UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,

PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
April
16,
2002
SUBJECT:
HED
Chapter
for
the
Linuron
Tolerance
Reassessment
Eligibility
Decision
PC
Code:
035506.
Case
0047.
DP
Barcode
D271950
FROM:
Carol
Christensen,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(7509C)

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

TO:
Dirk
Helder
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(7508C)

The
following
human
health
risk
assessment
has
been
prepared
by
the
Health
Effects
Division
(HED)
for
Phase
II­
Registrant
Error
Correction
­
of
the
tolerance
reassessment
process
for
linuron.
The
HED
chapter
reflects
the
Agency's
current
guidelines
concerning
the
retention
of
the
Food
Quality
Protection
Act
(FQPA)
safety
factor
and
risk
assessment.
The
chapter
is
based
upon
the
product
chemistry
review
by
Ken
Dockter,
the
toxicology
review
by
Robert
Fricke,
the
residue
chemistry
and
dietary
exposure
and
risk
analysis
by
John
Punzi,
the
drinking
water
exposure
assessment
by
Ibrahim
Abdel­
Saheb
of
the
Environmental
Fate
and
Effects
Division
(EFED),
and
the
incident
review
by
Jerry
Blondell.
HED
has
acknowledged
the
Registrant's
error­
only
comments
in
this
version
of
the
risk
assessment
as
well
as
in
a
separate
Response
to
Comment
document.
This
document
includes
corrections
from
John
Punzi
on
residue
chemistry
and
dietary
risk
assessment
and
Robert
Fricke
2
concerning
toxicology
comments,
as
well
as
risk
assessment
and
characterization
corrections
by
Carol
Christensen.

Table
of
Contents
1.0
Executive
Summary
..........................................................
3
2.0
Physical
and
Chemical
Properties
................................................
6
3.0
Hazard
Characterization
.......................................................
7
3.1
Hazard
Profile
........................................................
7
3.2
FQPA
Considerations
.................................................
19
3.3
Dose­
Response
Assessment
.............................................
20
3.3.1
Acute
Reference
Dose
(RfD)
­
Females
13­
50
.....................
23
3.3.2
Chronic
Reference
Dose
(RfD)
...................................
24
3.4
Endocrine
Disruption
..................................................
24
3.5
Potential
Tetrachloroazobenzene
Contamination
..............................
25
4.0
Exposure
Assessment
and
Characterization
.................................
26
4.1
Summary
of
Registered
Use
Patterns
......................................
26
4.2
Dietary
(Food)
Exposure/
Risk
Pathway
....................................
27
4.2.1
Residue
Profile
...............................................
27
4.2.2
Acute
Dietary
­
Females
13­
50
...................................
30
4.2.3
Chronic
Dietary
...............................................
32
4.3
Water
Exposure/
Risk
Pathway
...........................................
33
4.3.1
Environmental
Fate
............................................
34
4.3.2
Drinking
Water
Exposure
Estimates
...........................
34
4.4
Residential
Exposure/
Risk
Pathway
.......................................
37
5.0
Aggregate
Risk
Assessment
and
Risk
Characterization
...............................
38
5.1
Acute
Risk
..........................................................
39
5.1.1
Acute
Aggregate
Risk
Assessment
(Females
13­
50)
...................
39
5.1.2
Acute
DWLOC
Calculations
.....................................
40
5.2
Chronic
Risk
........................................................
40
5.2.1
Chronic
Aggregate
Risk
Assessment
...............................
40
5.2.2
Chronic
DWLOC
Calculations
...................................
41
6.0
Cumulative
Risk
............................................................
41
7.0
Incident
Data
..............................................................
42
3
8.0
Data
Needs
..............................................................
43
References:
..................................................................
45
4
1.0
Executive
Summary
Linuron
[3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea]
is
a
substituted
urea,
selective
herbicide.
Linuron
is
a
systemic,
photosynthesis
inhibitor
(Hill
reaction)
and
controls
a
variety
of
weed
species
including
annual
morning
glory,
rye
grass,
and
barnyard
grass.
Linuron
may
be
applied
preplant
pre­
emergence,
post­
emergence
or
post­
transplant
and
is
registered
for
use
on
asparagus,
carrots,
celery,
field
and
sweet
corn,
cotton,
parsley,
potatoes,
sorghum,
soybeans,
and
wheat.
Linuron
is
formulated
as
an
emulsifiable
concentrate,
flowable
concentrate,
water
dispersible
granules,
and
a
wettable
powder.
The
range
of
percentage
of
active
ingredient
in
the
end
use
product
formulations
is
40­
50%.
The
application
rates
range
from
0.5­
4.0
lbs
ai/
acre/
year
and
1
or
2
applications
are
allowed
per
year.
Linuron
is
mainly
used
in
the
early
season
and
consequently
has
fairly
long
pre­
harvest
intervals
(PHIs),
but
a
few
crops
have
short
PHIs,
notably
asparagus
(1
day)
and
carrot
(14
days).
Linuron
can
be
applied
using
ground
or
aerial
equipment
including
band
sprayer,
boom
sprayer,
sprayer,
sprinkler
irrigation,
and
tractor
mounted
sprayer.
There
are
1.2
million
pounds
of
linuron
active
ingredient
used
in
the
U.
S.
annually.

Linuron
has
low
acute
toxicity
(Toxicity
Category
III­
IV)
by
the
oral,
dermal
and
inhalation
exposure
routes.
Primary
eye
and
skin
irritation
studies
with
linuron
were
category
III
and
IV,
respectively.
Linuron
does
not
produce
dermal
sensitization.
In
chronic
studies,
linuron
affects
the
hematopoetic
system,
the
male
reproductive
system
and
the
renal
pelvis.
Blood
effects
were
seen
in
all
species
tested.
Chronic
toxicity
studies
in
the
dog,
mouse
and
rat
showed
altered
hematological
findings.
Beagles
fed
linuron
displayed
hemolytic
anemia
and
secondary
erythropogenic
activity
evidenced
by
slightly
reduced
hemoglobin,
hematocrit,
and
erythrocyte
counts
accompanied
by
hemosiderin
deposition
in
liver
Kupffer
cells
and
erythroid
hyperplasia
of
bone
marrow.
Systemic
toxicity
observed
in
mice
included
increased
methemoglobin
formation
and
vacuolation
and
hemosiderosis
of
the
spleen.
In
a
chronic
study
in
rats,
microscopic
observations
consistent
with
hemolysis
(hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes)
were
seen.
Other
findings
observed
in
the
chronic
rat
study
include,
a
significant
decrease
in
body
weight
gain
which
persisted
throughout
the
entire
study,
with
females
showing
consistently
lower
body
weight
gain
than
males.
The
decreases
in
body
weight
gain
correlated
to
some
degree
with
decreased
food
consumption.
Rats
also
showed
an
increased
incidence
of
microscopic
changes
in
the
epididymides
(perivasculitis/
vasculitis)
and
renal
pelvis
(transitional
cell
hyperplasia
and
mineralization/
calculi)
of
males
and
kidneys
(calculi
in
renal
tubules)
of
females.

