Document ID: EPA-HQ-OPP-2004-0235-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-09-08T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
WASHINGTON,
D.
C.
20460
August
17,
2004
MEMORANDUM:

SUBJECT:
Human
Health
Risk
Assessment
for
Fluridone
TRED
PC
Code
112900.
DP
Barcode
D306456.

FROM:
Timothy
C.
Dole,
CIH,
Industrial
Hygienist
Christine
Olinger,
Chemist
Paul
Chin,
Ph.
D.,
Toxicologist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THRU:
Whang
Phang,
Ph.
D.,
Branch
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

TO:
Wilhelmena
Livingston,
Chemical
Review
Manager
Special
Review
and
Registration
Division
Please
find
attached
the
Human
Health
Risk
Assessment
for
the
fluridone
Tolerance
Registration
Eligibility
Decision
(
TRED).
This
assessment
is
based
upon
the
Toxicology
Chapter
(
TXR
0052046)
and
the
Dietary
Exposure
Assessment
Memorandum
(
D299947).
Information
was
also
drawn
from
the
EFED's
Drinking
Water
Assessment
(
D300012).
Table
of
Contents
1.0
Executive
Summary
2.0
Ingredient
Profile
3.0
Metabolism
Assessment
4.0
Hazard
Characterization
4.1
Hazard
Characterization
4.2
FQPA
Hazard
Considerations
4.3
Recommendation
for
Development
Neurotoxicity
Study
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.5
Special
FQPA
Safety
Factor
4.6
Endocrine
disruption
5.0
Public
Health
Data
6.0
Non­
Occupational
Exposure
Assessment
6.1
Dietary
Exposure
and
Risk
6.2
Water
Exposure
and
Risk
6.3
Residential
Exposures
and
Risks
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
7.1
Aggregate
Risk
for
Fluridone
7.2
Aggregate
Risk
for
NMF
7.3
Risk
Characterization
8.0
Cumulative
Risk
9.0
Data
Gaps
and
Information
Requirements
10.1
Toxicology
10.2
Residue
Chemistry
10.3
Occupational
and
Residential
Exposure
Appendices
A
Table
of
Fluridone
Metabolites
and
Degradates
B
Fluridone
Toxicity
Profile
(
Subchronic,
Chronic
and
Other)
C
Recreational
Swimmer
Exposures
and
Risks
1
1.0
EXECUTIVE
SUMMARY
Overall
Summary
The
Health
Effects
Division
(
HED)
has
conducted
a
human
health
risk
assessment
for
the
active
ingredient
Fluridone
for
the
Tolerance
Registration
Eligibility
Decision
(
TRED).
HED
determined
that
the
currently
available
data
are
adequate
to
support
the
TRED.
The
food,
drinking
water
and
recreational
swimmer
risks
are
not
of
concern
either
separately
or
when
aggregated.

Introduction
Fluridone
is
a
systemic
herbicide
that
is
used
to
manage
aquatic
weeds
in
ponds
and
lakes.
It
is
particularly
useful
for
the
control
of
hydrilla
in
the
southern
states
and
eurasian
milfoil
in
the
northern
states.
It
inhibits
carotene
synthesis
which
causes
the
loss
of
chlorophyll.
It
is
typically
applied
to
the
whole
water
body
because
it
requires
a
contact
time
of
45
days
to
be
effective.
The
labels
permit
single
treatments
of
up
to
90
ppb
for
whole
lake
treatments
and
150
ppb
for
partial
lake
treatments,
with
a
maximum
cumulative
application
of
150
ppb
per
growth
cycle.
There
are
no
direct
food
uses
for
fluridone,
however,
water
from
areas
treated
with
fluridone
can
be
used
for
the
irrigation
of
crops
and
pastures.

Toxicology
of
Fluridone
The
acute
toxicity
of
fluridone
is
moderate
to
low
and
it
is
not
a
skin
sensitizer.

In
subchronic
dietary
feeding
studies,
fluridone
caused
increased
incidence
of
liver
hypertrophy
in
mice
and
no
effects
in
dogs
at
200
mg/
kg/
day,
the
highest
doses
tested.

In
developmental
toxicity
studies,
maternal
toxicity
(
abortions
and
decreased
body
weight
and
food
consumption)
were
seen
in
rabbits
at
300
mg/
kg/
day
or
above.
In
the
rats,
maternal
toxicity(
decreased
body
weight
gains
and
food
consumption)
were
seen
at
300
mg/
kg/
day.
Developmental
toxicity
such
as
decreased
fetal
weight,
increased
incidences
of
rudimentary
ribs,
and
delayed
ossification
in
sternebrae
and
pelvic
girdle
were
seen
at
1000
mg/
kg/
day.

In
a
3­
generation
reproduction
study
in
rats,
no
maternal
toxicity
was
seen
at
any
dose
levels.
Also,
the
test
chemical
did
not
significantly
affect
any
of
the
reproductive
parameters.
For
the
offspring,
there
was
a
increased
pup
weight
on
lactation
day
21
at
112
mg/
kg/
day.

In
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats,
chronic
toxicity
consisted
of
decreased
body
weights,
decreased
eosinophil
counts
and
decreased
absolute
and
relative
liver
and
kidney
weights
at
81
mg/
kg/
day
In
addition,
fluridone
at
81
mg/
kg/
day
also
caused
an
increased
incidence
of
small
testes,
ocular
keratitis
and
pale
or
granular
kidneys.
In
a
chronic
toxicity
study
in
dogs,
significant
increases
in
absolute
liver
weights
and
increases
in
alkaline
phosphatase
activity
in
female
dogs
were
seen
at
the
highest
dose­
tested
(
400
mg/
kg/
day).
2
No
neurotoxicity
was
reported
in
any
of
the
studies.

Mutagenicity
and
Cancer
Fluridone
was
negative
for
inducing
mutations
in
all
guideline
studies
of
the
standard
battery
of
mutagenicity
tests.

In
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats,
there
was
no
treatment­
related
increase
in
tumor
incidence
in
any
treated
groups
when
compared
to
controls.
The
Carcinogenicity
study
in
mice
showed
no
treatment­
related
increase
in
tumor
incidence
in
any
treated
groups
when
compared
to
controls.
Increase
in
alkaline
phosphatase
activity
and
increased
incidence
of
hepatocellular
hyperplasia
were
seen
at
50
mg/
kg/
day.

The
HED
Cancer
Assessment
Review
Committee
evaluated
the
available
data
and
concluded
that
the
data
did
not
provide
evidence
for
the
carcinogenicity
of
fluridone
in
either
rats
or
mice.

Dose
Response
and
Endpoint
Selection
for
Fluridone
The
following
endpoints
were
used
for
fluridone
risk
assessment:

A
developmental
NOAEL
of
125
mg/
kg/
day
was
selected
from
a
developmental
toxicity
study
in
rabbits
in
which
increased
incidences
of
abortions
were
observed
at
the
LOAEL
of
300
mg/
kg/
day.
This
NOAEL
was
selected
for
acute
dietary
exposures
of
adult
females
of
reproductive
age.

A
NOAEL
of
15
mg/
kg/
day
was
selected
from
a
2
yr
carcinogenicity
study
in
mice
in
which
increased
alkaline
phosphatase
activity
and
hepatocellular
hyperplasia
was
observed
at
the
LOAEL
of
50
mg/
kg/
day.
This
NOAEL
is
applicable
to
chronic
dietary
exposures
as
well
as
short
and
intermediate
term
dermal,
inhalation
and
incidental
oral
exposures.

A
dermal
absorption
factor
of
39
percent
was
selected
for
converting
dermal
exposures
to
oral
equivalent
doses.

The
target
Margin
of
Exposure
(
MOE)
for
both
occupational
and
residential
populations
is
100,
which
includes
the
standard
safety
factors
of
10X
for
intraspecies
variability
(
i.
e.
differences
among
humans)
and
10X
for
interspecies
variability
(
differences
between
humans
and
animals).
Addtional
factors
for
database
uncertainties
were
not
required
because
the
database
was
considered
complete
and
no
datagaps
were
identified.

The
FQPA
Safety
Factor
is
1X
based
upon
the
available
hazard
and
exposure
data
and
is
applicable
to
all
population
subgroups
and
exposure
scenarios.
There
was
no
evidence
of
pre­
or
post­
natal
susceptibility
from
in
utero
or
postnatal
exposure
to
fluridone.
There
are
no
residual
uncertainties.
Toxicology
of
N­
Methyl
Formamide
3
N­
methyl
Formamide
(
NMF)
is
the
most
toxic
and
prevalent
of
the
fluridone
metabolites
and
degradates.
It
is
formed
in
water
by
the
photolysis
of
fluridone.
The
toxicology
database
for
NMF
is
limited
to
one
developmental
study
that
was
reported
in
the
literature.
This
study
indicated
that
NMF
causes
skeletal
malformations
in
both
rats
and
rabbits
with
NOAEL
of
10
mg/
kg/
day.
NMF
is
not
a
metabolite
in
foods.

Dietary
Risk
Dietary
risks
for
fluridone
were
calculated
at
the
tier
1
level
by
using
tolerance
level
residues
and
the
assumption
that100
percent
of
the
crop
would
be
irrigated
with
fluridone
containing
water.
Acute
dietary
risk
estimates
were
calculated
only
for
females
of
child­
bearing
age,
as
no
endpoint
was
identified
for
the
other
populations.
At
the
95th
percentile
of
exposure,
the
acute
dietary
exposure
estimates
are
less
than
1%
of
the
aPAD,
which
means
that
the
risks
are
below
the
HED's
level
of
concern
(
100%
aPAD).
The
chronic
risks
were
calculated
for
all
of
the
populations
and
were
also
well
below
HED's
level
of
concern.
These
risks
ranged
from
1%
of
the
cPAD
for
the
U.
S.
population
to
3.6
%
of
the
cPAD
for
children
aged
1
to
2.
Dietary
risks
for
NMF
were
not
calculated
because
NMF
is
not
a
metabolite
in
foods.

