Document ID: EPA-HQ-OPP-2005-0537-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-08-30T04:00Z

Page
1
of
73
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
Date:
4/
24/
06
SUBJECT:
Ethofumesate
Human
Health
Risk
Assessment
for
Proposed
Uses
on
Onion,
Bulb.
PC
Code:
110601,
Petition
No:
5E6914,
DP
Num:
316086.

Regulatory
Action:
Section
3
Registration
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
W.
Cutchin,
Chemist
ARIA/
Technical
Review
Branch
Registration
Division
(
7505C)

THROUGH:
PV.
Shah,
Ph.
D.,
Branch
Senior
Scientist
Registration
Action
Branch
1
Health
Effects
Division
(
7509C)

TO:
B.
Madden/
D.
Rosenblatt
RIMUERB
Registration
Division
(
7505C)
Page
2
of
73
Table
of
Contents
1.0
Executive
Summary
............................................................................................................
5
2.0
Ingredient
Profile
...............................................................................................................
12
2.1
Summary
of
Proposed
Uses
....................................................................................
14
3.0
Hazard
Characterization/
Assessment..................................................................................
14
3.1
Hazard
and
Dose­
Response
Characterization
..........................................................
14
3.1.1
Database
Summary...................................................................................
14
3.1.2
Toxicological
Effects
...............................................................................
15
3.1.3
Dose­
response..........................................................................................
15
3.1.4
FQPA.......................................................................................................
16
3.1.5
Toxicity
Profiles.......................................................................................
16
3.2
FQPA
Hazard
Considerations
................................................................................
20
3.2.1
Adequacy
of
the
Toxicity
Database
..........................................................
21
3.2.2
Evidence
of
Neurotoxicity........................................................................
21
3.2.3
Developmental
Toxicity
Studies...............................................................
21
3.2.4
Reproductive
Toxicity
Study....................................................................
23
3.2.5
Additional
Information
from
Literature
Sources
.......................................
24
3.2.6
Pre­
and/
or
Postnatal
Toxicity
...................................................................
24
3.3
Recommendation
for
a
Developmental
Neurotoxicity
Study...................................
25
3.3.1
Evidence
That
Supports
Requiring
a
Developmental
Neurotoxicity
Study
...............................................................................................................
25
3.3.2
Evidence
That
Supports
Not
Requiring
a
Developmental
Neurotoxicity
Study......................................................................................................
25
3.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
...........................................
25
3.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
13­
49
Years
of
Age...................
26
3.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
.................................
27
3.4.3
Chronic
Reference
Dose
(
cRfD)­
Females
13­
49
Years
of
Age
.................
27
3.4.3
Chronic
Reference
Dose
(
cRfD)
­
General
Population
Including
Infants
and
Children
.................................................................................................
28
3.4.4
Incidental
Oral
Exposure
(
Short­
and
Intermediate
Term
Exposure)
.........
30
3.4.5
Dermal
Absorption...................................................................................
32
3.4.6
Dermal
Exposure
(
All
Durations)
­
Females
13­
49
Years
of
Age..............
32
3.4.7
Dermal
Exposure
(
Short­
and
Intermediate­
Term)
­
General
Population
Including
Infants
and
Children
...............................................................
33
3.4.8
Dermal
Exposure
(
Long
Term)
­
General
Population
Including
Infants
and
Children
.................................................................................................
33
3.4.9
Inhalation
Exposure
(
All
Exposure
Durations)
­
Females
13­
49
Years
of
Age
........................................................................................................
34
3.4.10
Inhalation
Exposure
(
Short­
and
Intermediate­
Term)
­
General
Population
Including
Infants
and
Children
...............................................................
34
3.4.11
Inhalation
Exposure
(
Long
Term)
­
General
Population
Including
Infants
and
Children...........................................................................................
35
Page
3
of
73
3.4.12
Margins
of
Exposure
..............................................................................
35
3.4.13
Recommendation
for
Aggregate
Exposure
Risk
Assessments
.................
36
3.4.14
Classification
of
Carcinogenic
Potential
.................................................
36
3.4.15
Mutagenicity
..........................................................................................
39
3.5
Special
FQPA
Safety
Factor
...................................................................................
42
3.6
Endocrine
Disruption..............................................................................................
42
4.0
Public
Health
and
Pesticide
Epidemiology
Data
.................................................................
43
5.0
Dietary
Exposure/
Risk
Characterization.............................................................................
43
5.1
Pesticide
Metabolism
and
Environmental
Degradation
...........................................
43
5.1.1
Metabolism
in
Plants................................................................................
43
5.1.2
Metabolism
in
Rotational
Crops
...............................................................
44
5.1.3
Metabolism
in
Livestock..........................................................................
45
5.1.4
Analytical
Methodology...........................................................................
45
5.1.5
Environmental
Degradation......................................................................
46
5.1.6
Comparative
Metabolic
Profile.................................................................
46
5.1.7
Toxicity
Profile
of
Major
Metabolites
and
Degradates..............................
47
5.1.8
Pesticide
Metabolites
and
Degradates
of
Concern.....................................
47
5.1.9
Drinking
Water
Residue
Profile................................................................
48
5.1.10
Food
Residue
Profile
..............................................................................
49
5.1.11
International
Residue
Limits...................................................................
51
5.2
Dietary
Exposure
and
Risk
.....................................................................................
51
5.3
Anticipated
Residue
and
Percent
Crop
Treated
(%
CT)
Information
.........................
52
6.0
Residential
(
Non­
Occupational)
Exposure/
Risk
Characterization
.......................................
52
6.1
Residential
Handler
Exposure.................................................................................
53
6.2
Residential
Postapplication
Exposure.....................................................................
53
6.3
Other
(
Spray
Drift,
etc.)..........................................................................................
57
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization.....................................................
58
7.1
Acute
Aggregate
Risk.............................................................................................
59
7.2
Short­
and
Intermediate­
Term
Aggregate
Risk........................................................
59
7.3
Long­
Term
Aggregate
Risk
....................................................................................
60
7.4
Cancer
Risk
............................................................................................................
61
8.0
Cumulative
Risk
Characterization/
Assessment
...................................................................
61
9.0
Occupational
Exposure/
Risk
Pathway
................................................................................
61
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
..........................................................
61
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk...............................................
63
10.0
Data
Needs
and
Label
Requirements
................................................................................
65
10.1
Toxicology
...........................................................................................................
65
10.2
Residue
Chemistry................................................................................................
65
Page
4
of
73
10.3
Occupational
and
Residential
Exposure
................................................................
65
References
................................................................................................................................
65
Appendix
A:
Toxicology
Assessment
......................................................................................
67
Page
5
of
73
1.0
Executive
Summary
The
Alternative
Risk
Integration
Assessment
Team
(
ARIA)/
Technical
Review
Branch
(
TRB)
has
conducted
a
human
health
risk
assessment
for
the
active
ingredient
ethofumesate
[(
±
)
­
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethylbenzofuran­
5­
yl­
methanesulfonate]
in
response
to
a
Section
3
petition
from
Interregional
Research
Project
#
4,
IR­
4,
for
the
use
of
ethofumesate
on
dry
bulb
onions.
ARIA
evaluated
the
toxicology,
residue
chemistry,
and
occupational/
residential
exposure
databases
for
ethofumesate
and
determined
that
the
data
are
adequate
to
support
the
Section
3
request.

Use
and
Usage
Information
Ethofumesate
is
a
member
of
the
benzofuranyl
alkanesulfonate
class
of
compounds.
It
is
a
selective
pre­
and
post­
emergent
soil­
incorporated
terrestrial
herbicide
that
is
used
to
control
grasses
and
broad­
leaf
weeds
in
sugar
and
other
beet
crops,
as
well
as
on
turf,
ryegrass
and
other
pasture
grasses.
The
herbicidal
mode
of
action
is
related
to
inhibition
of
mitosis
plus
reduced
photosynthesis
and
respiration.
Tolerances
are
established
for
ethofumesate
and
its
metabolites
in
40
CFR
§
180.345
on
sugar
beet
tops
and
roots,
sugar
beet
molasses,
and
for
meat,
meat
byproducts
and
fat
from
the
following
animals:
cattle,
goats,
sheep,
hogs
and
horses.
Existing
food
uses
consist
of
sugar
beets,
beets,
and
carrots.
The
maximum
application
rate
is
3.75
lb
ai/
A
(
sugar
beets).
The
non­
food
uses
consist
of
grasses
grown
for
seed,
golf
course
turf
and
sod
farms.
It
is
also
registered
for
professional
applications
to
lawns.
It
is
formulated
as
flowable
and
emulsifiable
concentrates
and
the
majority
of
formulations
are
emulsifiable
concentrates
(
EC);
however,
there
is
one
granular
product
for
turf
(
EPA
Reg.
No.
9198­
206).
Formulations
can
be
applied
as
banded
or
broadcast
pre­
plant,
preemergence,
and
postemergence
applications
using
ground
or
aerial
equipment.
The
current
petition
is
for
the
use
of
product
Nortron
®
SC
(
EPA
Reg.
No.
264­
613)
on
onion,
dry
bulb;
garlic,
bulb;
and
shallots,
bulb.
The
requested
use
is
for
a
single
application
at
planting
or
shortly
after
at
1.0
lb
ai/
A
followed
by
four
foliar
applications
at
0.5
lb
ai/
A.
A
30­
day
PHI
is
indicated.

Regulatory
Background
Ethofumesate
is
a
FIFRA
List
B
pesticide
assigned
to
Case
No.
2265.
Ethofumesate
as
NORTRON
was
registered
in
1977
and
the
name
was
officially
changed
to
ethofumesate
upon
acceptance
of
the
new
common
name
by
American
National
Standards
Institute
(
ANSI)
in
1978.
The
Final
Registration
Standard
and
Tolerance
Reassessment
(
FRSTR)
was
completed
in
1988
and
the
Phase
IV
Data
Call­
In
(
DCI)
was
issued
in
1991.
Since
that
time,
a
Reregistration
Eligibility
Decision
Document
(
RED)
has
been
published
(
EPA
738­
R­
05­
010,
9/
05).

Hazard
Profile
The
toxicity
database
is
essentially
complete.
The
only
data
gap
is
for
a
twenty­
eight
(
28)­
day
inhalation
toxicity
study
which
is
required
to
assess
toxicity
from
inhalation
exposure,
based
on
the
potential
for
inhalation
exposure
to
spray
applicators
under
current
use
patterns.
Page
6
of
73
Ethofumesate
showed
low
acute
toxicity
by
the
oral
and
dermal
exposure
routes
and
is
not
a
dermal
or
ocular
irritant
(
IV).
Although
the
Toxicity
Category
for
acute
inhalation
exposure
is
II,
this
classification
is
largely
associated
with
physical
limitations.
No
potential
for
dermal
sensitization
was
observed
in
a
guinea
pig
maximization
assay.
The
liver
is
the
main
target
organ
in
rats
and
dogs
and
the
major
critical
effects
seen
in
oral
studies
are
decreased
body
weight
gain
and
hepatic
toxicity
in
the
rat,
dog
and/
or
rabbit.
Mice
are
relatively
insensitive
to
ethofumesate
even
up
to
the
limit
dose
following
chronic
dietary
exposure.
In
rabbits,
effects
included
death,
decreased
body
weight,
abortions
and
complete
litter
resorption
at
levels
in
excess
of
the
limit
dose.
Additionally,
developmental
effects
were
noted
at
doses
that
were
not
maternally
toxic.
Although
the
mode
of
action
is
not
known,
the
critical
effects
are
considered
relevant
to
humans
because
they
are
observed
in
at
least
three
species
tested.
The
chemical
is
not
likely
to
be
carcinogenic
based
on
bioassays
in
the
rat
and
the
mouse
combined
with
a
lack
of
in
vitro
or
in
vivo
mutagenicity.
Ethofumesate
did
not
demonstrate
the
potential
to
cause
neurotoxicity
in
at
least
four
species
(
rats,
mice,
dogs
and
rabbits)
and
rats
did
not
show
evidence
of
developmental
toxicity
or
maternal
or
offspring
toxicity
in
a
3­
generation
reproduction
study.
By
contrast,
increased
prenatal
quantitative
susceptibility
was
seen
in
the
rabbit
developmental
study
at
a
dose
that
was
not
maternally
toxic.

Hazard
Identification
and
Food
Quality
Protection
Act
(
FQPA)
Decision
Based
on
the
toxicity
profile,
the
HED
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
selected
endpoints
for
human
health
risk
assessments.
The
HIARC
also
evaluated
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
ethofumesate
as
required
by
the
FQPA
of
1996.
All
doses
for
risk
assessment
purposes
were
assessed
using
uncertainty
factors
of
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variability.
HIARC
determined
that
the
special
FQPA
Safety
Factor
can
be
removed
(
1X)
because
acceptable
developmental
and
reproduction
studies
have
been
submitted
and
reviewed,
and
there
is
a
low
concern
and
no
residual
uncertainties
for
pre­
and
postnatal
toxicity.
Although
increased
prenatal
quantitative
sensitivity
was
observed
in
the
rabbit
developmental
toxicity
study,
the
developmental
toxicity
no
observable
adverse
effect
level
(
NOAEL)
and
lowest
observable
adverse
effect
level
(
LOAEL)
are
well
characterized
and
are
used
as
endpoints
for
risk
assessment
for
the
appropriate
population
subgroups.
The
specific
doses
and
endpoints
are
summarized
as
follows:

C
Acute
dietary
(
Females
13­
49
years
old)
­
NOAEL
=
30
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
developmental
LOAEL
of
300
mg/
kg/
day
in
a
developmental
toxicity
study
in
rabbits.
These
endpoints
are
presumed
to
occur
following
a
single
in
utero
exposure.

C
Acute
dietary
(
General
population
including
infants
and
children)
­
No
appropriate
single­
dose
endpoint
was
available.

C
Chronic
dietary
(
Females
13­
49
years
old)
­
NOAEL
=
30
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
developmental
LOAEL
of
300
mg/
kg/
day
in
a
developmental
toxicity
study
in
Page
7
of
73
rabbits.
A
separate
RfD
was
established
for
this
population
subgroup
because
the
developmental
toxicity
observed
at
30
mg/
kg/
day
in
the
developmental
toxicity
study
in
rabbits
resulted
in
an
acute
RfD
(
0.30
mg/
kg/
day)
which
was
lower
than
the
chronic
RfD
(
1.30
mg/
kg/
day)
established
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats.

C
Chronic
dietary
(
General
population
including
infants
and
children)
­
NOAEL
=
127
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
females
at
the
LOAEL
of
469
mg/
kg/
day
in
the
combined
chronic/
carcinogenicity
study
in
rats.

C
Incidental
oral
(
Short­
and
intermediate­
term)
­
NOAEL
=
190
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day
in
a
subchronic
(
90­
day)
oral
toxicity
in
rats
study.

C
Short­,
intermediate­
and
long­
term
dermal
(
Females
13­
49
years
old)
­
NOAEL
=
30
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
developmental
LOAEL
of
300
mg/
kg/
day
in
a
developmental
toxicity
study
in
rabbits.
The
oral
developmental
toxicity
NOAEL
in
the
rabbit
developmental
toxicity
study
was
selected
over
the
available
21­
day
dermal
toxicity
study
for
this
assessment
of
all
exposure
durations
and
for
this
subpopulation
because
of
the
concerns
for
developmental
effects
that
were
seen
in
this
study
and
which
were
not
evaluated
in
the
21­
day
dermal
toxicity
study
in
rabbits.

C
Short­
and
intermediate­
term
dermal
(
General
population
including
infants
and
children)
­
NOAEL
=
190
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day
in
a
subchronic
(
90­
day)
oral
toxicity
in
rats
study.

C
Long­
term
dermal
(
General
population
including
infants
and
children)
­­
NOAEL
=
127
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
females
at
the
LOAEL
of
469
mg/
kg/
day
in
the
combined
chronic/
carcinogenicity
study
in
rats.

C
Short­,
intermediate­
and
long­
term
inhalation
(
Females
13­
49
years
old)
­
NOAEL
=
30
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
developmental
LOAEL
of
300
mg/
kg/
day
in
a
developmental
toxicity
study
in
rabbits.
The
oral
developmental
toxicity
NOAEL
in
the
rabbit
developmental
toxicity
study
was
selected
for
all
exposure
durations
of
this
subpopulation
because
of
the
concerns
for
developmental
effects
that
were
seen
in
this
study
and
which
have
not
been
evaluated
using
inhalation
as
the
exposure
route.

C
Short­
and
intermediate­
term
inhalation
(
General
population
including
infants
and
children)
­
NOAEL
=
190
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day
in
a
subchronic
(
90­
day)
oral
toxicity
in
rats
study.
In
the
absence
of
repeated
inhalation
Page
8
of
73
toxicity
studies,
this
oral
study
was
selected
because
absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
absorption
via
the
oral
route.

C
Long­
term
inhalation
(
General
population
including
infants
and
children)
­­
NOAEL
=
127
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
females
at
the
LOAEL
of
469
mg/
kg/
day
in
the
combined
chronic/
carcinogenicity
study
in
rats.
In
the
absence
of
repeated
inhalation
toxicity
studies,
this
oral
study
was
selected
because
absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
absorption
via
the
oral
route.

C
Both
dermal
and
inhalation
exposure
assessments
used
an
absorption
factor
of
100%
of
the
oral
exposure.

Exposure
Assessment
The
use
pattern
for
ethofumesate
is
expected
to
result
in
exposure
to
the
general
population
via
food,
drinking
water
and
short­
term
post­
application
residential
exposure.
HED
has
also
identified
16
occupational
handler
scenarios
for
short­
and
intermediate­
term
exposure.
It
should
be
noted
that
exposures
for
the
general
population
and
infants
were
characterized
in
this
assessment
using
a
NOAEL
of
190
mg/
kg/
day.
For
informational
purposes,
exposures
for
women
of
child­
bearing
years
(
females
13­
49
yrs)
were
based
on
a
different
toxicological
endpoint
(
e.
g.,
NOAEL
of
30
mg/
kg/
day).

Food
Exposure
and
Risk
The
nature
of
the
residue
in
plants
and
animals
is
adequately
understood
for
the
purposes
of
the
new
use
on
onions
based
on
metabolism
studies
with
ryegrass,
sugar
beets,
hens,
rats
and
cows.
Ethofumesate
is
converted
via
the
hemiacetal
(
NC
8493,
loss
of
the
ethyl
group)
to
the
lactone
(
NC
9607)
and
acid
(
NC
20645)
in
all
of
the
above
species.
The
HED
Metabolism
Assessment
Review
Committee
(
MARC)
has
determined
that
the
parent
ethofumesate
and
all
metabolites,
NC
8493,
NC
9607,
and
NC
20645,
free
and
conjugated,
are
of
toxicological
concern
and
should
be
considered
for
tolerance
enforcement
and
dietary
risk
assessment
purposes.
However,
the
data
indicate
that
the
toxicity
of
the
metabolites
is
comparable
to
that
of
the
parent.
Therefore,
the
parent
and
the
metabolites
have
been
assessed
together
because
of
their
equivalent
toxicity.
Based
on
the
environmental
fate
properties
and
the
relatively
small
(
i.
e.,
<
10%)
amounts
of
degradates
detected
in
environmental
fate
studies,
MARC
also
determined
that
only
the
parent
should
be
assessed
for
drinking
water.

A
tolerance
enforcement
method
is
listed
as
Method
I
in
the
Pesticide
Analytical
Manual
Vol.
II
(
PAM
II,
Section
108.345)
for
determining
the
currently
regulated
residues
in
plants,
which
include
ethofumesate
and
its
metabolites
NC
8493
and
NC
9607
(
free
and
conjugated).
Although
this
method
does
not
specifically
address
the
recovery
of
free
and
conjugated
NC
20654,
the
acid
hydrolysis
step
used
in
the
method
most
likely
results
in
the
conversion
of
NC
20654
to
NC
9607.
Residues
are
determined
using
gas
chromatography
with
flame
ionization
detector
(
GC/
FID).
The
reported
limit
of
quantitation
(
LOQ)
for
each
analyte
is
Page
9
of
73
0.02
ppm.
PAM
Vol.
I,
Appendix
I
indicates
that
ethofumesate
is
completely
recovered
using
FDA
Multiresidue
Methods
Section
302
(
Luke
Method;
Protocol
D).
However,
no
data
are
available
on
the
recovery
of
the
metabolites
NC
8493,
NC
9607,
and
NC
20654.
These
data
should
be
submitted
for
any
future
action.
In
addition
to
Method
I
above,
the
registrant
has
proposed
a
gas
chromatography
with
flame
photometric
detector
in
the
sulfur
mode
(
GC/
FPD­
S)
method
for
enforcing
tolerances
in
plant
commodities.
This
method
was
most
recently
referred
to
as
Bayer
CropScience
Method
Number
XB/
01/
01,
is
the
same
as
the
data
collection
GC/
FPD­
S
Method
B­
93R­
03.
The
LOQ
for
each
analyte
is
0.05
ppm.
During
the
acid
hydrolysis
step,
free
and
conjugated
residues
of
NC
20645
are
released
and
recyclized
to
form
NC
9607.
Onion
samples
were
analyzed
for
ethofumesate
and
metabolites
NC
9607
and
NC
8493
using
AgrEvo
Report
No.
B­
93R­
03.
Minor
modifications
were
made
that
did
not
negatively
affect
the
performance
of
the
method.
Quantitation
was
accomplished
by
gas
chromatograph
wit
a
mass
selective
detector
(
GC­
MSD).
The
lower
limit
of
method
validation
(
LLMV)
for
dry
bulb
onions
is
0.05
ppm
for
all
three
analytes.
The
LOD
is
0.02
ppm
for
ethofumesate
and
the
limit
of
quantitation
(
LOQ)
is
0.055ppm.
There
is
sufficient
storage
stability
data
to
indicate
that
ethofumesate
residues
of
interest
do
not
degrade
in
onions
over
the
harvest
to
analysis
interval.

IR­
4
has
submitted
field
trial
data
for
ethofumesate
on
onion
(
dry
bulb).
The
number
and
locations
of
field
trials
are
in
accordance
with
OPPTS
Guideline
860.1500.
The
first
application
was
broadcast
to
the
soil
surface
prior
to
crop
emergence
at
a
rate
approximately
1.0
lb
ai/
A.
Subsequent
applications
were
foliar
and
made
at
approximate
even
intervals
at
a
rate
of
approximately
0.5
lb
ai/
A
each
for
a
total
of
approximately
3.0
lb
ai/
A,
with
the
last
application
timed
so
that
mature
or
near
mature
dry
bulb
onions
could
be
harvested
28
to
32
days
after
the
final
application.
In
treated
samples,
ethofumesate
residues
were
mostly
below
the
lowest
level
of
method
validation
(
LLMV)
of
0.05
ppm
and
ranged
to
0.087
ppm.
NC
9607
residues
ranges
from
the
LLMV
to
0.112
ppm.
No
NC
8493
residues
above
the
LLMV
were
observed
in
any
of
the
samples.
Total
residues
of
ethofumesate
and
metabolites
ranged
from
<
0.15
to
0.22
ppm
with
a
highest
average
field
trial
(
HAFT)
of
0.20
ppm.
PHIs
were
from
28­
32
days.
The
requested
tolerances
for
garlic,
bulb
and
shallot,
bulb
are
not
required
since
they
are
automatically
included
in
the
onion
tolerance.
In
addition,
the
preferred
term
for
the
commodity
should
be
onion,
bulb.
The
MRL
spreadsheet
indicates
that
the
requested
tolerance
is
not
appropriate
and
should
be
lowered.
The
petitioner
should
submit
a
revised
Section
F
requesting
a
tolerance
for
ethofumesate
residues
on
onion,
bulb
at
0.25
ppm.

Acute
and
Chronic
Dietary
­
Food
+
Water
An
acute
and
chronic
dietary
(
food+
water)
risk
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analysis
was
performed
to
support
the
Section
3
petition.
The
acute
and
chronic
dietary
exposure/
risk
analyses
were
conducted
using
tolerance
values,
default
processing
factors,
processing
factor
from
sugar
beet
processing
studies,
100%
crop
treated
for
all
commodities,
and
a
point
(
acute)
and
average
(
chronic)
concentration
for
drinking
water
from
PRZM/
EXAMS
DP
Barcode
D326518
/
46510101
Page
10
of
73
estimates.
Based
in
this
Tier
1
(
unrefined)
assessment,
the
team
selected
the
95th
percentile
of
exposure
to
estimate
acute
dietary
risk
from
food
and
water.
No
monitoring
data
are
available
for
ethofumesate.

The
values
used
in
the
dietary
risk
assessment
for
drinking
water
were
provided
by
the
Environmental
Fate
and
Effects
Division
(
EFED)
in
the
following
memo:
Ethofumesate
 
Drinking
Water
Assessment
for
the
Health
Effects
Division
(
HED)
Reregistration
Eligibility
Decision
Document
(
DP
Num:
296949,
M.
Corbin,
6/
9/
04)
and
updated
by
e­
mail
from
Amer
Al­
Mudallal
to
José
Morales
on
7/
5/
05.
Water
residues
were
incorporated
in
the
DEEM­
FCID
 
into
the
food
categories
"
water,
direct,
all
sources"
and
"
water,
indirect,
all
sources".

Based
on
modeling
results,
the
maximum
estimated
surface
water­
derived
drinking
water
concentrations
for
the
use
of
ethofumesate
is
154
Fg/
L
(
used
for
the
acute
analysis)
using
the
Florida
turf
scenario.
The
maximum
1
in
10
year
annual
average
concentration
is
45.5
Fg/
l
(
used
for
the
chronic
analysis)
using
the
Florida
turf
scenario,
and
26
Fg/
L
for
the
30
year
annual
mean
concentration
for
the
Minnesota
sugar
beet
scenario.

Acute
Dietary
Exposure
Results
and
Characterization
A
conservative
acute
dietary
(
food
+
water)
assessment
was
performed
using
DEEMFCIDTM
Tolerance
level
residues
and
100%
crop
treated
were
used
in
the
assessment.
This
assessment
concludes
that
for
all
supported
commodities,
the
acute
dietary
exposure
estimate
is
below
HED's
level
of
concern
for
females
13­
49
years
of
age
(
the
only
identified
population
subgroup
of
concern)
at
4%
of
the
acute
population
adjusted
dose
(
aPAD)
at
the
95th
percentile.

Chronic
Dietary
Exposure
Results
and
Characterization
A
conservative
chronic
dietary
(
food
+
water)
assessment
was
performed
using
DEEMFCIDTM
Tolerance
level
residues
and
100%
crop
treated
were
used
in
the
assessment.
Dietary
risk
estimates
are
provided
for
the
general
U.
S.
population
and
various
population
subgroups.
This
assessment
concludes
that
for
all
supported
commodities,
the
chronic
dietary
exposure
estimates
are
below
HED's
level
of
concern
for
all
population
subgroups
at
<
1%
of
the
chronic
population
adjusted
dose
(
cPAD).
The
most
highly
exposed
population
subgroup
was
all
infants
<
1
yr
old.