Developmental
studies
in
the
rat
and
rabbit
showed
no
quantitative
or
qualitative
susceptibility
in
the
offspring.
Effects
seen
include
decreased
body
weight
gain
and
food
consumption,
as
well
as
increased
postimplantation
loss,
fetal
resorptions,
fewer
fetuses
per
litter,
and
decreased
fetal
body
weight
in
rats,
and
an
increased
incidence
of
fetuses
with
skeletal
skull
variations
in
rabbits.
These
findings
do
not
indicate
increased
susceptibility
because
increases
in
resorptions
were
marginal
and
there
was
no
change
in
the
number
of
live
fetuses
to
corroborate
the
increases
in
post­
implantation
losses.
However,
in
a
2­
generation
reproductive
toxicity
study
using
rats,
linuron
caused
gross
lesions
of
the
5
testes
(including
reduction
in
size),
abnormally
large,
soft,
and
small
epididymides,
and
unspecified
deformities
of
the
epididymides
in
F1
animals.
These
were
all
noted
as
significant
incidences.
A
3­
generation
study
using
rats
showed
reduced
body
weights
and
fertility,
decreased
pup
survival,
and
decreased
weanling
body,
liver
and
kidney
weights,
as
well
as
liver
atrophy.
The
Hazard
Identification
Assessment
Review
Committee
(HIARC)
determined
that
these
results
illustrate
qualitative
susceptibility
in
the
rat
offspring.

There
is
ample
evidence
from
special
studies
submitted
to
the
Agency
by
the
registrant
as
well
as
open
literature
studies
which
indicate
that
linuron
is
an
endocrine
disruptor.
These
findings
include,
in
part:
(1)
competitive
androgen
receptor
antagonist;
but
not
an
estrogen
receptor
antagonist;
(2)
competitive
inhibition
of
the
transcriptional
activity
of
dihydrotestosterone
(DHT)­
human
androgen
receptor
(hAR)
in
vitro,
decreased
anogenital
distance
and/
or
an
increase
in
the
retention
of
areolae/
nipples
in
male
offspring
following
in
utero
exposure
to
linuron;
(3)
inhibition
of
steroidogenic
enzymes,
and
(4)
decreased
responsiveness
of
Leydig
cells
to
luteinizing
hormone
in
both
immature
(22
days)
and
mature
(11
months)
male
rats
treated
with
linuron,
mature
rats
were
less
responsive
that
immature
animals;
and,
(5)
F0
and
F1
males
had
significantly
increased
levels
of
estradiol
and
luteinizing
hormone.

Linuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells.
There
was
also
no
indication
of
a
clastogenic
effect
up
to
toxic
doses
in
vivo.
Tumors
were
observed
in
oncogenicity
studies
in
the
rat
and
mouse,
however,
no
sex
and
species
differences
were
noted
nor
did
they
show
consistent
tumor
profiles
between
sexes
and
species.
The
weight
of
evidence
suggested
that
the
carcinogenic
potential
of
linuron
in
humans
is
weak,
the
HIARC
decided
that
linuron
should
not
be
regulated
as
a
carcinogen.

The
major
metabolites
identified
in
the
rat
metabolism
study
are
hydroxy­
norlinuron,
desmethoxy
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methylurea
or
DCPMU)
and
norlinuron
(3,4­
dichlorophenylurea
or
DCPU).
The
metabolites
DCPU
and
DCPMU
were
identified
in
the
rat
metabolism
study,
the
plant
and
animal
metabolism
studies,
and
as
water
degradates
in
the
aerobic
soil
metabolism
study.
These
metabolites,
in
addition
to
desmethyl­
linuron,
are
among
the
metabolites
of
toxicological
concern
referenced
in
the
tolerance
expression
and
considered
in
this
risk
assessment.

Linuron
has
low
acute
toxicity
but
exhibits
developmental
and
neurotoxic
concerns
based
on
the
neuroendocrine
effects
seen
in
the
toxicological
database.
Toxicological
endpoints
were
established
for
all
exposure
scenarios,
populations
and
durations,
except
acute
dietary
exposure
to
the
general
population.
No
adverse
effects
attributed
to
a
single
exposure
were
identified
for
the
general
population.
For
the
purposes
of
this
tolerance
reassessment
eligibility
decision
(TRED)
for
linuron,
only
the
acute
and
chronic
dietary
exposure
scenarios
will
be
assessed.
There
are
no
registered
uses
for
linuron
in
the
residential
environment.
Occupational
exposure
and
risks
were
assessed
in
the
previous
re­
registration
eligibility
decision
(RED)
and
will
not
be
reassessed
here.
6
An
acute
dietary
endpoint
was
identified
for
females
13­
50
years
of
age.
This
endpoint
was
derived
from
a
developmental
toxicity
study
in
the
rat
and
is
based
on
increases
in
post­
implantation
loss
and
litter/
fetal
resorptions
[No
Observed
Adverse
Effect
Level
(NOAEL)
=
12.1
mg/
kg/
day].
The
chronic
dietary
endpoint
was
derived
from
an
oral
toxicity
study
in
the
dog
and
is
based
on
abnormal
hematology
findings
(increased
met­
and
sulfhemoglobin
levels
[NOAEL
=
0.77
mg/
kg/
day].
A
total
uncertainty
factor
(UF)
of
100
was
applied
(UF
of
100
to
account
for
both
interspecies
and
intraspecies
extrapolation).

The
FQPA
Safety
Factor
Committee
(SFC)
concluded
that
the
factor
should
be
retained
at
10x
because
there
is
a
qualitative
increase
in
susceptibility
seen
in
the
F1
males
in
the
rat
reproductive
toxicity
studies
(a
long­
term
study).
And,
a
developmental
neurotoxicity
study
in
rats
is
required
for
the
chemical
because
linuron
is
an
endocrine
disruptor
and
there
is
evidence
for
testicular
lesions
and
decreased
fertility
in
the
rat
reproductive
toxicity
study.
The
Committee
concluded
that
the
safety
factor
could
be
reduced
to
3x
for
acute
dietary
exposure
to
females
13­
50,
only,
because
there
was
no
indication
of
susceptibility
identified
following
in
utero
exposure,
the
toxicology
database
is
complete
for
FQPA
assessment;
the
dietary
(food
and
water)
exposure
assessments
will
not
underestimate
the
potential
exposures
for
infants,
children,
and/
or
women
of
childbearing
age;
and,
there
are
no
residential
uses.
Therefore,
when
assessing
chronic
dietary
exposure
and
risk,
the
FQPA
safety
factor
will
be
retained
(10x)
and
when
assessing
acute
dietary
exposure
and
risk
to
females
13­
50
the
FQPA
safety
factor
will
be
reduced
(3x).