Drinking
Water
Risks
The
drinking
water
risks
were
calculated
for
both
fluridone
and
NMF
because
fluridone
degrades
to
NMF
in
water.
The
fluridone
labels
permit
applications
of
up
to
20
ppb
at
potable
water
intakes
and
requires
that
applications
of
greater
than
20
ppb
must
be
further
than
1/
4
mile
from
potable
water
intakes.
Given
this
label
restriction
it
can
be
assumed
that
the
fluridone
EEC
for
drinking
water
drawn
from
lakes
would
be
20
ppb
or
less.
The
EECs
for
NMF
were
derived
from
the
fluridone
EECs
by
assuming
a
fluridone
to
NMF
conversion
efficiency
of
74%
and
by
adjusting
for
the
ratio
of
the
NMF
and
fluridone
molecular
weights.
Given
the
above
assumptions
a
fluridone
concentration
of
20
ug/
liter
will
yield
an
NMF
concentration
of
2.64
ug/
liter.
These
concentrations
were
used
along
standard
assumptions
of
body
weight
and
daily
water
consumption
to
calculate
MOEs
for
both
fluridone
and
NMF.
All
the
MOEs
exceeded
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude.

Recreational
Swimmer
Risks
These
exposures
were
evaluated
using
the
SWIMODEL
and
standard
assumptions
from
the
residential
SOPs.
Acute,
short
term
and
intermediate
term
exposures
were
evaluated
for
fluridone
and
acute
and
short
term
exposures
were
evaluated
for
NMF.
The
maximum
label
target
concentration
of
150
ppb
was
used
assess
fluridone
exposures.
The
corresponding
NMF
concentration
of
20
ppb
was
based
upon
the
fluridone
to
NMF
conversion
efficiency
of
74%
as
cited
by
EFED.
All
of
the
MOEs
for
both
fluridone
and
NMF
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude.

Aggregate
Risks
The
aggregate
risk
for
fluridone
were
calculated
by
combining
the
food,
drinking
water
and
4
swimmer
exposures
while
the
aggregate
risks
for
NMF
were
calculated
by
combining
drinking
water
and
swimmer
exposures.
All
of
the
aggregate
MOEs
for
both
fluridone
and
NMF
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude
which
means
that
the
aggregate
risks
are
not
of
concern.

Risk
Characterization
This
risk
assessment
was
based
upon
the
assumption
that
maximum
label
rates
would
be
used.
Literature
data
and
discussions
with
the
aquatic
plant
management
community
have
indicated,
however,
that
actual
use
rates
are
in
the
range
of
10
to
20
ppb
due
to
the
high
cost
of
fluridone
and
it's
proven
efficacy
at
these
lower
rates.
Therefore,
risks
values
provided
in
this
risk
assessment
are
bounding
estimates.

Data
Requirements
There
are
no
data
requirement
for
fluridone.

Tolerance
Reassessment
All
of
the
existing
fluridone
tolerances
established
at
40
CFR
180.420
are
adequately
supported.
These
tolerances
are
listed
in
Table
1.
5
Table
1.
List
of
Tolerances
for
Fluridone
Included
in
the
Dietary
Risk
Assessments
Commodity
Tolerance
(
ppm)
Commodity
Tolerance
(
ppm)

Avocado
0.1
Hog,
Meat
by­
products
0.05
Cattle,
Fat
0.05
Hops
0.1
Cattle,
Kidney
0.1
Horse,
Fat
0.05
Cattle,
Liver
0.1
Horse,
Kidney
0.1
Cattle,
Meat,
except
Kidney
and
Liver
0.05
Horse,
Liver
0.1
Cattle,
Meat
by­
products
0.05
Horse,
Meat,
except
Kidney
and
Liver
0.05
Citrus
0.1
Horse,
Meat
by­
products
0.05
Cotton,
Undelinted
Seed
0.1
Leafy
vegetables
0.1
Crayfish
0.5
Legume,
forage
0.15
Cucurbit
vegetables
group
0.1
Milk
0.05
Egg
0.05
Nut
0.1
Fish
0.5
Poultry,
Fat
0.05
Fruit,
Pome
0.1
Poultry,
Kidney
0.01
Fruit,
Stone
0.1
Poultry,
Liver
0.01
Goat,
Fat
0.05
Poultry,
Meat,
except
Kidney
and
Liver
0.05
Goat,
Kidney
0.1
Poultry,
Meat
by­
products
0.05
Goat,
Liver
0.1
Root
Crop
Vegetables
0.1
Goat,
Meat,
except
Kidney
and
Liver
0.05
Seed
and
Pod
Vegetables
0.1
Goat,
Meat
by­
products
0.05
Sheep,
Fat
0.05
Grain,
crop
0.1
Sheep,
Kidney
0.1
Grass,
Forage
0.15
Sheep,
Liver
0.1
Hog,
Fat
0.05
Sheep,
Meat,
except
Kidney
and
Liver
0.05
Hog,
Kidney
0.1
Sheep,
Meat
by­
products
0.05
Hog,
Liver
0.1
Small
Fruit
0.1
Hog,
Meat,
except
Kidney
and
Liver
0.05
Vegetables,
fruiting
0.1
6
N
O
CH
3
F
3
C
2.0
Ingredient
Profile
Chemical
Structure
and
Identification
Fluridone
{
1­
methyl­
3­
phenyl­
5­[
3­(
trifluoromethyl)
phenyl]­
4(
1H)­
pyridinone}
is
a
pyridazone
herbicide
registered
for
use
on
aquatic
weeds
in
lakes,
ponds
and
canals.
The
chemical
structure
of
fluridone
and
identifying
information
is
included
below:

Empirical
Formula:
C
19
H
14
F
3
NO
Molecular
Weight:
329.3
CAS
Registry
No.:
59756­
60­
4
PC
Code:
112900
Physical
Properties
of
Fluridone
Fluridone
is
an
off­
white
crystalline
solid
with
a
melting
point
of
154­
155o
C
and
a
bulk
density
of
1.4
g/
cm3
(
pyconometer
method).
It
has
a
log
octanol/
water
partition
coefficient
of
1.87
and
a
vapor
pressure
of
<
1
x
10­
7
mm
hg
at
25o
C.
Fluridone
in
the
environment
is
not
particularly
persistent
or
mobile
(
Kd
range
from
5.56
to
70.3
ml/
gram).
Fluridone
is
minimally
soluble
in
water
(
12
ppm)
and
soluble
in
organic
solvents
(
0.5
to
>
10
mg/
ml).

Summary
of
Registered
Uses
Fluridone
is
a
systemic
herbicide
that
is
used
to
manage
aquatic
weeds
in
ponds
and
lakes.
It
is
particularly
useful
for
the
control
of
eurasian
milfoil
in
the
northern
tier
states
and
for
hydrilla
in
the
southern
states.
It
inhibits
carotene
synthesis
which
causes
the
loss
of
chlorophyll.
It
is
typically
applied
to
the
whole
water
body
because
it
requires
a
contact
time
of
45
days
to
be
effective.
The
labels
permit
single
treatments
of
up
to
90
ppb
for
whole
lake
treatments
and
150
ppb
for
partial
lake
treatments,
with
a
maximum
cumulative
application
of
150
ppb
per
growth
cycle.
If
the
treatment
area
is
within
1/
4
mile
of
a
water
intake,
the
fluridone
concentration
must
be
maintained
below
20
ppb.

The
registered
fluridone
products
are
listed
in
Table
2.
7
Table
2
­
Active
Registrations
for
Fluridone
as
of
6/
01/
04
Product
Formulation
Reg
Number
Company
Name
%
of
Active
Ingredient
Fluridone
Technical
1812­
426
Griffin
L.
L.
C.
99.2
Fluridone
SC
Liquid
Concentrate
1812­
435
Griffin
L.
L.
C.
41.7
Fluridone
SRP
Granular
1812­
447
Griffin
L.
L.
C.
5
Sonar
Technical
67690­
4
SePRO
Corporation
99.2
Sonar
SRP/
5P
Granular
67690­
3
SePRO
Corporation
5
Sonar
A.
S.
Liquid
Concentrate
67690­
3
SePRO
Corporation
41.7
Sonar
X
Granular
67690­
3
SePRO
Corporation
5
Sonar*
Q
Quick
Release
Granular
67690­
3
SePRO
Corporation
5
3.0
Metabolism
Assessment
Metabolism
Profile
in
Rats/
Humans
In
a
metabolism
study
in
rats,
fluridone
was
rapidly
and
almost
completely
absorbed
into
the
systemic
circulation
and
eliminated
in
both
the
male
and
female
rats
within
3
days.
The
total
radioactivity
recovered
within
3
days
after
dosing
in
the
urine
and
feces
were
78­
90%
and
87­
97%
of
administered
dose
in
males
and
females,
respectively.
The
majority
(
approximately
70%)
of
the
radioactivity
was
eliminated
via
feces.
No
tissue
accumulation
was
observed.
The
major
components
in
the
feces
were
fluridone
and
fluridone
metabolites
produced
primarily
by
ring
hydroxylation
and
N­
demethylation.

Nature
of
the
Residue
in
Foods
Fluridone
is
not
applied
directly
to
crops.
However,
residues
of
fluridone
may
get
into
the
U.
S.
food
supply
when
water
from
treated
ponds
or
lakes
is
used
to
water
crops.
Fluridone
residues
could
end
up
in
livestock
commodities
if
livestock
drink
water
that
has
been
treated
with
fluridone
or
if
livestock
consume
crops
that
have
been
irrigated
with
fluridone­
treated
water.

