and
the
rat
developmental
toxicity
study
did
not
dose
the
dams
in
late
gestation
(
i.
e.,
during
a
critical
period
of
male
reproductive
system
development)
nor
follow
the
offspring
through
puberty
and
beyond.
Therefore,
the
effects
in
the
registrant
submitted
study
were
not
detected
because
they
were
not
evaluated.

10)
The
ETF
acknowledged
"
indications
of
potential
disruption
of
reproductive
hormones
in
males"
(
p.
12
ETF's
April
5,
2002
document).
This
statement
by
the
ETF
reaffirms
the
27
Agency's
position
of
the
potential
for
endocrine
disruption
by
endosulfan.

11)
The
ETF
asserted
that
the
Agency
suggested
that
the
sex­
hormone
binding
globulin
(
SHBG)
and
steroidogenic
acute
regulatory
protein
(
StAR)
may
be
involved
in
the
endocrine
disruption
effects
caused
by
endosulfan
and
that
no
evidence
exists
to
prove
this
"
supposition."
Given
the
pattern
of
endocrinopathology
seen
throughout
the
published
literature,
the
Agency
is
justified
in
suggesting
the
possible
involvement
of
these
proteins
in
the
endocrine
disruption
properties
exhibited
by
this
chemical.

12)
The
ETF
argued
that
the
effects
on
testosterone
levels
are
the
result
of
liver
and
kidney
toxicity.
However,
no
data
are
available
to
substantiate
this
statement.

13)
The
ETF
asserted
that
the
operant
learning
test,
in
which
increases
in
acquisition
time
(
learning)
and
decreases
in
pedal
presses
(
reward
­
associated
with
memory
deficits)
have
been
reported,
may
be
the
outcome
of
a
decrease
in
appetite
or
lethargy.
No
evidence
to
substantiate
this
statement
is
available.

14)
A
DNT
and
subchronic
neurotoxicity
studies
are
still
outstanding.
The
Agency
had
requested,
and
still
has
not
received,
the
subchronic
neurotoxicity
and
the
DNT
studies
to
address
the
uncertainty
concerning
a
thorough
characterization
of
the
neurotoxicity
properties
of
endosulfan.

15)
Both
the
Agency
and
the
ETF
recognize
the
conclusion
of
the
ATSDR
[
Toxicological
Profile
for
Endosulfan
(
Update),
September
2000],
stating
that
"
There
is
no
conclusive
evidence
to
suggest
that
young
animals
are
more
susceptible
than
older
ones."
The
EPA,
however,
does
not
interpret
this
ATSDR
statement
to
signify
a
dismissal
of
the
possibility
of
enhanced
susceptibility
of
the
young.
Moreover,
the
EPA
has
evaluated
additional
data
that
reaffirms
the
Agency's
position
regarding
enhanced
susceptibility
of
the
young
to
endosulfan
exposure.
Therefore,
the
conclusion
of
the
ATSDR
does
not
support
removing
the
default
10X
FQPA
safety
factor.

3.7.2
Residual
Uncertainties
Evaluation
by
the
Agency
of
the
currently
available
toxicological
data
for
endosulfan
has
revealed
two
distinct
aspects
of
residual
uncertainty,
namely
the
lack
of
adequate
endpoint
characterization
for
the
potential
of
this
chemical
to
elicit
neurotoxic
effects,
and
the
lack
of
both
endpoint
and
developmental
stage
assessments
for
endocrine
effects.
See
ENDOSULFAN
­
Supporting
documentation
for
findings
of
FQPA
Safety
Committee
on
February
11,
2002.
Elizabeth
Méndez.
May
9,
2002.
The
Agency
has
concerns
for
increased
susceptibility
of
the
young
given
the
effects
seen
in
studies
in
the
published
literature
indicative
of
endocrine
disruption
in
both
adults
and
immature
animals.

There
is
sufficient
evidence
of
neurotoxicity
reported
in
the
currently
available
guideline
studies,
thus
the
Agency
required
the
submission
of
subchronic
and
developmental
neurotoxicity
studies.
In
the
absence
of
these
data,
the
impact
of
endosulfan
exposure
on
the
function
of
the
28
nervous
system
of
adults
and
the
development
and
function
of
the
nervous
system
in
the
young
have
not
been
adequately
assessed.

Residual
uncertainty
regarding
the
potential
effect
of
endosulfan
exposure
on
the
endocrine
system
and
the
endpoint
currently
used
for
regulatory
purposes
remains.
While
the
current
acute
reference
dose
(
aRfD)
is
based
on
a
NOAEL
of
1.5
mg/
kg/
day
from
the
acute
neurotoxicity
study
in
rats,
published
literature
data
describe
effects
on
sperm
parameters,
lactate
dehydrogenase
and
sorbitol
dehydrogenase
activity,
as
well
as
testicular,
epididymal,
and
seminal
vesicle
weights
at
a
dose
level
of
1.0
and
1.5
mg/
kg/
day
(
the
lowest
doses
tested
in
the
studies,
i.
e.
no
NOAEL
for
these
effects
has
been
identified).
In
a
1999
study
by
Dalsenter
et
al.,
exposure
to
endosulfan
from
gestation
day
15
through
post­
natal
day
21
at
the
lowest
dose
tested
(
1.5
mg/
kg/
day)
elicited
a
21%
decrease
in
daily
sperm
production.
Additionally,
histopathological
assessments
demonstrated
that
the
percentage
of
seminiferous
tubules
with
complete
spermatogenesis
was
significantly
decreased
at
puberty
by
16%.
The
persistence
of
these
effects
is
noteworthy
since
dosing
ceased
on
PND21
yet
effects
were
noted
on
PND
65
(
i.
e.
puberty)
and
PND
100
(
young
adults).
Similar
results
were
reported
by
Sinha
et
al.
in
2001.
Sinha
and
his
coworkers
exposed
pregnant
rats
to
endosulfan
(
1
or
2
mg/
kg/
day)
beginning
on
GD12
through
parturition.
At
that
point,
the
offspring
were
fostered
to
naive
(
i.
e.
untreated)
dams.
Evaluation
of
offspring
on
PND100
revealed
a
37
and
53%
decrease
in
spermatid
count
in
the
testes
and
sperm
counts
in
the
cauda
epididymis,
respectively,
at
a
dose
of
1
mg/
kg/
day.
Also
noted
at
this
dose
level,
were
decreases
in
testicular
weight
(
16%),
epidydimal
weight
(
35%),
and
seminal
vesicle
weight
(
32%).
Finally,
a
32%
increase
in
lactate
dehydrogenase
(
LDH)
and
a
29%
decrease
in
sorbitol
dehydrogenase
(
SDH)
were
also
noted
after
endosulfan
exposure
at
a
dose
level
of
1
mg/
kg/
day.
The
effects
on
these
two
enzymes
indicate
a
possible
perturbation
of
germinal
epithelial
cell
function.
Since
exposure
to
endosulfan
occurred
solely
during
gestation,
these
findings
suggest
that
exposure
during
gonadal
differentiation
has
a
lasting
effect
on
germ
cells
at
sexual
maturity.
Given
the
published
literature
data
effects
at
the
dose
used
to
establish
the
aRfD
(
1.5
mg/
kg/
day),
the
Agency
has
valid
concerns
that
the
current
aRfD
may
not
be
adequately
protective;
thereby
prompting
the
need
to
retain
the
10X
FQPA
factor.
The
10X
FQPA
factor
would
also
be
applicable
to
the
chronic
reference
dose
(
cRfD)
since
a
NOAEL
for
effects
on
sperm
parameters,
testicular
histopathology,
and
reproductive
organ
weights
has
not
been
identified.
Furthermore,
a
thorough
endpoint
and
developmental
stages
evaluation
of
potential
endocrine
and
neurotoxic
effects
in
the
young
is
not
available.

In
conclusion,
given
the
effects
on
sperm
parameters
and
testicular
histopathology
seen
in
the
published
literature
at
doses
currently
used
for
regulatory
purposes,
the
lack
of
evaluation
of
sperm
parameters
in
the
submitted
guideline
multi­
generation
study,
the
data
gaps
for
subchronic
neurotoxicity
and
DNT
studies,
the
increased
susceptibility
of
the
young,
as
well
as
the
significant
uncertainty
associated
with
the
effects
of
endosulfan
on
the
endocrine/
neuroendocrine
system,
the
Agency
does
not
have
reliable
data
that
would
warrant
reduction
of
the
default
10X
FQPA
safety
factor.

3.7.3
Other
Considerations
The
Agency
has
considered
the
scientific
issues
raised
by
the
ETF
regarding
the
retention
29
of
the
default
10X
FQPA
Safety
Factor
(
FQPA
SF).
In
a
document
dated
May
9,
2002,
the
Agency
elaborated
on
its
rationale.
The
afore
mentioned
document
also
included
the
supporting
documentation
used
by
the
FQPA
Safety
Factor
Committee
during
its
deliberations
as
well
as
the
reports
of
the
committee's
decision.
Members
of
the
ETF
and
OPP
staff
met
on
May
15,
2002
to
discuss
the
Agency's
decision
to
retain
the
factor
as
stated
in
the
Agency
document
of
May
9th.
Dr.
Jim
Lamb
presented
the
ETF
position
in
support
of
reducing
the
FQPA
SF
to
3X.
The
ETF
claims
that
a
3X
factor
is
adequate
based
on
the
lack
of
developmental
and
subchronic
neurotoxicity
studies.
The
ETF
claims
that
"
the
database
is
complete
and
reliable;
the
EPA
has
relied
heavily
on
non­
core
(
literature)
studies
to
conclude
that
young
are
more
susceptible;
EPA
has
used
studies
equivalent
or
inferior
to
Tier
1
screening
to
label
endosulfan
an
EDC."
The
Agency
notes
that
while
the
core
toxicological
studies
have
been
submitted,
this
does
not
preclude
the
Agency
from
considering
published
literature
in
the
evaluation
of
a
chemical.
The
Agency
further
notes
that
the
open
literature
studies
evaluated
endpoints
not
examined
in
the
core
guidelines
studies
submitted
by
the
registrant
(
e.
g.,
sperm
parameters
and
behavioral
changes).
In
addition,
the
open
literature
studies
used
by
the
Agency
during
its
evaluation
of
endosulfan
have
been
published
in
recognized,
peer
reviewed
journals.
The
ETF
raised
the
issue
of
the
use
of
a
published
pre­
natal
toxicity
study
in
rats
(
i.
e.,
in
utero
exposure
only)
in
the
Agency's
evaluation
of
the
aRfD.
The
Agency
notes
that
it
is
presumed,
given
the
rapidly
changing
environment
during
development,
that
treatment­
related
effects
seen
in
fetuses
may
result
from
a
single
exposure
event.
Consequently,
the
Agency
is
justified
in
considering
the
2001
study
by
Sinha
et
al.
in
its
assessment
of
the
aRfD.
Since
the
effects
seen
in
the
Sinha
study
occur
at
a
dose
of
1
mg/
kg/
day
(
lower
than
the
dose
considered
a
NOAEL
in
the
guideline
study
and
used
for
regulatory
purposes),
there
is
valid
scientific
evidence
that
the
current
aRfD
may
underestimate
the
risk
posed
by
acute
endosulfan
exposure.
This
possibility
is
further
reinforced
by
similar
findings
reported
by
Dalsenter
et
al.
at
a
dose
of
1.5
mg/
kg/
day,
clearly
indicating
that
a
NOAEL
for
sperm
parameters
(
indicators
of
endocrine
disruption)
has
not
been
identified
and
a
thorough
evaluation
of
this
critical
endpoint
is
not
available.
These
data
limitations
also
extend
to
effects
that
may
arise
due
to
longer
exposures.
As
a
result,
the
default
10X
FQPA
factor
retained
by
the
Agency
would
also
be
applicable
to
the
cRfD.
Finally,
the
ETF
asserts
that,
in
their
opinion,
the
variability
noted
in
the
published
literature
make
the
results
in
these
studies
suspect.
The
Agency
acknowledges
the
variability
in
the
results
from
the
published
literature;
however,
the
different
experimental
conditions
[
e.
g.,
using
different
dosing
regimens
(
in
utero
exposure
versus
in
utero
and
post­
natal
exposure),
different
batches
of
the
test
article,
different
strains
(
Wistar
vs.
Drukrey),
conducted
at
different
times
(
e.
g.
1997
versus
2001)]
in
said
studies
precludes
a
meaningful
comparison
of
the
results.
Consequently,
the
Agency
does
not
consider
the
disparities
seen
in
the
published
literature
sufficient
evidence
to
discount
the
overall
indications
of
endocrine
disruption
seen
throughout
the
published
data.
In
conclusion,
the
Agency
reaffirms
its
position
regarding
the
significant
residual
uncertainties
described
in
the
May
9,
2002
document
and
thus
reiterates
its
position
pertaining
to
the
lack
of
reliable
data
that
would
warrant
reduction
of
the
default
10X
FQPA
SF
as
mandated
by
Food
Quality
Protection
Act
(
FQPA)
of
1996.

3.8
Dose
Selection
Due
to
the
availability/
submission
of
acceptable/
guideline
oral,
dermal,
and
inhalation
30
studies
using
endosulfan,
the
dietary
and
occupational
risk
assessments
were
conducted
using
route­
specific
endpoints
(
no
residential
uses
are
supported).
The
acute
dietary
endpoint
is
based
primarily
on
neurotoxicity.
The
neurotoxicity
is
believed
to
result
from
over­
stimulation
of
the
central
nervous
system.
Characteristic
clinical
signs
of
endosulfan­
induced
neurotoxicity
include
hyperactivity,
tonic
contractions,
involuntary
muscle
movements,
pronounced
sensitivity
to
noise
and
light,
incoordination,
seizures,
and
convulsions.
These
clinical
signs
are
observed
in
humans
accidentally
exposed
to
endosulfan,
and
in
animal
studies
of
varying
treatment
durations
following
different
routes
of
exposure
and
in
different
animal
species.
The
chronic
dietary,
and
short­,
intermediate­,
and
long­
term
dermal
and
inhalation
endpoints
are
based
on
the
toxic
effects
observed
in
animals
following
subchronic
or
chronic
exposure,
and
include:
neurotoxicity,
hematological
effects,
and
nephrotoxicity.
In
some
animal
studies
endosulfan
inhibited
plasma
cholinesterase
at
the
highest
doses
tested.
Endosulfan
is
not
a
dermal
sensitizer,
nor
is
it
mutagenic
or
carcinogenic.
See
Endosulfan:
Re­
evaluation
of
Toxicology
Endpoint
Selection
for
Dermal
and
Inhalation
Risk
Assessments
and
3X
Safety
Factor
for
Bioaccumulation
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
Robert
Fricke.
February
28,
2002.

3.8.1
Acute
Reference
Dose
(
RfD)

In
an
acute
neurotoxicity
study
(
MRID#
44403101),
male
and
female
Wistar
rats
(
10/
sex/
dose)
were
fasted
overnight
and
then
orally
gavaged
once
with
endosulfan
(
98.6%)
suspended
in
2%
starch
mucilage
at
a
constant
volume
of
10
ml/
kg
body
weights.
Two
separate
control
groups
of
10
rats/
sex
were
used
in
the
study.
One
control
group
was
assigned
to
males,
dosed
at
0
(
vehicle),
25,
50
and
100
mg/
kg
and
females
dosed
at
0
(
vehicle),
3,
6
and
12
mg/
kg.
The
other
control
group
was
assigned
to
males
dosed
at
0,
6.25
and
12.5
mg/
kg
and
females
at
0,
0.75
and
1.5
mg/
kg.
Rats
were
observed
for
15
days
and
survivors
were
sacrificed
at
week
three.
The
animals
were
evaluated
for
neurobehavioral
effects
(
FOB
and
motor
activity)
on
day
7
prior
to
dosing,
and
days
1
(
within
8
hours
after
dosing),
8
and
15
of
post­
dosing.
Neuropathological
examinations
were
carried
out
at
terminal
sacrifice
(
at
week
3)
on
ten
rats/
sex
of
controls
and
four
100
mg/
kg
male
rats
and
five
12
mg/
kg
female
rats.

Treatment­
related
clinical
signs
were
noted
within
8
hours
after
dosing
on
day
one
(
peaktime
of
effects)
in
males
at
50
and
100
mg/
kg
and
females
dosed
at
6
and
12
mg/
kg.
These
symptoms
were
not
observed
after
day
2
in
all
survivors.
Clinical
signs
noted
included
tonoclonic
convulsions,
decreased
spontaneous
activities,
stilted
gait,
stupor,
prone
position,
squatting
posture,
straddled
hindlimbs,
bristle
coat,
palpebral
fissure
narrowing,
and
irregular
respiration
and
panting
in
males
dosed
at
50
and
100
mg/
kg
and
females
dosed
at
6
and
12
mg/
kg.
In
addition,
increased
incidences
of
the
following
signs;
stilted
gait,
squatting
posture,
irregular
respiration
and
decreased
spontaneous
activities
in
males
dosed
at
25
mg/
kg;
increased
incidences
of
squatting
posture,
straddled
hindlimbs,
decreased
spontaneous
activities,
bristle
coat,
irregular
respiration
and
panting
were
also
noted
in
females
dosed
at
3
mg/
kg/
day.
Animals
with
"
drawn
in
flanks"
were
only
noted
in
females
dosed
at
3,
6,
12
mg/
kg.
Tremors
were
noted
in
three
and
four
females
dosed
at
6
mg/
kg
and
12
mg/
kg,
respectively
and
in
four
males
dosed
at
50
mg/
kg.
Salivation
was
noted
in
one
male
dosed
at
100
mg/
kg,
and
in
one
female
each
dosed
at
6
and
12
mg/
kg.
According
to
the
study,
the
clinical
effects
observed
were
due
to
interaction
31
of
endosulfan
with
the
brain
gamma
amino­
butyric
acid
(
GABA)
receptors.
No
compoundrelated
effects
on
motor
activity
were
noted
for
rats
that
survived.
No
treatment­
related
effects
were
seen
on:
the
rearing
frequency,
fore
and
hind­
limb
grip
strength,
and
on
landing
footspread
body
weight
and
food
consumption;
organ
weight;
gross
pathology;
or
histo(
neuro)
pathology.
The
NOAEL
was
12.5
mg/
kg
for
males
and
1.5
mg/
kg
for
females.
The
LOAEL
was
25
mg/
kg
for
males
based
increased
incidences
of
stilted
gait,
squatting
posture,
and
irregular
respiration,
as
well
as
decreased
spontaneous
activity.
The
LOAEL
was
3
mg/
kg
for
females,
based
on
an
increased
incidence
of
stilted
gait,
squatting
posture,
straddled
hindlimbs,
irregular
respirations,
panting
and
bristled
coat
and
decreased
spontaneous
activity.

The
dose
and
endpoint
for
establishing
the
RfD
is
the
NOAEL=
1.5
mg/
kg
based
on
increased
incidences
of
convulsions
seen
within
8
hours
after
dosing
in
females
at
3
mg/
kg.
Though,
the
database
included
a
lower
NOAEL
(
maternal)
of
0.7
mg/
kg/
day
in
the
rabbit
developmental
toxicity
study
(
MRID#
00094837),
based
on
salivation,
convulsions,
rapid
breathing,
and
hyperactivity
seen
at
1.8
mg/
kg/
day.
The
Committee,
however,
decided
not
to
use
this
NOAEL
for
this
(
acute)
scenario
because
the
clinical
signs
in
the
dams
were
seen
on
day
10
of
gestation
(
i.
e.,
after
4
treatments)
whereas
in
the
acute
neurotoxicity
study,
convulsions
were
seen
8
hours
after
a
single
oral
dose,
thus
making
this
endpoint
more
appropriate
for
this
risk
assessment.
An
uncertainty
factor
of
100
was
applied
to
account
for
inter­
species
variation
(
10x)
and
for
intra­
species
extrapolation
(
10x).