Estimated
acute
dietary
(food)
risks
for
females
13­
50
years
of
age
associated
with
the
use
of
linuron
does
not
exceed
the
Agency's
level
of
concern.
The
acute
dietary
risk
for
females
13­
50
is
approximately
10%
of
the
acute
Population
Adjusted
Dose
(PAD)
at
the
99.9th
percentile
of
exposure.
The
acute
exposure
analysis
was
a
highly
refined
probabilistic
analysis
which
utilized
field
trial
data
for
parent
linuron
and
its
metabolites
that
are
hydrolyzable
to
3,4­
dichloroaniline
(3,4­
DCA),
percent
of
crop
treated
data,
processing
data
and
residue
reduction
studies.
The
chronic
dietary
risk
estimate
did
not
exceed
the
Agency's
level
of
concern
for
any
population
subgroups
examined
including
the
most
highly
exposed
sub­
group,
children
ages
1­
6
years.
The
chronic
dietary
risk
for
children
1­
6
years
of
age
is
approximately
35%
of
the
chronic
PAD
and
approximately
15%
for
the
general
U.
S.
population.
The
chronic
exposure
analysis
is
also
highly
refined
and
utilized
field
trial
data
(including
the
parent
linuron
and
metabolites
hydrolyzable
to
3,4­
DCA),
percent
of
crop
treated
data,
and
residue
reduction
data.

Aggregate
acute
and
chronic
risk
estimates
include
the
contribution
of
risk
from
dietary
(food+
water).
There
are
no
uses
of
linuron
registered
for
the
residential
environment.
Acute
aggregate
risk
do
not
exceed
the
Agency's
level
of
concern.
However,
the
Agency
cannot
conclude
with
reasonable
certainty
that
residues
of
linuron,
plus
its
metabolites
hydrolyzable
to
3,4­
DCA
in
food
and
drinking
water
would
likely
result
in
an
aggregate
chronic
risk
to
infants
and
children
below
the
Agency's
level
of
concern.
The
Agency
based
this
determination
on
a
comparison
of
estimated
concentrations
of
linuron
and
its
metabolites
in
surface
water
and
groundwater
to
"drinking
water
levels
of
comparison"
7
N
H
Cl
Cl
O
N
O
CH
3
CH
3
(DWLOCs)
for
linuron
and
its
metabolites.
However,
since
the
drinking
water
exposure
estimates
are
based
on
upper­
end
input
parameters
such
as
the
maximum
application
rate,
the
assessment
indicates
a
need
to
refine
the
drinking
water
exposure
estimates
by
attaining
additional
information
about
the
persistence
and
mobility
of
linuron
water
degradates.

The
database
for
linuron
is
considered
adequate
for
risk
assessment,
however,
data
deficiencies
have
been
identified.
Studies
required
by
the
Agency
include
a
developmental
neurotoxcity
study,
a
28­
day
inhalation
study
in
the
rat,
in
addition
to
environmental
fate
data,
including
a
leaching/
adsorption/
desorption
study
and
a
terrestrial
field
dissipation
study.
There
are
also
a
number
of
outstanding
residue
chemistry
data
requirements
listed
in
Section
8.0.

2.0
Physical
and
Chemical
Properties
Linuron
[3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea]
is
a
selective
herbicide
used
for
preemergent
and
post­
emergent
control
of
many
annual
grasses
and
broadleaf
weeds
on
asparagus,
carrot,
celery,
field
corn,
sweet
corn,
cotton,
parsley,
parsnip,
potato,
sorghum,
soybean,
and
winter
wheat.
Linuron
end­
use
products
are
formulated
as
flowable
concentrate,
emulsifiable
concentrate,
wettable
powder,
and
granular
types
and
are
currently
registered
by
Griffin
Corporation,
Drexel
Chemical
Company,
and
Micro­
Flo
Company.

Identity:
3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea
Class:
Substituted
Urea
Empirical
Formula:
C9
H10
Cl2
N2
O2
Molecular
Weight:
249.1
CAS
Registry
No.:
330­
55­
2
PC
Code:
035506
Color:
off­
white
to
light
tan
Physical
state:
solid
Odor:
odorless
MP:
93­
94
C
Bulk
density:
1.45
g/
cc
Water
solubility:
75
ppm
@
25
C
vp:
1.5
x
10
­5
mm
Hg
@
24
C
log
Pow
:
2.76
Stability:
Stable
up
to
MP;
stable
at
concentrations
of
5
&
5000
ppm
in
aqueous
buffers
[pH
5,7
&9]
for
30
days
@
20
C.

Linuron
exhibits
relatively
low
water
solubility
and
low
lipophilic
potential
and,
thus
is
not
likely
to
bioaccumulate.
The
vapor
pressure
for
linuron
is
high;
there
is
a
likelihood
of
exposure
via
the
inhalation
route.
Based
on
the
physical
and
chemical
properties
of
linuron,
there
is
the
potential
for
exposure
to
the
chemical
via
all
routes,
oral,
dermal
and
inhalation.
However,
this
tolerance
8
reassessment
eligibility
decision
document
will
assess
the
exposure
and
risks
via
the
oral
route
(food
and
water
pathways),
only.
There
are
no
registered
uses
for
linuron
in
the
residential
environment.
Occupational
exposures
and
risk
will
not
be
considered
at
this
time
as
they
were
assessed
at
the
time
of
the
reregistration
eligibility
decision
(RED).

There
are
traces
of
manufacturing
impurities
which
may
be
of
toxicological
concern
reported
in
one
of
the
linuron
technical
product
confidential
statement
of
formula.
These
manufacturing
impurities
are
present
in
the
production
of
linuron
and
other
dichloroaniline
derivative
pesticides,
including
diuron
and
propanil.
However,
these
impurities
have
been
present
in
all
toxicological
test
materials,
and
the
Agency,
therefore,
does
not
believe
that
linuron
risk
has
been
underestimated
at
this
time.

3.0
Hazard
Characterization
3.1
Hazard
Profile
The
acute
toxicity
of
linuron
is
presented
in
Table
1.
All
studies
were
performed
using
linuron
as
the
test
substance.

Table
1:
Acute
Toxicity
of
Linuron
Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(Rat)
00027625
LD
50
=
2600
mg/
kg
III
870.1200
Acute
Dermal
(Rabbit)
00027625
LD
50
>
2000
mg/
kg
III
870.1300
Acute
Inhalation
(Rat)
00053769
LC
50
>
218
mg/
L
IV
870.2400
Primary
Eye
Irritation
42849001
Slight
conjunctival
redness
at
24
hrs;
clear
at
72
hrs
III
870.2500
Primary
Skin
Irritation
42849002
Not
an
irritant
IV
870.2600
Dermal
Sensitization
00146868
Not
a
sensitizer
N/
A
The
toxicity
profile
for
linuron
is
shown
in
Table
2.
9
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicityrat
Requirement
fulfilled
by
Chronic
rat
study870.4100a
N/
A
870.3150
90­
Day
oral
toxicitydog
Requirement
fulfilled
by
Chronic
dog
study870.4100b
N/
A
870.3200
21/
28­
Day
dermal
toxicity­
rabbit
No
study
available
N/
A
870.3250
90­
Day
dermal
toxicity
No
study
available
N/
A
870.3465
90­
Day
inhalation
toxicity
No
study
available
N/
A
870.4100
[83­
1(
b)]
1­
Year
Feeding
Study
­
Dog
40952601
(1988)

