UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
Office
of
Prevention,
Pesticides
and
Toxic
Substances
TXR#:
0050926
November
6,
2002
MEMORANDUM
SUBJECT:
Molinate
­
Review
of
60­
Day
Comments
and
Revised
Human
Health
Risk
Assessment
DP
Barcode:
D286216
Submission:
S618724
PC
Code:
041402
FROM:
Virginia
A.
Dobozy,
VMD,
MPH,
Veterinary
Medical
Officer
Reregistration
Branch
I,
Health
Effects
Division
(
7509C)

THROUGH:
Whang
Phang,
PhD,
Branch
Senior
Scientist
Reregistration
Branch
I,
Health
Effects
Division
(
7509C)

TO:
Robert
McNally/
Wilhelmena
Livingston
Special
Review
and
Reregistration
Branch
(
7508C)

Action
Requested:
Review
comments
received
as
a
result
of
the
Molinate
60­
day
comment
period
for
the
preliminary
risk
assessment
dated
January
9,
2001.

Recommendation:
RRB1
has
considered
comments
from
the
following:
Syngenta
Crop
Protection,
USA
Rice
Federation,
California
Rice
Commission
and
the
Pesticide
Action
Network.
The
comments
are
summarized
with
RRB1'
s
response
in
the
attached
document.
The
attached
Human
Health
Risk
Assessment
has
been
revised
as
follows:
1)
the
product
chemistry
data
gaps
have
been
deleted,
except
for
the
studies
on
stability
to
metals
and
metal
ions
(
GLN
830.6313)
and
UV/
visible
absorption
(
GLN
830.7050);
2)
the
irrigation
crop
study
has
been
waived;
3)
molinate
metabolites
to
be
included
in
water
monitoring
study
have
been
revised
based
on
EFED
Memorandum
(
D284308);
4)
the
section
concerning
taste
and
odor
issues
between
Sacramento
and
West
Sacramento
in
4.2.2
Water
Exposure
has
been
deleted
based
on
EFED
data;
5)
comments
concerning
inhalation
exposure
of
California
residents
to
molinate
have
been
addressed
in
4.4
Residential
Exposure;
and
6)
editorial
corrections
have
been
made.
2
Comments
Submitted
and
RRB1'
s
Response
1)
Syngenta
Crop
Protection
­
"
60­
Day
Response
to
Draft
Reregistration
Eligibility
Decision
(
RED)
for
Molinate
dated
June
3,
2002"

Some
of
the
comments
are
technical
error
corrections
while
others
are
challenges
involving
scientific
interpretation
of
data.
The
registrant
states
that
the
company
reserves
the
right
to
comment
on
the
document
titled
"
Molinate
­
review
of
the
Registrant's
Response
to
the
Assessment
of
Molinate
by
the
Mechanism
of
Toxicity
SARC"
dated
January
6,
2002
because
it
was
placed
in
the
docket
only
shortly
before
the
comment
period
expiration.

Toxicology
and
Report
of
the
FQPA
Safety
Factor
Committee
Most
of
the
comments
deal
with
the
mechanism
of
reproductive
toxicity
and
HED's
interpretation
of
increased
sensitivity
of
offspring
in
the
rat
developmental
and
developmental
neurotoxicity
studies.
Syngenta
requests
that
the
wording
indicating
molinate
is
a
reproductive
toxicant
be
changed
to
state
that
molinate
is
a
reproductive
toxicant
in
rats
and
that
humans
have
been
shown
to
be
less
sensitive.
Mechanism
of
action
data
were
reviewed
by
the
Mechanism
of
Toxicity
Science
Assessment
Review
Committee
on
January
13,
2000.
The
registrant
responded
in
a
March
10,
2000
submission
(
D266145;
TXR
#
0050457).
RRB1'
s
review
of
this
submission
concluded
that
the
available
data
do
not
provide
sufficient
evidence
that
reproductive
effects
observed
in
the
rodent
are
not
relevant
to
humans.

RRB1'
s
Response:
RRB1
has
considered
similar
proposed
language
revisions
regarding
reproductive
toxicity
from
the
California
Rice
Commission
(
CRC)
(
D278226;
TXR
#
0050244).
It
was
concluded
that
the
suggested
revisions
were
not
supported
by
currently
available
data.

Food
Exposure
The
one
food
exposure
comment
requests
waivers
of
the
multi­
residue
method
testing
for
metabolites
molinate
acid
and
4­
hydroxy
molinate
and
from
the
irrigation
crop
study
which
measures
sulfoxide
and
sulfone.

RRB1
Response:
A
separate
Memorandum
from
Christine
Olinger
to
Wilhelmena
Livingston
dated
September
5,
2002
(
D284879),
with
addendum
dated
November
6,
2002,
addresses
this
waiver
request.
RRB1
recommended
that
a
waiver
be
granted
for
the
irrigation
crop
study
only.

Exposure
Assessment
­
Epidemiology
Data
Syngenta
believes
EPA
misinterpreted
several
points
from
the
epidemiology
study,
including
conclusions
about
decrease
in
observed
vs.
expected
number
of
children
at
parity
3
and
4+,
participation
rate,
exposure
timing
and
variability,
within­
worker
variability,
confidence
interval,
chronic
low
level
exposure,
confounders
and
study
power.
3
RRB1'
s
Response:
HED
has
reviewed
three
separate
submissions
on
this
study.
Each
one
has
been
an
attempt
to
upgrade
the
study
and
address
deficiencies.
No
additional
data
have
been
submitted
with
these
comments
that
would
alter
HED's
conclusions
about
the
study.

Dietary
Exposure
­
Risk
Analysis
Syngenta
prepared
acute
and
chronic
dietary
and
aggregate
risk
assessments
using
the
following
deviations
from
the
HED
risk
assessment:

°
revised
percentage
crop
treated
(
31.4%
for
both
chronic
and
acute
dietary
exposure
as
compared
to
HED's
values
of
40%
for
chronic
and
54%
for
acute
exposures).
The
percent
crop
treated
was
calculated
from
the
1999­
2001
Doane
data
for
total
base
acres
of
rice
treated
at
least
once
with
molinate
divided
by
total
acres
grown.

°
used
DEEM
 
version
7.76
vs.
DEEM
 
version
6.76
used
by
HED
The
results
from
chronic,
acute
and
lifetime
exposure
assessments
were
all
<
100%
of
the
RfD
with
the
highest
risk
being
in
non­
nursing
infants
<
1
year,
i.
e.,
24%
and18.9%
of
the
RfD
for
the
acute
and
chronic
dietary
assessments,
respectively.
The
percentage
of
the
PAD
for
acute
and
chronic
dietary
risk
assessments
for
infants
<
1
year
were
55%
and
18%,
respectively.

RRB1'
s
Response:
The
use
of
the
7.76
version
of
DEEM
would
have
no
impact
on
the
dietary
analyses.
The
same
consumption
data
are
used
for
both
the
6.76
and
7.76
versions.

Aggregate
Risk
Assessment
Syngenta
questioned
EPA's
aggregate
risk
assessment
which
was
based
on
worst
case
water
exposure
for
children
(
most
sensitive
group)
and
dietary
(
food)
for
all
infants,
even
though
the
most
sensitive
subgroup
was
non­
nursing
infants.
Syngenta
questions
aggregation
of
exposure
to
two
different
subgroups
(
children
and
infants).
Syngenta
calculated
an
acute
aggregate
exposure
for
food
and
surface
water
of
92.3%
of
the
PAD
for
most
sensitive
subgroups
(
all
infants).
A
chronic
aggregate
exposure
of
molinate
in
food
and
surface
water
of
83.0%
of
the
PAD
was
calculated.

RRB1'
s
Response:
As
explained
in
section
5.0
Aggregate
Risk
Assessment
and
Risk
Characterization,
the
calculations
in
Table
5
for
the
category
"
children"
are
based
on
food
consumption
for
infants
<
1
year.
This
is
a
worst
case
scenario
for
all
children,
regardless
of
age.
4
Toxicology
Chapter
Page
6
­
Dermal
Toxicity
Study
in
Rabbits
should
be
in
rats.
Syngenta
disputes
EPA's
classification
of
this
study
as
unacceptable
because
plasma
and
brain
cholinesterase
(
ChE)
were
not
measured.
Syngenta
argues
that
plasma
ChE
was
measured.
RBC
ChE
was
only
slightly
decreased
(
mean
activity
did
not
exceed
20%).
The
registrant
thinks
the
NOAEL
should
be
10
mg/
kg/
day
based
on
slight
acanthosis
at
25
mg/
kg/
day.

RRB1'
s
Response:
This
comment
was
addressed
in
the
review
of
the
registrant's
30­
day
response
to
the
risk
assessment
(
D265730).
RRB1
acknowledged
that
the
heading
was
an
error;
the
study
was
conducted
in
rats.
Plasma
cholinesterase
measurements
were
conducted;
therefore,
the
basis
for
concluding
that
the
study
was
unacceptable
was
the
lack
of
brain
cholinesterase
measurements.
The
Toxicology
Chapter
will
not
be
revised;
changes
in
the
toxicology
data
will
be
reflected
in
the
risk
assessment.
This
study
was
not
discussed
in
the
body
of
the
risk
assessment
but
Appendix
Table
1
of
the
risk
assessment
will
be
revised
to
indicate
that
the
species
in
the
21­
day
dermal
study
(
MRID
40990601)
was
rats.

Page
7
­
Chronic
Toxicology
in
Dogs
EPA
concluded
that
no
NOAEL
for
neurotoxic
effects
was
observed
based
on
demyelination
of
the
sciatic
nerve
and
several
regions
of
the
spinal
cord.
Syngenta
disagrees
based
on
the
inconsistency
between
findings
in
some
nerves
at
different
levels.
In
addition,
the
finding
of
minimal
demyelination
in
2/
4
dogs
in
the
control
group
raises
questions
about
fixation
and
processing
of
the
tissue.

RRB1'
s
Response:
The
NOAEL/
LOAEL
in
the
Data
Evaluation
Report
(
DER)
were
found
acceptable
by
a
HED
peer
review
committee
[
October
30,
1998
Report
of
the
Hazard
Assessment
Identification
Review
Committee
(
HIARC)].
No
additional
data
have
been
submitted
with
these
comments
that
would
alter
HED's
conclusions
about
the
study.

Page
9
­
Developmental
Study
in
Rats
Syngenta
believes
that
the
NOAEL
is
35
mg/
kg/
day.
EPA
set
the
LOAEL
at
35
mg/
kg/
day
based
on
increased
incidence
of
runting.
Syngenta
thinks
that
occurrence
of
4
runts,
in
the
absence
of
any
effect
on
fetal
weight,
is
incidental
to
treatment.

RRB1'
s
Response:
The
conclusions
of
the
DER
were
found
acceptable
by
HED
peer
review
committees
(
October
30,
1998
Report
of
the
HIARC
and
December
17,
1998
Report
of
the
FQPA
Safety
Factor
Committee).
The
significance
of
runting
was
also
discussed
in
a
review
of
the
registrant's
rebuttal
(
D254376;
April
19,
1999)
and
in
an
October
30,
2001
Review
of
California
Rice
Commission
Submission
(
D27226;
TXR#
0050244).
5
Page
11
­
Reproduction
Study
in
Rats
HED
concluded
that
the
reproduction/
developmental
NOAEL
was
not
attained
based
on
decreased
brain
weight
in
offspring.
Syngenta
thinks
the
reproduction
NOAEL
should
be
10
ppm.
Although
there
was
a
slight
increase
in
the
proportion
of
abnormal
sperm
at
10
ppm,
this
was
not
associated
with
any
effects
on
fertility,
suggesting
there
was
no
reproduction
consequence.
It
is
also
Syngenta's
position
that
the
reproduction
NOAEL
for
females
is
50
ppm.
Although
there
were
changes
in
the
incidence
of
ovarian
lesions
at
this
level,
there
were
no
effects
on
fertility.
Regarding
the
decrease
in
the
absolute
weight
of
offspring
brain
weight,
the
registrant
argues
that
this
change
reflects
the
body
weight
decrease.

RRB1'
s
Response:
The
conclusions
of
the
DER
were
found
acceptable
by
HED
peer
review
committees
(
October
30,
1998
Report
of
the
HIARC
and
December
17,
1998
Report
of
the
FQPA
Safety
Factor
Committee).

Page
14
­
Developmental/
Reproductive
Toxicity
­
Four­
part
Investigative
Study,
Part
4
Syngenta
thinks
the
NOAEL
should
be
0.26
mg/
kg
as
this
was
the
actual
dose.
The
0.2
mg/
kg
dose
used
by
HED
was
the
target
dose.

RRB1'
s
Response:
As
stated
in
the
May
11,
2000
review
of
the
registrant's
30­
day
comments,
RRB1
acknowledges
that
the
actual
dose
was
0.26
mg/
kg/
day.
The
Toxicology
Chapter
will
not
be
revised;
changes
in
the
toxicology
data
will
be
reflected
in
the
risk
assessment.
This
dose
was
used
for
the
intermediate­
term
dermal
risk
assessment.
The
Margins
of
Exposure
(
MOEs)
for
most
of
the
scenarios
were
very
low
and
would
not
be
significantly
altered
if
the
NOAEL
was
0.26
mg/
kg/
day
rather
than
0.2
mg/
kg/
day.

Page
18
­
Neurotoxicity
­
Acute
Delayed
Neurotoxicity
Study
in
Hens
Syngenta
states
that
the
metabolite
molinate
sulfoxide
inhibits
neurotoxic
esterase
(
NTE)
weakly
while
the
parent
does
not.
Many
weak
NTE
inhibitors
do
not
cause
delayed
neuropathy.
The
registrant
cites
a
study
by
Moretto
et
al
(
2001)
that
shows
molinate
is
protective
against
the
onset
of
delayed
neuropathy
for
the
classical
delayed
neurotoxicants
such
as
tri­
ortho
cresyl
phosphate
(
TOCP).
This
study
is
not
listed
with
the
Delayed
Neuropathy
References
at
the
end
of
the
section.

Syngenta
states
that,
in
the
study
in
question,
the
molinate­
treated
hens
did
not
show
the
characteristic
brain
and
spinal
cord
changes
seen
with
TOCP.
TOCP­
treated
hens
had
leg
weakness
and
incoordination,
whereas
no
clinical
signs
were
observed
with
molinate­
treated
hens.

RRB1'
s
Response:
As
stated
in
the
January
9,
2001
Memorandum
with
the
revised
Human
Health
Risk
Assessment
(
D271384),
Dr.
Karl
Jensen,
a
neurotoxicologist
with
EPA's
National
Health
and
Environmental
Effects
Research
Laboratory,
reviewed
the
study
and
concluded
that
6
molinate
produces
delayed
neurotoxicity
in
the
hen.

The
Moretto
et
al
(
2001)
study
was
obtained
and
reviewed.
The
objective
of
the
study
was
to
determine
if
molinate
would
inhibit
or
promote
organophosphate­
induced
delayed
polyneuropathy
(
OPIDP)
in
hens
receiving
di­
n­
butyl
dichlorovinyl
phosphate
(
DBDVP).
Certain
esterase
inhibitors
protect
from
OPIDP
when
given
before
an
effective
dose
of
an
organophosphate
(
OP);
however,
when
given
after
the
OP,
they
cause
exacerbation
of
OPIDP.
Both
initiation
and
protection
from
OPIDP
are
related
to
interaction
with
neurotoxic
esterase
(
NTE).
Inhibition
of
a
phenyl
valerate
esterase
named
M200
has
been
associated
with
promotion.
In
the
study,
hens
were
protected
from
of
DBDVP­
induced
neuropathy
(
1
and
5
mg/
kg
SQ)
by
100
or
180
mg/
kg
molinate
SQ
when
given
prior
to
DBDVP.
A
dose
of
45
mg/
kg
molinate
SQ
offered
only
partial
protection.
When
180
mg/
kg
molinate
SQ
was
given
after
a
0.4
mg/
kg
dose
of
DBDVP,
there
was
an
increased
severity
of
clinical
effects
and
histopathology
in
the
spinal
cord
and
peripheral
nerves.
Lower
doses
of
molinate
did
not
promote
OPIDP
or
else
produced
a
milder
effect.
The
study
authors
concluded
that
protection
of
DBDVP
neuropathy
by
molinate
is
correlated
with
inhibition
of
NTE
whereas
promotion
DBDVP
neuropathy
is
associated
with
>
50%
M200
inhibition.

Hens
were
initially
treated
with
100­
180
mg/
kg
molinate
SQ.
NTE
and
M200
were
irreversibly
inhibited
(>
78%)
in
the
brain
and
peripheral
nerve.
No
clinical
or
morphological
signs
of
neuropathy
developed
in
these
animals.
In
the
hen
study
submitted
to
EPA
(
MRIDs
00133502
and
43136601),
effects
(
axonal
degeneration
in
brain
and
spinal
cord)
were
observed
at
higher
doses
(
LOAEL
=
630
mg/
kg).
The
NOAEL
in
this
study
was
200
mg/
kg.

RRB1
concludes
that
the
findings
of
the
Moretto
et
al
study
do
not
alter
the
conclusion
that
molinate
is
a
delayed
neurotoxicant.

Page
21
­
Developmental
Neurotoxicity
Study
Syngenta
thinks
the
NOAEL
should
be
20
ppm
because
of
the
variability
in
startle
amplitude,
the
parameter
HED
used
to
establish
the
developmental
neurotoxicity
LOAEL
at
this
dose.

RRB1'
s
Response:
The
conclusions
of
the
DER
were
found
acceptable
by
HED
peer
review
committees
(
October
30,
1998
Report
of
the
HIARC
and
December
17,
1998
Report
of
the
FQPA
Safety
Factor
Committee).
The
registrant's
rebuttal
was
also
previously
reviewed
(
D254376;
April
19,
1999)
and
in
the
Review
of
the
CRC's
submission
(
D278226,
TXR
#
0050244).

Occupational
Exposure
Pages
3
and
4
­
Syngenta
points
out
that
the
short
and
intermediate
term
exposure
periods
have
been
changed
since
the
risk
assessment
was
completed.
The
intermediate
term
is
now
30
days
to
several
months.
Since
molinate
exposures
do
not
exceed
30
days
per
year,
Syngenta
thinks
all
7
intermediate­
term
assessments
should
be
removed
from
the
risk
assessment.

RRB1'
s
Response:
The
occupational
exposure
assessment
was
based
on
27
application
days/
year
for
aerial
applicators
of
granular
and
liquid
molinate
from
data
supplied
by
Syngenta
at
the
September
23,
1998
SMART
meeting.
Pilots
making
multiple
applications
treating
a
number
of
farms
and
working
over
the
entire
planting/
early
growth
season
could
be
exposed
over
30
days.
There
was
no
information
on
the
number
of
application
days/
year
for
ground­
based
applications
for
liquid
and
granular
formulations
so
HED
assumed
30
days
per
year.
RRB1
maintains
that
intermediate
exposure
assessments
are
required
for
molinate.

Page
4
­
HED
used
the
oral
LOAEL
of
1.8
mg/
kg/
day
from
the
developmental
neurotoxicity
study.
Both
Syngenta
and
the
California
Department
of
Pesticide
Regulation
interpret
the
dose
of
1.8
mg/
kg/
day
as
the
NOAEL.
Using
the
1.8
mg/
kg/
day
as
the
NOAEL
would
require
a
100­
fold
safety
factor
instead
of
a
300­
fold
safety
factor.
Therefore,
the
risks
for
mixers/
loaders
and
applicators
for
all
but
one
use
pattern
would
be
acceptable.

RRB1'
s
Response:
As
stated
above,
the
conclusions
of
the
DER
which
set
the
LOAEL
at
1.8
mg/
kg/
day
were
reviewed
and
accepted
by
HED
peer
review
committees.

Page
4
­
Syngenta
disagrees
with
the
40%
absorption
rate
used
by
HED.
They
state
that
additional
data
comparing
absorption
in
rat
in
vivo/
in
vitro
and
in
human
in
vitro
indicate
that
a
10%
is
a
realistic
figure
for
absorption
through
the
human
epidermis.
Using
a
10%
value
and
a
NOAEL
of
1.8
mg/
kg/
day
results
in
acceptable
risks
to
pilots
applying
Ordram
15G
or
Ordram
15GM
by
air
as
well
as
acceptable
risk
to
pilots
applying
Ordram
8E
or
Arrosolo
by
air.

RRB1'
s
Response:
Syngenta
has
not
submitted
the
data
they
used
to
calculate
the
10%
absorption
value;
therefore,
RRB1
cannot
comment.

Page
4
­
Syngenta
points
out
that
quantification
of
carcinogenic
risk
is
no
longer
required
RRB1'
s
Response:
The
quantification
of
carcinogenic
risk
was
deleted
from
the
January
9,
2001
Human
Health
Risk
Assessment.