Acute
RfD:
1.5
mg/
kg
÷
100
(
UF)
=
0.015
mg/
kg
Acute
PAD
(
aPAD):
0.015
÷
10
(
FQPA)
=
0.0015
mg/
kg
3.8.2
Chronic
RfD
In
a
combined
chronic/
carcinogenicity
study
(
MRID#
41099502),
groups
of
50
Sprague­
Dawley
rats/
sex/
group
were
fed
(
in
the
diet)
with
technical
endosulfan
(
97.1%
ai)
at
0,
3.0,
7.5,
15.0,
and
75.0
ppm
(.
0,
0.1,
0.3,
0.6,
and
2.9
mg/
kg/
day
for
males
and
0,
0.1,
0.4,
0.7,
and
3.8
mg/
kg/
day
for
females)
for
104
weeks.
A
satellite
group
of
twenty
rats/
sex
was
dosed
in
a
similar
fashion
and
was
used
for
hematology
and
clinical
chemistry
evaluations.
No
treatmentrelated
effects
on
clinical
signs,
mortality,
food
consumption
and
urinalysis
were
observed.
Mean
body
weights
of
the
males
and
females
dosed
at
75.0
ppm
were
statistically
significantly
decreased
(
p<
0.01;
17.6%)
as
compared
to
their
respective
controls.
Grossly,
enlarged
kidneys
were
noted
in
females
in
the
satellite
group
dosed
at
75.0
ppm
(
8/
20
versus
2/
20
in
the
controls).

No
treatment­
related
changes
were
noted
in
the
clinical
chemistry
and
hematology
parameters
evaluated.
Marginal
decreases
of
leukocyte
(
at
week
26)
and
lymphocyte
counts
(
at
weeks
26
and
52)
were
noted
in
the
males
dosed
at
75.0
ppm.
At
week
13,
RBC
counts
and
MCV
values
were
decreased
in
all
treated
females
as
compared
to
the
controls.
Since
dose
related
trends
were
not
evident
and
since
no
changes
were
noted
at
other
intervals,
these
changes
were
not
judged
to
be
related
to
treatment.
Increased
incidences
of
blood
vessel
aneurysms
(
18/
70
versus
10/
70
in
controls)
and
enlarged
lumbar
lymph
nodes
(
19/
70
versus
14/
70
in
controls)
were
noted
in
the
male
rats
dosed
at
75.0
ppm
as
compared
to
the
controls.
Increased
32
incidences
of
enlarged
kidneys
were
seen
in
females
dosed
at
75
ppm
(
30/
70
versus
21/
70
in
controls)
as
compared
to
the
controls.
Other
organ
weights
were
not
affected
by
dosing.
Although
slightly
decreased
testes
weights
were
observed
in
males
dosed
at
15
and
75
ppm,
these
changes
were
not
considered
toxicologically
significant.
Histopathologically,
increased
incidences
of
blood
vessel
aneurysms
(
18/
70
versus
9/
70
in
controls)
were
noted
in
male
rats
dosed
at
75.0
ppm.
Also,
a
significant
increased
incidence
of
marked
progressive
glomerulonephrosis
in
the
kidneys
was
seen
in
male
(
30/
70
versus
20/
70
in
controls)
and
in
female
(
8/
70
versus
1/
70
in
controls)
rats
dosed
at
75.0
ppm.
The
incidence
of
the
glomerulonephrosis
in
the
kidneys
in
the
high­
dose
males
(
43%)
was
higher
than
that
observed
in
the
historical
controls
(
reported
at
19.7%).
These
data
were
re­
evaluated
because
of
some
concerns
expressed
by
one
member
of
the
RfD/
RfC
Work
Group
(
Memorandum:
Linda
Taylor
to
George
Ghali.
March
19,
1993).
It
was
stated
in
this
memo
that
the
increase
in
the
severity
of
progressive
glomerulonephrosis
in
rats
of
both
sexes
at
the
high­
dose
level
was
regarded
as
an
adverse
effect
and
that
the
spontaneously
occurring
renal
disease
was
exacerbated
by
exposure
to
the
test
material.
No
treatment­
related
neoplastic
lesions
were
evident
in
this
study.
A
slight
increased
incidence
of
pituitary
adenoma
in
males
and
females
dosed
at
75
ppm,
and
fibroma/
adenoma
of
the
mammary
glands
in
females
dosed
at
75
ppm,
was
not
judged
to
be
related
to
treatment,
because
dose­
related
trends
were
not
evident
The
doses
used
in
this
study
appear
to
be
adequate
to
test
the
carcinogenic
potential
of
the
test
compound,
as
evidenced
by
the
compound­
related
systemic
effects
noted
above.
Based
on
the
results
of
this
study,
the
systemic
NOAEL
is
15.0
ppm
(
0.6
and
0.7
mg/
kg/
day
for
males
and
females,
respectively)
and
the
systemic
LOAEL
is
75.0
ppm
(
2.9
and
3.8
mg/
kg
/
day
for
males
and
females,
respectively)
based
on
decreased
body
weight
gain
in
male
and
female
rats,
enlarged
kidneys
and
increased
incidences
of
marked
progressive
glomerulonephrosis
and
blood
vessel
aneurysms
in
males.

The
dose
and
endpoint
for
the
chronic
RfD
is
the
NOAEL=
0.6
mg/
kg/
day.
The
LOAEL
=
2.9
mg/
kg/
day,
based
on
reduced
body
weight
gain,
enlarged
kidneys
and
increased
incidences
of
marked
progressive
glomerulonephrosis
in
males
and
females,
and
blood
vessel
aneurysms
in
kidneys
of
male
rats.
The
RfD/
Peer
Review
considered
the
chronic
toxicity
study
in
dogs
(
MRID#
41099501)
with
a
NOAEL
of
0.65
mg/
kg/
day
to
be
a
co­
critical
study.
In
this
dog
study,
the
LOAEL
of
1.75
mg/
kg/
day
was
based
on
decreased
body
weight
gain
in
males
and
increased
incidences
of
neurologic
findings
in
males
and
females
(
loss
or
weakening
of
placing
and
righting
reactions,
tonic
contractions
of
abdominal
muscle
and
masticatory
muscles
a
few
hours
after
feeding).
The
HIARC
concurred
with
the
conclusions
reached
by
the
RfD/
Peer
Review
Committee
with
regard
to
the
study,
dose
and
endpoint
used
in
establishing
the
RfD.
An
uncertainty
factor
of
100
was
applied
to
account
for
inter­
species
variation
(
10x)
and
for
intraspecies
extrapolation
(
10x).

Chronic
RfD:
0.6
mg/
kg
÷
100
(
UF)
=
0.006
mg/
kg/
day
Chronic
PAD
(
cPAD):
0.006
÷
10
(
FQPA)
=
0.0006
mg/
kg/
day
3.8.3
Dermal
Absorption
Two
dermal
absorption
studies
were
available.
In
one
dermal
absorption
study
(
MRID#
33
40223601),
three
groups
of
24
male
Crl:
CD(
SD)
Br
rats/
group
were
dosed
topically
with
radiolabeled
endosulfan
dosing
suspension
(
94.6%
ai)
at
nominal
doses
of
0.1,
1,
and
10
mg/
kg
and
exposed
for
0.5,
1,
2,
4,
10
and
24
hours.
After
exposure,
the
application
sites
were
washed
with
5
ml
of
mild
soap
solution
and
three
5
ml
portions
of
water
for
further
analysis.
The
percent
doses
absorbed
over
a
24­
hour
period
were
2.2­
21.6,
0.32­
21.52,
and
0.08­
8.38
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.
The
percentages
of
endosulfan
absorbed
at
1,
10
and
24
hours
intervals,
were
1.8,
7.6
and
21.6%
for
rats
dosed
at
0.1
mg/
kg,
0.57,
5.77
and
21.52%,
for
rats
dosed
at
1.0
mg/
kg,
and
0.29,
3.86,
and
8.38%
for
rats
dosed
at
10
mg/
kg.
The
percent
of
doses
remaining
in/
on
the
skin
after
soap
and
water
washes
over
a
24­
hour
period
were
62.1­
56.5,
78.1­
57.7,
and
80.2­
66.7
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.
These
data
showed
that
significant
portions
of
the
dose
remained
on
the
skin
following
soap
and
water
washes.

In
another
dermal
absorption
study
(
MRID#
41048504),
three
groups
of
16
female
Crl:
CD(
SD)
BR
rats/
group
were
dosed
topically
with
radiolabeled
endosulfan
(
94.6%
ai)
at
nominal
doses
of
0.1,
1,
and
10
mg/
kg
(
1.9,
21.9,
and
231.4
mg/
cm2)
to
determine
the
fate
of
the
residue
that
was
left
in/
on
the
skin
following
10
hours
of
exposure.
Ten
hours
after
dosing,
the
application
sites
were
washed
with
1%
liquid
Ivory
soap
and
rinsed
with
water.
The
radioactive
labeled
endosulfan
presence
was
analyzed
in
four
live
rats/
group
at
24,
48,
72,
and
168
hours
after
dosing.
The
percent
dose
absorbed
at
24
hours
was
22.1,
16.1,
and
3.8%
and
at
168
hours
was
44.8,
46.4,
and
20.3%
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.
The
amount
of
the
dose
remaining
on/
in
the
skin
at
168
hours
was
41.4,
56.2,
and
72.8%
for
the
0.1,
1,
and
10
mg/
kg
dose
groups,
respectively.

The
HIARC
selected
the
dermal
absorption
factors
of
45
%
(
rounded
from
44.8%)
at
168
hours
post
exposure.
The
Committee
selected
the
dermal
absorption
rate
based
on
the
following
weight­
of­
evidence
considerations:
1)
at
24
hours,
the
percent
absorption
was
comparable
between
males
(
21.6%)
and
females
(
22.1%);
2)
in
female
rats,
even
after
washing
at
10
hours,
the
percent
absorption
increased
with
time,
the
final
measurement
was
44.8%
at
168
hours;
3)
the
concern
that
the
test
material
continued
to
be
absorbed
even
after
washing
at
10
hours;
4)
substantial
dermal
absorption
was
demonstrated
in
the
21­
day
dermal
toxicity
study
with
a
NOAEL
of
3
mg/
kg/
day
and
systemic
toxicity
(
increased
mortality,
and
increased
liver
abnormalities)
evident
at
9
mg/
kg/
day
(
LOAEL).
In
addition,
this
dermal
absorption
factor
is
supported
by
comparing
the
results
of
the
oral
and
dermal
studies
in
the
same
species.
The
ratio
of
the
oral
LOAEL
of
6
mg/
kg/
day
in
the
developmental
toxicity
study
in
rabbits
and
the
dermal
LOAEL
of
9
mg/
kg/
day
in
the
21­
day
dermal
toxicity
study
in
rabbits
with
the
same
endpoint
(
increased
mortality)
indicate
a
dermal
absorption
rate
of
67%
[(
6
÷
9]
x
100
=
67%)
as
compared
to
the
amount
absorbed
orally.

Dermal
Absorption
Factor
=
45%

3.8.4
Short­
term
(
1­
30
days)
Dermal
Occupational
Exposures
In
an
acceptable/
guideline
21­
day
dermal
toxicity
study
(
MRID#
00146841/
00147744)
in
rats,
endosulfan
(
97.2%
ai
w/
w)
was
applied
to
the
skin
of
five
groups
of
six
male
and
female
34
Wistar
rats
at
doses
of
0,
1,
3,
9,
and
27
mg/
kg/
day
and
onto
six
males
only
at
81
mg/
kg/
day,
for
21
applications
(
5
days
a
week)
over
30
days.
Five
of
the
six
(
83%)
high­
dose
(
27
mg/
kg/
day)
females
died
on
days
2
and
6
of
the
study.
Three
of
the
six
(
50%)
high­
dose
(
81
mg/
kg/
day)
males
died
on
days
2
and
3
of
study
(
females
were
not
tested
at
this
dose).
Two
of
the
three
81
mg/
kg/
day
males
that
died
had
shown
tonoclonic
convulsions,
increased
salivation
and
respiration.
Although
no
deaths
occurred
in
males
dosed
at
27
mg/
kg/
day,
2
of
the
6
(
33%)
males
dosed
at
9
mg/
kg/
day
died
on
days
5
and
8;
these
deaths
were
not
considered
to
be
treatment­
related
due
to
a
possible
pre­
existing
health
problem.
Increased
incidences
of
mortality
in
males
dosed
at
81
mg/
kg/
day
and
females
dosed
at
27
mg/
kg/
day
appear
to
be
a
compound­
related
effect.
No
changes
of
clinical
chemistry
and
hematology
parameters
can
be
attributed
to
treatment.
Changes
that
occurred
were
small
and
they
are
not
judged
to
be
doserelated
Females
dosed
at
9
mg/
kg/
day
showed
significantly
increased
absolute
and
relative
spleen
weights
and
absolute
adrenal
weights,
as
compared
to
controls.
Significant
dermal
irritation
was
not
produced
by
the
test
compound.
Dermal
irritation
for
all
groups
was
very
slight
at
all
evaluation
intervals.
It
appears
that
dermal
irritation
was
more
persistent
in
females
in
the
3
and
9
mg/
kg/
day
dose
groups,
as
evidenced
by
greater
dermal
irritation
scores
(
2­
3
times)
than
that
of
controls.
There
was
no
difference
between
the
average
scores
of
the
treated
males
as
compared
to
the
controls
at
any
dose
level.
Although
dermal
irritation
scores
were
zero
at
the
end
of
the
study,
and
although
the
pathology
report
described
the
dermal
effects
as
being
similar
in
treated
and
control
animals,
there
appears
to
be
an
increase
in
severity
or
prolongation
of
irritation
found
in
females
dosed
at
3
and
9
mg/
kg/
day.
The
LOAELs
were
determined
to
be
81
mg/
kg/
day
in
males
and
27
mg/
kg/
day
in
females
based
on
increased
mortality.
The
NOAELs
were
established
at
27
mg/
kg/
day
in
males
and
9
mg/
kg/
day
in
females.

In
another
acceptable/
guideline
21­
day
dermal
toxicity
study
(
MRID#
00146841),
endosulfan
(
97.2%)
was
applied
to
the
skin
of
five
groups
of
11
male
and
11
female
Wistar
rats
at
doses
of
0,
12,
48,
96,
and
192
mg/
kg
in
males
and
0,
3,
6,
12,
and
48
mg/
kg
in
females
for
21
applications
over
30
days.
Six
rats/
sex/
group
were
kept
as
the
main
treatment
group
for
29
days,
and
then
sacrificed.
After
being
treated
for
29
days,
the
remaining
five
rats/
sex/
group
were
held,
untreated,
for
another
14
days
before
they
were
sacrificed.
Treatment­
related
signs
of
toxicity
(
piloerection,
salivation
and
lacrimation)
were
noted
in
the
96
mg/
kg
males.
Non­
treatment
related
signs
of
toxicity
(
piloerection,
slight
lacrimation
and
auto­
aggression)
were
noted
in
one
female
(#
99)
dosed
at
the
12
mg/
kg
dose
level.
Eight
females
dosed
at
48
mg/
kg
showed
treatment­
related
clinical
signs
(
three
exhibited
hypersalivation,
2
of
which
died;
one
showed
crusted
eyes;
one
with
a
bloody
crusted
nose
which
subsequently
died;
one
showed
dacryohemorrhea
tonic
convulsions,
marked
salivation
and
bloody
exudate).
Two
males
dosed
at
192
mg/
kg
(
one
each
on
days
6
and
9)
and
four
females
dosed
at
48
mg/
kg
(
between
days
2
and
22)
died
after
exhibiting
tonoclonic
convulsions.
Increased
mortalities
in
the
males
dosed
at
192
mg/
kg
(
2
of
11
rats)
and
females
dosed
at
48
mg/
kg
(
4
of
11
rats)
are
considered
to
be
treatmentrelated
One
female
each
of
the
groups
dosed
at
3,
6,
and
12
mg/
kg
died
on
day
18
from
unknown
causes.
The
investigator
speculated
that
these
mortalities
were
attributed
to
the
application
technique
employed
and
for
this
reason
this
study
was
immediately
repeated
(
see
above
MRID#
00146841/
00147744)
using
a
modified
application
method
at
dose
levels
of
0,
1,
3,
9,
27
and
81
mg/
kg/
day
(
Hoechst
AG
Rept#
A30764,
p.
17).
Since
the
methods
were
not
sufficiently
described
in
the
report,
no
conclusion
can
be
made
whether
or
not
the
methods
used
35
were
improper.
The
deaths,
however,
did
not
appear
to
demonstrate
typical
endosulfan
toxicity.
Skin
dryness
and
desquamation
were
noted
in
all
groups.
The
body
weight,
food
consumption,
hematology,
and
urinalysis
values
were
not
affected
by
the
treatment.
Endosulfan
was
nonirritating
at
all
doses
tested.
On
day
30,
inhibition
of
serum
(­
33%),
RBC
(­
28%)
and
brain
ChE
(­
17%)
activity
was
noted
in
the
males
dosed
at
192
mg/
kg,
48
mg/
kg
and
96
mg/
kg,
respectively.
Only
the
depressed
serum
ChE
activity,
when
compared
to
the
controls,
appeared
to
be
treatment­
related.
At
day
30,
statistically
significant
increases
in
relative
kidney
weights
were
noted
in
the
males
dosed
at
12,
96,
and
192
mg/
kg;
the
absolute
kidney
weights,
however,
were
not
statistically
significantly
increased.
Discrete
deposition
of
pigments
in
a
few
cells
of
the
proximal
straight
tubule
of
the
kidneys
was
noted;
this
finding
is
of
interest,
because
similar
pigment
deposition
in
the
proximal
convoluted
tubules
was
noted
in
other
studies
with
endosulfan.
The
NOAELs
were
established
at
12
mg/
kg/
day
in
females
and
96
mg/
kg/
day
in
males.
The
LOAELs
were
determined
to
be
48
mg/
kg/
day
in
females
and
192
mg/
kg/
day
in
males
based
on
increased
mortality
in
males
and
females
and
increased
serum
ChE
activity
inhibition
in
males.

The
dose
and
endpoint
selected
for
risk
assessment
was
dermal
NOAEL=
12
mg/
kg/
day
based
on
mortality
in
female
rats
at
27
mg/
kg/
day
(
LOAEL).
The
endpoints
from
both
21­
day
dermal
toxicity
studies
discussed
above
were
considered
in
arriving
at
the
NOAEL
(
MRID#
00146841)
and
LOAEL
(
MRID#
00146841/
00147744).
These
21­
day
dermal
studies
are
appropriate
for
dermal
exposure
scenarios
up
to
30
days.
An
MOE
or
Level
of
Concern
(
LOC)
of
100
(
10x
for
inter­
species
extrapolation
and
10x
for
intra­
species
variability)
is
adequate
for
occupational
exposure.

short­
term
dermal
occupational
LOC
=
100
3.8.5
Intermediate­
term
(
one
to
several
months)
Dermal
Occupational
Exposures
The
21­
day
dermal
toxicity
studies
in
rats
(
MRID#
00146841
and
MRID#
00146841/
00147744)
were
also
selected
for
intermediate/
long­
term
dermal
exposure.
See
Short­
Term
Dermal
Occupational
Exposures
above.
The
dose
and
endpoint
selected
for
risk
assessment
is
dermal
NOAEL
=
12
mg/
kg/
day
based
on
mortality
in
females
at
27
mg/
kg/
day
(
LOAEL).