Acceptable/
Guideline
0,
10,
25,
125,
625
ppm
%%:
0,
0.29,
0.79,
4.17,
18.6
mg/
kg/
day
&&:
0,
0.30,
0.77,
3.49,
16.1
mg/
kg/
day
NOAEL=
0.77
mg/
kg/
day
LOAEL
=
3.49
mg/
kg/
day,
based
on
hematological
effects
in
males
and
females
(increased
methemoglobin
and
sulfhemoglobin
levels)
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
10
870.4100
[83­
1(
b)]
2­
Year
Feeding
Study
­
Dog
00018374
(1963)

Unacceptable/
Guideline
0,
25,
125,
625
ppm
0,
0.6,
3.1,
16
mg/
kg/
day
(based
on
standard
conversion
factor
of
0.025
.mg/
kg/
day
per
ppm)
NOAEL=
3.1
mg/
kg/
day
LOAEL
=
16
mg/
kg/
day,
based
on
mild
hemolytic
anemia,
slightly
deceased
hemoglobin,
hematocrit,
and
RBC
counts
870.4200
[83­
2
(b)]

Oncogenicity
Study
Mouse
0124195
(1981)

Acceptable/
Guideline
0,
50,
150,
and
1500
ppm
0,
8,
23,
and
261
mg/
kg/
day
in
males
and
0,
12,
35,
and
455
mg/
kg/
day
in
females
NOAEL=
23
mg/
kg/
day
LOAEL
=
261
mg/
kg/
day,
based
on
microscopic
liver
changes,
methemoglobinemia,
and
deceased
body
weight
gain
throughout
the
study
Histopathology:
hepatocytomegaly,
hepatocellular
cytoplasmic
alterations,
vacuolation,
and
necrosis
in
liver,
slightly
increased
incidence
of
hemosiderosis
in
spleens
of
both
sexes;
Significant
increase
in
hepatocellular
adenomas
in
females
870.4300
[83­
5(
a)]

Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
0029680,
00029679
(1980)
00167411
(1986)

Acceptable/
Guideline
0,
50,
125,
625
ppm
0,2.09,
5.11,
27.1
mg/
kg/
day
in
males
and
0,
3.13,
7.75,
48.3
mg/
kg/
day
in
females
NOAEL=
2.09
mg/
kg/
day
LOAEL
=
5.11
mg/
kg/
day,
based
on
hematological
effects,
decreased
body
weight
gains
in
both
sexes,
microscopic
observations
consistent
with
hemolysis
(hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes)
Histopathology:
Significant
(p
=
0.004)
increase
(27%,
5.7%
control)
in
benign
interstitial
cell
adenomas
in
testes
incidences.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
11
870.3700
[83­
3(
a)]

Developmental
Toxicity
Study
­
Rat
00018167
(1979)

Acceptable/
Guideline
0,
50,
125,
625
ppm
&&:
0,
5.0,
12,
50
mg/
kg/
day
Maternal
Systemic
NOAEL:
12
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
decreased
maternal
body
weight
(9%)
and
food
consumption
(7­
8%).
Developmental
NOAEL:
12
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
litters
with
early
resorptions.

870.3700
[83­
3(
b)]

Developmental
Toxicity
­
Rabbit
00153867
(1985),
40437201(
1985)

Acceptable/
Guideline
0,
5,
25,
100
mg/
kg/
day
Maternal
Systemic
NOAEL=
5
mg/
kg/
day
LOAEL
=
25
mg/
kg/
day,
based
on
decreased
maternal
body
weight
gain.
Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
alterations
of
the
bones
and
skull
(irregularly
shaped
fontanelle,
hole
in
parietals,
parietals
contain
intraparietals,
and
unossified).

870.3800
[83­
4]

3­
Generation
Reproduction
­
Rat
00146071
(1984)
00155168
(1985)

Unacceptable/
Guideline
0,
25,
125,
625
ppm
%%:
0,
2,
10­
11,
48­
50
mg/
kg/
day
&&:
0,
2,
9,
44­
50
mg/
kg/
day
Systemic
NOAEL=
2
mg/
kg/
day
LOAEL
=
9
mg/
kg/
day,
based
on
decreased
body
weight
gains
in
males
and
females
and
anemia
in
females.
Reproductive
NOAEL
=
10
mg/
kg/
day
LOAEL
=
44
mg/
kg/
day
based
on
reduced
fertility,
decreased
pup
survival,
and
lower
pup
body
weights.
Offspring
NOAEL
=
9
mg/
kg/
day
LOAEL
=
44
mg/
kg/
day,
based
on
decreased
pup
survival,
and
lower
pup
body
weights.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
12
870.3800
[83­
4]
2­
Generation
Reproduction
­
Rat
41463401
(1990)
41864701
(1991)

Acceptable/
Guideline
0,
12.5,
100,
625
ppm
%%:
0,
0.74,
5.8,
36
mg/
kg/
day
&&:
0,
0.92,
7.3,
45
mg/
kg/
day,
Systemic
NOAEL=
0.74
mg/
kg/
day
LOAEL
=
5.8
mg/
kg/
day,
based
on
decreased
body
weight
gains
in
males
and
females
in
both
generations
Reproductive
NOAEL
=
36
mg/
kg/
day
LOAEL
=
not
established
Offspring
NOAEL=
0.74
mg/
kg/
day
LOAEL
=
5.8
mg/
kg/
day,
based
on
decreased
pup
survival
and
lower
pup
body
weights
of
F1a,
b
and
F2a,
b
litters
870.7485
(85­
1)
Metabolism
Study
Rat
00146489
(1985),
40142401
(1985)
41960001
(1991
42006801
(1991)
Linuron
(single
doses
at
24
mg/
kg
and
400
mg/
kg)
was
administered
by
gavage
to
male
and
female
rats.
The
biological
half­
lives
ranged
from
21
hr
in
the
low
dose
males
to
56
hr
in
the
high
dose
females.
Total
recovery
of
radioactivity
was
96%
in
males
and
97%
in
females,
the
majority
of
the
administered
C­
linuron
was
eliminated
in
the
urine
(>
80%)
and,
to
a
lesser
extent,
in
the
feces
(~
15%).
Tissue
and
organ
residues
were
very
low
(<
l%)
at
both
dose
levels,
and
there
was
no
indication
of
accumulation
or
retention
of
linuron
or
its
metabolites.
The
major
metabolites
identified
in
the
urine
were
hydroxy­
norlinuron,
desmethoxy
linuron
and
norlinuron,
and
in
feces,
hydroxy­
norlinuron,
and
norlinuron.
Neither
hydroxy­
3,4­
dichloroanaline
nor
3,4­
dichloroanaline
were
present
in
any
of
the
samples.
Exposure
to
linuron
appeared
to
induce
mixed­
function
oxidative
enzymes.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
13
870.7600
(85­
2)
Dermal
Penetration
Rat
00163837
(1984)
Acceptable/
Guideline
14
C
(2.35
:Ci/
mg)
0.12,
1.00,
or
7.4
mg/
2
in2
2.82,
23.5,
or
17.4
:Ci
Dermal
absorption
factor
=
16%
over
8
to
10
hr
(2%/
hr).