Studies
have
been
conducted
to
determine
if
fluridone
is
transformed
when
it
is
applied
to
crops
in
irrigation
or
if
residues
are
consumed
by
livestock.
Fluridone,
14C­
labeled
in
the
4­
position
of
the
pyridinone
ring,
was
used
in
irrigated
crop
metabolism
studies
conducted
on
grapefruit,
corn,
soybeans,
lettuce,
and
alfalfa.
All
applications
were
foliar
applications
at
a
rate
of
4
acre­
inches
of
water
containing
fluridone
at
a
concentration
of
123
ppb.
In
addition,
soil
applications
were
conducted
with
corn
and
alfalfa.
Greater
than
73%
of
the
residue
in
all
crops
was
identified
as
the
parent
compound,
fluridone.
This
chemical
has
never
been
reviewed
by
the
Metabolism
Committee.
The
risk
assessment
team
has
reviewed
the
applicable
studies
and
has
determined
8
that
if
finite
residues
are
present,
fluridone
is
the
most
likely
species
present.

Livestock
metabolism
studies
have
been
conducted
with
cattle,
swine,
and
chickens.
All
studies
have
shown
considerable
metabolism
of
the
parent
compound
with
subsequent
incorporation
into
the
livestock
tissues.
Fluridone
and
its
4­
hydroxy
metabolite
were
found
in
cattle
and
swine
liver
at
levels
less
than
4%
each
of
the
total
radioactive
residue
(
TRR)
for
cattle,
and
0.5%
each
for
swine.
No
attempt
was
made
to
identify
the
TRR
in
poultry,
due
to
low
levels.
Given
the
relatively
low
dietary
burden
of
fluridone,
and
the
extensive
metabolism
of
fluridone
and
the
low
residues
expected
in
edible
commodities,
the
risk
assessment
team
has
concluded
that
the
residue
of
concern
for
risk
assessment
and
tolerance­
setting
purposes
is
the
parent,
fluridone.

Environmental
Degradation
As
discussed
in
the
EFED
Drinking
Water
Assessment
(
D300012
of
4/
1/
04)
N­
methyl
formamide
(
NMF)
is
the
major
degradate
of
fluridone
when
fluridone
is
applied
to
water
bodies.
The
maximum
daily
conversion
efficiency
of
74%
of
the
applied
fluridone
was
observed
in
an
aquatic
photolysis
study
(
MRID
419401­
04)
that
was
conducted
under
laboratory
conditions
using
distilled
water.
A
limited
number
of
studies
have
been
conducted
under
field
conditions
and
these
studies
suggest
that
NMF
is
generally
undetectable
in
water
bodies
treated
with
fluridone
at
the
maximum
application
rate.
In
one
study,
NMF
was
not
detected
(
LOD
=
2
ppb)
in
any
of
the
192
water
samples
collected
following
the
application
of
fluridone
to
two
ponds
in
Florida.
Ponds
were
used
in
this
study
instead
of
lakes
or
canals
to
maximize
the
concentration
and
persistence
of
fluridone
and
NMF.

Summary
of
Metabolites
and
Degradates
A
summary
listing
of
the
metabolites
and
degradates
of
fluridone
is
included
in
Appendix
A.

Toxicity
Profile
of
Major
Metabolites
and
Degradates
NMF
is
the
most
toxic
and
prevalent
of
the
fluridone
metabolites
and
degradates.
The
toxicology
database
for
NMF
is
limited
to
one
developmental
study
that
was
reported
in
the
literature.
This
study
indicated
that
NMF
causes
skeletal
malformations
in
both
rats
and
rabbits
with
NOAEL
of
10
mg/
kg/
day.
The
results
of
this
study
are
summarized
in
Table
3.
9
Table
3
­
Toxicology
Profile
of
NMF
STUDY*
­
DOSE
LEVELS
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
EFFECTS
Developmental
toxicity
 
rats
0,
1,
5,
10,
or
75
mg/
kg/
day
by
gavage
maternal
10
developmental
10
maternal
75
developmental
75
decreased
body
weight
gain
and
food
consumption
decreased
fetal
viability;
decreased
fetal
weight;
significant
increase
in
the
incidence
of
malformations
including
cephalocele
and
sternoschisis;
increased
incidence
of
incomplete
ossification
of
various
skeletal
structures
Developmental
toxicity
 
rabbits
0,
5,
10,
or
50
mg/
kg/
day
by
gavage
maternal
10
developmental
10
maternal
50
developmental
50
decreased
body
weight
gain
and
food
consumption
decreased
fetal
viability;
decreased
fetal
weight;
malformations
including
gastroschisis,
cephalocele,
domed
head,
flexed
paw,
and
skull
and
sternum
anomalies.

*
Fundamental
and
Applied
Toxicology
27
(
2),
239­
246,
1995.

Metabolites/
Degradates
Included
in
the
Risk
Assessment
and
Tolerance
Expression
A
summary
of
the
fluridone
metabolites
and
degradates
included
in
the
risk
assessment
and
tolerance
expression
is
included
in
Table
4.
No
major
plant
metabolites
were
found
in
the
irrigated
crop
study,
so
only
the
parent
compound
is
included.
Extensive
metabolism
of
the
low
total
residues
were
found
in
the
ruminant,
poultry,
and
swine
metabolism
studies,
so
no
major
degradates
were
identified.
Fluridone
and
4­
hydroxyfluridone
are
the
major
degradates
in
fish
and
are
assumed
to
have
approximately
equivalent
toxicity,
so
both
are
included
in
the
risk
assessment
and
tolerance
expression.
Benzoic
acid
and
its
3­
trifluroromethyl
benzoic
acid
are
aqueous
photolysis
products
found
in
laboratory
studies
conducted
with
lake
water.
Although
it
would
not
have
a
toxicity
profile
similar
to
the
parent,
there
is
not
a
concern
for
adverse
health
effects
at
the
levels
found
as
a
result
of
fluridone
applications.
Finally,
another
aqueous
photoproduct
found
in
laboratory
studies,
N­
methylformamide
(
NMF),
is
more
toxic
than
the
parent
compound
and
requires
a
separate
assessment.
10
Table
4
­
Metabolites/
Degradates
Included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
Irrigated
Crops
Fluridone
Fluridone
Rotational
Crop
N/
A
N/
A
Livestock
Ruminant
Fluridone
Fluridone
Poultry
Fluridone
Fluridone
Fish
Fluridone,
4­
hydroxy­
fluridone
Fluridone,
4­
hydroxy­
fluridone
Drinking
Water
Fluridone,
N­
methylformamide
Not
Applicable
4.0
HAZARD
CHARACTERIZATION
AND
ASSESSMENT
4.1
Hazard
Characterization
of
Fluridone
The
Fluridone
Toxicity
Profile
is
included
in
Appendix
B
and
the
following
is
a
summary
of
the
effects
observed
during
the
toxicology
studies.

Acute
Effects
The
acute
toxicity
of
Fluridone
is
moderate
to
low.
It
is
a
moderate
irritant
to
the
eyes.
The
acute
toxicity
values
are
included
in
Table
5.

Table
5
­
Acute
Toxicity
of
Fluridone
Guideline
Study
Type
Results
Tox
Category
81­
1
81­
2
81­
381­
4
81­
5
81­
6
Acute
Oral
­
rat
Acute
Dermal
­
rabbit
Acute
Inhalation
­
rat
Eye
irritation
­
rabbit
Dermal
irritation
­
rabbit
Dermal
sensitization
­
guinea
pig
LD50
>
10000
mg/
kg
LD50
>
2000
mg/
kg
LC50
>
2.13
mg/
L
moderate
effects*
no
dermal
effects
not
sensitizing
IV
III
IV
III
IV
N/
A
*
Slight
to
moderate
corneal
dullness,
iritis,
and
conjuctivitis
with
clearing
by
4
days.
11
Non­
Cancer
Toxicity
The
results
of
the
subchronic
dietary
feeding
studies
showed
that
fluridone
caused
increased
incidence
of
hepatic
centrilobular
hypertrophy
in
mice
and
increased
absolute
and
relative
liver
weights
and
relative
kidney
weights
in
rats.
It
produced
no
effects
in
subchronic
dietary
feeding
study
in
dogs
at
200
mg/
kg/
day,
the
highest
doses
tested.
In
developmental
toxicity
studies,
maternal
toxicity
such
as
increased
incidence
of
abortions
and
slight
decreases
in
the
body
weight
and
food
consumption
were
seen
in
rabbits
at
300
mg/
kg/
day
or
above.
In
the
rats,
maternal
toxicity
such
as
decreased
body
weight
gains
and
food
consumption
were
seen
at
300
mg/
kg/
day.
Developmental
toxicity
such
as
decreased
fetal
weight,
increased
incidences
of
rudimentary
ribs,
and
delayed
ossification
in
sternebrae
and
pelvic
girdle
were
seen
at
1000
mg/
kg/
day.

In
a
3­
generation
reproduction
study
in
rats,
no
maternal
toxicity
was
seen
at
any
dose
levels.
Also,
the
test
chemical
did
not
significantly
affect
any
of
the
reproductive
parameters.
For
the
offspring,
there
was
a
decreased
pup
weight
on
lactation
day
21
at
112
mg/
kg/
day.

In
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats,
chronic
toxicity
consisted
of
decreased
body
weights,
decreased
eosinophil
counts
and
decreased
absolute
and
relative
liver
and
kidney
weights
at
81
mg/
kg/
day.
In
addition,
fluridone
at
81
mg/
kg/
day
also
caused
an
increased
incidence
of
small
testes,
ocular
keratitis
and
pale
or
granular
kidneys.
In
a
chronic
toxicity
study
in
dogs,
significant
increases
in
absolute
liver
weights
and
increases
in
alkaline
phosphatase
activity
in
female
dogs
were
seen
at
the
highest
dose­
tested
(
400
mg/
kg/
day).

No
neurotoxicity
was
reported
in
any
of
the
studies.

Mutagenicity
and
Cancer
Fluridone
was
negative
for
inducing
mutations
in
all
guideline
studies
of
the
standard
battery
of
mutagenicity
tests.

In
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats,
there
was
no
treatment­
related
increase
in
tumor
incidence
in
any
treated
groups
when
compared
to
controls.
The
Carcinogenicity
study
in
mice
showed
no
treatment­
related
increase
in
tumor
incidence
in
any
treated
groups
when
compared
to
controls.
Increase
in
alkaline
phosphatase
activity
and
increased
incidence
of
hepatocellular
hyperplasia
were
seen
at
50
mg/
kg/
day.