These
21­
day
dermal
studies
can
also
be
used
for
intermediate­
term
dermal
risk
assessments
because
of
the
appropriateness
for
the
route
of
exposure
and
the
toxicity
is
defined
and
characterized.
Though
previous
assessments
included
an
additional
(
FIFRA)
factor
of
3x
to
address
the
uncertainty
in
extrapolating
data
from
less
than
30
days
up
to
several
months,
since
there
is
no
evidence
to
indicate
that
long­
term
exposure
increases
toxicity
in
target
organs
due
to
bioaccumulation,
the
HIARC
recommended
that
the
factor
be
removed.
This
conclusion
was
based
on
the
results
of
a
toxicokinetic
study
(
MRID#
45546201)
with
14C­
labeled
endosulfan
which
showed
that
endosulfan
does
not
bioaccumulate.
Based
on
the
proposed
use
pattern
(
the
ETF
is
no
longer
supporting
any
of
the
uses
that
may
have
resulted
in
long­
term
exposures),
no
long­
term
(
several
months
to
one
year)
exposures
are
expected.
An
LOC
or
MOE
of
100
(
10x
for
inter­
species
extrapolation
and
10x
for
intra­
species
variability)
is
adequate
for
occupational
3
Conversion
of
mg/
L
to
oral
dose
(
mg/
kg/
day)
=
mg/
L
x
absorption
(
1.0)
x
[
Respiratory
Volume
(
Wistar
rats)
for
6
hours/
day]
x
Duration
of
Exposure
(
5
days/
wk)/
body
weight
x
7
days/
week
=
0.001
mg/
L
x
1.0
x
[
8.46(
RV)
x
6
hrs)
x
5
d/
wk
=
0.194
mg/
kg/
day
0.187
kg
x
7
d/
wk
36
exposure.

intermediate­
term
dermal
occupational
LOC
=
100
3.8.6
Short­
term
(
1­
30
days)
Inhalation
Occupational
Exposures
In
a
range­
finding
inhalation
study
(
MRID
41667501)
two
groups
of
5
Wistar
rats/
sex
were
exposed,
nose­
only,
to
aerosol
concentrations
of
endosulfan
(
97.2%
ai)
at
0.0024
and
0.0065
mg
a.
i./
L
for
6
hours/
day,
five
days/
week
for
a
total
of
7
exposures.
Two
females
exposed
to
0.0065
mg/
L
died
by
day
8
of
the
study.
Female
survivors
had
clinical
signs
including
tremors,
trembling,
tonic­
clonic
convulsions,
and
reduced
corneal
reflexes.
Males
exposed
to
the
highest
concentration
were
ataxic
and
had
irregular
breathing.
Body
weight
loss
was
noted
in
males
and
females
at
both
concentrations
early
in
the
study
(
days
3­
4).
Based
on
the
results
of
this
range
finding
study,
the
highest
concentration
for
the
21­
day
subchronic
study
was
set
at
0.0020
mg
a.
i./
L.
In
the
21­
day
inhalation
toxicity
study
(
MRID#
00147183),
ten
male
and
ten
female
Wistar
rats
were
exposed,
nose­
only,
to
technical
endosulfan
(
97.2%
ai)
at
concentrations
of
0
(
air),
0.0005,
0.0010,
and
0.0020
mg/
L
(
0.097,
0.194,
and
0.387
mg/
kg/
d)
3
for
6
hours/
day,
5
days/
week
for
a
total
of
21
exposures
over
29
days.
An
additional
group
of
5
animals/
sex/
dose
was
held
for
a
4­
week
recovery
period
after
receiving
the
test
aerosol.
No
mortality
or
clinical
signs
of
toxicity
occurred
during
the
study.
Group
mean
body
weights
were
similar
to
controls
with
the
exception
of
males
in
the
highest
dosed
group
that
had
lower
body
weight
(
3­
5%)
from
day
20
through
29.
In
the
highest
dosed
males
from
the
recovery
group,
the
decrements
in
body
weights
were
more
pronounced
(
12­
16%)
from
recovery
days
34­
60.
Although
neither
sex
had
any
statistically
significantly
body
weight
changes
during
the
exposure
period
and
the
number
of
recovery
animals
for
each
sex
was
only
5,
the
apparent
effect
suggested
a
possible
delay
in
its
manifestation.

Erythrocyte
counts
in
the
low
and
mid
dose
males
at
the
end
of
the
exposure
period
(
Day
29)
were
significantly
elevated.
No
effects
on
erythrocyte
counts
were
observed
at
the
high
dose.
Hence,
the
changes
did
not
demonstrate
a
pattern
of
toxicity
because
the
toxicological
significance
of
an
increased
RBC
count
is
unknown.
In
addition,
the
test
report
stated
that
the
values
were
apparently
within
the
norm
for
the
species
and
strain
studied.
Some
slight
effects
on
clinical
chemistry
and
in
hematology
counts
were
noted
but
these
did
not
demonstrate
significant
toxicity
of
the
test
compound.
There
were
statistically
significant
decreases
in
leucocyte
counts
(
20.1%)
in
the
high­
dose
males,
which
seemed
to
be
marginally
dose
related
but
did
not
indicate
significant
toxicity.
High­
dose
females
had
increased
creatinine
(
21%)
values
suggestive
of
kidney
toxicity
and
were
judged
to
be
treatment
related
but
there
were
no
other
signs
supporting
kidney
toxicity
in
the
histopathology
or
organ
weight
changes.
The
study
NOAEL
was
0.0010
mg
a.
i./
L
(
0.20
mg/
kg/
day),
and
the
LOAEL
was
0.0020
mg
a.
i./
L
(
0.40
mg/
kg/
day)
based
on
decreased
body­
weight
gain
and
decreased
leukocyte
counts
in
the
males
and
increased
37
creatinine
values
in
the
females.

The
dose
and
endpoint
selected
for
risk
assessment
was
NOAEL
=
0.0010
mg
a.
i./
L
(
0.2
mg/
kg/
d)
based
on
decreased
body­
weight
gain
and
decreased
leukocyte
counts
in
males
and
increased
creatinine
values
in
females
at
the
LOAEL
of
0.0020
mg
a.
i./
L
(
0.4
mg/
kg/
d
).
The
inhalation
study
in
rats
is
route
appropriate
for
the
short­
term
inhalation
exposure
up
to
30
days
and
the
toxicity
effects
(
decreased
body
weight
gain
and
nephrotoxicity)
are
noted
in
other
longer
term
studies
by
the
oral
route.
An
LOC
of
100
(
10x
for
inter­
species
extrapolation
and
10x
for
intra­
species
variability)
is
adequate
for
occupational
exposure.

short­
term
inhalation
occupational
LOC
=
100
3.8.7
Intermediate­
Term
(
one
to
several
months)
Inhalation
Occupational
Exposures
The
21­
day
inhalation
study
(
MRID#
00147183)
in
the
rat
was
also
selected
for
the
intermediate­
term
endpoint.
See
Short­
Term
Inhalation
Occupational
Exposures
above.
The
dose
and
endpoint
for
risk
assessment
was
NOAEL
=
0.0010
mg
a.
i./
L
(
0.2
mg/
kg/
d)
based
on
decreased
body­
weight
gain
in
both
sexes
and
decreased
leukocyte
counts
in
males
and
increased
creatinine
values
in
females
at
the
LOAEL
of
0.0020
mg
a.
i./
L
(
0.4
mg/
kg/
d
).

The
21­
day
study
is
also
appropriate
for
intermediate­
term
exposure
scenarios
because
of
the
route
of
exposure.
The
toxic
effects
(
decreased
body
weight
gain
and
increased
creatinine
in
females)
are
appropriate
early
markers
for
the
effects
observed
in
rats
following
long­
term
oral
exposure
(
decreased
body
weight
and
kidney
disease).
Again,
based
on
the
proposed
use
pattern,
no
long­
term
exposures
are
expected.
An
LOC
of
100
(
10x
for
inter­
species
extrapolation
and
10x
for
intra­
species
variability)
is
adequate
for
occupational
exposure.

intermediate­
term
inhalation
occupational
LOC
=
100
3.8.8
Carcinogenic
Potential
There
was
no
evidence
of
carcinogenicity
in
either
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats
(
MRID#
41099502)
or
the
carcinogenicity
study
in
mice
(
MRID#
40792401).
The
doses
were
considered
adequate
in
both
studies.
Endosulfan
technical
was
also
inactive
in
the
primary
rat
hepatocyte
unscheduled
DNA
synthesis
(
UDS)
assay
(
MRID#
00148265),
and
was
non­
mutagenic
in
the
mouse
lymphoma
forward
mutation
assay
(
MRID#
00148266).
Endosulfan
is
classified
as
"
not
likely"
a
human
carcinogen.

Table
3.
Summary
of
Toxicology
Endpoint
Selection
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
38
Acute
Dietary
NOAEL
=
1.5
UF
=
100
FQPA
SF
=
10
Oral
LOAEL
=
3
mg/
kg/
day;
based
on
increased
incidence
of
convulsions
seen
in
female
rats
within
8
hours
after
dosing.
Acute
neurotoxicity
study
in
rats
MRID#
44403101
Acute
RfD
=
0.015
mg/
kg/
day
aPAD
=
0.0015
mg/
kg/
day
Chronic
Dietary
NOAEL
=
0.6
UF
=
100
FQPA
SF
=
10
LOAEL
=
2.9
mg/
kg/
day
based
on
reduced
body
weight
gain,
increased
incidences
of
marked
progressive
glomerulonephrosis
&
blood
vessel
aneurysms
in
male
rats.
Combined
chronic
toxicity/
carcinogenicity
study
in
rats
MRID#
41099502
Chronic
RfD
=
0.006
mg/
kg/
day
cPAD
=
0.0006
mg/
kg/
day
Dermal,
Short
(
1­
30
days)­
&
Intermediate
(
1­
6
months)­
Term
NOAEL
=
12
UF
=
100
LOAEL
is
27
mg/
kg/
day
based
on
mortality
in
females.
21­
Day
dermal
toxicity
study
in
male
&
female
rats
MRID#
00146841/
00147744
LOC
for
occupational
MOE
=
100
Inhalation,
Short
(
1­
30
days)­
&
Intermediate
(
1­
6
months)­
Term
NOAEL=
0.2
(
0.001
mg
ai/
L)

UF
=
100
LOAEL
=
0.4
mg/
kg/
day
(
0.0020
mg/
L),
based
on
decreased
body
weight
gain
&
decreased
leukocyte
counts
in
males,
&
increased
creatinine
values
in
females.
21­
Day
inhalation
toxicity
study
in
male
&
female
rats
MRID#
00147183
LOC
for
occupational
MOE
=
100
Cancer
Group
E
­
Evidence
of
non­
carcinogenicity
for
humans
No
increase
in
the
frequency
of
tumors
in
either
the
rat
or
mouse
studies.
Chronic
toxicity/
carcinogenicity
study
in
rats
(
MRID#
41099502)
&
carcinogenicity
study
in
mice
(
MRID#
40792401)

Q
1*
not
calculated
4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
4.1
Summary
of
Registered
Uses
Products
containing
endosulfan
are
registered
for
occupational
uses
only.
The
ETF
is
not
supporting
residential
uses,
and
therefore,
residential
uses
have
not
been
included
in
this
assessment.
Occupational
uses
include
applications
to
agricultural
food
and
non­
food
crops,
ornamental
and/
or
shade
trees,
fruit
and
nut
crops,
ornamental
herbaceous
trees
and
shrubs,
and
as
a
root
dip.

Endosulfan
is
formulated
for
occupational
use
as
a
technical
grade
manufacturing
product
(
95%
active
ingredient
[
ai]),
emulsifiable
concentrate
(
9
­
34%
ai),
and
a
wettable
powder
(
1
­
39
50%
ai).
The
wettable
powder
is
frequently
packaged
in
water
soluble
bags.
Depending
on
the
crop
to
be
treated
and
the
formulation
to
be
used,
formulations
containing
endosulfan
may
be
applied
by
groundboom
sprayer,
fixed­
wing
aircraft,
chemigation
(
potatoes
only),
airblast
sprayer,
rights­
of­
way
sprayer,
low
pressure
handwand,
high
pressure
handwand,
backpack
sprayer,
and
dip
treatment.
The
application
rate
and
number
of
allowable
applications
varies,
depending
upon
use
(
Third
Revision
of
"
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document
for
Endosulfan."
Renee
Sandvig.
February
26,
2002).
On
the
majority
of
product
labels,
the
number
of
maximum
allowable
applications
ranges
between
1
and
3
per
season
or
year,
and
does
not
exceed
5.

Endosulfan
has
been
registered
for
occupational­
use
on
terrestrial
food
and
feed
crops,
indoor
food
crops,
and
terrestrial
non­
food
crops.
The
occupational
use
sites
included
in
this
assessment
have
been
grouped
as
follows
(
Table
8):

°
Vegetables
and
Field
Crops:
alfalfa
(
seed
only),
barley,
beans
(
dry
and
succulent),
blueberries,
broccoli,
brussels
sprouts,
cabbage,
carrots,
cauliflower,
celery,
clover
(
seed
only),
collards,
cotton,
corn
(
fresh
only),
cucumbers,
eggplants,
grapes,
kale,
kohlrabi
(
seed
only),
lettuce,
melons,
mustard
greens,
oats,
peas,
peppers,
pineapples,
potatoes,
pumpkins,
radish
(
seed
only),
rutabaga
(
seed
only),
rye,
spinach,
squash,
sweet
potatoes,
strawberries,
tobacco,
tomato,
turnip,
and
wheat.

C
Fruit
and
Nut
Trees
(
orchard
crops),
including
apples,
apricots,
almonds,
cherries,
filberts,
macadamia
nuts,
nectarines,
pecans,
peach,
pear,
pistachio
nuts,
plums,
prunes,
and
walnuts.

°
Ornamental
Trees
and
Shrubs,
including
shade
trees,
citrus
(
non­
bearing
&
nursery
stock),
shrubs,
nursery
stock,
Christmas
tree
plantations,
and
woody
plants.

°
Root
dip,
including
cherry,
peaches,
and
plum
roots
and
crowns,
and
whole
strawberry
plants.

C
Agriculture
in
greenhouses
(
tomatoes
and
ornamental
trees
and
shrubs).

The
crop
groupings
with
their
corresponding
maximum
label
application
rates
are
as
follows
(
both
formulations
unless
noted,
EC
=
emulsifiable
concentrate,
WP
=
wettable
powder
formulations):

°
Agricultural
crops,
including
vegetables
and
field
crops:
alfalfa
(
seed
only,
1
lb
ai/
A
EC),
barley,
rye,
oats
and
wheat
(
0.75
lb
ai/
A),
beans
and
tomatoes
(
1
lb
ai/
A),
clover
(
0.5
lbs
ai/
A
EC),
blueberries
(
1.5
lb
ai/
A),
broccoli,
cabbage,
collard,
lettuce,
melons,
and
mustard
greens
(
1
lb
ai/
A
or
2
lb
ai/
A
for
seed),
Brussel
sprouts,
carrots,
cauliflower,
celery,
cucumbers,
eggplants,
peas,
peppers,
potatoes,
pumpkins,
spinach,
and
squash
(
1
lb
ai/
A),
cotton
and
corn
(
fresh
only)
(
1.5
lb
ai/
A),
grapes
(
1.5
lb
ai/
A
or
0.005
lb
ai/
gallon),
kale
(
0.75
lb
ai/
A
or
2
lb
ai/
A
for
seed),
kohlrabi,
radish,
turnip
and
rutabaga
(
2
lb
ai/
A
seed
only),
strawberries,
pineapples
and
sweet
potato
(
2
lb
ai/
A),
and
tobacco
40
(
1.5
lb
ai/
A
WP,
1
lbs
ai/
A
EC).

C
Fruit
and
nut
trees
(
orchard
crops),
including
apples
(
2.5
lb
ai/
A
or
0.005
lb
ai/
gal),
apricots,
peach,
and
nectarines
(
3
lb
ai/
A
or
0.0025
lb
ai/
gal),
almonds
and
pistachio
nuts
(
2.5
lb
ai/
A
or
0.025
lb
ai/
gallon),
cherries,
pears,
plums,
and
prunes
(
2.5
lb
ai/
A
or
0.04
lb
ai/
gallon),
filberts
(
hazelnuts
2lb
ai/
A
or
0.005
lb
ai/
gallon),
macadamia
nuts
(
3.0
lb
ai/
A
or
0.01
lb
ai/
gallon),
pecans
(
3
lbs
ai/
A
or
0.0075
lb
ai/
A),
and
walnuts
(
2
lb
ai/
A
or
0.02
lb
ai/
gallon
WP,
2.5
lb
ai/
A
or
0.04
lb
ai/
gallon
EC).
Note:
A
currently
registered
label
(
EPA
reg
#
34704­
516)
contains
a
higher
application
rate
(
7.5
lb
ai/
A)
for
pecans
and
macadamia
nuts
than
is
listed
above.
At
this
time
only
the
3.0
lb
ai/
A
rate
for
pecans
and
macadamia
nuts
is
being
supported
and
this
assessment
therefore
only
assesses
these
crops
for
a
3.0
lb
ai/
A
maximum
application
rate.
All
currently
registered
endosulfan
labels
should
be
amended
after
the
risk
mitigation
phase
of
endosulfan
to
reflect
the
new
3.0
lb
ai/
A
maximum
application
rate.

°
Ornamental
Trees
and
Shrubs,
including
shade
trees,
citrus
(
non­
bearing
and
nursery
stock),
shrubs,
nursery
stock,
Christmas
tree
plantations,
and
woody
plants
(
1
lb
ai/
A
or
0.01
lb
ai/
gallon).

°
Root
dip,
including
cherry,
peaches,
and
plum
roots
and
crowns
(
0.05
lb
ai/
gallon)
and
whole
strawberry
plants
(
0.01
lb
ai/
gallon
EC).

C
Bark
Treatment,
includes
apricot,
cherry,
grapes,
nectarines,
peach,
plums
and
prunes
(
see
above
for
application
rates,
applied
with
high
pressure
handwands
and
rights­
of­
way
sprayers).

4.2
Dietary
Exposure/
Risk
Pathway
4.2.1
Residue
Profile
Endosulfan
is
currently
registered
for
food/
feed
uses
on
a
variety
of
field,
fruit,
and
vegetable
crops.
In
a
meeting
held
on
April
21,
1997
the
Metabolism
Assessment
Review
Committee
(
MARC)
concluded
that
the
residues
of
toxicological
concern
are
endosulfan
and
the
sulfate
metabolite;
therefore,
tolerances
for
crop
and
livestock
commodities
should
be
expressed
as
residues
of
the
parent
and
the
sulfate
metabolite.
The
MARC
also
recommended
that
the
tolerance
expression
be
revised
to
specify
the
"­
and
$­
isomers
of
endosulfan.