Page
12
­
HED
normalized
the
handler's
exposure
to
mg
ai/
lb
handled
and
used
default
body
weight
and
anticipated
application
rates
for
handlers
to
estimate
a
daily
dose.
Syngenta
believes
that
the
actual
weight
of
workers
in
studies
should
have
been
used
in
the
normalization
process.
The
workers
weighed
substantially
more
than
the
default
70
kg.
Using
the
actual
weights
will
result
in
larger
margins
of
exposure
(
MOE)
for
aerial
mixers/
loaders
handling
both
granular
and
liquid
formulations.

RRB1'
s
Response:
The
March
3,
2000
ORE
assessment
(
D263662)
calculated
short­
and
intermediate­
term
MOEs
using
both
actual
body
weight
from
the
biomonitoring
studies
and
the
default
value
of
70
kg
for
comparison.
Tables
comparing
the
findings
are
on
page
37
and
38
of
8
the
assessment.
While
using
the
actual
weights
did
result
in
larger
MOEs,
they
still
exceeded
HED's
level
of
concern
(
short­
and
intermediate­
term
MOEs
of
300
and
100,
respectively),
except
for
drivers
and
loaders
wearing
carbon
coveralls.
In
addition,
the
actual
mean
weights
of
the
men
in
the
biomonitoring
study
loading
granulars
were
so
large
(
81­
95
kg)
that
they
are
not
representative
of
the
population
doing
this
activity.

Page
13
­
Concerning
three
biological
monitoring
scenarios,
Syngenta
says
the
conclusions
on
page
13
contradict
page
3
and
Tables
12
and
13
regarding
short­
term
MOEs
>
300
and
intermediate­
term
MOE>
100
being
below
the
Agency's
level
of
concern.

RRB1'
s
Response:
Without
some
more
detailed
information
citing
specific
scenarios
in
Tables
12
and
13,
RRB1
cannot
respond
to
the
comment
at
this
time.

General
Comments
°
Syngenta
will
be
phasing
out
Ordram
15G
at
the
end
of
2002;
only
Ordram
15GM
will
be
manufactured
after
that.

°
Ordram
is
no
longer
available
in
50
lb
bags.
Ordram
15G
comes
in
500
and
1200
lb
bulk
bags.
Ordram
15GM
is
available
in
500
and
1500
lb
bags.

°
Liquid
applications
of
Ordram
8E
and
Arrosolo
by
air
are
prohibited
in
CA.
The
only
use
for
liquid
formulations
in
CA
is
via
chemigation.

°
It
is
now
rare
for
aerial
applicators
to
use
flaggers.
Therefore,
Syngenta
thinks
the
flagger
exposures
should
be
removed
from
the
risk
assessment.

RRB1'
s
Response:
As
long
as
products
are
currently
registered,
they
will
be
included
in
the
risk
asssessment.
RRB1
acknowledges
that
Global
Positioning
Systems
(
GPS)
are
commonly
used
for
aerial
application;
however,
flaggers
are
still
used
in
some
locations.

MARC
Memorandum
on
Water
Degradates
(
November
3,
2000)

The
MARC
concluded
that
all
degradates
with
an
intact
thiocarbamate
moiety
should
be
included
in
the
drinking
water
risk
assessment.
Syngenta
argues
that
molinate
sulfone
has
not
been
found
in
any
of
the
soil
or
water
metabolism
studies.
It
is
also
unstable
and
therefore
not
appropriate
for
monitoring.
Syngenta
assumes
that
the
reference
to
the
2­
hydroxy
molinate
is
the
side
chain
hydroxy
degradate
identified
in
the
anerobic
aquatic
metabolism
study.
This
degradate
was
only
found
at
very
low
levels
and
only
detected
at
three
time
points
in
the
study.
It
is
a
transition
product
and
undergoes
oxidation
to
form
molinate
acid
which
is
found
at
higher
levels.
In
any
surface
water
monitoring,
Syngenta
proposes
monitoring
for
molinate
sulfoxide,
3­
keto
and
4­
keto
molinate,
3­
hydroxy
and
4­
hydroxy
molinate,
molinate
acid
and
S­
ethyl­
5­
carboxypentyl
thiocarbamate.
9
RRB1'
s
Response:
These
comments
were
addressed
in
the
October
7,
2002
Memorandum
(
D284308)
from
James
Breithaupt,
Environmental
Fate
and
Effects
Division
(
EFED).
EFED
agrees
that
monitoring
for
minor
metabolites
or
unstable
transition
products
will
not
provide
useful
information
on
the
extent
of
exposure
to
total
toxic
molinate
residues
in
drinking
water.
It
would
be
more
productive
to
focus
on
residues
of
molinate
sulfoxide,
3­
and
4­
keto
molinate,
3­
and
4­
hydroxy
molinate,
molinate
acid
(
carboxymethyl
molinate),
and
S­
ethyl­
5­
carboxypentyl
thiocarbamate
in
drinking
water.

Mechanism
of
Toxicity
SARC
Report
These
arguments
will
be
considered
when
the
registrant
submits
comments
on
the
January
6,
2002
HED
review
titled
"
Molinate
­
review
of
the
Registrant's
Response
to
the
Assessment
of
Molinate
by
the
Mechanism
of
Toxicity
SARC".

Revised
Drinking
Water
Assessment
EPA
recommended
that
Syngenta
collects
monitoring
data
for
the
parent
and
all
residues
in
the
tolerance
at
locations
with
estimated
concentrations
that
are
similar
to
Drinking
Water
Level
of
Comparisons.
Syngenta
agrees
to
collect
monitoring
data
from
water
treatment
plants
measuring
the
metabolites
proposed
under
the
MARC
section
of
this
review.
However,
they
reserve
the
right
to
not
conduct
the
studies
if
the
toxicology
endpoints
change
so
that
the
need
to
conduct
the
study
is
negated.

RRB1'
s
Response:
The
toxicology
endpoints
have
not
changed.
The
October
7,
2002
Memorandum
(
D284308)
from
James
Breithaupt,
EFED,
recommends
that
a
monitoring
protocol
be
developed
and
submitted
to
the
Agency
prior
to
initiation.
EFED
also
recommends
that
any
monitoring
protocol
be
submitted
to
the
appropriate
personnel
at
Sacramento
and
West
Sacramento
for
their
comment.

Product
and
Residue
Chemistry
A
separate
Memorandum
from
Christine
Olinger
to
Wilhelmena
Livingston
dated
September
5,
2002
(
D284879),
with
addendum
dated
November
6,
2002,
addresses
the
product
and
residue
chemistry
comments.
All
of
the
outstanding
product
chemistry
requirements
have
been
satisfied,
except
for
the
studies
on
stability
to
metals
and
metal
ions
(
GLN
830.6313)
and
UV/
visible
absorption
(
GLN
830.7050).

2)
USA
Rice
Federation
This
submission
contains
the
following
papers
which
has
been
previously
submitted
under
DP
Barcode
D266985:

°
Analysis
of
Carcinogenic
Potential
of
Molinate
dated
May
31,
2000
10
°
Molinate
Does
Not
Cause
Delayed
Neurotoxicity
dated
May
31,
2000
Also
included
is
a
previously
submitted
paper
on
worker
risk
and
one
on
environmental
fate
and
effects
of
molinate
in
the
rice
belt.

RRB1'
s
Response:
These
papers
were
considered
when
comparing
the
HED
and
California
EPA
risk
assessments
(
D272593;
February
7,
2001)
and
in
revising
the
Human
Health
Risk
Assessment
(
January
9,
2001).

3)
CA
Rice
Commission
(
CRC)
dated
May
31,
2002
Developmental
Toxicity
The
CRC
makes
some
of
the
same
arguments
as
the
registrant,
including:
1)
the
NOAEL
in
the
rat
developmental
study
should
be
35
mg/
kg/
day,
not
2.2
mg/
kg/
day;
2)
in
the
developmental
neurotoxicity
study,
the
changes
in
brain
morphometrics
and
decreased
startle
response
at
6.9
mg/
kg/
day
in
pups
are
transient
and
unlikely
to
be
of
biological
significance
(
HED
concluded
that
the
LOAEL
was
1.8
mg/
kg/
day
based
on
changes
in
startle
response);
3)
in
the
developmental
neurotoxicity
study,
it
cannot
be
concluded
that
offspring
are
more
susceptible
than
dams
because
the
two
were
not
compared
using
the
same
endpoints
(
i.
e.,
startle
amplitude
and
brain
morphometrics).

Toxicology
Paper
­
"
Comments
on
Selected
Toxicology
Issues
Relating
to
the
U.
S.
EPA's
Reregistration
Eligibility
Evaluation
of
Molinate",
dated
May
19,
2000.

Review
of
Developmental
and
Reproduction
Studies
­
CRC
has
submitted
their
rebuttals
to
HED's
conclusions
on
various
developmental
and
reproduction
studies.

Other
Reviews
­
"
Further
Comments
on
Reproduction
Toxicity
of
Molinate",
dated
May
25,
2002,
includes
detailed
reviews
of
multiple
studies
prepared
by
Dr.
Chris
Wilkinson
of
Jellinek,
Schwartz
&
Connolly,
Inc.
Dr.
Wilkinson's
arguments
on
the
following
are
identical
to
those
of
the
registrant:
endpoints
of
the
developmental
studies
and
the
developmental
neurotoxicity
study;
the
lack
of
a
need
for
a
10x
FQPA
Safety
Factor;
rodent­
specific
reproductive
toxicity
;
and
a
mechanism
of
reproductive
toxicity
in
rodents
that
is
consonant
with
the
current
state
of
science.

"
Comments
on
the
Reproductive
Toxicity
of
Molinate",
dated
November
5,
2000,
was
also
prepared
by
Dr.
Wilkinson.

Literature
Articles­
Included
are
two
literature
articles
on
the
mechanism
of
molinate's
reproductive
toxicity
which
were
previously
reviewed
by
HED
along
with
a
manuscript
prepared
for
publication.

Summary
of
Research
Projects
­
A
summary
of
the
projects
sponsored
by
the
CRC
1995
through
11
2000
is
submitted.

Benefits
Information
­
Information
on
benefits
of
molinate
to
US
and
CA
rice
production
is
submitted.

RRB1'
s
Response:
All
of
the
above,
except
for
the
paper
titled
"
Further
Comments
on
Reproduction
Toxicity
of
Molinate",
May
25,
2002,
have
been
previously
submitted
and
considered
by
RRB1.
OPP
is
awaiting
the
results
of
a
mechanistic
study
in
primates
conducted
by
Dr.
Marion
Miller
and
supported
by
the
CRC.
The
mechanism
of
reproductive
toxicity
and
the
relevance
to
humans
will
be
reevaluated
based
on
the
data
from
this
study.

4)
Pesticide
Action
Network
The
Pesticide
Action
Network
submitted
comments
concerning
the
failure
to
consider
exposure
to
molinate
via
inhalation.
These
comments
have
been
considered
in
a
separate
Memorandum
from
Jeff
Dawson
to
Wilhelmena
Livingston
dated
August
22,
2002
(
D284305).
HUMAN
HEALTH
RISK
ASSESSMENT
Molinate
U.
S.
Enviro
nmental
Protection
Agency
Office
of
Pesticide
Programs
Health
Effects
Division
(
7509C)
Virginia
A.
Dobozy,
VMD,
MPH,
Risk
Assessor
Revision
Date:
November
6,
2002
2
TABLE
OF
CONTENTS
1.0
Executive
Summary
4
2.0
Physical/
Chemical
Properties
Characterization
8
3.0
Hazard
Characterization
3.1
Hazard
Profile
9
3.2
FQPA
Considerations
11
3.3
Dose
Response
Assessment
and
Hazard
Endpoint
Selection
12
4.0
Exposure
Assessment
4.1
Summary
of
Registered
Uses
15
4.2
Dietary
Exposure
4.2.1
Food
Exposure
15
4.2.2.
Water
Exposure
18
4.3
Occupational
Exposure
4.3.1
Handler
26
4.3.2
Postapplication
31
4.4
Residential
Exposure
31
4.5
Epidemiology
Data
32
4.6
Incident
Data
35
5.0
Aggregate
Risk
Assessment
and
Risk
Characterization
37
6.0
Data
Needs
40
3
APPENDIX
Table
1:
Toxicology
Profile
of
Molinate
42
Table
2:
Exposure
and
Risk
Assessment
for
Workers
Loading
Granulars
into
Airplane
Hoppers
from
Biomonitoring
Study
48
Table
3:
Exposure
and
Risk
Assessment
for
Workers
Loading
Liquids
into
Airplane
Hoppers
from
Biomonitoring
Study
49
Table
4:
Numerical
Inputs
from
PHED
Version
1.1
Used
for
Molinate
Handler
Exposure
Assessment
51
Table
5:
Non­
cancer
Risks
For
Occupational
Molinate
Handlers
at
Baseline
Clothing
Scenario
(
Unit
Exposures
from
PHED)
54
Table
6:
Non­
cancer
Risks
For
Occupational
Molinate
Handlers
Using
Additional
Protective
Clothing
and
PPE
to
Mitigate
Exposures
(
Unit
Exposures
from
PHED)
56
Table
7:
Non­
cancer
Risks
For
Occupational
Molinate
Handlers
Using
Engineering
Controls
to
Mitigate
Exposures
(
Unit
Exposures
from
PHED
58
4
1.0
EXECUTIVE
SUMMARY
The
Health
Effects
Division
(
HED)
of
EPA's
Office
of
Pesticide
Programs
has
evaluated
the
molinate
data
base
and
conducted
a
human
health
risk
assessment
for
the
reregistration
of
the
chemical.
Molinate
is
a
list
B
reregistration
chemical.
It
was
the
subject
of
a
Phase
4
Review
dated
February
21,
1991.
Risk
reduction
mitigation
occurred
in
1996
because
of
concern
about
the
health
risks
of
workers
exposed
to
molinate.
Beginning
with
the
1997
growing
season,
the
use
of
activated
carbon
impregnated
body
suits
was
required.
In
addition,
the
amount
of
emulsifiable
concentrate
used
by
workers
in
a
single
growing
season
was
restricted.

Molinate
(
s­
ethyl
hexahydro­
1H­
azepine­
1­
carbothiate)
is
a
herbicide
registered
for
use
primarily
for
the
control
of
watergrass
in
rice.
Rice
is
grown
in
California
and
the
south
central/
south
eastern
states
of
Arkansas,
Louisiana,
Missouri,
Texas
and
Tennessee.
There
are
four
active
enduse
products
(
EPs)
with
food/
feed
uses
registered
to
Zeneca
Ag
Products
under
the
trade
names
Ordram
®
or
Arrosolo
®
(
combination
of
molinate
and
propanil).
Emulsifiable
concentrate
(
33.1%­
90.9%
a.
i.)
and
granular
(
15%
a.
i.)
formulations
may
be
applied
to
rice
preemergence
and/
or
postemergence
using
ground
and
aerial
equipment.
Another
registrant,
RICECO,
recently
registered
a
molinate
technical
and
two
end­
use
products,
a
granular
(
15%
a.
i.)
and
an
emulsifiable
concentrate
(
combination
of
molinate
and
propanil)
formulation.

Tolerances
are
presently
established
(
40
CFR
§
180.228)
for
residues
of
molinate
per
se
in/
on
rice
and
rice
straw
each
at
0.1
ppm.
However,
HED
is
recommending
that
the
tolerances
for
residues
in/
on
rice
grain
be
increased
to
0.75
ppm.
The
tolerances
for
residues
in/
on
rice
straw
should
be
increased
to
7.0
ppm.
Tolerances
for
hulls
and
bran
processed
from
molinate­
treated
rice
grain
should
be
3.0
and
2.0
ppm,
respectively.
HED
is
also
recommending
that
residues
to
be
regulated
in
plants
include
molinate
and
its
metabolites
4­
hydroxy
molinate
and
molinate
acid.
Residues
of
molinate
and
its
metabolites
of
concern
are
not
expected
to
transfer
to
edible
livestock
commodities
at
the
maximum
dietary
burden
based
on
current
uses.

Molinate
is
a
thiocarbamate.
In
general,
thiocarbamates
are
less
potent
cholinesterase
(
ChE)
inhibitors
than
other
carbamates.
Multiple
studies
in
various
species
indicate
that
molinate
produces
ChE
inhibition
(
plasma,
red
blood
cell
and
brain)
via
multiple
routes
of
exposure.
Molinate
also
inhibits
neurotoxic
esterase
(
NTE)
and
is
positive
for
delayed
neurotoxicity
in
the
hen.
The
findings
in
multiple
studies
demonstrate
that
molinate
is
a
neurotoxin
after
single
and
multiple
doses
via
the
oral,
dermal
and
inhalation
routes
of
exposure
and
across
species
(
rat,
dog,
mouse).
In
neurotoxicity
studies
of
varying
durations,
clinical
signs
indicative
of
nervous
system
effects,
ChE
and
NTE
inhibition
and
neuropathology
were
observed.
In
the
subchronic
neurotoxicity
study,
the
Lowest
Observed
Adverse
Effect
Level
(
LOAEL)
was
4.0
mg/
kg/
day
in
males
and
4.5
mg/
kg/
day
in
females
based
on
decreased
red
blood
cell
and
brain
cholinesterase
and
neurotoxic
esterase
in
both
sexes;
a
No
Observed
Adverse
Effect
Level
(
NOAEL)
was
not
established.

In
the
developmental
neurotoxicity
study,
pups
born
to
molinate­
treated
dams
exhibited
5
treatment­
related
functional
and
anatomical
nervous
system
effects.
Evidence
of
reproductive
toxicity
was
found
in
studies
in
rats,
mice,
rabbits
and
dogs;
however,
the
male
rat
appeared
to
be
the
most
sensitive
species/
sex.
A
wide
range
of
male
reproductive
parameters
have
been
altered
adversely
in
the
studies
with
both
oral
and
inhalation
exposures,
including
testes
weight,
sperm
number
and
morphology,
fertility
and
testicular
histopathology.
Reproduction
studies
in
both
rats
and
mice
demonstrated
treatment­
related
effects
on
fertility
and
gestation.
In
a
special
five­
week
fertility
study,
a
dose
of
0.5
mg/
kg/
day
in
males
produced
adverse
effects
on
sperm
parameters;
a
NOAEL
was
not
established.
There
was
also
evidence
that
molinate
causes
increased
sensitivity
to
offspring
following
prenatal
exposure
in
rats.

Special
mechanistic
studies
have
been
conducted
to
demonstrate
a
proposed
mechanism
of
toxicity
for
the
male
reproductive
effects.
The
registrant
position's
is
that
the
reproductive
effects
of
molinate
require
the
production
of
molinate
sulfoxide
and
the
dependence
of
the
enzyme
cholesterol
ester
hydrolase
for
steroid
sex
hormone
production.
The
registrant
also
concludes
this
mechanism
is
specific
to
rodents
and
not
relevant
to
humans.
The
currently
available
mechanistic
studies
have
been
reviewed
by
the
HED
Mechanism
of
Toxicity
Assessment
Review
Committee,
which
concluded
that
the
data
are
not
adequate
to
demonstrate
the
proposed
mechanism.
Some
of
the
reasons
for
this
conclusion
include
the
following:
lack
of
concordance
between
dose
levels
where
effects
on
testosterone
and
precursor
hormone
levels
are
observed
and
dose
levels
where
fertility/
sperm
effects
are
observed;
lack
of
data
to
show
that
sulfoxidation
is
occurring
at
the
dose
levels
where
fertility/
sperm
effects
are
observed
in
the
rat;
and
lack
of
data
demonstrating
an
inhibition
of
n­
CEH
in
vivo
at
dose
levels
where
fertility/
sperm
effects
occur.

In
the
rat
combined
chronic
toxicity/
carcinogenicity
study,
there
was
an
increase
in
kidney
tumors
in
males
at
the
high
dose
level.
Molinate
was
reviewed
by
the
HED
Cancer
Assessment
Review
Committee
(
CARC)
on
November
1,
2000,
and
based
on
the
kidney
tumors,
was
classified
as
Suggestive
Evidence
of
Carcinogenicity,
but
Not
Sufficient
to
Assess
Human
Carcinogenic
Potential
using
the
1999
draft
Guidelines
for
Carcinogen
Risk
Assessment.
Dose­
response
assessments
are
not
recommended
for
chemicals
in
this
classification.

Molinate
was
negative
in
a
Salmonella
tymphimurium
assay
and
for
aberrations
in
cultured
human
lymphocytes.
Because
suggestive
increases
were
found
for
mutations,
aberrations,
and
sister
chromatid
exchange
[
SCE]
in
mouse
lymphoma
cells,
and
there
was
conflicting
data
in
two
mouse
micronucleus
assays,
a
dominant
lethal
test
was
requested.
Subsequently,
molinate
was
shown
to
be
negative
in
this
assay.

