Document ID: EPA-HQ-OPP-2003-0294-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-11-19T05:00Z

Overview
of
Lactofen
FQPA
Risk
Assessment
for
Tolerance
Reassessment
September
24,
2003
Introduction
This
document
summarizes
EPA's
human
health
risk
findings
for
the
herbicide
lactofen,
as
presented
fully
in
the
documents:
Lactofen:
Revisions
to
HED
Tolerance
Reassessment
Risk
Assessment,
dated
August
12,
2003;
Lactofen,
Preliminary
Human
Health
Risk
Assessment
for
Tolerance
Reassessment,
dated
October
12,
2000;
Lactofen­
Report
of
the
Cancer
Assessment
Review
Committee,
dated
May
21,
2002;
Lactofen:
Report
of
the
Mechanism
of
Toxicity
Review
Committee,
dated
March
12,
2002;
and
Drinking
Water
Exposure
Assessment
for
Lactofen
Updated
for
Prospective
Ground
Water
(
PGW)
Monitoring
Study,
dated
January
21,
2003.
The
purpose
of
this
summary
is
to
assist
the
reader
by
identifying
the
key
features
and
findings
of
the
risk
assessments
so
that
he
or
she
may
better
understand
the
conclusions
reached
in
the
assessments.
This
summary
was
developed
in
response
to
comments
and
requests
from
the
public
which
indicated
that
the
risk
assessments
were
difficult
to
understand,
that
they
were
too
lengthy,
and
that
it
was
not
easy
to
compare
the
assessments
for
different
chemicals
due
to
the
use
of
different
formats.

The
Food
Quality
Protection
Act
(
FQPA)
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
"
available
information"
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
"
other
substances
that
have
a
common
mechanism
of
toxicity."
Lactofen
is
a
member
of
the
diphenyl
ether
group
of
herbicides,
which
includes
sodium
acifluorfen
(
which
shares
a
major
environmental
degradate,
acifluorfen,
with
lactofen),
nitrofen,
oxyfluorfen,
and
fomesafen.
The
Agency
has
evidence
that
the
diphenyl
ether
group
of
compounds
induce
similar
toxic
effects
but
has
not
yet
determined
whether
they
exhibit
a
common
mechanism
of
toxicity.
The
Agency
will
determine
whether
a
cumulative
risk
assessment
of
lactofen
and
the
other
diphenyl
ethers
is
appropriate
at
a
later
date.
For
the
purposes
of
tolerance
reassessment
for
lactofen,
EPA
is
assuming
no
common
mechanism.
To
date,
EPA
has
only
identified
two
classes
of
chemicals
that
share
a
common
mechanism
of
action.
A
cumulative
assessment
is
being
conducted
for
these
classes
(
i.
e.,
the
organophosphates
and
a
subset
of
the
carbamates).
However,
EPA
did
consider
the
contribution
of
the
acifluorfen
degradate
from
use
of
the
herbicide
sodium
acifluorfen
by
conducting
an
aggregate
assessment
for
acifluorfen
derived
from
both
lactofen
and
sodium
acifluorfen
sources.

Because
lactofen
is
under
review
for
tolerance
reassessment
only,
no
occupational
or
ecological
risk
assessment
was
conducted.
The
purpose
of
this
review
is
to
reassess
lactofen
tolerances,
for
which
the
Agency
only
considers
risk
from
food,
drinking
water,
and
residential
exposures,
if
appropriate.
At
this
time,
there
are
no
residential
uses
of
lactofen;
therefore,
residential
exposure
and
risk
is
not
considered.
The
FQPA
risk
assessments
for
lactofen
and
other
technical
support
documents
are
available
on
the
Internet
at
www.
epa.
gov/
edockets
under
docket
2
number
OPP­
2003­
0194
and
in
the
public
docket
(
under
the
same
docket
number)
for
viewing.