Tolerances
have
been
established
for
residues
of
endosulfan
in/
on
various
plant
and
animal
commodities
under
40
CFR
§
180.182
and
in
processed
food
commodities
under
40
CFR
§
185.2600.
These
tolerances
range
from
0.1
­
24
ppm
and
are
currently
expressed
in
terms
of
endosulfan
and
its
metabolite,
endosulfan
sulfate.
Adequate
methods
are
available
for
data
collection
and
tolerance
enforcement.
Codex
maximum
residue
limits
(
MRLs)
are
expressed
as
the
sum
of
"­
and
$­
endosulfan
and
endosulfan
sulfate
(
fat
soluble).
When
the
U.
S.
tolerance
expression
is
revised
to
specify
the
 
and
 
isomers
of
the
parent,
Codex
MRLs
and
U.
S.
tolerances
will
be
harmonized.
A
numerical
comparison
of
the
Codex
MRLs
and
the
41
corresponding
reassessed
U.
S.
tolerances
is
presented
in
Table
10
of
the
Revised
Residue
Chemistry
chapter.
Table
10
indicates
that
U.
S.
tolerances
and
the
Codex
MRLs
for
endosulfan
are
compatible
for
carrot,
cottonseed,
fruits,
meat,
pome
fruits
(
apples),
potato,
spinach,
and
sweet
potato.
For
the
remainder
of
commodities
listed
in
Table
10,
the
U.
S.
tolerances
and
the
Codex
MRLs
are
incompatible
because
of
differences
in
registrations
or
good
agricultural
practices
[
Revised
Residue
Chemistry
Chapter
for
the
Endosulfan
Reregistration
Eligibility
Decision
(
RED)
Document.
John
Punzi.
February
14,
2002].

Dietary
risk
estimates
are
based,
in
part,
on
estimates
of
the
percent
usage
of
endosulfan
on
each
registered
crop.
BEAD
has
estimated
endosulfan
use
(
Quantitative
Usage
Analysis
for
Endosulfan.
Steven
Nako.
October
13,
1999;
Updated
QUA.
David
Donaldson.
September
10,
2000)
based
on
available
pesticide
survey
usage
data
for
the
years
1987
through
1998.
BEAD
estimates
are
provided
to
HED
as
a
weighted
average
and
as
an
estimated
maximum.
This
risk
assessment
assumed
1%
CT
for
any
BEAD
estimate
less
than
1%.
The
estimated
maximum
%
CT
for
each
commodity
was
used
for
the
acute
risk
assessment
and
the
estimated
weighted
average
%
CT
for
each
commodity
for
the
chronic
dietary
risk
assessments.
Where
no
further
information
was
available,
100
%
CT
was
assumed.

Endosulfan
residue
estimates,
or
anticipated
residues
(
AR)
in
this
assessment
are
based
primarily
on
three
data
sources:
1)
field
trial
data,
submitted
by
the
registrant
to
support
tolerances;
2)
USDA
PDP
food
sampling
data;
and
3)
FDA
Surveillance
Monitoring
data.
Where
data
were
not
available,
tolerance
levels
were
used
incorporating
the
%
CT
estimates
from
BEAD.
The
order
of
preference
for
the
purpose
of
risk
assessment
is:
PDP
data
>
FDA
data
>
field
trial
data
>
tolerance.
PDP
data
are
preferred
over
FDA
data
because
the
statistical
design
of
the
PDP
program
is
specific
for
dietary
risk
assessment
(
i.
e.
sampling
is
done
at
grocery
store
distribution
points
instead
of
directly
from
the
field),
and
because
the
foods
are
prepared
before
analysis
as
they
would
typically
be
before
consumption
(
i.
e.
peeling,
washing).
Many
endosulfan
treated
commodities
not
sampled
by
the
PDP
program
are
assessed
based
on
translation
of
data
from
PDP
sampled
commodities
in
the
same
crop
group,
FDA
surveillance
data,
or
field
trial
data
where
available.
Tolerance
values
were
used
for
sugarcane
and
tea;
however,
an
adjustment
factor
is
applied
to
raw
tea
leaves
to
better
estimate
residues
in
drinking
tea.
Field
trial
residue
data
are
generally
considered
by
HED
as
an
upper­
end
or
a
worse
case
scenario
of
possible
residues
and
are
more
suited
to
the
requirements
of
tolerance
setting,
because
it
requires
the
highest
rates
of
application
and
shortest
PHI,
than
to
the
requirements
of
dietary
risk
assessment
(
when
the
most
realistic
estimate
is
desired).

Potential
transfer
of
pesticide
residues
from
treated
feed
items
to
livestock
commodities
are
estimated
by
calculating
a
livestock
dietary
burden,
and
are
based
on
livestock
feeding
studies
conducted
at
the
appropriate
dose
levels.
For
endosulfan,
HED
estimated
a
realistic
dietary
burden
to
cattle
using
the
following
formula:
Dietary
burden
(
ppm)
=
%
of
Diet/
%
Dry
Matter
X
Anticipated
Residue
(
ppm).
The
ARs
calculated
for
beef
cattle
were
also
used
in
this
dietary
assessment
for
goat,
horse,
rabbit,
sheep,
and
veal.
HED
used
PDP
data
(
1996­
97)
for
milk
which
showed
all
residues
to
be
less
than
the
level
of
detection
(
LOD
0.001
ppm).
The
chronic
AR
for
milk
incorporated
½
LOD
for
each
parent
("­
and
$­
isomers)
and
½
LOD
for
the
metabolite
(
endosulfan
sulfate);
however,
for
the
acute
dietary
assessment,
a
residue
data
file
42
was
used
for
milk
which
also
incorporated
½
LOD
for
each
parent
("­
and
$­
isomers)
and
metabolite.
Potential
transfer
of
pesticide
residues
from
treated
feed
items
to
swine
commodities
were
estimated
by
calculating
a
swine
dietary
burden
based
on
submitted
swine
feeding
studies.
No
endosulfan
tolerances
are
established
in
eggs
and
poultry
tissues.
Submitted
poultry
feeding
data
(
MRID#
00003840)
suggest
that
there
is
no
reasonable
expectation
of
finite
residues;
therefore,
eggs
and
poultry
were
not
included
in
this
dietary
assessment
(
CFR
§
180.683).

Endosulfan
residues
may
be
either
concentrated
or
reduced
by
the
activities
of
drying
(
prunes
etc.),
processing
(
juice,
catsup,
etc.),
washing,
peeling,
and
cooking;
since
processing
data
were
limited,
the
Dietary
Exposure
Evaluation
Model
(
DEEM
 
)
default
factors
were
used
in
this
assessment
for
most
commodities
except
apples,
cottonseed,
grapes,
pineapples,
potatoes,
and
tomatoes,
for
which
acceptable
processing
studies
were
available.
The
Agency
has
reviewed
additional
processing
data
that
was
submitted
by
the
ETF
(
April
19,
2002).
These
additional
processing
data
were
deemed
inappropriate
for
use
in
the
dietary
assessment;
therefore,
they
were
not
incorporated
(
D282897).
The
additional
data
were
unacceptable
because,
among
other
things,
duration
of
steaming
times
was
missing
and/
or
excessive
cooking
and
washing
times
were
used.
Washing
is
already
incorporated
into
PDP
monitoring
data.

HED
has
developed
procedures
for
handling
FDA
surveillance
monitoring
data
in
dietary
exposure
analyses
with
the
goal
of
generating
more
realistic
probabilistic
dietary
exposure
estimates
by
features
of
version
7.76
DEEM
software.
Version
7.76
DEEM
software
now
permits
non­
representative,
stratified
sampling
of
data
to
be
incorporated
into
dietary
risk
assessments.
Currently
the
use
of
FDA
surveillance
monitoring
data
and
its
incorporation
into
HED
risk
assessments
is
"
case­
by­
case"
relying
on
the
judgement
of
the
reviewer
and
depends
on
the
degree
of
over­
sampling
of
imported
produce
observed,
the
differences
in
residue
concentrations
between
domestic
and
imported
produce,
and
the
sample
size.
If
there
are
significant
differences
between
domestic
and
import
samples,
either
in
terms
of
likelihood
of
detected
residues
or
residue
levels
themselves,
then
it
would
be
most
desirable
to
"
weight"
the
FDA
data
such
that
it
better
reflects
the
proportionate
"
mix"
between
domestic
and
foreign
produce
which
the
U.
S.
population
consumes.
Additional
estimates
of
the
percent
of
commodity
imported
as
well
as
imported
%
CT
from
BEAD
are
also
incorporated.
The
crops
for
which
these
procedures
were
incorporated
are
dried
beans,
blueberries,
cauliflower,
fresh
sweet
corn,
melons
(
except
cantaloupe),
fresh
succulent
peas,
hot
peppers,
plums,
and
summer
squash.
The
additional
refinements
include
modifications
to
the
above
mentioned
crops
only.

4.2.2
Acute
Dietary
To
estimate
acute
dietary
exposure,
one­
day
consumption
data
were
summed
and
a
food
consumption
distribution
was
calculated
for
the
general
population
and
each
population
subgroup
of
interest.
The
consumption
distribution
was
used
with
a
residue
distribution
in
a
probabilistictype
(
Monte
Carlo)
exposure
assessment.
Exposure
estimates
were
expressed
in
mg/
kg/
day.

To
assess
human
health
risks
resulting
from
consumption
of
foods
that
contain
residues
of
endosulfan,
estimates
of
acute
dietary
food
exposure
of
the
general
U.
S.
population
and
specific
population
subgroups
were
compared
to
the
aPAD.
The
risk
estimate
for
a
given
43
population
is
made
from
a
comparison
of
the
anticipated
dietary
food
exposure
of
the
population
to
the
aPAD
established
for
that
population.
Dietary
exposure
is
expressed
as
a
percentage
of
the
aPAD
(
anticipated
exposure
÷
PAD
x
100
=
%
PAD).
Dietary
exposure
estimates
that
exceed
the
aPAD
values
(
i.
e.,
that
are
greater
than
100%
of
the
PAD)
are
of
concern
to
the
Agency.
The
estimated
maximum
%
CT
for
each
commodity
was
used
for
the
acute
risk
assessment.
Where
no
further
information
was
available,
100
%
CT
was
assumed.

The
results
of
the
acute
dietary
food
exposure
and
risk
estimates
are
shown
in
Table
4.
Based
on
the
acute
dietary
exposure
analysis
as
described
above
and
using
an
aPAD
of
0.0015
mg/
kg/
d
for
the
U.
S.
population
and
all
population
subgroups,
the
acute
dietary
exposure
to
infants
less
than
1
year
of
age
and
children
1­
6
years
of
age
exceed
the
aPAD
(>
100%)
at
the
99.9th
exposure
percentile.
Children
1­
6
years
have
been
identified
as
the
most
highly
exposed
population
subgroup.
Estimated
acute
dietary
exposure
to
infants
and
children
does
not
exceed
the
aPAD
at
the
99th
or
95th
exposure
percentiles.
A
complete
listing
of
the
acute
dietary
results
is
in
attachment
4
of
Endosulfan.
New
FQPA
and
PDP
Data,
Anticipated
Residues,
and
Revised
Acute
and
Chronic
Dietary
Exposure
Analyses.
Sherrie
Kinard.
April
22,
2002.

Several
crops
have
been
identified
as
making
significant
contributions
to
the
dietary
risk.
Residues
measured
on
these
crops
and
the
surveyed
consumption
of
these
crops,
factored
together,
result
in
these
crops
taking
up
a
significant
percentage
of
the
aPAD
and
thereby,
making
significant
contributions
to
the
risk.
A
number
of
crops
had
significant
residues
from
monitoring
data
and
are
high
consumption
items.
The
significant
acute
contributors
have
been
identified
as
succulent
green
beans,
garden
green
peas,
summer
squash,
spinach,
and
tomatoes.
For
all
the
significant
contributors,
PDP
and/
or
FDA
monitoring
data
have
shown
measurable
residues
of
endosulfan,
some
greater
than
tolerance.

Table
4.
Acute
Dietary
Risk
Estimates
with
"
Weighted"
FDA
Data
Population
aPAD
(
95th
percentile)
(
99th
percentile)
(
99.9th
percentile)

Exposure
%
aPAD
Exposure
%
aPAD
Exposure
%
aPAD
U.
S.
Population
0.0015
mg/
kg
0.000098
<
1
0.000278
2
0.001252
8
All
Infants
<
1
year
0.0015
mg/
kg
0.000175
12
0.000381
25
0.001695
113
Children
1­
6
years
0.0015
mg/
kg
0.000184
12
0.000492
33
0.002194
146
Children
7­
12
years
0.0015
mg/
kg
0.000122
8
0.000338
23
0.001477
98
Females
13­
50
years
0.0015
mg/
kg
0.000070
5
0.000228
15
0.001037
69
Males
13­
19
years
0.0015
mg/
kg
0.000082
5
0.000222
15
0.000984
66
Population
aPAD
(
95th
percentile)
(
99th
percentile)
(
99.9th
percentile)

Exposure
%
aPAD
Exposure
%
aPAD
Exposure
%
aPAD
44
Males
20+
years
0.0015
mg/
kg
0.000075
5
0.000223
15
0.001018
68
Seniors
55+
years
0.0015
mg/
kg
0.000071
5
0.000265
18
0.001209
81
Exposure
estimates
include
exposure
to
all
endosulfan
residues
of
toxicological
concern
(
i.
e.,
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate).

4.2.3
Chronic
Dietary
For
chronic
dietary
risk
assessments,
residue
estimates
for
foods
(
e.
g.
apples)
or
foodforms
(
e.
g.
apple
juice)
of
interest
are
multiplied
by
the
averaged
consumption
estimate
of
each
food/
food­
form
of
each
population
subgroup.
Exposure
estimates
are
expressed
in
mg/
kg
bw/
d
and
as
a
percent
of
the
cPAD.
For
the
chronic
dietary
exposure
assessment,
residue
data
from
USDA's
PDP,
FDA,
or
field
trials
were
averaged.
If
a
commodity
had
no
reported
detections
by
the
PDP
and
FDA
programs,
and
the
expectation
of
no
detection
was
confirmed
by
field
trial
data,
the
residue
concentration
was
assumed
to
be
the
weighted
average
of
one­
half
the
LOD
of
each
residue
of
toxicological
concern
(
½
LOD
"­
endosulfan
+
½
LOD
$­
endosulfan
+
½
LOD
endosulfan
sulfate).
For
commodities
with
no
detections
from
FDA
data,
half
the
LOQ
was
used
for
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate.
The
weighted
average
estimate
of
%
CT
was
incorporated
into
all
chronic
residue
estimates.

The
results
of
the
acute
dietary
food
exposure
and
risk
estimates
are
shown
in
Table
5.
Children
1­
6
years
of
age
have
again
been
identified
as
the
most
highly
exposed
population
subgroup.
Based
on
the
chronic
dietary
exposure
analysis
as
described
above
and
using
a
cPAD
of
0.0006
mg/
kg/
day,
chronic
dietary
exposure
to
the
general
U.
S.
population
and
all
population
subgroups
does
not
exceed
the
cPAD.
A
complete
listing
of
the
chronic
dietary
results
is
in
attachment
6
of
Endosulfan.
New
FQPA
and
PDP
Data,
Anticipated
Residues,
and
Revised
Acute
and
Chronic
Dietary
Exposure
Analyses.
Sherrie
Kinard.
April
22,
2002.

Table
5.
Chronic
Dietary
Risk
Estimates
with
"
Weighted"
FDA
Data
Population
cPAD
mg/
kg/
day
Exposure
(
mg/
kg/
day)
%
Chronic
PAD
U.
S.
Population
0.0006
0.000040
<
1
All
Infants
(<
1
year)
0.0006
0.000057
10
Children
1­
6
years
0.0006
0.000104
17
Children
7­
12
years
0.0006
0.000063
11
Females
13­
50
years
0.0006
0.000028
5
Population
cPAD
mg/
kg/
day
Exposure
(
mg/
kg/
day)
%
Chronic
PAD
45
Males
13­
19
years
0.0006
0.000043
7
Males
20+
years
0.0006
0.000030
5
Seniors
55+
years
0.0006
0.000028
5
Exposure
estimates
include
exposure
to
all
endosulfan
residues
of
toxicological
concern
(
i.
e.,
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate).

4.2.4
Cancer
Dietary
Endosulfan
is
classified
as
"
not
likely"
a
human
carcinogen;
therefore,
no
dietary
assessment
for
cancer
risk
was
conducted.

4.3
Drinking
Water
Exposure/
Risk
Pathway
Based
on
the
environmental
fate
properties
of
each
isomer
("­
and
$­
endosulfan),
technical
grade
endosulfan
represents
a
mixture
of
two
chemically
distinct
pesticides
which
differ
in
persistence
and
volatility.
Endosulfan
is
a
persistent,
semi­
volatile
compound
that
has
been
detected
in
nearly
all
environmental
compartments,
including
surface­
and
ground­
water
and
in
areas
where
it
is
not
used
(
e.
g.,
the
Arctic
and
national
parks).
The
end­
use
product
is
a
mixture
of
two
endosulfan
isomers,
typically
70%
"­
endosulfan
and
30%
$­
endosulfan.
The
$­
isomer
is
generally
more
persistent
and
the
"­
isomer
is
more
volatile.
For
both
isomers,
hydrolysis
at
pH
values
greater
than
7
is
an
important
degradation
route;
however,
at
pH
values
below
7,
both
isomers
are
rather
persistent.
At
a
pH
of
7,
"­
endosulfan
and
$­
endosulfan
hydrolyze
with
half­
lives
of
11
and
19
days,
respectively,
and
at
a
pH
of
9,
the
isomers
have
half­
lives
of
4
to
6
hours.
Some
open
literature
studies
indicate
that
the
hydrolysis
half­
life
may
be
somewhat
longer
(
but
of
the
same
order
of
magnitude)
at
pH
7.
Under
acidic
conditions,
both
isomers
are
stable
to
hydrolysis,
and
microbial
degradation
in
soils
becomes
the
predominant
route
of
degradation.
Half­
lives
in
acidic
to
neutral
soils
range
from
one
to
two
months
for
"­
endosulfan
and
from
three
to
nine
months
for
$­
endosulfan
under
aerobic
conditions.
Dissipation
rates
observed
in
field
studies,
which
capture
a
combination
of
degradation,
transport,
and
uptake,
suggest
that
endosulfan
will
persist
in
the
surface
soil
for
weeks
to
months
after
application.
Field
dissipation
rates
were
similar
to
those
reported
in
laboratory
soil
metabolism
studies.

The
major
transformation
products
found
in
the
fate
studies
are
endosulfan
diol
(
hydrolysis)
and
endosulfan
sulfate
(
soil
metabolism).
Both
the
diol
and
sulfate
degradates
have
backbone
structures
similar
to
the
parent
compound
and
are
also
of
toxicological
concern.
Available
data
suggest
that
endosulfan
sulfate
will
be
more
persistent
than
the
parent
under
all
environmental
conditions.
The
estimated
half­
lives
for
the
combined
toxic
residues
(
endosulfan
plus
endosulfan
sulfate)
ranged
from
roughly
9
months
to
6
years.
See
Final
EFED
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
on
Endosulfan
(
Thiodan).
Nelson
Thurman,
et
al.
February
26,
2002.
Laboratory
studies
indicate
that
"­
and
$­
endosulfan
have
a
46
high
affinity
for
sorption
onto
soil
and
are
not
expected
to
be
highly
mobile
in
the
soil
environment.
However,
because
of
endosulfan's
resistance
to
degradation,
it
can
persist
long
enough
to
be
transported
to
both
ground­
and
surface­
waters,
as
monitoring
studies
have
shown.
Endosulfan
can
contaminate
surface
waters
through
spray
drift
and
transport
in
runoff.
In
addition,
endosulfan
may
move
to
targets
beyond
its
use
area
through
atmospheric
transport
(
via
volatilization,
transport
on
dust
particles,
or
a
combination).
Within
the
water
bodies,
endosulfan
tends
to
be
sorbed
onto
sediment
and
plants.
The
sorbed
endosulfan
may
be
slowly
released
back
into
the
water.