Residential
Exposure
Post­
application
exposure
for
adults
and
children
resulting
from
turf
(
lawn
care)
and
golf
course
uses
are
the
only
expected
residential
exposure
scenarios.
Based
on
the
use
pattern,
HED
performed
screening
level
calculations
on
the
scenarios
most
likely
to
have
the
highest
possible
exposure
for
toddlers
and
adults.
For
toddlers,
these
included:
incidental
ingestion
(
hand­
tomouth
turf­
to­
mouth
and
soil
­
to­
mouth)
and
used
the
NOAEL
of
190
mg/
kg/
day
from
the
90­
day
subchronic
rat
study.
For
adults,
Jazzercise
(
on
treated
turf),
a
NOAEL
of
190
mg/
kg/
day
from
the
90­
day
subchronic
rat
study
was
used
and
a
NOAEL
of
30
mg/
kg/
day
from
a
developmental
study
in
rabbits
was
used
for
females
13­
49
years
of
age.
HED
believes
that
this
screening
level
assessment
will
be
protective
of
other
possible
residential
exposures
to
DP
Barcode
D326518
/
46510101
Page
11
of
73
ethofumesate
such
as
golfing
or
mowing
the
lawn.

Exposures
were
calculated
by
considering
the
potential
sources
of
exposure
(
i.
e.,
lawns)
then
calculating
dermal
exposure
and
risk.
With
the
exception
of
women
of
child­
bearing
years,
residential
post­
application
MOEs
for
toddlers
and
adults
to
ethofumesate
on
treated
turf,
regardless
of
the
pathway
of
exposure,
do
not
exceed
HED'
levels
of
concern
for
the
most
common
rate
of
1.5
lb
ai/
A
and
the
occasional
rate
of
3.0
lb
ai/
A.
In
the
case
of
women
of
childbearing
years,
MOEs
of
73
for
1.5
lb
ai/
A
rate
and
37
for
the
3.0
lb
ai/
A
were
estimated
based
on
an
oral
endpoint
from
a
developmental
study
in
rabbits)
and
the
conservative
assumption
that
dermal
absorption
will
be
100%,
and
screening­
level
assumptions
regarding
exposure
from
HED
SOPs
including
high
contact
activities
(
Jazzercise)
on
turf
immediately
posttreatment.
Additionally,
the
endpoint
used
for
females
13+
years
of
age
comes
from
a
developmental
study
in
rabbits
that
has
a
steep
dose­
response
curve
resulting
from
a
NOAEL
(
30
mg/
kg/
day)
that
is
10X
lower
than
the
LOAEL
(
300
mg/
kg/
day);
thus,
a
dose
spacing
issue
may
likely
exists.
HED,
therefore,
considers
this
a
highly
conservative
estimate
of
post­
application
risk
for
the
population
females
13­
49
years
of
age
exposed
to
ethofumesate
on
turf.

Aggregate
Exposure
In
examining
aggregate
exposure,
the
ARIA
takes
into
account
all
the
available
and
reliable
information
concerning
exposures
from
pesticide
residues
in
food
and
other
exposures
including
drinking
water
and
non­
occupational
exposures,
[
e.
g.,
exposure
to
pesticides
used
in
and
around
the
home
(
residential)].

For
the
acute
aggregate
risk
scenario,
the
food
and
drinking
water
exposures
were
taken
into
account
in
the
dietary
exposure
assessment.
The
estimated
dietary
exposures
(
food
and
water)
for
females
13­
49
years,
the
only
population
subgroup
of
toxicological
concern
identified
at
this
time,
at
4%
of
the
aPAD
does
not
exceed
the
Agency's
level
of
concern.

For
short­
and
intermediate­
term
assessments,
the
oral,
dermal
and
inhalation
pathways
can
be
combined
due
to
the
common
toxicity
endpoint
via
the
oral,
dermal
(
oral
equivalent)
and
inhalation
(
oral
equivalent)
routes
for
the
appropriate
population
of
concern.
For
the
short­
and
intermediate­
term
aggregate
risk
scenarios,
food,
drinking
water
and
residential
exposures
are
taken
into
account.
The
chronic
dietary
(
food
+
water)
exposure
estimate
for
all
population
subgroups
was
<
1%
of
the
cPAD
with
the
most
highly
exposed
subgroup
being
all
infants
<
1
yrs
old.
The
aggregate
short­
term
MOEs,
combining
food,
drinking
water
and
residential
exposures
ranged
from
160
for
all
infants
<
1
yrs
old
to
270
for
the
U.
S.
population.
Risk
estimates
for
these
population
subgroups
are
below
the
Agency's
level
of
concern
(
MOEs
of
100
or
less).
In
the
case
of
women
of
childbearing
years,
a
residential
risk,
and
subsequently
for
the
aggregate
risk
assessment,
an
MOE
of
37
was
estimated,
based
on
an
oral
endpoint
from
a
developmental
study
in
rabbits.
ARIA
notes
that
this
risk
estimate
is
driven
by
the
conservative
assumptions
used
in
the
risk
assessment:
1)
screening­
level
unrefined
Tier
1
assessment
was
used,
2)
100%
dermal
absorption
was
assumed,
and
3)
an
endpoint
used
for
females
13+
years
of
age
from
a
developmental
study
in
rabbits
with
a
steep
dose­
response
curve
resulting
from
a
NOAEL
(
30
mg/
kg/
day)
that
is
10X
lower
than
the
LOAEL
(
300
mg/
kg/
day);
thus,
a
dose
spacing
issue
likely
exists.
ARIA,
therefore,
considers
this
a
highly
conservative
estimate
of
post­
application
risk
for
DP
Barcode
D326518
/
46510101
Page
12
of
73
the
population
females
13­
49
years
of
age
exposed
to
ethofumesate
on
turf.

There
are
no
long­
term
residential
exposure
use
patterns
for
ethofumesate,
therefore
an
aggregate
risk
assessment
was
not
conducted.

For
the
chronic
aggregate
risk
scenario,
food,
drinking
water,
and
residential
exposures
were
taken
into
account.
In
this
case,
chronic
exposure
in
residential
settings
is
not
expected
and
the
aggregate
chronic
assessment
included
food
and
drinking
water
only.
Since
the
dietary
exposure
assessment
already
includes
the
highest
chronic
exposure
from
the
drinking
water
modeling
data,
no
further
calculations
are
necessary.
The
dietary
exposure
estimate
for
all
population
subgroups
was
<
1%
of
the
cPAD
with
the
most
highly
exposed
subgroup
being
all
infants
<
1
yrs
old.
Risk
estimates
for
all
population
subgroups
are
below
the
Agency's
level
of
concern
(
100%
of
the
cPAD).

Occupational
Exposure
No
chemical­
specific
handler
exposure
data
were
submitted
in
support
of
this
Section
3
registration.
It
is
the
policy
of
the
HED
to
use
data
from
the
Pesticide
Handlers
Exposure
Database
(
PHED)
Version
1.1
as
presented
in
PHED
Surrogate
Exposure
Guide
(
8/
98)
to
assess
handler
exposures
for
regulatory
actions
when
chemical­
specific
monitoring
data
are
not
available
(
HED
Science
Advisory
Council
for
Exposure
[
ExpoSAC]
Draft
Policy
#
7,
dated
1/
28/
99).

Occupational
handlers'
MOEs
range
from
2,740
for
exposure
from
mixing
and
loading
liquid
formulations
with
gloves
to
4,500
for
open­
cab
ground­
boom
applicators.
These
MOEs
are
well
above
the
level
of
concern
for
occupational
scenarios,
which
is
an
MOE
of
100.

It
is
possible
for
agricultural
workers
to
have
post­
application
exposure
to
pesticide
residues
during
the
course
of
typical
agricultural
activities.
In
this
case,
there
is
only
one
postapplication
agricultural
activity
that
is
likely
to
occur,
scouting
for
pesticide
efficacy.
HED
does
not
expect
post­
application
exposures
to
exceed
short
term
exposure.
Therefore,
only
short
term
exposures
are
assessed.
The
MOE
for
scouting
for
pesticide
efficacy
is
2500.
A
MOE
of
100
is
adequate
to
protect
agricultural
workers
from
post­
application
exposures
to
ethofumesate.
Since
the
estimated
MOEs
are
>
100,
the
proposed
use
pattern
does
not
exceed
HED's
level
of
concern.

Ethofumesate
is
classified
in
acute
toxicity
category
IV
for
acute
dermal
toxicity,
category
II
for
acute
inhalation
toxicity
and
category
V
for
acute
eye
irritation
and
dermal
irritation.
It
is
not
a
dermal
sensitizer.
The
interim
worker
protection
standard
(
WPS)
REI
of
12
hours
is
adequate
to
protect
agricultural
workers
from
post­
application
exposures
to
ethofumesate.
The
product
label
lists
a
12
hr
REI.

Recommendation
for
Tolerances
Provided
a
revised
Section
F
is
received,
the
Agency
recommends
establishing
a
permanent
tolerance
for
the
combined
residues
of
ethofumesate
as
ethofumesate
(
2­
ethoxy­
2,3­
DP
Barcode
D326518
/
46510101
Page
13
of
73
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate)
and
its
metabolites
2­
hydroxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate
and
2,3­
dihydro­
3,3­
dimethyl­
2­
oxo­
5­
benzofuranyl
methanesulfonate
(
both
calculated
as
the
parent
compound)
in/
on
onion,
bulb
at
0.25
ppm.

2.0
Ingredient
Profile
Ethofumesate
is
a
selective,
benzofuranyl
alkylsulfonate
type,
herbicide
used
for
the
control
of
broadleaf
and
grass
weeds.
In
the
U.
S.,
ethofumesate
products
registered
to
Bayer
CropScience,
the
basic
producer,
include
a
4
lb/
gal
flowable
concentrate
(
FlC)
and
several
emulsifiable
concentrates
(
0.05­
1.5
lb/
gal
EC),
marketed
primarily
under
the
trade
names
Norton
®
and
Progress
®
Herbicides.
These
formulations
can
be
applied
as
banded
or
broadcast
pre­
plant,
preemergence,
and
postemergence
applications
using
ground
or
aerial
equipment.

Table
2.0.
a
Test
Compound
Nomenclature
Compound
Chemical
Structure
Common
name
Ethofumesate
Company
experimental
name
Nortron
SC
IUPAC
name
(
RS)­
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethylbenzofuran­
5­
yl
methanesulfonate
CAS
name
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate
CAS
#
26225­
79­
6
End­
use
product/(
EP)
Nortron
®
SC,
EPA
Reg.
No.
264­
613
Table
2.0.
b
Physicochemical
Properties
of
the
Technical
Grade
Test
Compound
Parameter
Value
Reference
DP
Barcode
D326518
/
46510101
Page
14
of
73
Melting
point/
range
75.5­
77.0EC
pH
4.49
(
approx.
1%
aqueous
slurry);
Product
Chemistry
for
FOE
5043
Technical.

MRID's
438500­
01,
438500­
02,
438500­
03
Density
1.312
g/
mL
(
at
20
E
C)

Water
solubility
(
20
°
C)
56
mg/
L
Solvent
solubility
(
20
°
C)
n­
hexane
8.7
g/
L
toluene
>
200
g/
L
dichloromethane
>
200
g/
L
2­
propanol
170
g/
L
1­
octanol
88
g/
L
polyethylene
glycol
74
g/
L
polyethylene
glycol
+
ethanol
160
g/
L
acetone
>
200
g/
L
dimethylformamide
>
200
g/
mL
acetonitrile
>
200
g/
mL
dimethylsulfoxide
>
200
g/
L
Vapor
pressure
at
25
°
C
2
X
10­
6
h
Pa
at
25
E
C
(
N­
isomer)
(
equivalent
to
4
X
10­
6
torr)

Dissociation
constant
(
pKa)
Does
not
dissociate
in
water.

Octanol/
water
partition
coefficient
Log(
KOW)
Pow
=
1600
at
24
E
C
UV/
visible
absorption
spectrum
NA
2.1
Summary
of
Proposed
Uses
Table
2.1
Summary
of
Directions
for
Use
of
Ethofumesate.

Applic.
Timing,
Type,
and
Equip.
Formulation
[
EPA
Reg.
No.]
Applic.
Rate
(
lb
ai/
A)
Max.
No.
Applic.
per
Season
Max.
Seasonal
Applic.
Rate
(
lb
ai/
A)
PHI
(
days)
Use
Directions
and
Limitations
Onion,
dry
bulb;
Garlic;
Shallot
Apply
at
planting
or
shortly
after,
before
weed
germination
1
1
Foliar
Applic.
Nortron
®
SC
[
264­
613]

0.5
4
3
30
Use
low
pressure
sprayer
at
10­
40
gpa.
Do
not
exceed
3.0
lb
ai/
A.
Do
not
rotate
to
any
crop
other
than
sugar
beets
or
ryegrass
for
12
months
following
applications
totaling
more
than
0.375
lb
ai/
A
and
for
6
months
following
postemergence
applications
totaling
#
0.375
lb
ai/
A.
DP
Barcode
D326518
/
46510101
Page
15
of
73
3.0
Hazard
Characterization/
Assessment
3.1
Hazard
and
Dose­
Response
Characterization
3.1.1
Database
Summary
3.1.1.
a
Studies
available
and
considered
(
animal,
human,
general
literature)

Acute
­
none
­
see
Table
4.1a
for
LD50
data
Subchronic
­
Oral
90­
day
rat;
oral
90­
day
dog;
Dermal
21­
day
rat;
Inhalation 
none
Chronic
­
Oral
rat
and
dog
Repro/
developmental
­
Oral
developmental
rabbit,
rat
and
3­
generation
reproductive
Other
­
Oral
rat
and
mouse
cancer
studies
and
mutagenicity
screens
3.1.1.
b
Mode
of
action,
metabolism,
toxicokinetic
data
Ethofumesate
is
a
benzofuranyl
alkyl
sulfonate
herbicide;
the
mode
of
action
for
this
structural
group
is
not
known.
A
metabolism
study
in
rats
indicated
that
this
herbicide
is
excreted
primarily
in
the
urine
with
most
of
the
administered
dose
excreted
by
5
days
postdosing.
The
same
metabolites
are
formed
in
plants,
livestock
and
in
the
rat.
Ethofumesate
is
converted
via
the
hemiacetal
(
NC
8493,
loss
of
the
ethyl
group)
to
the
lactone
(
NC9607)
and
acid
(
NC20645)
in
all
of
the
above
species.
However,
the
data
indicate
that
the
toxicity
of
the
metabolites
is
comparable
to
that
of
the
parent.

3.1.1.
c
Sufficiency
of
studies/
data
The
toxicity
database
is
essentially
complete
The
only
data
gap
is
for
a
28­
day
inhalation
toxicity
study
which
is
required
to
assess
toxicity
from
inhalation
exposure,
based
on
the
potential
for
inhalation
exposure
to
spray
applicators
under
the
current
use
patterns.
Nevertheless,
data
are
sufficient
for
each
exposure
scenario
and
for
FQPA
evaluation.
Data
are
sufficient
for
important
endpoints
and
dose­
response
evaluation
for
three
species.

3.1.2
Toxicological
Effects
The
liver
is
the
main
target
organ
in
rats
and
dogs
and
the
major
critical
effects
seen
in
oral
studies
are
decreased
body
weight
gain
and
hepatic
toxicity
in
the
rat,
dog
and/
or
rabbit.
Mice
are
relatively
insensitive
to
ethofumesate
even
up
to
the
limit
dose
following
chronic
dietary
exposure.
In
rabbits,
effects
included
death,
decreased
body
weight
abortions
and
complete
litter
resorption
at
levels
in
excess
of
the
limit
dose.
Additionally,
developmental
effects
were
noted
at
doses
that
were
not
maternally
toxic.
Although
the
mode
of
action
is
not
known,
the
critical
effects
are
considered
relevant
to
humans
because
they
are
observed
in
at
least
three
species
tested.
The
chemical
is
not
likely
to
be
carcinogenic
based
on
bioassays
in
the
rat
and
the
mouse
combined
with
a
lack
of
in
vitro
or
in
vivo
mutagenicity.
Ethofumesate
did
not
demonstrate
the
potential
to
cause
neurotoxicity
in
at
least
four
species
(
rats,
mice,
dogs
and
rabbits)
and
rats
did
not
show
evidence
of
developmental
toxicity
or
maternal
or
offspring
toxicity
in
a
3­
generation
reproduction
study.
By
contrast,
increased
prenatal
quantitative
susceptibility
DP
Barcode
D326518
/
46510101
Page
16
of
73
was
seen
in
the
rabbit
developmental
study
(
i.
e,
increased
resorptions,
increased
postimplantation
loss
and
incomplete
ossification
at
a
dose
that
was
not
maternally
toxic);
these
NOAELs/
LOAELs
are
well
characterized
and
are
used
as
endpoints
for
appropriate
risk
assessment.

3.1.3
Dose­
response
Studies
showing
body
weight
decrements,
liver
toxicity
or
adverse
effects
on
fetuses
were
considered
for
oral,
dermal
and
inhalation
routes
of
exposure.

The
oral
exposure
limits
for
the
acute
and
chronic
RfDs
(
females
13­
49
years
old)
were
based
on
the
developmental
rabbit
study.
No
appropriate
single­
dose
endpoint
was
available
for
the
acute
oral
exposure
of
the
general
population,
including
infants
and
children.
However,
the
combined
chronic/
carcinogenicity
study
in
rats
was
selected
as
the
chronic
RfD
for
this
subgroup.
The
subchronic
(
90­
day)
oral
toxicity
study
in
rats
was
chosen
for
the
incidental
oral
(
short­
and
intermediate­
term)
exposure
scenarios.
In
all
cases,
the
rat
was
the
most
sensitive
species
and
the
selected
endpoints
provide
protective
limits
for
human
effects
potential.

A
default
assumption
of
100%
dermal
absorption
is
used
for
all
dermal
exposure
assessments
because
of
the
unavailability
of
data
on
dermal
penetration
and
the
unavailability
of
comparative
oral
and
dermal
toxicity
data
with
a
common
endpoint
in
the
same
species.
Accordingly,
dermal
exposure
limits
for
all
durations
and
for
females
13­
49
years
of
age
are
based
on
the
oral
developmental
toxicity
study
in
rabbits
because
of
the
concerns
for
developmental
effects
that
are
seen
in
this
study
which
were
not
evaluated
in
the
21­
day
dermal
toxicity
study
in
the
rabbit.
Toxicology
studies
selected
for
the
general
population,
including
infants
and
children
are
the
90­
day
oral
toxicity
study
in
rats
for
the
short
and
intermediate­
term
dermal
exposures
and
the
combined
oral
chronic
toxicity/
carcinogenicity
study
in
rats
for
the
long­
term
dermal
exposure.

The
inhalation
exposure
used
a
100%
default
assumption
in
the
absence
of
a
21/
28­
day
inhalation
study.

The
uncertainty
factors
used
in
determining
RfD
exposure
limits
were
10X
default
factors
for
intra­
and
interspecies
variability,
respectively.

3.1.4
FQPA
The
database
is
adequate
in
terms
of
endpoint
studies
and
dose
response
information
to
characterize
any
potential
prenatal
or
postnatal
risk
for
infants
and
children.
No
increase
in
susceptibility
of
rats
was
seen
in
developmental
studies
or
in
a
rat
3­
generation
reproductive
study.
Although
increased
prenatal
quantitative
sensitivity
was
observed
in
the
rabbit
developmental
toxicity
study,
the
developmental
toxicity
NOAELs
and
LOAELs
are
well
characterized
and
are
used
as
endpoints
for
risk
assessment
for
the
appropriate
population
subgroups.
Since
there
are
no
residual
uncertainties
that
indicate
the
need
for
a
special
safety
factor,
the
hazard
factor
is
1X.
DP
Barcode
D326518
/
46510101
Page
17
of
73
3.1.5
Toxicity
Profiles
The
database
for
acute
toxicity
for
ethofumesate
is
considered
complete
and
is
summarized
in
Table
4.
As
shown,
ethofumesate
exhibited
low
acute
toxicity
by
the
oral
and
dermal
exposure
routes
(
Toxicity
Category
IV)
and
is
not
a
dermal
or
ocular
irritant.
The
Toxicity
Category
for
acute
inhalation
exposure
is
II,
but
it
was
not
tested
at
higher
dose
levels
due
to
reported
technical
limitations.
No
potential
for
dermal
sensitization
was
observed
in
a
guinea
pig
maximization
assay.

Table
3.1.5.
a
Acute
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
[
Rat]
00030418,
41214215
LD50
>
6400
mg/
kg
IV
870.1200
Acute
dermal
toxicity
[
Rat
or
rabbit]
00030419­
21
LD50
>
20,050
mg/
kg
IV
870.1300
Acute
inhalation
toxicity
[
Rat]
41554101
LC50
>
0.49
mg/
L
II
870.2400
Acute
eye
irritation
[
Rat]
00030421,
41949204
Not
an
ocular
irritant
IV
870.2500
Acute
dermal
irritation
[
Rabbit]
00030420,
41949205
Not
a
dermal
irritant
IV
870.2600
Skin
sensitization
[
Guinea
Pigs]
41404601
Not
a
dermal
sensitizer
NA
NA
Not
applicable
Table
3.1.5.
b
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Subchronic
Toxicity
Studies
870.3100
90­
Day
oral
toxicity
rodents
[
Crl:
CD(
SD)
rats]
44093601
(
1989)
Acceptable/
guideline
0,
300,
3000
or
30,000
ppm
in
diet
(
males
0,
18.2,
190
or
1900
mg/
kg/
day;
females
0,
23.4,
230
or
2309
mg/
kg/
day)
NOAEL
=
190
mg/
kg/
day,
males
(
230
mg/
kg/
day,
females)
LOAEL
=
1900
mg/
kg/
day
based
on
reduced
body
weight
gain,
microscopic
lesions
in
liver
and
kidney
(
2309
mg/
kg/
day
in
females
based
on
reduced
body
weight/
weight
gain).
DP
Barcode
D326518
/
46510101
Page
18
of
73
Table
3.1.5.
b
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
[
Crl:
CD­
1(
ICR)
BR(
VAF
plus)
mice]
44156201
(
1990)
Acceptable/
nonguideline
rangefinding
study
for
cancer
study
0,300,
3000
or
10,000
ppm
in
diet
(
0,
45,
450
or
1500
mg/
kg/
day,
estimated)
NOAEL
=
1500
mg/
kg/
day
LOAEL
=
not
established
(>
1500
mg/
kg/
day)

870.3100
90­
Day
oral
toxicity
nonrodent
[
Beagle
dog]
See
870.4100b,
below
870.3200
21­
Day
dermal
toxicity
[
New
Zealand
White
rabbits]
41997204,
42689902
(
1991)
Acceptable/
guideline
0,
100,
300
or
1000
mg/
kg/
day
moistened
with
water
to
shaved
skin
NOAEL
=
1000
mg/
kg/
day
(
HDT)
LOAEL
=
not
established
(
mild
clinical
chemistry
effects
in
males,
not
considered
adverse
at
1000
mg/
kg/
day).

Developmental
and
Reproductive
Toxicity
Studies
870.3700a
Prenatal
developmental
in
rodents
[
Crl:
CD(
SD)
BR
rats]
42067701,
42689901
(
1991)
Acceptable/
guideline
0,
10,
100
or
1000
mg/
kg/
day
by
gavage,
gestation
days
6
through
15
Maternal
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
established
(>
1000
mg/
kg/
day
based
on
postdosing
salivation
and
transiently
decreased
food
consumption
not
considered
adverse).
Developmental
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
not
established
(>
1000
mg/
kg/
day).

870.3700b
Prenatal
developmental
in
nonrodents
[
New
Zealand
White
Rabbit]
00156606,
40263701,
41652501
(
1986)
Acceptable/
guideline
0,
30,
300
or
3000
mg/
kg/
day
by
gavage
on
gestation
days
6
through
18
Maternal
NOAEL
=
300
mg/
kg/
day
LOAEL
=
3000
mg/
kg/
day
based
on
decreased
body
weights
and
increased
mortality,
abortions
and
complete
litter
resorptions.
Developmental
NOAEL
=
30
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.
DP
Barcode
D326518
/
46510101
Page
19
of
73
Table
3.1.5.
b
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3800
Reproduction
and
fertility
effects
[
Crl:
CD
rats]
00062823,
00062924
(
1980)
Acceptable/
guideline
0,
200,
1000
or
5000
ppm
in
diet
(
Premating
0,
15.6,
77.6
or
396.8
mg/
kg/
day,
males;
0,
18.0,
91.2
or
462.5
mg/
kg/
day,
females)
Parental/
Systemic
NOAEL
=
396.8
mg/
kg/
day
males
(
462.5
mg/
kg/
day
females).
LOAEL
=
not
established
(>
396.8
mg/
kg/
day
males,
462.5
mg/
kg/
day
females).
Reproductive
NOAEL
=
396.8
mg/
kg/
day
males
(
462.5
mg/
kg/
day
females).
LOAEL
=
not
established
(>
396.8
mg/
kg/
day
males,
462.5
mg/
kg/
day
females).
Offspring
NOAEL
=
396.8
mg/
kg/
day
(
males
(
462.5
mg/
kg/
day
females).
LOAEL
=
not
established
(>
396.8
mg/
kg/
day
males,
462.5
mg/
kg/
day
females).
[
Note:
although
study
did
not
test
to
limit
dose,
HDT
was
similar
to
doses
in
rat
chronic/
onco
that
showed
effects
and
new
study
not
required].

Chronic
Toxicity
Studies
870.4100a
Chronic
toxicity
rodents,
52­
week
interim
report
for
2
year
rat
study
[
Sprague­
Dawley
rats]
44093602
(
1990)
Acceptable/
guideline
0,
2000,
7000
or
20,000
ppm
in
diet
(
Males
0,
115,
398
or
1135
mg/
kg/
day;
females
0,
144,
577
or
1697
mg/
kg/
day)
NOAEL
=
115
mg/
kg/
day,
males
(
144
mg/
g/
day,
females).
LOAEL
=
398
mg/
kg/
day
based
on
microscopic
liver
lesions,
males
(
577
mg/
kg/
day,
females
based
on
reduced
body
weight/
weight
gain).

870.4100b
Chronic
toxicity
nonrodent
[
Beagle
dog]
00062822
(
1980)
Acceptable/
guideline
0,
800,
4000
or
20,000
ppm
in
diet
(
Males
0,
24.5,
117.8,
632.4
mg/
kg/
day;
females
0,
23.7,
109.0
or
618.9
mg/
kg/
day)
NOAEL
=
117.8
mg/
kg/
day,
males
(
109.0
mg/
kg/
day,
females).
LOAEL
=
632.4
mg/
kg/
day,
males
(
618.9
mg/
kg/
day,
females)
based
on
increased
liver
weight
and
circulating
levels
of
alkaline
phosphatase
and
alanine
aminotransferase.

Chronic
Toxicity/
Carcinogenicity
Studies
870.4200
Carcinogenicity
(
80
week)
[
Crl:
CD­
1(
ICR)
BR(
VAF
plus)
mice]
44156202
(
1992)
Acceptable/
guideline
0,
1000,
3000
or
10,000
ppm
in
diet
(
Males
0,
161,
477
or
1601
mg/
kg/
day;
females
204,
644
or
2145
mg/
kg/
day)
NOAEL
=
1601
mg/
kg/
day
males
(
2145
mg/
kg/
day
females).

LOAEL
=
not
established
(>
1601
mg/
kg/
day
males,
2145
mg/
kg/
day
females).
No
evidence
of
carcinogenicity
at
dose
exceeding
limit
dose.
DP
Barcode
D326518
/
46510101
Page
20
of
73
Table
3.1.5.
b
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.4300
Combined
Chronic
Toxicity/
Carcinogenic
ity
(
104
week)
[
Sprague
Dawley
rats]
44093603,
44093604
(
1991)
Acceptable/
guideline
0,
2000,
7000
or
20,000
ppm
in
diet
(
Males
0,
97,
332
or
1003
mg/
kg/
day;
females
0,
127,
469
or
1466
mg/
kg/
day)
NOAEL
=
127
mg/
kg/
day,
females
(
332
mg/
kg/
day,
males).