Use
Profile
Selective
Herbicide:
Lactofen
is
registered
for
use
on
snap
beans,
soybeans,
and
cotton
(
nonfood
use)
for
both
pre­
and
post­
emergent
control
of
broad
leaf
weeds.
In
the
past,
lactofen
was
also
registered
for
use
on
tomatoes
in
Florida
under
an
emergency
exemption
(
FIFRA
Section
18
registration).
Lactofen
is
not
registered
for
residential
use.
Although
not
currently
registered,
the
proposed
new
food
uses
of
lactofen
on
peanuts
and
cotton
were
included
in
the
risk
assessment
to
support
establishment
of
tolerances.

Formulations:
Lactofen
is
sold
in
the
United
States
under
the
trade
names
Cobra
®
and
Stellar
®
.
Lactofen
is
formulated
as
technical
grade
(
71.7%
active
ingredient),
manufacturing
use
product
(
60%
active
ingredient),
and
emulsifiable
concentrate
(
23.2
to
26.6%
active
ingredient).

Methods
of
Application:
Aerial
and
ground
application;
band
treatment,
broadcast,
directed
spray,
low
volume
spray,
soil
broadcast
treatment,
and
soil
incorporation.

Use
Rates:
Lactofen
is
generally
applied
at
a
rate
of
1
lb
active
ingredient
(
ai)
per
acre
(
A)
or
less
per
application
with
a
total
application
of
1
lb
ai/
A/
year.

Annual
Poundage:
Approximately
235,000
pounds
of
lactofen
a.
i.
are
applied
annually
to
nearly
2.2
million
acres.
Lactofen's
largest
markets
in
terms
of
total
pounds
of
a.
i.
applied
annually
are
soybeans
(
85%)
and
cotton
(
12%).
The
remaining
use
is
primarily
on
fresh
beans.
Very
limited
use
has
been
reported
on
tomatoes
in
Florida
from
a
FIFRA
Section
18
registration
which
is
now
expired.

Percent
Crop
Treated:
Sites
on
which
lactofen
has
the
highest
percent
of
crop
treated
include
soybeans
(
3%)
and
cotton
(
2%,
non­
food
use).

Registrant:
Valent
USA
Corporation
Human
Toxicity
°
Lactofen
has
low
acute
toxicity
via
the
oral,
dermal,
and
inhalation
routes
of
exposure;
causes
mild
skin
irritation;
and
is
not
a
dermal
sensitizer.
The
manufacturing
use
product
(
60%
active
ingredient)
is
a
moderate
eye
irritant.

°
Lactofen
is
in
Acute
Toxicity
Category
IV
for
acute
oral
and
inhalation
toxicity
and
Category
III
for
acute
dermal
toxicity.
3
Human
Health
Risk
Assessment
Acute
Dietary
(
Food)
Risk
Acute
dietary
risk
from
food
is
calculated
considering
what
is
eaten
in
one
day.
A
risk
estimate
that
is
less
than
100%
of
the
acute
Population
Adjusted
Dose
(
aPAD)
(
the
dose
at
which
an
individual
could
be
exposed
on
any
given
day
and
no
adverse
health
effects
would
be
expected)
does
not
exceed
the
Agency's
level
of
concern.
The
aPAD
is
the
reference
dose
(
RfD)
adjusted
for
the
FQPA
safety
factor.

The
acute
dietary
analysis
uses
high­
end
food
residue
values
from
field
trial
studies
and
percent
crop
treated
information.
The
dietary
risk
assessment
was
based
only
on
residues
of
lactofen
because
metabolites
are
not
expected
to
be
present
at
significant
levels.
Because
no
relevant
effects
following
a
single
exposure
of
lactofen
were
identified
for
the
U.
S.
general
population,
an
acute
dietary
risk
assessment
for
the
entire
U.
S.
population
was
not
conducted.
However,
an
assessment
was
conducted
for
the
population
subgroup
of
"
females
13­
50
years
old"
because
developmental
effects
were
noted
in
a
rat
developmental
toxicity
study.
The
Agency
believes
these
effects
are
only
relevant
to
women
of
child
bearing
age.