As
mentioned
above,
the
environmental
fate
profile
for
endosulfan
indicates
that
both
the
"­
and
$­
isomers
of
endosulfan,
as
well
as
the
endosulfan
sulfate
transformation
product,
may
reach
water
resources.
Existing
water
monitoring
data
confirm
the
presence
of
endosulfan
residues
in
surface
and
ground
water
on
a
qualitative
basis.
Because
endosulfan
is
persistent
in
neutral
to
acidic
soils
for
months,
the
pesticide
will
be
susceptible
to
transport
via
runoff
for
prolonged
periods
after
initial
application.
With
repeated
applications,
or
even
applications
in
consecutive
years,
endosulfan
may
accumulate
in
the
soil,
especially
in
acidic
soils.
Endosulfan
is
expected
to
be
less
persistent
in
alkaline
soils
due
to
its
susceptibility
to
hydrolysis.

Its
high
affinity
to
sorb
to
soil
indicates
that
endosulfan
is
likely
to
be
associated
predominantly
with
the
sediment
phase
in
runoff.
Endosulfan
reaching
the
water
column,
through
spray
drift
or
runoff,
will
have
a
propensity
to
sorb
to
benthic
sediment,
and
this
sediment
may
eventually
become
a
source
of
endosulfan
redistribution
into
the
overlying
waters.
Published
literature
(
details
in
Final
EFED
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
on
Endosulfan.
Nelson
Thurman,
et
al.
February
26,
2002)
suggests
that
endosulfan
may
also
be
sorbed/
taken
up
by
macrophytes
and
algae,
and
released
back
into
the
water
column
when
these
plants
die
off.
Because
of
its
tendency
to
sorb
onto
soil,
endosulfan
should
not
be
frequently
detected
in
ground
water;
however,
endosulfan
is
a
persistent
chemical,
and
available
monitoring
data
have
revealed
endosulfan
detections
in
wells.
Aquifers
below
acidic
soils
are
likely
to
be
more
vulnerable
to
endosulfan
contamination
than
those
below
neutral
or
alkaline
soils,
due
to
the
lack
of
hydrolysis
under
acidic
conditions.
Endosulfan
sulfate,
the
major
transformation
product
identified
in
soil,
is
more
persistent
than
the
parent.
Comparative
studies
indicate
that
endosulfan
sulfate
is
similar
in
mobility
to
the
parent
endosulfan.

Limited
water
monitoring
data
exist
for
endosulfan.
Endosulfan
was
not
included
in
the
U.
S.
Geological
Survey
National
Water
Quality
Assessment
(
NAWQA)
program.
The
STORET
database
includes
a
variety
of
monitoring
reports
for
the
endosulfan
isomers
and
for
endosulfan
sulfate.
The
results
reported
in
the
database
vary
in
terms
of
data
quality,
sampling
and
analytical
methods,
detection
limits,
and
level
of
quality
assurance/
quality
control.
Insufficient
information
exists
with
the
reported
studies
to
determine
whether
sampling
occurred
in
actual
endosulfan
use
areas
or
during
times
when
endosulfan
might
potentially
occur
in
water.
Despite
these
limitations,
the
available
studies
have
shown
that
endosulfan
and
its
degradate,
endosulfan
sulfate,
have
contaminated
numerous
surface­
and
ground­
water
bodies
throughout
the
United
States.
Both
surface­
and
ground­
water
modeling
simulations
show
that
endosulfan
and
endosulfan
sulfate
may
reach
ecologically
significant
water
bodies
as
well
as
drinking
water
supplies.
47
4.3.1
Ground
Water
Resources
While
both
"­
and
$­
endosulfan
appear
to
be
persistent
in
most
laboratory
studies,
particularly
in
acidic
to
neutral
soils,
its
high
affinity
to
sorb
onto
soils
suggests
that
it
should
not
move
extensively
through
the
soil
and
vadose
zone
to
ground
water.
The
Agency
believes
that
the
potential
for
endosulfan
to
reach
ground
water
is
limited
to
acidic
to
neutral
soils
and
aquifers
where
preferential
flow
may
be
a
prevalent
pathway
to
ground
water
or
where
the
ground
water
is
shallow
and
is
overlain
by
highly
permeable
soils.
Available
evidence
suggests
that
the
transformation
products
 
endosulfan
sulfate
and
endosulfan
diol
 
may
be
persistent.
Endosulfan
sulfate
is
similar
in
mobility
to
the
parent
endosulfan
while
endosulfan
diol
appears
to
be
more
mobile.

The
Pesticides
in
Ground
Water
Database
(
USEPA
OPP,
1992)
reports
detections
of
endosulfan,
ranging
from
trace
to
#
20
:
g/
L,
in
1.3%
of
2410
discrete
samples
(
32
wells).
Detections
were
reported
in
California,
Maine,
and
Virginia.
All
sampling
was
conducted
on
or
before
the
year
1989.
The
abbreviated
nature
of
the
PGWDB
does
not
capture
important
factors
such
as
depth
of
the
water
table,
soil
permeability,
proximity
of
crops
to
wells,
usage
(
application)
of
the
chemical
in
the
years
prior
to
sampling,
suitability
of
the
analytical
methodology
used
and/
or
limits
of
detection.
Endosulfan
sulfate
was
detected
in
0.3%
of
the
samples
(
6
out
of
1969),
with
detections
ranging
from
<
0.005
to
1.4
:
g/
L.
The
detections
were
reported
in
Indiana
and
New
York.
Sampling
occurred
at
or
prior
to
1990.
No
data
were
available
for
endosulfan
diol.

4.3.2
Surface
Water
Resources
Endosulfan
can
contaminate
surface
water
through
spray
drift
or
runoff.
The
persistence
of
"­
and
$­
endosulfan
is
sufficient
to
expect
accumulation
on
soil
after
repeated
applications
and
possible
accumulation
from
year
to
year.
Such
persistence
suggests
that
endosulfan
will
be
available
to
move
to
surface
waters
via
runoff
for
several
months
or
longer
after
application.
Its
high
affinity
to
sorb
onto
soil
indicates
that
endosulfan
may
move
primarily
while
adsorbed
to
eroding
soil
and
will
preferentially
partition
into
the
sediment
fraction
of
the
surface
water
system.
Conditions
which
may
favor
runoff
include
poorly
draining
or
wet
soils
with
readily
visible
slopes
toward
adjacent
surface
waters,
frequently
flooded
areas,
areas
overlaying
shallow
ground
water,
areas
not
separated
from
adjacent
surface
water
with
vegetated
strips,
and
highly
erodible
soils
cultivated
using
poor
agricultural
practices
(
such
as
conventional
tillage).

The
degradate
endosulfan
sulfate
is
probably
formed
in
the
soil
and,
due
to
its
very
high
persistence,
is
likely
to
reach
surface
waters
as
well.
Endosulfan
diol
may
be
formed
in
neutral
to
basic
surface
waters
as
a
hydrolysis
product.
Comparative
studies
indicate
that
endosulfan
sulfate
will
be
similar
in
mobility
to
$­
endosulfan,
and
thus
have
an
affinity
to
bind
to
sediment,
while
endosulfan
diol
is
likely
to
be
more
mobile
than
the
parent.

A
review
of
the
STORET
data
for
"­
and
$­
endosulfan,
unspecified
endosulfan
residues,
and
endosulfan
sulfate
showed
numerous
incidences
of
detections.
The
STORET
data
are
not
48
reliable
enough
to
enable
an
accurate
quantitative
assessment
of
the
endosulfan
distribution
throughout
the
U.
S.,
but
it
does
give
some
insight
into
where
endosulfan
is
being
found.
Confirmed
detections
of
one
or
more
endosulfan
residues
were
reported
in
38
states.
States
that
reported
relatively
high
numbers
of
endosulfan
detections
(
with
respect
to
other
reporting
states)
included
California,
Florida,
Louisiana,
Washington,
Mississippi,
and
Ohio.
An
analysis
of
the
monitoring
data
which
reported
detects
for
total
endosulfan
show
a
highly
skewed
distribution,
as
would
be
expected
with
monitoring
data.
The
mean
concentration
is
0.17
:
g/
L,
with
a
standard
deviation
of
0.98
:
g/
L.
The
90th
percentile
value
was
0.31
:
g/
L
and
the
median
value
was
0.03
:
g/
L.
The
mean
STORET
concentrations
are
not
expected
to
exceed
peak
estimated
environmental
concentrations
(
EECs)
predicted
by
the
PRZM/
EXAMS
model
because
they
do
not
necessarily
represent
the
most
vulnerable
sites
or
sampled
peak
times.
Little
is
known
about
actual
sample
conditions.
In
addition,
the
limits
of
detection
vary
widely
depending
on
the
purpose
of
the
monitoring
and
the
availability
of
analytical
methods
and
equipment
so
that
reported
nondetections
do
not
necessarily
mean
that
endosulfan
was
not
present
where
a
non
detect
was
reported.

The
National
Sediment
Quality
Survey
(
U.
S.
EPA,
1997)
reported
detections
of
endosulfan
residues
in
stream
sediments
in
30
out
of
76
watersheds
in
which
endosulfan
was
analyzed.
The
watersheds
occurred
in
12
states,
ranging
from
Rhode
Island
to
California
and
from
Mississippi
to
Michigan.
As
with
the
STORET
data,
one
of
the
sources
of
data
used
in
the
survey,
this
summary
provides
more
of
a
qualitative
evaluation
of
the
extent
to
which
endosulfan
may
be
found
in
the
environment
rather
than
a
quantitative
assessment
of
endosulfan
occurrence.

4.3.3
Estimated
Environmental
Concentrations
Drinking
water
EECs
for
surface
and
ground
water
were
determined
from
the
PRZM/
EXAMS
and
SCIGROW
models,
respectively.
EFED
based
the
"­
and
$­
endosulfan
drinking
water
EECs
for
surface­
water
sources
on
PRZM/
EXAMS
simulations
with
the
maximum
allowable
application
of
endosulfan
(
1.0
lb
a.
i.
/
acre,
3
times
per
year)
to
a
Mississippi
cotton
scenario
with
the
standard
index
reservoir
and
percent
crop
area
(
PCA)
factor
included.
Procedures
for
calculating
the
EECs
followed
the
method
described
in
the
section
on
water
assessment
for
ecological
effects
in
Final
EFED
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
on
Endosulfan.
Nelson
Thurman,
et
al.
February
26,
2002:
for
the
"­
and
$­
endosulfan
isomers,
the
output
was
adjusted
by
70%
for
"­
endosulfan
and
30%
for
$­
endosulfan;
endosulfan
sulfate
concentrations
were
determined
by
multiplying
the
total
endosulfan
concentration
by
0.55,
the
median
ratio
of
endosulfan­
sulfate
to
combined
isomer
concentrations
found
in
the
STORET
database.
Chemical­
specific
input
parameters
used
for
the
PRZM/
EXAMS
simulations,
as
well
as
application­
specific
parameters
for
the
cotton
scenario
used
in
the
drinking
water
assessment
are
given
in
EFED's
chapter.
All
other
parameters
were
used
according
to
standard
EFED
practice.
Both
the
peak
and
chronic
surface
water
EECs
are
well
within
the
range
of
measured
endosulfan
concentrations
in
the
EPA
STORET
database
(
where
total
endosulfan
concentrations
range
from
less
than
the
level
of
detection
to
a
maximum
peak
of
180
:
g/
L).
The
groundwater
EECs
were
generated
with
SCIGROW.
For
K
oc
values
greater
than
10,000
ml/
g,
SCIGROW
gives
the
default
value
of
0.006
ppb,
regardless
of
other
input
parameters.
The
default
SCIGROW
value
is
within
the
range
of
reported
groundwater
49
detections
of
0
to
20
ppb
(
USEPA
OPP,
1992).
Table
6
summarizes
the
estimated
drinking
water
EECs
for
the
"
and
$
isomers
of
endosulfan
and
the
degradate
endosulfan
sulfate.

Table
6.
Tier
2
EECs
for
Endosulfan
and
Endosulfan
Sulfate
in
Drinking
Water
Isomer
Surface
Water
Acutea
EEC
Surface
Water
Chronicb
EEC
Ground
Water
EEC
"­
endosulfan
3.5
:
g/
L
0.56
:
g/
L
­­
$­
endosulfan
1.7
:
g/
L
0.24
:
g/
L
­­
total
endosulfan
("+$)
5.2
:
g/
L
0.80
:
g/
L
0.006
:
g/
L
endosulfan
sulfate
2.9
:
g/
L
0.45
:
g/
L
0.006
:
g/
L
a
Acute
EEC
represents
the
upper
1­
in­
10
year
peak
concentration.
b
Chronic
EEC
represents
the
upper
1­
in­
10
year
mean
annual
concentration.

4.3.4
Drinking
Water
Levels
of
Comparison
Generally,
the
Agency
calculates
Drinking
Water
Levels
of
Comparison
(
DWLOC)
for
comparison
to
measured
or
modeled
drinking
water
concentrations
for
the
risk
analysis.
The
DWLOC
is
the
concentration
in
drinking
water,
as
part
of
the
aggregate
exposure,
that
occupies
no
more
than
100%
of
the
PAD.
The
dietary
exposure
from
food
and
the
DWLOC
together,
cannot
be
greater
than
100%
of
the
PAD.
Any
measured
or
modeled
drinking
water
estimates
that
are
less
than
the
DWLOC
are
not
of
concern.

The
Agency
has
calculated
DWLOCs
for
acute
and
chronic
exposure
to
endosulfan
in
surface
and
ground
water
for
the
population
subgroups;
children
1­
6
years
(
the
most
highly
exposed
subgroup),
infants
<
1
year,
females
13­
50
years,
and
the
general
U.
S.
population.
To
calculate
the
DWLOC
for
acute
or
chronic
(
non­
cancer)
exposure
relative
to
an
acute
or
chronic
toxicity
endpoint,
the
dietary
food
exposure
(
from
DEEM
 
)
was
subtracted
from
the
PAD
to
obtain
the
exposure
to
endosulfan
in
drinking
water
that
would
not
be
of
concern.

An
acute
DWLOC
(
DWLOC
acute)
was
calculated
using
the
following
formulae:

DWLOC
acute
(:
g/
L)
=
acute
water
exposure
(
mg/
kg/
d)
x
body
weight
(
kg)
consumption
(
L/
d)
x
10­
3
mg/:
g
acute
water
exposure
(
mg/
kg/
d)
=
[
aPAD
­
acute
food
(
mg/
kg/
d)]

The
current
Agency
default
body
weight
and
consumption
values
are
10
kg
and
1
liter/
day,
respectively,
for
all
infants
and
children,
70
kg
and
2
liters/
day
for
adult
males,
and
60
kg
and
2
liters/
day
for
adult
females.
These
default
values
and
others
are
presently
under
review
in
the
Agency
(
Office
of
Research
and
Development).
If
at
a
future
time,
the
Agency
decides
to
change
the
default
assumptions
used,
the
impact
of
the
changes
on
the
endosulfan
risk
assessment
will
be
considered.
50
A
chronic
DWLOC
(
DWLOC
chronic)
was
calculated
using
the
following
formulae:

DWLOC
chronic
(:
g/
L)
=
chronic
water
exposure
(
mg/
kg/
d)
x
body
weight
(
kg)
consumption
(
L/
d)
x
10­
3
mg/:
g
chronic
water
exposure
(
mg/
kg/
d)
=
[
cPAD
­
(
chronic
food
+
residential(
ADD)(
mg/
kg/
d))]

Where
ADD
=
average
daily
dose
Residential
exposures
were
not
factored
into
the
DWLOC
chronic
since
no
residential
uses
are
being
supported
by
the
ETF.

Table
7a.
Endosulfana
Drinking
Water
Levels
of
Comparison
for
Acute
Dietary
Exposure
Population
Subgroup
Acute
PAD
(
mg/
kg/
day)
Food
Exposure
(
mg/
kg/
d)
@
99.9th
percentile
Water
Exposure
(
mg/
kg/
d)
DWLOC
acute
(
µ
g/
L)
Surface
Water
Peak
EECb
(
µ
g/
L)
Ground
Water
EECb
(
µ
g/
L)

U.
S.
Population
0.0015
0.0013
0.00025
8.7
8.1
0.012
Females
(
13­
50
yrs)
0.0015
0.0010
0.00046
14
8.1
0.012
Infants
<
1
yr
0.0015
0.0017
0
0
8.1
0.012
Children
1­
6
yrs
0.0015
0.0022
0
0
8.1
0.012
a
Includes
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate.
B
Estimated
Environmental
Concentrations.

Table
7b.
Drinking
Water
Levels
of
Comparison
for
Chronic
Dietary
Exposure
Population
Subgroup
Chronic
PAD
(
mg/
kg/
day)
Food
Exposure
(
mg/
kg/
d)
Max.
Water
Exposure
(
mg/
kg/
d)
DWLOC
chronic
(
µ
g/
L)
Surface
Water
Chronic
EECb
(
µ
g/
L)
Ground
Water
EECb
(
µ
g/
L)

U.
S.
Population
0.0006
0.000040
0.00056
20
1.3
0.012
Females
(
13­
50
yrs)
0.0006
0.000028
0.00057
17
1.3
0.012
Infants
<
1
yr
0.0006
0.000057
0.00054
5.4
1.3
0.012
Children
1­
6
yrs
0.0006
0.00010
0.00050
5
1.3
0.012
a
Includes
"­
endosulfan,
$­
endosulfan,
and
endosulfan
sulfate.
B
Estimated
Environmental
Concentrations.
51
4.4
Residential
Exposure/
Risk
Pathway
4.4.1
Home
and
Recreational
Uses
As
mentioned
earlier,
the
ETF
is
not
supporting
any
uses
of
endosulfan
in
or
around
the
home,
around
public
buildings
or
recreational
areas,
or
on
rights­
of­
way.
Therefore,
the
Agency
did
not
include
the
affected
non­
agricultural
and
residential
uses
in
its
revised
risk
assessment.
Previous
risk
assessments
showed
unacceptable
risks
associated
with
home
and
recreational
uses.

4.4.2
Other
The
Agency's
current
approach
for
completing
residential
exposure
assessments
(
when
applicable)
is
based
on
the
guidance
provided
in
the
Draft:
Series
875­
Occupational
and
Residential
Exposure
Test
Guidelines,
Group
B­
Postapplication
Exposure
Monitoring
Test
Guidelines,
the
Draft:
Standard
Operating
Procedures
(
SOPs)
for
Residential
Exposure
Assessment,
and
the
Overview
of
Issues
Related
to
the
Standard
Operating
Procedures
for
Residential
Exposure
Assessment
presented
at
the
September
1999
meeting
of
the
FIFRA
Scientific
Advisory
Panel
(
SAP).
The
Agency
is,
however,
currently
in
the
process
of
revising
its
guidance
for
completing
these
types
of
assessments.
Modifications
to
this
assessment
shall
be
incorporated
as
updated
guidance
becomes
available.
This
will
include
expanding
the
scope
of
the
residential
exposure
assessments
by
developing
guidance
for
characterizing
exposures
from
other
sources
not
already
addressed,
such
as
from
spray
drift;
residential
residue
track­
in;
exposures
to
farm
worker
children;
and
exposures
to
children
in
schools.