LOAEL
=
469
mg/
kg/
day,
females
based
on
reduced
body
weight/
weight
gain
(
1003
mg/
kg/
day,
males
based
on
liver
cell
histopathology).

Equivocal
evidence
of
carcinogenicity,
not
considered
treatment­
related:
Incidence
of
interstitial
cell
adenomas
of
the
tested
was
0/
50,
5/
50
(
p<
0.05),
6/
50
(
p<
0.05)
and
8/
60
(
p<
0.01)
but
all
were
within
the
laboratory's
historical
control
range
of
4%
to
20%
(
average
11%);
concurrent
controls
had
unusually
low
incidence
(
0%).

870.4300
Combined
Chronic
Toxicity/
Carcinogenic
ity
(
104
week)[
CFHB
Wistar
rats]
00041853
(
1976)
Chronic
toxicity
Acceptable/
guideline;
Carcinogenicity
Unacceptable/
guideline
0,
8,
40,
200,
1000
or
5000
ppm
(
males
0,
0.29,
1.47,
7.36,
37.6
and
207.0
mg/
kg/
day;
females
0,
0.36,
1.73,
8.68,
44.5
or
236.0
mg/
kg/
day)
NOAEL
=
37.6
mg/
kg/
day,
males
(
44.5
mg/
kg/
day,
females)

LOAEL
=
207
mg/
kg/
day,
males
(
236
mg/
kg/
day,
females),
based
on
reduced
survival
in
males
and
decreased
body
weight
gain
in
both
males
and
females.

No
evidence
of
carcinogenicity
but
study
not
adequate
for
assessment
due
to
several
deficiencies
in
conduct.

Genotoxicity
Studies
Gene
Mutation
870.5100
In
vitro
bacterial
reverse
gene
mutation
assay
43529501
(
1994)
Acceptable/
guideline
15­
5000
Fg/
plate
±
metabolic
activation
(
rat
liver
S9)
in
S.
typhimurium
TA98,
TA100,
TA1535,
TA1537;
50­
5000
Fg/
plate
±
metabolic
activation
(
rat
liver
S9)
in
E.
coli
CM881
(
WP2
pKM101)
and
CM891
(
WP2
uvrA
pKM101)
No
evidence
of
increased
mutant
colonies
over
background
at
treatment
levels
causing
cytotoxicity.

Gene
Mutation
870.5300
In
vitro
mammalian
cell
in
culture
gene
mutation
assay
41710501
(
1986)
Acceptable/
guideline
7.9­
250
Fg/
mL
±
metabolic
activation
(
rat
liver
S9)
in
mouse
lymphoma
6TG
cells
No
evidence
of
increased
mutation
frequencies
up
to
dose
levels
that
were
insoluble
but
not
cytotoxic.
DP
Barcode
D326518
/
46510101
Page
21
of
73
Table
3.1.5.
b
Toxicity
Profile
­
Ethofumesate
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Cytogenetics
870.5375
In
vitro
mammalian
cytogenetics
assay
41214203
(
1986)
Acceptable/
guideline
11­
110
Fg/
mL
±
metabolic
activation
(
rat
liver
S9)
in
cultures
human
lymphocytes
No
evidence
of
increased
frequency
of
chromosomal
aberrations
up
to
dose
levels
that
were
insoluble
but
not
cytotoxic.

Cytogenetics
870.5395
In
vivo
mammalian
cytogenetics
assay
41214217
(
1985)
Acceptable/
guideline
8100
mg/
kg
bw
administered
by
gavage
to
male
and
female
CD­
1
mice
No
evidence
of
induced
clastogenic
or
aneugenic
response
up
to
dose
levels
exceeding
the
limit
dose
of
5000
mg/
kg
bw,
tested
at
24,
48
and
72
hrs
postdosing.

Other
Effects
870.5550
In
vitro
unscheduled
DNA
synthesis
41214204
(
1988)
Acceptable/
guideline
1.56­
200
Fg/
mL
in
primary
rat
hepatocytes
No
evidence
of
increased
UDS
up
to
dose
levels
that
were
cytotoxic
with
precipitation
of
test
material.

Metabolism
studies
870.7485
Metabolism
and
pharmacokinetics
[
Crl:
CD/
BR
rats]
42364503,
42689903
(
1992)
Acceptable/
guideline
Ring­
labeled
[
C­
14]­
ethofumesate
administered
as
single
gavage
dose
of
(
1)
10
or
(
2)
500
mg/
kg;
or
(
3)
14
daily
gavage
doses
of
unlabeled
ethofumesate
followed
by
single
dose
of
radiolabeled
ethofumesate.
Excretion
96­
99%
complete
by
5
days'
postdosing,
with
primary
route
of
excretion
via
urine
(
70­
92%
of
dose;
65­
78%
within
6
hr
postdosing).
Absorption
was
high
but
slightly
reduced
(
10­
15%)
at
500
mg/
kg,
suggesting
saturation.
Radioactivity
did
not
accumulate
in
tissues
but
was
highest
in
the
liver
(
0.007
to
1.50
Fg/
g
tissue)
and
kidney
(<
0.010
to
0.542
Fg/
g
tissue)
and
at
high
dose,
in
brain,
fat,
bone
and
testes
(
0.232­
0.452
Fg/
g
tissue).
Parent
was
excreted
only
in
feces
(
10­
15%
of
dose
at
500
mg/
kg).
Major
metabolite
identified
was
Met­
1
["­(
2­
hydroxy­
5­
methanesulfonyloxyphenyl)
isobutyric
acid].
Major
biotransformation
occurred
via
dealkylation
and
oxidation.
Metabolism
was
similar
for
males
and
females,
with
males
excreting
slightly
more
radioactivity
in
the
feces
than
females
(
6­
10%
of
dose).

3.2
FQPA
Hazard
Considerations
On
February
26,
2004,
HIARC
concluded
that
based
on
the
weight­
of­
the­
evidence
considerations,
there
is
no
concern
for
pre­
and/
or
post­
natal
toxicity
resulting
from
exposure
to
ethofumesate.

3.2.1
Adequacy
of
the
Toxicity
Database
At
this
time,
the
data
base
for
ethofumesate
is
adequate
for
reregistration
of
ethofumesate.
A
28­
day
inhalation
toxicity
study
is
requested,
however,
to
assess
DP
Barcode
D326518
/
46510101
Page
22
of
73
inhalation
exposure,
due
to
the
potential
for
inhalation
exposure
during
application.

3.2.2
Evidence
of
Neurotoxicity
HIARC
concluded
that
there
is
no
concern
for
neurotoxicity
resulting
from
exposure
to
ethofumesate.

3.2.3
Developmental
Toxicity
Studies
Developmental
Toxicity
in
Rats
In
a
prenatal
developmental
toxicity
study
(
MRIDs
42067701,
main
study
and
42689901,
addendum),
ethofumesate
technical
(
97%
a.
i.,
Lot/
Batch
#
CR19291/
1)
in
1.0%
(
w/
v)
aqueous
methylcellulose
was
administered
to
pregnant
Crl:
CD(
SD)
BR
rats
(
24/
dose)
daily
via
gavage
in
a
dosing
volume
of
10
mL/
kg
at
concentrations
of
0,
10,
100
or
1000
mg/
kg/
day
on
gestation
days
(
GD)
6
through
15.
All
dams
were
sacrificed
on
GD
20
and
their
uterine
contents
examined.

At
1000
mg/
kg,
maternal
food
consumption
was
decreased
(
p#
0.01)
by
16%
during
GD
6­
9
compared
to
concurrent
controls.
Post­
dosing
salivation
was
observed
in
dams
during
GD
7­
15;
salivation
began
immediately
following
dosing
and
lasted
for
up
to
70
minutes,
with
the
number
of
animals
affected
generally
increasing
as
the
dosing
period
progressed.
Water
consumption
was
increased
by
11­
14%
during
GD
6­
12.
This
finding
may
be
related
to
the
increased
salivation
in
these
animals.
Although
these
effects
are
considered
treatment­
related,
they
are
not
considered
adverse
and
therefore
were
not
used
to
establish
a
LOAEL
for
maternal
toxicity.
There
were
no
unscheduled
deaths
during
the
study
and
no
effects
of
treatment
on
maternal
body
weight
gains,
food
efficiency
or
gross
pathology.
There
were
no
effects
of
treatment
at
10
or
100
mg/
kg.
The
maternal
toxicity
LOAEL
was
not
established
in
this
study
(>
1000
mg/
kg/
day,
limit
dose).
The
maternal
NOAEL
is
$
1000
mg/
kg/
day.

There
were
no
treatment­
related
effects
on
the
numbers
of
fetuses
(
live
or
dead),
resorptions
(
early
or
late),
post­
implantation
loss,
sex
ratio,
fetal
weight
or
fetal
external,
visceral
or
skeletal
examinations.
The
developmental
toxicity
LOAEL
was
not
established
in
this
study
(>
1000
mg/
kg/
day,
limit
dose).
The
developmental
NOAEL
is
$
1000
mg/
kg/
day.

This
developmental
toxicity
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700;
§
83­
3a)
and
satisfies
the
requirement
for
a
developmental
toxicity
study
in
the
rat.

Developmental
Toxicity
in
Rabbits
In
a
developmental
toxicity
study
(
MRIDs
00156606,
main
study
and
40263701
and
41652501,
addenda
to
main
study
report),
ethofumesate
(
96.3%
a.
i.,
Lot/
batch
#
CR
4805/
10;
purity
information
obtained
from
MRID
41214207/
see
reviews
in
TXR#
s
010615
and
0051567)
was
administered
in
0.5%
(
w/
v)
aqueous
carboxymethylcellulose
daily
via
oral
gavage,
in
a
dosing
volume
of
10
mL/
kg,
to
25
female
New
Zealand
White
DP
Barcode
D326518
/
46510101
Page
23
of
73
rabbits/
group,
at
dose
levels
of
0,
30,
300
or
3000
mg/
kg/
day,
on
gestation
days
(
GD)
6
through
18.
All
surviving
does
were
sacrificed
on
GD
28
and
their
uterine
contents
examined.

At
3000
mg/
kg,
differences
were
observed
in
the
following
maternal
parameters:
(
i)
increased
number
of
does
that
died
or
were
sacrificed
moribund
(
12/
25
treated
vs
1/
25
controls);
(
ii)
decreased
percentage
of
does
with
live
fetuses
(
78%
treated
vs
90%
controls);
(
iii)
increased
percentage
of
does
with
complete
litter
resorption
(
22%
treated
vs
10%
controls);
and
(
iv)
slightly
increased
number
of
abortions
(
3/
23
treated
vs
1/
23
controls).
Pyosis
of
the
oral
cavity
was
noted
in
all
dose
groups,
along
with
possible
pneumonia,
thorax
findings
and
other
findings
in
the
lungs.
In
a
previous
review,
it
was
stated
that
these
findings,
in
conjunction
with
notations
of
"
application
failure"
by
the
Sponsor,
may
be
indicative
of
either
gavage
error
or
a
problem
with
the
health
status
of
the
animals.
However,
the
cases
of
gavage
error,
pneumonia
and
other
thorax
and/
or
lung
infections
could
account
for
approximately
4
deaths
at
the
high
dose
but
do
not
account
for
the
majority
of
the
mortalities
at
this
dose
(
approximately
9).
Body
weight
gains
were
decreased
(
p#
0.05)
during
GD
6­
13
(­
0.3
kg
treated
vs
0.1
kg
controls).
The
maternal
LOAEL
is
3000
mg/
kg/
day
based
on
decreased
body
weights
and
increased
mortality,
abortions
and
complete
litter
resorption.
The
maternal
NOAEL
is
300
mg/
kg/
day.

At
$
300
mg/
kg,
increases
(
p#
0.05)
were
observed
in
resorptions
(
29.2%
treated
vs
13.9%
controls)
and
post­
implantation
loss
(
32.3%
treated
vs
15.2%
controls).
Fetal
and
litter
incidences
of
incomplete
ossification
of
one
or
more
vertebral
arches
(
25%
fetuses;
68­
71%
litters)
and
litter
incidences
of
incomplete
ossification
of
three
or
more
vertebral
arches
(
10­
18%
fetuses;
32­
57%
litters)
were
increased
(
p#
0.05)
over
concurrent
controls
(
1­
6%
fetuses;
5­
37%
litters).
There
were
no
treatment­
related
external
or
visceral
findings
in
the
fetuses.
Additionally
at
3000
mg/
kg,
decreases
were
observed
in
the
number
of
does
with
live
fetuses
and
in
fetal
body
weights.
Incomplete
ossification
of
the
foot
bones
was
increased
(
p#
0.05)
at
this
dose
(
55%
fetuses;
86%
litters)
compared
to
concurrent
(
12%
fetuses;
42%
litters)
and
historical
(
fetal
incidence
not
provided;
12­
39%
litters)
controls.
Fetal
and
litter
incidences
of
incomplete
ossification
of
the
hyoid
were
increased
(
p#
0.05;
43%
fetuses,
57%
litters)
compared
to
concurrent
controls
(
3%
fetuses,
5%
litters).
Fetal
incidences
of
incomplete
ossification
of
the
parietal
bone
were
increased
(
p#
0.05;
29%
fetuses,
29%
litters)
compared
to
concurrent
controls
(
5%
fetuses;
11%
litters).
The
developmental
toxicity
LOAEL
is
300
mg/
kg
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.
The
developmental
toxicity
NOAEL
is
30
mg/
kg/
day.

This
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700b;
§
83­
3b)
and
satisfies
the
requirements
for
a
developmental
study
in
the
rabbit.

3.2.4
Reproductive
Toxicity
Study
In
a
three­
generation
reproduction
toxicity
study
(
MRIDs
00062823
and
00062924,
reformatted
in
92063034),
NC
8438
(
ethofumesate
tech.,
97.8%
a.
i.;
Lot/
batch
#
DP
Barcode
D326518
/
46510101
Page
24
of
73
CR/
4805/
4)
was
administered
continuously
in
the
diet
to
CD:
Crl
albino
rats
(
30/
sex/
dose)
at
nominal
dose
levels
of
0,
200,
1000
or
5000
ppm
(
equivalent
to
0/
0,
15.6/
18.0,
77.6/
91.2
or
396.8/
462.5
mg/
kg/
day
[
M/
F]).
The
P
(
F0)
animals
were
given
test
article
diet
formulations
for
90
days
prior
to
mating
to
produce
the
F1a
litter.
The
P
animals
were
mated
again
(
with
different
males)
to
produce
the
F1b
litter.
After
weaning,
F1b
animals
were
selected
(
30/
sex/
dose)
to
become
the
parents
of
the
F2
generation
and
beginning
on
postnatal
day
21,
were
given
the
same
dietary
concentration
test
formulations
as
their
dam.
The
mating
procedures
were
continued
for
a
total
of
three
generations,
with
the
F2b
animals
(
30/
sex/
dose)
mated
twice
to
produce
the
F3a
and
F3b
litters.
Litters
were
not
culled
in
any
generation
to
allow
3
teratology
segments
for
this
study.

At
5000
ppm,
very
slight
decreases
(
5­
7%)
in
body
weight
and
body
weight
gains
were
noted
in
the
males
and
females
throughout
most
of
the
generations;
however,
these
small
differences
were
not
considered
to
be
biologically
adverse.
Absolute
and
relative
(
to
body)
thyroid
weights
were
decreased
(
p#
0.05)
by
17­
19%
in
the
P
females
at
this
dose
but
there
were
no
treatment­
related
microscopic
findings
in
the
thyroid.
Five
P
males,
five
P
females,
five
F2
males
and
one
F2
female
died
or
were
sacrificed
in
extremis;
however,
none
of
these
deaths
were
attributed
to
treatment.
There
were
no
effects
of
treatment
on
clinical
signs,
maternal
food
consumption,
food
efficiency,
water
consumption,
gross
pathology
or
histopathology.
The
LOAEL
for
parental
toxicity
was
not
established
in
this
study
(>
5000
ppm;
396.8/
462.5
mg/
kg/
day
[
M/
F]).
The
NOAEL
is
$
5000
ppm.

There
were
no
effects
of
treatment
on
litter
size.
Body
weights
were
decreased
(
p#
0.05)
by
6­
11%
in
the
F3a
pups
at
1000
and
5000
ppm
and
in
the
F3b
pups
at
200
and
5000
ppm.
However,
these
decreases
corresponded
to
increased
(
not
significant)
litter
sizes
in
these
groups
and,
in
the
F3b
pups,
were
not
dose­
related.
(
A
slightly
increased
incidence
in
hydroureter
in
some
high
dose
offspring
in
the
teratology
segment
was
not
corroborated
by
findings
of
the
developmental
toxicity
study
in
the
rat,
MRIDs
42067701,
42689901).
The
LOAEL
for
offspring
toxicity
was
not
established
in
this
study
(>
5000
ppm;
396.8/
462.5
mg/
kg/
day
[
M/
F]).
The
NOAEL
is
$
5000
ppm.

There
were
no
effects
of
treatment
on
mating,
fertility
or
pregnancy
indices.
The
LOAEL
for
reproductive
toxicity
was
not
established
in
this
study
(>
5000
ppm;
396.8/
462.5
mg/
kg/
day
[
M/
F]).
The
NOAEL
is
$
5000
ppm.

This
study
did
not
test
to
the
limit
dose
(
1000
mg/
kg/
day)
and
parental,
reproductive
and/
or
offspring
toxicity
LOAELs
were
not
established.
Establishment
of
a
parental,
reproductive
and/
or
offspring
toxicity
LOAEL
is
usually
required
for
acceptance
of
a
multigeneration
reproductive
toxicity
study
when
the
highest
dose
is
below
the
limit
dose.
In
the
Agency
publication
entitled
"
Pesticide
Reregistration
Rejection
Rate
Analysis­
Toxicology"
(
July,
1993),
this
issue
was
not
specifically
discussed
for
multigeneration
reproductive
toxicity
studies
but
was
addressed
for
developmental
toxicity
studies
where
no
maternal
toxicity
was
observed
at
dose
levels
below
the
limit
dose
of
1000
mg/
kg/
day.
The
Guidance
(
Guideline
83­
3a
Developmental
Toxicity­
Rodents,
Rejection
Factor
6,
pp.
116­
118)
states
that
"
The
Agency
will
accept
1000
DP
Barcode
D326518
/
46510101
Page
25
of
73
mg/
kg/
as
the
limit
dose
for
developmental
toxicity
studies
when
no
maternal
toxicity
or
fetotoxicity
has
been
observed.
The
Agency
would
like
to
suggest
that
(
for
studies
not
performed
at
the
limit
dose)
the
range­
finding
study
be
appended
to
the
study
report
as
additional
justification
for
the
dose
levels."
This
guidance
may
also
apply
to
reproductive
toxicity
studies.
In
lieu
of
range­
finding
data
as
support
for
dosing
in
this
reproductive
toxicity
study,
the
results
of
the
52­
week
chronic
toxicity
study
(
MRID
44093602)
and
104­
week
chronic
toxicity/
carcinogenicity
study
(
MRID
44093603,
­
04)
on
ethofumesate
may
be
used
to
support
the
dose
selection.
Although
no
parental
toxicity
was
reported
in
the
3­
generation
reproductive
toxicity
study
at
396.8/
462.5
mg/
kg/
day
(
males/
females),
a
systemic
toxicity
LOAEL
of
398/
577
mg/
kg/
day
(
males/
females)
was
identified
in
the
52­
week
chronic
toxicity
study
and
a
systemic
toxicity
LOAEL
of
469
mg/
kg/
day
for
females
was
identified
in
the
104­
week
chronic
toxicity/
carcinogenicity
study
at
mg/
kg/
day
(
males/
females).
A
new
multigeneration
reproductive
toxicity
study
is
therefore
not
considered
necessary
at
this
time.

This
study
is
classified
as
acceptable/
gu
ideline
and
satisfies
the
guideline
requirement
for
a
multigeneration
reproduction
study
in
the
rat
(
OPPTS
870.3800;
§
83­
4).

3.2.5
Additional
Information
from
Literature
Sources
No
additional
studies
from
the
open
literature
were
found.

3.2.6
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
concluded
that
there
is
no
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
ethofumesate.

3.2.6a
Determination
of
Susceptibility
There
is
evidence
for
increased
quantitative
susceptibility
following
in
utero
exposure
to
rabbits.
At
300
mg/
kg/
day,
no
maternal
toxicity
was
reported
but
developmental
toxicity
was
observed
as
increased
resorptions,
postimplantation
loss
and
skeletal
abnormalities
(
incomplete
ossification
of
vertebral
arches).

No
evidence
of
increased
susceptibility
was
observed
in
the
rat
in
either
the
DP
Barcode
D326518
/
46510101
Page
26
of
73
developmental
or
reproductive
toxicity
study.
In
the
rat
developmental
toxicity
study,
no
developmental
effects
were
reported
at
the
highest
dose
tested
(
limit
dose
of
1000
mg/
kg/
day).
In
the
three­
generation
rat
reproductive
toxicity
study,
maternal,
reproductive
and
offspring
toxicity
were
not
observed
at
any
dose
tested
up
to
5000
ppm
(
396.8
and
462.5
mg/
kg/
day,
males
and
females,
respectively).

3.2.6b
Degree
of
Concern
Analysis
and
Residual
Uncertainties
The
HIARC
concluded
that
there
is
low
concern
and
no
residual
uncertainties
for
preand
postnatal
toxicity.
Although
increased
prenatal
quantitative
susceptibility
was
observed
in
the
rabbit
developmental
toxicity
study,
the
developmental
toxicity
NOAELs/
LOAELs
are
well
characterized
and
are
used
as
endpoints
for
risk
assessment
for
the
appropriate
population
subgroups.

3.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
not
a
concern
for
developmental
neurotoxicity.

3.3.1
Evidence
That
Supports
Requiring
a
Developmental
Neurotoxicity
Study
Based
on
the
available
data,
there
is
no
evidence
that
would
support
the
need
for
a
developmental
neurotoxicity
study.

3.3.2
Evidence
That
Supports
Not
Requiring
a
Developmental
Neurotoxicity
Study
Ethofumesate
did
not
cause
clear
clinical
or
microscopic
signs
of
neurotoxicity
in
at
least
four
species
tested
(
rats,
rabbits,
mice
and
dogs).
The
only
clinical
observation
that
could
potentially
be
interpreted
as
neurological,
increased
salivation
in
pregnant
rabbit
in
the
developmental
toxicity
study,
was
observed
only
for
the
first
hour
following
gavage
dosing
at
the
limit
dose
of
1000
mg/
kg/
day,
was
not
observed
in
any
other
study,
including
the
rabbit
at
a
dose
exceeding
the
limit
dose,
and
is
considered
unlikely
to
indicate
neurotoxicity.

Based
on
the
weight
of
evidence
presented,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
not
required
for
ethofumesate.

3.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
NOTE:
Because
of
the
toxicity
profile
of
this
chemical,
hazard
identification
and
toxicity
endpoint
selection
were
made
for
two
different
population
subgroups:
(
1)
Females
13­
49
years
of
age
and
(
2)
General
Population
including
infants
and
children.
Doses
and
endpoints
were
selected
for
each
pathway
(
i.
e.,
oral,
dermal
and
inhalation),
depending
upon
the
appropriateness
DP
Barcode
D326518
/
46510101
Page
27
of
73
of
the
endpoint
and
the
relevancy
of
these
endpoints
to
the
population
of
concern.
Developmental
(
in
utero
exposure)
endpoints
were
selected
to
assess
dietary
and
non­
dietary
(
occupational)
risks
for
Females
13­
49
years
of
age,
whereas
non­
developmental
(
systemic
toxicity)
endpoints
were
selected
to
assess
dietary
and
non­
occupational
(
residential)
risks
to
the
general
population,
including
infants
and
children.

3.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
13­
49
Years
of
Age
Study
Selected:
Developmental
Toxicity
in
Rabbits
OPPTS
870.3700b
§
83­
3b
MRID
Nos.:
00156606,
40263701,
41652501
Executive
Summary:
In
a
developmental
toxicity
study
(
MRIDs
00156606,
main
study
and
40263701
and
41652501,
addenda
to
main
study
report),
ethofumesate
(
96.3%
a.
i.,
Lot/
batch
#
CR
4805/
10;
purity
information
obtained
from
MRID
41214207/
see
reviews
in
TXR#
s
010615
and
0051567)
was
administered
in
0.5%
(
w/
v)
aqueous
carboxymethylcellulose
daily
via
oral
gavage,
in
a
dosing
volume
of
10
mL/
kg,
to
25
female
New
Zealand
White
rabbits/
group,
at
dose
levels
of
0,
30,
300
or
3000
mg/
kg/
day,
on
gestation
days
(
GD)
6
through
18.
All
surviving
does
were
sacrificed
on
GD
28
and
their
uterine
contents
examined.

At
3000
mg/
kg,
differences
were
observed
in
the
following
maternal
parameters:
(
i)
increased
number
of
does
that
died
or
were
sacrificed
moribund
(
12/
25
treated
vs
1/
25
controls);
(
ii)
decreased
percentage
of
does
with
live
fetuses
(
78%
treated
vs
90%
controls);
(
iii)
increased
percentage
of
does
with
complete
litter
resorption
(
22%
treated
vs
10%
controls);
and
(
iv)
slightly
increased
number
of
abortions
(
3/
23
treated
vs
1/
23
controls).
Pyosis
of
the
oral
cavity
was
noted
in
all
dose
groups,
along
with
possible
pneumonia,
thorax
findings
and
other
findings
in
the
lungs.
In
a
previous
review,
it
was
stated
that
these
findings,
in
conjunction
with
notations
of
"
application
failure"
by
the
Sponsor,
may
be
indicative
of
either
gavage
error
or
a
problem
with
the
health
status
of
the
animals.
However,
the
cases
of
gavage
error,
pneumonia
and
other
thorax
and/
or
lung
infections
could
account
for
approximately
4
deaths
at
the
high
dose
but
do
not
account
for
the
majority
of
the
mortalities
at
this
dose
(
approximately
9).
Body
weight
gains
were
decreased
(
p#
0.05)
during
GD
6­
13
(­
0.3
kg
treated
vs
0.1
kg
controls).
The
maternal
LOAEL
is
3000
mg/
kg/
day
based
on
decreased
body
weights
and
increased
mortality,
abortions
and
complete
litter
resorption.
The
maternal
NOAEL
is
300
mg/
kg/
day.