The
metabolism
data
indicate
that
molinate
is
well
absorbed
and
extensively
metabolized
following
both
oral
and
intravenous
exposure
and
is
rapidly
excreted,
mainly
in
the
urine.
Data
indicate
that
the
metabolism
of
molinate
in
mammals
is
primarily
via
three
routes:
carbon
oxidation,
sulfur
oxidation,
and
thiocarbamate
cleavage.
The
data
also
suggest
that
carbon
oxidation
predominates
at
low
doses
and
sulfur
oxidation
at
high
doses
of
molinate
in
both
rodents
and
humans.
It
is
not
known
at
what
dose
level
the
predominate
pathway
becomes
saturated.
The
only
toxicology
studies
with
any
metabolites
are
mechanistic
studies
conducted
to
6
demonstrate
the
mechanism
of
molinate
toxicity
on
the
male
reproductive
system.
Based
on
a
study
in
the
rat
with
radiolabeled
molinate,
dermal
absorption
was
determined
to
be
40%.

The
10x
FQPA
Safety
Factor
has
been
retained
based
on
the
following:
increased
fetal
susceptibility
observed
in
the
prenatal
developmental
study
in
rats;
increased
fetal
susceptibility
in
the
developmental
neurotoxicity
study
in
rats;
reproductive
effects
in
mice
and
rats;
and
uncertainty
associated
with
the
molinate
surface
water
exposure
in
some
rice­
growing
areas.

The
toxicology
profile
for
molinate
is
presented
in
Table
1
of
the
Appendix.

The
results
of
the
acute
and
chronic
dietary
assessments
showed
that,
for
all
population
subgroups
(
general
population,
females
13­
50,
infants
<
1
year,
children
1­
6
years
and
children
7­
12
years),
risk
estimates
were
below
HED's
level
of
concern
[<
100%
of
the
Population
Adjusted
Dose
(
PAD)].
The
most
highly
exposed
subgroup
was
infants
(<
1
year)
for
both
assessments
consuming
18%
of
the
chronic
PAD
(
cPAD)
and
21%
of
the
acute
PAD
(
aPAD)
at
the
95th
percentile
of
exposure.
Even
at
the
99.9th
percentile,
the
acute
risk
estimate
was
approximately
55%
of
the
aPAD.

Exposure
to
molinate
in
drinking
water
is
based
on
monitoring
data
in
rice­
growing
areas
where
the
chemical
is
used.
Raw
water
data
were
used
for
exposure
to
ground
and
surface
water
for
risk
assessment
purposes.
The
exposure
values
were
increased
by
a
factor
of
1.56
to
account
for
the
lack
of
analyses
for
molinate
metabolites
in
the
monitoring
studies.

Aggregate
risk
assessments
using
percentage
of
the
PAD
calculations
were
quantitated
for
dietary
exposure
to
food
and
water
(
ground
and
surface
water)
for
three
separate
subpopulations
(
adult
males,
adult
females
and
children)
for
acute
and
chronic
exposures.
There
are
no
residential
uses
to
be
considered
in
this
aggregate
assessment.
The
aggregate
risk
assessment
of
acute
exposure
to
food
and
surface
water
in
children
(
110%
of
the
aPAD)
exceeded
HED's
level
of
concern
(>
100%
of
aPAD).
However,
HED
thinks
that
this
assessment
may
overestimate
the
risk
and
that
refinement
of
either
the
food
or
water
exposure
may
bring
the
risks
into
an
acceptable
range.
The
anticipated
residues
in
food
were
based
on
field
trial
residues.
Monitoring
studies
closer
to
the
point
of
consumption
or
cooking
studies
would
refine
exposure.

HED
has
determined
that
there
is
a
potential
for
exposure
from
handling
molinate
products
during
the
application
process
(
i.
e.,
mixer/
loaders,
applicators,
flaggers,
mixer/
loader/
applicators)
and
from
entering
agricultural
areas
previously
treated
with
molinate.
Occupational
postapplication
exposures,
however,
are
expected
to
be
minimal
because
of
the
nature
of
the
activities
associated
with
rice
cultivation
(
e.
g.,
scouting
and
water
management)
and
the
protective
equipment
that
is
commonly
used
during
these
activities
(
e.
g.,
waterproof
rubber
boots
for
walking
through
rice
paddies).
The
exposure
and
risk
for
three
mixer/
loader
scenarios
were
assessed
using
biomonitoring
exposure
data.
The
exposure
and
risk
of
another
eight
scenarios
involving
mixing/
loading,
flagging
and
applying
granular
and
liquid
formulations
using
aerial
and
groundbased
equipment
were
assessed
using
PHED
data.
The
short­
term
and
intermediate­
term
risks
7
were
calculated
using
the
biomonitoring
data.

With
the
PHED
data,
individual
short­
and
intermediate­
term
dermal
and
inhalation
risks
were
calculated
and
then
combined.
HED
determined
that
the
dermal
and
inhalation
exposures
could
be
combined
due
to
the
common
endpoints
for
short­
term
(
neurotoxicity)
and
intermediate­
term
(
reproductive
effects)
exposures.
Assessing
short­
term
and
intermediate­
term
exposure
using
biomonitoring
data,
the
risks
exceeded
the
Agency's
level
of
concern
for
liquid
and
granular
mixer/
loaders
at
the
baseline
level
of
personal
protective
equipment
(
PPE)
and
for
additional
PPE.
Assessing
short­
term
dermal
risks
using
PHED
data,
risks
exceeded
the
Agency's
level
of
concern
for
all
eight
scenarios
at
the
baseline
level
of
personal
PPE
and
for
additional
PPE.
With
engineering
controls,
the
risks
still
exceeded
the
level
of
concern
for
five
of
the
scenarios.
Shortterm
inhalation
risks
using
PHED
data
did
not
exceed
the
level
of
concern
for
the
eight
scenarios
at
the
baseline
level
of
PPE.
When
the
short­
term
dermal
and
inhalation
exposures
and
risks
were
combined,
the
risks
exceeded
the
level
of
concern
for
all
scenarios
at
the
baseline
level
and
when
additional
protective
clothing/
PPE
were
added.
When
engineering
controls
were
added,
the
risks
still
exceeded
the
level
of
concern
for
pilots
applying
granular
and
liquid
formulations
and
for
handlers
mixing/
loading
liquids
for
ground­
based
application
and
applying
liquids
using
groundbased
equipment.

Intermediate­
term
dermal
risks
data
estimated
for
eight
handler
scenarios
using
PHED
data
all
exceeded
the
Agency's
level
of
concern
at
the
baseline
clothing
and
additional
levels
of
PPE.
With
the
addition
of
engineering
controls,
the
risks
of
six
scenarios
still
exceeded
the
level
of
concern.
Intermediate­
term
inhalation
MOEs
all
exceeded
the
level
of
concern
at
the
baseline
PPE
level.
The
addition
of
a
full
face
respirator
resulted
in
intermediate­
term
inhalation
risks
above
the
level
of
concern
for
all
the
scenarios.
Risks
for
pilots
applying
liquids
and
granulars
were
only
assessed
with
engineering
controls;
both
exceeded
the
Agency's
level
of
concern.
When
intermediate­
term
dermal
and
inhalation
risks
were
combined,
the
risks
exceeded
the
Agency's
level
of
concern
for
all
scenarios
at
baseline
and
with
added
protective
clothing/
PPE.
When
engineering
controls
are
added,
the
risks
still
exceed
the
level
of
concern
for
pilots
applying
both
granular
and
liquid
formulations
and
for
handlers
applying
both
granular
and
liquid
formulations
using
ground­
based
equipment
and
for
handlers
mixing/
loading
liquids
for
ground­
based
application.

The
toxicology
data
base
is
adequate,
except
the
21­
day
dermal
toxicity
study
and
the
acute
neurotoxicity
study
were
both
unacceptable
and
not
upgradeable.
Repeating
these
studies
would
complete
the
data
requirements;
however,
the
results
may
not
alter
the
endpoints
and
doses
selected
for
risk
assessment.
Outstanding
residue
chemistry
studies
include
a
multiresidue
method
testing
for
molinate,
4­
hydroxy
molinate
and
molinate
acid.
A
waiver
from
conducting
a
crop
irrigation
study
(
GLN
860.1400)
has
been
granted.
Outstanding
product
chemistry
requirements
are
detailed
in
the
October
28,
1999
Product
and
Residue
Chemistry
Chapter
and
updated
in
a
September
5,
2002
Memorandum,
with
addendum
dated
November
6,
2002,
from
Christine
Olinger
to
Wilhelmena
Livingston
(
D284879).
8
N
S
O
CH
3
N
S
O
CH
3
O
H
N
S
O
OH
O
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
Molinate
[
S­
ethyl
hexahydro­
1H­
azepine­
1­
carbothioate]
is
a
selective
thiocarbamate
herbicide.
The
chemical
name
and
structures
of
molinate
and
its
metabolites
of
concern
are
depicted
in
Figure
A.

Figure
A.
Chemical
names
and
molecular
structures
of
molinate
and
its
metabolites
of
concern
in
plants.

Chemical
Name
Common
Name
Structure
s­
ethyl
hexahydro­
1H­
azepine­
1­
carbothioate
Molinate
s­
ethyl
hexahydro­
4­
hydroxy­
1H­
azepine­
1­
carbothioate
4­
Hydroxy
molinate
s­(
carboxymethyl)­
hexahydro­
1H­
azepine­
1­
carbothioate
Molinate
acid
9
A.
Physical
Properties
of
Molinate
Physical
state:
Liquid
Boiling
point:
136.50C
at
10
torr
Solubility:
soluble
in
water
at
970
mg/
L
at
250C,
miscible
with
acetone,
chlorobenzene,
ethanol,
kerosene,
n­
octanol
and
xylenes
Vapor
pressure:
5.3
X
10­
3mm
Hg
at
250C
Specific
gravity:
1.0663
at
200C
Octanol/
water
partition
coefficient
(
K
ow):
756
at
250C
B.
Other
Identifying
Characteristics
and
Codes
for
Molinate
Empirical
Formula:
C9H17NOS
Molecular
Weight:
187.3
CAS
Registry
No.:
2212­
67­
1
Shaughnessy
No.:
041402
3.0
HAZARD
CHARACTERIZATION
3.1
Hazard
Profile
The
Toxicology
Chapter
of
the
RED
was
prepared
by
Dr.
Linda
Taylor
(
D249717
dated
January
4,
1999).
Molinate
is
a
thiocarbamate.
In
general,
thiocarbamates
are
less
potent
cholinesterase
(
ChE)
inhibitors
than
other
carbamates.
Multiple
studies
in
various
species
indicate
that
molinate
produces
ChE
inhibition
(
plasma,
red
blood
cell
and
brain)
via
multiple
routes
of
exposure.
Molinate
also
inhibits
neurotoxic
esterase
(
NTE)
and
is
positive
for
delayed
neurotoxicity
in
the
hen.
In
addition,
molinate
is
a
reproductive
and
developmental
toxicant
and
a
suggestive
human
carcinogen.

The
toxicological
data
base
on
molinate
is
adequate,
except
the
21­
day
dermal
toxicity
study
and
the
acute
neurotoxicity
study
were
both
unacceptable
and
not
upgradeable.
Repeating
these
studies
would
complete
the
data
requirements;
however,
the
results
may
not
alter
the
endpoints
and
doses
selected
for
risk
assessment.
The
existing
data
base
supports
reregistration
eligibility.
The
quality
of
the
data
from
the
toxicology
studies
is
generally
good;
however,
a
NOAEL
was
not
established
in
several
guideline
studies,
including
the
subchronic
inhalation
study,
21­
day
dermal
toxicity
study
(
systemic
effects),
chronic
dog
study,
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
and
reproduction
study
(
brain
weight
effect).
In
general,
molinate
was
not
acutely
toxic
via
the
oral,
dermal,
and
inhalation
routes
of
exposure
in
the
acute
studies
required
for
labeling.
It
was
a
mild
skin
and
a
moderate
eye
irritant,
but
not
a
dermal
1The
hen
study
(
MRIDs
00133562
and
43136601)
was
evaluated
by
Dr.
Karl
Jensen,
a
neurotoxicologist
at
EPA's
National
Health
and
Environmental
Effects
Research
Laboratory
(
NHEERL).
He
concluded
that
molinate
produces
delayed
neurotoxicity
in
the
hen.

10
sensitizer.
Molinate
produced
delayed
neurotoxicity
in
the
hen
[
axonal
degeneration].
1
Acute
and
subchronic
neurotoxicity
studies
in
the
rat
demonstrated
adverse
effects
of
molinate
on
motor
activity
and
various
functional
observational
battery
[
FOB]
measurements,
in
addition
to
cholinesterase
and
neurotoxic
esterase
[
NTE]
activity
inhibition.
In
the
subchronic
neurotoxicity
study,
the
Lowest
Observed
Adverse
Effect
Level
(
LOAEL)
was
4.0
mg/
kg/
day
in
males
and
4.5
mg/
kg/
day
in
females
based
on
decreased
red
blood
cell
and
brain
cholinesterase
and
neurotoxic
esterase
in
both
sexes;
a
No
Observed
Adverse
Effect
Level
(
NOAEL)
was
not
established.
The
subchronic
and
chronic
toxicity
studies
demonstrated
that
molinate
inhibits
cholinesterase
activity
in
plasma,
red
blood
cell
[
RBC],
and
brain
in
rats,
dogs,
monkeys,
and
rabbits
in
a
doseresponsive
manner.
Clinical
signs
associated
with
cholinesterase
activity
inhibition
were
observed
and
included
ataxia,
tremors,
salivation,
reduced
motor
activity,
splayed/
adducted
hindlimbs,
and
abnormal
gait.

Delayed
fetal
development
was
observed
in
the
rabbit
at
the
same
dose
level
where
maternal
toxicity
was
observed.
In
the
rat,
developmental
toxicity/
developmental
neurotoxicity
were
observed
[
increase
in
runting/
reduction
in
startle
amplitude]
at
dose
levels
below
the
maternal
NOAEL.
Molinate
is
a
reproductive
toxicant,
and
the
rat
is
the
most
sensitive
species
for
this
effect.
Abnormal
sperm,
decreased
percent
motile
sperm,
decreased
sperm
numbers,
decreased
litter
size,
decreased
percentage
of
pups
born
live,
decreased
pup
viability,
increased
incidence
of
microscopic
lesions
in
the
ovary,
testes,
and
adrenal,
delayed
vaginal
opening,
reproductive
organ
weight
effects,
and
decreased
brain
weight
were
consistent
findings
in
studies
in
the
rat.
In
a
special
five­
week
fertility
study,
a
dose
of
0.5
mg/
kg/
day
in
males
produced
adverse
effects
on
sperm
parameters;
a
NOAEL
was
not
established.

It
is
the
registrant's
position
that
the
reproductive
effect
of
molinate
"
requires
the
production
of
molinate
sulfoxide
and
the
dependence
on
the
enzyme
cholesterol
ester
hydrolase
(
CEH)
for
steroid
sex
hormone
production."
Additionally,
the
registrant
concludes
that
the
reproductive
toxicity
in
the
rat
is
induced
by
a
mechanism
that
is
specific
to
rodents.
Special
studies
data
submitted
to
establish
the
proposed
mechanism
of
toxicity
were
reviewed
and
evaluated
by
the
HED
Mechanism
of
Toxicity
Assessment
Review
Committee.
The
Committee
concluded
that
the
submitted
studies
are
not
adequate
to
demonstrate
the
proposed
mechanism
of
toxicity.
The
details
of
the
reasons
for
the
Committee's
conclusions
are
included
in
the
memorandum
of
that
meeting.
Some
of
the
reasons
include
the
following:
lack
of
concordance
between
dose
levels
where
effects
on
testosterone
and
precursor
hormone
levels
are
observed
and
dose
levels
where
fertility/
sperm
effects
are
observed;
lack
of
data
to
show
that
sulfoxidation
is
occurring
at
the
dose
levels
where
fertility/
sperm
effects
are
observed
in
the
rat;
and
lack
of
data
demonstrating
an
inhibition
of
n­
CEH
in
vivo
at
dose
levels
where
fertility/
sperm
effects
occur.

In
the
rat
combined
chronic
toxicity/
carcinogenicity
study,
there
was
an
increase
in
kidney
tumors
11
in
males
at
the
high
dose
level.
Molinate
was
reviewed
by
the
HED
Cancer
Assessment
Review
Committee
on
November
1,
2000
and,
based
on
the
kidney
tumors,
was
classified
as
Suggestive
Evidence
of
Carcinogenicity,
but
Not
Sufficient
to
Assess
Human
Carcinogenic
Potential
using
the
EPA's
1999
draft
Guidelines
for
Carcinogen
Risk
Assessment.
Dose­
response
assessments
are
not
recommended
for
chemicals
in
this
classification.
(
See
December
14,
2000
CARC
report.)

Molinate
was
negative
in
a
Salmonella
tymphimurium
assay
and
for
aberrations
in
cultured
human
lymphocytes.
Because
suggestive
increases
were
found
for
mutations,
aberrations,
and
sister
chromatid
exchange
[
SCE]
in
mouse
lymphoma
cells,
and
there
were
conflicting
data
in
two
mouse
micronucleus
assays,
a
dominant
lethal
test
was
requested.
Subsequently,
molinate
was
shown
to
be
negative
in
this
assay.

The
metabolism
data
indicate
that
molinate
is
well
absorbed
and
extensively
metabolized
following
both
oral
and
intravenous
exposure
and
is
rapidly
excreted,
mainly
in
the
urine.
The
data
also
indicate
that
the
metabolism
of
molinate
involves
s­
oxidation
to
form
the
intermediate
molinate
sulfoxide,
which
is
either
hydrolyzed
to
hexamethyleneimine
or
conjugated
with
glutathione,
ultimately
forming
molinate
mercapturic
acid;
ring
hydroxylation
at
the
3
and
4
positions
followed
by
glucuronide
conjugation
is
also
a
significant
route
of
metabolism.
More
recent
information
indicates
that
the
metabolism
of
molinate
in
mammals
is
primarily
via
three
routes:
carbon
oxidation,
sulfur
oxidation,
and
thiocarbamate
cleavage,
and
the
proportion
of
metabolism
through
each
of
these
pathways
varies
among
the
species,
including
man.
The
data
also
suggests
that
carbon
oxidation
predominates
at
low
doses
of
molinate,
and
this
pathway
saturates
on
increasing
dose.
Then
the
metabolism
switches
to
sulfur
oxidation.
It
is
not
known
at
what
dose
level
the
predominate
pathway
becomes
saturated.
Based
on
a
study
in
the
rat
with
radiolabeled
molinate,
dermal
absorption
was
determined
to
be
40%.

The
toxicology
profile
for
molinate
is
presented
in
Table
1
of
the
Appendix.

3.2
FQPA
Considerations
There
is
evidence
of
neurotoxicity
in
multiple
studies
with
several
species.
Increased
susceptibility
of
offspring
was
observed
in
the
prenatal
developmental
toxicity
study
and
the
developmental
neurotoxicity
study
in
rats.
The
HED
FQPA
Safety
Factor
Committee
evaluated
the
hazard
and
exposure
data
for
molinate
as
the
bases
for
making
a
recommendation
on
the
magnitude
of
the
FQPA
Safety
Factor.
The
FQPA
Safety
Factor
Committee
recommendation
in
the
December
17,
1998
report
of
the
October
30,
1998
meeting
was
that
the
FQPA
Safety
Factor
be
retained
at
10X
for
molinate.
The
rationale
for
the
retention
of
the
10X
is:

$
Increased
susceptibility
observed
in
the
prenatal
developmental
toxicity
study
in
rats.

°
Increased
susceptibility
observed
in
the
developmental
neurotoxicity
study
in
rats.

$
Reproductive
effects
were
seen
in
mice
(
anti­
fertility
study)
and
rats
(
sperm
12
morphology
study)
following
oral
administration
(
although
there
was
no
evidence
of
increased
susceptibility
in
the
2­
generation
reproduction
study).

$
Uncertainty
associated
with
the
lack
of
characterization
for
the
surface
water
monitoring
data
used
for
drinking
water
exposure
assessments.
The
environmental
fate
data
base
indicates
that
the
parent
molinate
is
persistent
and
expected
to
reach
surface
water.
Monitoring
data
are
available,
however
there
is
a
lack
of
characterization
of
the
exposure
levels
for
localities
downstream
of
rice
fields
in
the
Southeast.

The
Committee
determined
that
the
10x
FQPA
safety
factor
is
applicable
for
the
following:

Acute
Dietary
Assessment:
The
Committee
determined
that
the
FQPA
Safety
Factor
should
be
retained
(
10x)
for
acute
dietary
risk
assessment
because
the
increased
susceptibility
was
demonstrated
in
both
the
prenatal
developmental
toxicity
and
developmental
neurotoxicity
studies.

Chronic
Dietary
Assessment:
The
Committee
determined
that
the
FQPA
Safety
Factor
should
be
retained
(
10x)
for
chronic
dietary
risk
assessment
because
of
the
concern
for
the
severe
reproductive
effects
seen
following
repeated
oral
exposures
in
studies
with
rats
and
mice.