5.0
AGGREGATE
RISK
ASSESSMENT
AND
RISK
CHARACTERIZATION
5.1
Overview
Risk
is
a
function
of
exposure
multiplied
by
hazard
(
Risk
=
Exposure
x
Hazard).
Exposure
may
be
measured
or
modeled,
depending
on
the
available
data.
Ideally
the
exposure
data
would
be
chemical­
specific
occupational
or
residential
monitoring
data,
at­
the­
tap
drinking
water
data,
and
close­
to­
the­
plate
food
residue
data
on
all
crops.
In
the
absence
of
an
ideal
data
set,
surrogate
data,
and
other
factors
are
incorporated
into
the
exposure
assessments
(
dietary
and
non­
dietary)
to
present
a
reasonable
exposure
picture
based
on
the
best
available
data.
The
hazard
portion
of
the
risk
equation
has
several
layers
of
safety
built
into
it
to
provide
a
cushion
between
exposure
and
the
dose
at
which
adverse
effects
were
seen
in
an
animal
study.
Generally,
endpoints
are
based
on
the
dose
at
which
no
observable
adverse
effect
is
seen
in
an
animal
study.
This
is
the
No
Observable
Adverse
Effect
Level
(
NOAEL).
The
Lowest
Observable
Adverse
Effect
Level
(
LOAEL)
is
the
next
highest
dose
in
an
animal
study,
up
from
the
NOAEL,
at
which
the
adverse
effect
of
concern
is
seen.
Since
the
toxicity
studies
used
for
endpoint
selection
are
conducted
in
animals,
and
there
are
differences
between
individual
humans,
additional
uncertainty
factors
for
inter­
and
intra­
species
variability
are
integrated
into
the
hazard
portion
of
the
risk
equation.
Since
the
passage
of
the
FQPA,
an
additional
layer
of
52
protection
is
factored
in
(
when
appropriate)
to
provide
an
even
greater
safety
cushion
between
exposure
and
toxic
effects
for
particularly
sensitive
populations.
It
is
in
this
light
that
expressions
of
risk
(
risk
numbers)
should
be
viewed
with
an
understanding
that
they
are
not
portrayals
of
imminent
toxic
effects
to
humans
but
as
a
measure
of
the
distance
between
potential
exposure
and
possible
toxic
effects.

In
accordance
with
current
HED
policy
(
effective
03/
11/
99)
the
acute
and
chronic
dietary
endpoints
are
expressed
as
acute
Population
Adjusted
Dose
(
aPAD)
and
chronic
PAD
(
cPAD),
and
no
longer
as
an
adjusted
Reference
Dose
(
RfD).

RfD
=
acute
or
chronic
NOAEL
Uncertainty
Factor
(
UF)

Generally,
an
UF
of
100
is
applied
for
intra­
and
inter­
species
differences.

PAD
=
acute
or
chronic
RfD
FQPA
factor
The
use
of
the
PAD
will
apply
whether
the
FQPA
factor
is
retained
(
10x
or
3x)
or
not
(
1x).
When
a
PAD
is
used,
such
as
in
the
dietary
assessment,
the
risk
is
expressed
as
a
percentage
of
the
PAD
which
is
equal
to
the
measured
exposure
divided
by
the
PAD
and
then
multiplied
by
100
or:

Risk
(%
PAD)
=
Exposure
x
100
PAD
Occupational,
residential
(
when
applicable),
and
the
aggregate
risk
(
when
appropriate)
will
still
be
expressed
as
the
Margin
of
Exposure
(
MOE).

MOE
=
NOAEL
(
mg/
kg/
d
Exposure
(
mg/
kg/
d)

Current
HED
policy
requires
that
FQPA
safety
factors
be
retained
for
dietary
and
nonoccupational
exposures,
when
appropriate,
not
occupational
exposures
(
Memorandum,
Special
Report
of
the
FQPA
Safety
Factor
Committee,
B.
Tarplee
and
J.
Rowland,
April
15,
1998).
Therefore,
an
MOE
of
>
100
is
needed
in
the
occupational
exposure
risk
assessment.

Due
to
the
availability
of
acceptable/
guideline
oral,
dermal,
and
inhalation
studies
using
endosulfan,
the
dietary
and
occupational
risk
assessments
were
conducted
using
route­
specific
endpoints.
However,
to
fully
characterize
the
hazard
and
potential
risk
from
exposures
to
endosulfan,
subchronic
neurotoxicity
and
developmental
neurotoxicity
studies
in
rats,
are
requested.
The
acute
dietary
endpoint
is
based
primarily
on
neurotoxicity.
The
neurotoxicity
is
believed
to
result
from
over­
stimulation
of
the
CNS.
Characteristic
clinical
signs
of
endosulfaninduced
neurotoxicity
include,
in
part:
hyperactivity,
tonic
contractions,
involuntary
muscle
movements,
pronounced
sensitivity
to
noise
and
light,
incoordination,
seizures,
and
convulsions.
53
These
clinical
signs
are
observed
in
humans
accidentally
exposed
to
endosulfan,
and
in
animal
studies
of
varying
treatment
durations
following
different
routes
of
exposure
and
in
different
animal
species.
The
chronic
dietary,
and
short­,
intermediate­,
and
long­
term
dermal
and
inhalation
endpoints
are
based
on
the
toxic
effects
observed
in
animals
following
subchronic
or
chronic
exposure
and
include:
neurotoxicity,
hematological
effects,
and
nephrotoxicity.
In
some
animal
studies,
endosulfan
inhibited
plasma
cholinesterase
at
the
highest
doses
tested.
Endosulfan
is
not
a
dermal
sensitizer,
nor
is
it
mutagenic
or
carcinogenic
("
Not
Likely"
a
human
carcinogen).

5.2
Acute
Risk
5.2.1
Aggregate
Acute
Risk
Assessment
The
acute
aggregate
risk
estimate
includes
the
contribution
of
risk
from
dietary
(
food
+
drinking
water)
sources
only.
Acute
risk
estimates
from
exposures
to
food,
associated
with
the
use
of
endosulfan
exceed
the
Agency's
level
of
concern
at
the
99.9th
exposure
percentile
for
infants
less
than
1
year
of
age
(
113%
aPAD)
and
children
1­
6
years
of
age
(
146%
aPAD).
The
acute
Tier
3
dietary
risk
analysis
estimated
the
distribution
of
single
day
exposures
for
the
overall
U.
S.
population
and
certain
population
subgroups
and
evaluated
exposure
to
endosulfan
for
each
food
commodity.
The
input
values
included
the
ARs,
incorporating
%
CT
and
processing
factors,
for
commodities
on
which
endosulfan
is
used.
Chemical­
specific
monitoring
data
on
food
were
used
for
the
majority
of
commodities.
Where
monitoring
data
were
not
available,
translations
from
similar
commodities
or
field
trial
data
were
used.

Some
chemical­
specific
water
monitoring
data
are
available
but
they
are
limited
and
not
at­
the­
tap
data.
Though
they
may
be
indicative
of
surface
and
ground
water
levels
of
endosulfan
under
limited
conditions,
the
Agency
believes
that
they
are
unsuitable
to
be
quantitatively
included
in
aggregate
risk
assessment.
Therefore,
estimated
environmental
concentrations
(
EECs)
were
calculated
by
EFED
to
estimate
the
potential
contribution
to
the
acute
exposure
from
drinking
water,
and
the
EECs
were
compared
to
the
acute
DWLOCs.

5.2.2
Acute
DWLOC
Calculations
Taking
into
account
the
present
uses
and
uses
proposed
in
this
action,
the
Agency
can
conclude
with
reasonable
certainty
that
residues
of
endosulfan
and
endosulfan
sulfate,
combined,
in
drinking
water
would
likely
result
in
an
acute
dietary
risk
above
the
Agency's
level
of
concern,
particularly
to
infants
and
children.
The
Agency
based
this
determination
on
a
comparison
of
estimated
concentrations
of
endosulfan
in
surface
waters
to
back­
calculated
"
levels
of
comparison"
for
endosulfan
in
drinking
water.
The
estimates
of
endosulfan
in
surface
waters
were
derived
from
water
quality
models
that
used
conservative
assumptions
(
healthprotective
regarding
the
pesticide
transport
from
the
point
of
application
to
surface
and
ground
water,
and
were
supplemented
with
limited
monitoring
data.

Modeled
Tier
2
(
PRZM/
EXAMS)
estimates
of
endosulfan
and
endosulfan
sulfate
concentrations
in
surface
water,
combined,
were
above
the
acute
DWLOCs
and
are
of
concern.
54
Since
exposures
to
endosulfan
in
food
alone
pose
a
potential
risk
of
concern
for
children
1­
6
years
of
age
and
infants,
additional
exposures
from
water
would
increase
the
concern
and
therefore
the
DWLOCs
for
these
populations
are
"
0."
The
EECs
calculated
by
EFED
were
based
on
the
maximum
allowable
application
of
endosulfan
(
1
lb
a.
i/
acre,
3
times/
year)
to
a
Mississippi
cotton
scenario
with
the
standard
index
reservoir
and
percent
crop
area
factor
included.
The
available
monitoring
data
indicate
that
90th
percentile
values
would
not
be
expected
to
exceed
peak
EEC
values.
One
should
keep
in
mind
that
these
estimates,
as
well
as
the
available
monitoring
data,
do
not
represent
dilution
from
source
to
tap
nor
concentrations
after
drinking
water
treatment,
and
may
actually
be
lower.
Common
drinking
water
treatment
methods
such
as
flocculation
and
sedimentation
are
known
to
remove
some
organochlorines
but
no
endosulfan­
specific
treatment
data
are
available.

The
ground
water
EECs
were
generated
using
the
SCIGROW
(
Tier
1)
model
applied
to
the
Mississippi
cotton
scenario
and
appropriate
fate
and
transport
factors.
The
ground
water
estimates
of
endosulfan
and
endosulfan
sulfate
concentrations,
combined,
as
well
as
available
monitored
concentrations,
are
low.
However,
the
DWLOCs
for
infants
and
children
1­
6
years
of
age
are
"
0"
and
therefore,
exposures
from
groundwater
are
of
concern.

5.3
Short­
and
Intermediate­
term
Aggregate
Risk
Aggregate
short­
and
intermediate­
term
risk
includes
the
contribution
of
risk
from
dietary
(
food
+
water)
and
residential
sources
to
the
total
risk.
Since
residential
uses
are
not
being
supported
by
the
ETF,
exposures
from
these
uses
were
not
included
in
the
risk
assessment.
Steps
have
already
been
taken
to
remove
residential
uses
from
endosulfan
labels,
but
further
steps
are
needed.

5.4
Chronic
Risk
5.4.1
Aggregate
Chronic
Risk
Assessment
Aggregate
chronic
(
noncancer)
risk
estimates
include
the
contribution
of
risk
from
dietary
sources
(
food
+
water)
and
residential
sources;
however,
as
mentioned
above,
no
residential
uses
are
being
supported.
Chronic
risk
estimates
from
exposures
to
food,
do
not
exceed
the
Agency's
level
of
concern
for
the
U.
S.
general
population
and
all
population
subgroups.
The
chronic
dietary
(
food
only)
risk
estimate
is
17%
of
the
cPAD,
for
the
most
highly
exposed
population
subgroup,
children
ages
1­
6
years
of
age.

As
in
the
acute
aggregate
assessment,
EECs
were
calculated
by
EFED
to
estimate
the
potential
contribution
to
the
chronic
exposure
from
drinking
water,
and
the
EECs
were
compared
to
the
chronic
DWLOCs.

5.4.2
Chronic
DWLOC
Calculations
Taking
into
account
the
present
uses
and
uses
proposed
in
this
action,
the
Agency
can
conclude
with
reasonable
certainty
that
residues
of
endosulfan
and
endosulfan
sulfate,
55
combined,
in
drinking
water
would
not
likely
result
in
a
chronic
dietary
risk
to
infants,
children,
and
adults
above
the
Agency's
level
of
concern.

Modeled
Tier
2
(
PRZM/
EXAMS)
estimates
of
endosulfan
and
endosulfan
sulfate
concentrations
in
surface
water,
combined,
were
below
the
chronic
DWLOCs
and
are
not
of
concern.
Again,
the
EECs
calculated
by
EFED
were
based
on
the
maximum
allowable
application
of
endosulfan
to
a
Mississippi
cotton
scenario
with
the
standard
index
reservoir
and
percent
crop
area
factor
included.
Since
the
SCIGROW
model
does
not
allow
for
the
generation
of
chronic
ground
water
estimates,
the
acute
values
are
used,
resulting
in
a
highly
conservative
estimate.
Even
these
highly
conservative
ground
water
estimates
of
endosulfan
and
endosulfan
sulfate
concentrations,
combined,
were
below
the
chronic
DWLOCs
and
are
not
of
concern.

6.0
CUMULATIVE
RISK
Endosulfan,
as
well
as
its
metabolite
endosulfan
sulfate,
belong
to
the
chlorinated
cyclodiene
(
organochlorine)
class
of
insecticide/
acaricides.
The
Agency
does
not
currently
have
data
available
to
determine
with
certainty
whether
endosulfan
or
endosulfan
sulfate
have
a
common
mechanism
of
toxicity
with
any
other
substances.
For
the
purposes
of
this
human
health
risk
assessment,
the
Agency
has
not
assumed
that
endosulfan
or
endosulfan
sulfate
have
a
common
mechanism
of
toxicity
with
other
pesticides.
The
Agency
has
proposed
guidance
for
conducting
cumulative
risk
assessment
(
proposal
is
available
on
EPA's
website,
USEPA,
2002).
When
the
guidance
is
finalized,
endosulfan
and
its
metabolite(
s)
will
be
revisited
to
assess
the
cumulative
effects
of
exposure
to
multiple
organochlorines.

7.0
OCCUPATIONAL
EXPOSURE
7.1
Handler
Exposure
Scenarios
The
Agency
has
determined
that
there
are
potential
exposures
to
mixers,
loaders,
applicators,
and
other
handlers
during
usual
use­
patterns
associated
with
endosulfan.
Based
on
the
use
patterns,
21
major
occupational
exposure
scenarios
were
identified
for
endosulfan:
(
1a)
mixing/
loading
liquid
formulations
for
aerial
application;
(
1b)
mixing/
loading
liquid
formulation
for
chemigation;
(
1c)
mixing/
loading
liquid
formulations
for
groundboom
application;
(
1d)
mixing/
loading
liquid
formulations
for
airblast
application;
(
1e)
mixing/
loading
liquid
formulations
for
rights­
of­
way
sprays;
(
1f)
mixing/
loading
liquid
formulations
for
plant
and
root
dip;
(
2a)
mixing/
loading
wettable
powders
for
aerial
application;
(
2b)
mixing/
loading
wettable
powders
for
groundboom
application;
(
2c)
mixing/
loading
wettable
powders
for
airblast
application;
(
2d)
mixing/
loading
wettable
powder
for
rights
of
way
spray
application;
(
2e)
mixing/
loading
wettable
powders
for
plant
and
root
dip;
(
3)
applying
sprays
with
aerial
equipment;
(
4)
applying
sprays
with
a
groundboom
sprayer;
(
5)
applying
sprays
with
an
airblast
sprayer;
(
6)
applying
sprays
with
a
rights­
of­
way
sprayer;
(
7)
56
applying
dip
treatment
to
roots,
or
whole
plants;
(
8)
mixing/
loading/
applying
liquids
with
a
low
pressure
hand
wand;
(
9)
mixing/
loading/
applying
wettable
powders
with
a
low
pressure
handwand;
(
10)
mixing/
loading/
applying
liquids
with
a
high
pressure
hand
wand;
(
11)
mixing/
loading/
applying
liquids
with
backpack
sprayer;
and
(
12)
flagging
aerial
spray
applications.

On
current
endosulfan
labels,
personal
protective
equipment
(
PPE)
requirements
range
from
no
PPE
listed,
to
long
sleeved
shirt
and
long
pants,
waterproof
gloves,
shoes,
socks,
chemical
resistant
headgear,
respirator
with
either
an
organic
vapor
removing
cartridge
with
a
prefilter
or
canister
approved
for
pesticides.
Mixers
and
loaders
must
also
wear
a
chemical
resistant
apron.

Submitted
Data/
Information
In
support
of
the
reregistration
process
for
endosulfan,
AgrEvo
USA
submitted
a
worker
exposure
study
for
review
by
the
Agency.
The
1987
study,
Exposure
of
Mixer/
Loader/
Applicators
to
Thiodan
®
3EC
Insecticide
Applied
to
Fruit
Trees
by
Airblast
Equipment
in
California
was
originally
submitted
as
MRID#
410485­
02.
The
registrant
subsequently
made
revisions
and
resubmitted
the
study
in
1990
as
MRID#
417152­
01.
The
Agency
determined
that
both
the
original
and
revised
study
do
not
meet
Agency
guidelines
for
acceptability
under
Series
875
of
the
Occupational
and
Residential
Test
Guidelines.
Therefore,
the
data
in
MRID#
s
410485­
02
and
417152­
01
were
not
used
in
the
assessment.
Instead,
surrogate­
based
exposure
assessments
for
each
scenario
were
developed,
where
appropriate
data
were
available,
using
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1.

The
registrant
also
submitted
a
risk
assessment
titled,
Evaluation
of
the
Human
Hazards
and
Risks
Associated
with
the
Application
of
Endosulfan
dated
March
1989
(
MRID#
410485­
01).
This
submission
was
not
used
in
this
risk
assessment
for
the
following
reasons:
the
exposure
data
used
was
from
the
above
study
(
MRID#
417152­
01)
which
was
found
to
be
unacceptable,
acres
treated
per
day
used
were
not
justified
and
vary
widely
from
the
Agency
standard
values,
and
the
monkey
dermal
penetration
study
which
is
critical
in
interpreting
the
biological
monitoring
data
was
not
acceptable.

The
Agency
has
reviewed
Aventis'
Submission
of
an
Application
Exposure
Assessment
for
Endosulfan
and
an
Evaluation
of
Possible
Endocrine
Effects
in
Mammalian
Species
dated
August
4,
1999
(
MRID#
449391­
01)
and
concludes
that
the
submission
does
not
follow
standard
Agency
policies
or
use
Agency
standard
default
values.
The
Agency
calculates
highend
single­
day
exposures
to
occupational
workers,
based
on
maximum
label
application
rates
and
standard
values
for
the
number
of
acres
that
can
be
treated
in
a
single
day
by
various
types
of
agricultural
equipment.
These
standard
acres
treated
per
day
values
are
representative
of
most
crops
treated
with
endosulfan,
including
both
low
(
strawberries)
and
high
(
potatoes)
acreage
crops,
and
are
protective
of
commercial
applicators
who
may
treat
multiple
farms
or
fields
in
one
day.
Although
the
1992
U.
S.
Census
of
Agriculture
data
used
by
Aventis
does
represent
the
national
average
crop
acreage
per
farm,
it
is
only
representative
of
individual
farmers
and
not
of
commercial
applicators,
who
are
likely
to
treat
more
acres
in
a
day
than
individual
growers.
57
Aventis'
exposure
assessment
incorporates
a
50%
reduction
factor
to
dermal
exposure
for
workers,
based
on
the
label
requirement
for
chemical
resistant
headgear.
HED
does
not
assign
a
reduction
factor
to
dermal
exposure
due
to
the
use
of
chemical
resistant
headgear.
Although
HED
agrees
that
chemical
resistant
headgear
may
reduce
pesticide
exposure,
a
protection
factor
has
not
been
established
for
the
use
of
such
headgear,
due
to
a
lack
of
data.
Therefore,
HED
does
not
quantitatively
reduce
exposure
risk
estimates
to
take
chemical
resistant
headgear
into
account.

Occupational
Exposures
and
Risks
HED
notes
that
the
revised
dermal
endpoints
are
based
on
the
21­
dermal
study
in
the
rat
for
the
short­
term
and
intermediate­
term
(
postapplication
only)
exposure
durations.
This
study
replaces
the
two­
year
chronic
toxicity/
carcinogenicity
study
in
rats
that
was
originally
used
to
assess
for
intermediate­
term
dermal
exposure.
The
Agency
considered
Aventis'
submission
for
inclusion
in
the
endosulfan
assessment,
but
because
of
the
aforementioned
discrepancies,
it
was
not
included
in
this
assessment.