At
$
300
mg/
kg,
increases
(
p#
0.05)
were
observed
in
resorptions
(
29.2%
treated
vs
13.9%
controls)
and
post­
implantation
loss
(
32.3%
treated
vs
15.2%
controls).
Fetal
and
litter
incidences
of
incomplete
ossification
of
one
or
more
vertebral
arches
(
25%
fetuses;
68­
71%
litters)
and
litter
incidences
of
incomplete
ossification
of
three
or
more
vertebral
DP
Barcode
D326518
/
46510101
Page
28
of
73
arches
(
10­
18%
fetuses;
32­
57%
litters)
were
increased
(
p#
0.05)
over
concurrent
controls
(
1­
6%
fetuses;
5­
37%
litters).
There
were
no
treatment­
related
external
or
visceral
findings
in
the
fetuses.
Additionally
at
3000
mg/
kg,
decreases
were
observed
in
the
number
of
does
with
live
fetuses
and
in
fetal
body
weights.
Incomplete
ossification
of
the
foot
bones
was
increased
(
p#
0.05)
at
this
dose
(
55%
fetuses;
86%
litters)
compared
to
concurrent
(
12%
fetuses;
42%
litters)
and
historical
(
fetal
incidence
not
provided;
12­
39%
litters)
controls.
Fetal
and
litter
incidences
of
incomplete
ossification
of
the
hyoid
were
increased
(
p#
0.05;
43%
fetuses,
57%
litters)
compared
to
concurrent
controls
(
3%
fetuses,
5%
litters).
Fetal
incidences
of
incomplete
ossification
of
the
parietal
bone
were
increased
(
p#
0.05;
29%
fetuses,
29%
litters)
compared
to
concurrent
controls
(
5%
fetuses;
11%
litters).
The
developmental
toxicity
LOAEL
is
300
mg/
kg
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.
The
developmental
toxicity
NOAEL
is
30
mg/
kg/
day.

This
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700b;
§
83­
3b)
and
satisfies
the
requirements
for
a
developmental
study
in
the
rabbit.

Dose
and
Endpoint
for
Establishing
aRfD:
Developmental
toxicity
NOAEL
=
30
mg/
kg/
day,
based
on
increased
resorptions,
postimplantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
LOAEL
of
300
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variations)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
HIARC
selected
this
study
and
endpoint
because
the
endpoints
of
concern
are
presumed
to
occur
following
a
single
in
utero
exposure
and
thus
appropriate
for
this
population
subgroup.

3.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
Study
Selected:
None
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
HIARC
determined
that
there
was
no
appropriate
single­
dose
endpoint
available
for
acute
oral
exposure
of
the
general
population
to
ethofumesate.

3.4.3
Chronic
Reference
Dose
(
cRfD)­
Females
13­
49
Years
of
Age
Study
Selected:
Developmental
Toxicity
in
Acute
RfD
(
Females
13­
49
years
of
age)
=
30
mg/
kg
(
NOAEL)
=
0.30
mg/
kg
100
(
UF)
DP
Barcode
D326518
/
46510101
Page
29
of
73
Rabbits
OPPTS
870.3700b
§
83­
3b
MRID
Nos.:
00156606,
40263701,
41652501
Executive
Summary:
See
Executive
Summary
for
rabbit
developmental
toxicity
study,
above,
under
Section
III,
Part
1
[
Acute
Oral
RfD
(
aRfD)­
Females
13­
49
Years
of
Age].

Dose
and
Endpoint
for
Establishing
cRfD
(
Females
13­
49
Years
of
Age):
Developmental
toxicity
NOAEL
=
30
mg/
kg/
day,
based
on
increased
resorptions,
postimplantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
LOAEL
of
300
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variations)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
A
separate
RfD
was
established
for
this
population
subgroup
(
Females
13­
49
years
of
age)
because
the
developmental
toxicity
observed
at
30
mg/
kg/
day
in
the
developmental
toxicity
study
in
rabbits
resulted
in
an
acute
RfD
(
0.300
mg/
kg/
day)
which
is
lower
than
the
chronic
RfD
(
1.30
mg/
kg/
day)
established
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats.
The
chronic
RfD
for
Females
13­
49
years
of
age
should
not
exceed
the
acute
RfD
value.
Therefore,
the
in
utero
effects
were
the
basis
for
the
chronic
RfD
for
this
population
subgroup
and
a
separate
chronic
RfD
was
established
for
the
general
population
including
infants
and
children.
3.4.3
Chronic
Reference
Dose
(
cRfD)
­
General
Population
Including
Infants
and
Children
Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
in
Rats
870.4300
§
83­
5
MRID
Nos.:
44093603,
44093604
Executive
Summary:
In
a
chronic
toxicity/
oncogenicity
study
(
MRIDs
44093603
and
44093604),
ethofumesate
(
97%
a.
i.;
Lot
No.
not
reported)
was
administered
to
groups
of
50
male
and
50
female
Sprague­
Dawley
rats
at
dietary
concentrations
of
0,
2000,
7000
or
20,000
ppm
(
0,
97,
332
or
1003
mg/
kg/
day,
respectively,
for
males
and
0,
127,
469
or
1466
mg/
kg/
day
for
females,
respectively)
for
up
to
104
weeks.
The
results
of
the
52­
week
interim
evaluation
of
an
additional
20
animals/
sex/
dose
administered
the
same
concentrations
(
MRID
44093602)
were
discussed
in
a
separate
Data
Evaluation
Record.
Chronic
RfD
­
Females
13­
49
Years
of
Age
=
30
(
NOAEL)
mg/
kg/
day
=
0.3
mg/
kg/
day
100
(
UF)
DP
Barcode
D326518
/
46510101
Page
30
of
73
Females
at
7000
and
20,000
ppm,
respectively,
showed
treatment
related
decreases
in
absolute
body
weights
up
to
10%
(
p<
0.01)
and
19%
(
p<
0.01)
less
than
controls
during
the
first
year
of
the
study
and
up
to
19%
(
p<
0.01)
and
27%
(
p<
0.01)
less
during
the
second
year.
High­
dose
group
females
gained
30%
less
weight
than
controls
over
the
entire
study,
and
mid­
dose
group
females
gained
only
7%
less,
because
they
gained
13%
more
weight
than
controls
during
the
second
year.
Except
for
a
few
sporadic
time
points,
body
weights
and
body
weight
gain
for
low­
dose
group
females
were
similar
to
those
of
controls.
At
20,000
ppm
(
highest
dose
tested),
absolute
mean
body
weights
of
male
rats
were
reduced
by
as
much
as
12%
(
p<
0.01)
below
controls
during
the
first
80
weeks
and
by
as
much
as
23%
(
p<
0.01)
for
the
remainder
of
the
study.
Males
at
7000
ppm
weighed
slightly,
but
significantly
less
(
9%)
than
controls
at
the
end
of
the
study.
Overall,
highdose
group
males
gained
30%
less
weight
than
the
controls,
whereas
mid­
and
low­
dose
males
gained
12%
and
15%
less,
respectively.
However,
the
decrease
in
body
weight
in
low­
and
mid­
dose
males
was
observed
only
during
the
final
weeks
of
the
study
and
was
not
used
to
set
a
LOAEL
for
males.
Total
food
consumption
was
not
significantly
affected
in
either
male
or
female
rats,
consequently,
overall
food
efficiency
values
were
24%
and
27%
less
in
high­
dose
male
and
female
rats.
Covariate
liver
weight
was
increased
over
controls
by
26%
(
p<
0.01)
in
females
at
20,000
ppm.
Microscopic
examination
showed
centrilobular
hypertrophy
in
5/
50,
5/
50,
11/
50
(
N.
S.)
and
21/
50
(
p<
0.01),
males
and
1/
49,
0/
50,
7/
50
(
p<
0.05)
and
21/
50
(
p<
0.010),
females
in
the
control,
low­,
mid­,
and
high­
dose
groups,
respectively
(
graded
severe
in
33%
of
highdose
rats
with
the
lesion).
Periportal
cellular
alteration
was
observed
in
15/
50
(
p<
0.01)
high­
dose
group
males
only.
At
20,000
ppm,
increased
tubular
pigment
deposition
in
the
kidney
was
observed
in
22/
50
(
p<
0.01)
females
and
9/
49
controls,
focal
hypertrophy
in
the
pancreas
in
6/
50
(
p<
0.05)
females
and
0/
50
controls,
and
retinal
atrophy
in
the
eyes
of
14/
49
(
p<
0.01)
females
and
3/
45
controls.
No
treatment­
related
effects
were
observed
in
males
or
females
at
any
dose
for
mortality,
clinical
signs,
eyes
(
ophthalmoscopic),
hematology
and
urinalysis
parameters.
No
toxicologically
significant
clinical
chemistry
changes
were
observed
in
male
or
female
rats
at
any
dose.
The
lowest­
observedadverse
effect
level
(
LOAEL)
for
ethofumesate
is
7000
ppm
(
469
mg/
kg/
day),
based
on
slightly
decreased
body
weight
gain
in
females
(
20,000
ppm
or
1003
mg/
kg/
day
for
males,
based
on
reduced
body
weight
gain
and
liver
lesions).
The
no­
observedadverse
effect
level
(
NOAEL)
is
2000
ppm
(
127
mg/
kg/
day)
for
females
(
7000
ppm
or
332
mg/
kg/
day
for
males).

The
incidence
of
interstitial
cell
adenomas
in
the
testes
of
males
was
0/
50,
5/
50
(
p<
0.05),
6/
50
(
p<
0.05)
and
8/
50
(
p<
0.01)
in
the
control,
low­,
mid­
and
high­
dose
groups,
respectively.
The
incidence
at
all
dose
levels
was
within
historical
control
incidence
range
and
control
incidence
was
below
the
range
of
in­
house
historical
controls
(
range
4­
20%,
mean
11%;
data
from
15
studies,
dates
unspecified).
Interstitial
cell
hyperplasia
of
the
testes
occurred
in
1/
50,
4/
50,
2/
50
and
6/
50
(
p=
0.056)
males,
respectively;
no
clear
dose
response
was
observed.
In
females,
slightly
increased
incidences
of
hepatocellular
adenoma
(
0/
49,
1/
50,
1/
50
and
3/
50,
control
to
high
dose)
and
hepatocellular
carcinoma
(
0/
49,
1/
50,
1/
50
and
0/
50,
control
to
high
dose)
were
observed.
In­
house
historical
DP
Barcode
D326518
/
46510101
Page
31
of
73
control
data
were
not
provided
for
these
tumors
but
Charles
River
data
for
female
CD
rats
showed
the
hepatocellular
adenoma
incidence
to
be
at
the
high
normal
border
(
0­
5.5%)
and
carcinoma
within
historical
control
range.
Therefore,
under
the
conditions
of
this
study,
the
evidence
for
carcinogenic
activity
of
ethofumesate
is
equivocal.
Dosing
was
considered
adequate
based
on
reduced
body
weight
gain
in
high­
dose
males
and
mid­
and
high­
dose
females
and
microscopic
lesions
in
the
high
dose
groups.

This
chronic
toxicity/
oncogenicity
study
in
the
rat
is
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
oncogenicity
oral
study
[
OPPTS
870.4300
(
§
83­
5)]
in
the
rat.
It
is
requested
that
the
lot
or
batch
number
of
the
test
material
be
provided
by
the
Registrant
as
confirmatory
data.
Homogeneity
and
stability
data
were
not
made
available
with
the
current
study.
The
lack
of
significant
variance
in
analytical
concentrations
in
the
diets
indicate
that
the
treated
diets
were
well
mixed.
In
addition,
stability
data
reported
in
a
13­
week
study
by
another
laboratory
(
MRID
44093601)
indicated
that
the
test
substance
was
stable
in
diets.

Dose
and
Endpoint
for
Establishing
cRfD:
Systemic
toxicity
NOAEL
=
127
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain
in
females
at
the
LOAEL
of
469
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variations).

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
RfD
is
applicable
for
the
general
population
including
infants
and
children.
A
separate
RfD
was
established
for
females
13­
49
years
of
age
as
described
previously.
HIARC
selected
this
study
because
it
provided
the
most
appropriate
systemic
toxicity
endpoint
in
a
long­
term
study.
Selection
of
this
study
is
also
supported
by
(
1)
the
systemic
toxicity
NOAEL
of
109
mg/
kg/
day
(
liver
toxicity
at
LOAEL
of
618.9
mg/
kg/
day)
in
the
dog
chronic
oral
toxicity
study
(
MRIDs
42067701,
42689901)
and
(
2)
the
NOAEL
of
115
mg/
kg/
day
in
males
(
decreased
body
weight
at
LOAEL
of
398
mg/
kg/
day)
in
the
52­
week
rat
chronic
toxicity
study
(
MRID
44093602).
A
NOAEL
of
37.6
mg/
kg/
day
(
LOAEL
of
207.0
mg/
kg/
day,
based
on
decreased
body
weight
gain)
was
observed
in
an
earlier
rat
104­
week
chronic
toxicity/
carcinogenicity
study
(
MRID
00041853;
reformatted
in
92063031);
however,
this
NOAEL
was
not
used
because
(
1)
several
deficiencies
in
the
study
conduct
were
identified
and
(
2)
because
the
NOAEL
of
127
mg/
kg/
day
in
the
newer
rat
chronic
toxicity/
carcinogenicity
study
was
well­
characterized
and
supported
by
other
chronic
guideline
studies.
DP
Barcode
D326518
/
46510101
Page
32
of
73
3.4.4
Incidental
Oral
Exposure
(
Short­
and
Intermediate
Term
Exposure)

Study
Selected:
90­
Day
Oral
Toxicity
in
Rats
870.3100a
§
82­
1a
MRID
No.:
44093601
Executive
Summary:
In
a
subchronic
oral
toxicity
study
(
MRID
44093601)
ethofumesate
(
98.9%
a.
i.,
Lot
No.
KLP­
87­
17)
was
administered
continuously
to
groups
of
10
male
and
10
female
Crl:
CD(
SD)
rats
at
dietary
concentrations
of
0,
300,
3000
or
30,000
ppm
for
90
days.
Weight­
normalized
doses
were
0,
18.2,
190
or
1900
mg/
kg/
day,
respectively,
for
males
and
0,
23.4,
230
or
2309
mg/
kg/
day,
respectively,
for
females.

At
30,000
ppm
(
HDT),
male
rats
weighed
up
to
8%
(
N.
S.)
less
than
controls
during
the
13­
week
study,
gained
21%
(
p<
0.01)
less
weight
during
the
first
week
of
treatment
and
gained
15%
less
weight
overall.
High­
dose
female
rats
weighed
up
to
17%
(
N.
S.)
less
than
controls
during
the
13­
week
study,
gained
67%
(
p<
0.01)
less
weight
than
controls
during
the
first
week
and
gained
47%
(
p<
0.01)
less
weight
overall.
Food
consumption
in
high­
dose
males
was
similar
to
that
of
controls
and
was
reduced
in
females
by
18%
(
p<
0.05)
and
10%
(
p<
0.01)
for
weeks
0­
1
and
0­
13,
respectively.
The
food
utilization
ratio
(
g
food/
g
body
weight
gain)
was
increased
in
high­
dose
males
by
23%
and
15%
for
week
1
and
weeks
1­
13,
respectively
and
increased
in
high­
dose
female
rats
by
2.6­
and
1.7­
fold,
respectively,
indicating
that
reduced
weight
gain
was
not
due
entirely
to
reduced
food
consumption.
Treatment­
related
postmortem
changes
were
observed
only
in
high­
dose
male
rats.
The
mean
covariate
liver
weight
was
increased
by
12%
(
N.
S.),
eosinophilic
periportal
hepatocytes
were
observed
in
the
liver
of
3/
10
males
and
in
none
of
the
controls
or
lower
dose
groups,
and
periportal
fat
deposition
was
observed
in
the
liver
of
3/
10
high­
dose,
1/
10
mid­
dose
and
none
of
the
low­
dose
or
control
rats.
The
mean
covariate
kidney
weight
was
increased
by
18%
(
p<
0.01)
in
high­
dose
male
rats.
Tubular
basophilia,
dilation,
inflammation
and/
or
fibrosis
were
observed
in
0/
10,
2/
10,
0/
10
and
4/
10
control,
low­,
mid­
and
high­
dose
group
male
rats,
respectively.
The
mean
covariate
kidney
weight
of
high­
dose
females
was
increased
by
23%
(
p<
0.01),
but
no
corresponding
microscopic
lesions
were
observed.
No
treatment­
related
effects
were
observed
on
clinical
signs
of
toxicity,
mortality
(
all
rats
survived
treatment),
hematologic
and
clinical
pathology
parameters
or
eyes
of
male
or
female
rats
administered
the
high
dose,
and
no
treatment­
related
effects
were
observed
on
low­
or
mid­
dose
male
or
female
rats.
The
lowest­
observed­
adverse­
effect
level
(
LOAEL)
was
30,000
ppm
for
male
and
female
rats
(
1900
and
2309
mg/
kg/
day,
respectively)
based
on
reduced
body
weight
gain
Chronic
RfD
(
general
population
including
infants
and
children)
=
127
(
NOAEL)
mg/
kg/
day
=
1.3
mg/
kg/
day
100
(
UF)
DP
Barcode
D326518
/
46510101
Page
33
of
73
and
microscopic
lesions
in
the
liver
and
kidney
of
males
and
reduced
body
weights
and
body
weight
gain
in
females.
The
corresponding
no­
observed­
adverse­
effect
level
(
NOAEL)
was
3000
ppm
(
190
mg/
kg/
day
for
males
and
230
mg/
kg/
day
for
females).

This
subchronic
toxicity
study
is
classified
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
subchronic
oral
study
in
rats
[
OPPTS
870.3100
(
§
82­
1a)].

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
190
mg/
kg/
day,
based
on
decreased
body
weight
and
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10x
for
interspecies
extrapolation
and
10x
for
intraspecies
variations).

Comments
about
Study/
Endpoint:
HIARC
selected
this
study
because
(
1)
endpoints
identified
were
observed
at
the
appropriate
duration
of
exposure
and
(
2)
the
route
of
exposure
(
oral)
and
endpoints
are
appropriate
for
the
population
(
infants
and
children)
of
concern.

On
January
27,
2004,
the
HED
HIARC
reviewed
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
ethofumesate
according
to
the
February
2002
OPP
FQPA
10X
Safety
Factor
guidance
document.
Studies
available
for
FQPA
consideration
include
developmental
toxicity
studies
in
rats
and
rabbits
and
a
threegeneration
reproduction
toxicity
in
rats.

Based
on
currently
available
data,
there
are
no
clear
and
convincing
data
to
demonstrate
increased
susceptibility
following
in
utero
exposure
to
ethofumesate.
The
HIARC
concluded
that
there
was
no
indication
of
increased
susceptibility
of
rat
fetuses
following
in
utero
exposure
to
ethofumesate
in
the
prenatal
developmental
study
in
rats.
No
rat
developmental
effects
were
seen
at
the
highest
dose
tested
(
limit
dose
of
1000
mg/
kg).
There
is,
however,
quantitative
evidence
for
increased
susceptibility
following
in
utero
exposure
to
ethofumesate
in
an
adequate
developmental
toxicity
study
in
the
rabbit.
At
300
mg/
kg/
day,
no
maternal
toxicity
was
reported
but
developmental
toxicity
was
observed
as
increased
resorptions,
postimplantation
loss
and
skeletal
abnormalities
(
incomplete
ossification
of
vertebral
arches).

There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
the
3­
generation
reproduction
study
in
rats
with
ethofumesate
since
maternal,
reproductive
and
offspring
toxicity
were
not
observed
at
any
dose
tested
up
to
5000
ppm
(
396.8
and
462.5
mg/
kg/
day,
males
and
females,
respectively).
Although
a
limit
dose
was
not
achieved
and
no
maternal
toxicity
reported,
a
new
study
was
not
required
because
the
highest
dose
tested
was
similar
to
the
dose
level
that
caused
toxicity
to
rats
in
the
chronic/
carcinogenicity
dietary
study.
DP
Barcode
D326518
/
46510101
Page
34
of
73
3.4.5
Dermal
Absorption
Dermal
Absorption
Factor:
100%
(
default
factor)

Data
on
dermal
penetration
of
ethofumesate
are
unavailable
at
this
time.
A
default
assumption
of
100%
dermal
absorption
is
selected
due
to
the
unavailability
of
comparative
oral
and
dermal
toxicity
data
with
a
common
endpoint
in
the
same
species.

3.4.6
Dermal
Exposure
(
All
Durations)
­
Females
13­
49
Years
of
Age
Study
Selected:
Developmental
Toxicity
Study
in
the
Rabbit
870.3700b
§
83­
3b
MRID
Nos.:
00156606,
40263701,
41652501
Executive
Summary:
See
Executive
Summary
for
rabbit
developmental
toxicity
study,
above,
under
Section
III,
Part
1
[
Acute
Oral
RfD
(
aRfD)­
Females
13­
49
Years
of
Age].

Dose
and
Endpoint
for
Risk
Assessment:
Developmental
toxicity
NOAEL
=
30
mg/
kg/
day,
based
on
increased
resorptions,
postimplantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
LOAEL
of
300
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
oral
developmental
toxicity
NOAEL
in
the
rabbit
developmental
toxicity
study
was
selected
for
assessment
of
dermal
exposure
(
all
durations)
because
of
the
concerns
for
developmental
effects
that
were
seen
in
this
study
and
which
were
not
evaluated
in
the
21­
day
dermal
toxicity
study
in
rabbits
(
MRID
Nos.
41997204,
42689902).
This
dose/
endpoint
is
applicable
only
to
assess
the
dermal
risk
for
this
population
subgroup
(
Females
13­
49
years
of
age).

3.4.7
Dermal
Exposure
(
Short­
and
Intermediate­
Term)
­
General
Population
Including
Infants
and
Children
Study
Selected:
90­
Day
Oral
Toxicity
in
Rats
870.3100a
§
82­
1a
MRID
No.:
44093601
Executive
Summary:
See
Executive
Summary
for
Rat
90­
Day
Oral
Toxicity
Study,
above,
under
Section
III,
Part
5
(
Incidental
Oral
Exposure).
DP
Barcode
D326518
/
46510101
Page
35
of
73
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
190
mg/
kg/
day,
based
on
decreased
body
weight
and
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day.

Comments
about
Study/
Endpoint:
HIARC
selected
this
study
because
the
endpoints
identified
were
observed
at
the
appropriate
duration
of
exposure
and
are
appropriate
for
the
population
of
concern.

3.4.8
Dermal
Exposure
(
Long
Term)
­
General
Population
Including
Infants
and
Children
Study
Selected:
Combined
Oral
Chronic
Toxicity/
Carcinogenicity
in
Rats
870.4300
§
83­
5
MRID
Nos.:
44093603,
44093604
Executive
Summary:
See
Executive
Summary
for
rat
oral
combined
chronic
toxicity/
carcinogenicity
study,
above,
under
Section
III,
Part
4.

Comments
about
Study/
Endpoint:
HIARC
selected
this
study
because
the
endpoints
identified
were
observed
at
the
appropriate
duration
of
exposure
and
are
appropriate
for
the
population
of
concern.

3.4.9
Inhalation
Exposure
(
All
Exposure
Durations)
­
Females
13­
49
Years
of
Age
Study
Selected:
Developmental
Toxicity
Study
in
the
Rabbit
870.3700b
§
83­
3b
MRID
No.:
00156606,
40263701,
41652501
Executive
Summary:
See
Executive
Summary
for
rabbit
developmental
toxicity
study,
above,
under
Section
III,
Part
1
[
Acute
Oral
RfD
(
aRfD)­
Females
13­
49
Years
of
Age].

Dose/
Endpoint
for
Risk
Assessment:
Developmental
toxicity
NOAEL
=
30
mg/
kg/
day,
based
on
increased
resorptions,
postimplantation
loss
and
incomplete
ossification
of
the
vertebral
arches
at
the
LOAEL
of
300
mg/
kg/
day.

Comments
about
Study/
Endpoint:
There
are
no
repeated
exposure
inhalation
toxicity
studies
available
for
ethofumesate.
In
the
absence
of
repeated
exposure
inhalation
toxicity
studies,
oral
doses
were
selected.
Since
rabbits
were
the
most
sensitive
species,
the
in
utero
effects
were
selected
to
assess
risks
via
this
route
for
Females
13­
49
years
of
age
for
all
exposure
durations.
Absorption
via
the
inhalation
exposure
is
presumed
to
be
DP
Barcode
D326518
/
46510101
Page
36
of
73
equivalent
to
oral
exposure.

3.4.10
Inhalation
Exposure
(
Short­
and
Intermediate­
Term)
­
General
Population
Including
Infants
and
Children
Study
Selected:
90­
Day
Oral
Toxicity
in
Rats
870.3100a
§
82­
1a
MRID
No.:
44093601
Executive
Summary:
See
Executive
Summary
for
Rat
90­
Day
Oral
Toxicity
Study,
above,
under
Section
III,
Part
5
(
Incidental
Oral
Exposure).

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
190
mg/
kg/
day,
based
on
decreased
body
weight
and
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg/
kg/
day.

Comments
about
Study/
Endpoint:
In
the
absence
of
repeated
exposure
inhalation
toxicity
studies,
HIARC
selected
an
oral
study
for
this
population
subgroup
(
also
see
Section
III.
9)
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.

3.4.11
Inhalation
Exposure
(
Long
Term)
­
General
Population
Including
Infants
and
Children
Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
in
Rats
870.4300
§
83­
5
MRID
Nos.:
44093603,
44093604
Executive
Summary:
See
Executive
Summary
for
rat
oral
combined
chronic
toxicity/
carcinogenicity
study,
above,
under
Section
III,
Part
4
[
Chronic
Oral
RfD
(
cRfD)­
General
Population
Excluding
Females
13­
49
Years
of
Age].

Comments
about
Study/
Endpoint:
This
dose/
endpoint/
study
was
also
selected
for
longterm
dermal
exposure
risk
assessments
for
this
population
subgroup.
Absorption
via
inhalation
is
presumed
to
be
equivalent
to
oral
absorption.

3.4.12
Margins
of
Exposure
A
summary
of
target
Margins
of
Exposure
(
MOEs)
for
this
risk
assessment
are
presented
below.

Table
3.4.12
Target
MOES
for
Ethofumesate
DP
Barcode
D326518
/
46510101
Page
37
of
73
Route
Du
ration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
100
100
100
Residential
(
Non­
Dietary)
Exposure
Oral
100
100
NA
Dermal
100
100
100
Inhalation
100
100
100
NA­
Not
applicable
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation).

For
Residential
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation).

3.4.13
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
HIARC
determined
that
for
ethofumesate
there
is
the
potential
for
residential
exposures
via
postapplication
exposure
to
turf;
hence,
an
aggregate
risk
is
required.
For
short,
intermediate
and
long­
term,
the
oral,
dermal
and
inhalation
pathways
can
be
combined
due
to
the
common
toxicity
endpoint
via
the
oral,
dermal
(
oral
equivalent)
and
inhalation
(
oral
equivalent)
routes
for
the
appropriate
population
of
concern.

3.4.14
Classification
of
Carcinogenic
Potential
3.4.14a
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
Nos.
44093603,
44093604
Executive
Summary:
In
a
chronic
toxicity/
oncogenicity
study
(
MRIDs
44093603
and
44093604),
ethofumesate
(
97%
a.
i.;
Lot
No.
not
reported)
was
administered
to
groups
of
50
male
and
50
female
Sprague­
Dawley
rats
at
dietary
concentrations
of
0,
2000,
7000
or
20,000
ppm
(
0,
97,
332
or
1003
mg/
kg/
day,
respectively,
for
males
and
0,
127,
469
or
DP
Barcode
D326518
/
46510101
Page
38
of
73
1466
mg/
kg/
day
for
females,
respectively)
for
up
to
104
weeks.
The
results
of
the
52­
week
interim
evaluation
of
an
additional
20
animals/
sex/
dose
administered
the
same
concentrations
(
MRID
44093602)
were
discussed
in
a
separate
Data
Evaluation
Record.