The
acute
dietary
exposure
analysis
for
food
is
a
Tier
2
assessment
based
on
the
Dietary
Exposure
Evaluation
Model
(
DEEM
 
)
.
The
DEEM
 
analysis
evaluated
the
individual
food
consumption
as
reported
by
respondents
in
the
USDA
1989­
92
Continuing
Surveys
for
Food
Intake
by
Individuals
(
CSFII)
and
accumulated
exposure
to
the
chemical
for
each
commodity.

°
The
acute
dietary
(
food)
risk
estimate
is
not
of
concern
for
any
population
group.
Acute
dietary
exposure
to
lactofen
comprises
less
than
0.1%
of
the
aPAD
for
females
13­
50
years
old.

°
A
No
Observed
Adverse
Effect
Level
(
NOAEL)
of
50
mg/
kg/
day
was
established
for
females
13­
50
years
old
based
on
decreased
fetal
weight
and
skeletal
abnormalities
at
a
Lowest
Observed
Adverse
Effect
Level
(
LOAEL)
of
150
mg/
kg/
day
in
a
rat
developmental
toxicity
study.
The
skeletal
abnormalities
are
presumed
to
occur
after
a
single
exposure
(
dose)
and,
thus,
are
appropriate
for
this
acute
risk
assessment.

°
The
uncertainty
factor
(
UF)
is
100
to
account
for
inter­
species
extrapolation
(
10X)
and
intra­
species
variation
(
10X).

°
A
3X
FQPA
safety
factor
was
retained
for
acute
dietary
exposures
for
females
13­
50
years
old
based
on
the
following:
4

no
increased
susceptibility
from
in
utero
and/
or
postnatal
exposure
to
lactofen
in
rats,

adequate
data
are
available
to
satisfactorily
assess
food
exposure
and
to
provide
a
screening­
level
drinking
water
exposure
assessment,
and

uncertainty
due
to
a
data
gap
for
a
rabbit
developmental
toxicity
study.

°
The
aPAD
for
females
13­
50
years
old
is
0.17
mg/
kg/
day.
No
aPAD
has
been
established
for
the
general
population.

Chronic
Dietary
(
Food)
Risk
For
the
chronic
(
non­
cancer)
dietary
(
food
)
risk
assessment,
the
average
consumption
value
for
each
population
subgroup
is
combined
with
average
residue
values
in/
on
commodities
to
determine
average
exposure
(
in
mg/
kg/
day).
A
risk
estimate
that
is
less
than
100%
of
the
chronic
Population
Adjusted
Dose
(
cPAD)
(
the
dose
at
which
an
individual
could
be
exposed
over
the
course
of
a
lifetime
and
no
adverse
health
effects
would
be
expected)
does
not
exceed
the
Agency's
level
of
concern.
The
chronic
dietary
analysis
utilized
anticipated
residue
values
based
on
field
trial
studies,
concentration
factors
from
processing
studies,
and
percent
crop
treated
information.

°
The
chronic
dietary
(
food)
risk
estimate
is
not
of
concern.
Dietary
exposure
to
lactofen
constitutes
less
than
0.1%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups.

°
The
NOAEL
used
in
the
chronic
dietary
assessment
is
0.79
mg/
kg/
day
based
on
kidney
lesions
and
weight
changes
to
the
thyroid
and
adrenal
glands
at
a
LOAEL
of
3.96
mg/
kg/
day,
and
is
derived
from
a
chronic
oral
toxicity
study
in
dogs.

°
The
uncertainty
factor
(
UF)
is
100
to
account
for
inter­
species
extrapolation
(
10X)
and
intra­
species
variation
(
10X).

°
The
FQPA
safety
factor
is
1X
for
chronic
dietary
exposures
because
the
data
gap
for
a
developmental
toxicity
study
in
rabbits
has
no
bearing
on
chronic
exposure.

°
The
cPAD
is
0.008
mg/
kg/
day
for
all
population
subgroups.