The
HED
Cancer
Assessment
Review
Committee
(
TXR
007726,
July
15
and
October
7,
1985)
evaluated
the
available
data
and
concluded
that
the
data
did
not
provide
evidence
for
the
carcinogenicity
of
fluridone
in
either
rats
or
mice.
12
4.2
FQPA
Hazard
Characterization
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
for
fluridone
is
adequate.
There
are
sufficient
data
available
to
adequately
assess
the
potential
for
toxicity
to
young
animals
following
pre­
and/
or
postnatal
exposure
to
fluridone.
These
include
acceptable
developmental
toxicity
studies
in
rats
and
rabbits,
as
well
as
a
2­
generation
reproduction
studies
in
rats.

Evidence
of
Neurotoxicity
The
available
database
indicated
that
this
chemical
does
not
induce
neurotoxicity.

Developmental
Toxicity
Studies
The
developmental
toxicity
studies
in
rats
and
rabbits
showed
no
evidence
of
additional
sensitivity
to
young
rats
or
rabbits
following
pre­
or
postnatal
exposure
to
fluridone
and
comparable
NOAELs
were
established
for
adults
and
offspring.

Reproductive
Toxicity
Studies
In
a
3­
generation
reproduction
study
in
rats,
no
maternal
toxicity
was
seen
at
any
dose
levels.
Also,
the
test
chemical
did
not
significantly
affect
any
of
the
reproductive
parameters.
For
the
offspring,
there
was
a
decreased
pup
weight
on
lactation
day
21
at
112
mg/
kg/
day.

Additional
Information
from
Literature
Sources
A
literature
search
did
not
find
additional
neurotoxicity
studies
or
developmental
neurotoxicity
studies.

Determination
of
Susceptibility
for
Pre­
and/
or
post
Natal
Susceptibility
Prenatal
developmental
toxicity
studies
in
rats
and
rabbits
provided
no
indication
of
increased
susceptibility
of
rat
or
rabbit
fetuses
to
in
utero
exposure
to
fluridone.
There
was
indication
of
increased
susceptibility
in
the
offspring
as
compared
to
parental
animals
in
the
3­
generation
reproduction
study.

Degree
of
Concern
and
Residual
Uncertainties
for
Pre­
and/
or
post­
natal
Susceptibility
The
results
of
the
3­
generation
reproduction
study
in
rats
showed
increased
quantitative
susceptibility
of
offspring
to
fluridone
based
on
reduced
pup
weight
(
90.7%
controls;
p
<
0.05)
on
lactation
day
21.
However,
considering
the
overall
toxicity
profile
and
the
doses
and
endpoints
selected
for
risk
assessment
for
fluridone,
the
degree
of
concern
for
the
effects
observed
in
this
study
was
considered
as
low,
noting
that
the
study
was
well­
conducted,
clear
NOAELs/
LOAELs
were
established,
and
the
dose
response
for
the
observed
effects
are
well
characterized.
In
13
addition,
the
NOAEL
of
8
mg/
kg/
day
identified
to
established
the
chronic
RfD
is
more
than
4
times
less
than
that
of
36
mg/
kg/
day
for
offspring
toxicity.
Therefore,
no
residual
uncertainties
were
identified
for
pre­
and/
or
postnatal
toxicity.

4.3
Recommendation
for
a
developmental
Neurotoxicity
Study
The
available
toxicity
data
showed
no
neurotoxicity
or
offspring
toxicity
in
a
reproduction
study
which
would
warrant
a
recommendation
for
requiring
a
developmental
neurotoxicity
study.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
The
toxicity
endpoints
and
doses
for
fluridone
and
NMF
risk
assessment
are
shown
in
Tables
6
and
7.
The
endpoint
selected
for
acute
fluridone
exposures
is
conservative
because
the
observed
effects
(
abortions
in
the
rabbit)
may
not
be
indicative
of
a
single
dose
exposure
because
they
occurred
late
in
gestation
(
between
days
20
and
25)
in
the
presence
of
maternal
toxicity.
The
use
of
the
long
term
endpoint
for
short
and
intermediate
term
fluridone
exposures
was
done
to
simplify
the
risk
assessment
process.
This
endpoint
is
conservative
because
only
minor
effects
were
observed
during
90
day
studies.
These
effects
include
centrilobular
hypertrophy
and
increased
liver
and
kidney
weights
and
they
were
observed
at
LOAELs
of
25
mg/
kg/
day
in
mice
and
44
mg/
kg/
day
in
rats
with
NOAELs
of
15
mg/
kg/
day
in
mice
and
25
mg/
kg/
day
in
rats.

Table
6
­
Endpoints
Used
for
Fluridone
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Dietary
Risk
Assessments
Acute
Dietary
(
Females
13­
50
years
of
age)
Dev.
NOAEL
=
125
mg/
kg/
day
UF
=
100
Acute
RfD
=
1.25
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
1.25mg/
kg/
day
Developmental
Toxicity
­
Rabbit
LOAEL
=
300
mg/
kg/
day
based
on
increased
incidences
of
abortions
Acute
Dietary
(
General
population
including
infants
and
children)
NOT
APPLICABLE.
A
dose
and
endpoint
were
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
oral
toxicology
studies
including
maternal
toxicity
in
the
developmental
toxicity
studies
in
rats
and
rabbits
that
are
attributable
to
a
single
exposure
(
dose).

Chronic
Dietary
(
All
populations)
NOAEL=
15
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.15
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.15
mg/
kg/
day
2
yr
cancer
study
in
mice
LOAEL
=
50
mg/
kg/
day
based
on
increased
alkaline
phosphatase
activity
and
increased
incidence
of
heptocellular
hyperplasia
Table
6
­
Endpoints
Used
for
Fluridone
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
14
Non­
Dietary
Risk
Assessments
Short
Term
Exposures
Dermal,
Inhalation
and
Incidental
Oral
NOAEL=
15
mg/
kg/
day
MOE
=
100
FQPA
SF
=
1X
2
yr
cancer
study
in
mice
(
Same
as
above)

Intermediate­
Term
Exposures
­
Dermal,
Inhalation
and
Incidental
Oral
NOAEL=
15
mg/
kg/
day
MOE
=
100
FQPA
SF
=
1X
2
yr
cancer
study
(
Same
as
above)

Long
term
dermal,
Inhalation
and
Incidental
Oral
The
endpoint
is
not
applicable
because
use
pattern
does
not
indicate
long
term
exposure.

Dermal
Absorption
Factor
39%
­
Estimated
from
the
ratios
of
LOAELs
from
a
21
day
dermal
toxicity
study
and
a
developmental
toxicity
study
in
rabbits.

Cancer
Classification:
Not
likely
to
be
carcinogenic
to
humans
Table
7
­
Endpoints
Used
for
NMF
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Study
and
Toxicological
Effects
Acute
Oral
and
Dermal
(
Females
13­
50
years)
Dev.
NOAEL
=
10
mg/
kg/
day
UF
=
100
Developmental
Toxicity
in
Rats
and
Rabbits1
­
Developmental
effects
of
decreased
fetal
viability
and
weight;
increased
incidence
of
skeletal
malformations
with
a
LOAEL
of
75
mg/
kg/
day
for
rats
and
50
mg/
kg/
day
for
rabbits
Acute
Oral
and
Dermal
(
General
population
including
infants
and
children)
NOT
APPLICABLE.
A
dose
and
endpoint
were
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
the
developmental
toxicity
study
in
rats
and
rabbits
that
are
attributable
to
a
single
exposure
(
dose).

Short/
Intermediate
Term
Oral
and
Dermal
NOAEL=
10
mg/
kg/
day
UF
=
100
Developmental
Toxicity
in
Rats
and
Rabbits1
­
Maternal
effects
of
decreased
body
weight
and
food
consumption
with
a
LOAEL
=
75
mg/
kg/
day
for
rats
and
50
mg/
kg/
day
for
rabbits.

Chronic
Oral
and
Dermal
None
Chronic
exposures
are
not
anticipated.

1.
Fundamental
and
Applied
Toxicology
27
(
2),
239­
246,
1995.
15
4.5
Special
FQPA
Safety
Factor
The
special
FQPA
Safety
Factor
can
be
removed
(
i.
e.
lX)
because
of
the
following
reasons:

1)
acceptable
developmental
and
reproduction
studies
have
been
submitted
and
reviewed;
2)
there
is
no
evidence
of
susceptibility
following
in
utero
exposure
to
rats;
3)
there
is
low
level
of
concern
and
no
residual
uncertainties
for
the
effects
seen
in
the
developmental
toxicity
study
in
rabbits
and
in
the
2­
generation
reproduction
studies
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment.

NOTE:
The
recommended
Special
FQPA
Safety
Factor
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

A
summary
of
the
FQPA
factors
for
Fluridone
is
included
in
Table
8.

Table
8
­
Summary
of
FQPA
Safety
Factors
for
Fluridone
LOAEL
to
NOAEL
(
UF
L)
Subchronic
to
Chronic
(
UFS)
Incomplete
Database
(
UFDB)
Special
FQPA
Safety
Factor
(
Hazard
and
Exposure)

Magnitude
of
Factor
1X
1X
1X
1X
Rationale
for
the
Factor
No
LOAEL
to
NOAEL
extrapolations
performed
No
subchronic
to
Chronic
extrapolations
performed
Database
is
sufficiently
complete
to
assess
risks
to
infants
and
children.
No
residual
concerns
regarding
pre­
or
postnatal
toxicity
or
completeness
of
the
toxicity
or
exposure
databases
Endpoints
to
which
the
Factor
is
Applied
Not
Applicable
Not
Applicable
Not
Applicable
Not
Applicable
4.6
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
16
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).

In
the
available
toxicity
studies
on
fluridone,
there
were
no
estrogen,
androgen
and/
or
thyroid
mediated
toxicity.