Handler
exposure
assessments
were
completed
using
a
baseline
exposure
scenario
and,
if
required,
increasing
levels
of
risk
mitigation
(
PPE
and
engineering
controls)
in
an
attempt
to
achieve
an
appropriate
margin
of
exposure.
The
baseline
scenario
generally
represents
a
handler
wearing
long
pants,
a
long­
sleeved
shirt,
no
respirator,
and
no
chemical­
resistant
gloves
(
there
are
exceptions
pertaining
to
the
use
of
gloves,
and
these
are
noted).

It
is
desirable
that
short­
term
occupational
risks,
expressed
as
margins
of
exposure
(
MOEs),
be
>
100.
MOEs
below
100
are
of
concern.
In
accordance
with
current
Agency
guidance,
the
FQPA
factor
is
not
retained
for
the
occupational
risk
assessment
(
Memorandum,
Special
Report
of
the
FQPA
Safety
Factor
Committee.
Brenda
Tarplee
and
Jess
Rowland.
April
15,
1998).
Dermal
and
inhalation
risks
for
handlers
were
assessed
separately
since
the
end
effects
for
the
toxicological
endpoints
chosen
for
these
exposures
are
dissimilar
and
Agency
policy
prevents
aggregation
of
the
risks
(
inhalation
plus
dermal)
if
the
toxicological
effects
are
not
the
same.
Handler
exposures
to
endosulfan
are
expected
to
be
short­
term
only
(
1­
30
days).

Of
the
21
identified
occupational
handler
exposure
scenarios,
5
of
them
are
a
risk
of
concern,
having
calculated
MOEs
less
than
the
target
MOE
of
100,
at
the
highest
level
of
mitigation
for
short­
term
dermal
exposure.
For
short­
term
inhalation
exposure,
4
of
the
21
identified
occupational
handler
exposure
scenarios
are
a
risk
of
concern,
having
calculated
MOEs
less
than
the
target
MOE
of
100,
at
the
highest
level
of
mitigation.
See
Table
9a,
Summary
of
Occupational
Handler
Risks.
Three
scenarios
lack
data
to
assess
their
risk.
Data
are
needed
to
assess
the
following
occupational
handler
scenarios:
applying
dip
treatments
to
trees
and
roots
or
whole
plants
and
mixing/
loading/
applying
wettable
powders
with
a
backpack
sprayer
and
a
high
pressure
handwand.

Several
issues
must
be
considered
when
interpreting
the
occupational
exposure
risk
assessment.
These
include:

C
Several
generic
protection
factors
(
PF)
were
used
to
calculate
handler
exposures
(
e.
g.,
58
90%
PF
over
baseline
for
inhalation
unit
exposure
to
account
for
use
of
an
organic
vapor
removing
respirator).
These
protection
factors
are
considered
conservative,
but
have
not
been
completely
evaluated
by
HED.

°
Low
confidence
data,
based
on
PHED
grading
criteria,
were
used
to
calculate
the
risks
to
handlers
from
the
following
scenarios
for
any
body
part
and/
or
level
of
mitigation:
Mixing/
loading
wettable
powders,
applying
sprays
with
an
airblast
sprayer
(
enclosed
cabs),
applying
sprays
with
a
rights
of
way
sprayer,
mixing/
loading/
applying
liquids
and
wettable
powders
with
a
low
pressure
handwand,
mixing/
loading/
applying
liquids
with
a
high
pressure
handwand
and
backpack
sprayer,
and
flagging
aerial
applications.

7.2
Postapplication
The
Agency
has
determined
that
there
are
potential
short­
and
intermediate­
term
postapplication
exposures
to
individuals
entering
treated
fields.
Current
endosulfan
labels
show
a
restricted
entry
interval
(
REI)
requirement
of
24
hours
with
the
following
early
entry
PPE
required:
coveralls,
waterproof
gloves,
shoes,
socks
and
chemical
resistant
headgear
for
overhead
exposures.

For
the
purpose
of
conducting
this
assessment,
crops
were
grouped
in
order
to
assign
the
most
representative
dislodgeable
foliar
residue
(
DFR)
data
to
the
crops.
The
crop
groups
listed
below
were
chosen
because
appropriate
residue
data
were
available
(
MRID
444031­
02).
The
crop
groups
and
corresponding
surrogate
residue
data
sources
are
as
follows:

°
Tree
Crops:
DFR
data
for
peaches
were
used,
based
on
a
study
using
an
application
rate
of
3
lbs.
ai/
acre,
to
determine
exposure
from
postapplication
activities
associated
with
all
tree
crops
(
15
tree
crops
other
than
peaches).
This
application
rate
is
consistent
with
the
application
rates
for
most
fruit
and
nut
trees.
For
the
crops
where
the
application
rates
were
not
3
lbs.
ai/
acre,
the
DFR
data
were
adjusted
(
linear)
to
the
appropriate
application
rate
for
the
individual
crops.

°
Grape
Harvesting,
Girdling
and
Irrigating:
This
scenario
was
based
on
DFR
data
for
grapes
using
an
application
rate
of
1.5
lbs
ai/
acre.
This
is
the
labeled
application
rate
for
grapes.

°
Field
Crops:
DFR
data
for
melons
were
used
and
were
assumed
to
be
representative
of
exposure
from
postapplication
activities
associated
with
all
the
remaining
crops
registered
for
endosulfan
(
37
crops
other
than
melons)
except
for
grapes
and
tree
crops.
The
DFR
data
were
based
on
an
application
rate
of
1
lb.
ai/
acre.
However,
most
of
the
labeled
application
rates
for
these
crops
range
from
0.25
to
3
lbs.
ai/
acre.
Thus,
the
DFR
data
were
adjusted
(
linear)
to
the
appropriate
application
rate
for
the
individual
crops.

Submitted
Data
A
DFR
study
was
conducted
for
endosulfan
and
its
metabolites,
$­
endosulfan
and
endosulfan
sulfate.
The
study
evaluated
dislodgeable
residue
dissipation
for
endosulfan
applied
59
to
peaches,
grapes,
and
melons
(
MRID#
444031­
02).
In
summary,
the
DFR
study
completed
in
support
of
the
regulatory
requirements
for
endosulfan
did
not
completely
meet
the
criteria
contained
in
Series
875,
Occupational
and
Residential
Test
Guidelines.
Despite
the
uncertainties
associated
with
the
study
(
see
Third
Revision
of
"
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document
for
Endosulfan."
Renee
Sandvig.
February
26,
2002),
the
Agency
used
the
data
from
the
DFR
study
in
assessing
the
appropriate
postapplication
exposure
from
agricultural
activities
using
endosulfan
(
fruit
trees
and
low
growing
fruit
crops).

A
second
DFR
study
(
MRID#
403039­
01)
was
conducted
for
endosulfan.
This
study
examined
DFR
residues
on
apples,
apricots,
processing
tomatoes,
and
cherry
tomatoes.
However,
this
study
was
unacceptable
and
was
not
used
in
estimating
the
postapplication
exposures.
All
postapplication
exposure
estimates
were
based
on
MRID#
444031­
02.
It
should
be
noted
that
the
half
lives
from
the
unacceptable
study
were
similar
to
or
higher
than
the
half
lives
from
the
study
used
to
determine
postapplication
exposure
in
this
assessment.
This
indicates
that
the
DFR
data
from
the
unacceptable
study
would
result
in
restricted
entry
interval
calculations
similar
to
or
even
longer
than
the
ones
calculated
in
this
assessment.

Short­
and
Intermediate­
term
Postapplication
Exposures
and
Risks
Short­
and
intermediate­
term
postapplication
exposure
is
expected
because
endosulfan
is
registered
for
over
50
crops
and
postapplication
workers
may
move
from
treated
field
to
treated
field.
This
is
especially
possible
when
application
is
repeated
every
seven
days
for
two
to
three
applications,
as
is
allowable
on
current
labels.
A
dose
and
an
MOE
are
determined
from
the
declining
predicted
DFR
values
until
the
LOC
or
target
MOE
of
100
is
reached
for
every
crop
for
both
the
EC
and
WP
formulations.
The
NOAEL
used
in
the
short­
and
intermediate­
term
dermal
assessment
is
12.0
mg/
kg/
day.
For
short­
and
intermediate­
term
exposure
to
the
EC
formulation,
the
day
after
treatment
when
the
calculated
MOE
equals
or
exceeds
the
LOC
or
target
MOE
of
100
ranges
from
0
days
(
day
of
application)
for
pruning
pecan
trees
to
17
days
for
detasseling
corn
at
an
application
rate
of
1.5
lbs
ai/
acre.
For
short
and
intermediate
term
exposures
to
the
WP
formulation,
the
day
after
treatment
when
the
calculated
MOE
equals
or
exceeds
the
target
MOE
of
100
ranges
from
0
days
for
pruning
pecan
trees
to
30
days
for
girdling
grapes
at
an
application
rate
of
1.5
lbs
ai/
acre.
Occupational
postapplication
risks
from
dermal
exposure
are
of
concern.
See
Table
9b
for
a
summary.
60
7.3
Incident
Data
The
Agency
has
reviewed
the
Incident
Data
System
(
IDS),
the
Poison
Control
Center,
the
California
Department
of
Food
and
Agriculture
(
Department
of
Pesticide
Regulation),
and
the
National
Pesticide
Telecommunications
Network
(
NPTN)
databases
for
reported
incident
information
for
endosulfan
(
Review
of
Endosulfan
Incident
Reports.
Jerome
Blondell
&
Monica
Spann.
January
18,
2000).
A
number
of
accidental
human
poisonings
from
exposure
to
endosulfan
in
both
occupational
and
residential
settings
have
been
reported.
The
data
from
these
sources
often
lacked
specific
information
on
the
extent
of
exposure
and
the
circumstances
of
exposure.
Collectively,
however,
the
incidence
information
indicate
definite
poisoning
risks
from
misuse
of
products
that
contain
endosulfan,
or
from
not
wearing
personal
protective
equipment.

Several
incidents
of
acute
accidental
human
exposure
to
endosulfan
have
been
reported.
The
clinical
signs
and
symptoms
observed
in
humans
following
acute
accidental
exposure
to
endosulfan
are
similar
to
those
observed
in
acute
toxicity
studies
in
animals.
In
humans,
acute
toxicity
caused
by
endosulfan
is
characterized
by
nervousness,
agitation,
tremors,
convulsions,
and
death.
In
one
incident,
a
70
year
old
woman
died
about
three
hours
after
she
swallowed
"
drops"
of
an
endosulfan
formulation.
Prior
to
death
the
woman
experienced
vomiting,
diarrhea,
agitation,
tonoclonic
convulsions,
dyspnea,
cyanosis,
and
loss
of
consciousness.
In
another
incident,
nine
workers
experienced
at
least
one
convulsion
after
bagging
a
50%
wettable
powder
formulation
of
endosulfan.
Five
of
the
men
were
said
to
be
wearing
a
respirator
and
protective
clothing
at
the
time
of
exposure.
Prodromal
symptoms
included
malaise,
vomiting,
dizziness
and
confusion.
California
data
show
a
consistent
risk
of
skin
illness
among
field
workers
who
come
into
substantial
contact
with
foliage.

Brandt
et
al.
(
2001)
reported
on
a
forty­
three
year
old
farmer
in
Kentucky
that
mixed
and
sprayed
endosulfan
on
tobacco
for
five
hours
and
had
repeated
hand,
and
possibly
oral,
contact.
The
farmer,
who
did
not
wear
gloves
or
a
respirator,
mixed
about
five
or
six
quarts
of
endosulfan
concentrate
with
three
hundred
gallons
of
pond
water
without
washing
or
wiping
off
his
hands.
The
tank
mix
was
blown
into
his
face
by
the
wind
while
he
was
pulling
a
boom
sprayer
behind
an
unenclosed
tractor.
The
farmer's
clothes
were
soaked
with
spray
and
he
did
not
shower
or
change
his
clothes
immediately
after
being
exposed
to
the
product.
While
driving
the
tractor
from
the
tobacco
field,
the
farmer
slumped
forward
and
displayed
jerking
motions.
The
tractor
then
overturned
and
pinned
his
legs
underneath.
About
twenty
minutes
later,
medical
personnel
arrived
to
transport
him
to
the
hospital.
The
farmer
reported
repeated
convulsions
for
five
or
six
hours,
hypoxia,
acidosis,
and
status
epilepticus.
A
lumbar
puncture
revealed
bloody
cerebrospinal
fluid.
The
man
was
transferred
to
a
tertiary
medical
center
three
days
after
exposure.
About
three
days
after
being
exposed
to
the
product,
blood
samples
were
taken
and
were
analyzed
two
weeks
later.
Endosulfan
was
not
detected
in
a
residual
aliquot.
There
was
a
concern
about
the
validity
of
the
negative
endosulfan
test
because
the
handling
and
storage
of
the
residual
aliquot
could
not
be
verified
with
the
external
laboratory
that
was
responsible
for
the
test.
About
four
weeks
after
exposure,
a
fat
biopsy
was
performed
that
did
not
detect
endosulfan.
Five
years
after
exposure,
the
farmer
was
profoundly
impaired
neurologically
and
under
full
custodial
care.
61
Available
incidence
data
clearly
show
that
flagrant
misuse
of
concentrated
formulations
of
endosulfan
could
result
in
exposures
that
cause
serious,
life­
threatening
poisoning,
or
permanent
neurological
toxicity.
Both
handler
and
postapplication
workers
have
experienced
moderate
systemic
poisoning
as
a
result
of
exposure
to
endosulfan.
In
addition,
the
California
data
in
particular
show
that
there
appears
to
be
a
consistent
risk
of
skin
rash
or
irritation
among
field
workers
who
have
substantial
contact
with
treated
foliage.
There
are
also
reports
of
poisoning
from
endosulfan
exposure
occurring
in
other
countries.
Though
many
of
these
cases
involve
misuse
of
endosulfan,
they
should
not
be
characterized
as
just
"
anecdotal,"
as
the
ETF
suggests
(
February
28,
2002).
These
cases
are
investigated
and
documented
by
scientists
in
peer­
reviewed
literature.
The
Agency
often
uses
cases
in
other
countries
to
establish
what
health
effects
may
occur
among
those
over­
exposed
and
these
cases
can
be
valuable
in
determining
precautionary
labeling.
Endosulfan
does
not
appear
to
pose
risks
of
concern
from
spray
drift
exposure.
Results
from
the
incidence
data
indicate
that
all
skin
surfaces
should
be
protected
when
workers
are
handling
endosulfan
formulations,
particularly
concentrated
formulations.
Special
effort
is
warranted
to
keep
concentrated
endosulfan
away
from
the
lay
public
who
may
misuse
it
in
a
manner
leading
to
life­
threatening
or
fatal
poisoning.
Restricted
entry
intervals
sufficient
to
minimize
substantial
contact
with
treated
foliage
are
warranted.

8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
Additional
data
needs/
requirements
have
been
identified
in
the
referenced
discipline
chapters
and
are
summarized
here.

8.1
Toxicology
Two
additional
toxicity
studies
are
warranted
as
a
result
of
the
uncertainties
regarding
increased
sensitivity
of
infants
and
children
to
endosulfan
following
prenatal
or
postnatal
exposure.
These
toxicity
studies
are:

1)
a
subchronic
neurotoxicity
study
(
870.6200)
and;

2)
a
developmental
neurotoxicity
(
870.6300)
assay.

Note:
Protocols
for
these
studies
have
been
received.

8.2
Product
Chemistry
Product
chemistry
data
requirements
that
remain
outstanding
for
the
7
registered
technicals
include
specific
details
pertaining
to
the
process
used
to
manufacture
endosulfan:
a
statement
as
to
whether
the
process
is
batch
or
continuous;
the
duration
of
each
step
of
the
process;
the
relative
amounts
of
the
materials
used;
a
description
of
the
manufacturing
equipment;
a
more
complete
description
of
the
reaction
conditions
controlled
during
each
step
of
the
process;
a
description
of
the
sampling
regimen
and
quality
control
procedures
necessary
to
assure
product
consistency;
an
updated
confidential
statement
of
formula
(
CSF)
including
62
nominal
concentrations
for
the
active
ingredient
and
impurities
present
in
concentrations
greater
than
0.1%.

8.3
Residue
Chemistry
The
existing
residue
chemistry
database
is
incomplete.
Label
revisions
are
required
for
many
crops
in
order
to
reflect
the
parameters
of
use
patterns
for
which
residue
data
are
available.
Most
of
the
required
label
revisions
pertain
to
the
establishment
of
preharvest
intervals
and
livestock
feeding
and/
or
grazing
restrictions.

The
reregistration
requirements
for
magnitude
of
the
residue
in/
on
the
following
RACs
have
not
been
fulfilled,
and
field
trial
data
are
required:
barley
hay,
and
pearled
barley;
oat
forage,
hay,
and
rolled
oats;
rye
forage;
wheat
forage,
and
hay.

The
reregistration
requirements
for
magnitude
of
the
residue
in/
on
tobacco
have
not
been
fulfilled
and
field
trial
data
and
a
pyrolysis
study
are
required.

The
need
for
additional
tolerances
and
for
revisions
to
dietary
exposure/
risk
assessments
will
be
determined
upon
receipt
of
the
required
residue
chemistry
data.

8.4
Occupational
Exposure
Data
gaps
exist
for
the
following
scenarios:

C
Applying
dip
treatments
to
trees
and
roots
or
whole
plants.

°
No
exposure
data
exist
for
mixing/
loading/
applying
wettable
powders
with
a
high
pressure
handwand
and
a
backpack
sprayer.
These
two
scenarios
are
expected
to
have
risks
of
concern
since
similar
scenarios
assessed
in
this
document,
mixing/
loading
wettable
powders
and
mixing/
loading/
applying
liquids
with
a
high
pressure
handwand,
have
risks
of
concern.

If
the
registrant
is
interested
in
refining
the
Agency's
calculated
REIs,
additional
DFR
data
and/
or
worker
exposure
monitoring
data
may
be
submitted.

9.0
ATTACHMENTS
Assessment
of
the
Dietary
Cancer
Risk
of
Hexachlorobenzene
and
Pentachlorobenzene
as
impurities
in
Chlorothalonil,
PCNB,
Picloram,
and
several
other
pesticides.
William
Smith.
February
26,
1998.
63
Endosulfan:
Evaluation
of
Registrant
Submission,
Endosulfan:
Evaluation
of
Possible
Endocrine
Effects
in
Mammalian
Species.
Elizabeth
Mendez,
December
11,
2000.

Endosulfan.
New
FQPA
and
PDP
Data,
Anticipated
Residues,
and
Revised
Acute
and
Chronic
Dietary
Exposure
Analyses.
Sherrie
Kinard.
April
22,
2002.

ENDOSULFAN
(
PC
Code:
079401).
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Document.
Robert
F.
Fricke.
May
9,
2002.

Endosulfan,
Product
Chemistry
Chapter
for
Reregistration
Eligibility
Decision.
Ken
Dockter.
December
18,
1998.

Endosulfan:
Re­
evaluation
of
Toxicology
Endpoint
Selection
for
Dermal
and
Inhalation
Risk
Assessments
and
3X
Safety
Factor
for
Bioaccumulation
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
Robert
Fricke.
February
28,
2002.

Endosulfan­
Report
of
the
FQPA
Safety
Factor
Committee.
Carol
Christensen.
February
14,
2002.