Cancer
Dietary
(
Food)
Risk
Chronic
(
cancer)
dietary
risk
is
also
calculated
by
using
the
average
consumption
values
for
food
and
average
residue
values
for
those
foods
over
a
70­
year
lifetime.
Because
lactofen
is
now
considered
to
be
unlikely
to
be
carcinogenic
at
low
doses,
the
chronic
exposure
value
is
compared
with
a
NOAEL
to
determine
the
cancer
risk
estimate.
Cancer
risk
for
lactofen
is
now
expressed
as
a
Margin
of
Exposure
(
MOE),
and
cancer
MOEs
greater
than
100
for
lactofen
are
not
of
concern.
5
°
The
results
of
the
cancer
risk
assessment
for
lactofen
show
that
the
cancer
MOEs
from
food
alone
are
300,000
for
the
general
U.
S.
population,
which
is
not
of
concern.

°
The
Agency
revised
the
cancer
classification
of
lactofen
based
on
several
toxicity
studies
showing
that
lactofen
acts
via
a
peroxisome
proliferation
mechanism
of
action.
These
studies
were
evaluated
using
criteria
established
by
the
International
Life
Science
Institute
(
ILSI).
Details
of
EPA's
review
of
the
mechanism
of
action
and
the
cancer
classification
for
lactofen
may
be
found
in
the
following
documents:
Lactofen:
Report
of
the
Mechanism
of
Toxicity
Review
Committee,
dated
March
12,
2002
and
Lactofen­
Report
of
the
Cancer
Assessment
Review
Committee,
dated
May
21,
2002.

°
Lactofen
is
now
classified
under
EPA's
1999
Cancer
Risk
Assessment
Guidelines
as
"
likely
to
be
carcinogenic
to
humans
at
high
enough
doses
to
cause
these
biochemical
and
histopathological
effects
[
peroxisome
proliferation]
in
the
livers
of
rodents
but
unlikely
to
be
carcinogenic
at
doses
below
those
causing
these
changes."
Lactofen
is
now
considered
to
be
a
threshold
carcinogen.

°
The
revised
cancer
risk
assessment
for
lactofen
is
based
on
a
NOAEL
of
0.3
mg/
kg/
day
from
a
special
7­
week
rodent
study
which
evaluated
peroxisome
proliferation
in
the
liver
of
rats
and
mice.
Effects
observed
at
the
study
LOAEL
of
10
mg/
kg/
day
included
increased
liver
enzyme
activity
and
histopathological
findings
in
mice.
The
selected
NOAEL
is
considered
to
be
protective
of
cancer
effects
because
the
changes
in
liver
enzymes
and
histopathology
are
believed
to
precede
liver
tumor
formation
for
a
peroxisome
proliferation
mode
of
action.

Fate
and
Transport
°
Lactofen
is
not
persistent
in
the
environment
and
has
a
high
affinity
for
binding
and
low
solubility.
The
primary
degradate
of
lactofen
is
acifluorfen,
which
is
also
a
degradate
of
sodium
acifluorfen,
another
herbicide
registered
for
use
in
agricultural
and
residential
settings.

°
Environmental
fate
data
suggest
that,
while
lactofen
is
not
likely
to
reach
water
resources
in
any
significant
quantities,
its
degradate
acifluorfen
is
both
persistent
and
mobile
in
the
environment.

°
The
acifluorfen
degradate
derived
from
sodium
acifluorfen
is
expected
to
be
more
likely
to
leach
to
groundwater
than
the
same
degradate
derived
from
lactofen
because
the
two
pesticides
degrade
using
different
pathways.
Sodium
acifluorfen
degrades
rapidly,
sometimes
instantaneously,
to
acifluorfen
in
the
environment.
Lactofen
degrades
via
two
different
metabolic
pathways.
Also,
100
percent
of
sodium
acifluorfen
degrades
to
acifluorfen,
whereas,
at
most,
only
58
percent
of
lactofen
is
expected
to
degrade
to
acifluorfen.
The
acifluorfen
degradate
from
use
of
lactofen
is
not
expected
to
move
through
the
soil
matrix
as
a
single
pulse
as
would
be
expected
with
use
of
sodium
acifluorfen.
6
Drinking
Water
Dietary
Risk
Drinking
water
exposure
to
pesticides
can
occur
through
groundwater
and
surface
water
contamination.
EPA
considers
acute
(
one
day)
and
chronic
(
lifetime)
drinking
water
risks
and
uses
either
screening­
level
modeling
or
actual
monitoring
data,
if
available,
to
estimate
those
risks.
Estimated
drinking
water
concentrations
(
EDWCs)
in
groundwater
and
surface
water
sources
of
drinking
water
were
determined
for
lactofen
and
the
acifluorfen
degradate
derived
from
both
lactofen
and
sodium
acifluorfen
uses.