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
Fluridone
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
6.0
Exposure
Characterization
and
Assessment
6.1
Dietary
Exposure
and
Risk
The
dietary
exposure
assessment
is
discussed
in
detail
in
the
Dietary
Exposure
Assessment
Memorandum
that
was
prepared
by
Christine
Olinger
(
D299947
of
June
10,2004).
Fluridone
acute
and
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
1.30),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
96,
98
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
"
as
consumed"
(
e.
g.,
apple
pie)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
For
chronic
exposure
assessment,
consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups,
but
for
acute
exposure
assessment
are
retained
as
individual
consumption
events.
Based
on
analysis
of
the
1994­
96,
98
CSFII
consumption
data,
which
took
into
account
dietary
patterns
and
survey
respondents,
HED
concluded
that
it
is
most
appropriate
to
report
risk
for
the
following
population
subgroups:
the
general
U.
S.
population,
all
infants
(<
1
year
old),
children
1­
2,
children
3­
5,
children
6­
12,
youth
13­
19,
adults
20­
49,
females
13­
49,
and
adults
50+
years
old.

For
chronic
dietary
exposure
assessment,
an
estimate
of
the
residue
level
in
each
food
or
foodform
(
e.
g.,
orange
or
orange
juice)
on
the
food
commodity
residue
list
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form
to
produce
a
residue
intake
estimate.
The
resulting
residue
intake
estimate
for
each
food/
food
form
is
summed
with
the
residue
intake
estimates
for
all
other
food/
food
forms
on
the
commodity
residue
list
to
arrive
at
the
total
average
estimated
exposure.
Exposure
is
expressed
in
mg/
kg
body
weight/
day
and
as
a
percent
of
the
cPAD.
This
procedure
is
performed
for
each
population
subgroup.
17
For
acute
exposure
assessments,
individual
one­
day
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
deterministic
exposure
assessment,
or
"
matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(
i.
e.,
only
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(
i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.
However,
for
tiers
1
and
2,
any
significant
differences
in
user
vs.
per
capita
exposure
and
risk
are
specifically
identified
and
noted
in
the
risk
assessment.

Acute
and
chronic
dietary
exposure
estimates
were
also
conducted
using
the
Lifeline
 
model
(
Version
2.0).
These
Lifeline
 
assessments
were
also
conducted
using
the
same
consumption
data
as
the
DEEM­
FCID
 
(
CSFII,
1994­
1996
and
1998
consumption
data
with
FCID).
Lifeline
 
uses
the
recipe
file
to
relate
RACs
to
foods
"
as­
eaten."
Lifeline
 
converts
the
RAC
residues
into
food
residues
by
randomly
selecting
a
RAC
residue
value
from
the
"
user
defined"
residue
distribution
(
created
from
the
residue,
percent
crop
treated,
and
processing
factors
data),
and
calculating
a
net
residue
for
that
food
based
on
the
ingredients'
mass
contribution
to
that
food
item.
For
example,
`
apple
pie'
will
have
a
residue
distribution
based
on
the
residues
provided
for
apples
(
adjusted
by
the
appropriate
processing
factors
and
percent
crop
treated),
as
well
as
the
residues
for
each
of
the
other
ingredients
in
the
apple
pie
recipe
for
which
there
may
be
tolerances.
Lifeline
 
calculates
dietary
exposure
from
`
apple
pie'
based
on
the
amount
eaten,
and
the
residue
drawn
from
the
`
apple
pie'
residue
distribution
for
that
eating
occasion.
Lifeline
 
models
the
individual's
dietary
exposures
over
a
season
by
selecting
a
new
CSFII
diary
each
day
from
a
set
of
similar
individuals
based
on
age
and
season
attributes.
Lifeline
 
groups
CSFII
diaries
based
on
the
respondents'
age
and
the
season
during
which
the
food
diary
was
recorded.

Dietary
risk
assessment
incorporates
both
exposure
and
toxicity
of
a
given
pesticide.
For
acute
and
chronic
assessments,
the
risk
is
expressed
as
a
percentage
of
the
aPAD
or
cPAD,
respectively.
For
acute
and
non­
cancer
chronic
exposures,
HED
is
concerned
when
estimated
dietary
risk
exceeds
100%
of
the
PAD.

Acute
Dietary
Exposure
and
Risk
An
unrefined
Tier
1
(
tolerance
level
and
100%
crop
treated(%
CT))
acute
dietary
risk
assessment
was
conducted
for
fluridone
using
all
existing
tolerances.
Dietary
risk
estimates
are
provided
only
for
females
of
child­
bearing
age,
because
no
other
acute
effects
were
observed
in
the
oral
toxicity
studies
that
are
applicable
to
the
general
population.
At
the
95th
percentile
of
exposure,
the
acute
dietary
exposure
estimates
are
below
the
HED's
level
of
concern
(<
100%
aPAD1)
for
females
aged
13­
49
years,
with
the
exposure
at
less
than
1%
of
the
aPAD.
Similar
results
were
found
using
the
Lifeline
model.

Chronic
Dietary
Exposure
and
Risk
18
A
Tier
1
assessment,
tolerance
level
residues
and
the
assumption
of
100%
crop
treated,
was
also
conducted
for
chronic
exposure
and
risk
assessment.
Chronic
dietary
exposure
and
risk
were
also
below
HED's
level
of
concern
using
the
DEEM
 
and
Lifeline
 
models,
with
approximately
1%
of
the
cPAD
occupied
for
the
U.
S.
population.
The
most
highly
exposed
sub­
population
were
children
aged
1­
2,
with
a
risk
estimate
of
3.6
%
of
the
cPAD.
These
exposures
are
all
well
below
100%
of
the
PAD
and
are
not
of
concern.
A
summary
of
the
dietary
risks
are
shown
in
Table
9.

Table
9
­
Summary
of
Dietary
Exposure
and
Risk
for
Fluridone
Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
PAD
1
DEEM­
FCID
 
Lifeline
 
DEEM­
FCID
 
Lifeline
 
Chronic
Assessment
General
U.
S.
Population
0.001599
0.001514
1.1
1.0
All
Infants
(<
1
year
old)
0.002661
0.002545
1.8
1.7
Children
1­
2
years
old
0.005345
0.005181
3.6
3.5
Children
3­
5
years
old
0.004123
0.004043
2.7
2.7
Children
6­
12
years
old
0.002529
0.002339
1.7
1.6
Youth
13­
19
years
old
0.001454
0.001341
1.0
0.9
Adults
20­
49
years
old
0.001154
0.001218
0.8
0.8
Adults
50+
years
old
0.001074
0.001191
0.7
0.8
Females
13­
49
years
old
0.001134
0.001377
0.8
0.9
Acute
Assessment
Females
13­
49
years
old
0.002352
0.003009
0.19
0.24
19
6.2
Water
Exposure
and
Risk
Fluridone
is
applied
directly
to
water
bodies
to
achieve
a
target
water
concentration
of
10
ppb
to
90
ppb
for
whole
lake
treatments
and
30
to
150
ppb
for
partial
lake
treatments.
The
target
concentration
depends
upon
the
flow
characteristics
of
the
water
body
and
the
species
of
weed
to
be
controlled.
Typically
more
than
one
application
is
made
to
maintain
the
target
concentration
for
the
required
contact
time
(
approximately
45
days),
however,
the
maximum
cumulative
concentration
cannot
exceed
150
ppb
during
the
growing
season.
This
means
that
if
the
first
application
is
made
at
90
ppb
the
second
application
can
not
exceed
60
ppb.

The
label
contains
restrictions
regarding
fluridone
use
near
potable
water
intakes.
Applications
of
greater
than
20
ppb
are
not
allowed
within
a
quarter
mile
of
intakes
while
applications
of
6
to
20
ppb
are
allowed
at
intakes.
Given
this
label
restriction
it
can
be
assumed
that
the
fluridone
EEC
for
drinking
water
drawn
from
lakes
would
be
20
ppb
or
less.

The
Estimated
Environmental
Concentrations
(
EECs)
for
NMF
were
derived
from
the
fluridone
EECs
by
assuming
a
fluridone
to
NMF
conversion
efficiency
of
74%
and
by
adjusting
for
the
ratio
of
the
fluridone
molecular
weight
of
329
to
the
NMF
molecular
weight
of
59.
The
conversion
efficiency
is
the
maximum
daily
value
that
was
observed
in
an
aquatic
photolysis
study
(
MRID
419401­
04)
that
was
conducted
under
laboratory
conditions
using
distilled
water.
Given
the
above
assumptions
a
fluridone
concentration
of
20
ug/
liter
would
yield
an
NMF
concentration
of
2.64
ug/
liter.

Ground
Water
Modeling
EFED
was
unable
to
perform
groundwater
modeling
and
recommends
the
use
of
the
maximum
surface
water
EECs
for
fluridone
(
20
ppb)
and
NMF
be
used
as
ground
water
EECs.
For
fluridone,
adsorption
Koc
values
ranged
from
260
to
740
cm3/
gm,
indicating
medium
potential
for
leaching.

Monitoring
Data
EFED
has
no
monitoring
data
for
fluridone
or
NMF
in
surface
or
ground
water.

Drinking
Water
Risk
Calculations
The
risks
of
exposure
from
drinking
water
were
calculated
using
the
EECs
from
EFED
and
the
following
assumptions:

Body
weights
(
kg)
of
70,
60,
10
and
10
were
used
for
adults,
adult
females,
children
and
infants.

Water
consumption
values
(
liters
per
day)
of
2
,
2,
1
and
1
were
used
for
adults,
adult
females,
children
and
infants.
20
Drinking
Water
MOEs
The
MOEs
for
drinking
water
exposures
are
summarized
in
Tables
10
and
11
and
the
calculations
are
included
in
Appendix
B.
The
fluridone
and
NMF
MOEs
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude.