Females
at
7000
and
20,000
ppm,
respectively,
showed
treatment
related
decreases
in
absolute
body
weights
up
to
10%
(
p<
0.01)
and
19%
(
p<
0.01)
less
than
controls
during
the
first
year
of
the
study
and
up
to
19%
(
p<
0.01)
and
27%
(
p<
0.01)
less
during
the
second
year.
High­
dose
group
females
gained
30%
less
weight
than
controls
over
the
entire
study,
and
mid­
dose
group
females
gained
only
7%
less,
because
they
gained
13%
more
weight
than
controls
during
the
second
year.
Except
for
a
few
sporadic
time
points,
body
weights
and
body
weight
gain
for
low­
dose
group
females
were
similar
to
those
of
controls.
At
20,000
ppm
(
highest
dose
tested),
absolute
mean
body
weights
of
male
rats
were
reduced
by
as
much
as
12%
(
p<
0.01)
below
controls
during
the
first
80
weeks
and
by
as
much
as
23%
(
p<
0.01)
for
the
remainder
of
the
study.
Males
at
7000
ppm
weighed
slightly,
but
significantly
less
(
9%)
than
controls
at
the
end
of
the
study.
Overall,
highdose
group
males
gained
30%
less
weight
than
the
controls,
whereas
mid­
and
low­
dose
males
gained
12%
and
15%
less,
respectively.
However,
the
decrease
in
body
weight
in
low­
and
mid­
dose
males
was
observed
only
during
the
final
weeks
of
the
study
and
was
not
used
to
set
a
LOAEL
for
males.
Total
food
consumption
was
not
significantly
affected
in
either
male
or
female
rats,
consequently,
overall
food
efficiency
values
were
24%
and
27%
less
in
high­
dose
male
and
female
rats.
Covariate
liver
weight
was
increased
over
controls
by
26%
(
p<
0.01)
in
females
at
20,000
ppm.
Microscopic
examination
showed
centrilobular
hypertrophy
in
5/
50,
5/
50,
11/
50
(
N.
S.)
and
21/
50
(
p<
0.01),
males
and
1/
49,
0/
50,
7/
50
(
p<
0.05)
and
21/
50
(
p<
0.010),
females
in
the
control,
low­,
mid­,
and
high­
dose
groups,
respectively
(
graded
severe
in
33%
of
highdose
rats
with
the
lesion).
Periportal
cellular
alteration
was
observed
in
15/
50
(
p<
0.01)
high­
dose
group
males
only.
At
20,000
ppm,
increased
tubular
pigment
deposition
in
the
kidney
was
observed
in
22/
50
(
p<
0.01)
females
and
9/
49
controls,
focal
hypertrophy
in
the
pancreas
in
6/
50
(
p<
0.05)
females
and
0/
50
controls,
and
retinal
atrophy
in
the
eyes
of
14/
49
(
p<
0.01)
females
and
3/
45
controls.
No
treatment­
related
effects
were
observed
in
males
or
females
at
any
dose
for
mortality,
clinical
signs,
eyes
(
ophthalmoscopic),
hematology
and
urinalysis
parameters.
No
toxicologically
significant
clinical
chemistry
changes
were
observed
in
male
or
female
rats
at
any
dose.
The
lowest­
observedadverse
effect
level
(
LOAEL)
for
ethofumesate
is
7000
ppm
(
469
mg/
kg/
day),
based
on
slightly
decreased
body
weight
gain
in
females
(
20,000
ppm
or
1003
mg/
kg/
day
for
males,
based
on
reduced
body
weight
gain
and
liver
lesions).
The
no­
observedadverse
effect
level
(
NOAEL)
is
2000
ppm
(
127
mg/
kg/
day)
for
females
(
7000
ppm
or
332
mg/
kg/
day
for
males).

Discussion
of
Tumor
Data
The
incidence
of
interstitial
cell
adenomas
in
the
testes
of
males
was
0/
50,
5/
50
(
p<
0.05),
6/
50
(
p<
0.05)
and
8/
50
(
p<
0.01)
in
the
control,
low­,
mid­
and
high­
dose
groups,
respectively.
The
incidence
at
all
dose
levels
was
within
historical
control
incidence
range
and
control
incidence
was
below
the
range
of
in­
house
historical
controls
(
range
4­
DP
Barcode
D326518
/
46510101
Page
39
of
73
20%,
mean
11%;
data
from
15
studies,
dates
unspecified).
Interstitial
cell
hyperplasia
of
the
testes
occurred
in
1/
50,
4/
50,
2/
50
and
6/
50
(
p=
0.056)
males,
respectively;
no
clear
dose
response
was
observed.
In
females,
slightly
increased
incidences
of
hepatocellular
adenoma
(
0/
49,
1/
50,
1/
50
and
3/
50,
control
to
high
dose)
and
hepatocellular
carcinoma
(
0/
49,
1/
50,
1/
50
and
0/
50,
control
to
high
dose)
were
observed.
In­
house
historical
control
data
were
not
provided
for
these
tumors
but
Charles
River
data
for
female
CD
rats
showed
the
hepatocellular
adenoma
incidence
to
be
at
the
high
normal
border
(
0­
5.5%)
and
carcinoma
within
historical
control
range.
There
was
no
evidence
of
carcinogenicity
of
ethofumesate
at
the
dose
levels
tested
in
this
study.

Adequacy
of
the
Dose
Level
Tested
Dosing
was
considered
adequate
based
on
reduced
body
weight
gain
in
high­
dose
males
and
mid­
and
high­
dose
females
and
microscopic
lesions
in
the
high
dose
groups.

This
chronic
toxicity/
oncogenicity
study
in
the
rat
is
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity/
oncogenicity
oral
study
[
OPPTS
870.4300
(
§
83­
5)]
in
the
rat.
It
is
requested
that
the
lot
or
batch
number
of
the
test
material
be
provided
by
the
Registrant
as
confirmatory
data.
Homogeneity
and
stability
data
were
not
made
available
with
the
current
study.
The
lack
of
significant
variance
in
analytical
concentrations
in
the
diets
indicate
that
the
treated
diets
were
well
mixed.
In
addition,
stability
data
reported
in
a
13­
week
study
by
another
laboratory
(
MRID
44093601)
indicated
that
the
test
substance
was
stable
in
diets.

3.4.14b
Carcinogenicity
Study
in
Mice
MRID
No.
44156202
Executive
Summary:
In
an
oncogenicity
feeding
study
(
MRID
44156202),
ethofumesate
(
tech.,
97%
w/
w;
Batch
Nos.
PO
4414/
2
and
PO
4414/
1)
was
administered
to
50
Crl:
CD­
1(
ICR)
BR
(
VAF
plus)
mice/
sex/
dose
in
the
diet
for
80
weeks
at
doses
of
0,
1000,
3000
or
10,000
ppm
(
intake
of
161,
477
or
1601
mg/
kg/
day
for
males
and
204,
644
or
2145
mg/
kg/
day
for
females,
respectively).

Mortality,
body
weights,
body
weight
gains,
food
consumption
and
efficiency,
clinical
observations
and
differential
leukocyte
counts
were
not
affected
by
treatment.
The
absolute
and/
or
relative
liver
weights
were
increased
in
all
groups
of
treated
females
(
12­
27%,
p
<
0.05
or
0.01),
although
the
increases
were
not
clearly
dose­
related
and
there
were
no
supporting
histopathological
correlates.
No
significant
gross
or
microscopic
pathological
lesions
were
found
in
either
sex
of
mice;
the
lesions
found
were
not
doserelated
and/
or
not
toxicologically
significant.
Under
the
conditions
of
this
study,
a
systemic
toxicity
LOAEL
was
not
established
for
either
male
or
female
mice
based
on
the
available
parameters
evaluated.
There
were
no
clearly
treatment­
related
findings,
despite
use
of
ethofumesate
levels
exceeding
the
limit
dose
of
1000
mg/
kg/
day.
The
NOAEL
was
$
10,000
ppm;
($
1601
mg/
kg/
day
for
males;$
2145
DP
Barcode
D326518
/
46510101
Page
40
of
73
mg/
kg/
day
for
females).

Discussion
of
Tumor
Data
There
was
no
evidence
of
carcinogenicity
of
ethofumesate.
All
neoplasms
found
were
of
a
type
that
occur
spontaneously
in
this
strain
of
mice.
The
overall
number
of
tumorbearing
animals
and
their
total
number
of
primary
or
benign
neoplasms
were
similar
in
treated
and
control
groups
for
both
sexes.

Adequacy
of
the
Dose
Level
Tested
Dosing
was
considered
adequate.
Although
a
systemic
toxicity
LOAEL
was
not
established
for
either
males
or
females,
testing
was
conducted
up
to
dose
levels
that
exceeded
the
limit
dose
(
1000
mg/
kg/
day).
This
study
is
classified
as
acceptable/
guideline
(
OPPTS
870.4200;
§
83­
2b).
It
satisfies
the
guideline
requirements
for
an
oncogenicity
study
in
the
mouse.

3.4.14c
Classification
of
Carcinogenic
Potential
Prior
to
this
HIARC
evaluation,
ethofumesate
was
reviewed
for
carcinogenic
potential
by
the
HED
RfD
Committee
on
November
10,
1993.
Based
on
deficiencies
in
the
carcinogenicity
database
at
that
time,
the
RfD
Committee
classified
ethofumesate
as
a
Group
D
carcinogen
(
inadequate
information
to
classify
as
a
carcinogen)
using
the
EPA's
1986
Guidelines
for
Carcinogen
Risk
Assessment.

HIARC
concluded
in
2004
that
ethofumesate
should
be
classified
as
"
not
likely
to
be
carcinogenic
to
humans"
according
to
EPA's
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999).
This
conclusion
is
based
on
the
lack
of
carcinogenicity
in
the
mouse
carcinogenicity
study
and
lack
of
convincing
evidence
for
carcinogenicity
in
the
rat
chronic
toxicity/
carcinogenicity
study.
Although
a
statistically
significant
increase
in
the
incidence
of
testicular
interstitial
cell
adenoma
was
reported
in
male
rats
at
the
highest
dose
tested
(
1003
mg/
kg/
day
in
males),
(
1)
the
incidence
at
that
dose
(
16%)
was
within
the
historical
control
range
for
the
laboratory
(
4­
20%;
mean
11%);
(
2)
the
concurrent
control
group
showed
an
unusually
low
incidence
of
0%
and
(
3)
the
increase
was
only
observed
at
dietary
doses
equivalent
to
the
limit
dose
of
1000
mg/
kg/
day.
There
was
no
evidence
of
increased
incidence
of
testicular
interstitial
cell
carcinoma.
Both
studies
tested
at
adequate
dose
levels
to
assess
carcinogenic
potential
and
were
considered
to
be
well­
conducted
studies.
In
addition,
no
evidence
of
genotoxicity
of
ethofumesate
has
been
observed
in
the
available
genotoxicity
studies
(
see
below).

3.4.15
Mutagenicity
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
ethofumesate.
Ethofumesate
technical
was
negative
in
all
five
genotoxicity
studies
that
were
performed,
including
an
in
vivo
mouse
bone
marrow
micronucleus
DP
Barcode
D326518
/
46510101
Page
41
of
73
assay
(
MRID
41214217)
and
four
in
vitro
studies:
bacterial
reverse
mutation
assay
in
Salmonella
and
E.
coli
(
MRID
43529501),
forward
gene
mutation
assay
in
cultured
mouse
lymphoma
cells
(
MRID
41710501),
chromosomal
aberration
assay
in
cultured
human
lymphocytes
(
MRID
41214203)
and
unscheduled
DNA
synthesis
in
cultured
primary
rat
hepatocytes
(
MRID
41214204).

Two
potential
contaminants
of
ethofumesate
technical
are
ethyl
methylsulfonate
(
EMS)
and
isobutylmethylsulfonate
(
iBMS).
EMS
is
a
potent,
direct­
acting
mutagen
(
DNA
alkylating
agent)
that
is
used
as
a
positive
control
in
many
types
of
genotoxicity
studies,
and
is
a
known
carcinogen.
IBMS
is
also
mutagenic
but
less
potent
that
EMS;
carcinogenicity
data
are
unavailable
for
iBMS
at
this
time.
However,
the
limits
of
EMS
and
iBMS
levels
in
the
Bayer
CropScience
ethofumesate
technical
grade
product
are
extremely
low
(<
0.001
ppm),
all
genotoxicity
studies
conducted
on
this
product
to
date
are
negative
and
there
is
no
convincing
evidence
of
carcinogenicity
from
long­
term
exposure
to
ethofumesate.
Although
the
relevance
of
the
EMS
and
iBMS
impurities
to
developmental
effects
in
the
rabbit
developmental
study
(
MRID
Nos.
00156606,
40263701,
41652501)
cannot
be
positively
defined
at
this
time,
the
lack
of
developmental
or
reproductive
toxicity
in
the
rat
study,
lack
of
positive
mutagenic
data
on
ethofumesate
and
the
low
levels
of
impurity
present
in
ethofumesate
technical
suggest
that
the
developmental
effects
in
rabbits
are
due
to
other
mechanisms
of
toxicity
(
TXR
No.
0051939,
MRID
45879002,
N.
McCarroll,
1/
20/
04).

Table
3.4.15
Summary
of
Toxicological
Dose
and
Endpoints
for
Ethofumesate.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
49
years
of
age)
Developmental
NOAEL
=
30
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.30
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.30
mg/
kg/
day
Developmental
toxicity
study
in
rabbits
MRIDs
00156606,
40263701,
41652501
Developmental
LOAEL
=
300
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.

Acute
Dietary
(
General
population
including
infants
and
children)
No
appropriate
acute
endpoint
identified
DP
Barcode
D326518
/
46510101
Page
42
of
73
Table
3.4.15
Summary
of
Toxicological
Dose
and
Endpoints
for
Ethofumesate.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Chronic
Dietary
(
Females
13­
49
years
of
age)
Developmental
NOAEL
=
30
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.30
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.30
mg/
kg/
day
Developmental
toxicity
study
in
rabbits
MRIDs
00156606,
40263701,
41652501
Developmental
LOAEL
=
300
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.

Chronic
Dietary
(
General
population
including
infants
and
children)
NOAEL=
127
mg/
kg/
day
UF
=
100
Chronic
RfD
=
1.3
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
1.3
mg/
kg/
day
Chronic
oral
toxicity/
carcinogenicity
study
in
rat
MRIDs
44093603,
44093604
LOAEL
=
469
mg/
kg/
day
based
on
decreased
body
weight
gain
in
females.

Incidental
Oral
(
Short­
and
Intermediate
Term)(
Infants
and
children
only)
NOAEL=
190
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
90­
day
oral
toxicity
study
in
rats
MRID
44093601
LOAEL
=
1900
mg/
kg/
day
based
on
decreased
body
weight
gain
and
liver
microscopic
lesions.

Dermal
(
ALL
DURATIONS)
females
13­
49
years
of
age
Developmental
NOAEL
=
30
mg/
kg/
day
(
dermal
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Developmental
toxicity
study
in
rabbits
MRIDs
00156606,
40263701,
41652501
Developmental
LOAEL
=
300
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.

Dermal­
Short­
Term
(
1­
30
days)
and
Intermediate­
Term
(
1
to
6
months)
­
General
population
including
infants
and
children
Oral
study
NOAEL=
190
mg/
kg/
day
(
dermal
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
90­
day
oral
toxicity
study
in
rats
MRID
44093601
LOAEL
=
1900
mg/
kg/
day
based
on
decreased
body
weight
gain
and
liver
microscopic
lesions.

Long­
Term
Dermal
(>
6
months)
­
General
population
including
infants
and
children
Oral
study
NOAEL=
127
mg/
kg/
day
(
dermal
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic
oral
toxicity/
carcinogenicity
study
in
rat
MRIDs
44093603,
44093604
LOAEL
=
469
mg/
kg/
day
based
on
decreased
body
weight
gain
in
females.
DP
Barcode
D326518
/
46510101
Page
43
of
73
Table
3.4.15
Summary
of
Toxicological
Dose
and
Endpoints
for
Ethofumesate.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Inhalation
(
ALL
DURATIONS)
­
Females
13­
49
years
of
age
Oral
study
Developmental
NOAEL=
30
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Developmental
toxicity
study
in
rabbits
MRIDs
00156606,
40263701,
41652501
Developmental
LOAEL
=
300
mg/
kg/
day
based
on
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.

Inhalation
­
Short­
Term
(
1
to
30
days)
and
Intermediate­
Term
(
1
to
6
months)
­
General
population
including
infants
and
children
Oral
NOAEL
=
190
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
90­
day
oral
toxicity
study
in
rats
MRID
44093601
LOAEL
=
1900
mg/
kg/
day
based
on
decreased
body
weight
gain
and
liver
microscopic
lesions.

Long­
Term
Inhalation
(>
6
months)
­
General
population
including
infants
and
children
Oral
NOAEL
=
127
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic
oral
toxicity/
carcinogenicity
study
in
rat
MRIDs
44093603,
44093604
LOAEL
=
469
mg/
kg/
day
based
on
decreased
body
weight
gain
in
females.

Cancer
(
oral,
dermal,
inhalation)
Classification:
"
Not
likely
to
be
carcinogenic
to
humans"

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
3.5
Special
FQPA
Safety
Factor
HIARC
concluded
that
the
special
FQPA
Safety
Factor
can
be
removed
(
1X)
because
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.
HIARC
determined
that
the
special
FQPA
Safety
Factor
can
be
reduced
to
1X
because
acceptable
developmental
and
reproduction
studies
have
been
submitted
and
reviewed,
and
there
is
a
low
concern
and
no
residual
uncertainties
for
pre­
and
postnatal
toxicity.
The
ethofumesate
risk
assessment
team
evaluated
the
quality
of
the
exposure
data;
and,
based
on
these
data,
recommended
that
the
DP
Barcode
D326518
/
46510101
Page
44
of
73
special
FQPA
SF
be
reduced
to
1x.
The
recommendation
is
based
on
the
following:

°
The
dietary
food
exposure
assessment
utilizes
proposed
tolerance
level
or
higher
residues
and
100%
CT
information
for
all
commodities.
By
using
these
screening­
level
assessments,
chronic
exposures/
risks
will
not
be
underestimated.

°
The
dietary
drinking
water
assessment
(
Tier
1
estimates)
utilizes
values
generated
by
model
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.

°
The
residential
exposure
assessment
utilizes:
activity
specific
transfer
coefficients
and
chemicalspecific
turf
transferable
residue
(
TTR)
studies
for
the
post­
application
scenario.
The
refined
residential
assessment
is
based
on
reliable
data
and
is
unlikely
to
underestimate
exposure/
risk.

3.6
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

The
available
data
on
ethofumesate
indicated
that
there
was
no
toxicologically
significant
evidence
of
endocrine
disruption
effects.
When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
ethofumesate
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
4.0
Public
Health
and
Pesticide
Epidemiology
Data
Relatively
few
incidents
of
illness
have
been
reported
due
to
ethofumesate.
Six
incidents
related
to
ethofumesate
use
were
reported
between
1995
and
2003
under
OPP's
Incident
Data
System
(
IDS).
Four
cases
involved
throat,
eye,
respiratory,
and
nose
irritation.
One
case
involved
dizziness
and
flu­
like
symptoms,
and
another
involved
cramps,
loss
of
appetite,
nausea,
dizziness
and
vomiting.

Poison
Control
Center
data
was
reviewed
for
the
years
1993
through
2001.
There
were
just
seven
cases
related
to
ethofumesate.
Of
these
seven,
four
were
seen
in
a
health
care
facility
and
four
had
outcomes
that
could
be
determined.
For
those
with
a
determined
outcome,
two
DP
Barcode
D326518
/
46510101
Page
45
of
73
were
asymptomatic
and
two
had
minor
symptoms.
There
were
too
few
reports
to
draw
conclusions
regarding
the
effects
of
ethofumesate.
Symptoms
did
not
fit
any
pattern.

Detailed
descriptions
of
three
cases
submitted
to
the
California
Pesticide
Illness
Surveillance
Program
(
1982­
2000)
were
reviewed.
In
two
of
these
cases,
ethofumesate
was
used
alone
or
was
judged
to
be
responsible
for
the
health
effects.
In
the
first
case,
a
mixer/
loader,
who
did
not
wear
eye
protection,
mixed
the
product
and
some
of
it
splashed
in
his
eyes.
The
worker
was
diagnosed
with
an
allergic
reaction
to
chemicals.
In
the
second
case,
an
applicator,
who
wore
goggles,
applied
the
product
with
a
power
sprayer
to
turf.
The
worker
was
diagnosed
with
irritation
and
injected
sclera
of
the
right
eye.

No
scientific
literature
was
located
concerning
acute
poisoning
due
to
exposure
to
ethofumesate.

5.0
Dietary
Exposure/
Risk
Characterization
5.1
Pesticide
Metabolism
and
Environmental
Degradation
5.1.1
Metabolism
in
Plants
The
qualitative
nature
of
ethofumesate
residues
in
plants
is
adequately
understood
for
the
purposes
of
the
new
use
on
onions
based
on
adequate
sugar
beet
and
ryegrass
metabolism
studies.
The
MARC
has
determined
that
the
residues
of
concern
in
plants
are
the
combined
residues
of
ethofumesate
and
its
free
and
conjugated
metabolites
NC
8493,
NC
9607,
and
NC
20645
(
S.
Funk,
8/
29/
95).
Although
the
current
tolerance
expression
does
not
include
the
metabolite
NC
20645,
the
expression
is
adequate
for
plant
commodities
as
the
acid
treatment
used
in
the
tolerance
enforcement
and
data
collection
methods
converts
NC
20654
to
NC
9607.

There
are
no
onion
livestock
feed
items
of
regulatory
interest,
therefore
a
discussion
of
the
nature
of
ethofumesate
residues
in
livestock
commodities
is
not
germane
to
this
action.

5.1.2
Metabolism
in
Rotational
Crops
The
metabolism
of
ethofumesate
in
rotational
crops
was
similar
to
the
primary
crops.
An
adequate
confined
rotational
crop
study
indicated
that
14C­
residues
(
expressed
as
ethofumesate
equivalents)
accumulated
at
levels
above
0.01
ppm
in/
on
all
commodities
of
radish,
cabbage,
and
wheat
that
were
planted
at
various
rotation
intervals
(
96,
157,
276,
and
366
days)
after
[
U­
14C­
phenyl]
ethofumesate
was
applied
to
sandy
loam
soil
under
greenhouse
conditions
at
4.1
lb
ai/
A
(­
1x).
14C­
Residues
in
the
various
commodities
were
adequately
identified
and/
or
characterized,
and
the
metabolism
of
ethofumesate
in
rotational
crops
was
similar
to
the
primary
crops.
Ethofumesate
was
the
principal
residue
identified
radish
roots
(#
60%
TRR)
but
was
a
minor
(<
3%
TRR)
component
in/
on
cabbage,
wheat
straw,
and
wheat
grain.
The
metabolite
NC
9607
was
DP
Barcode
D326518
/
46510101
Page
46
of
73
the
major
residue
identified
in
cabbage
(#
57%
of
TRR),
wheat
straw
(#
31%
of
TRR),
and
wheat
grain
(#
15%
TRR),
and
substantial
levels
of
metabolite
NC
20645
were
also
detected
in
radish
roots
(#
15%
TRR),
cabbage
(#
26%
TRR),
wheat
straw
(#
12%
TRR),
and
wheat
grain
(#
6%
TRR).
Metabolite
NC
8493
accounted
for
<
10%
of
the
TRR
on
all
commodities.

The
available
limited
rotational
crop
studies
indicate
the
potential
for
accumulation
of
residues
in
rotated
crops
planted
at
the
established
plant­
back
interval
(
PBI)
following
applications
at
the
maximum
seasonal
use
rate.
In
one
set
of
limited
field
rotational
crop
trials
conducted
during
1990
at
two
sites
(
DP
Barcode
D207770,
L.
Cheng,
6/
16/
97),
ethofumesate
was
applied
to
sugar
beets
at
rates
totaling
3.1
or
5.0
lb
ai/
A
(
0.8x
and
1.3x).
Representative
rotational
crops
were
planted
at
PBIs
of
­
3
and
7
months
at
one
site
(
CA)
and
at
­
10
months
at
the
other
site
(
ND).
Quantifiable
residues
($
0.05
ppm)
of
ethofumesate
were
detected
only
in
carrots
(
0.15
ppm)
from
the
3­
month
PBI,
and
residues
of
NC
8493
were
detected
only
in
spinach
(
0.08
ppm)
and
barley
fodder
(
0.05
ppm)
from
the
3­
month
PBI.
However,
residues
of
NC
9607
were
detectable
at
up
to
the
10­
month
PBI
in
cabbage
(
0.08
ppm)
and
oat
fodder
(
0.09
ppm).

In
another
set
of
limited
studies
(
MRID
45855502)
conducted
during
1993
in
CA
(
2
sites),
ID
(
2
sites),
MI
(
2
sites),
and
NE,
ethofumesate
was
applied
to
sugar
beets
twice
as
a
combination
of
pre­
and
post­
emergence
applications,
totaling
4.1­
4.6
lb
ai/
A
(
1­
1.2x).
With
a
few
exceptions,
representative
rotational
crops
were
planted
at
a
­
10­
month
PBI.
A
single
treated
sample
of
each
RAC
from
each
crop
was
harvested
and
analyzed
using
an
adequate
GC/
FPD­
S
Method
(
Aventis
Method
B­
93R­
03),
which
determines
ethofumesate,
NC
8493,
NC
9607
and
NC
20654
(
recovered
as
NC
9607).
The
method
has
an
LOQ
of
0.05
ppm
for
each
analyte.

Residues
of
NC
8493
were
<
0.05
ppm
in
all
RAC
samples
from
the
rotational
crops,
and
residues
of
ethofumesate
were
<
0.05
ppm
in
all
samples
of
lettuce
and
wheat/
barley
forage,
straw,
and
grain.
At
the
10­
month
PBI,
ethofumesate
was
detected
only
in
1
out
of
6
samples
of
carrot
tops
(
0.207
ppm)
and
in
2
out
of
6
samples
of
carrot
roots
(
0.051
and
0.115
ppm).
Most
samples
from
the
10­
month
PBI
also
had
residues
of
NC
9607
that
were
<
LOQ;
however,
NC
9607
was
quantifiable
in
at
least
one
sample
of
every
RAC
except
carrot
tops.
Residues
of
NC
9607
were
detected
in
1
sample
each
of
carrot
tops
(
0.064
ppm),
lettuce
(
0.108
ppm),
and
cereal
grain
(
0.052
ppm),
and
were
detected
in
2
out
of
4
samples
of
forage
(
0.069­
0.126
ppm)
and
2
out
of
3
samples
of
straw
(
0.066­
0.070
ppm).

The
rotational
crop
restrictions
on
the
Nortron
®
SC
label
are
appropriate:
do
not
rotate
to
any
crop
other
than
sugar
beets
or
ryegrass
for
12
months
following
applications
totaling
more
than
0.375
lb
ai/
A
and
for
6
months
following
post­
emergence
applications
totaling
#
0.375
lb
ai/
A.
Should
the
registrant
wish
to
change
the
existing
rotational
crop
restrictions,
extensive
field
trials
at
the
maximum
seasonal
use
rate
should
be
conducted
in
the
representative
sugar
beet
growing
regions
on
all
crops
which
could
be
planted
in
a
typical
crop
rotation
sequence
with
sugar
beets.
DP
Barcode
D326518
/
46510101
Page
47
of
73
5.1.3
Metabolism
in
Livestock
There
are
no
onion
livestock
feed
items
of
regulatory
interest,
therefore
a
discussion
of
the
nature
of
ethofumesate
residues
in
livestock
commodities
is
not
germane
to
this
action.