For
dietary
risk
assessments,
the
target
exposure
level
above
which
risk
is
considered
to
be
of
concern
is
referred
to
as
the
Population
Adjusted
Dose
(
PAD).
An
acute
PAD
(
aPAD)
and
a
chronic
PAD
(
cPAD)
are
calculated
by
dividing
the
respective
acute
and
chronic
RfDs
(
aRfD
and
cRfD)
by
the
FQPA
Safety
Factor
(
see
Table
2).

3.3
Dose
Response
Assessment
and
Hazard
Endpoint
Selection
On
October
1
and
7,
1998,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicology
database
for
molinate,
re­
assessed
the
existing
reference
dose,
and
selected
the
doses
and
toxicological
endpoints
for
dietary
and
nondietary
exposure
risk
assessments.
Table
1
contains
the
acute
toxicity
endpoints,
which
are
especially
important
for
labeling
purposes.
Table
2
contains
a
summary
of
the
doses
and
endpoints
selected
for
use
in
the
various
human
health
risk
assessments.
13
Table
1:
Acute
Toxicity
of
Molinate
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
870.1100
Acute
Oral
­
rat
40593301
LD50
=
730
mg/
kg
(
679­
785)
Males
=
700
mg/
kg
(
620­
791)
Females
III
81­
2
870.1200
Acute
Dermal
­
rabbit
40593301
LD50
>
2000
mg/
kg
III
81­
3
870.1300
Acute
Inhalation
­
rat
00245675
LC50
=
2.9
mg/
L
(
2.5­
3.3)
Males
=
2.4
mg/
L
(
2.2­
2.6)
Females
IV
81­
4
870.2400
Primary
Eye
Irritation
40593301
moderate
irritant
II
81­
5
870.2500
Primary
Skin
Irritation
00247547
mild
dermal
irritant
IV
81­
6
870.2600
Dermal
Sensitization
40593302
Negative
81­
7
870.6100
Acute
Delayed
Neurotoxicity
(
Hen)
00133562
43136601
NOAEL
=
0.2
g/
kg,
based
on
axonal
degeneration
in
brain
and
cervical
spinal
cord;
delayed
neurotoxicant.
N/
A
81­
8
870.6200
Acute
Neurotoxicity
­
rat
43188001

motor
activity,

time
to
tail
flick;
NTE,
ChE,
GFAP
activities
were
not
assessed
at
appropriate
times
N/
A
Unacceptable
14
Table
2:
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
LOAEL
=
1.8
Developmental
neurotoxic
effect
(
reduction
in
startle
amplitude)
Developmental
Neurotoxicity
UF
=
300
Acute
RfD
=
0.006
mg/
kg
Acute
PAD
=
0.0006
mg/
kg
Chronic
Dietary
non­
carcinogenic
effects
LOAEL=
0.3
Degeneration/
demyelination
in
sciatic
nerve
and
atrophy/
reserve
cell
hyperplasia
of
muscle
Rat
Chronic
Toxicity/
Carcinogenicity
UF=
300
Chronic
RfD
=
0.001
mg/
kg/
day
Chronic
PAD
=
0.0001
mg/
kg/
day
Short­
Term*
(
Dermal)
Oral
LOAEL
=
1.8
Developmental
neurotoxic
effect
(
reduction
in
startle
amplitude)
Developmental
Neurotoxicity
Intermediate­
Term*
(
Dermal)
Oral
NOAEL
=
0.2a
Reproductive
effects
including
decrease
in
following:
%
viable
sperm,
%
motile
sperm,
%
normal
sperm,
sperm
counts,
number
of
implants,
number
of
viable
fetuses;
increase
in
implantation
loss
5­
week
rat
fertility
Long­
Term
(
Dermal
/
Non­
cancer)
None
The
use
pattern
(
1­
2
applications
per
season
to
rice)
does
not
indicate
potential
long­
term
dermal
exposure;
risk
assessment
is
NOT
required.

Short­
Term
(
Inhalation)
NOAEL
=
0.12
mg/
L
Hindleg
muscle
weakness
Acute
inhalation
­
rat
Intermediate­
Term
(
Inhalation)
NOAEL
=
0.0003
mg/
mL
Reproductive
effects
including
decreased
number
of
implants
and
increased
%
of
abnormal
sperm
4­
week
inhalation
­
rat
Long­
Term
(
Inhalation)
None
The
use
pattern
(
1­
2
applications
per
season
to
rice)
does
not
indicate
potential
long­
term
inhalation
exposure;
risk
assessment
is
NOT
required.

*
=
Since
an
oral
LOAEL
was
selected
a
dermal
absorption
factor
of
40%
should
be
used
for
dermal
risk
assessments.
a
Actual
dose
was
0.26
mg/
kg/
day;
0.2
mg/
kg/
day
was
the
target
dose.

NOTE:
For
Short­
term
dermal
risk
assessments,
an
MOE
of
300
is
required
because
a
NOAEL
was
not
achieved
in
the
developmental
neurotoxicity
study;
an
MOE
of
100
is
adequate
for
all
other
exposure
(
dermal
and
inhalation)
risks.
2Two
Zenca
products,
Ordram
6E
and
Ordram
10­
G,
were
recently
canceled
(
Federal
Register,
September
6,
2000,
Volume
67,
Number
173,
page
54113­
54128).
The
cancellation
order
permits
the
registrant
to
continue
to
sell
and
distribute
existing
stocks
of
the
canceled
products
until
January
15,
2001.
Existing
stocks
already
in
the
hands
of
dealers
or
users
can
generally
be
distributed,
sold
or
used
legally
until
they
are
exhausted.

3
Molinate
Use
Closure
Memo
from
Lois
Rossi
to
Margaret
Stasikowski
summarizing
September
23,
1998
SMART
meeting
with
registrant.

15
4.0
EXPOSURE
ASSESSMENT
4.1
Summary
of
Registered
Uses
Molinate
is
currently
registered
for
use
on
rice
for
grass
weed
control,
including
barnyard
grass,
springletop
and
broadleaf
grass,
as
well
as
flatsedge,
dayflower
and
other
small
seed
broadleaf
weeds.
There
are
four
active
end­
use
products
(
EPs)
with
food/
feed
uses
registered
to
Zeneca
Ag
Products
under
the
trade
names
Ordram
®
or
Arrosolo
®
(
combination
of
molinate
and
propanil).
2
Emulsifiable
concentrate
(
33.1%­
90.9%
a.
i.)
and
granular
(
15%
a.
i.)
formulations
may
be
applied
to
rice
preemergence
and/
or
postemergence
using
ground
and
aerial
equipment.
Another
registrant,
RICECO,
recently
registered
a
molinate
technical
and
two
end­
use
products,
a
granular
(
15%
a.
i.)
and
an
emulsifiable
concentrate
(
combination
of
molinate
and
propanil)
formulation.
Molinate
products
can
be
used
at
various
intervals
in
rice
production.
The
maximum
per
season
application
rate
range
is
6
to
9
lbs
a.
i./
acre.
Products
may
be
applied
two
to
three
times
per
growing
season.
3
In
the
southern
states,
usual
planting
times
typically
range
from
early
to
mid
April
through
late
May.
In
California,
most
planting
is
completed
during
May.

4.2
Dietary
Exposure
4.2.1
Food
Exposure
The
Product
and
Residue
Chemistry
Chapter
of
the
RED
was
prepared
by
Christine
Olinger
(
DP
Barcode:
D249755,
dated
October
28,
1999).
The
Acute
and
Chronic
Dietary
Exposure
Risk
Analyses
were
completed
by
Felicia
Fort
(
D262577
dated
February
9,
2000).

Molinate
Residues
Most
residue
chemistry
guideline
studies
have
been
submitted.
All
that
are
necessary
for
dietary
exposure
assessment
are
available.
Tolerances
are
currently
established
for
residues
of
molinate
per
se
(
40
CFR
§
180.228).
The
HED
Metabolism
Committee
(
Memoranda
dated
March
2,
1994
and
April
25,
1994
from
Christine
Olinger)
has
determined
that
the
residues
to
be
regulated
in
plant
commodities
are
molinate
and
the
metabolites
4­
hydroxy
16
molinate
and
molinate
acid.
Therefore,
the
tolerance
definition
in
40
CFR
§
180.228
should
be
amended
to
include
all
residues
to
be
regulated.

Sufficient
data
are
available
to
ascertain
the
adequacy
of
the
established
tolerances
for
molinate
residues
in/
on
rice
grain
and
rice
straw.
The
tolerance
for
residues
in/
on
rice
grain
should
be
increased
to
0.75
ppm
based
on
combined
residues
of
<
0.73
ppm
in/
on
grain
from
field
trials.
The
tolerance
for
residues
in/
on
rice
straw
should
be
increased
to
7.0
ppm
based
on
combined
residues
of
<
6.27
ppm
in/
on
straw
from
field
trials.
Molinate
per
se
was
<
0.05
ppm
(<
LOQ)
in/
on
rice
grain
and
straw
from
all
field
trials.

An
adequate
processing
study
indicated
that
residues
concentrated
in
hulls
and
bran
processed
from
molinate­
treated
rice
grain;
tolerances
of
3.0
and
2.0
ppm,
respectively,
are
required.

The
livestock
metabolism
studies
indicate
that
molinate
residues
of
concern
are
not
present
in
tissues,
milk,
or
eggs
from
animals
dosed
with
molinate
at
levels
greater
than
the
theoretical
maximum
dietary
exposure.
These
diets
are
exaggerated
and
represent
the
maximum
dietary
exposure
assuming
all
rice
is
treated
and
bears
residues
at
the
tolerance
level.
Tolerances
for
molinate
residues
in
livestock
commodities
are
not
required
based
on
current
uses.

Studies
which
are
outstanding
include
multiresidue
method
testing
for
molinate,
4­
hydroxy
molinate,
and
molinate
acid.
A
waiver
from
conducting
a
crop
irrigation
study
(
GLN860.1400)
was
granted
(
September
5,
2002
Memorandum,
D284879).

Anticipated
Residues
In
a
March
31,
1999
Memorandum,
the
Biological
and
Economic
Analysis
Division
provided
information
on
the
percent
of
rice
treated
with
molinate.
Anticipated
residues
for
chronic
and
acute
dietary
exposures
were
generated
based
on
field
trial
data
for
the
raw
agricultural
commodity,
rice
grain.
Anticipated
residues
generated
from
the
grain
are
adjusted
by
a
processing
factor
and
include
the
combined
residues
of
molinate,
4­
hydroxy
molinate,
and
molinate
acid.
USDA
and
FDA
monitoring
data
are
not
available
for
molinate.
Rice
and
its
food
forms
are
all
considered
to
be
blended;
therefore
an
average
residue
was
used
for
both
the
chronic
and
acute
assessments.
Although
an
average
concentration
was
used
for
the
anticipated
residue,
it
is
a
higher
level
than
that
to
which
the
consumer
is
likely
to
be
exposed,
since
the
levels
are
based
on
field
trial
residues.
A
more
refined
value
could
be
estimated
if
the
registrant
were
to
conduct
monitoring
studies
closer
to
the
point
of
consumption
or
if
cooking
studies
were
submitted.
17
Dietary
Risk
Assessment
The
doses
and
endpoints
for
dietary
risk
assessment
selected
by
the
HED
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
were
discussed
previously
and
are
summarized
in
Table
2.

Also
previously
discussed
(
section
3.2),
the
HED
FQPA
Safety
Factor
Committee
determined
that
the
FQPA
Safety
Factor
should
be
retained
(
10x)
for
both
chronic
and
acute
dietary
risk
assessment
for
all
populations
(
B.
Tarplee,
12/
17/
98).

HED
conducts
dietary
risk
assessments
using
the
Dietary
Exposure
Evaluation
Model
(
DEEMTM)
which
incorporates
consumption
data
generated
in
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1989­
1992.
For
acute
dietary
risk
assessments,
one­
day
consumption
data
are
summed
and
a
food
consumption
distribution
is
calculated
for
each
population
subgroup
of
interest.
The
consumption
distribution
was
multiplied
by
a
residue
point
estimate
for
a
deterministic
(
Tier
#
I/
II
type)
exposure/
risk
assessment.
Exposure
estimates
are
expressed
in
mg/
kg
bw/
day
and
as
a
percent
of
the
aPAD.
For
chronic
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/
day
and
as
a
percent
of
the
cPAD.

The
results
of
both
the
chronic
and
acute
exposure
assessments
showed
that
for
all
population
subgroups,
risk
estimates
were
below
HED's
level
of
concern
(<
100%
cPAD
or
aPAD).
The
most
highly
exposed
subgroup
was
infants
(<
1
year)
for
both
assessments
consuming
18%
of
the
cPAD
and
21%
of
the
aPAD
at
the
95th
percentile
of
exposure.
Even
at
the
99.9th
percentile,
the
acute
risk
estimate
was
approximately
55%
of
the
aPAD.
The
dietary
risk
estimates
are
presented
in
Table
3.
18
Table
3.
Dietary
Risk
Estimates
for
Molinate.

Population
Subgroup
Chronic
Acute
(
95th
%
ile)
Acute
(
99.9th
%
ile)

Exposure
%
cPAD
Exposure
%
aPAD
Exposure
%
aPAD
U.
S.
Population
0.000005
5
0.000039
7
0.000186
31
All
Infants
(<
1
years)
0.000018
18
0.000128
21
0.000328
55
Children
(
1­
6
years)
0.000010
10
0.000083
14
0.000249
42
Children
(
7­
12
years)
0.000006
6
0.000049
8
0.000193
32
Females
(
13­
50
years)
0.000004
4
0.000033
6
0.000152
25
aPAD
=
0.0006mg/
kg,
cPAd
=
0.0001
mg/
kg/
day
4.2.2
Water
Exposure
The
Drinking
Water
Assessment
for
molinate
was
prepared
by
James
Breithaupt
of
the
Environmental
Fate
and
Effects
Division
(
EFED)
(
DP
Barcode
D252252
dated
February
16,
1999,
D253406
dated
March
17,
1999,
D254562
dated
April
2,
1999,
D259945
dated
January
13,
2000,
D262859
dated
February
8,
2000
and
D271004
dated
December
7,
2000).
Potential
exposure
to
molinate
in
the
drinking
water
is
limited
to
those
ricegrowing
regions
where
the
chemical
is
used.

To
obtain
both
ground
and
surface
water
concentrations
for
the
purpose
of
risk
assessment,
EFED
received
monitoring
data
from
the
U.
S.
Geological
Survey
(
USGS),
the
State
of
Arkansas
Department
of
Pollution
Control
and
Ecology,
the
City
of
Sacramento,
CA,
the
State
of
California
Department
of
Environmental
Regulation,
and
the
State
of
Texas.
EFED
used
monitoring
data
for
the
drinking
water
assessment
since
the
data
were
available
for
the
areas
where
molinate
was
applied
except
for
Tennessee,
where
only
3,000­
5,000
acres
of
rice
were
grown
in
Lake
County.
EFED
has
conducted
a
stateby
state
regional
assessment
since
molinate
was
applied
only
in
California
and
in
the
south
central/
south
eastern
states
of
Arkansas,
Louisiana,
Missouri,
Texas,
and
Tennessee.
EFED
has
no
official
models
to
generate
estimated
environmental
concentrations
(
EECs)
from
aquatic
crops.

The
effect
of
water
treatment
appears
to
be
an
important
factor
in
removing
molinate
from
finished
water.
EFED
has
reviewed
laboratory
studies
on
the
efficiency
of
parent
molinate
removal
simulating
the
city
of
Sacramento's
water
treatment
process.
If
chlorination
is
the
only
oxidant
chemical
used
in
treatment,
up
to
80%
of
molinate
has
been
shown
to
remain
after
treatment
as
the
metabolite
molinate
sulfoxide,
which
still
has
the
carbamate
functional
group.
Further
degradation
is
likely
to
be
achieved
only
if
more
effective
oxidants
are
used
(
e.
g.,
ozone,
chlorine
dioxide,
KMnO
4).
Potassium
permanganate
(
KMnO
4)
appears
to
be
a
more
effective
oxidant
for
molinate,
since
it
degrades
>
98
%
of
4
Domagalski,
J.
Pesticides
and
Pesticide
Degradation
Products
in
Stormwater
Runoff:
Sacramento
River
Basin,
California,
Water
Resources
Bulletin,
Volume
32,
Issue
5,
October,
1996,
pp.
953­
964
19
parent
molinate
to
a
non­
carbamate
degradate.
However,
since
the
extent
of
use
of
stronger
oxidants
than
chlorine
is
uncertain,
EFED
recommended
using
the
raw
water
concentrations.

Adjustment
of
parent
molinate
concentrations
in
ground
water
and
surface
water
for
molinate
degradates
was
necessary
since
there
was
no
monitoring
for
any
degradates
with
the
exception
of
the
photoproduct
4­
keto
molinate.
At
an
October
31,
2000
meeting,
the
HED
Metabolism
Assessment
Review
Committee
concluded
that
the
following
molinate
metabolites
and
degradation
products
should
be
included
in
the
water
assessment:
molinate
sulfoxide,
molinate
sulfone,
3­
keto
and
4­
keto
molinate,
hydroxy
molinate
(
2,
3,
and
4),
molinate
acid
(
carboxymethyl
molinate),
and
ring­
opened
molinate
(
S­
ethyl­
5­
carboxypentyl
thiocarbamate).
EFED
re­
evaluated
the
molinate
metabolites
to
be
included
in
water
monitoring
studies
and
concluded
that
residues
of
molinate
sulfoxide,
3­
and
4­
keto
molinate,
3­
and
4­
hydroxy
molinate,
molinate
acid
(
carboxymethyl
molinate),
and
Sethyl
5­
carboxypentyl
thiocarbamate
in
drinking
water
should
be
focused
on
in
these
studies
(
D284308
dated
October
7,
2002).

Calculation
of
a
factor
to
account
for
the
lack
of
monitoring
data
on
the
molinate
metabolites/
degradation
products
was
based
on
data
from
laboratory
studies
and
aquatic
field
dissipation
studies
for
dry­
seeded
rice
(
MRID
41421803)
and
water­
seeded
rice
(
MRID
41421804).
The
field
studies
provided
data
on
molinate
acid
and
molinate
sulfoxide
degradates
relative
to
parent.
The
average
percent
of
parent
molinate
was
9.4
%
for
dry­
seeded
rice
and
11
%
for
water­
seeded
rice,
leading
to
adjustment
factors
of
1.094
and
1.11,
respectively.
To
account
for
2­,
3­,
and
4­
hydroxy
molinate,
the
estimated
environmental
concentrations
(
EECs)
were
increased
by
another
14.7
%
(
average
percent
observed
in
an
aerobic
aquatic
metabolism
laboratory
study,
MRID
44956603).
The
use
of
a
laboratory
study
was
necessary
because
no
metabolites
other
than
molinate
acid
and
molinate
sulfoxide
were
analyzed
for
in
the
aquatic
field
dissipation
studies.

EFED
used
a
recent
publication
of
a
study
by
Joseph
Domagalski
to
recommend
increasing
molinate
exposures
by
30%
to
account
for
the
amount
of
4­
keto
molinate.
4
Monitoring
was
conducted
in
the
Sacramento
Basin
below
the
confluence
of
the
Colusa
Drain
and
the
Sacramento
River
to
downstream
of
the
City
of
Sacramento.
The
metabolite
4­
keto
molinate
was
detected
at
10­
30
%
(
one
detection
of
50
%)
of
parent
molinate
in
every
sample
where
molinate
was
detected
in
surface
water
from
storm
water
runoff.
In
the
Southern
region
of
the
U.
S.,
4­
keto
molinate
levels
in
water
of
10­
50
%
of
detected
parent
molinate
have
also
been
observed.

To
adjust
for
all
molinate
metabolites
and
degradates,
EFED
recommended
using
a
1.56
20
adjustment
factor
for
both
California
and
the
Southern
Region
for
both
surface
and
ground
estimates
of
parent
molinate.

Drinking
Water
from
Ground
Water
For
estimates
of
dietary
exposure
from
ground
water
used
as
drinking
water,
EFED
recommended
the
use
of
0.056
ug/
L
for
acute
and
chronic
assessment
for
parent
molinate
and
0.087
ug/
L
for
total
toxic
residues
of
molinate
(
molinate
plus
metabolites).
The
0.056
ug/
L
concentration
was
the
maximum
observed
in
recent
USGS
monitoring
data
from
both
California
and
the
Southern
Region
(
Mississippi
and
Arkansas).
Some
of
the
wells
in
which
detections
were
observed
were
drinking
water
wells.

EFED
did
not
run
the
SCI­
GROW2
ground
water
model
because
it
is
inappropriate
for
rice.
SCI­
GROW2
assumes
vulnerable
soils
with
a
shallow
water
table,
but
rice
fields
require
impermeable
layers
to
hold
the
floodwater.
Also,
SCI­
GROW2
does
not
directly
take
into
account
the
volatility
of
a
given
compound.

Drinking
Water
from
Surface
Water
Table
4
provides
the
estimates
of
drinking
water
exposure
levels
from
parent
molinate
and
the
residues
of
toxic
concern
recommended
by
EFED
for
the
aggregate
risk
assessments.