°
Because
lactofen
is
not
persistent
in
the
environment
and
has
a
high
affinity
for
binding
(
low
mobility),
it
is
not
expected
to
leach
to
groundwater.
Moreover,
based
on
a
recently
conducted
prospective
groundwater
study,
which
featured
highly
vulnerable
soils,
lactofen
was
not
detected.

°
To
assess
risks
of
lactofen
in
drinking
water,
screening­
level
modeling
was
used
to
estimate
the
concentration
of
lactofen
in
groundwater
and
surface
water.
Modeling
is
generally
considered
to
provide
high­
end
estimates
of
drinking
water
exposure.
The
EDWCs
of
lactofen
from
model
results
are
summarized
in
Table
1.

Table
1.
Summary
of
Lactofen
Drinking
Water
Assessment
Crop
Scenario
Surface
Water
EDWC
(
ppb)
Ground
Water
EDWC
(
ppb)

Acute
Cotton
0.39
0.006
Soybean
0.18
0.006
Chronic
(
Noncancer)

Cotton
0.008
0.006
Soybean
0.008
0.006
Cancer
Cotton
0.005
0.006
Soybean
0.007
0.006
EDWC,
Estimated
Drinking
Water
Concentration
°
To
determine
the
EDWCs
of
the
degradate
acifluorfen
derived
from
lactofen
in
surface
water
sources
of
drinking
water,
a
Tier
II
screening­
level
model
was
used.
However,
due
to
the
complexity
of
the
fate
properties
of
acifluorfen
and
groundwater
model
limitations,
monitoring
data
were
considered
to
estimate
potential
acifluorfen
contamination
of
groundwater
from
lactofen.

°
To
consider
the
contribution
of
the
acifluorfen
degradate
derived
from
use
of
the
herbicide
7
sodium
acifluorfen,
screening­
level
models
were
utilized
to
determine
EDWCs
in
both
groundwater
and
surface
water
sources
of
drinking
water.
The
individual
and
total
EDWCs
of
the
acifluorfen
degradate
from
both
lactofen
and
sodium
acifluorfen
are
summarized
in
Table
2.

Table
2.
Summary
of
Acifluorfen
Degradate
Drinking
Water
Assessment
Crop
Scenario
Surface
Water
EDWC
(
ppb)
1
Groundwater
EDWC
(
ppb)
Acute
Chronic
(
Noncancer)
Cancer
Acifluorfen
Derived
from
Sodium
Acifluorfen
Soybeans
7.47
1.91
1.10
3.67
Peanuts
4.98
1.84
1.10
3.67
Acifluorfen
Derived
From
Lactofen
Cotton
2.99
0.53
0.21
0.0352
Soybeans
2.65
0.52
0.24
0.0352
Total
Acifluorfen
from
all
Sources
Soybeans
10.12
2.43
1.34
3.71
1
EDWCs
were
calculated
using
the
Tier
II
PRZM/
EXAMS
model,
which
utilizes
the
Index
Reservoir
Model
and
is
adjusted
for
the
Percent
Crop
Area
(
PCA)
factor.
2
EDWCs
were
derived
from
prospective
groundwater
monitoring
study
Residential
Risk
Lactofen
is
not
registered
for
residential
uses;
therefore,
the
Agency
did
not
assess
residential
risk.