ENDOSULFAN
­
Supporting
documentation
for
findings
of
FQPA
Safety
Committee
on
February
11,
2002.
Elizabeth
Méndez.
May
9,
2002.

Quantitative
Usage
Analysis
for
Endosulfan.
Steven
Nako.
October
13,
1999.

Quantitative
Usage
Analysis
for
Endosulfan,
Updated.
David
Donaldson.
September
10,
2000.

Review
of
Endosulfan
Incident
Reports.
Jerome
Blondell
and
Monica
Spann.
January
18,
2000.

Revised
Residue
Chemistry
Chapter
for
the
Endosulfan
Reregistration
Eligibility
Decision
(
RED)
Document.
John
Punzi.
February
14,
2002.

Third
Revision
of
Occupational
and
Residential
Exposure
Assessment
and
Recommendations
for
the
Reregistration
Eligibility
Decision
Document
for
Endosulfan.
Renee
Sandvig.
February
26,
2002.
64
Table
8.
Use
Pattern
Summary
for
Endosulfan.

Formulation
types
(%
ai)
Equipment
used
Use
sites
Application
Rates
Range
Timing
and
Frequency
of
Application
Technical
grade
manufacturing
product
(
95%

active
ingredient
[
ai]),

emulsifiable
concentrate
(
9
to
34%
ai),
and
a
wettable
powder
(
1
to
50%
ai).
Commercial
use:

groundboom
sprayer,

fixedwing
aircraft,
chemigation
(
potatoes
only),
airblast
sprayer,
rights
of
way
sprayer,
low
pressure
handwand,
high
pressure
handwand,
backpack
sprayer,
&
dip
treatment.
Alfalfa
(
seed
only),
barley,

beans
(
dry
and
succulent),

blueberries,
broccoli,
brussel
sprouts,
cabbage,
carrots,

cauliflower,
celery,
clover
(
seed
only),
collards,
cotton,

corn
(
fresh
only),

cucumbers,
eggplants,

grapes,
kale,
kohlrabi
(
seed
only),
lettuce,
melons,

mustard
greens,
oats,
peas,

peppers,
pineapples,

pistachio
nuts,
potatoes,

pumpkins,
radish
(
seed
only),
rutabaga
(
seed
only),

rye,
spinach,
squash,
sweet
potatoes,
strawberries,

tobacco,
tomato,
turnip,

wheat,
apples,
apricots,

almonds,
cherries,
filberts,

macadamia
nuts,
nectarines,

pecans,
peach,
pear,
plums,

prunes,
walnuts,
shade
trees,

citrus
(
non­
bearing
&

nursery
stock),
shrubs,

nursery
stock,
Christmas
tree
plantations,
&
root
dip
(
cherry,
peaches,
&
plum
roots
&
crowns,
whole
strawberry
plants).
Application
rates
range
from
0.5
lbs
ai/
acre
for
clover
to
3
lbs
ai/
acre
for
apricots.
Endosulfan
can
be
applied
at
any
time
of
the
growing
season.
It
may
be
applied
from
1
to
6
times
a
year,

with
an
average
of
2
times
per
year.
65
Table
9a.
Summary
of
Occupational
Handler
Risks
Exposure
Scenario
(
Scenario
#)
Crop
Type/
Usea
Range
of
Application
Rates
(
lb
ai/
A)
b
Amount
Handled
per
Dayc
Baselinef
Minimum
PPEg
Maximum
PPEh
Engineering
Controlsi
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Mixer/
Loader
Exposures
Mixing/
Loading
Liquid
Formulations
for
Aerial
Application
(
1a)
clover
0.5
lb
ai/
A
350
Acres
2
67
210
330
­
­
­
­

pineapple
2.0
lb
ai/
A
0.41
17
52
83
71
170
140
­

pecans
3.0
lb
ai/
A
0.28
11
35
56
47
110
93
­

small
grains
0.75
lb
ai/
A
1200
Acres
0.32
13
41
65
55
130
110
­

cotton
1.5
lb
ai/
A
0.16
7
20
32
27
65
54
94
Mixing/
Loading
Liquid
Formulation
for
Chemigation
(
1b)
potatoes
(
Idaho)
1.0
lb
ai/
A
350
Acres
0.83
33
100
170
­
­
­
­

Mixing/
Loading
Liquid
Formulations
for
Groundboom
Application
(
1c)
clover
0.5
lb
ai/
A
80
Acres
7
290
910
­
­
­
­
­

pineapple
2.0
lb
ai/
A
2
73
230
360
­
­
­
­

small
grains
0.75
lb
ai/
A
200
Acres
2
78
240
390
­
­
­

cotton
1.5
lb
ai/
A
1
39
120
190
­
­
­

Mixing/
Loading
Liquid
Formulations
for
Airblast
Application
(
1d)
Ornamental
Trees/
Shrubs
1.0
lb
ai/
A
10
Acres
29
1,200
3,700
­
­
­
­
­

Hazelnuts
2.0
lbs
ai/
A
40
Acres
4
150
460
­
­
­
­
­

pecans
3.0
lb
ai/
A
2
97
300
490
­
­
­
­

Mixing/
Loading
Liquids
for
Rights­
of­
way
Spray
Application
(
1e)
grapes
0.005
lb
ai/
gal
1000
Gallons
58
2,300
7,300
­
­
­
­
­

cherry
0.04
lb
ai/
gal
7
290
910
­
­
­
­
­

Mixing/
Loading
Liquids
for
Plant
and
Root
Dip
(
1f)
cherry,
peach
and
plums
0.05
lbs
ai/
gal
100
Gallons
58
2,300
7,300
­
­
­
­
­
Table
9a.
Summary
of
Occupational
Handler
Risks
(
continued)

Exposure
Scenario
(
Scenario
#)
Crop
Type/
Usea
Range
of
Application
Rates
(
lb
ai/
A)
b
Amount
Handled
per
Dayc
Baselinef
Minimum
PPEg
Maximum
PPEh
Engineering
Controlsi
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
66
Mixing/
Loading
Wettable
Powders
for
Aerial
Application
(
2a)
beans
1.0
lb
ai/
A
350
Acres
0.65
0.93
14
5
18
10
240
170
sweet
potato
2.0
lb
ai/
A
0.32
0.47
7
2
9
5
120
83
peach
3.0
lb
ai/
A
0.22
0.31
5
2
6
3
82
56
small
grains
0.75
lb
ai/
A
1200
Acres
0.25
0.36
6
2
7
4
95
65
cotton
1.5
lb
ai/
A
0.13
0.18
3
1
4
2
48
32
Mixing/
Loading
Wettable
Powders
for
Groundboom
Application
(
2b)
beans
1.0
lb
ai/
A
80
Acres
3
4
62
20
81
41
1,100
730
sweet
potato
2.0
lb
ai/
A
1.4
2
31
10
40
20
540
360
small
grains
0.75
lb
ai/
A
200
Acres
1.5
2
33
11
43
22
570
390
cotton
1.5
lb
ai/
A
0.76
1
16
5
22
11
290
190
Mixing/
Loading
Wettable
Powders
for
Airblast
Application
(
2c)
Ornamental
Trees/
Shrubs
1.0
lb
ai/
A
10
Acres
23
33
490
160
­
­
­
­

hazelnuts
2.0
lb
ai/
A
40
Acres
3
4
62
20
81
41
1,100
730
peaches
3.0
lb
ai/
A
2
3
41
14
54
27
710
490
Mixing/
Loading
Wettable
Powders
for
Rights­
of­
way
Spray
Treatment
(
2d)
grapes
0.005
lb
ai/
gal
1000
Gallons
45
65
990
330
­
­
­
­

walnut
0.02
lb
ai/
gal
11
16
250
81
­
160
­
­

Mixing/
Loading
Wettable
Powders
for
Plants
and
Root
Dip
(
2e)
cherry,
peach,

and
plum
0.05
lb
ai/
gal
100
Gallons
45
65
990
330
­
­
­
­

Applicator
Exposures
Applying
Spray
with
Aerial
Equipment
(
3)
clover
0.5
lb
ai/
A
350
Acres
See
Eng.
Controls
See
Eng.
Controls
See
Eng.

Controls
See
Eng.

Controls
See
Eng.

Controls
See
Eng.

Controls
960
1,200
pineapple
2.0
lb
ai/
A
240
290
pecans
3.0
lb
ai/
A
160
200
small
grains
0.75
lb
ai/
A
1200
Acres
190
230
cotton
1.5
lb
ai/
A
93
110
Table
9a.
Summary
of
Occupational
Handler
Risks.
(
Continued)

Exposure
Scenario
(
Scenario
#)
Crop
Type/
Usea
Range
of
Application
Rates
(
lb
ai/
A)
b
Amount
Handled
per
Dayc
Baselinef
Minimum
PPEg
Maximum
PPEh
Engineering
Controlsi
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
67
Applying
Sprays
with
a
Groundboom
Sprayer
(
4)
clover
0.5
lb
ai/
A
80
Acres
1,500
470
­
­
­
­
­
­

pineapple
2.0
lb
ai/
A
380
120
­
­
­
­
­
­

small
grains
0.75
lb
ai/
A
200
Acres
400
130
­
­
­
­
­
­

cotton
1.5
lb
ai/
A
200
63
­
310
­
­
­
­

Applying
Sprays
with
an
Airblast
Sprayer
(
5)
ornamental
trees1.0
lb
ai/
A
10
Acres
230
310
­
­
­
­
­
­

hazelnuts
2.0
lb
ai/
A
40
Acres
29
39
48
190
48
­
550
­

pecans
3.0
lb
ai/
A
19
26
32
130
32
­
370
­

Applying
Sprays
with
a
Rights­
of­
way
Sprayer
(
6)
grapes
0.005
lb
ai/
gal
1000
Gallons
130
720
­
­
­
­
NF
NF
cherries
0.04
lb
ai/
gal
16
90
54
450
72
­
NF
NF
Applying
Dip
Treatment
to
Roots,
or
Whole
Plants
(
7)
cherry,
peach,

plum
roots
0.05
lb
ai/
gal
100
gallons
No
Data
No
Data
ND
ND
ND
ND
ND
ND
Mixer/
Loader/
Applicator
Exposure
Mixing/
Loading/
Applying
Liquid
Formulations
with
a
Low
Pressure
Handwand
(
8)
tobacco
(
drench)
0.005
lb
ai/
gal
40
Gallons
42
2,300
9,800
­
­
­
NF
NF
tomato
(
greenhouse)
0.01
lb
ai/
gal
21
1,200
4900
­
­
­
NF
NF
cherries
0.04
lb
ai/
A
5
290
1,200
­
­
­
NF
NF
Mixing/
Loading/
Applying
Wettable
Powders
with
a
Low
Pressure
Handwand
(
9)
tomato/
tobacco
0.005
lb
ai/
gal
40
Gallons
140
64
­
320
­
­
NF
NF
walnut
0.02
lb
ai/
gal
36
16
120
80
­
160
NF
NF
Mixing/
Loading/
Applying
Liquid
with
a
High
Pressure
Handwand
(
10)
tobacco
(
drench)
0.005
lb
ai/
gal
1000
Gallons
48
23
67
120
110
­
NF
NF
tomato
(
greenhouse)
0.01
lb
ai/
gal
24
12
34
58
53
120
NF
NF
cherries
0.04
lb
ai/
gal
6
3
9
15
13
29
NF
NF
Mixing/
Loading/
Applying
Liquid
with
Backpack
Sprayer
(
11)
tobacco
(
drench)
0.025
lb
ai/
gal
40
Gallons
1,700
2,300
­
­
­
­
NF
NF
Exposure
Scenario
(
Scenario
#)
Crop
Type/
Usea
Range
of
Application
Rates
(
lb
ai/
A)
b
Amount
Handled
per
Dayc
Baselinef
Minimum
PPEg
Maximum
PPEh
Engineering
Controlsi
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
Dermal
MOEd
Inhalation
MOEe
68
tomato
(
greenhouse)
0.01
lb
ai/
gal
840
1,200
­
­
­
­
NF
NF
cherries
0.04
lb
ai/
gal
210
290
­
­
­
­
NF
NF
Flagger
Exposures
Flagging
Aerial
Spray
Applications
(
12)
clover
0.5
lb
ai/
A
350
Acres
440
230
­
­
­
­
­
­

pineapple
2.0
lb
ai/
A
110
57
­
290
­
­
­
­

pecans
3.0
lb
ai/
A
73
38
67
190
80
­
3,600
­

Footnotes:

a
Crops
named
are
index
crops
which
are
chosen
to
represent
all
other
crops
at
or
near
that
application
rate
for
that
use.
See
the
application
rates
listing
in
the
use
summary
section
of
this
document
for
further
information
on
application
rates
used
in
this
assessment.

b
Application
Rates
are
based
on
the
maximum
application
rates
listed
on
the
endosulfan
labels.

c
Daily
amount
treated
are
based
on
Science
Advisory
Council
for
Exposure
Policy
#
9.1.

d
Short­
term
Dermal
MOE
=
Short­
term
NOAEL
(
mg/
kg/
day)/
Daily
Dermal
Dose
(
mg/
kg/
day).

e
Short­
term
MOE
=
Short­
term
NOAEL
(
mg/
kg/
day)/
Daily
Inhalation
Dose
(
mg/
kg/
day).

f
Baseline
clothing:
long
pants,
long
sleeved
shirt,
shoes,
socks.
Chemical
resistant
gloves
are
included
for
mixing/
loading/
applying
liquids
with
a
backpack
sprayer
and
wettable
powders
with
a
low
pressure
handwand
(
scenarios
9
and
11).

g
Minimum
PPE
clothing:
Baseline
clothing
plus
dust/
mist
respirator,
and
chemical
resistant
gloves.

h
Maximum
PPE
clothing:
Baseline
clothing
plus
organic
vapor
respirator,
double
layer
of
clothes,
and
chemical
resistant
gloves.

i
Engineering
controls:
Enclosed
mixing/
loading,
closed
cab,
truck
or
cockpit.
Baseline
level
clothing.
Chemical
resistant
gloves
for
airblast
sprayer
application
and
mixing/
loading
liquid
formulation
(
scenarios
1
and
5).

­
Scenario's
calculated
MOE
exceeds
the
target
MOE
at
the
previous
level
of
mitigation.
(
MOE
>
100)

NF
=
Not
feasible
for
this
scenario
(
no
available
engineering
controls).
ND
=
No
data.

Bolded
MOE
values
show
a
risk
of
concern
at
the
highest
possible
level
of
mitigation
for
the
corresponding
scenario.
69
Table
9b.
Summary
of
Short­
and
Intermediate­
term
Postapplication
Exposures
and
Risks
Cropa
Maximum
Label
Application
Rate
(
lbs
ai/
acre)
d
Transfer
Coefficiente
(
cm2/
hr)
Activityf
Day
after
Application
When
MOE
$
100g
WPb
ECc
WPb
ECc
Table
Grapes
/
Raisins
1.5
1.5
10,000
Cane
turning
and
tying,
and
girdling
30
6
Juice
Grapes
1.5
1.5
5,000
Tying,
training,
hand
harvesting,
hand
pruning,

and
thinning.
20
0
Grapes,
Table
and
Juice
1.5
1.5
1,000
Scouting
and
irrigating
0
0
Apple,
Apricot,
Cherry,
Nectarines,
Peach,
Pear,
Plum,

Prune,
Christmas
Trees,
Ornamental
Trees
/
Shrubs
including
Evergreen
Trees
and
Non­
bearing
Citrus
Trees.
3
3
3,000
Thinning,
staking,
topping,
training,
hand
harvest,

hand
pruning
and
seed
cone
harvesting
5
0
Apple,
Apricot,
Cherry,
Nectarines,
Peach,
Pear,
Plum,

Prune,
Ornamental
Trees
/
Shrubs
including
Evergreen
Trees,
Non­
bearing
Citrus
Trees.
and
Christmas
Trees.
3
3
1,000
Scouting
and
irrigating
0
0
Macadamia
nuts,
Pistachio
Nuts,
Pecans
Hazelnut,
Almonds
and
Walnut
2
3
2,500
Hand
harvesting,
pruning,
and
thinning
0
0
500
Scouting
and
irrigating
0
0
Blueberries,
Kohlrabi,
Broccoli,
and
Cabbage.
2
2
5,000
Hand
harvesting,
pruning,
thinning,
and
irrigating.
14
9
Kohlrabi,
Broccoli,
and
Cabbage.
2
2
4,000
Scouting
and
irrigating
12
7
Blueberries
2
2
1,000
Scouting
and
irrigating
3
0
Brussel
Sprouts
and
Cauliflower
1
1
5,000
Topping,
irrigating,
hand
harvesting,
and
tying.
9
4
4,000
Scouting
and
irrigating
7
2
Corn
1.5
1.5
17,000
Detassling
21
17
1,000
Scouting
and
irrigating
1
0
Cucumber,
Melons,
Pumpkin,
Squash,
Beans,
Peas,
Celery,

Lettuce,
Spinach,
and
Carrots.
1
1
2,500
Hand
harvesting,
pruning,
thinning,
turning,
and
leaf
pulling
4
0
Alfalfa,
Barley
,
Clover,
Oats,
Rye,
Wheat,
White
Potatoes,

Cucumber,
Melon,
Pumpkin,
Squash,
Bean,
Peas,
Celery,

Lettuce,
and
Spinach.
1
1
1,500
Scouting
and
irrigating
0
0
Carrots
1
1
300
Scouting
and
irrigating
0
0
Pepper,
Eggplant,
and
Tomato
1
1
1,000
Hand
harvesting,
staking,
tying,
pruning,
thinning,

and
training.
0
0
700
Scouting
and
irrigating
0
0
Pineapple
2
2
1000
Hand
harvesting
3
0
Cropa
Maximum
Label
Application
Rate
(
lbs
ai/
acre)
d
Transfer
Coefficiente
(
cm2/
hr)
Activityf
Day
after
Application
When
MOE
$
100g
WPb
ECc
WPb
ECc
70
500
Scouting
and
irrigating
0
0
Strawberry
2
2
1,500
Hand
harvesting,
pinching,
pruning,
and
training.
5
0
400
Scouting
and
irrigating
0
0
Cotton,
Collard
Greens,
Kale,
Mustard
Greens,
Sweet
Potato,
Radish,
Rutabaga,
and
Turnip.
2
2
2500
Hand
harvesting,
pruning,
and
thinning.
9
3
Cotton,
Collard
Greens,
Kale,
Mustard
Greens
and
Sweet
Potato.
2
2
1,500
Scouting
and
irrigating
5
0
Radish,
Rutabaga,
and
Turnip.
2
2
300
Scouting
and
irrigating
0
0
Tobacco
1.5
1
2,000
Hand
harvesting,
pruning,
striping,
thinning,

topping,
and
hand
weeding
5
0
1,300
Scouting
and
irrigating
2
0
Footnotes:

Day
0
=
day
of
application
after
sprays
have
dried
(
12
hours).

a
Crops
were
grouped
according
to
similar
application
rates,
transfer
coefficients,
and
surrogate
DFR
data
sources.

b
WP
=
wettable
powder
formulation
c
EC
=
emulsifiable
concentrate
formulation
d
maximum
application
rates
as
stated
on
current
endosulfan
labels.

e
Transfer
Coefficients
from
Science
Advisory
Council
on
Exposure
Policy
3.1
f
Activities
are
from
Science
Advisory
Council
on
Exposure
Policy
3.1.
Each
activity
many
not
occur
for
every
crop
listed
in
group.

g
Day
after
application
when
the
calculated
MOE
is
greater
than
the
target
MOE
of
100.