The
surface
water
intakes
with
the
highest
exposure
are
Sacramento
and
West
Sacramento.
Maximum
concentrations
of
parent
molinate
in
these
areas
ranged
from
1.52­
2.13
ug/
L,
and
the
annual
mean
concentrations
ranged
from
0.29­
0.41
ug/
L.
The
intakes
on
the
Mississippi
and
Atchafalaya
Rivers
in
Louisiana
had
similar
maximum
parent
molinate
concentrations
of
0.109­
0.117
ug/
L
and
annual
mean
concentrations
of
0.014­
0.018
ug/
L.
Arkansas,
Mississippi,
Missouri,
and
Tennessee
have
no
surface
water
intakes
in
rice­
production
areas,
and
therefore
no
exposure
in
drinking
water
from
surface
water.
The
only
intake
in
Texas
found
to
receive
molinate
residues
was
Anahuac.
Maximum
and
annual
mean
concentrations
of
molinate
were
0.073
and
0.0029
ug/
L,
respectively.
21
Table
4.
Monitoring
estimated
environmental
concentrations
(
EECs)
for
parent
molinate
and
residues
of
concern
that
may
be
used
for
acute
and
chronic
risk
assessment
for
molinate+

Location
(
Source
of
Data)

[
Population]
Frequency
of
Detection
(
Range
of
detection
limits)
Parent
Molinate
Adjustment
Factor
for
degradates
of
concern2
Parent
+
degradates
of
concern
(
See
Table
3
below)

Maximum
Concentration
(
ug/
L)
Annual
Means
(
ug/
L)
1
Maximum
Concentration
(
ug/
L)
Annual
Means
(
ug/
L)

Sacramento,
California
(
Upper
95th
percentile
of
parent
molinate
levels
in
raw
water
from
the
Sacramento
River
after
holding
periods
(
1991­
2000
data),
[
374,600
people]
65/
117
(
0.1
ug/
L)
1.52
0.29
1.56
2.37
0.45
West
Sacramento,
California
(
Upper
95th
percentile
of
parent
molinate
levels
in
raw
water
from
the
Sacramento
River
after
holding
periods
(
1991­
2000
data)
adjusted
for
the
percent
flow
data
at
City
of
Sacramento,
[
30,000
people]
3
65/
117
(
0.1
ug/
L)
2.13
0.41
1.56
3.32
0.64
Arkansas,
Mississippi,
Missouri,
and
Tennessee
(
no
surface
water
intakes
in
rice­
production
areas)
Not
Applicable
0
0
1.56
0
0
New
Orleans
Area
(
Upper
95th
percentile
of
parent
molinate
levels
in
raw
water
from
1996­
1999
USGS
data
in
the
Mississippi
River
at
St.

Francisville,
LA),

[
1.21
million
people]
4
13/
58
(
0.004
ug/
L)
0.117
0.014
1.56
0.18
0.022
22
St.
Mary
Parish,
Louisiana
Intakes
at
Atchafalaya
River
(
Upper
95th
percentile
of
parent
molinate
levels
in
raw
water
from
1996­
1999
USGS
data
at
Melville,
LA),
[
61,374
people]
4
15/
57
(
0.004
ug/
L)
0.109
0.018
1.56
0.17
0.028
Lake
Anahuac
in
Texas,
(
from
dilution
calculations)
[
1,960
people]
5
20/
20
(
0.004
ug/
L)
0.073
0.00296
1.56
0.114
0.0057
+
Drinking
water
exposure
estimates
from
surface
water.

1
Time­
weighted
annual
mean
concentrations
were
requested
by
the
Health
Effects
Division.

2
Based
on
a
meeting
between
EFED
and
the
HED
MARC
committee,
EFED
calculated
an
adjustment
factor
of
1.56
for
the
parent
molinate
monitoring
data
to
account
for
degradates
of
concern
(
See
EFED
Chapter).

3
The
City
of
West
Sacramento
gets
all
of
its
water
from
the
Sacramento
River,
while
the
City
of
Sacramento
gets
71.4
%
of
its
water
from
the
Sacramento
River
and
28.6
%

from
the
American
River.
EFED
divided
the
Sacramento
concentrations
by
71.4
%
to
estimate
concentrations
for
West
Sacramento.
Even
though
West
Sacramento
gets
more
molinate
in
their
water,
they
do
not
get
taste
and
odor
complaints.
The
two
cities
are
investigating
this
discrepancy.

4
The
intakes
below
the
USGS
sampling
points
at
St.
Francisville
in
the
Mississippi
River
and
at
Melville
in
the
Atchafalaya
River
are
at
diluted
portions,
and
both
rivers
are
channelized.
There
are
no
significant
downstream
sources
of
water
to
dilute
the
residues
further.
As
a
result,
EFED
expects
concentrations
similar
to
the
estimates
at
these
intakes.
The
annual
means
using
zero
for
non­
detections
for
1996,
1998,
and
1999
were
at
or
below
the
limit
of
detection,
while
the
means
calculated
using
the
limit
of
detection
were
above
the
limit
of
detection,
indicating
high
uncertainty
in
these
estimates
for
these
locations.

5
White's
Bayou
drains
rice
fields
directly
into
Lake
Anahuac,
a
drinking
water
supply
for
1,960
people.
However,
there
are
other
sources
of
water
for
this
intake
and
EFED
does
not
know
the
exact
proportions.
Also,
rice
production
along
White's
Bayou
has
declined
by
approximately
two­
thirds
since
the
year
the
data
were
generated
(
1994).

6
These
estimates
have
additional
uncertainty
because
it
is
below
the
lowest
detection
limit
of
0.004
ug/
L.
23
Assumptions,
Certainties,
Uncertainties,
and
Limitations
1)
Water
Treatment
EFED
assumed
that
drinking
water
facilities
use
only
chlorination
as
an
oxidative
process,
and
therefore
80
%
of
parent
molinate
present
in
raw
water
would
still
be
present
as
molinate
sulfoxide
after
treatment.
Potassium
permanganate
may
be
a
more
effective
oxidant
for
molinate
as
it
degraded
>
98%
of
parent
molinate
to
a
non­
carbamate
degradate
in
laboratory
studies.
However,
the
extent
of
the
use
of
oxidants
rather
than
chlorine
is
unknown.

The
efficiency
of
water
treatment
practices
varies
from
intake
to
intake.
The
studies
dealing
with
water
treatment
were
laboratory
simulations
of
the
water
treatment
practices
at
Sacramento,
California.
Other
intakes
may
have
different
practices
that
may
provide
very
different
removal
efficiencies.
Variables
such
as
spiking
rates
of
oxidants,
size
of
the
distribution
system,
and
storage/
treatment
times
may
provide
different
pesticide
removal
efficiencies.
Therefore,
using
the
results
of
one
intake's
treatment
may
not
be
accurate
for
another
intake.

The
water
treatment
practices
at
the
Mississippi
and
Atchafalaya
River
intakes
was
not
provided
by
the
registrant.
EFED
is
assuming
that
chlorination
is
the
only
oxidative
treatment
at
these
intakes.

2)
Use
of
Monitoring
Data
EFED
is
very
certain
about
the
drinking
water
conclusions
for
California,
Missouri,
Tennessee,
and
Arkansas
for
parent
molinate.
EFED
is
less
certain
about
the
Mississippi
and
Atchafalaya
River
intakes
in
Louisiana
because
of
fewer
years
of
monitoring
data
(
4
years
or
less)
compared
to
California
(
19
years).
EFED
is
uncertain
about
the
extent
of
exposure
at
Anahuac,
Texas,
because
the
amount
of
water
from
other
sources
and
the
number
of
days
that
Lake
Anahuac
receives
rice
drainage
is
unknown.

The
amount
of
the
degradate
4­
keto
molinate
exposure
in
the
use
season
is
uncertain.
The
Domagalski
article
states
that
between
10­
30
%
of
detected
molinate
was
present
in
the
Sacramento
River
in
California.
However,
this
study
was
conducted
in
January,
and
molinate
is
applied
in
May­
June
primarily.

The
use
of
monitoring
data
to
assess
dietary
exposure
creates
uncertainties.
Monitoring
24
data
are
not
available
everywhere
for
all
uses
of
a
given
compound.
In
a
given
year,
it
is
highly
likely
that
peak
concentrations
are
missed
since
sampling
is
not
always
conducted
on
a
daily
schedule
or
over
the
time
necessary
to
detect
peaks.
Also,
peak
concentrations
are
not
likely
to
be
detected
unless
sampling
is
conducted
in
a
stratified
sampling
pattern
in
highly
vulnerable
sites.
Sampling
is
also
not
necessarily
representative
of
the
entire
year
unless
sampling
is
conducted
over
a
year.
Since
monitoring
data
are
dependent
on
the
weather
in
a
particular
year,
data
may
not
always
be
available
for
enough
years
to
cover
the
range
of
weather
in
a
given
area
of
application.
The
associated
information
to
interpret
monitoring
information,
such
as
amount
of
use
and
the
area
treated
in
a
watershed,
the
timing
and
amount
of
rainfall
events
that
drive
runoff
events,
and
specific
cultural
practices
are
not
always
available.
Inclusion
of
data
from
an
area
where
no
pesticide
is
applied
tends
to
bias
estimates
of
exposure
downward
when
considered
with
data
from
use
areas.
In
analyzing
these
data,
efforts
were
made
to
only
include
data
from
areas
where
molinate
was
known
to
have
been
used.

3)
Estimation
of
degradate
concentrations
based
on
field
and
laboratory
studies
Estimation
of
degradate
concentrations
in
surface
water
based
on
laboratory
and
field
studies
introduces
uncertainties
because
levels
of
degradates
relative
to
parent
compound
vary
with
time.
Degradate
concentrations
are
lowest
relative
to
parent
compounds
immediately
following
the
application
and
increase
with
time.
As
a
result,
no
single
adjustment
factor
for
monitoring
data
will
perfectly
represent
the
contribution
of
degradates
to
ecological
and
drinking
water
exposure.
However,
the
1.56
factor
is
an
average
number
will
reasonably
represent
the
contribution
of
degradates
for
both
ecological
and
drinking
water
exposure.
Monitoring
for
all
residues
of
concern
is
the
only
certain
method
to
assess
exposure.

4)
Time­
weighting
of
monitoring
data
Time­
weighting
of
monitoring
to
provide
annual
exposure
data
from
seasonal
data
introduces
uncertainties
because
of
extrapolation
and
censored
data.
Extrapolation
introduces
potential
error
because
a
concentration
represents
a
point
in
time.
Extrapolation
of
high
concentrations
increases
the
estimates.
On
the
other
hand,
extrapolation
of
non­
detections
(
censored
data)
decreases
the
estimates
depending
on
the
level
of
detection
(
LOD).

5)
Uncertainties
of
using
dilution
calculations
25
Dilution
calculations
were
used
to
estimate
dietary
exposure
at
Lake
Anahuac,
Texas.
At
this
location,
White's
Bayou
drains
rice
fields
into
Lake
Anahuac,
which
is
a
drinking
water
source
for
1,960
people.
However,
other
sources
of
water
that
do
not
receive
rice
drainage
are
used
to
supplement
the
lake.
Also,
rice
production
along
White's
Bayou
has
declined
by
approximately
two­
thirds
since
the
year
the
data
were
generated
(
1994).
As
a
result,
the
predicted
EEC's
are
probably
higher
than
actual
exposure.
EFED
has
no
information
on
the
proportion
of
water
from
the
other
source
and
from
rice
fields
and
the
number
of
days
Lake
Anahuac
receives
rice
drainage
so
that
the
estimates
of
drinking
water
concentrations
can
be
refined.

4.3
Occupational
Exposure
The
Occupational/
Residential
Exposure
Assessment
for
the
RED
was
prepared
by
Steven
Weiss
(
DP
Barcode
D249751
dated
December
21,
1999
and
D263662
dated
March
3,
2000).

Molinate
use
on
rice
differs
based
on
cultural
practices
(
e.
g.,
wet
versus
dry
seeding
and
water
management).
Application
parameters
are
generally
defined
by
the
physical
nature
of
the
use
site,
by
the
equipment
required
to
deliver
the
chemical
to
the
use
site,
and
by
the
application
rate
required
to
achieve
efficacy.
Molinate
applications
intended
for
weed
control
in
rice
are
predominantly
made
by
aircraft
(
approximately
90
percent
of
total
applied)
while
the
remaining
applications
are
completed
by
ground­
based
equipment
designed
to
apply
granulars
or
by
typical
groundboom
spray
rigs.
Most
ground­
based
applications
occur
by
pre­
plant/
incorporation.
Information
obtained
at
the
September
1998
SMART
meeting
indicates
molinate
is
apparently
sold
mostly
in
bulk
packaging.
This
is
supported
by
the
fact
that
the
predominant
applicators
are
pilots
who
would
use
larger
quantities
of
molinate
compared
to
a
typical
grower
(
i.
e.,
bulk
packaging
is
easier
to
handle
for
larger
quantity
users).

The
predominant
rice
producing
states
are
Arkansas,
California,
Louisiana,
Mississippi,
Missouri,
and
Texas.
Cropping
time
for
rice
ranges
from
approximately
120
to
140
days.
In
the
southern
states,
usual
planting
times
typically
range
from
early
to
mid
April
through
late
May.
In
California,
most
planting
is
completed
during
May.
Harvest
in
the
southern
states
can
range
from
the
beginning
of
August
through
the
end
of
October.
Likewise,
harvest
in
California
essentially
occurs
throughout
October.
The
occupational
risk
assessment
does
not
differentiate
risks
to
workers
in
the
various
rice­
growing
areas.

4.3.1
Handler
26
HED
has
determined
that
there
is
a
potential
for
exposure
from
handling
molinate
products
during
the
application
process
(
i.
e.,
mixer/
loaders,
applicators,
flaggers,
mixer/
loader/
applicators)
and
from
entering
agricultural
areas
previously
treated
with
molinate.

The
non­
dietary
exposure
database
that
has
been
developed
in
support
of
the
reregistration
of
molinate
is
extensive
when
compared
to
that
for
other
similar
chemicals.
This
database
contains
exposure
monitoring
data
that
have
been
developed
using
both
passive
dosimetry
and
biological
monitoring
techniques.
A
molinate­
specific
epidemiology
assessment
has
also
been
completed
(
discussed
under
4.5).
HED
policy
dictates
that
chemical­
specific
data
be
used
in
conjunction
with
other
sources
of
exposure
data
commonly
used
by
HED
to
complete
risk
assessments
(
e.
g.,
Pesticide
Handlers
Exposure
Database).
As
such,
several
data
sources
were
considered
in
this
assessment
including
the
Pesticide
Handlers
Exposure
Database
(
PHED)
and
the
array
of
molinate­
specific
data
that
have
been
submitted.

HED
anticipates
that
occupational
molinate
exposures
will
only
occur
in
a
short­
term
or
intermediate­
term
pattern.
HED
anticipates
that
occupational
exposures
will
not
be
chronic
because
HED
defines
chronic
exposures
as
use
of
the
chemical
for
approximately
180
days
per
year
and
it
is
anticipated
that
molinate
as
with
other
typical
pesticide
compounds
will
not
be
used
in
this
manner.

In
October
1998,
the
Hazard
Identification
Assessment
and
Review
Committee
(
HIARC)
reassessed
toxicological
endpoints
for
non­
dietary
exposure
to
molinate.
For
details
on
the
dose
and
endpoints
selected
for
risk
assessment,
see
Table
2.
For
short­
term
dermal
risk
assessments,
an
MOE
of
300
is
required
because
a
NOAEL
was
not
achieved
in
the
developmental
neurotoxicity
study;
an
MOE
of
100
is
adequate
for
all
other
exposure
(
dermal
and
inhalation)
risks.

Handler
Risk
Assessment
Assumptions
and
Factors
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
handler
risk
assessment.
The
following
assumptions
and
factors
were
used
to
complete
this
assessment:

°
Average
body
weight
of
an
adult
handler
is
70
kg.
This
body
weight
is
used
in
all
assessments.
27
°
The
number
of
application
days/
year,
the
amount
of
ai/
handled
per
day
by
loaders
and
areas
treated/
day
were
defined
for
each
handler
scenario.

For
aerial
applications,
the
following
assumptions
were
used
and
are
based
on
information
provided
to
the
HED
during
the
SMART
meeting
on
9/
23/
98,
subsequent
conversations
with
Zeneca,
and
the
best
professional
judgement
of
the
HED.

*
aerial
applications
of
granulars:
27
application
days/
year
with
average
of
300
acres
treated
/
day
*
aerial
applications
of
liquids:
27
application
days/
year
with
average
of
300
acres
treated
/
day
*
loading
granulars
for
aerial
applications:
1,680
lb
ai
handled/
day
(
average
in
1993
study
MRID#
431656­
02
was
approximately
900
lb
ai
handled/
day)

*
mixing/
loading
liquids
for
aerial
applications:
900
lb
ai
handled/
day
(
average
in
1996
study
MRID#
442122­
01
was
approximately
300
lb
ai
handled/
day)

No
information
on
the
number
of
application
days/
year
for
ground­
based
applications
was
provided
to
HED.
Therefore,
HED
assumed
that
ground­
based
applications
for
liquid
or
granular
formulations
could
occur
for
30
application
days/
year.

All
short­
term
and
intermediate­
term
handler
calculations
were
completed
at
the
maximum
labeled
application
rate
for
each
scenario.

There
are
three
basic
risk
mitigation
approaches
considered
appropriate
for
controlling
occupational
exposures.
These
include
administrative
controls,
the
use
of
personal
protective
equipment
or
PPE,
and
the
use
of
engineering
controls.
Occupational
handler
exposure
assessments
are
completed
by
HED
using
a
baseline
exposure
scenario
and,
if
required,
increasing
levels
of
risk
mitigation
(
PPE
and
engineering
controls)
to
achieve
an
appropriate
margin
of
exposure
or
cancer
risk.
[
Note:
Administrative
controls
available
generally
involve
altering
application
rates
for
handler
exposure
scenarios.
These
are
typically
not
utilized
for
completing
handler
exposure
assessments
because
of
the
negotiation
requirements
with
registrants.]
The
baseline
clothing/
PPE
ensemble
for
occupational
exposure
scenarios
is
generally
an
individual
wearing
long
pants,
a
longsleeved
shirt,
no
chemical­
resistant
gloves
(
there
are
exceptions
pertaining
to
the
use
of
gloves
and
these
are
noted),
and
no
respirator.
The
first
level
of
mitigation
generally
applied
is
PPE.
This
involves
the
use
of
an
additional
layer
of
clothing,
chemical­
resistant
28
gloves,
and
a
respirator.
The
next
level
of
mitigation
considered
in
the
risk
assessment
process
is
the
use
of
appropriate
engineering
controls
which,
by
design,
attempt
to
eliminate
the
possibility
of
human
exposure.
Examples
of
commonly
used
engineering
controls
include
closed
tractor
cabs,
closed
mixing/
loading/
transfer
systems,
and
watersoluble
packets.

Occupational
Exposure
Patterns
The
anticipated
use
patterns
and
current
labeling
indicate
11
major
occupational
exposure
scenarios.
These
scenarios
include:

(
1)
loading
granulars
for
aerial
applications;
(
2)
truck
drivers
supporting
loading
granulars
for
aerial
applications;
(
3)
pilots
applying
granulars
using
aerial
equipment;
(
4)
flagging
during
aerial
application
of
granulars;
(
5)
mixing/
loading
liquids
for
aerial
applications;
(
6)
pilots
applying
liquids
using
aerial
equipment;
(
7)
flagging
during
aerial
application
of
liquids;
(
8)
loading
granulars
for
ground­
based
applications;
(
9)
applying
granulars
using
ground­
based
equipment;
(
10)
mixing/
loading
liquids
for
ground­
based
applications;
(
11)
applying
liquids
using
ground­
based
equipment
Estimating
Exposure
and
Risk
Using
Biomonitoring
Exposure
Data
Exposure
and
risk
for
the
three
mixer/
loading
scenarios
[(
1)
loading
granulars
for
aerial
applications;
(
2)
truck
drivers
supporting
loading
granulars
for
aerial
applications;
(
5)
mixing/
loading
liquids
for
aerial
applications]
were
evaluated
using
biomonitoring
exposure
data.
Calculations
of
exposure
(
combined
dermal
and
inhalation)
and
risk
were
based
on
the
assumption
that
loaders
of
granulars
are
using
bulk
bags
and
are
wearing
long
sleeve
shirts,
long
pants,
coveralls
(
Tyvek
or
carbon),
and
a
full
face
respirator.
Risks
for
truck
drivers
were
calculated
for
those
wearing
carbon
suits
and
those
wearing
no
suits.
For
loaders
of
liquids
for
aerial
applications,
three
levels
of
PPE
were
evaluated:

Level
1:
Activated
carbon
suit
worn
underneath
"
Kleenguard"
coveralls
Level
2:
"
Kleenguard"
coveralls
worn
over
normal
work
clothing
Level
3:
Normal
work
clothing,
recommended
as
long
sleeved
shirt
and
long
pants
Estimating
Exposure
and
Risk
Using
Unit
Exposures
from
PHED
29
Since
adequate
biomonitoring
data
were
only
usable
for
the
three
scenarios,
the
other
eight
scenarios
[(
3)
pilots
applying
granulars
using
aerial
equipment;
(
4)
flagging
during
aerial
application
of
granulars;
(
6)
pilots
applying
liquids
using
aerial
equipment;
(
7)
flagging
during
aerial
application
of
liquids;
(
8)
loading
granulars
for
ground­
based
applications;
(
9)
applying
granulars
using
ground­
based
equipment;
(
10)
mixing/
loading
liquids
for
ground­
based
applications;
and
(
11)
applying
liquids
using
ground­
based
equipment]
were
evaluated
using
the
unit
exposures
from
the
Pesticide
Surrogate
Exposure
Guide
(
8/
98).