5.1.4
Analytical
Methodology
A
tolerance
enforcement
method
is
listed
as
Method
I
in
PAM
Vol.
II
(
Section
108.345)
for
determining
the
currently
regulated
residues
in
plants,
which
include
ethofumesate
and
its
metabolites
NC
8493
and
NC
9607
(
free
and
conjugated).
Although
this
method
does
not
specifically
address
the
recovery
of
free
and
conjugated
NC
20654,
the
acid
hydrolysis
step
used
in
the
method
most
likely
results
in
the
conversion
of
NC
20654
to
NC
9607.
Residues
are
determined
using
gas
chromatography
with
flame
ionization
detector
(
GC/
FID)
in
the
sulfur
mode
with
an
internal
standard.
The
reported
LOQ
for
each
analyte
is
0.02
ppm.

In
addition
to
Method
I
above,
the
registrant
has
proposed
a
gas
chromatography
with
flame
photometric
detector
in
the
sulfur
mode
(
GC/
FPD­
S)
method
for
enforcing
tolerances
in
plant
commodities.
This
method
was
most
recently
referred
to
as
Bayer
CropScience
Method
Number
XB/
01/
01,
is
the
same
as
the
data
collection
GC/
FPD­
S
Method
B­
93R­
03.
The
LOQ
for
each
analyte
is
0.05
ppm.
During
the
acid
hydrolysis
step,
free
and
conjugated
residues
of
NC
20645
are
released
and
recyclized
to
form
NC
9607.
The
above
GC/
FPD­
S
method
has
undergone
a
successful
independent
laboratory
validation
trial
(
MRID
45818104)
and
has
been
successfully
validated
(
MRID
45818101)
using
radiolabeled
samples
of
tops
and
roots
from
red
beets
treated
with
[
14C]
ethofumesate.
This
method
should
be
forwarded
to
the
Analytical
Chemistry
Branch
(
ACB)
for
an
method
validation
trial.

Onion
samples
were
analyzed
for
ethofumesate
and
metabolites
NC
9607
and
NC
8493
using
AgrEvo
Report
No.
B­
93R­
03,
At
Harvest
Ethofumesate­
Derived
Residues
in
or
on
Sugar
Beet
Roots
and
Tops
Following
Sequential
Applications
of
NORTRON
SC
and
BETA
Mix
at
the
Highest
Recommended
Pre­
Emergence
Plus
Post
Emergence
Rate
Combination,
distributed
on
April
25,
1995.
Minor
modifications
were
made
that
did
not
negatively
affect
the
performance
of
the
method..
Quantitation
was
accomplished
by
GC­
MSD.
Results
were
calculated
by
comparison
of
sample
versus
a
standard
curve.
The
LLMV
for
dry
bulb
onions
is
0.05
ppm
for
all
three
analytes.
The
LOD
is
0.02
ppm
for
ethofumesate
and
the
LOQ
is
0.055ppm.

There
are
adequate
enforcement
methods
for
determination
of
ethofumesate
residues
of
regulatory
interest.
The
data
collection
method
is
adequate
for
the
determination
of
ethofumesate
residues
of
regulatory
interest
in
onion,
dry
bulb
commodities.

The
second
proposed
enforcement
method,
Bayer
CropScience
Method
Number
DP
Barcode
D326518
/
46510101
Page
48
of
73
XB/
01/
01,
should
be
sent
to
ACB
for
petition
method
validation
(
PMV).
This
is
not
a
deficiency
for
this
action.

5.1.5
Environmental
Degradation
The
major
route
of
dissipation
for
ethofumesate
in
surface
soil
appears
to
be
photodegradation
(
photolysis
half
lives
were
28
to
31
hours
in
water
and
165
hours
in
soil).
However,
ethofumesate
below
the
soil
surface
appears
more
stable.
It
may
dissipate
by
microbial
metabolism
with
aerobic
metabolism
half
lives
between
83
and
253
days.
Laboratory
data
indicate
that
ethofumesate
is
stable
to
hydrolysis
and
anaerobic
soil
metabolism.
Furthermore,
laboratory
mobility
data
indicate
that
ethofumesate
is
very
mobile
in
sand
with
a
Kd
of
0.73
and
moderately
mobile
in
most
other
soils
with
Kds
ranging
from
2.35
to
6.16.
Available
data
indicate
that
degradate
mobility
is
similar
to
that
of
parent
ethofumesate.
Supplemental
terrestrial
field
dissipation
data
indicate
half
lives
of
approximately
100
days
with
no
detection
of
ethofumesate
below
12
inches.

5.1.6
Comparative
Metabolic
Profile
In
a
rat
metabolism
study,
excretion
was
complete
(
96­
99%)
by
5
days'
postdosing,
with
primary
route
of
excretion
via
urine
(
70­
92%
of
dose;
65­
78%
within
6
hr
postdosing).
Absorption
was
high
but
slightly
reduced
(
10­
15%)
at
500
mg/
kg,
suggesting
saturation.
Radioactivity
did
not
accumulate
in
tissues
but
was
highest
in
the
liver
(
0.007
to
1.50
Fg/
g
tissue)
and
kidney
(<
0.010
to
0.542
Fg/
g
tissue)
and
at
high
dose,
in
brain,
fat,
bone
and
testes
(
0.232­
0.452
Fg/
g
tissue).
Parent
was
excreted
only
in
feces
(
10­
15%
of
dose
at
500
mg/
kg).
Major
metabolite
identified
was
Met­
1
["­(
2­
hydroxy­
5­
methanesulfonyloxyphenyl)
isobutyric
acid].
Major
biotransformation
occurred
via
dealkylation
and
oxidation.
Metabolism
was
similar
for
males
and
females,
with
males
excreting
slightly
more
radioactivity
in
the
feces
than
females
(
6­
10%
of
dose).

As
observed
in
the
rat,
the
major
metabolic
pathway
of
ethofumesate
in
plants
and
livestock
involves
dealkylation
of
the
parent
to
form
NC
8493,
oxidization
to
a
lactone
(
NC
9607),
followed
by
the
opening
of
lactone
to
yield
an
acid
(
NC
20645).
The
HED
Metabolism
Committee
has
determined
that
the
parent
ethofumesate
and
all
metabolites,
free
and
conjugated,
are
of
toxicological
concern
and
should
be
considered
for
tolerance
enforcement
and
dietary
risk
assessment
purposes.
This
includes
parent
ethofumesate
(
free
and
conjugated),
NC
8493
(
free
and
conjugated),
NC
9607
(
free
and
conjugated),
and
NC
20645
(
free
and
conjugated).
However,
the
MARC
also
determined
that
based
on
the
environmental
fate
properties
of
this
chemical
and
the
relatively
low
amounts
of
the
degradates
detected
in
the
laboratory
environmental
fate
studies,
that
only
parent
ethofumesate
needs
to
be
assessed
for
drinking
water.
The
conservative
EECs
should
not
underestimate
the
risk
from
drinking
water.

5.1.7
Toxicity
Profile
of
Major
Metabolites
and
Degradates
DP
Barcode
D326518
/
46510101
Page
49
of
73
The
metabolism
of
ethofumesate
in
ryegrass,
sugar
beets,
poultry,
lactating
cows
and
the
rat
has
been
reviewed
by
HED
and
found
to
be
adequate.
Ethofumesate
is
converted
via
the
hemiacetal
(
NC
8493,
loss
of
the
ethyl
group)
to
the
lactone
(
NC9607)
and
acid
(
NC20645)
in
all
of
the
above
species.
Presented
in
Table
3.0.1
are
the
structures
for
ethofumesate
and
the
residues
of
concern.
The
HED
Metabolism
Committee
has
determined
that
the
parent
ethofumesate
and
all
metabolites,
free
and
conjugated,
are
of
toxicological
concern
and
should
be
considered
for
tolerance
enforcement
and
dietary
risk
assessment
purposes.
However,
the
available
data
(
i.
e.,
LD50
values,
results
from
rat
developmental
and
a
1­
year
dietary
study
in
rats
with
NC
8438,
all
of
which
show
little
or
no
toxicity)
indicate
that
the
toxicity
of
the
metabolites
is
comparable
to
that
of
the
parent.
Therefore,
the
parent
and
the
metabolites
have
been
assessed
together.
Similarly,
the
MARC
determined
that
based
on
the
environmental
fate
properties
of
this
chemical
and
the
relatively
low
amounts
(<
10%)
of
the
degradates
detected
in
the
laboratory
environmental
fate
studies,
that
only
the
parent,
ethofumesate
needs
to
be
assessed
for
drinking
water.

5.1.8
Pesticide
Metabolites
and
Degradates
of
Concern
The
MARC
has
determined
that
the
residues
of
concern
in
plants
are
the
combined
residues
of
ethofumesate
and
its
free
and
conjugated
metabolites
NC
8493,
NC
9607,
and
NC
20645
(
S.
Funk,
8/
29/
95).
Although
the
current
tolerance
expression
does
not
include
the
metabolite
NC
20645,
the
expression
is
adequate
for
plant
commodities
as
the
acid
treatment
used
in
the
tolerance
enforcement
and
data
collection
methods
converts
NC
20654
to
NC
9607.

TABLE
5.1.8
Chemical
Names
and
Structures
of
Ethofumesate
and
its
Residues
of
Concern.

Company
Name
(
Codes)
Chemical
Name
Structure
Ethofumesate
(
NC
8438;
AE
B049913)
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate
NC
8493
(
AE
C508493)
2,3­
dihydro­
2­
hydroxy­
3,3­
dimethylbenzofuran­
5­
yl
methanesulfonate
O
OH
C
H
3
CH
3
CH
3
SO
2
O
NC
9607
(
AE
C509607)
3,3­
dimethyl­
5­[(
methylsulfonyl)
oxy]­
2(
3H)­
benzofuranone
O
O
C
H
3
CH
3
CH
3
SO
2
O
DP
Barcode
D326518
/
46510101
Page
50
of
73
TABLE
5.1.8
Chemical
Names
and
Structures
of
Ethofumesate
and
its
Residues
of
Concern.

Company
Name
(
Codes)
Chemical
Name
Structure
NC
20645
(
AE
C639175)
2­
hydroxy­%,%­
dimethyl­
5­
[(
methylsulfonyl)
oxy]­
benzeneacetic
acid
OH
CH
3
SO
2
O
CH
3
CH
3
O
OH
5.1.9
Drinking
Water
Residue
Profile
The
MARC
concluded
that
while
three
degradates
of
ethofumesate
were
identified,
they
were
of
toxicological
equivalence
to
the
parent
and
were
detected
in
environmental
fate
studies
in
relatively
low
amounts
(
10%),
only
the
parent
needs
to
be
assessed
for
drinking
water.
Since
no
monitoring
data
were
available
for
use
in
this
drinking
water
assessment,
the
EFED
provided
the
drinking
water
assessments
using
simulation
models
to
estimate
the
potential
concentration
of
ethofumesate
in
ground
and
surface
water.

Table
5.1.9
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Ethofumesate
Exposure
Duration
Surface
Water
Conc.,
ppb
(
Fg/
l)
a
Ground
Water
Conc.,
ppb
(
Fg/
l)
b
Acute
154
8.4
Chronic
(
non­
cancer)
45.5
Chronic
(
cancer)
26
a
From
the
Tier
II
PRZM­
EXAMS
­
Index
Reservoir
model.
Input
parameters
are
based
on
standard
model
parameters
(
i.
e.,
application
rates
spray
drift
scenario,
aerobic
and
anaerobic
metabolism,
aerobic
and
anaerobic
aquatic
degradation,
aqueous
photolysis,
hydrolysis
t1/
2,
Kd/
Koc,
molecular
weight,
foliar
decay
rate,
water
solubility,
Henry's
Law
Constant
and
vapor
pressure).
b
From
the
SCI­
GROW
model
assuming
a
maximum
seasonal
use
rate
of
3.0
lb
ai/
A,
a
Koc
of
156.3
and
a
half­
life
of
83
and
days
for
aerobic
metabolism.

5.1.10
Food
Residue
Profile
Ethofumesate
[
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate]
is
a
selective
herbicide
for
the
control
of
broadleaf
and
grass
weeds
in
sugar
beets
and
grasses.
In
the
U.
S.,
ethofumesate
products
registered
to
Bayer
CropScience,
the
basic
producer,
include
a
flowable
concentrate
(
FlC;
4
lb/
gal),
a
soluble
concentrate
(
SC;
4
lb/
gal),
and
several
emulsifiable
concentrates
(
EC;
0.05­
1.5
lb/
gal)
that
can
be
applied
as
pre­
plant,
preemergence,
and
postemergence
applications
using
ground
or
aerial
equipment.
Tolerances
for
the
residues
of
ethofumesate
are
established
in
40
CFR
§
180.345
as
ethofumesate
(
2­
ethoxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
benzofuranyl
methanesulfonate)
and
its
metabolites
2­
hydroxy­
2,3­
dihydro­
3,3­
dimethyl­
5­
DP
Barcode
D326518
/
46510101
Page
51
of
73
benzofuranyl
methanesulfonate
and
2,3­
dihydro­
3,3­
dimethyl­
2­
oxo­
5­
benzofuranyl
methanesulfonate
(
both
calculated
as
the
parent
compound)
ranging
from
0.05
ppm
on
animal
commodities
to
1.0
ppm
on
sugar
beet
tops.

Interregional
Research
Project
#
4,
IR­
4,
is
requesting
the
use
of
ethofumesate
in
the
product
Nortron
®
SC
(
EPA
Reg.
No.
264­
613)
on
dry
bulb
onions.
The
requested
use
is
for
a
single
application
at
planting
or
shortly
after
at
1.0
lb
ai/
A
followed
by
four
applications
at
0.5
lb
ai/
A.
A
30­
day
PHI
is
indicated.

The
residues
of
concern
in
plants
are
the
combined
residues
of
ethofumesate
and
its
free
and
conjugated
metabolites
NC
8493,
NC
9607,
and
NC
20645.
Although
the
current
tolerance
expression
does
not
include
the
metabolite
NC
20645,
the
expression
is
adequate
for
plant
commodities
as
the
acid
treatment
used
in
the
tolerance
enforcement
and
data
collection
methods
converts
NC
20654
to
NC
9607.
The
metabolism
of
ethofumesate
in
rotational
crops
was
similar
to
the
primary
crops.

A
tolerance
enforcement
method
is
listed
as
Method
I
in
the
Pesticide
Analytical
Manual
Vol.
II
(
PAM
II,
Section
108.345)
for
determining
the
currently
regulated
residues
in
plants,
which
include
ethofumesate
and
its
metabolites
NC
8493
and
NC
9607
(
free
and
conjugated).
Although
this
method
does
not
specifically
address
the
recovery
of
free
and
conjugated
NC
20654,
the
acid
hydrolysis
step
used
in
the
method
most
likely
results
in
the
conversion
of
NC
20654
to
NC
9607.
Residues
are
determined
using
gas
chromatography
with
flame
ionization
detector
(
GC/
FID).
The
reported
limit
of
quantitation
(
LOQ)
for
each
analyte
is
0.02
ppm.
PAM
Vol.
I,
Appendix
I
indicates
that
ethofumesate
is
completely
recovered
using
FDA
Multiresidue
Methods
Section
302
(
Luke
Method;
Protocol
D).
However,
no
data
are
available
on
the
recovery
of
the
metabolites
NC
8493,
NC
9607,
and
NC
20654.
These
data
should
be
submitted
for
any
future
action.

In
addition
to
Method
I
above,
the
registrant
has
proposed
a
gas
chromatography
with
flame
photometric
detector
in
the
sulfur
mode
(
GC/
FPD­
S)
method
for
enforcing
tolerances
in
plant
commodities.
This
method
was
most
recently
referred
to
as
Bayer
CropScience
Method
Number
XB/
01/
01,
is
the
same
as
the
data
collection
GC/
FPD­
S
Method
B­
93R­
03.
The
LOQ
for
each
analyte
is
0.05
ppm.
During
the
acid
hydrolysis
step,
free
and
conjugated
residues
of
NC
20645
are
released
and
recyclized
to
form
NC
9607.
The
above
GC/
FPD­
S
method
has
undergone
a
successful
independent
laboratory
validation
trial
and
has
been
successfully
validated
using
radiolabeled
samples
of
tops
and
roots
from
red
beets
treated
with
[
14C]
ethofumesate.
This
method
should
be
forwarded
to
the
Analytical
Chemistry
Branch
(
ACB)
for
an
method
validation
trial,
however
this
is
not
a
deficiency
for
this
action.
Onion
samples
were
analyzed
for
ethofumesate
and
metabolites
NC
9607
and
NC
8493
using
AgrEvo
Report
No.
B­
93R­
03.
Minor
modifications
were
made
that
did
not
negatively
affect
the
performance
of
the
method.
Quantitation
was
accomplished
by
gas
chromatograph
with
a
mass
selective
detector
(
GC­
MSD).
The
lower
limit
of
method
validation
(
LLMV)
for
dry
bulb
onions
is
0.05
ppm
for
all
three
analytes.
The
LOD
is
0.02
ppm
for
ethofumesate
and
the
limit
DP
Barcode
D326518
/
46510101
Page
52
of
73
of
quantitation
(
LOQ)
is
0.055ppm.

Storage
stability
data
are
available
indicating
that
ethofumesate,
NC
9607
and
NC
8493
are
stable
frozen
for
up
to
35
months
in
various
commodities.
A
storage
stability
study
was
conducted
in
conjunction
with
the
onion
residue
study.
The
results
indicate
that
residues
of
ethofumesate
are
stable
for
up
to
approximately
24.3
months.
The
maximum
frozen
storage
interval
for
onion
residue
samples,
from
harvest
to
analysis,
was
approximately
28.2
months.
There
is
sufficient
storage
stability
data
to
indicate
that
ethofumesate
residues
of
interest
do
not
degrade
in
onions
over
the
harvest
to
analysis
interval.

IR­
4
has
submitted
field
trial
data
for
ethofumesate
on
onion
(
dry
bulb).
The
number
and
locations
of
field
trials
are
in
accordance
with
OPPTS
Guideline
860.1500.
Each
of
the
10
field
sites
the
treated
plot
received
five
applications
of
the
test
substance
with
the
exception
of
the
98­
CA03
trial
which
received
four
applications.
The
first
application
was
broadcast
to
the
soil
surface
prior
to
crop
emergence
at
a
rate
approximately
1.0
lb
ai/
A.
Subsequent
applications
were
foliar
and
made
at
approximate
even
intervals
at
a
rate
of
approximately
0.5
lb
ai/
A
each
for
a
total
of
approximately
3.0
lb
ai/
A,
with
the
last
application
timed
so
that
mature
or
near
mature
dry
bulb
onions
could
be
harvested
28
to
32
days
after
the
final
application.
Samples
were
analyzed
for
residues
of
ethofumesate
and
metabolites
NC
9607
and
NC
8493
using
B­
93R­
03.
For
method
validation,
control
samples
of
onions
were
fortified
with
ethofumesate
at
0.05
ppm;
recoveries
were
114%
±
5%,
n=
3.
Concurrent
recoveries
from
onion
samples
fortified
at
0.05
ppm
with
NC
9607
were
119%
±
2%,
n=
3
and
0.05ppm
with
NC
8493
were
117%
±
6%,
n=
3.
The
LOD
and
LOQ
for
residues
of
ethofumesate
in
onion
are
0.02
ppm
and
0.055
ppm,
respectively.
In
treated
samples,
ethofumesate
residues
were
mostly
below
the
lowest
level
of
method
validation
(
LLMV)
of
0.05
ppm
and
ranged
to
0.087
ppm.
NC
9607
residues
ranges
from
the
LLMV
to
0.112
ppm.
No
NC
8493
residues
above
the
LLMV
were
observed
in
any
of
the
samples.
Total
residues
of
ethofumesate
and
metabolites
ranged
from
<
0.15
to
0.22
ppm
with
a
HAFT
of
0.20
ppm.
PHIs
were
from
28­
32
days.
The
requested
tolerances
for
garlic,
bulb
and
shallot,
bulb
are
not
required
since
they
are
automatically
included
in
the
onion
tolerance.
In
addition,
the
preferred
term
for
the
commodity
should
be
onion,
bulb.
The
MRL
spreadsheet
indicates
that
the
requested
tolerance
is
not
appropriate
and
should
be
lowered.
The
petitioner
should
submit
a
revised
Section
F
requesting
a
tolerance
for
ethofumesate
residues
on
onion,
bulb
at
0.25
ppm.

Since
there
are
no
onion,
dry
bulb
livestock
feed
items
of
regulatory
interest,
a
discussion
of
the
nature
of
the
residue,
analytical
methods,
and
magnitude
of
the
residue
in
livestock
commodities
is
not
germane
to
this
action.

The
limited
field
rotational
crop
trials
are
adequate
and
indicate
that
extensive
field
rotational
crop
studies
are
required
to
support
tolerances
for
inadvertent
ethofumesate
residues
in
rotational
crops.
Without
additional
data
on
rotational
crops,
the
current
rotational
crop
restrictions
on
the
Nortron
®
SC
label
are
appropriate:
do
not
rotate
to
any
DP
Barcode
D326518
/
46510101
Page
53
of
73
crop
other
than
sugar
beets
or
ryegrass
for
12
months
following
applications
totaling
more
than
0.375
lb
ai/
A
and
for
6
months
following
post­
emergence
applications
totaling
#
0.375
lb
ai/
A.

5.1.11
International
Residue
Limits
There
are
currently
no
Codex,
Canadian,
or
Mexican
MRLs
established
for
ethofumesate,
therefore
there
are
no
international
harmonization
issues
for
this
action.

5.2
Dietary
Exposure
and
Risk
An
acute
and
chronic
dietary
(
food+
water)
risk
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analysis
was
performed
to
support
the
registration
decision.
The
acute
and
chronic
dietary
exposure/
risk
analyses
were
conducted
using
tolerance
values,
default
processing
factors,
and
100%
crop
treated
for
all
commodities.
The
maximum
concentration
for
acute
dietary
risk
assessment,
and
the
average
concentration
for
chronic
dietary
risk
assessment,
from
PRZM/
EXAMS
was
used
for
drinking
water
contribution
to
exposure.
Based
on
this
Tier
1
(
unrefined)
assessment,
the
team
selected
the
95th
percentile
of
exposure
to
estimate
acute
dietary
risk
from
food
and
water.
No
monitoring
data
are
available
for
ethofumesate.

The
water
values
used
in
the
dietary
risk
assessment
were
incorporated
in
the
DEEMFCID
 
into
the
food
categories
"
water,
direct,
all
sources"
and
"
water,
indirect,
all
sources".
Based
on
modeling
results,
the
maximum
estimated
surface
water­
derived
drinking
water
concentrations
for
the
use
of
ethofumesate
is
154
Fg/
L
(
used
for
the
acute
analysis)
using
the
Florida
turf
scenario.
The
maximum
1
in
10
year
annual
average
concentration
is
45.5
Fg/
l
(
used
for
the
chronic
analysis)
using
the
Florida
turf
scenario,
and
26
Fg/
L
for
the
30
year
annual
mean
concentration
for
the
Minnesota
sugar
beet
scenario.

Conservative
acute
and
chronic
dietary
(
food
+
water)
assessments
were
performed
using
DEEM­
FCIDTM.
Tolerance
level
residues
and
100%
crop
treated
were
used
in
the
assessments.
The
acute
assessment
concludes
that
for
all
supported
commodities,
the
acute
dietary
exposure
estimate
is
below
HED's
level
of
concern
for
females
13­
49
years
of
age
(
the
only
population
subgroup
of
concern
toxicologically
identified
at
this
time)
at
5
%
of
the
aPAD
at
the
95th
percentile.
The
chronic
assessment
concludes
that
for
all
supported
commodities,
the
chronic
dietary
exposure
estimates
are
below
HED's
level
of
concern
for
all
population
subgroups
at
1%
or
less
of
the
cPAD.

Table
5.2.
Result
of
Acute
and
Chronic
Dietary
Exposure
(
Food
+
Water)
and
Risk
Estimates
for
Ethofumesate.

DEEM­
FCID
Population
Subgroup
PAD,
mg/
kg/
day
Exposure,
mg/
kg/
day
%
PAD
DP
Barcode
D326518
/
46510101
Page
54
of
73
Acute
Dietary
Estimates
95th
Percentile
of
Exposure
Females
13­
49
yrs
0.3
0.011837
4
Chronic
Dietary
Estimates
U.
S.
Population
1.3
0.002604
<
1
All
infants
(<
1
yr)
1.3
0.011013
<
1
Children
1­
2
yrs
1.3
0.006256
<
1
Children
3­
5
yrs
1.3
0.004442
<
1
Children
6­
12
yrs
1.3
0.002944
<
1
Youth
13­
19
yrs
1.3
0.001756
<
1
Adults
20­
49
yrs
1.3
0.002142
<
1
Adults
50+
yrs
1.3
0.002341
<
1
Females
13­
49
yrs
0.3
0.002179
<
1
Cancer
Dietary
Estimate
U.
S.
Population
NA
NA
NA
5.3
Anticipated
Residue
and
Percent
Crop
Treated
(%
CT)
Information
No
anticipated
residue
or
%
CT
data
were
used
in
the
dietary
exposure
analysis.

6.0
Residential
(
Non­
Occupational)
Exposure/
Risk
Characterization
Residential
risk
is
expressed
as
a
MOE,
which
measures
how
close
the
residential
exposure
comes
to
the
NOAEL
from
animal
studies.
Generally,
MOEs
that
are
greater
than
100
do
not
exceed
the
Agency's
level
of
concern
(
the
standard
target
MOE
incorporates
the
standard
uncertainty
factors
of
10x
for
interspecies
variability
and
10x
for
intraspecies
variability).
EPA
determined
that
the
available
data
supports
the
removal
of
the
default
10x
FQPA
factor.
Thus,
scenarios
that
yield
MOEs
that
are
less
than
100
may
trigger
concern.

An
oral
NOAEL
of
190
mg/
kg/
day
was
selected
from
a
90­
day
oral
study
in
rats
for
assessing
the
dermal
exposure
route.
The
LOAEL
in
this
study
was
1900
mg/
kg/
day
with
the
effects
of
decreased
body
weight
gain
and
liver
microscopic
lesions.
Data
on
dermal
absorption
are
unavailable
at
this
time;
therefore,
a
default
assumption
of
100%
absorption
was
used.
Inhalation
exposure
is
not
expected
because
residues
are
likely
to
be
diluted
outdoors
in
the
air
and
ethofumesate
has
a
low
vapor
pressure
(
4.9
x
10­
6
torr).

Some
residential
(
dermal)
scenarios
were
assessed
for
females
13­
49
yrs.
based
on
an
oral
endpoint
from
a
developmental
study
in
rabbits
with
effects
manifested
by
increased
resorptions,
post­
implantation
loss
and
incomplete
ossification
of
the
vertebral
arches.
While
the
residential
postapplication
scenarios
resulted
in
apparent
risks
of
concern
(
see
Table
6.2),
the
Agency
believes
that
these
scenarios
are
very
conservative
and
unlikely
to
occur.
The
developmental
endpoint
was
based
on
a
study
with
a
NOAEL
(
30
mg/
kg/
day)
that
is
10X
lower
DP
Barcode
D326518
/
46510101
Page
55
of
73
than
the
LOAEL
(
300
mg/
kg/
day);
therefore
the
NOAEL
may
be
an
artifact
of
dose
selection.
Additionally,
for
the
residential
exposures,
the
endpoint
is
oral
while
the
assessed
exposures
are
dermal
and
conservative
SOP­
based
default
assumptions
such
as
100%
dermal
absorption,
default
turf
transferable
residue
dissipation
assumptions,
contact
with
turf
immediately
posttreatment
and
maximum
application
rates
were
used
in
this
assessment.
The
rate
of
1.5
lb
ai/
A
covers
the
majority
of
uses;
however,
the
label
does
permit
a
3.0
lb
ai/
A
rate
specifically
for
suppression
of
Bermuda
grass
in
St
Augustine
grass
turf.