870.5100­
Bacterial
reverse
gene
mutation
assay
MRID
00131738
Acceptable/
Guideline
.5,
0.75,
1.0,
2.5,
and
5.0
:g/
plate(
S9­
mix)
1,
5,
10,
50,
and
100
:g/
plate
+S­
9
mix.
In
a
reverse
gene
mutation
assay
in
bacteri,
S.
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537
were
exposed
to
Linuron
(95­
97%,
lot
number
not
given)
in
dimethylsulfoxide
at
concentrations
of
0
There
was
no
evidence
of
induced
mutant
colonies
over
background
with
or
without
S9
activation.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
14
870.5300
CHO/
HGPRT
cell
forward
gene
mutation
assay
MRID
00137152
Acceptable/
Guideline
0.05,
0.25,
0.35,
0.40,
0.45,
and
0.50
mM
(S9­
mix)
0.25,
0.50,
0.75,
0.90,
and
1.0
mM
(+
S9­
mix)
In
a
mammalian
cell
gene
mutation
assay
in
vitro,
triplicate
(in
the
absence
of
activation)
or
duplicate
(in
the
presence
of
activation)
cultures
of
Chinese
hamster
ovary
(CHO)
CHO­
K1­
BH4
cells
were
exposed
to
Linuron
(Lot
No.
1N2­
326­
141,
94.5%
a.
i.)
in
F12
medium.
The
S9­
fraction
was
obtained
from
Aroclor
1254­
induced
8
to
9
week­
old
male
Charles
River
CD
rats.
Linuron
was
tested
up
to
concentrations
limited
by
cytotoxicity.
Cytotoxicity
was
observed
at
0.45
and
0.5
mM
under
nonactivated
conditions
and
at
0.75
mM
and
above
with
0.5
mg
S9
protein/
mL
and
at
1.0mM
and
above
with
1.0
mg
S9
protein/
mL.
(Percentage
cell
survival
were
not
provided
in
the
DER).
There
was
no
increase
in
mutant
frequency
in
cells
treated
with
linuron
in
either
the
presence
or
absence
of
metabolic
activation.
The
positive
(ethyl
methane
sulfonate
(EMS)
without
S9­
mix
and
dimethylbenzanthracene
with
S9­
mix)
and
solvent
(DMSO)
controls
responded
appropriately.
No
evidence
of
an
increased
mutant
frequency
was
observed
in
the
presence
or
absence
of
metabolic
activation.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
15
870.5385­
In
vivo
bone
marrow
chromosomal
aberration
assay
MRID
00137153
Acceptable/
Guideline
0,
100,
300,
or
1000
mg/
kg.
In
a
mammalian
cell
cytogenetics
chromosomal
aberration
assay
in
bone
marrow
cells
of
Sprague­
Dawley
rats,
5
rats
per
sex
per
harvest
time
were
administered
Linuron
(94.5%,
lot
number
not
given)
by
single
gavage
at
doses.
Bone
marrow
cells
were
harvested
6­,
12­,
24­,
or
48­
hours
after
test
compound
administration
and
48
hours
after
the
positive
control
dose.
The
vehicle
was
corn
oil
(20
mL/
kg)
and
the
positive
control
was
a
single
40
mg/
kg
dose
of
cyclophosphamide.

One
high­
dose
rat
in
the
24­
hour
group
was
found
dead
and
8
of
10
high­
dose
rats
in
the
48­
hour
group
died
prior
to
sacrifice
on
day
2.
Lowand
mid­
dose
animals
exhibited
slight
depression,
ataxia,
and/
or
prostration.
Treated
animals
also
had
decreased
body
weights
compared
to
controls.
There
was
no
significant
increase
in
the
frequency
of
aberrations
in
bone
marrow
cells
of
treated
animals
compared
to
controls
at
any
sampling
time.
Values
in
treated
animals
ranged
from
0.3­
0.8%
aberrant
cells/
group;
the
positive
control
group
had
19.6%
aberrant
cells,
indicating
that
this
control
responded
appropriately.
There
was
no
change
in
mitotic
index
of
dosed
groups
compared
to
controls.
There
is
no
evidence
that
Linuron
induced
chromosomal
aberrations
in
bone
marrow
cells
of
rats
over
background
levels.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
16
870.5550
­
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
00132583
Acceptable/
Guideline
0.00001,
0.0001,
0.001,
0.01,
0.1,
1.0,
10,
and
50.0
mM
(trial
1)

0.01,
0.1,
1.0,
10,
and
50.0
mM
(trial
2)
In
an
unscheduled
DNA
synthesis
assay,
primary
rat
hepatocyte
cultures
were
exposed
to
Linuron
(94.5%
a.
i.
in
dimethylsulfoxide;
Lot
No.
T80311­
81)
in
Williams'
Medium
E
(WME)
for
18
hours.
There
is
no
evidence
that
Linuron
induced
chromosomal
aberrations
in
bone
marrow
cells
of
rats
over
background
levelS
Special
Study
Leydig
cell
tumorigenesis
in
rats
41630101
(1990)
Acceptable/
Nonguideline
0
or
200
mg/
kg/
day
for
14
days
to
32
to
33
and
93
day
old
rats
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
Body
weight
and
body
weight
change
were
significantly
less
than
controls
and
decreased
accessory
sex
organ
weights
for
growing
and
adult
rats.

0,
0.74,
5.8,
36
mg/
kg/
day
in
males
and
0,
0.92,
7.3,
45
mg/
kg/
day
in
females
F0
and
F1
animals
from
2­
generation
reproduction
study
(41463401),
Selected
animals
from
the
2­
generation
reproduction
study
were
used
to
evaluate
changes
in
serum
hormone
levels,
accessory
sex
organ
weights.
Increased
serum
luteinizing
hormone
and
estradiol
levels
were
observed
in
F0
and
F1
males.
High­
dose
F0
males
had
decreased
absolute
epididymides,
dorsal
lateral
prostate,
and
levator
ani
muscle
weights
and
increased
relative
testes,
epididymides,
and
ventral
prostate
weights.
Organ
weights
were
unaffected
in
the
two
lower
dose
groups.

These
data
support
the
hypothesis
that
rats
exposed
to
linuron
could
develop
interstitial
hyperplasia
and
subsequent
adenomas
(Leydig
cell
tumors)
via
a
mechanism
of
sustained
hypersecretion
of
luteinizing
hormone
induced
by
the
antiandrogenic
potential
of
linuron.
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
17
Special
Study
­
Cross
Mating
­
Rats
00159846
(1985)

Acceptable/
Nonguideline
0,
625
ppm
%%:
0,
48
mg/
kg/
day
&&:
0,
44
mg/
kg/
day
The
cross­
mating
results
suggest
that
linuron
may
cause
paternally­
mediated
effects
based
on
decreased
fertility
and
fecundity
as
well
as
maternally­
mediated
effects
based
on
decreased
pup
viability
and
litter
survival.

Special
Study
­
Aged
male
rats
45506501
(1986)

Acceptable/
Nonguideline
0,
625
ppm
0,
22
mg/
kg/
day
Linuron
induced
hyperplasia
and
adenomas
of
the
testes
in
aged
rats.
In
addition,
life­
time
feeding
was
not
necessary
to
induce
oncogenic
responses
in
this
tissue.
Exposure
duration
was
6
to
12
months.