Short­
and
intermediate­
term
risks
were
calculated
for
dermal,
inhalation
and
the
combined
dermal
and
inhalation
exposures.
It
was
concluded
that
the
dermal
and
inhalation
exposures
could
be
combined
due
to
the
common
endpoint
for
short­
term
(
neurotoxicity)
and
intermediate­
term
(
reproductive
effects)
exposures.
Since
the
shortterm
dermal
endpoint
was
based
on
a
LOAEL
with
an
additional
uncertainty
factor
of
3,
the
LOAEL
was
divided
by
3
before
calculating
the
combined
short­
term
dermal
and
inhalation
MOEs.
The
intermediate­
term
dermal
and
inhalation
endpoints
were
both
based
on
a
NOAEL
so
this
additional
step
was
not
necessary
for
the
combined
intermediate
MOEs.
The
combined
MOEs
were
calculated
using
the
following
equation:

1
1
+
1
(
Dermal
MOE)
(
Inhalation
MOE)
3
A
combined
MOE
of
less
than
100
exceeds
the
Agency's
level
of
concern.

Summary
of
Risks
to
Occupational
Handlers
Using
Biomonitoring
Data
(
Appendix
Tables
2­
3)

Short­
term
MOE's
estimated
for
liquid
and
granular
mixers/
loaders
using
biomonitoring
data
are
less
than
300
at
the
baseline
level
of
personal
protective
equipment
(
i.
e.,
long
pants,
long
sleeved
shirts,
gloves)
and
for
the
additional
PPE
of
coveralls
over
long
pants,
long
sleeved
shirts,
chemical
resistant
gloves
and
full
face
respirators.
Short­
term
total
MOEs
estimated
for
truck
drivers
supporting
loading
of
granulars
for
aerial
applications
are
greater
than
300.

Intermediate­
term
MOEs
estimated
for
liquid
and
granular
mixer/
loaders
using
biomonitoring
data
are
less
than
100
at
the
baseline
and
additional
levels
of
PPE
(
MOEs
ranged
from
17
to
73).
Intermediate­
term
total
MOEs
for
truck
drivers
supporting
loading
of
granulars
for
aerial
applications
are
greater
than
100.
30
Summary
of
Risks
to
Occupational
Handlers
Using
PHED
Data
(
Appendix
Tables
4­
7)

Short­
term
dermal
MOEs
estimated
for
8
handler
scenarios
using
PHED
data
are
all
less
than
300
at
the
baseline
clothing
and
additional
PPE
levels
(
MOEs
ranged
from
32
to
230).
Engineering
controls
resulted
in
short­
term
dermal
MOEs
above
300
for
only
3
of
the
8
scenarios.

Short­
term
inhalation
MOEs
estimated
for
8
handler
scenarios
using
PHED
data
are
above
100
at
the
baseline
level
of
clothing/
PPE.

When
the
short­
term
dermal
and
inhalation
MOEs
are
combined,
the
MOEs
were
below
100
for
all
scenarios
at
the
baseline
level
and
when
additional
protective
clothing/
PPE
are
added.
When
engineering
controls
are
added,
the
MOEs
are
still
below
100
for
pilots
applying
both
granular
and
liquid
formulations
and
for
handlers
mixing/
loading
liquids
for
ground­
based
application
and
applying
liquids
using
ground­
based
equipment.

Intermediate­
term
dermal
MOEs
estimated
for
8
handler
scenarios
using
PHED
data
are
all
less
than
100
at
the
baseline
clothing
and
additional
levels
of
PPE
(
MOEs
ranged
from
4
to
26).
Engineering
controls
resulted
in
MOEs
above
100
for
only
2
of
the
8
scenarios.

Intermediate­
term
inhalation
MOEs
estimated
for
8
handler
scenarios
using
PHED
data
are
all
less
than
100
at
the
baseline
PPE
level
(
MOEs
ranged
from
8
to
31).
The
addition
of
a
full
face
respirator
resulted
in
intermediate­
term
inhalation
MOEs
above
100
for
6
scenarios
assessed
using
PHED
data.
Risks
for
pilots
applying
liquids
and
granulars
were
only
assessed
with
engineering
controls;
the
MOEs
were
89
and
3,
respectively.

When
intermediate­
term
dermal
and
inhalation
risks
are
combined,
the
MOEs
are
less
than
100
for
all
scenarios
at
baseline
and
when
added
protective
clothing/
PPE
are
added.
When
engineering
controls
are
added,
the
MOEs
are
still
less
than
100
for
pilots
applying
both
granular
and
liquid
formulations
and
for
handlers
applying
both
granular
and
liquid
formulations
using
ground­
based
equipment
and
for
handlers
mixing/
loading
liquids
for
ground­
based
application.

The
handler
assessments
are
believed
to
be
reasonable
high
end
representations
of
molinate
uses.
There
are,
however,
many
uncertainties
in
these
assessments.
The
uncertainties
include
but
are
not
limited
to
the
following:
extrapolating
exposure
data
by
the
amount
of
active
ingredient
handled
or
applied;
not
all
of
the
exposure
data
are
of
high
confidence
because
of
the
lack
of
replicates
and/
or
inadequate
QA/
QC
in
the
studies.
31
4.3.2
Postapplication
Occupational
postapplication
exposures
are
expected
to
be
minimal
because
of
the
nature
of
the
activities
associated
with
rice
cultivation
(
e.
g.,
scouting
and
water
management)
and
the
protective
equipment
that
is
commonly
used
during
these
activities
(
e.
g.,
waterproof
rubber
boots
for
walking
through
rice
paddies).
Thus,
a
quantitative
exposure
and
risk
assessment
for
post­
application
activities
was
not
performed.
Since
the
acute
toxicity
categories
for
the
technical
grade
are
III
for
oral
and
dermal,
II
for
primary
eye
irritation,
and
IV
for
inhalation
and
primary
skin
irritation,
the
24­
hour
restrictive
entry
interval
(
REI)
that
appears
on
molinate
product
labels
is
in
compliance
with
the
Agency's
Worker
Protection
Standard
(
WPS).

4.4
Residential
Exposure
HED
has
not
addressed
any
residential
exposure
scenarios
because
there
are
no
residential
uses
of
molinate.
This
assessment
for
molinate
reflects
the
Agency's
current
approaches
for
completing
residential
exposure
assessments
based
on
the
guidance
provided
in
the
Draft:
Series
875­
Occupational
and
Residential
Exposure
Test
Guidelines,
Group
BPostapplication
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
already
not
addressed
such
as
from
spray
drift;
residential
residue
track­
in;
exposures
to
farmworker
children;
and
exposures
to
children
in
schools.

OPP
received
comments
from
the
Pesticide
Action
Network
North
America
(
PANNA)
concerning
inhalation
exposure
of
people
in
California
that
live
in
close
proximity
to
molinate­
treated
rice
fields.
A
study
conducted
in
the
early
1990s
by
the
California
Air
Resources
Board
was
used
by
PANNA
to
calculate
risk
estimates
for
varying
durations
of
exposure.
OPP
concurred
with
the
use
of
this
study.
However,
OPP
does
not
concur,
with
a
number
of
the
values
and
approaches
used
by
PANNA,
such
as
route­
to­
route
extrapolation
and
use
of
data
presented
in
a
California
Air
Resources
Board
(
CARB)
study
in
some
cases.
A
detailed
discussion
is
contained
in
a
August
22,
2002
Memorandum
from
Jeff
Dawson
to
Wilhelmena
Livingston
(
D284305).
5
The
1999
review
dated
December
16,
1999
(
D249804
and
D260965)
provides
a
summary
of
the
study
protocol
and
results.

6
Tomenson
JA
et
al
(
1999)
An
assessment
of
fertility
in
male
workers
exposed
to
molinate.
J
Occup
Environ
Med
41(
9):
771­
87.

32
4.5
Epidemiology
Data
A
molinate
epidemiology
study
of
exposed
male
workers,
begun
in
the
early
1980s,
has
been
reviewed
three
times
by
Dr.
Ruth
Allen
(
1991,
1993
and
1999).
5
The
purpose
of
the
registrant­
sponsored
study
was
to
determine
whether
workers
in
molinate
production
and
formulation
plants
showed
any
adverse
reproductive
effects,
changes
in
sperm
parameters,
or
reduced
fertility.
Each
successive
submission
to
EPA
has
been
an
attempt
to
upgrade
the
study
report
and
address
deficiencies
in
previous
reviews.
The
study
was
published
in
a
peer­
reviewed
journal
in
1999
after
a
reanalysis
of
the
statistical
data.
6
A
total
of
225
male
workers
donated
at
least
two
semen
samples
between
1980
and
1982
at
a
molinate
production
plant
in
Cold
Creek,
Alabama,
and
two
molinate
formulation
plants
in
Richmond,
California
and
in
North
Little
Rock,
Arkansas.
A
total
of
43
employees
provided
semen
samples
at
a
single
period.
Male
workers
were
known
by
job
title
and
duties
to
be
exposed
to
molinate
in
manufacturing
and
formulating
at
one
of
the
three
facilities.

The
study
was
conducted
over
four
distinct
time
periods
with
and
without
chemical
production
or
formulation.
Due
to
seasonal
and
individual
variation
in
sperm
parameters,
each
worker
served
as
his
own
control.
Measurements
were
made
on
such
reproductive
structure
and
function
indicators
as:
sperm
concentration,
motility
score,
percent
normal
morphology,
percent
non­
motility,
percent
live,
serum
FSH,
LH
and
testosterone.
Questionnaire
data
were
also
collected
on
fertility
and
infertility
from
222
wives
of
workers.

Exposure
assessment
was
based
on
660
personal
and
335
area
air
monitoring
samples
that
were
collected
the
year
before
or
during
the
study
period.

The
study
author
concluded
"
the
reanalysis
of
the
study
data
has
provided
no
evidence
of
a
real
molinate
exposure
effect
on
sperm
or
serum
hormone
parameters
despite
the
use
of
a
wide
range
of
statistical
approaches
and
characterizations
of
exposure
and
effect.
Supplemental
analyses
of
the
fertility
or
the
wives
of
employees
and
seasonality
patterns
of
births
also
provided
no
indication
of
a
molinate
exposure
effect."
33
HED
concluded
that
there
was
a
small
decrease
in
the
observed
compared
to
expected
number
of
children
at
parity
3
and
4+,
especially
for
the
high
exposure
classification,
both
between
production
cycles
and
during
peak
production
exposure.
These
results
are
suggestive
of
a
possible
effect
for
the
high­
exposure
group,
and
a
number
of
subtle
questions
and
issues
remain
to
be
clarified.
Those
issues
are
as
follows:

$
Participation
Rate.
At
49%,
the
study
participation
rate
is
low,
and
this
could
introduce
error/
bias.
Study
participation
rates
are
needed
by
population
strata,
including
more
highly
exposed
workers
and
families
at
higher
parity.
A
participation
rate
above
85%
is
desired.
The
lower
response
rate
precludes
total
reliance
on
this
one
molinate
epidemiology
study
to
make
any
sweeping
health
and
safety
claims.
In
addition,
there
was
a
difference
in
the
demographics
of
the
three
plants.
At
Richmond
and
Cold
Creek,
the
workers
were
75
and
78%
white,
respectively,
whereas
those
at
North
Little
Rock
were
62%
black
and
10
years
younger.

$
Exposure
Timing
and
Variability.
Job
title
is
an
imprecise
but
commonly
used
surrogate
for
actual
exposure
measurements.
The
same
job
title
may
be
associated
with
different
levels
of
exposure
depending
on
personal
hygiene
practices
and
proximity
to
other
concurrent
exposures.
In
addition,
molinate
was
not
the
only
chemical
produced
or
formulated
at
the
various
plants.

Within
worker
variability
is
not
fully
examined.
The
study
design
is
reasonable
for
the
1980'
s
with
multiple
testing
of
the
same
person.
The
study
does
not
address
timing
of
exposure
adequately
and
changes
in
biomarkers,
such
as
increases
in
FSH
via
feedback
in
shorter
intervals
than
4­
6
months.
These
would
not
be
detected
in
the
intermittent
screening
of
the
current
design.

$
Confidence
Intervals.
There
should
be
a
shift
in
presentation
of
results
to
measure
effects
of
molinate
with
characterization
of
the
precision
of
estimates
with
confidence
intervals
not
significance
testing
of
patterns
and
coefficients.

$
Chronic
Low
Level
Exposure.
Estimates
of
exposure
for
each
area/
job
are
given.
The
highest
exposure
for
an
area/
job
was
633

g/
M3
(
geometric
mean
TWA),
and
at
each
site
at
least
one
value
reached
250

g/
M3.
The
highest
cumulative
exposure
for
a
single
period
of
study
was
230,000

g/
M3.

The
current
results
do
not
differentiate
workers
with
changing
exposure
and
a
possible
better
outcome
compared
to
chronic
low
level
exposure.

$
Confounders.
No
explanation
is
given
for
the
marked
variability
in
responses
in
workers
in
formulation
plants
compared
production
plants.

$
Study
Power.
Study
power
for
analysis
is
weak
for
Cold
Creek
and
North
Little
River
plants
which
raises
concerns
about
the
Generalized
Estimating
Equation
(
GEE)
statistical
34
analysis.

Additional
comments
regarding
the
study
report
can
be
found
in
the
December
16,
1999
review.

HED
recommendations
based
on
review
of
the
epidemiology
study:

Molinate
is
used
for
weed
control
in
rice
fields
world­
wide
(
India,
Iran,
Japan,
China,
Philippines,
Australia,
Hungary,
Italy,
Spain)
in
addition
to
various
U.
S.
rice
growing
regions.
In
these
other
countries,
use
of
protective
equipment
and
label
compliance
are
unpredictable
and
cannot
be
assured.
Any
adverse
male
reproductive
health
effects
could
go
unreported
or
under
reported.
Therefore,
prudent
public
health
measures
are
advised,
including
labeling
products
with
the
National
Pesticide
Telecommunications
Network
international
phone
number
or
equivalent
poison
control
center
in
country
number
to
facilitate
the
use
of
existing
health
surveillance
and
disease
reporting
system
for
pesticide
poisoning
prevention.
Reporting
of
incidents
to
a
central
organization
would
serve
as
an
international
biomonitoring
of
workers
exposed
to
molinate.

Moreover,
pesticide
poisoning
surveillance
reporting
on
adverse
health
effects
is
very
uneven
globally,
and
efficacy
of
multi­
lingual
translations
of
worker
protection
label
precautionary
measures
world­
wide
is
uncertain.
Therefore,
publication
of
all
human
health
findings
from
the
molinate
epidemiology
study
in
the
open
epidemiologic
literature
is
recommended
as
a
normal
part
of
prudent
public
health
practice
and
good
product
stewardship.
Given
the
worldwide
use
of
this
chemical,
such
precautional
measures
are
one
responsible
way
to
demonstrate
a
commitment
to
public
health.

4.6
Incident
Data
A
review
of
the
incidents
of
human
adverse
effects
reported
with
molinate
exposure
was
prepared
by
Dr.
Ruth
Allen
(
D262407,
January
14,
2000).
Four
separate
data
bases
were
consulted
with
the
following
results:

1)
OPP
Incident
Data
System
(
IDS)
­
reports
of
incidents
from
various
sources,
including
registrants,
other
federal
and
state
health
and
environmental
agencies
and
individual
consumers,
submitted
to
OPP
since
1992.
Reports
submitted
to
the
Incident
Data
System
represent
anecdotal
reports
or
allegations
only,
unless
otherwise
stated.
Typically
no
conclusions
can
be
drawn
implicating
the
pesticide
as
a
cause
of
any
of
the
reported
health
effects.
Nevertheless,
sometimes
with
enough
cases
and/
or
enough
documentation
risk
mitigation
measures
may
be
suggested.

There
were
11
incidents
in
IDS.
Two
involved
ecological
(
aquatic)
effects.
Four
reported
molinate
detections
in
water
in
California.
One
was
for
molinate
residues
on
rice.
Two
were
summaries
of
incident
reports
involving
multiple
pesticides;
no
details
were
provided.
In
an
incident
from
1999,
according
to
pesticide
industry
reports,
molinate
was
reportedly
35
associated
with
7
individual
incidents,
including
eye
irritation
and
swelling,
hives,
second
degree
burns,
kidney
problems,
and
ear
infections.
In
another
1999
incident,
after
molinate
was
sprayed
on
rice
fields
next
to
a
house,
dizziness
in
the
whole
family
was
reported
due
to
over
spraying.

2)
Poison
Control
Centers
­
as
the
result
of
a
data
purchase
by
EPA,
OPP
received
Poison
Control
Center
data
covering
the
years
1993
through
1996
for
all
pesticides.
Most
of
the
national
Poison
Control
Centers
(
PCCs)
participate
in
a
national
data
collection
system,
the
Toxic
Exposure
Surveillance
System
which
obtains
data
from
about
65­
70
centers
at
hospitals
and
universities.
PCCs
provide
telephone
consultation
for
individuals
and
health
care
providers
on
suspected
poisonings,
involving
drugs,
household
products,
pesticides,
etc.

A
total
of
2
exposures
were
reported
to
the
Toxic
Exposure
Surveillance
System
of
the
American
Association
of
Poison
Control
Centers.
Both
cases
were
in
adults.
One
case
did
not
receive
follow
up
but
potentially
had
moderately
toxic
effects
and
the
other
had
symptoms
judged
unrelated
to
their
exposure.
This
is
too
few
cases
to
permit
meaningful
comparisons
with
other
pesticides.

3)
California
Department
of
Food
and
Agriculture
(
replaced
by
the
Department
of
Pesticide
Regulation
in
1991)
­
California
has
collected
uniform
data
on
suspected
pesticide
poisonings
since
1982.
Physicians
are
required,
by
statute,
to
report
to
their
local
health
officer
all
occurrences
of
illness
suspected
of
being
related
to
exposure
to
pesticides.
The
majority
of
the
incidents
involve
workers.
Information
on
exposure
(
worker
activity),
type
of
illness
(
systemic,
eye,
skin,
eye/
skin
and
respiratory),
likelihood
of
a
causal
relationship,
and
number
of
days
off
work
and
in
the
hospital
are
provided.

There
are
13
total
reported
incidents
for
molinate.
This
includes
10
incidents
for
molinate
alone,
and
3
incidents
for
molinate
with
combinations,
including
copper
sulfate,
thiobencarb,
and/
or
bensulfuron
methyl.

Eye
irritation,
burning
pain,
and/
or
blurred
vision
were
reported
in
1
molinate
and
two
molinate
mixture
cases.
Skin
irritation,
including
rash
on
contact
with
dust
were
reported
in
2
molinate
and
1
molinate
mixture
case.
These
cases
were
mainly
in
workers,
including
flaggers
and
applicators.

Systemic
and
respiratory
symptoms
were
reported
for
5
molinate
cases,
including
coughing,
dizziness,
vomiting,
nausea,
and/
or
mild
perspiration.

In
1991,
a
case
included
non­
occupational
exposure
to
molinate
when
store
merchandise
was
delivered
on
molinate
contaminated
pallets
and
3000
people
were
evacuated
by
the
fire
dept.
from
the
store
with
a
few
being
seen
by
doctors.
Also
in
1991,
a
non­
employee
doing
a
demonstration
at
a
store
developed
mild
nausea,
headaches
and
dizziness
when
exposed
to
the
odor
of
molinate.
36
In
1992
a
shop
worker
exposed
to
molinate
fumes
from
a
mixer/
loader
150
feet
away
became
ill
with
shortness
of
breath,
headaches
and
nausea.

In1996,
a
worker
loading
a
crop
duster
with
molinate
experienced
eye
problems
and
pain,
sought
medical
help
two
days
later,
but
the
ophthalmologist
could
not
determine
the
cause
of
the
eye
injury,
pain
and
redness
in
both
eyes.

A
total
of
13
days
off
work
and
0
days
hospitalized
were
reported.