Table
10
­
Drinking
Water
Exposure
Fluridone
MOEs
Exposed
Person
­
Body
Weight
Water
Concentration
(
ug/
l)
Water
Consumption
(
liter/
day)
Dose
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
MOE
Acute
Exposure
Adult
­
60
kg
20
2
0.00067
125
187500
Short/
Intermediate
Term
and
Chronic
Exposures
Adult
­
60
kg
20
2
0.00067
15
22500
Adult
­
70
kg
20
2
0.00057
15
26250
Infant/
Child
­
10
kg
20
1
0.00200
15
7500
Table
11
­
Drinking
Water
Exposure
NMF
MOEs
Exposed
Person
­
Body
Weight
Water
Concentration
(
ug/
l)
Water
Consumption
(
liter/
day)
Dose
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
MOE
Acute
Exposure
Adult
­
60
kg
2.64
2
0.000088
10
113636
Short/
Intermediate
Term
Exposure
Adult
­
70
kg
2.64
2
0.000075
10
132576
Infant/
Child
­
10
kg
2.64
1
0.000264
10
37879
21
6.3
Residential
Exposure/
Risk
Pathway
Recreational
Swimmer
Exposures
and
Risks
There
is
a
possibility
that
swimmer
exposure
could
occur
following
fluridone
applications
because
these
applications
are
often
made
at
recreational
lakes.
To
address
the
risks
of
these
exposures,
the
SWIMODEL
was
used
with
the
following
assumptions.
*
The
skin
surface
area
of
adults
is
assumed
to
be
21,000
cm2
as
cited
in
the
Residential
SOPs.
This
is
the
95th
percentile
value
for
females
(
EPA
Exposure
Factors
Handbook,
1997).

The
body
weight
for
children
is
assumed
to
be
22
kg
as
cited
in
the
Residential
SOPs.
This
is
a
mean
value
for
6
year
old
children.

The
skin
surface
area
for
children
is
assumed
to
be
9,000
cm2
as
cited
in
the
Residential
SOPs.
This
is
the
90th
percentile
value
for
male
and
female
children.

The
assumed
mean
ingestion
rate
is
0.05
liters
per
hour
for
both
adults
and
children
as
cited
in
the
Residential
SOP.
This
value
may
be
greater
for
young
children
playing
in
water
and
accidentally
ingesting
a
remarkable
quantity
of
water
(
U.
S.
EPA
SAP,
1999).

The
exposure
time
is
assumed
to
be
3
hours
per
day.
This
is
the
90th
percentile
value
for
time
spent
swimming
in
a
freshwater
pool.
(
EPA
Child
Specific
Exposure
Factors
Handbook,
2002).

The
body
weight
for
adult
acute
exposure
is
assumed
to
be
60
kg
because
the
endpoint
is
gender
specific.

The
body
weight
for
adult
short
and
intermediate
term
exposures
is
assumed
to
be
70
kg
because
the
endpoint
are
not
gender
specific.

The
maximum
label
application
rate
of
0.15
mg/
liter
(
150
ppb
)
was
used
to
assess
acute
and
short/
intermediate
term
fluridone
exposures.

A
concentration
of
0.020
mg/
liter
(
20
ppb)
was
used
to
assess
the
acute
and
short
term
NMF
exposures.
This
concentration
was
derived
from
the
fluridone
concentration
of
150
ppb
by
assuming
a
fluridone
to
NMF
conversion
rate
of
74%
and
adjusting
for
molecular
weight.

Calculation
Methods
The
above
factors
were
used
in
the
SWIMODEL
formulae
for
the
dermal,
ingestion,
aural,
buccal/
sublingual
and
nasal/
orbital
routes
of
exposure.

Results
The
MOEs
for
recreational
swimmers
are
summarized
in
Tables
12
and
13
and
the
calculations
are
included
in
Appendix
C.
The
fluridone
and
NMF
MOEs
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude.
22
Table
12
­
Recreational
Swimmer
Fluridone
MOEs
Exposed
Person
Exposure
Duration
Water
Concentration
(
ug/
l)
Dose
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
MOE
Adult
­
60
kg
Acute
150
0.0012
125
100,000
Adult
­
60
kg
Short/
Intermediate
Term
150
N/
A
N/
A
N/
A
Adult
­
70
kg
150
0.0010
15
15,000
Child
­
22
kg
150
0.0031
15
4,800
Table
13
­
Recreational
Swimmer
NMF
MOEs
Exposed
Person
Exposure
Duration
Water
Concentration
(
ug/
l)
Dose
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
MOE
Adult
­
60
kg
Acute
20
0.00015
10
66,000
Adult
­
60
kg
Short/
Intermediate
Term
20
N/
A
N/
A
N/
A
Adult
­
70
kg
20
0.00013
10
77,000
Child
­
22
kg
20
0.00040
10
24,000
Other
Residential
Exposures
Spray
drift
Liquid
applications
of
fluridone
are
made
via
subsurface
injection
while
aerial
applications
are
made
only
with
granular
materials.
These
methods
of
application
have
a
relatively
low
drift
potential.
In
addition,
is
unlikely
that
drift
exposures
would
exceed
the
swimmer
exposures
because
fluridone
is
applied
directly
to
water
bodies.
23
7.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
In
examining
aggregate
exposure,
FQPA
directs
EPA
to
take
into
account
available
information
concerning
exposures
from
pesticide
residues
in
food
and
other
exposures
for
which
there
is
reliable
information.
Although
fluridone
is
not
a
food
use
chemical,
fluridone
residues
may
be
present
in
fish
harvested
from
fluridone
treated
waters
or
in
crops
irrigated
with
fluridone
treated
water.
Aggregate
risks
have
been
calculated
for
Fluridone
and
the
degradate
N­
methyl
Formamide
(
NMF)
There
are
residential
(
recreational
swimmer)
exposures
to
Fluridone
and
NMF;
therefore,
the
considerations
for
aggregate
exposure
are
those
from
food,
drinking
water
and
residential
exposure.

7.1
Aggregate
Risk
Assessment
for
Fluridone
The
aggregate
risks
were
calculated
for
the
various
fluridone
exposure
durations
and
populations
by
adding
the
applicable
exposures
scenarios
and
comparing
the
aggregate
doses
to
the
appropriate
fluridone
endpoints.
Body
weights
of
70,
60,
10
and
10
kg
were
used
for
adults,
adult
females,
children
and
infants,
respectively.
The
acute
aggregate
risks
were
calculated
only
for
females
because
the
acute
NOAEL
is
based
upon
developmental
effects
and
only
applies
to
females.
Short
and
intermediate
term
aggregate
risk
were
calculated
based
on
chronic
food
exposure
plus
the
swimmer
exposure
for
adults
and
children
1
to
6
and
based
upon
the
chronic
food
exposure
only
for
infants.
Long
term
aggregate
risks
were
calculated
based
on
food
exposure
only
because
the
swimmer
exposure
does
occurs
on
long
term
basis.
All
of
the
aggregate
MOEs
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude
which
means
that
the
aggregate
risks
are
not
of
concern.
A
listing
of
the
fluridone
aggregate
MOEs
is
included
in
Table
14.

Table
14
­
Fluridone
Aggregate
MOEs
Population
Subgroup
Exposure
Duration
Food
Exposure
(
mg/
kg/
day)
Swimmer
Exposure
(
mg/
kg/
day)
Drinking
Water
Exposure
(
mg/
kg/
day)
Aggregate
ExposureA
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
Aggregate
MOEB
Females
13­
49
yrs
Acute
0.0030
0.0012
0.00067
0.0049
125
25667
U.
S.
Population
Short/
Intermediate
Term
0.0016
0.0010
0.00057
0.0032
15
4732
Children
1­
6
yr
0.0044
0.0031
0.00200
0.0095
15
1579
All
Infants
0.0027
N/
A
0.00200
0.0047
15
3191
U.
S.
Population
Long
Term
0.0016
N/
A
0.00057
0.0022
15
6912
Females
13­
50
yrs
0.0013
N/
A
0.00067
0.0020
15
7614
Children
1­
6
yr
0.0044
N/
A
0.00200
0.0064
15
2344
All
Infants
0.0027
N/
A
0.00200
0.0047
15
3191
A.
Aggregate
Exposure
=
Swimmer
Exposure
+
Drinking
Water
Exposure
+
Drinking
Water
Exposure
B.
Aggregate
MOE
=
NOAEL/
Aggregate
Exposure
24
7.2
Aggregate
Risk
Assessment
for
NMF
The
aggregate
risks
were
calculated
for
drinking
water
and
swimmer
exposure
only
because
NMF
is
not
found
in
foods.
The
acute
risks
were
calculated
only
for
females
because
the
acute
NOAEL
is
based
upon
developmental
effects
and
only
applies
to
females.
Short
term
risks
were
calculated
based
the
swimmer
exposure
for
adults
and
children
1
to
6
and
based
upon
the
drinking
water
exposure
only
for
infants.
All
of
the
aggregate
MOEs
exceed
the
target
MOE
of
100
by
one
or
more
orders
of
magnitude
which
means
that
the
aggregate
risks
are
not
of
concern.
A
listing
of
the
NMF
aggregate
MOEs
is
included
in
Table
15.

Table
15
­
NMF
Aggregate
MOEs
Population
Subgroup
Exposure
Duration
Swimmer
Exposure
(
mg/
kg/
day)
Drinking
Water
Exposure
(
mg/
kg/
day)
Aggregate
ExposureA
(
mg/
kg/
day)
NOAEL
(
mg/
kg/
day)
Aggregate
MOEB
Females
13­
50
yrs
Acute
0.00015
0.00067
0.00082
10
12245
U.
S.
Population
Short/
Intermediate
Term
0.00013
0.00057
0.00070
10
14257
Children
1­
6
yr
0.00041
0.00200
0.00241
10
4149
All
Infants
N/
A
0.00200
0.00200
10
5000
A.
Aggregate
Exposure
=
Swimmer
Exposure
+
Drinking
Water
Exposure
B.
Aggregate
MOE
=
NOAEL/
Aggregate
Exposure
7.3
Risk
Characterization
This
risk
assessment
was
based
upon
the
assumption
that
maximum
label
rates
of
90
to
150
ppb
would
be
used.
Literature
data
and
discussions
with
the
aquatic
plant
management
community
have
indicated,
however,
that
actual
use
rates
are
in
the
range
of
10
to
20
ppb
due
to
the
high
cost
of
fluridone
and
it's
proven
efficacy
at
these
lower
rates.