Special
Study
Biochemical
and
Histopathological
effects
164093
(1986)

Acceptable/
Nonguideline
0,
12.5,
100,
625
ppm
%%:
0,
0.75,
4.1,
22
mg/
kg/
day
&&:
0,
1.1,
6.1,
37
mg/
kg/
day
The
biochemical
and
histopathological
data
presented
in
this
report
suggest
that
linuron
may
affect
testosterone
metabolism
in
horse
testicular
microsomes
for
a
range
of
concentrations
which
overlap
the
dose
levels
given
rats
chronically.
However,
the
net
effect
of
these
enzyme
changes
and
the
relevance
to
the
rat
in
vivo
are
uncertain.
Evidence
in
young
and
old
rats
exposed
repeatedly
(3­
7x)
or
for
11
or
19
months
suggests
that
Leydig
cell
incubates
are
differentially
altered
in
their
sensitivity
to
LH.
Microscopic
lesions
in
the
testes
and
cervix
have
been
confirmed
in
other
studies.

The
toxicological
database
for
linuron
is
considered
adequate
for
hazard
characterization.
The
toxicity
profile
of
linuron
can
be
characterized
for
all
effects
including
potential
developmental,
reproductive,
and
neuroendocrine
effects.
Linuron
elicits
effects
primarily
upon
the
hematopoetic
system
and
also
displays
evidence
of
endocrine
disruption.
There
was
evidence
of
qualitative
susceptibility
in
both
the
2­
and
3­
generation
rat
reproduction
studies
in
the
toxicological
database.
Based
upon
a
dermal
penetration
study
in
the
rat,
a
dermal
absorption
factor
of
16%
for
8­
10
hours
of
18
exposure
was
determined.
In
addition,
linuron
is
not
regulated
as
a
carcinogen,
and,
there
is
an
adequate
metabolism
study
in
the
rat.
However,
there
are
toxicological
data
gaps
for
linuron.
The
HIARC
requires
that
both
a
28­
day
inhalation
study
and
a
developmental
neurotoxicity
(DNT)
study
be
performed
to
provide
better
hazard
characterization.
The
requirement
of
the
DNT
is
based
upon
the
finding
that
linuron
is
an
endocrine
disruptor.

Linuron
has
low
acute
toxicity,
with
toxicity
categories
of
III
for
oral
(LD50
2600
mg/
kg),
dermal
(LD50
>
2000
mg/
kg)
and
toxicity
category
IV
for
inhalation
(
LC50
>
218
mg/
L/
hr).
Primary
eye
and
skin
irritation
studies
were
category
III
and
IV,
respectively;
no
dermal
sensitization
was
observed
in
rabbits.

The
major
finding
in
chronic
toxicity
studies
in
the
dog,
mouse
and
rat
was
altered
hematological
parameters.
Dogs
fed
linuron
at
concentration
of
16.1
mg/
kg/
day,
resulted
in
hemolytic
anemia
and
secondary
erythropogenic
activity
evidenced
by
slightly
reduced
hemoglobin,
hematocrit,
and
erythrocyte
counts
accompanied
by
hemosiderin
deposition
in
liver
Kupffer
cells
and
erythroid
hyperplasia
of
bone
marrow.
Methemoglobinemia
was
seen
at
the
LOAEL
dose
in
the
chronic
dog
study.
Systemic
toxicity
observed
in
mice
included
increased
methemoglobin
formation
and
vacuolation
and
hemosiderosis
of
the
spleen.
In
another
chronic
study,
ChR­
CD
rats
fed
linuron
at
5.11
mg/
kg/
day
in
males
and
7.75
mg/
kg/
day
in
females,
displayed
microscopic
observations
consistent
with
hemolysis
(hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes).

Other
findings
observed
in
the
chronic
toxicity
study
in
the
rat
include,
a
significant
decrease
in
body
weight
gain
after
one
week
of
treatment
which
was
observed
at
600
ppm
in
males
(59%
of
control)
and
females
(53%
of
control).
These
decreases
persisted
throughout
the
entire
study,
with
females
showing
consistently
lower
body
weight
gains
(68
to
76%)
than
males
(82
to
93%).
The
decreases
in
body
weight
gains
correlated
to
some
degree
with
decreased
food
consumption.
Rats
also
showed
increased
incidences
of
microscopic
changes
in
the
epididymides
(perivasculitis/
vasculitis)
and
renal
pelvis
(transitional
cell
hyperplasia
and
mineralization/
calculi)
of
males
and
kidneys
(calculi
in
renal
tubules)
of
females.

In
a
developmental
toxicity
study
using
rats,
the
highest
dose
level
caused
decreased
body
weight
gain
and
food
consumption
in
the
dams,
as
well
as
the
developmental
effect
of
increased
postimplantation
loss
and
fetal
resorptions.
In
a
study
using
rabbits,
linuron
caused
decreases
in
maternal
body
weight,
food
consumption
and
liver
weight,
as
well
as
abortions,
fewer
fetuses
per
litter,
decreased
fetal
body
weight,
and
an
increased
incidence
of
fetuses
with
skeletal
skull
variations.
However,
the
HIARC
determined
that
neither
quantitative
nor
qualitative
susceptibility
was
indicated
by
these
test
results
since
increases
in
resorptions
were
marginal
and
there
was
no
change
in
the
number
of
live
fetuses
to
corroborate
the
increases
in
post­
implantation
losses.

There
was
no
quantitative
evidence
of
susceptibility
either
in
the
2­
generation
or
the
3­
generation
19
reproduction
studies.
In
the
2­
generation
study,
reduced
body
weight
gains
of
pups
were
seen
at
the
same
dose
that
caused
decreases
in
parental
body
weights.
In
the
3­
generation
study,
offspring
effects
(deceased
pup
survival
and
pup
body
weight)
were
seen
a
dose
(
44
mg/
kg/
day)
higher
than
the
dose
that
caused
decreases
in
body
weight
gain
in
the
parental
animals
(9
mg/
kg/
day).
However,
when
the
reproductive
effects
were
examined,
testicular
atrophy
was
seen
at
the
same
dose
(625
ppm,
45
mg/
kg/
day)
in
both
studies.
In
both
studies,
while
the
F0
males
were
not
affected,
testicular
lesions
and
reduced
fertility
were
seen
in
the
F1
males.
This
effect
in
the
F1
males
is
an
indication
of
qualitative
evidence
of
susceptibility.
In
addition,
there
is
ample
evidence
from
special
studies
submitted
by
the
registrant
as
well
as
open
literature
studies
which
indicate
that
linuron
is
an
endocrine
disruptor.
These
findings
include,
in
part:
(1)
competitive
androgen
receptor
antagonist;
but
not
an
estrogen
receptor
antagonist;
(2)
competitive
inhibition
of
the
transcriptional
activity
of
dihydrotestosterone
(DHT)­
human
androgen
receptor
(hAR)
in
vitro,
(3)
decreased
anogenital
distance
and/
or
an
increase
in
the
retention
of
areolae/
nipples
in
male
offspring
following
in
utero
exposure
to
linuron;
(4)
inhibition
of
steroidogenic
enzymes,
and
(5)
decreased
responsiveness
of
Leydig
cells
to
luteinizing
hormone
in
both
immature
(22
days)
and
mature
(11
months)
male
rats
treated
with
linuron
(mature
rats
were
less
responsive
than
immature
ones);
(6)
F0
and
F1
males
had
significantly
increased
levels
of
estradiol
and
luteinizing
hormone.