4)
National
Pesticide
Telecommunications
Network
(
NPTN)
­
NPTN
is
a
toll­
free
information
service
supported
by
OPP.
A
ranking
of
the
top
200
active
ingredients
for
which
telephone
calls
were
received
during
calendar
years
1984­
1991,
inclusive
has
been
prepared.
The
total
number
of
calls
was
tabulated
for
the
categories
human
incidents,
animal
incidents,
calls
for
information,
and
others.

On
the
list
of
the
top
200
chemicals
for
which
NPTN
received
calls
from
1984­
1991
inclusively,
molinate
was
not
reported
to
be
involved
in
human
incidents.

In
summary,
the
only
data
base
which
would
provide
an
accurate
gauge
of
poisoning
incidents
in
workers
exposed
to
molinate
is
the
one
from
California.
Although
the
number
of
incidents
was
small,
there
were
reports
of
both
local
and
systemic
effects.
Also,
there
was
no
assessment
of
the
number
of
incidents
in
relation
to
the
amount
of
molinate
used
in
the
state.
No
appropriate
data
bases
assess
worker
incidents
in
the
southern
U.
S.
where
rice
is
also
grown.

5.0
AGGREGATE
RISK
ASSESSMENT
AND
RISK
CHARACTERIZATION
An
aggregate
exposure
risk
assessment
was
prepared
for
dietary
exposure
to
food
and
water.
These
assessments
apply
only
to
rice­
growing
areas.
EFED
has
determined
that
the
monitoring
data
are
suitable
for
quantification
of
drinking
water
risks.
Using
the
suggested
raw
water
concentrations
for
both
ground
and
surface
water
and
the
dietary
exposure
from
DEEMJ,
HED
calculated
the
percentage
of
the
Population
Adjusted
Dose
(
PAD)
for
acute
and
chronic
risk
assessments.
The
following
equations
were
used:

Adult
Males
Water
Exposure
=
Concentration
of
water
(
ug/
L)
x
10­
3
(
mg/
ug)
x
2
L/
day
(
mg/
kg/
day)
70
kg
Adult
Females
Water
Exposure
=
Concentration
of
water
(
ug/
L)
x
10­
3
(
mg/
ug)
x
2
L/
day
(
mg/
kg/
day)
60
kg
37
Children
Water
Exposure
=
Concentration
of
water
(
ug/
L)
x
10­
3
(
mg/
ug)
x
1
L/
day
(
mg/
kg/
day)
10
kg
Percentage
of
PAD
=
Aggregate
Exposure
(
Food
+
Water)
(
mg/
kg/
day)
x
100
PAD
(
mg/
kg/
day)

For
ground
water,
EFED
determined
that
0.087
ug/
L
(
0.056
x
1.56)
should
be
used
as
an
estimate
of
total
residues
of
molinate
in
drinking
water
for
acute
and
chronic
aggregate
risk
assessments.
For
surface
water,
HED
performed
the
risk
assessment
calculations
using
the
data
from
West
Sacramento,
California
as
a
worse
case
[
3.32
ug/
mL
(
2.13
x
1.56)
for
acute
exposure
and
0.64
ug/
mL
(
0.41
x
1.56)
for
chronic
exposure)].

For
food
exposure,
separate
calculations
were
done
for
adult
males
(
using
general
population
food
exposure),
adult
females
(
using
females
13­
50
food
exposure)
and
children
(
using
infants
<
1
year
food
exposure)
for
acute
(
using
the
99.9
percentile)
and
chronic
risk
assessments.

Greater
than
100%
of
the
PAD
for
the
aggregate
exceeds
the
Agency's
level
of
concern.
The
data
are
presented
in
Table
5.

The
percentage
of
the
aPAD
for
acute
aggregate
exposure
to
molinate
in
food
and
surface
water
for
children
(
110%)
exceeded
the
Agency's
level
of
concern.
However,
HED
believes
this
assessment
may
overestimate
the
risk
and
that
refinement
of
the
exposure
to
either
food
or
water
exposure
may
bring
the
risks
into
an
acceptable
range.
The
anticipated
residues
of
food
were
based
on
field
trial
residues.
Monitoring
studies
closer
to
the
point
of
consumption
or
cooking
studies
would
refine
exposure.
Better
monitoring
data
for
molinate
and
its
metabolites
and
degradates
in
water
would
also
refine
the
risks.
38
Table
5:
Percentage
of
Population
Adjusted
Dose
(
PAD)
for
Aggregate
Dietary
(
Food
and
Water)
Exposure
Water
Exposure
(
mg/
kg/
day)
Food
Exposure
(
mg/
kg/
day)
aPAD/
cPAD
(
mg/
kg/
day)
Percentage
of
PAD
Molinate
Molinate
+
Metabolitesa
Molinate
Molinate
+
Metabolitesa
Acute
Risk
Assessment
­
Surface
Water
Adult
Males
0.000061
0.000095
0.000186
0.0006
41%
47%

Adult
Females
0.000071
0.00011
0.000152
0.0006
37%
44%

Children
0.00021
0.00033
0.000328
0.0006
90%
110%*

Acute
Risk
Assessment
­
Ground
Water
Adult
Males
0.0000016
0.0000025
0.000186
0.0006
31%
31%

Adult
Females
0.0000019
0.0000030
0.000152
0.0006
26%
26%

Children
0.0000056
0.000087
0.000328
0.0006
56%
56%

Chronic
Risk
Assessment
­
Surface
Water
Adult
Males
0.000012
0.000019
0.000005
0.0001
17%
24%

Adult
Females
0.000014
0.000022
0.000004
0.0001
18%
26%

Children
0.000041
0.000064
0.000018
0.0001
59%
82%

Chronic
Risk
Assessment
­
Ground
Water
Adult
Males
0.0000016
0.0000025
0.000005
0.0001
7%
8%

Adult
Females
0.0000013
0.0000029
0.000004
0.0001
5%
7%

Children
0.0000056
0.0000087
0.000018
0.0001
24%
27%

a
Water
exposure
values
were
increased
by
56%
to
account
for
metabolites
not
included
in
the
monitoring
data.

*
>
100%
exceeds
the
Agency's
level
of
concern.
39
6.0
DATA
NEEDS
Product
Chemisty:
the
registrant
must
submit
additional
studies
as
described
below
before
all
guideline
requirements
can
be
considered
fulfilled.

$
Studies
on
stability
to
metals
and
metal
ions
(
GLN
830.6313)
and
UV/
visible
absorption
(
GLN
830.7050).

.
Residue
Chemistry:
Studies
which
are
outstanding
include
multiresidue
method
testing
for
molinate,
4­
hydroxy
molinate,
and
molinate
acid.
A
waiver
from
conducting
a
crop
irrigation
study
(
GLN860.1400)
was
granted
(
September
5,
2002
Memorandum,
D284879),
with
addendum
dated
November
6,
2002.
40
APPENDIX
41
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
81­
1/
870.1100
acute
oral
­
rats
40593301
see
Table
1:
Acute
Toxicity
of
Molinate
81­
2/
870.1200
acute
dermal
­
rabbits
40593301
see
Table
1:
Acute
Toxicity
of
Molinate
81­
3/
870.1300
acute
inhalation
­
rats
[
0.06,
0.12,
0.28,
0.83,
0.9,
1.6,
2.2,
2.4,
2.8,
4.0,
&
4.9
mg/
L]

mouse
(
0.034,
0.09,
0.23,
1.1,
1.8,
2.0,
2.3,
&
3.2
mg/
L)
00245675
NOAEL
hindleg
weakness
=
0.12
mg/
L
LOAEL
hindleg
weakness
=
0.28
mg/
L.

NOAEL
ataxia
=
2.4
mg/
L
LOAEL
ataxia
=
2.8
mg/
L
NOAEL
aggression/
hyperexcitability
=
0.83
mg/
L
LOAEL
aggression/
hyperexcitability
=
0.9
mg/
L
no
NOAEL
for
depression/
leg
weakness.

NOAEL
decreased
testes
weight
=
1.8
mg/
L
LOAEL
decreased
testes
weight
=
2.0
mg/
L
NOAEL
microscopic
lesions
of
testes
=
1.1
mg/
L
LOAEL
microscopic
lesions
of
testes
=
1.8
mg/
L
81­
4/
870.2400
primary
eye
irritation
40593301
see
Table
1:
Acute
Toxicity
of
Molinate
81­
5/
870.2500
primary
dermal
irritation
00247547
see
Table
1:
Acute
Toxicity
of
Molinate
81­
6/
870.2600
dermal
sensitization
40593302
see
Table
1:
Acute
Toxicity
of
Molinate
81­
7/
870.6100
acute
delayed
neurotoxicity
­
hen
00133562
43136601
NOAEL
=
200
mg/
kg
LOAEL
=
630
mg/
kg,
based
on
axonal
degeneration
in
brain
&
spinal
cord
[
delayed
neurotoxicant]

81­
8/
870.6200
acute
neurotoxicity
­
rat
43188001
no
NOAEL;
LOAEL
=
25
mg/
kg,
based
on
decreased
motor
activity
&
increased
time
to
tail
flick;
ChE
activity,
NTE,
&
GFAP
were
not
assessed
at
appropriate
times
immediately
after
dosing
82­
1/
870.3100
subchronic
feeding
­
rats
­
­

82­
1/
870.3150
subchronic
feeding
­
dog
12­
week
fertility
­
male
monkey
[
0.2,
10,
50
mg/
kg/
day]
­

00246520
42361302
­

NOAEL
=
10
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
decreased
plasma
ChE
activity
[
brain
ChE
not
measured].
Repeat
study
NOAEL
0.2
mg/
kg/
day
LOAEL
10
mg/
kg/
day,
based
on
decreased
RBC
ChE
[
brain
ChE
not
affected]
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
42
82­
2/
870.3200
21­
day
dermal
­
rats
[
10,
25,
50
mg/
kg/
day]
40990601
no
NOAEL
for
RBC
ChE
inhibition.

NOAEL
skin
effects
=
10
mg/
kg/
day
LOAEL
skin
effects
=
25
mg/
kg/
day,
based
on
skin
irritation
&
acanthosis
82­
4/
870.3465
90­
day
inhalation
­
rodent
[
2,
10,
50
mg/
m3]

4­
week
inhalation
[
0.1,
0.2,
0.4,
0.8,
1.6
mg/
m3]
00241965
41589203
no
NOAEL;
LOAEL
=
0.002
mg/
L,
based
on
testicular
degeneration
&
abnormal
spermatoza,
a
dose­
related
decrease
in
mean
number
of
implantations
&
mean
number
of
fetuses
NOAEL
=
0.0003
mg/
L;
LOAEL
=
0.0006
mg/
L,
based
on
decreased
number
of
implants
&
increased
%
abnormal
sperm
82­
5/
870.6200
subchronic
neurotoxicity
­
rats
[
50,
150,
450
ppm;
males
4,
11.7,
35.5/
females
4.5,
13.9,
41
mg/
kg/
day]
43270701
43965901
no
NOAEL;
LOAEL
=
males
4/
females
4.5
mg/
kg/
day,
based
on
decreased
brain
&
RBC
ChE
activity
and
decreased
NTE
in
both
sexes
at
all
dose
levels
83­
1(
a)/
870.4100
chronic
toxicity
­
rats
[
7,
40,
300
ppm
(
males:
0.3,
1.8,
13/
females
0.4,
2,
15
mg/
kg/
day]
for
24
months;
600
ppm
[

30
mg/
kg/
day]
for
12
months
41815101
no
NOAEL
for
neurotoxic
effects;

NOAEL
=
7
ppm
[
males
0.3/
females
0.4
mg/
kg/
day]

LOAEL
=
40
ppm
[
males
1.8/
females
2.0
mg/
kg/
day],
based
on
ovarian
lesions;
at
HDT
[
300
ppm
(
males
13/
females
15
mg/
kg/
day)]
degeneration
w/
atrophy
of
testes
&
decreased
testes
weight
83­
1(
b)/
870.4100
chronic
toxicity
­
dog
[
1,
10,
50
mg/
kg/
day
for
1
year;
100
mg/
kg/
day
for
14
weeks]
41781101
no
NOAEL
for
neurotoxic
effects;

NOAEL
=
10
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
decreased
BWG,
anemia,
decreased
ejaculate
volume
&
decreased
%
mobile
sperm
&
increased
adrenal
weight
[
both
sexes]

83­
2/
870.4200
carcinogenicity
­
mice
[
10,
100,
1000,
2000
ppm
[
males
1,
10.4,
105,
200
mg/
kg/
day,/

females
1.3,
13.9,
133,
249
mg/
kg/
day]
41809201
NOAEL
[
testicular
effects]
=
10
ppm
[
1.0
mg/
kg/
day];
LOAEL
[
testicular
effects]
=
100
ppm
[
10.4
mg/
kg/
day],
based
on
testicular
degeneration
NOAEL
[
other
effects]
=
100
ppm
[
males
10.4/
females
13.9
mg/
kg/
day]

LOAEL
[
other
effects]
=
1000
ppm
[
males
105/
females
133
mg/
kg/
day,
based
on
decreased
survival,
BW/
BWG/
FC,
increased
incidence
of
non­
neoplastic
lesions
in
brain,
spinal
cord,
sciatic
nerve
&
ovaries
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
43
83­
3(
a)/
870.3700
developmental
toxicity
­
rat
[
2.2,
35,
140
mg/
kg/
day]
41473401
maternal
NOAEL
=
35
mg/
kg/
day
maternal
LOAEL
=
140
mg/
kg/
day,
based
on
decreased
BW/
BWG/
FC,
increased
salivation
&
dehydration,
RBC
ChE
inhibition.

developmental
NOAEL
=
2.2
mg/
kg/
day
developmental
LOAEL
=
35
mg/
kg/
day,
based
on
increase
in
runting
83­
3(
b)/
870.3700
developmental
toxicity
­
rabbits
[
0,
2,
20,
200
mg/
kg/
day]

13­
week
oral
­
male
rabbit
[
40,
80,
160/
120
mg/
kg/
day
8­
week
oral
­
male
rabbit
[
10,
100
for
49
days,
200
mg/
kg/
day
for
16
days]

12­
week
oral
­
male
rabbit
[
10,
100,
200
mg/
kg/
day]

28­
day
oral
­
male
rabbit
2
range­
finding
studies
[
100,
200,
300
mg/
kg/
day]

[
40,
100,
250
mg/
lg/
day]
14021015
42361301
42361304
42361305
42361306
42361307
maternal
NOAEL
=
20
mg/
kg/
day
maternal
LOAEL
=
200
mg/
kg/
day,
based
on
increased
abortions,
decreased
[
negative]
BWG
during
days
14­
21,
&
increased
liver
weight.

developmental
NOAEL
=
20
mg/
kg/
day
developmental
LOAEL
=
200
mg/
kg/
day,
based
on
a
delay
in
fetal
development
as
evidenced
by
reduced
ossification
of
sternebrae.

male
fertility
NOAEL
=
40
mg/
kg/
day
male
fertility
LOAEL
=
80
mg/
kg/
day,
based
on
sperm
effects
[
increased
incidence
of
atypically­
stained
heads
in
ejaculated
&
epididymal
sperm
samples]

deaths
at
100
&
200
mg/
kg/
day
[
fertility
assessed
only
during
week
4;
limited
data
at
100
mg/
kg/
day
suggest
a
reduction
in
male
fertility
associated
w/
an
increased
incidence
of
sperm
abnormalities
[
total
&
midpiece]
&
increase
in
preimplantation
loss
&
decrease
in
#
live
fetuses
at
week
4
due
to
poor
survival,
no
definitive
statement
possible
w/
respect
to
male
rabbit
fertility
no
deaths
at

250
mg/
kg/
day;
no
NOAEL
for
RBC
ChEI
LOAEL
=
300
mg/
kg/
day
,
based
on
deaths
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
44
83­
4/
870.3800
2­
generation
reproduction
­
rats
[
both
sexes
dosed]

[

5,
10,
15
ppm
(
0.4,
0.8,
1.3
mg/
kg/
day/

20,
50,
300
ppm
(
1.9,
4.7,
28.8
mg/
kg/
day)]

[
only
females
dosed]

[
6,
50,
450
PPM]
44403201
41333402
no
NOAEL
for
decreased
brain
weight
LOAEL
for
decreased
brain
weight
=
5
ppm/
20
ppm
[
males
0.4/
females
1.9
mg/
kg/
day]

paternal
NOAEL
=
5
ppm
[
0.4
mg/
kg/
day]

paternal
LOAEL
=
10
ppm
[
0.8
mg/
kg/
day],
based
on
increased
incidence
of
abnormal
sperm
&
decreased
right
cauda
weight
in
F0
males.

maternal
NOAEL
=
20
ppm
[
1.9
mg/
kg/
day]

maternal
NOAEL
=
50
ppm
[
4.7
mg/
kg/
day],
based
on
microscopic
lesions
in
the
ovary
&
adrenal.

neonatal
NOAEL
=
5
ppm/
20
ppm
[
males
0.4/
females
1.9
mg/
kg/
day]

neonatal
LOAEL
=
10
ppm/
50
ppm
[
males
0.8/
females
4.7
mg/
kg/
day],
based
on
decreased
brain
weight
in
F2B
females,
decreased
testes
&
spleen
weights
in
F1A
males,
&
delayed
vaginal
opening
in
females.

reproductive
NOAEL
=
5
ppm/
20
ppm
[
males
0.4/
females
1.9
mg/
kg/
day]

reproductive
LOAEL
=
10
ppm/
50
ppm
[
males
0.8/
females
4.7
mg/
kg/
day],
based
on
microscopic
lesions
in
ovary,
increased
incidence
of
abnormal
sperm
morphology
[
both
generations],
decreased
absolute
right
cauda
weight
[
F0
males],
decreased
%
pups
born
live
[
F1A
&
F2B],
decreased
F2B
survival
&
decreased
litter
size
[
F1A,
F2A,
F2B]

maternal
NOAEL
=
6
ppm
[
0.34
mg/
kg/
day]

maternal
LOAEL
=
50
ppm
[
2.9
mg/
kg/
day],
based
on
decreased
fecundity
[
F1],
increased
incidence
of
vacuolation/
hypertrophy
of
ovary,
decreased
brain
weight
[
F1
females].

reproductive
NOAEL
=
6
ppm
[
0.34
mg/
kg/
day]

reproductive
LOAEL
=
50
ppm
[
2.9
mg/
kg/
day],
based
on
occurrence
of
vacuolation/
hypertrophy
of
ovary.

neonatal
NOAEL
=
6
ppm
[
0.34
mg/
kg/
day]

neonatal
LOAEL
=
50
ppm
[
2.9
mg/
kg/
day],
based
on
ovarian
lesions.