The
use
of
the
aural,
buccal/
sublingual
and
nasal/
orbital
components
of
the
swim
model
are
conservative
because
these
components
are
based
upon
head
immersion
which
is
less
likely
to
occur
for
significant
time
periods
during
recreational
lake
swimming.
In
addition
the
buccal/
sublingual
and
nasal/
orbital
components
of
the
swim
model
use
an
absorption
rate
of
1
percent
(
of
the
chemical
dissolved
in
the
water)
which
is
based
upon
the
rate
of
sublingual
absorption
of
nitroglycerin.
Nitroglycerin
is
rapidly
absorbed
through
the
skin
and
mucous
membranes
and
for
this
reason
it
is
administered
sublingually
for
the
rapid
relief
of
angina.
25
8.0
Cumulative
Risk
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
fluridone
and
any
other
substances
and
fluridone
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
fluridone
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
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
Data
Gaps
and
Label
Requirements
Toxicology
No
data
gaps
have
been
identified.

Residue
Chemistry
No
data
gaps
have
been
identified.
26
N
O
CH
3
F
3
C
H
N
CH
3
O
H
N
O
CH
3
F
3
C
OH
N
O
CH
3
F
3
C
OH
Appendix
A
­
Summary
of
Fluridone
Metabolites
and
Degradates
Chemical
Name
Commodity
Percent
TRR
1
Structure
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)

Fluridone
Irrigated
Crops
2
73­
90%

Ruminant
liver
1.8%

Swine
liver
0.2%

Rat
Excreta
60%
max
Bluegill
61%

Water
N­
Methyl
Formamide
Water
74%
max
2­
hydroxy­
Fluridone
Bluegill
1.7%

4­
hydroxy­
Fluridone
Bluegill
10%

Ruminant
liver
2%

Swine
liver
0.4%

Rat
3
excreta
2.4%
max
3­
CF3­
benzoic
acid
Water
29%
max
benzoic
acid
Water
14.6%
max
3­
CF3­
benzaldehyde
Water
<
0.4%

benzaldehyde
Water
<
0.5%
Appendix
A
­
Summary
of
Fluridone
Metabolites
and
Degradates
Chemical
Name
Commodity
Percent
TRR
1
Structure
Matrices
­
Major
Residue
(>
10%
TRR)
Matrices
­
Minor
Residue
(<
10%
TRR)

27
1
Results
are
reported
as
percent
of
the
total
radioactive
residue
(
TRR)
from
the
metabolism
studies.
Maximum
levels
from
laboratory
environmental
fate
studies
are
reported
as
percent
of
applied
dose.

2
Irrigated
crop
studies
were
conducted
on
grapefruit,
lettuce,
soybean,
corn,
and
alfalfa.

3
The
rat
metabolism
data
have
not
been
reviewed
by
HED.
No
other
rat
metabolites
identified
in
the
excreta
exceeded
10%
of
the
administered
dose,
with
the
exception
of
the
total
of
four
isomeric
forms
of
a
polar
metabolite
tat
ranged
from
4.34­
19.56%
of
the
applied
dose.
This
metabolite
retains
the
three
ring
structure,
but
has
lost
the
trifluromethyl
group
and
is
extensively
hydroxylated.

Note:
Metabolism
studies
were
also
conducted
on
cotton
(
as
a
direct
treatment)
and
poultry.
TRRs
were
very
low
and
no
characterization
of
residues
was
conducted.
In
addition
no
characterization
of
residues
was
done
in
the
lactating
cow,
steer,
and
swine
metabolism
studies
on
any
matrix
but
liver
as
radioactivity
levels
were
very
low
or
non­
detectable.
28
Appendix
B
­
Fluridone
Toxicity
Profile
(
Subchronic,
Chronic
and
Other)

DER
#
STUDY
TYPE
 
DOSE
LEVELS
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
EFFECTS
1
2­
year
combined
chronic/
carcinogenicity
(
1980)
 
RAT
0,
200,
650,
2000
ppm
for
2
years
(
0,7.65,
25.15,
80.8
mg/
kg/
day
in
males
and
9.17,
30.11,
97.00
mg/
kg/
day
in
females)

MRID
103305
and
103251
7.65
ADI
=

8
mg/
kg/
d
25.15

body
weights
(
92%
of
controls;
p<
0.05)


absolute
and
relative
liver
and
kidney
weights
Treatment
related
increase
in
tumor
incidence
was
not
found.

At
80.8
mg/
kg/
day
(
HDT)


mortality
(
87%
in

;
37%
in

)


chromorhinorrhea,
anorexia,
cloudy
eyes,
pale
eyes

body
weight
(
59­
66%
in

;
81­
89%
in

)

food
consumption

RBC
counts,
Hb,
hematocrit,
MCV,
MCH

lymphocyte
and
eosinophil
counts

nucleated
erythrocytes,
leukocyte
and
neutrophil
counts

total
leukocyte
count

BUN,
creatinine,
bilirubin

small
testes,
dose­
related
trends
in
number
of
enlarged,
pale
and/
or
granular
kidneys;

opaque,
cloudy,
pale,
red,
or
ulcerated
eyes;
and
skin
nodules
or
masses.


absolute
and
relative
liver
and
kidney
weights

atrophy
of
testes,
ocular
keratitis,
epidermal
inclusion
cyst
2
2­
year
carcinogenicity
 
mouse
(
1981­
1982)

0,
33,
100,
or
330
ppm
for
2
years
(
equivalent
to
0,
5,
15
or
50
mg/
kg/
day)

MRID
No.
103252
&
103335
15
50

alkaline
phosphatase
activity
(
209%
of
controls)


incidence
of
hepatocellular
hyperplasia
(
2,
2,
4,
and
6
cases
in
control,
low­,
mid­,
and
high­
doses)

Treatment
related
increase
in
tumor
incidence
was
not
found.

3
1­
year
chronic
study
in
dog
(
1981)

of
0,
75,
150,
or
400
mg/
kg/
day
MRID
No.
103336
150
400

absolute
liver
weights

alkaline
phosphatase
activity
(
in
female
dogs)

4
Developmental
toxicity
 
rats
(
1986)

CD
rats
0,
100,
300,
or
1000
mg/
kg/
day
by
oral
gavage
on
gestation
days
6
through
15
inclusive
MRID
159963
maternal
100
developmental
300
maternal
300
developmental
1000

body
weight
gain
and
food
consumption

fetal
body
weight,


rudimentary
ribs

delayed
ossification
in
sternebrae
and
pelvic
girdle
Appendix
B
­
Fluridone
Toxicity
Profile
(
Subchronic,
Chronic
and
Other)

DER
#
STUDY
TYPE
 
DOSE
LEVELS
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
EFFECTS
29
5
Developmental
toxicity
 
rabbits
(
1980)

Dutch
Belted
rabbits
(
15/
sex/
dose)
on
days
6­

18
of
gestation
at
dose
levels
of
0,
125,
300,

or
750
mg/
kg/
day
MRID
103302
maternal
125
developmental
125
maternal
300
developmental
300

body
weight
and
food
consumption

incidences
of
abortions
(
4/
14
aborted
between
days
20
and
25
of
gestation)


incidences
of
abortions
(
see
above)

At
750
mg/
kg/
day,
6/
11
aborted
between
days
20
and
25
of
gestation
6
3­
generation
reproduction
study
 
rat
(
1980)

0,
200,
650,
or
2000
ppm.
calculated
intake
of
fluridone
during
the
growth
phases
over
the
3
generations
were
10.6­
11.1,
35.5­
36.6,
or
111.9­
112.3
mg/
kg/
day
for
males
and
12.4­

13.2,
40.4­
44,
or
128­
131.4
mg/
kg/
day
for
females.

MRID
103304
parental
toxicity
>
112,
HDT
offspring
toxicity
36
Reproductive
toxicity
>
112,
HDT
Developmental
toxicity
>
112,
HDT
parental
toxicity
>
112
offspring
toxicity
112
Reproductive
toxicity
>
112
Developmenta
l
toxicity
>
112

pup
weight
(
90.7%
of
controls;
p<
0.05;
on
lactation
day
21)

7a
Metabolism
study
 
RAT
(
1981)

14C­
labeled
Fluridone
(
14C
labeled
in
the
4­

position
of
the
pyridinone
ring)

10,
100,
250,
500
or
1000
mg/
kg
MRID
103261
&
103262
Readily
absorbed
and
eliminated.

Total
recovery
of
dosed
radioactivity
=
78­
90%
(
3
days)

4­
19
%
(
urine)

68­
85
%
(
feces)

Negligible%
(
tissues
and
carcasses)

66%
(
bile)

Component
in
urine
and
feces
 
not
identified
Major
component
(
37%
of
dose)
in
bile
 
not
identified
Minor
component
in
bile:

Fluridone
(
8%
of
dose)

4­
hydroxyphenyl
fluridone
(
6%
of
dose)
Appendix
B
­
Fluridone
Toxicity
Profile
(
Subchronic,
Chronic
and
Other)

DER
#
STUDY
TYPE
 
DOSE
LEVELS
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
EFFECTS
30
7b
Metabolism
study
 
RAT
(
1997)

14C­
labeled
Fluridone
10
or
1000
mg/
kg
MRID
44265101
Eight
(
8)
metabolites
were
identified
from
feces.
Fluridone
was
extensively
metabolized
primarily
through
ring
hydroxylation
and
N­
demethylation.

8
21­
Day
Dermal
Toxicity
­
Rabbit
(
1981)

0,
192,
384
or
768
mg/
kg/
day
for
21
days
(
6
hours/
day
and
5
days/
week).