Oncogenicity
studies
in
the
rat
and
mouse
did
not
show
consistent
tumor
profiles
between
sexes
and
species.
In
the
combined
chronic
toxicity/
oncogenicity
study
in
rats,
common
neoplasms,
included
pituitary
adenomas
of
the
pars
anterior
in
both
male
and
female
rats
and
mammary
fibroadenomas
in
female
rats.
Testicular
adenomas
were
observed
in
6%,
28%
and
54%,
respectively
for
control,
125
and
625
ppm
dose
groups.
Decreased
incidences
of
both
these
tumor
types
were
noted
in
the
highdose
female
group.
In
the
mouse
oncogenicity
study,
treatment
of
up
to
104
weeks
with
1500
ppm
resulted
in
a
significant
increase
in
the
incidence
of
hepatocellular
adenomas
(control,
6%;
1500
ppm,
25%,
p
<
0.05)
in
females.
Linuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells.
There
was
also
no
indication
of
a
clastogenic
effect
up
to
toxic
doses
in
vivo.
Based
on
the
results
of
these
studies,
linuron
was
classified
as
an
unquantifiable
Group
C
carcinogen
(a
possible
human
carcinogen
for
which
there
is
limited
animal
evidence)
requiring
no
quantification
of
human
cancer
risk.

A
rat
metabolism
study
demonstrates
that
the
biological
half­
lives
of
linuron
ranged
from
21
hr
in
the
low
dose
males
to
56
hr
in
the
high
dose
females.
Total
recovery
of
radioactivity
was
96%
in
males
and
97%
in
females,
the
majority
of
the
administered
14
C­
linuron
was
eliminated
in
the
urine
(>
80%)
and,
to
a
lesser
extent,
in
the
feces
(~
15%).
Tissue
and
organ
residues
were
very
low
(<
l%)
at
both
dose
levels,
and
there
was
no
indication
of
accumulation
or
retention
of
linuron
or
its
metabolites.
The
major
metabolites
identified
in
the
urine
were
hydroxy­
norlinuron,
desmethoxy
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methylurea
or
DCPMU)
and
norlinuron
(3,4­
dichlorophenylurea
or
DCPU),
and
in
feces,
hydroxy­
norlinuron,
and
norlinuron.
The
major
metabolites
DCPU
and
DCPMU
were
identified
in
the
rat
metabolism
study,
in
both
plant
and
animal
metabolism
studies,
and
as
water
metabolites
in
the
aerobic
soil
metabolism
study.
These
metabolites,
in
addition
to
desmethyl­
linuron,
are
the
metabolites
of
toxicological
concern
referenced
in
the
tolerance
expression
and
considered
in
this
risk
assessment.
20
Neither
hydroxy­
3,4­
dichloroanaline,
3,4­
dichloroanaline
nor
3,3',
4,4'­
tetrachloroazobenzene
(TCAB)
were
present
in
any
of
the
samples
in
the
rat
metabolism
study.
Exposure
to
linuron
appeared
to
induce
mixed­
function
oxidative
enzymes
in
mammals.

3.2
FQPA
Considerations
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
in
the
rabbit
developmental
study;
developmental
effects
were
seen
at
a
dose
higher
than
that
causing
maternal
toxicity.
In
the
rat
developmental
toxicity
study,
increases
in
post­
implantation
losses
and
increases
in
fetal
resorptions/
litter
were
seen
at
a
dose
that
caused
decreases
in
maternal
body
weight
and
food
consumption.
The
HIARC
determined
that
the
developmental
effects
are
not
a
concern
for
qualitative
evidence
of
susceptibility,
since
increases
in
resorptions
were
marginal
and
there
was
no
change
in
the
number
of
live
fetuses
to
corroborate
the
increases
in
post­
implantation
losses.

There
was
no
quantitative
evidence
of
susceptibility
identified
in
either
the
2­
generation
or
the
3­
generation
reproduction
studies.
In
the
2­
generation
study,
reduced
body
weight
gains
of
pups
were
seen
at
the
same
dose
that
caused
decreases
in
parental
body
weights.
In
the
3­
generation
study,
offspring
effects
(deceased
pup
survival
and
pup
body
weight)
were
seen
a
dose
higher
than
the
dose
that
caused
decreases
in
body
weight
gain
in
the
parental
animals.
In
both
the
2­
generation
and
the
3­
generation
rat
reproductive
toxicity
studies,
testicular
atrophy
was
seen
at
the
same
dose
that
caused
parental/
systemic
toxicity.
The
HIARC
determined
that
these
findings
were
of
a
concern
and
provide
qualitative
evidence
of
increased
susceptibility
because
in
both
studies
they
were
seen
in
the
F1
males
but
not
in
F0
males.
This
indicates
an
adverse
effect
on
the
male
reproductive
system
of
the
F1
generation.

The
HIARC
concluded
that
a
development
neurotoxicity
study
in
the
rat
is
required
by
the
available
evidence.
This
conclusion
is
based
on
the
findings
that
linuron
is
an
endocrine
disruptor,
as
evidenced
by
the
observation
of
increased
testicular
lesions
and
decreased
fertility
in
the
reproduction
studies.

The
FQPA
SFC
concluded
that
a
safety
factor
should
be
retained
at
10x
because:

1.
A
qualitative
increase
in
susceptibility
was
seen
in
the
F1
males
in
the
rat
reproductive
toxicity
study
(a
long­
term
study);
and
2.
A
developmental
neurotoxicity
study
in
rats
is
required
for
the
chemical
because
linuron
is
an
endocrine
disruptor
and
there
is
evidence
for
testicular
lesions
and
decreased
fertility
in
the
rat
reproductive
toxicity
study.

However,
the
Committee
concluded
that
the
safety
factor
could
be
reduced
to
3x
for
acute
dietary
exposure
to
females
13­
50
years
of
age
because:

1.
There
was
no
susceptibility
identified
in
following
in
utero
exposure;
21
2.
The
toxicology
database
is
complete
for
FQPA
assessment;
3.
The
dietary
(food
and
water)
exposure
assessments
will
not
underestimate
the
potential
exposures
for
infants,
children,
and/
or
women
of
childbearing
age;
and,
4.
There
are
no
residential
uses.