The
acute
toxicity
profile
for
ethofumesate
shows
that
the
dermal
LD50
for
ethofumesate
was
>
20,050
mg/
kg
which
was
approximately
three
times
higher
than
the
highest
dose
tested
for
the
oral
route
(
oral
LD50
=
>
6,400
mg/
kg).
Additionally,
no
effects
were
seen
at
the
highest
dose
tested
(
1000
mg/
kg/
day)
in
a
21­
day
dermal
study
in
rabbits.
Although
the
LD50
studies
and
the
short
term
dermal
study
did
not
reach
the
desired
endpoint
and
cannot
be
directly
compared,
the
information
from
these
studies
gives
the
Agency
confidence
that
high
dermal
exposures
such
as
calculated
for
the
residential
risk
assessments
are
unlikely
to
be
a
risk
concern.
However,
the
Agency
intends
to
call
in
a
dermal
absorption
(
or
penetration)
study
to
permit
more
realistic
estimation
of
dermal
absorption.

6.1
Residential
Handler
Exposure
Since
all
ethofumesate
products
are
intended
for
either
agricultural
use
or
require
professional
application
for
ornamental
turf,
no
residential
handler
use
is
expected.

6.2
Residential
Postapplication
Exposure
For
potential
ethofumesate
residential
post­
application
exposure,
HED
conducted
screening
level
calculations
on
the
scenarios
most
likely
to
result
in
highest
possible
exposure
to
the
herbicide.
The
other
aspects
of
the
turf
exposure
scenario
involves
calculating
dose
from
non­
dietary
ingestion
that
arises
from
the
hand­
to­
mouth,
object­
to­
mouth
and
soil
ingestion
pathways.
These
process
are:

for
toddlers:
incidental
ingestion
(
hand­
to­
mouth)
incidental
ingestion
(
turf­
to­
mouth)
incidental
ingestion
(
soil­
to­
mouth)
incidental
dermal
for
adults:
Jazzercise
(
on
treated
turf)

HED
believes
that
this
screening
level
assessment
will
be
protective
of
other
possible
residential
exposures
to
ethofumesate
such
as
golfing,
mowing
the
lawn.
Exposures
were
calculated
by
considering
the
potential
sources
of
exposure
(
i.
e.,
TTRs
on
lawns)
then
calculating
dermal
exposure,
and
risks
in
the
same
manner
as
described
for
the
occupational
post
application
risk
assessments.

The
SOPs
For
Residential
Exposure
Assessment
(
Reference
B)
define
several
pathways
DP
Barcode
D326518
/
46510101
Page
56
of
73
that
apply
to
post
application
exposure
on
treated
turf.
The
SOPs
and
the
associated
pathways
are
presented
below:

C
Dose
from
dermal
exposure
on
treated
turf
calculated
using
SOP
2.2:
Postapplication
dermal
dose
among
toddlers
from
playing
on
treated
turf,
adults
working
or
exercising
on
treated
turf.

C
Dose
from
object­
to­
mouth
activity
from
treated
turf
calculated
using
SOP
2.3.3:
Postapplication
dose
among
toddlers
from
incidental
non­
dietary
ingestion
of
pesticide
residues
on
treated
turf
from
object­
and/
or
hand­
to­
mouth
transfer
(
i.
e.,
those
residues
that
end
up
in
the
mouth
from
a
child
mouthing
a
handful
of
treated
turf,
pesticide
residues
on
the
hand;
pesticide
residues
in
the
soil).

The
algorithms
used
for
each
type
of
calculation
are
presented
below:

Dermal
Exposure
from
Treated
Turf
Dermal
exposure
from
treated
turf
is
calculated
using
the
following
formula
(
SOP
2.2):

Dermal
exposure
(
mg/
day)
=
(
TTR
at
day
t)
x
CF1
x
TC
x
DA
*
x
#
hours/
day)

Where:

TTR
=
transferable
turf
residue
(
ug/
cm
2
)
at
day
(
t)
after
application
CF1
=
conversion
factor
(
0.001)
to
convert
TTR
value
in
ug/
cm
2
to
mg/
cm
2
TC
=
transfer
coefficient
(
cm
2
/
hour)
DA
=
dermal
absorption
factor
=
100%
for
ethofumesate
Hours/
day
=
standard
assumption
is
2
to
4
hours
of
exposure
per
day
depending
upon
the
activity
Exposures
from
Hand
to
Mouth
Behavior
on
Treated
Turf:

The
following
formula
illustrates
the
approach
used
to
calculate
the
non­
dietary
ingestion
exposures
that
are
attributable
to
hand­
to­
mouth
behavior
on
treated
turf
(
SOP
2.3.2).

PDR
=
TTR
*
(
SE/
100)
*
SA
*
Freq
*
Hours
*
(
1
mg/
1000
ug)
where:

PDR
=
potential
dose
rate
from
hand­
to­
mouth
activity
(
mg/
day);
TTR
=
Turf
Transferable
Residue
where
dissipation
is
based
on
TTR
study
and
the
0­
day
value
is
based
on
the
5%
initial
transferability
factor
(
Fg/
cm2);
SE
=
saliva
extraction
factor
(
50%);
SA
=
surface
area
of
the
hands
(
20
cm2);
Freq
=
frequency
of
hand­
to­
mouth
events
(
20
events/
hour);
and
Hours
=
exposure
duration
(
2
hours).

When
used
for
hand
to
mouth
exposures,
the
TTR
value
is
based
upon
the
default
DP
Barcode
D326518
/
46510101
Page
57
of
73
assumption
of
5
percent
of
the
application
rate.

The
formula
for
calculating
the
TTR
value
on
Day
0
is
given
below:

TTR
=
Application
Rate
*
F
*
CF1
*
CF2
*
CF3
Where:
Application
Rate
=
lbs
ai/
acre
F
=
fraction
of
applied
ai
that
is
available
for
hand
to
mouth
exposure
(
5
percent)
CF1
=
1.0
lb
ai/
acre
equals
2.3
x
10
­
5
lbs
ai
per
ft
2
CF2
=
4.54
x
10
8
ug/
lb
CF3
=
0.00108
ft
2
/
cm
2
Note:
CF1
*
CF2
*
CF3
=
11.23
Exposures
from
Object
to
Mouth
Behaviors
on
Treated
Turf:

The
following
formula
illustrates
the
approach
used
to
calculate
exposures
that
are
attributable
to
object­
to­
mouth
behavior
on
treated
turf
that
is
represented
by
a
child
mouthing
on
a
handful
of
turf
(
SOP
2.3.3):

PDR
=
TTR
*
IGR
*
(
1mg/
1000ug)
where:
PDR
=
potential
dose
rate
from
mouthing
activity
(
mg/
day);
TTR
=
Turf
Transferable
Residue
where
dissipation
is
based
on
TTR
study
and
the
0­
day
value
is
based
on
the
20%
initial
transferability
factor
(
Fg/
cm2);
and
IgR
=
ingestion
rate
for
mouthing
of
grass
per
day
(
25
cm2/
day).

Exposures
from
Soil
Ingestion
on
Treated
Turf:

The
following
formula
illustrates
the
approach
used
to
calculate
exposures
that
are
attributable
to
soil
ingestion
(
SOP
2.3.4):

PDR
=
SR
*
IgR
*
(
0.000001
gm/
1
ug)

Where:
PDR
=
dose
from
soil
ingestion
activity
(
mg/
day)
SR
=
Soil
Residue
where
dissipation
is
based
on
TTR
study
and
the
0­
day
value
is
based
on
the
application
rate,
1
cm
depth
of
surface
soil,
and
the
density
of
soil
(
Fg/
cm3)
IgR
=
ingestion
rate
for
daily
soil
ingestion
(
mg/
day)

MOE
Calculations
for
Each
Pathway:

The
MOEs
are
calculated
for
each
individual
pathway
using
the
MOE
formula:

MOE
(
unitless)
=
NOAEL
/
(
Dose
/
BW)
DP
Barcode
D326518
/
46510101
Page
58
of
73
where
NOAEL
=
mg/
kg/
day
Dose
=
mg/
day
BW
=
15
kg
(
toddlers),
60
kg
(
adults)

MOEs
Calculations
for
All
of
the
Pathways
Combined:

When
assessing
adult
exposures
only
the
dermal
pathway
is
considered
and
when
assessing
toddler
exposures
all
of
the
pathways
are
considered
in
total.
The
doses
from
the
four
pathways
are
combined
as
shown
below
to
yield
a
total
dose:

Total
Dose
=
(
Dermal
Dose
+
Hand­
to
Mouth
Dose
+
Object
to
Mouth
Dose
+
Soil
Ingestion
Dose)/
BW
Where:
Total
Dose
=
mg/
kg/
day
BW
=
15
kg
for
toddlers
The
total
dose
is
then
used
to
calculate
a
Total
MOE
as
presented
in
Table
6.2
Table
6.2
Residential
Exposure
Estimates
&
MOEs
for
Ethofumesate
Treated
Turf
Resident
Activity
DAT
Tc
or
Equivalent
Body
wgt
kg
ADD*
NOAEL
MOE
toddler
dermal
contact
0
5200
15
0.58
190
330
toddler
(
at
3
lb
ai/
acre)
dermal
contact
0
5200
15
1.17
190
160
Highest
Toddler
Dermal
MOE
160
toddler
hand
to
mouth
0
PDR**
15
0.022
190
8600
toddler
turf
to
mouth
0
TTR**
15
0.0056
190
34000
toddler
soil
to
mouth
0
PDR**
15
0
190
2.5
e6
Total
Toddler
Oral
MOE
6900
Total
Toddler
Residential
150
adult
Jazzercise
0
14500
70
0.35
190
540
adult
(
at
3
lb
ai/
acre)
working
0
14500
70
0.7
190
270
DP
Barcode
D326518
/
46510101
Page
59
of
73
females
13­
19
Jazzercise
0
14500
60
0.41
30***
73
females
13­
19
(
at
3
lb
ai/
acre)
Jazzercise
0
14500
60
0.81
30***
37
*
ADD=
Average
Daily
Dose
(
mg
ai/
kg
bw/
day)
*
from
Standard
Operating
Procedures
for
Residential
Exposure
Assessment
Science
Advisory
Council
for
Exposure
Policy
No.
12;
revised
February
22,
2001.
**
based
on
a
developmental
toxicity
study
in
rabbits;
developmental
LOAEL
=
300,
and
assumes
100%
dermal
absorption.

With
the
exception
of
women
of
childbearing
years,
residential
post­
application
MOEs
for
toddlers
and
adults
to
ethofumesate
on
treated
turf,
regardless
of
the
pathway
of
exposure,
do
not
exceed
the
Agency's
levels
of
concern.
In
the
case
of
women
of
childbearing
years,
a
MOE
of
37
was
estimated,
based
on
an
oral
endpoint
from
a
developmental
study
in
rabbits.
ARIA
notes
that
this
risk
estimate
is
driven
by
the
conservative
assumptions
used
in
the
risk
assessment:
1)
screening­
level
unrefined
Tier
1
assessment
was
used,
2)
100%
dermal
absorption
was
assumed,
and
3)
an
endpoint
used
for
females
13+
years
of
age
from
a
developmental
study
in
rabbits
with
a
steep
dose­
response
curve
resulting
from
a
NOAEL
(
30
mg/
kg/
day)
that
is
10X
lower
than
the
LOAEL
(
300
mg/
kg/
day);
thus,
a
dose
spacing
issue
likely
exists.
ARIA,
therefore,
considers
this
a
highly
conservative
estimate
of
post­
application
risk
for
the
population
females
13­
49
years
of
age
exposed
to
ethofumesate
on
turf.

6.3
Other
(
Spray
Drift,
etc.)

Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
ground
application
method
employed
for
ethofumesate.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
On
a
chemical
by
chemical
basis,
the
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
with
specific
products
with
significant
risks
associated
with
drift.

In
the
case
of
the
residential
turf
use
of
ethofumesate,
the
risks
addressed
in
the
residential
turf
assessment
provide
a
worst
case
estimate
of
potential
exposure
from
spray
drift.
DP
Barcode
D326518
/
46510101
Page
60
of
73
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
OPP
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
OPP
considers
both
the
route
and
duration
of
exposure.

The
Agency
has
developed
several
guidance
documents
describing
the
mathematical
approaches
used
in
calculating
aggregate
risks
and
the
theoretical
basis
for
these
calculations.
The
underlying
approach,
regardless
of
the
calculation
type,
is
the
same.
The
overall,
allowable
risks
associated
with
an
individual
chemical
is
first
determined
by
its
hazard
database
and
its
associated
uncertainty
factors
or
negligible
risks
if
the
concern
is
cancer
(
i.
e.,
an
exposure
limit
is
defined).
Once
limits
have
been
defined,
contributions
from
different
sources
are
then
added
to
obtain
aggregate
exposures
(
diet­
food
+
water
and
residential)
which
are
compared
to
the
exposure
limit
to
see
if
it
has
been
exceeded
which
would
indicate
a
risk
concern.

Ethofumesate
is
a
food
use
chemical.
There
are
residential
(
non­
occupational)
uses
of
ethofumesate,
resulting
from
postapplication
exposure
to
turf;
therefore,
the
considerations
for
aggregate
exposure
are
those
from
food,
drinking
water
and
residential
exposure.

In
the
past,
EPA
has
not
directly
combined
pesticide
exposure
estimates
from
drinking
water
with
pesticide
exposures
from
food
because
EPA
was
concerned
that
combining
high­
end
modeling
values
for
drinking
water
with
more
realistic
food
exposure
data
might
be
confusing.
Although
EPA
retains
this
concern,
it
is
now
outweighed
by
the
advantages
of
using
EPA's
current
aggregate
exposure
assessment
models,
Lifeline
and
DEEM.
Advances
in
these
models
allow
EPA
to
incorporate
actual
water
consumption
data
and
body
weight
data
in
assessing
exposure
to
pesticides
in
drinking
water
as
well
as
conduct
probabilistic
assessments
for
food,
water,
and
residential
exposures
to
pesticides.
These
more
sophisticated
exposure
assessments
are
not
possible
under
the
drinking
water
levels
of
comparison
(
DWLOC)
approach.
Rather
than
using
back­
calculated
DWLOCs,
estimates
of
pesticide
residues
in
drinking
water
were
incorporated
directly
into
the
dietary
exposure
analysis
to
assess
aggregate
acute
and
chronic
risk
7.1
Acute
Aggregate
Risk
As
part
of
the
acute
dietary
exposure
analysis,
the
evaluation
of
the
acute
aggregate
exposure
and
risk
was
prepared
(
see
5.2,
Dietary
Exposure
and
Risk).
The
analysis
was
performed
for
females
13­
49
years
of
age
since
this
is
the
only
population
subgroup
of
toxicological
concern
identified
at
this
time.
As
shown
in
Table
5.2,
the
resulting
food
+
water
exposure
estimate
is
below
the
Agency's
level
of
concern
for
this
population
subgroup.
The
contribution
of
food
and
food
forms
to
this
estimate,
at
the
95th
percentile,
is
4%.
Therefore,
there
are
no
acute
food
+
water
aggregate
risk
concerns
for
ethofumesate
7.2
Short­
and
Intermediate­
Term
Aggregate
Risk
DP
Barcode
D326518
/
46510101
Page
61
of
73
Risk
assessments
for
aggregate
exposure
(
food
+
drinking
water
+
residential)
were
considered
for
the
short­
and
intermediate­
term
exposure.
Because
there
are
concerns
for
the
post­
application
residential
exposure
of
females
13+
years
of
age
(
MOE
=
37,
see
Table
6.2),
an
aggregate
assessment
was
not
conducted
for
this
subgroup.
The
aggregate
exposure
for
food
and
drinking
water
has
already
been
calculated
for
all
of
these
subgroups
and
found
not
to
pose
a
health
concern
(
See
Section
5.2).
However,
there
are
post­
application
residential
exposures
to
ethofumesate,
and
the
considerations
for
aggregate
exposure
are
those
from
food,
water,
and
residential
uses.
The
short­
and
intermediate­
term
aggregate
risk
assessment
values
are
presented
in
Table
7.2.
As
shown,
target
MOEs
are
the
same
for
all
populations.
The
toxicology
study,
showing
decreased
body
weight
gain
and
microscopic
lesions
in
the
liver
(
NOAEL
=
190
mg/
kg/
day
in
90­
day
oral
rat
study),
is
appropriate
for
this
exposure
duration
and
the
target
populations.

Table
7.2
Short­
and
Intermediate­
Term
Aggregate
Risk
Short
and/
or
Intermediate­
Term
Scenarios
Chronic
Dietary
Residential
Exposure
Population
LOC1
Exposure
(
food+
water)
mg/
kg/
day
MOE
(
food
+
water2)
MOE
oral3
MOE
dermal4
MOE
inhalation5
Aggregate
MOE
(
food
+
water
and
residential)
6
U.
S.
General
Population
100
0.002604
73049
NA
270
NA
270
All
Infants
(<
1
year
old)
100
0.011013
17252
6900
160
NA
160
Adult
50+
years
old
100
0.002341
81161
NA
270
NA
270
Females
13­
19
years
old
100
0.002179
87196
NA
37
NA
37
1
Level
of
Concern
(
LOC)
is
an
MOE
of
100
based
on
using
uncertainty
factors
(
UF)
of
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variability.
2
MOE
food
+
water,
which
incorporated
the
dietary
values
for
drinking
water
(
Food
+
Water),
=
[(
short
or
intermediate­
term
oral
NOAEL)/(
chronic
dietary
exposure)].
Short
or
intermediate­
term
NOAEL
=
190
mg/
kg/
day
from
the
subchronic
oral
rat
study,
MRID
44093601
3
MOE
oral
=
[(
short
or
intermediate­
term
oral
NOAEL)/(
hand­
to­
mouth
residential
exposure)]
Short
or
intermediate­
term
NOAEL
=
190
mg/
kg/
day
from
the
subchronic
oral
rat
study,
MRID
44093601;
hand­
to­
mouth
exposure
=
0.35,
Jazzercise
adult
or
general
population
or
0.022,
toddler
hand
to
mouth
(
see
Table
6.2).
4
MOE
dermal
=
[(
short
or
intermediate­
term
dermal
NOAEL)/(
high­
end
dermal
residential
exposure)]
Short
or
intermediate­
term
NOAEL
=
190
mg/
kg/
day
from
the
subchronic
oral
rat
study,
MRID
44093601;
high
end
dermal
residential
=
0.58,
toddler
playing
or
0.35,
Jazzercise
adult
(
see
Table
6.2).
DP
Barcode
D326518
/
46510101
Page
62
of
73
5
MOE
inhalation
=
[(
inhalation
NOAEL)/(
high­
end
inhalation
residential
exposure)]
Short
or
intermediate­
term
NOAEL
=
190
mg/
kg/
day
from
the
subchronic
oral
rat
study,
MRID
44093601;
high
end
inhalation
residential
=
0.58,
toddler
playing
or
0.35,
Jazzercise
adult
(
see
Table
6.3.1).
6
Aggregate
MOE
(
food
+
water
and
residential)
=
1
÷
[
[(
1
÷
MOE
food+
water)
+
(
1
÷
MOE
oral)
+
(
1
÷
MOE
dermal)
+
(
1
÷
MOE
inhalation)]]

Based
on
the
analysis
of
the
general
population,
which
appeared
to
have
the
highest
oral
exposure,
the
subpopulations
adult
male
(
50
+
years
old)
and
all
infants
(<
1
year
old)
with
the
highest
dietary
(
food
+
water)
exposure,
aggregate
MOEs
ranged
from
160
to
270,
which
are
all
higher
than
the
level
of
concern
MOE
of
100
and,
therefore,
not
a
cause
for
concern
by
the
Agency.
Hence,
there
are
no
aggregate
short­
or
intermediate­
term
risk
concerns
for
children
ages
1
to
12,
youths,
ages
13­
19
or
adults
ages
20­
49
from
exposure
to
ethofumesate.

In
the
case
of
women
of
childbearing
years,
a
residential
risk,
and
subsequently
for
the
aggregate
risk
assessment,
an
MOE
of
37
was
estimated,
based
on
an
oral
endpoint
from
a
developmental
study
in
rabbits.
ARIA
notes
that
this
risk
estimate
is
driven
by
the
conservative
assumptions
used
in
the
risk
assessment:
1)
screening­
level
unrefined
Tier
1
assessment
was
used,
2)
100%
dermal
absorption
was
assumed,
and
3)
an
endpoint
used
for
females
13+
years
of
age
from
a
developmental
study
in
rabbits
with
a
steep
dose­
response
curve
resulting
from
a
NOAEL
(
30
mg/
kg/
day)
that
is
10X
lower
than
the
LOAEL
(
300
mg/
kg/
day);
thus,
a
dose
spacing
issue
likely
exists.
ARIA,
therefore,
considers
this
a
highly
conservative
estimate
of
post­
application
risk
for
the
population
females
13­
49
years
of
age
exposed
to
ethofumesate
on
turf.

7.3
Long­
Term
Aggregate
Risk
Since
there
are
no
long­
term
residential
exposure
scenarios
of
regulatory
interest
and
the
chronic
food
and
water
dietary
risk
assessment
is
below
the
Agency's
level
of
concern,
there
are
no
aggregate
long­
term
risk
concerns
for
any
population
subgroup
exposure
to
ethofumesate.

7.4
Cancer
Risk
Ethofumesate
is
not
likely
to
be
carcinogenic
based
on
bioassays
in
the
rat
and
the
mouse;
therefore,
a
cancer
aggregate
risk
assessment
was
not
performed.

8.0
Cumulative
Risk
Characterization/
Assessment
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
ethofumesate
and
any
other
substances
and
ethofumesate
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
ethofumesate
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
DP
Barcode
D326518
/
46510101
Page
63
of
73
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.

9.0
Occupational
Exposure/
Risk
Pathway
The
product
proposed
for
use
is
Nortron
®
SC
Herbicide
(
EPA
Reg.
No.
264
 
613)
which
is
a
4.0
lb
active
ingredient
(
ai)
per
gallon
suspension
concentrate
liquid.
Ethofumesate
may
be
applied
pre­
emergence
and/
or
post­
emergence.
As
a
pre­
emergence
application
it
should
be
applied
broadcast
to
the
soil
surface
at
the
rate
of
32
fl
oz
product
per
acre
(
1.0
lb
ai/
A).
Postemergence
it
may
be
applied
up
to
4
times
as
foliar
applications
at
the
rate
of
16.0
fl
oz
product/
A
(
0.5
lb
ai/
A).
There
is
a
maximum
of
3.0
lb
ai/
A/
season
that
may
be
applied.
Whether
pre­
emergence
or
post­
emergence
application,
ethofumesate
should
be
applied
in
5
 
10
gallons
of
water/
A
as
a
banded
application
or
in
10
 
40
gallons
of
water/
A
as
a
broadcast
application.
The
pre­
harvest
interval
(
PHI)
is
30
days.
The
target
pests
are
numerous
species
of
broadleaf
weeds
and
grasses.

The
registered
label
directs
applicators
and
other
handlers
to
wear
the
following
personal
protective
equipment
(
PPE):
long­
sleeved
shirt,
long
pants,
shoes
plus
socks
and
waterproof
gloves.

9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
Based
upon
the
proposed
new
use
pattern,
HED
believes
the
most
highly
exposed
occupational
pesticide
handlers
are
likely
to
be
mixer/
loaders
using
open­
pour
loading
of
liquids
and
applicators
using
open­
cab,
ground­
boom
sprayers.
HED
expects
most
exposures
will
be
short­
term
duration
(
1
­
30
days).
Typical
field
size
is
expected
to
be
small
as
compared
to
field
crops
such
as
corn,
cotton,
soybeans
or
wheat.
HED
believes
most
applications
are
likely
to
be
made
by
the
grower.
There
may
be
several
short­
term
duration
exposures
but
it
is
not
likely
that
any
particular
applicator
would
be
exposed
from
1
­
6
months
(
intermediate­
term
duration
exposure)
applying
ethofumesate
to
dry
bulb
onions.

It
is
expected
that
some
private
(
i.
e.,
grower)
applicators
may
perform
all
tasks,
that
is
mix,
load
and
apply
the
material.
However,
the
HED
Science
Policy
Council
for
Exposure
(
ExpoSAC)
draft
Standard
Operating
Procedure
(
SOP)
(
29
March
2000)
directs
that
although
the
same
individual
may
perform
all
tasks,
in
some
cases
they
shall
be
assessed
separately.

The
available
exposure
data
for
combined
mixer/
loader/
applicator
scenarios
are
limited
in
comparison
to
the
data
available
for
monitoring
of
these
two
activities
separately.
These
exposure
scenarios
are
outlined
in
the
Pesticide
Handler
Exposure
Database
(
PHED)
Surrogate
Exposure
Guide
(
August
1998).
HED
has
adopted
a
methodology
to
present
the
exposure
and
risk
estimates
separately
for
the
job
functions
in
some
scenarios
and
to
present
them
as
combined
in
other
cases.
Most
exposure
scenarios
for
hand­
held
equipment
(
such
as
hand
wands,
backpack
sprayers,
and
push­
type
granular
spreaders)
are
assessed
as
a
combined
job
function.
With
these
types
of
hand
held
operations,
all
handling
activities
are
assumed
to
be
conducted
by
the
same
individual.
The
available
monitoring
data
support
this
and
HED
presents
them
in
this
way.
DP
Barcode
D326518
/
46510101
Page
64
of
73
Conversely,
for
equipment
types
such
as
fixed­
wing
aircraft,
ground­
boom
tractors,
or
air­
blast
sprayers,
the
applicator
exposures
are
assessed
and
presented
separately
from
those
of
the
mixers
and
loaders.
By
separating
the
two
job
functions,
HED
determines
the
most
appropriate
levels
of
personal
protective
equipment
(
PPE)
for
each
aspect
of
the
job
without
requiring
an
applicator
to
wear
unnecessary
PPE
that
might
be
required
for
a
mixer/
loader
(
e.
g.,
chemical
resistant
gloves
may
only
be
necessary
during
the
pouring
of
a
liquid
formulation).

No
chemical
specific
data
were
available
with
which
to
assess
potential
exposure
to
pesticide
handlers.
The
estimates
of
exposure
to
pesticide
handlers
are
based
upon
surrogate
study
data
available
in
the
PHED.
For
pesticide
handlers,
it
is
HED
standard
practice
to
present
estimates
of
dermal
exposure
for
"
baseline"
that
is,
for
workers
wearing
a
single
layer
of
work
clothing
consisting
of
a
long
sleeved
shirt,
long
pants,
shoes
plus
socks
and
no
protective
gloves
as
well
as
for
"
baseline"
and
the
use
of
protective
gloves
or
other
PPE
as
might
be
necessary.
The
proposed
product
label
involved
in
this
assessment
directs
applicators
and
other
handlers
to
wear
long­
sleeved
shirt,
long
pants,
shoes
plus
socks
and
waterproof
gloves.