83­
5/
870.4300
chronic
toxicity/
carcinogenicity
­
rat
41815101
see
under
chronic
rat
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
45
83­
6/
870.6300
developmental
neurotoxicity
­
rat
[
0,
20,
75,
and
300
ppm
(
0,
1.8,
6.9,
and
26.1
mg/
kg/
day]
44079201
maternal
toxicity
NOAEL
=
75
ppm
[
6.9
mg/
kg/
day]

maternal
toxicity
LOAEL
=
300
ppm
[
26.1
mg/
kg/
day],
based
on
decreased
BW/
BWG/
FC.

no
NOAEL
for
developmental
neurotoxicity
developmental
neurotoxicity
LOAEL*
=
20
ppm
[
1.8
mg/
kg/
day],
based
on
a
reduction
in
startle
amplitude
in
auditory
startle
test
in
females
on
day
23
84­
2/
870.5100
gene
mutation
40918301
­

84­
2/
870.5375
chromosomal
aberration
40946701
­

84­
2/
870.5300
in
vitro
mammalian
cell
gene
mutation
00163790
­

84­
2/
870.5550
unscheduled
DNA
synthesis
41052701
43192301
­

­

84­
2/
870.5450
dominant
lethal
assay
43986701
44562201
­

85­
1/
870.7485
metabolism
41781801­
41781805
­

85­
2/
870.7600
dermal
penetration
43284101
­

86­
1\
870.7200
domestic
animal
safety
­
­

none
5­
week
fertility
[
males]

[
0.2,
4,
12,
30,
60
mg/
kg/
day]

7­
week
gavage
[
males]

[
2,
20,
100,
200
mg/
kg/
day]
00245675
NOAEL
=
0.2
mg/
kg/
daya
LOAEL
=
4
mg/
kg/
day,
based
on
decreased
%
viable
sperm
%
normal
sperm,
sperm
counts,
#
implants,
#
viable
fetuses,
increased
resorptions
&
pre­
implantation
loss
NOAEL
=
20
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
decreased
male
fertility,
#
implants,
#
fetuses/
pregnancy
none
vaginal
opening
[
day
7
gestation
til
day
22
post
partum]

[
300
ppm]
44373601
no
NOAEL
[
only
one
dose]

LOAEL
=
300
ppm,
based
on
delayed
vaginal
opening.

none
male
fertility
[
5
weeks]

[
0.5,
1,
2,
3,
4,
8
mg/
kg/
day]
43158202
no
NOAEL
LOAEL
0.5
mg/
kg/
day,
based
on
increased
incidence
of
headless
sperm,
midpiece
abnormality,
tail
abnormality,
total
abnormal
sperm
Table
1.
Toxicology
Profile
of
Molinate
Guideline
[
§
/
OPPTS]
Study
Type
MRID
#
NOAEL/
LOAEL
46
none
mechanistic
study
­
female
[
gestation
days
7­
10]

[
75,
135,
200
mg/
kg/
day]
42361308
no
NOAEL
for
microscopic
lesions
in
adrenal
cortex
&
ovary;
no
evidence
of
effect
on
ability
to
maintain
a
pregnancy,
no
deaths
at
75
mg/
kg/
day.


there
is
a
chronic
study
available;

ChEI
was
not
monitored;

only
females
were
administered
Molinate;


a
28­
day
hen
study
is
not
available;

NTE,
ChE,
GFAP
activities
were
not
assessed
at
appropriate
times
*
altered
by
HIARC
and
Toxicology
Science
Assessment
Committee
from
original
Data
Evaluation
Record
a
Actual
dose
was
0.26
mg/
kg/
day;
target
dose
was
0.2
mg/
kg/
day.
47
Table
2.
Exposure
and
Risk
Assessment
for
Workers
Loading
Granulars
into
Airplane
Hoppers
from
Biomonitoring
Study
Using
actual
exposure
from
biomonitoring
study
(
MRID
43165602)

Task
PPE
lb
ai
handled/

3
days
(
mean)
mean
body
wt
(
kg)
mg/
lb
ai
handled
(
geometric
mean)
Daily
Dose
1
mg/
kg/
day
(
geometric
mean)
Short­
term
MOE2
Intermediate­
term
MOE3
Dir­
Lo
Tyvek
2797
95.0
0.000676
0.0062
290
33
Carbon
1927
94.7
0.000469
0.0028
660
73
Both
Tyvek
2462
90.9
0.000839
0.0065
280
31
Carbon
3264
85.7
0.000948
0.0116
160
17
Driver
none
­
82.7
­
0.00081
2,200
250
carbon
­
81.0
­
0.00059
3,000
340
1
see
Tables
1
through
4
of
Appendix
C
of
Occupational/
Residential
Exposure
Chapter
2
Short­
term
MOE
=
Oral
LOAEL
(
1.8
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)

3
Intermediate­
term
MOE
=
Oral
LOAEL
(
0.2
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)

Using
default
body
weight
of
70
kg
and
unit
exposures
normalized
to
mg/
lb
ai
handled
Task
PPE
lb
ai
handled/

day
mg/
lb
ai
handled
Default
body
wt
(
kg)
Daily
Dose1
mg/
kg/
day
Short­
term
MOE2
Intermediateterm
MOE3
Max
Avg
w\
Max
lb
ai/
day
w\
Avg
lb
ai/
day
Dir­
Lo
Tyvek
1,680
900
0.000676
70
0.0162
0.0087
110
12
Dir­
Lo
Carbon
1,680
900
0.000469
70
0.0113
0.0060
160
18
Both
Tyvek
1,680
900
0.000839
70
0.0201
0.0108
90
10
Both
Carbon
1,680
900
0.000948
70
0.0227
0.0122
80
9
1
Daily
Dose
(
mg/
kg/
day)
=
[
Max
use
rate
(
lb
ai
handheld/
day)
x
Unit
exposure
(
mg/
lb
ai
handled)]
/
Body
weight
2
Short­
term
MOE
=
Oral
LOAEL
(
1.8
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)

3
Intermediate­
term
MOE
=
Oral
LOAEL
(
0.2
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)
48
Table
3.
Exposure
and
Risk
Assessment
for
Workers
Loading
Liquids
into
Airplane
Hoppers
from
Biomonitoring
Study
Using
actual
exposures
from
biomonitoring
study
(
MRID
44212201)

Work
Task
PPE
lb
ai
1
handled/

3
days
Body
weight
1
(
mean)
Unit
exposure
1
mg/
lb
ai
handled
(
geometric
mean)
Daily
Dose
1
mg/
kg/
day
(
geometric
mean)
Short­
term
MOE2
Intermediate­
term
MOE3
Loading
Arrosolo
(
liquid)
Level
1:
Activated
carbon
suit
worn
underneath
'
Kleenguard'

coveralls
839
83
0.00076
0.0072
250
28
Level
2:
'
Kleenguard'
coveralls
worn
over
normal
work
clothing
857
82
0.00117
0.0111
162
18
Level
3:
Normal
work
clothing,

recommended
as
long
sleeved
shirt
and
long
pants
750
82
0.00340
0.0284
63
7
1
see
Tables
1
through
4
of
Appendix
D
of
the
Occupational/
Residential
Exposure
Chapter
2
Short­
term
MOE
=
Oral
LOAEL
(
1.8
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)

3
Intermediate­
term
MOE
=
Oral
LOAEL
(
0.2
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)
49
Using
default
body
weight
of
70
kg,
loading
rate
of
900
lb
ai/
day,
and
unit
exposures
normalized
to
mg/
lb
ai
handled
Work
Task
PPE
lb
ai/

day
body
wt
(
kg)
Unit
exposure
mg/
lb
ai
handled
(
geometric
mean)
Daily
Dose1
mg/
kg/
day
Short­
term
MOE2
Intermediateterm
MOE3
Max
Avg
w\
Max
lb
ai/
day
w\
Avg
lb
ai/
day
Loading
Arrosolo
(
liquid)
Level
1:
Activated
carbon
suit
worn
underneath
'
Kleenguard'

coveralls
900
300
70
0.00076
0.0098
0.0033
184
20
Level
2:
'
Kleenguard'
coveralls
worn
over
normal
work
clothing
900
300
70
0.00117
0.0150
0.0050
120
13
Level
3:
Normal
work
clothing,

recommended
as
long
sleeved
shirt
and
long
pants
900
300
70
0.00340
0.0437
0.0146
41
5
1
Daily
Dose
(
mg/
kg/
day)
=
[
Use
rate
(
lb
ai
handheld/
day)
x
Unit
exposure
(
mg/
lb
ai
handled)]
/
Body
weight
2
Short­
term
MOE
=
Oral
LOAEL
(
1.8
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)

3
Intermediate­
term
MOE
=
Oral
LOAEL
(
0.2
mg/
kg/
day)/
Daily
Dose
(
mg/
kg/
day)
50
Table
4:
Numerical
Inputs
from
PHED
Version
1.1
Used
for
Molinate
Handler
Exposure
Assessment
No.
Exposure
Scenario
Unit
Exposures
from
Pesticide
Surrogate
Exposure
Guide
(
8/
98)
Application
Parameters
Baselinea
Additional
PPEb
Engineering
Controlsc
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Application
Rate
(
lb
ai/
A)
d
Area
Treated
(
acre/
day)
e
Application
Days/
year
Maximum
Typical
Aerial
Applications
­
Granulars:

3
pilots
applying
granulars
using
aerial
equipment
na
na
na
na
1.7
1.3
5
4
300
27
4
flagging
during
aerial
application
of
granulars
2.75
(
single
layer,

no
gloves)
0.15
(
single
layer,

no
gloves)
1.17
(
additional
layer,
no
gloves)
0.0075
(
full­
face
resp)
0.0462
(
enclosed
truck
cab)
0.003
(
enclosed
truck
cab)
5
4
300
27
Aerial
Applications­
Liquids:

6
pilots
applying
liquids
using
aerial
equipment
na
na
na
na
5.0
(
single
layer,

no
gloves,

close
cab)
0.068
(
single
layer,

no
gloves,

close
cab)
3
3
300
25
7
flagging
during
aerial
application
of
liquids
11.0
(
single
layer,

no
gloves)
0.35
(
single
layer,

no
gloves)
10.22
(
additional
layer,
no
gloves)
0.018
(
full­
face
resp)
0.22
(
single
layer,

no
gloves,

enclosed
truck
cab)
0.007
(
single
layer,

no
gloves,

enclosed
truck
cab)
3
3
300
25
No.
Exposure
Scenario
Unit
Exposures
from
Pesticide
Surrogate
Exposure
Guide
(
8/
98)
Application
Parameters
Baselinea
Additional
PPEb
Engineering
Controlsc
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Dermal
(

g/
lb
ai)
Inhalation
(

g/
lb
ai)
Application
Rate
(
lb
ai/
A)
d
Area
Treated
(
acre/
day)
e
Application
Days/
year
Maximum
Typical
51
Ground
Applications
­
Granulars:

8
loading
granulars
for
ground­
based
applications
6.9
(
single
layer,

gloves,
open
mixing)
1.7
(
single
layer,

gloves,
open
mixing)
3.4
(
additional
layer,
gloves)
0.085
(
full­
face
resp)
NF
NF
5
4
80
30
9
applying
granulars
using
ground­
based
equipment
7.2
(
single
layer,

gloves,
open
cab)
1.2
(
single
layer,

gloves,
open
cab)
4.18
(
additional
layer,
gloves)
0.06
(
full­
face
resp)
2.0
(
single
layer,

gloves,
enclosed
truck
cab)
0.220
(
single
layer,

gloves,
enclosed
truck
cab)
5
4
80
30
Ground
Applications­
Liquids:

10
mixing/
loading
liquids
for
ground­
based
applications
23
(
single
layer,

gloves,
open
mixing)
1.2
(
single
layer,

gloves,
open
mixing)
17.5
(
additional
layer,
gloves)
0.06
(
full­
face
resp)
8.6
(
single
layer,

gloves,

closed
mixing
system)
0.083
(
single
layer,

gloves,

closed
mixing
system)
3
3
80
30
11
applying
liquids
using
ground­
based
equipment
14
(
single
layer,

gloves,
open
cab)
0.74
(
single
layer,

gloves,
open
cab)
11.0
(
additional
layer,
gloves)
0.037
(
full­
face
resp)
5.1
(
single
layer,

gloves,

closed
cab)
0.43
(
single
layer,

gloves,

closed
cab)
3
3
80
30
"
No
Data"
or
'"
na"
indicates
that
no
appropriate
data
are
available
for
incorporation
into
this
cell.
"
N/
F"
indicates
that
this
exposure
scenario
is
not
considered
feasible
by
HED
due
to
engineering
or
other
practical
considerations
(
e.
g.,
an
open
cockpit
aerial
application
scenario
is
not
considered
feasible
as
aircraft
appropriate
for
this
use
are
not
manufactured
52
with
open
cockpits).

a
Baseline
clothing
and
PPE
scenario:
Workers
wearing
single
layer
clothing,
chemical
resistant
gloves,
and
no
respirator.
Also
open
cab
for
applicators
and
flaggers.

Exceptions
are
noted
on
an
individual
basis.

b
PPE:
Workers
typically
wear
double
layer
of
clothing,
chemical
resistant
gloves,
and
respirator.
Exceptions
are
noted
on
an
individual
basis.

c
Engineering
controls:
Workers
wearing
single
layer
clothing
and
no
gloves
while
using
an
appropriate
engineering
control
system
(
e.
g.,
closed
mixing,
enclosed
cabs).

d
See
Section
3.2.3.
for
derivation
of
application
rates.

e
HED
believes
these
values
represent
a
reasonable
estimation
of
the
median
to
upper
percentile
of
what
can
be
treated
in
a
single
day
based
on
the
exposure
scenario
of
concern.
Users
of
this
table
are
cautioned
to
note
that
these
values
are
based
on
professional
judgement
when
appropriate
data
are
not
available.
53
Table
5.
Non­
Cancer
Risks
For
Occupational
Molinate
Handlers
at
Baseline
Clothing
Scenario
(
Unit
Exposures
from
PHED)

No.
Exposure
Scenario
Absorbed
Daily
Dose
using
Max
Application
Rate
(
mg/
kg/
day)
Short­
Term
Risk
(
MOE)
Intermediate­

Term
Risk
(
MOE)

Dermal
a
Inhalation
b
Dermal
c
Inhalation
d
Combined
e
Dermal
f
Inhalation
g
Combined
h
Aerial
Applications
­
Granulars:

3
pilots
applying
granulars
using
aerial
equipment
4
flagging
during
aerial
application
of
granulars
0.0236
0.0032
76
6500
25
8
24
6
Aerial
Applications­
Liquids:

6
pilots
applying
liquids
using
aerial
equipment
7
flagging
during
aerial
application
of
liquids
0.0566
0.0045
32
4600
11
4
17
3
Ground
Applications
­
Granulars:

8
loading
granulars
for
ground­
based
applications
0.0158
0.0097
110
2200
38
13
8
5
9
applying
granulars
using
ground­
based
equipment
0.0165
0.0069
110
3000
36
12
11
6
Ground
Applications­
Liquids:

10
mixing/
loading
liquids
for
ground­
based
applications
0.0315
0.0041
57
5100
19
6
19
5
11
applying
liquids
using
ground­
based
equipment
0.0192
0.0025
94
8200
31
10
31
8
"
No
Data"
indicates
that
no
appropriate
data
are
available
for
incorporation
into
this
cell.
"
N/
F"
indicates
that
this
exposure
scenario
is
not
considered
feasible
by
HED
due
to
engineering
or
other
practical
considerations
(
e.
g.,
an
open
cockpit
aerial
application
scenario
is
not
considered
feasible
as
aircraft
appropriate
for
this
use
are
not
manufactured
with
open
cockpits).
N/
A
indicates
that
an
appropriate
risk
level
has
been
obtained
and
there
is
no
need
for
imposition
of
a
more
protective
level
of
risk
mitigation.

a
Absorbed
daily
dermal
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)*(
1E­
3
mg/
ug)
unit
conversion
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
dermal
absorption
(
40%)

body
weight
(
70
kg)

b
Absorbed
daily
inhalation
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)
*
1E­
3
mg/
ug
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
inhalation
absorption
(
100%)

body
weight
(
70
kg)

c
Short­
Term
Dermal
MOE
=
[
LOAEL
(
1.8
mg/
kg/
day)]
/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
300
indicate
a
risk
concern
54
d
Short­
Term
Inhalation
MOE
=
NOAEL
(
20.9
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern
e
Combined
MOE
=
1
1
+
1
(
Dermal
MOE)
(
Inhalation
MOE)

3
f
Intermediate­
Term
Dermal
MOE
=
NOAEL
(
0.2
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

g
Intermediate­
Term
Inhalation
MOE
=
NOAEL
(
0.078
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

h
Combined
MOE
=
1
÷
(
1/
Dermal
MOE)
+
(
1/
Inhalation
MOE)
55
Table
6.
Non­
Cancer
Risks
For
Occupational
Molinate
Handlers
at
Additional
Protective
Clothing
and
PPE
to
Mitigate
Exposures
(
Unit
Exposures
from
PHED)

No.
Exposure
Scenario
Absorbed
Daily
Dose
using
Max
Application
Rate
(
mg/
kg/
day)
Short­
Term
Risk
(
MOE)
Intermediate­

Term
Risk
(
MOE)

Dermal
a
Inhalation
b
Dermal
c
Inhalation
d
Combined
e
Dermal
f
Inhalation
g
Combined
h
Aerial
Applications
­
Granulars:

3
pilots
applying
granulars
using
aerial
equipment
4
flagging
during
aerial
application
of
granulars
0.010
0.00016
180
130,000
60
20
490
19
Aerial
Applications­
Liquids:

6
pilots
applying
liquids
using
aerial
equipment
7
flagging
during
aerial
application
of
liquids
0.0526
0.00023
34
90,000
11
4
340
4
Ground
Applications
­
Granulars:

8
loading
granulars
for
ground­
based
applications
0.0078
0.00049
230
43,000
77
26
160
22
9
applying
granulars
using
ground­
based
equipment
0.0096
0.00034
190
61,000
63
21
230
19
Ground
Applications­
Liquids:

10
mixing/
loading
liquids
for
ground­
based
applications
0.0240
0.00021
75
100,000
25
8
380
8
11
applying
liquids
using
ground­
based
equipment
0.0151
0.00013
120
160,000
40
13
620
13
"
No
Data"
indicates
that
no
appropriate
data
are
available
for
incorporation
into
this
cell.
"
N/
F"
indicates
that
this
exposure
scenario
is
not
considered
feasible
by
HED
due
to
engineering
or
other
practical
considerations
(
e.
g.,
an
open
cockpit
aerial
application
scenario
is
not
considered
feasible
as
aircraft
appropriate
for
this
use
are
not
manufactured
with
open
cockpits).
N/
A
indicates
that
an
appropriate
risk
level
has
been
obtained
and
there
is
no
need
for
imposition
of
a
more
protective
level
of
risk
mitigation.

a
Absorbed
daily
dermal
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)*(
1E­
3
mg/
ug)
unit
conversion
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
dermal
absorption
(
40%)
body
weight
(
70
kg)

b
Absorbed
daily
inhalation
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)
*
1E­
3
mg/
ug
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
inhalation
absorption
(
100%)

body
weight
(
70
kg)
56
c.
Short­
Term
Dermal
MOE
=
[
LOAEL
(
1.8
mg/
kg/
day)]
/
absorbed
daily
dose
(
mg/
kg/
day)
MOEs
<
100
indicate
a
risk
concern
d
Short­
Term
Inhalation
MOE
=
NOAEL
(
20.9
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern
e
Combined
MOE
=
1
1
+
1
(
Dermal
MOE)
(
Inhalation
MOE)

3
f
Intermediate­
Term
Dermal
MOE
=
NOAEL
(
0.2
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

g
Intermediate­
Term
Inhalation
MOE
=
NOAEL
(
0.078
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

h
Combined
MOE
=
1
÷
(
1/
Dermal
MOE)
+
(
1/
Inhalation
MOE)
57
Table
7.
Non­
Cancer
Risks
For
Occupational
Molinate
Handlers
at
Engineering
Controls
to
Mitigate
Exposures
(
Unit
Exposures
from
PHED)

No.
Exposure
Scenario
Absorbed
Daily
Dose
using
Max
Application
Rate
(
mg/
kg/
day)
Short­
Term
Risk
(
MOE)
Intermediate­

Term
Risk
(
MOE)

Dermal
a
Inhalation
b
Dermal
c
Inhalation
d
Combined
e
Dermal
f
Inhalation
g
Combined
h
Aerial
Applications
­
Granulars:

3
pilots
applying
granulars
using
aerial
equipment
0.0146
0.0279
120
750
39
14
3
2
4
flagging
during
aerial
application
of
granulars
0.00040
0.000064
4500
330,000
1,500
500
1,200
360
Aerial
Applications­
Liquids:

6
pilots
applying
liquids
using
aerial
equipment
0.0257
0.00087
70
24,000
23
8
89
7
7
flagging
during
aerial
application
of
liquids
0.0011
0.000090
1600
230,000
530
180
870
150
Ground
Applications
­
Granulars:

8
loading
granulars
for
ground­
based
applications
N/
F
9
applying
granulars
using
ground­
based
equipment
0.0046
0.0013
390
17,000
130
44
62
26
Ground
Applications­
Liquids:

10
mixing/
loading
liquids
for
ground­
based
applications
0.0118
0.00028
150
73,000
51
17
270
16
11
applying
liquids
using
ground­
based
equipment
0.0070
0.0015
260
14,000
86
29
53
19
"
No
Data"
indicates
that
no
appropriate
data
are
available
for
incorporation
into
this
cell.
"
N/
F"
indicates
that
this
exposure
scenario
is
not
considered
feasible
by
HED
due
to
engineering
or
other
practical
considerations
(
e.
g.,
an
open
cockpit
aerial
application
scenario
is
not
considered
feasible
as
aircraft
appropriate
for
this
use
are
not
manufactured
with
open
cockpits).
N/
A
indicates
that
an
appropriate
risk
level
has
been
obtained
and
there
is
no
need
for
imposition
of
a
more
protective
level
of
risk
mitigation.

a
Absorbed
daily
dermal
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)*(
1E­
3
mg/
ug)
unit
conversion
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
dermal
absorption
(
40%)
body
weight
(
70
kg)

b
Absorbed
daily
inhalation
dose
(
mg/
kg/
day)
=
unit
exposure
(

g/
lb
ai)
*
1E­
3
mg/
ug
*
application
rate
(
lb
ai/
A)
*
acres
treated
(
acres/
day)
*
inhalation
absorption
(
100%)
58
body
weight
(
70
kg)

c
Short­
Term
Dermal
MOE
=
[
LOAEL
(
1.8
mg/
kg/
day)]
/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern
d
Short­
Term
Inhalation
MOE
=
NOAEL
(
20.9
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern
e
Combined
MOE
=
1
1
+
1
(
Dermal
MOE)
(
Inhalation
MOE)

3
f
Intermediate­
Term
Dermal
MOE
=
NOAEL
(
0.2
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

g
Intermediate­
Term
Inhalation
MOE
=
NOAEL
(
0.078
mg/
kg/
day)/
absorbed
daily
dose
(
mg/
kg/
day).
MOEs
<
100
indicate
a
risk
concern.

h
Combined
MOE
=
1
÷
(
1/
Dermal
MOE)
+
(
1/
Inhalation
MOE)