Aggregate
Risk
Aggregate
risk
considers
the
combined
exposure
to
pesticides
through
food,
drinking
water,
and,
if
appropriate,
residential
uses.
Because
there
are
no
residential
uses
of
lactofen,
there
is
no
residential
exposure
to
consider
in
the
aggregate
risk
assessment;
therefore
the
aggregate
assessment
for
lactofen
includes
exposures
only
from
food
and
drinking
water.
To
determine
the
maximum
contribution
from
water
allowed
in
the
diet,
EPA
first
looks
at
how
much
of
the
overall
allowable
risk
is
contributed
by
food
and
then
calculates
a
Drinking
Water
Level
of
Comparison
(
DWLOC).
The
EDWC
derived
from
either
monitoring
or
modeling
is
then
compared
with
the
DWLOC.
EDWCs
that
are
above
the
corresponding
DWLOC
exceed
the
Agency's
level
of
concern.

°
An
aggregate
assessment
for
lactofen
was
conducted
by
comparing
the
surface
water
and
groundwater
EDWCs
with
the
corresponding
DWLOCs.
As
indicated
in
Table
3,
the
EDWCs
for
all
exposures
were
less
than
the
corresponding
DWLOCs;
therefore,
the
Agency
has
no
concern
for
the
aggregate
risk
of
lactofen.
8
Table
3.
Aggregate
Risk
of
Lactofen
Exposure
Surface
Water
EDWC
(
ppb)
Groundwater
EDWC
(
ppb)
DWLOC
(
ppb)

Acute
0.18­
0.39
0.006
5100
Chronic
(
Noncancer)
0.008
0.006
80
Cancer
0.005­
0.007
0.006
105
°
The
Agency
also
conducted
an
aggregate
assessment
for
acifluorfen,
derived
from
the
use
of
the
herbicides
lactofen
and
sodium
acifluorfen,
by
comparing
the
total
acifluorfen
surface
water
and
groundwater
EDWCs
with
the
corresponding
DWLOCs.
As
indicated
in
Table
4,
the
EDWCs
for
all
exposures
were
less
than
the
corresponding
DWLOCs;
therefore,
the
Agency
has
no
concern
for
the
aggregate
risk
of
the
acifluorfen
degradate
from
both
lactofen
and
sodium
acifluorfen.

Table
4.
Aggregate
Risk
of
Total
Acifluorfen
from
All
Sources
Exposure
Surface
Water
EDWC
(
ppb)
Groundwater
EDWC
(
ppb)
DWLOC
(
ppb)

Acute
10.12
3.71
600
Chronic
(
Noncancer)
2.43
3.71
40
Cancer
1.34
3.71
455
°
The
Agency
previously
had
a
cancer
risk
concern
for
aggregate
exposure
to
the
acifluorfen
degradate
via
groundwater.
EPA's
conclusions
about
the
cancer
risk
from
the
acifluorfen
degradate
in
groundwater
have
changed
as
a
result
of
new
information
on
both
the
nature
of
the
cancer
effect
and
the
ability
of
lactofen
(
and
its
acifluorfen
degradate)
to
leach
to
groundwater.
The
Agency
has
no
concern
for
the
aggregate
cancer
risk
from
either
lactofen
or
acifluorfen.

Occupational
and
Ecological
Risk
As
stated
previously,
no
occupational
or
ecological
risk
assessment
was
conducted
for
lactofen.
This
review
is
limited
to
food
and
drinking
water
exposures;
hence,
review
of
occupational
and
ecological
risks
is
not
necessary
for
tolerance
reassessment.
9
Data
Needs
The
following
confirmatory
data
requirements
have
been
identified
for
lactofen:

°
Prenatal
Developmental
Toxicity
Study
in
Rabbits
(
OPPTS
Guideline
870.3700,
current
data
gap,
two
developmental
toxicity
studies
are
required
for
every
food
use
chemical)

°
Confined
Rotational
Crop
Study
(
OPPTS
Guideline
860.1850,
required
because
confined
rotational
crop
study
in
root
crops
indicated
minimal
uptake
of
radioactivity
in
carrots
and
radishes
planted
after
lactofen
application).

In
addition,
product
chemistry
studies
are
required
for
the
60
and
76%
a.
i.
formulations,
because
the
composition
of
these
two
products
has
changed
significantly
as
a
result
of
a
change
in
the
manufacturing
process.