The
most
recent
consideration
of
the
toxicological
database
for
ethofumesate
was
presented
in
a
2004
HED
Registration
Eligibility
Document
(
DP
Num:
278571,
N.
McCarroll,
11/
23/
04).
With
regards
to
the
assessment
herein,
the
HED
identified
dermal
and
inhalation
toxicological
endpoints
for
use
in
risk
assessment.
The
dermal
endpoint
has
a
NOAEL
of
190
mg
ai/
kg
bw/
day.
The
effects
seen
were
decreased
body
weight
and
weight
gain
in
both
sexes
and
liver
and
kidney
microscopic
effects
in
males
at
1900
mg
ai/
kg
bw/
day
and
were
identified
from
a
90­
day
oral
toxicity
study
in
rats.
HED
assumed
100
%
dermal
absorption
due
to
a
lack
of
appropriate
dermal
absorption
data
to
the
contrary.

The
HED
identified
inhalation
toxicological
endpoints
from
the
same
90­
day
oral
toxicity
study
in
the
rat.
The
NOAEL
is
190.0
mg
ai/
kg
bw/
day.
The
toxicological
effects
seen
were
the
same
as
were
noted
above
for
the
dermal
route
of
exposure.

With
regards
to
carcinogenic
potential,
HED
classified
ethofumesate
as
"
not
likely
to
be
carcinogenic
to
humans",
therefore
a
cancer
risk
assessment
is
not
necessary.
Table
9.1
Estimated
Exposures
and
Risks
to
Pesticide
Handlers
Applying
Ethofumesate
to
Dry
Bulb
Onion
Unit
Exposure1
mg
a.
i./
lb
handled
Application
Rate2
lb
a.
i./
A
Units
Treated3
Acres/
Day
Avg.
Daily
Dose4
mg
a.
i./
kg
bw/
day
NOAEL5
mg
a.
i./
kg
bw/
day
MOE
Mixer/
Loader
­
Liquid
Open
Pour
Dermal
SLNG
2.9
HC
SLWG
0.023
HC
Inhal
0.0012
LC
1
200
Dermal
NG
8.29
WG
0.066
Inhal
0.00343
190
No
Gloves
23
With
Gloves
2,740
Applicator
­
Open­
cab
Ground­
boom
DP
Barcode
D326518
/
46510101
Page
65
of
73
Dermal
SLNG
0.014
HC
SLWG
0.014
MC
Inhal
0.00074
LC
1
200
Dermal
NG
0.04
WG
0.04
Inhal
0.00211
190
No
Gloves
4,500
With
Gloves
4,500
1.
Unit
Exposure
=
mg
a.
i./
lb
a.
i.
handled;
taken
from
the
Pesticide
Handler's
Exposure
Database
PHED
Surrogate
Exposure
Guide
version
1.1;
August
1998;
Dermal:
SLNG
=
Single
Layer
of
Work
Clothing
[
long
sleeved
shirt,
long
pants,
shoes
+
socks]
NO
Gloves.
SLWG
=
single
layer
work
clothing
[
long
sleeved
shirt,
long
pants,
shoes
+
socks]
WITH
Gloves;
Inhalat.
=
Inhalation.
HC
=
high
confidence
data;
LC
=
low
confidence
data
2.
Application
Rate
from
proposed
label
in
IR­
4
request.

3.
Acres
Treated
are
derived
from
Sci.
Adv.
Coun
SOP.
No.
9.1
Rev.
25
SEP
01;

4.
Average
Daily
Dose
(
ADD)
=
Unit
Exposure
*
Application
Rate
*
Units
Treated
÷
70
kg
body
weight.

5.
NOAEL
=
No
Observed
Adverse
Effect
Level
(
mg
a.
i./
kg
bw/
day).
Short­
term
dermal
and
inhalation
NOAELs
=
190
mg
a.
i./
kg
bw/
day
based
on
a
90­
day
oral
toxicity
study
in
the
rat.

6.
MOE
=
NOAEL
÷
ADD.
Since
the
dermal
and
inhalation
NOAEL's
are
the
same,
are
identified
from
the
same
study
and
list
the
same
toxic
effects,
the
dermal
and
inhalation
exposures
are
summed
and
then
divided
into
the
NOAEL
to
determine
MOE.

9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
It
is
possible
for
agricultural
workers
to
have
post­
application
exposure
to
pesticide
residues
during
the
course
of
typical
agricultural
activities.
HED
in
conjunction
with
the
Agricultural
Re­
entry
Task
Force
(
ARTF)
has
identified
a
number
of
post­
application
agricultural
activities
that
may
occur
and
which
may
result
in
post­
application
exposures
to
pesticide
residues.
HED
has
also
identified
Transfer
Coefficients
(
TC)
(
cm
²
/
hr)
relative
to
the
various
activities
which
express
the
amount
of
foliar
contact
over
time,
during
each
of
the
activities
identified.

The
transfer
coefficients
used
in
this
assessment
are
from
an
interim
transfer
coefficient
Standard
Operating
Procedure
(
SOP)
developed
by
HED's
ExpoSAC
using
proprietary
data
from
the
ARTF
database
(
SOP
#
3.1).
It
is
the
intention
of
HED's
ExpoSAC
that
this
SOP
will
be
periodically
updated
to
incorporate
additional
information
about
agricultural
practices
in
crops
and
new
data
on
transfer
coefficients.
Much
of
this
information
will
originate
from
exposure
studies
currently
being
conducted
by
the
ARTF,
from
further
analysis
of
studies
already
submitted
to
the
Agency,
and
from
studies
in
the
published
scientific
literature.

In
this
case,
there
is
only
one
post­
application
agricultural
activity
that
is
likely
to
occur,
scouting
for
pesticide
efficacy.
Scouting
onions
at
low
crop
development/
height
has
a
TC
of
300
cm2/
hr.
Lacking
compound
specific
DFR
data,
post­
application
worker
exposure
is
estimated
using
HED
procedure
that
assumes
20%
of
the
application
rate
is
available
as
dislodgeable
foliar
residue
on
the
day
of
treatment.
HED
does
not
expect
post­
application
exposures
to
exceed
short
term
exposure.
Therefore,
only
short
term
exposures
are
assessed.

The
following
convention
may
be
used
to
estimate
post­
application
exposure.
DP
Barcode
D326518
/
46510101
Page
66
of
73
Average
Daily
Dose
(
ADD)
(
mg
a.
i./
kg
bw/
day)
=
DFR
Fg/
cm2
*
TC
cm2/
hr
*
hr/
day
*
0.001
mg/
Fg
*
1/
70
kg
bw
and
where:

Surrogate
Dislodgeable
Foliar
Residue
(
DFR)
=
application
rate
*
20.0
%
available
as
dislodgeable
residue
*
(
1­
D)
t
*
4.54
x
108
Fg/
lb
*
2.47
x
10­
8
A/
cm2.

1.0
lb
a.
i./
A
*
0.20
*
(
1­
0)
0
*
4.54
x
108
Fg/
lb
*
2.47
x10­
8
A/
cm
²
=
2.24
Fg/
cm2
,
therefore,

2.24
:
g/
cm2
*
300
cm2/
hr
*
8
hr/
day
*
0.001
mg/:
g
*
1/
70
kg
bw
=
0.077
mg
ai/
kg
bw/
day
MOE
=
NOAEL
÷
ADD
then
190.0
mg/
kg
bw/
day
÷
0.077
mg/
kg
bw/
day
=
2500.

A
MOE
of
100
is
adequate
to
protect
agricultural
workers
from
post­
application
exposures
to
ethofumesate.
Since
the
estimated
MOEs
are
>
100,
the
proposed
use
pattern
does
not
exceed
HED's
level
of
concern.

Ethofumesate
is
classified
in
acute
toxicity
category
IV
for
acute
dermal
toxicity,
category
II
for
acute
inhalation
toxicity
and
category
V
for
acute
eye
irritation
and
dermal
irritation.
It
is
not
a
dermal
sensitizer.
The
interim
worker
protection
standard
(
WPS)
REI
of
12
hours
is
adequate
to
protect
agricultural
workers
from
post­
application
exposures
to
ethofumesate.
The
product
label
lists
a
12
hr
REI.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
At
this
time,
the
database
for
ethofumesate
is
essentially
complete
for
ethofumesate.
Nevertheless,
a
21/
28­
day
inhalation
toxicity
study
is
requested
to
assess
inhalation
exposure,
due
to
the
potential
for
exposure
via
this
route
during
application.

10.2
Residue
Chemistry
The
requested
tolerances
for
garlic,
bulb
and
shallot,
bulb
are
not
required
since
they
are
automatically
included
in
the
onion
tolerance.
In
addition,
the
preferred
term
for
the
commodity
should
be
onion,
bulb.
The
petitioner
should
submit
a
revised
Section
F
requesting
a
tolerance
for
ethofumesate
residues
on
onion,
bulb
at
0.25
ppm.
DP
Barcode
D326518
/
46510101
Page
67
of
73
10.3
Occupational
and
Residential
Exposure
None.

References
Ethofumesate
RED,
EPA
738­
R­
05­
010,
9/
05
ETHOFUMESATE:
HED
Human
Health
Risk
Assessment
For
Phase
2;
Response
to
Error
Only
Comments
from
the
Registrant.,
DP
Num:
296943,
N.
McCarroll,
3/
10/
05
ETHOFUMESATE:
HED
Revised
Human
Health
Risk
Assessment
For
Phase
4;
Response
to
Bayer
CropScience
Phase
3
Comments.,
DP
Num:
304056,
N.
McCarroll,
8/
4/
05
Ethofumesate
­
Report
for
the
Hazard
Identification
Assessment
Review
Committee,
TXR
NO.
0051567a,
2/
26/
04
Ethofumesate
HED
Metabolism
Assessment
Committee,
S.
Funk,
5/
16/
04
Ethofumesate.
Request
for
the
use
on
Onion,
Dry
Bulb.
Summary
of
Analytical
Chemistry
and
Residue
Data.,
Petition
#
5E6914,
DP
Number:
326470,
W.
Cutchin,
3/
28/
06
Ethofumesate
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
Section
3
Registration
Action
on
Onion,
Dry
Bulb.,
Petition
#
5E6914,
DP
Num:
326518,
N.
Negron,
3/
28/
06
Ethofumesate
 
Drinking
Water
Assessment
for
the
Health
Effects
Division
(
HED)
Reregistration
Eligibility
Decision
Document,
DP
Num:
296949,
M.
Corbin,
6/
9/
04
RDI:
T.
Bloem,
G.
Kramer
(
4/
18/
06)
DP
Barcode
D326518
/
46510101
Page
68
of
73
Appendix
A:
Toxicology
Assessment
1.
Toxicology
Data
Requirements
The
requirements
(
CFR
158.340)
for
food/
feed
use
patterns
for
ethofumesate
are
shown
below
in
Table
A.
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
A.
1.
Guideline
Toxicology
Data
Requirements
for
Food/
Feed
Use
Patterns
Technical
Test
Required
Satisfied
870.1100...................................................................................
870.1200...................................................................................
870.1300...................................................................................
870.2400...................................................................................
870.2500...................................................................................
870.2600...................................................................................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100...................................................................................
870.3150...................................................................................
870.3200...................................................................................
870.3250...................................................................................
870.3465...................................................................................
yes
yes
yes
no
yes1
yes
yes
yes
­
no
870.3700a.................................................................................
870.3700b.................................................................................
870.3800...................................................................................
yes
yes
yes
yes
yes
yes
870.4100a.................................................................................
870.4100b.................................................................................
870.4200a.................................................................................
870.4200b.................................................................................
870.4300...................................................................................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100...................................................................................
870.5300...................................................................................
870.5375............................................................................
Muta
870.5550...................................................................................
yes
yes
yes
yes
yes
yes
yes
yes
DP
Barcode
D326518
/
46510101
Page
69
of
73
Table
A.
1.
Guideline
Toxicology
Data
Requirements
for
Food/
Feed
Use
Patterns
Technical
Test
Required
Satisfied
870.6100a.................................................................................
870.6100b.................................................................................
870.6200a.................................................................................
870.6200b.................................................................................
870.6300...................................................................................
no
no
no
no
no
­
­
­
­
­

870.7485...................................................................................
870.7600...................................................................................
yes
no
yes
­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
...........................................................
Subchronic
Oral
(
rat)...................................................
Six­
month
Oral
(
dog)
..................................................
no
no
no
­
­
­

1
A
28­
day
inhalation
toxicity
is
required
to
satisfy
subchronic
inhalation
toxicity
study
requirement
2.
Non­
Critical
Toxicology
Studies
OPPTS
870.3100
90­
Day
Oral
Toxicity
­
Mouse
In
a
range­
finding
oral
toxicity
study
(
MRID
44156201)
performed
to
assist
in
dose
selection
for
a
carcinogenicity
study,
ethofumesate
(
97%
a.
i.,
batch
P
04407)
was
administered
to
10
Crl:
CD­
1(
ICR)
BR
(
VAF
plus)
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
300,
3000
or
10,000
ppm
(
0,
45,
450
or
1500
mg/
kg/
day,
respectively,
calculated
using
a
food
factor
of
0.15)
for
at
least
13
weeks.

There
were
no
treatment­
related
deaths
or
effects
on
body
weights,
body
weight
gains
or
food
consumption.
Overall
food
efficiencies
were
unaffected
in
males;
the
20%
decrease
in
high­
dose
females
was
not
clearly
toxicologically
significant.
The
incidence
of
gross
pathological
changes
in
treated
and
control
groups
was
similar
for
both
sexes.
Microscopic
examination
of
organs/
tissues
with
gross
lesions
revealed
only
pathological
changes
commonly
seen
in
laboratory
mice
of
the
same
strain
and
age.
Clinical
chemistry,
hematology
and
urinalysis
parameters
were
not
evaluated
and
ophthalmologic
examinations
were
not
performed.

Under
the
conditions
of
this
study,
a
systemic
toxicity
LOAEL
could
not
be
identified
and
the
13­
week
NOAEL
was
10,000
ppm
(
about
1500
mg/
kg/
day)
for
both
sexes
of
mice.
Based
on
the
lack
of
toxic
effects,
the
same
concentrations
as
were
used
in
this
study
are
not
precluded
from
use
in
the
subsequent
carcinogenicity
study.
DP
Barcode
D326518
/
46510101
Page
70
of
73
This
subchronic
toxicity
study
is
classified
as
acceptable
(
non­
guideline).
It
satisfies
the
intended
purpose
of
estimating
dietary
ethofumesate
concentrations
to
be
administered
in
a
subsequent
carcinogenicity
study.

OPPTS
870.3150
90­
Day
Oral
Toxicity
­
Dog
A
90­
day
oral
toxicity
study
in
the
dog
was
not
submitted.
However,
the
guideline
requirement
for
a
subchronic
toxicity
study
in
the
dog
is
satisfied
by
the
chronic
toxicity
study
in
the
dog
(
MRID
00062822)
and
no
additional
data
are
required
at
this
time.

OPPTS
870.3200
21­
Day
Dermal
Toxicity
 
Rat
In
a
21­
day
dermal
toxicity
study
(
MRID
41997204,
main
study
and
MRID
42689902,
addendum),
ethofumesate
technical
(
96%
a.
i.,
Lot/
Batch
#
CR
19291/
3),
moistened
with
4
mL
of
1%
(
w/
v)
methylcellulose/
distilled
water,
was
applied
to
the
shaved,
intact
dorsal
skin
of
5
New
Zealand
White
rabbits/
sex/
group
at
dose
levels
of
0,
100,
300
or
1000
mg/
kg
bw/
day,
6
hours/
day
for
21
consecutive
days.
Skin
irritation
was
assessed
daily
pre­
and
posttreatment
and
graded
using
a
modified
Draize
scale.

There
were
no
biologically
significant
treatment­
related
findings
observed
in
this
study.
The
following
statistically
significant
differences
(
p#
0.05)
were
observed
at
1000
mg/
kg
in
males
only,
but
were
not
considered
adverse
based
on
the
small
magnitude
of
the
changes
and/
or
lack
of
associated
microscopic
alterations:
increased
basophils
(+
17%
above
controls)
and
potassium
(+
21.1%),
and
decreased
protein
(­
9.8%),
albumin
(­
10.3%)
and
aspartate
aminotransferase
or
SGOT
(­
21.1%).
There
were
no
compound­
related
effects
on
mortality,
clinical
signs,
body
weight,
body
weight
gains,
food
consumption,
gross
pathology,
organ
weight
or
histopathology
observed
at
any
dose
level
in
either
sex.
The
control,
100
and
300
mg/
kg
animals
showed
signs
of
mild
skin
irritation,
mainly
during
Weeks
2
and
3
of
treatment;
however,
no
signs
of
dermal
irritation
were
observed
in
the
1000
mg/
kg
animals
during
the
study.
The
systemic
toxicity
NOAEL
is
1000
mg/
kg/
day
(
limit
dose).
A
LOAEL
for
systemic
toxicity
was
not
established
in
this
study.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.3200;
OECD
410)
for
a
21­
day
dermal
toxicity
study
in
rabbits.

OPPTS
870.4100b
Chronic
Toxicity
­
Dog
In
a
chronic
oral
toxicity
study
(
MRID
00062822),
NC
8438
(
ethofumesate
tech.,
96.6­
98.0%
a.
i.;
Lot/
Batch
#:
CR
4805/
3)
was
administered
daily
in
the
diet
to
8
beagle
dogs/
sex/
dose
at
0,
800,
4000
or
20,000
ppm
(
equivalent
to
average
daily
intakes
of
0,
24.5,
117.8
or
632.4
DP
Barcode
D326518
/
46510101
Page
71
of
73
mg/
kg/
day
in
males
and
0,
23.7,
109.0
or
618.9
mg/
kg/
day
in
females)
for
104
weeks.

At
20,000
ppm,
alkaline
phosphatase
was
increased
(
p#
0.01)
by
33­
110%
over
controls
throughout
the
study
and
alanine
aminotransferase
was
increased
(
p#
0.05)
by
39­
49%
at
Weeks
78
and
102
(
values
were
calculated
for
males
and
females
combined).
Absolute
liver
weights
were
increased
(
p#
0.05)
in
females
by
20%
and
in
males
by
21%.
There
were
no
treatment­
related
deaths.
One
20,000
ppm
male
was
sacrificed
during
Week
69
due
to
a
massive
lipoma
caudal
to
the
axilla
on
the
left
side.
This
dog
showed
no
clinical
signs
of
toxicity
prior
to
sacrifice,
and
no
other
lesions
were
noted
at
necropsy.
There
were
no
treatment­
related
effects
on
clinical
signs,
body
weight,
body
weight
gains,
food
consumption,
ophthalmoscopy,
urinalysis,
hematology,
gross
pathology
or
microscopic
pathology.
There
were
no
effects
of
treatment
at
800
or
4000
ppm.
The
systemic
toxicity
LOAEL
is
20,000
ppm
(
632.4
and
618.9
mg/
kg/
day
in
males
and
females,
respectively)
based
on
increases
in
alkaline
phosphatase,
alanine
aminotransferase
and
absolute
liver
weights.
The
systemic
toxicity
NOAEL
is
4000
ppm
(
117.8
and
109.0
mg/
kg/
day
in
males
and
females).

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirement
(
OPPTS
870.4100b,
OECD
452)
for
a
chronic
oral
study
in
dogs.
However,
because
the
study
was
conducted
prior
to
adoption
of
current
GLP
standards,
the
Registrant
is
requested
to
provide
additional
information
(
clinical
observations,
statistical
analyses
for
body
weight,
weight
change
and
relative
organ
weights,
separate
data
for
males
and
females)
as
confirmatory
data.

OPPTS
Series
870.5100­
8705915
Mutagenicity
Adequacy
of
data
base
for
mutagenicity:
The
database
for
mutagenicity
is
considered
adequate
based
on
1991
mutagenicity
guidelines.
Ethofumesate
technical
was
negative
in
all
five
genotoxicity
studies
that
were
performed,
including
an
in
vivo
mouse
bone
marrow
micronucleus
assay
(
MRID
41214217)
and
four
in
vitro
studies:
bacterial
reverse
mutation
assay
in
S
typhimurium
and
E.
coli
(
MRID
43529501),
forward
gene
mutation
assay
in
cultured
mouse
lymphoma
cells
(
MRID
41710501),
chromosomal
aberration
assay
in
cultured
human
lymphocytes
(
MRID
41214203)
and
unscheduled
DNA
synthesis
in
cultured
primary
rat
hepatocytes
(
MRID
41214204).

Gene
Mutation
Guideline
870.5100,
Bacterial
reverse
gene
mutation
in
vitro
MRID
43529501
Dose
range
15­
5000
Fg/
plate
±
rat
liver
S9
metabolic
activation
in
S.
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537.

50­
5000
Fg/
plate
±
rat
liver
S9
metabolic
activation
in
E.
coli
CM881
(
WP2
pKM101)
and
CM891
(
WP2uvrA
pKM101).

NEGATIVE
up
to
dose
levels
causing
cytotoxicity.
DP
Barcode
D326518
/
46510101
Page
72
of
73
Guideline
870.5300,
Mammalian
forward
gene
mutation
in
vitro
MRID
41710501
Dose
range
7.9
to
250
Fg/
mL
±
rat
liver
S9
metabolic
activation
in
cultured
mouse
lymphoma
6TG
cells.

NEGATIVE
up
to
dose
levels
that
were
insoluble
but
not
cytotoxic.

Cytogenetics
Guideline
870.5375,
Mammalian
chromosomal
aberration
in
vitro
MRID
41214203
Dose
range
11­
110
Fg/
mL
±
rat
liver
S9
metabolic
activation
in
cultured
human
lymphocytes.

NEGATIVE
up
to
dose
levels
that
were
insoluble
but
not
cytotoxic.

Guideline
870.5395,
Mammalian
in
vivo
bone
marrow
micronucleus
assay
MRID
41214217
8100
mg/
kg
bw
administered
by
gavage
to
male
and
female
CD­
1
mice.

NEGATIVE
up
to
dose
levels
exceeding
the
limit
dose
of
5000
mg/
kg
bw,
tested
at
24,
48
and
72
hrs
postdosing.

Other
Genotoxicity
Guideline
870.5550,
Mammalian
in
vitro
unscheduled
DNA
synthesis
MRID
41214204
Dose
range
1.56
to
200
Fg/
mL
in
primary
rat
hepatocyte
cultures.

NEGATIVE
up
to
cytotoxic
dose
levels
with
precipitation
of
the
test
material.

OPPTS
870.7485
Metabolism
­
Rat
In
a
rat
metabolism
study
(
MRIDs
42364503,
main
study
report
and
42689903,
addendum),
14C­
ethofumesate
(
tech.,
batch
no.
DR/
87/
18/
B­
4/
RPI;
radiochemical
purity
>
98%)
in
1%
carboxymethylcellulose
(
2.5
mL/
kg
all
low
dose
groups;
high
dose
not
specified)
was
administered
to
5
Sprague
Dawley
Crl:
CD/
BR
rats/
sex/
dose
as
a
single
gavage
dose
at
10
or
500
mg/
kg.
In
addition,
unlabeled
ethofumesate
(
tech.,
batch
no.
19291/
3,
98.0%
a.
i.)
was
administered
to
5
rats/
sex/
dose
as
14
daily
gavage
doses
at
10
mg/
kg
followed
by
a
single
gavage
dose
of
14C­
ethofumesate
at
10
mg/
kg
on
Day
15.
DP
Barcode
D326518
/
46510101
Page
73
of
73
In
all
dose
groups,
overall
recovery
of
the
radioactive
dose
was
96­
99%
by
5
days
postdosing
Absorption
of
the
dose
was
extensive
based
on
high
levels
of
urinary
excretion
but
was
about
10­
15%
lower
in
the
500
mg/
kg
group
than
the
10
mg/
kg
group,
indicating
possible
saturation
of
absorption.
Excretion
was
rapid
and
primarily
via
the
urine
(
70­
92%
dose).
Within
6
hours
post­
dose,
65­
78%
of
the
total
urinary
radioactivity
was
eliminated
in
the
single
and
repeated
10
mg/
kg
groups,
but
44­
45%
was
eliminated
in
the
500
mg/
kg
group.
Fecal
excretion
accounted
for
6­
28%
dose
and
was
essentially
complete
within
24
hours.
Within
each
dose
group,
excretion
of
radioactivity
was
similar
between
the
sexes,
although
males
excreted
slightly
more
of
the
dose
in
the
feces
(
6­
10%
more)
and
correspondingly
less
in
urine
than
females.
There
was
no
difference
in
the
pattern
of
excretion
between
the
single
and
repeated
low­
dose
groups.
However,
fecal
excretion
of
radioactivity
was
increased
and
urinary
excretion
decreased
in
the
high­
dose
group
(
males
27.6%
and
females
17.1%
of
dose)
compared
to
the
low­
dose
groups
(
13.3­
16.1%,
males
and
5.8%­
6.3%,
females).
Excluding
the
GI
tract
and
carcass,
radioactivity
in
each
tissue
accounted
for
<
0.02%
dose
at
5
days
post­
dose.
Concentrations
of
radioactivity
were
highest
in
the
liver
(
0.007­
0.026
:
g/
g
in
the
single
and
repeated
10
mg/
kg
groups
and
0.891­
1.50
:
g/
g
in
the
500
mg/
kg
group)
and
kidney
(<
0.010­
0.012
:
g/
g
in
the
single
and
repeated
10
mg/
kg
groups
and
0.506­
0.542
:
g/
g
in
the
500
mg/
kg
group,
with
males
having
higher
levels
than
females).
In
the
500
mg/
kg
group,
both
males
and
females
also
showed
relatively
high
levels
of
radioactivity
in
the
brain,
fat,
bone
and
testes
ranging
from
0.232
to
0.452
Fg/
g
tissue).
Repeat
dosing
did
not
significantly
affect
distribution
of
radioactivity.
TLC,
HPLC
and
MS
analyses
were
used
to
identify
parent
and
3
metabolites
in
excreta
and
profiles
were
not
altered
by
treatment
with
$­
glucuronidase.
Males
and
females
showed
similar
profiles.
Parent
was
not
detected
in
the
urine,
but
accounted
for
10­
13%
dose
in
the
feces
at
500
mg/
kg.
Identified
compounds
generally
accounted
for
approximately
85%
of
administered
dose
in
each
group.
The
major
metabolite
was
Met­
1,
or
"­(
2­
hydroxy­
5­
methanesulphonyloxyphenyl)
isobutyric
acid,
accounting
for
approximately
62­
87%
dose
in
all
dose
groups,
depending
on
the
group
and
the
TLC
solvent
system
used.
NC9607
and
NC8493
were
also
identified
in
urine
at
#
2%
dose.
An
unidentified
acid­
labile
metabolite
in
the
urine
may
have
been
present
at
>
5%
dose.
The
metabolism
of
ethofumesate
consists
of
dealkylation
(­
OH
replaces
the
2­
OC2H5
group)
to
form
NC8493,
which
is
then
oxidized
at
the
2­
OH
to
a
lactone,
NC9607
(
ring­
closed
form).
NC9607
is
a
metabolic
intermediate
to
the
free
acid,
"­(
2­
hydroxy­
5­
methanesulphonyloxyphenyl)
isobutyric
acid
(
ring­
opened
form
of
the
lactone
NC9607).
Due
to
changes
in
the
pH
during
isolation
and
analytical
procedures,
low
quantities
of
NC9607
were
sometimes
formed
from
the
free
acid.

This
metabolism
study
in
the
rat
is
classified
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
Tier
1
metabolism
study
[
OPPTS
870.7485,
OECD
417]
in
rats.