MRID
No.
103299
systemic
384
dermal
toxicity
lower
than
192
(
LDT)
systemic
768
dermal
toxicity
lower
than
192
(
LDT)
decreased
relative
kidney
weights
(
85%
of
controls,
p<
0.05)

transient,
slight
erythema
in
9/
10
animals
accompanied
by
slight
desquamation
at
192
mg/
kg
(
LDT)

9
90­
day
oral
toxicity­
mice
(
1978)

0,
62,
110,
200,
330,
or
560
ppm
(
equivalent
to
0,
9.3,
16.5,
30,
49.5
or
84
mg/
kg/
day
based
on
1
ppm
=
0.15
mg/
kg/
day)

MRID
82342
NOTE:
50%
of
the
theoretical
concentration
was
present
in
the
feed
sample
after
3
months
storage.
Therefore,
corrected
doses
administered
are
4.6,
8.3,
15,
25,
and
42
mg/
kg/
day.
15
 
see
note
under
study
type
25
 
see
note
under
study
type

centrilobular
hypertrophy
of
the
liver
(
incidences
of
centrilobular
hypertrophy
of
the
liver
were
0/
30,
1/
28,
2/
29,
3/
29,
and
6/
30
cases
in
control,
low­,
mid­,
high­
and
highest­
doses)

NOTE:
The
dose
related
findings
of
this
lesion
was
also
observed
in
other
90­
day
mouse
study
with
fluridone
(
MRID
No.
82341
10
90­
day
oral
toxicity­
rat
(
1978)

0,
330,
560,
1000,
1400,
or
2000
ppm
(
males:

0,
30,
54,
106,
139,
or
178.4;
females:
0,
34,

53,
94,
126,
or
202
mg/
kg/
day
based
on
initial
food
consumption)

MRID
135209
NOTE:
81.9%
of
the
theoretical
concentration
was
present
in
the
feed
sample
after
1
week
storage.
Therefore,
corrected
doses
administered
are
25,
44,
87,
114,
or
146
m/
k/
d
for
males.
25
 
see
note
under
study
type
44
 
see
note
under
study
type

absolute
and
relative
liver
(
112­
113%
of
controls)
and
relative
kidney
weights
(
106%
of
controls)
(
males
only)

In
males
at
2
highest
doses
(
114
and
146
m/
k/
d)


centrilobular
hypertrophy
of
the
liver
(
1/
15
of
114
m/
k/
d
group)

(
12/
15
of
146
m/
k/
d
group)

11
90­
day
oral
toxicity­
dog
(
1978)

0,
50,
100,
or
200
mg/
kg/
day
(
oral
capsules)

MRID:
82344
>
250
(
HDT)
not
established
Appendix
B
­
Fluridone
Toxicity
Profile
(
Subchronic,
Chronic
and
Other)

DER
#
STUDY
TYPE
 
DOSE
LEVELS
NOAEL
mg/
kg/
day
LOAEL
mg/
kg/
day
EFFECTS
31
12
dermal
absorption
rat
not
available
13
Microbial
mutagenicity
assay
(
Ames
assay)

MRID
255339
not
mutagenic
14
In
Vivo
Mammalian
Cytogenetics
­
Sister
Chromatid
Exchange
assay
in
Chinese
hamsters
MRID
070942
Not
mutagenic
15
Unscheduled
DNA
damage/
repair
MRID
070942
Not
mutagenic
16
Unscheduled
DNA
damage/
repair
MRID
070942
Not
mutagenic
32
Appendix
C
­
Recreational
Swimmer
Risks
in
Aquatic
Areas
Treated
With
Fluridone
Spreadsheet
C1:
Fluridone
Exposures
Dermal
Exposure
Exposed
Person
Fluridone
Water
Concentration
(
mg/
l)
Exposed
Surface
Area
(
cm2)
Exposure
Time
(
Hours/
day)
Kp
(
cm/
hr)
Conversion
factor
(
L/
1000
cm3)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.15
21000
3
0.00040
0.001
6.3E­
005
1984127
N/
A
Adult
­
70
kg
0.15
21000
3
0.00040
0.001
5.4E­
005
N/
A
277778
Child
­
22
kg
0.15
9000
3
0.00040
0.001
7.4E­
005
N/
A
203704
Ingestion
Exposure
Exposed
Person
Fluridone
Water
Concentration
(
mg/
l)
Ingestion
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.15
0.05
3
3.8E­
004
333333
N/
A
Adult
­
70
kg
0.15
0.05
3
3.2E­
004
N/
A
46667
Child
­
22
kg
0.15
0.05
3
1.0E­
003
N/
A
14667
Aural
Exposure
Exposed
Person
Fluridone
Water
Concentration
(
mg/
l)
Exposed
Surface
Area
(
cm2)
Exposure
Time
(
Hours/
day)
Kp
(
cm/
hr)
Kow
Conversion
factor
(
L/
1000
cm3)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.15
4
3
0.00040
74.1
0.001
8.9E­
007
1.4E+
008
N/
A
Adult
­
70
kg
0.15
4
3
0.00040
74.1
0.001
7.6E­
007
N/
A
2.0E+
007
Child
­
22
kg
0.15
4
3
0.00040
74.1
0.001
2.4E­
006
N/
A
6.2E+
006
Buccal/
Sublingual
Exposure
Exposed
Person
Fluridone
Water
Concentration
(
mg/
l)
Water
Intake
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorption
Rate
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.15
5
3
0.01
3.8E­
004
333333
N/
A
Adult
­
70
kg
0.15
5
3
0.01
3.2E­
004
N/
A
46667
Child
­
22
kg
0.15
5
3
0.01
1.0E­
003
N/
A
14667
Nasal/
Orbital
Exposure
Exposed
Person
Fluridone
Water
Concentration
(
mg/
l)
Water
Intake
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorption
Rate
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.15
5
3
0.01
3.8E­
004
333333
N/
A
Adult
­
70
kg
0.15
5
3
0.01
3.2E­
004
N/
A
46667
Child
­
22
kg
0.15
5
3
0.01
1.0E­
003
N/
A
14667
Combined
Exposure
Exposed
Person
Acute
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
Dose
(
mg/
kg/
BW)
ST
MOE
Adult
­
60
kg
0.0012
105140
N/
A
N/
A
Adult
­
70
kg
N/
A
0.0010
14720
Child
­
22
kg
N/
A
0.0031
4771
Notes
KOW
value
of
74.1
is
from
ARS
Database
KP
value
is
calculated
from
MW
and
KOW
using
swim
model
formula.

NOAEL
=
125
mg/
kg/
day
for
acute
exposures
(
females
13
to
50
only)
NOAEL
=
15
mg/
kg/
day
for
short/
intermediate
term
exposures
(
All
other
adults
and
children)
33
Appendix
C
­
Recreational
Swimmers
Risks
in
Aquatic
Areas
Treated
With
Fluridone
Spreadsheet
C2:
NMF
Exposures
Dermal
Exposure
Exposed
Person
NMF
Water
Concentration
(
mg/
l)
Exposed
Surface
Area
(
cm2)
Exposure
Time
(
Hours/
day)
Kp
(
cm/
hr)
Conversion
factor
(
L/
1000
cm3)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.0198
21000
3
0.00017
0.001
3.6E­
006
2764371
N/
A
Adult
­
70
kg
0.0198
21000
3
0.00017
0.001
3.1E­
006
3225099
3225099
Child
­
22
kg
0.0198
9000
3
0.00017
0.001
4.2E­
006
2365073
2365073
Ingestion
Exposure
Exposed
Person
NMF
Water
Concentation
(
mg/
l)
Ingestion
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.0198
0.05
3
5.0E­
005
202020
N/
A
Adult
­
70
kg
0.0198
0.05
3
4.2E­
005
N/
A
235690
Child
­
22
kg
0.0198
0.05
3
1.4E­
004
N/
A
74074
Aural
Exposure
Exposed
Person
NMF
Water
Concentation
(
mg/
l)
Exposed
Surface
Area
(
cm2)
Exposure
Time
(
Hours/
day)
Kp
(
cm/
hr)
Kow
Conversion
factor
(
L/
1000
cm3)
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.0198
4
3
0.00017
0.11
0.001
7.6E­
011
1.3E+
011
N/
A
Adult
­
70
kg
0.0198
4
3
0.00017
0.11
0.001
6.5E­
011
N/
A
1.5E+
011
Child
­
22
kg
0.0198
4
3
0.00017
0.11
0.001
2.1E­
010
N/
A
4.8E+
010
Buccal/
Sublingual
Exposure
Exposed
Person
NMF
Water
Concentation
(
mg/
l)
Water
Intake
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorption
Rate
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.0198
5
3
0.01
5.0E­
005
202020
N/
A
Adult
­
70
kg
0.0198
5
3
0.01
4.2E­
005
N/
A
235690
Child
­
22
kg
0.0198
5
3
0.01
1.4E­
004
N/
A
74074
Nasal/
Orbital
Exposure
Exposed
Person
NMF
Water
Concentation
(
mg/
l)
Water
Intake
Rate(
L/
hr)
Exposure
Time
(
Hours/
day)
Absorption
Rate
Absorbed
Dose
(
mg/
kg/
BW)
Acute
MOE
ST
MOE
Adult
­
60
kg
0.0198
5
3
0.01
5.0E­
005
202020
N/
A
Adult
­
70
kg
0.0198
5
3
0.01
4.2E­
005
N/
A
235690
Child
­
22
kg
0.0198
5
3
0.01
1.4E­
004
N/
A
74074
Combined
Exposure
Exposed
Person
Acute
Dose
(
mg/
kg/
BW)
Acute
Combined
MOE
ST
Dose
(
mg/
kg/
BW)
ST
Combined
MOE
Adult
­
60
kg
0.00015
65739
0.00015
N/
A
Adult
­
70
kg
N/
A
N/
A
0.00013
76695
Child
­
22
kg
N/
A
N/
A
0.00041
24436
Notes
KOW
value
is
from
TOXNET
HSDB
(
antilog
of
­
0.97).
KP
value
is
calculated
from
MW
and
KOW
using
swim
model
formula.
NOAEL
=
10
mg/
kg/
day
for
acute
exposures
(
females
13
to
50
only)
and
short
term
exposures
(
all
other
adults
and
children)