When
assessing
acute
dietary
exposure
of
females
13­
50
years
of
age,
the
safety
factor
should
be
reduced
to
3x
since
the
developmental
neurotoxicity
study
in
rats
is
required
and
may
further
define
the
potential
neuro­
endocrine
effects
observed
in
rats
that
were
exposed
in
pre­
and
post­
natal
time
periods.
However,
when
assessing
chronic
dietary
exposure
to
all
other
population
sub­
groups,
the
safety
factor
should
be
retained
at
10x
since
there
is
concern
for
the
qualitative
increase
in
susceptibility
observed
in
the
rat
reproductive
toxicity
study
(a
long­
term
study),
and,
since
the
developmental
neurotoxicity
study
in
rats
is
required.
The
developmental
neurotoxicity
study
may
further
define
the
potential
neuro­
endocrine
effects
observed
in
rats
due
to
pre­
and
post­
natal
exposure.

3.3
Dose­
Response
Assessment
Toxicological
endpoints
were
established
for
all
exposure
scenarios.
Acute
dietary
exposure
to
the
general
population
is
not
assessed
since
there
was
no
appropriate
endpoint
attributable
to
a
single­
dose
available
in
the
database.
Three
toxicological
studies
determined
toxicological
endpoint
doses:
a
prenatal
developmental
toxicity
study
in
the
rat,
a
chronic
oral
study
in
the
dog,
and,
a
2­
generation
reproduction
study
in
the
rat.
For
this
tolerance
reassessment
eligibility
decision
for
linuron,
only
the
acute
and
chronic
dietary
exposure
scenarios
will
be
assessed
because
there
are
no
registered
uses
for
linuron
in
the
residential
environment.
Occupational
exposures
and
risks
will
not
be
considered
at
this
time
as
they
were
assessed
at
the
time
of
the
reregistration
eligibility
decision
(RED).
A
discussion
of
the
dose­
response
relationships
for
acute
and
chronic
dietary
endpoints
follows
presentation
of
Table
3.
(Linuron
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee,
HED
Doc.
No.
0050286,
Robert
Fricke
November
20,
2001.)

Table
3:
Toxicological
Endpoints
for
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
12
UF
=
100
Acute
RfD
=
0.12
mg/
kg/
day
FQPA
SF
=
3
aPAD
=
acute
RfD
FQPA
SF
=
0.04
mg/
kg/
day
Prenatal
Oral
Developmental
/
Rat
LOAEL
=
50
mg/
kg/
day
based
on
increased
post­
implantation
loss
and
fetal/
litter
resorptions.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
22
Acute
Dietary
general
population
including
infants
and
children
N/
A
N/
A
No
appropriate
effects
attributed
to
a
single
exposure
were
identified.

Chronic
Dietary
all
populations
NOAEL=
0.77
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.007
mg/
kg/
day
FQPA
SF
=
10
cPAD
=
chr
RfD
FQPA
SF
=
0.00077
mg/
kg/
day
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Oral
(1­
7
days)

(Residential)
NOAEL=
5.8
mg/
kg/
day
LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
2­
Generation
Reproduction
Study/
Rat
LOAEL
=
36
mg/
kg/
day
based
on
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
IntermediateTerm
Oral
(1
week
­
several
months)

(Residential)
NOAEL=
0.77
mg/
kg/
day
LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Dermal
(1­
30
days)

(Occupational/
Residential)
Oral
NOAEL=
5.8
mg/
kg/
day
dermal
absorption
rate
=
16%
LOC
for
MOE
=
100
(Occupational)

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
2­
Generation
Reproduction
Study/
Rat
LOAEL
=
36
mg/
kg/
day
based
on
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
23
IntermediateTerm
Dermal
(1
­
6
months)

(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
dermal
absorption
rate
=
16%
LOC
for
MOE
=
100
(Occupational)

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels
after
3
and
6
months
of
treatment
Long­
Term
Dermal
(Longer
than
6
months)
(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
dermal
absorption
rate
=
16%
LOC
for
MOE
=
100
(Occupational)

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Inhalation
(1­
30
days)

(Occupational/
Residential)
Oral
NOAEL=
5.8
mg/
kg/
day
(inhalation
absorption
rate
=
100%
LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
2­
Generation
Reproduction
Study/
Rat
LOAEL
=
36
mg/
kg/
day
based
on
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
IntermediateTerm
Inhalation
(1
to
6
months)

(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
(inhalation
absorption
rate
=
100%
LOC
for
MOE
=1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
24
Long­
Term
Inhalation
(Longer
than
6
months)

(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
inhalation
absorption
rate
=
100%
LOC
for
MOE
=
100
(Occupational)

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Cancer
(oral,
dermal,
inhalation)
Group
C
carcinogen
Does
not
require
quantification
of
human
cancer
risk
Based
on
a
dose­
related
increase
in
interstitial
cell
hyperplasia
and
adenomas
in
a
two­
year
rat
feeding
study
and
hepatocellular
tumors
that
appeared
in
low­
dose
male
and
highdose
female
mice
in
a
two­
year
feeding
study
1
UF
=
uncertainty
factor,
FQPA
SF
=
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,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
3.3.1
Acute
Reference
Dose
(RfD)
­
Females
13­
50
The
study
selected
to
define
the
dose­
response
relationship
for
risk
assessment
is
a
prenatal
oral
developmental
study
in
the
rat
(MRID
00018167).
In
this
study,
27
presumed
pregnant
Crl:
CD
rats
per
group
were
administered
0,
50,
125,
or
625
ppm
of
linuron
(97%
a.
i.;
Lot
No.
INZ­
326­
118)
in
the
diet
on
gestation
days
(GD)
6­
15,
inclusive.
All
animals
survived
to
scheduled
termination
without
the
appearance
of
any
treatment­
related
clinical
signs
of
toxicity.
Gross
necropsy
was
unremarkable.
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
The
maternal
toxicity
LOAEL
is
625
ppm
(50
mg/
kg/
day)
based
on
reduced
body
weight
gains
and
food
consumption.
The
maternal
toxicity
NOAEL
is
125
ppm
(12
mg/
kg/
day).

No
dose­
or
treatment­
related
effects
were
observed
on
fetal
sex
ratios,
numbers
of
corpora
lutea/
dam,
implantations/
dam,
live
or
dead
fetuses/
dam,
fetal
body
weights,
or
crown­
rump
length
in
the
low
and
mid­
dose
groups.
In
the
high­
dose
group,
bipartite
thoracic
vertebral
centra
was
observed
in
7
fetuses
from
7
litters
and
unopposed
sternebrae
were
observed
in
3
fetuses
from
3
litters.
These
anomalies
were
not
found
in
the
control
group
and
were
considered
indicative
of
developmental
delays.
Therefore,
the
developmental
toxicity
LOAEL
is
50
mg/
kg/
day
based
on
increases
in
post­
implantation
25
loss
and
in
litter/
fetal
resorptions.
The
developmental
toxicity
NOAEL
is
12
mg/
kg/
day.

Therefore,
the
dose
and
endpoint
for
establishing
the
acute
reference
dose
(RfD)
is
a
NOAEL
=
12
mg/
kg/
day,
based
on
increases
in
post­
implantation
loss
and
litter/
fetal
resorptions
at
the
LOAEL
of
625
ppm
(50
mg/
kg/
day).
An
uncertainty
factor
of
100x
(10x
intraspecies
variability,
10x
interspecies
extrapolation)
is
recommended.
The
developmental
effects
are
presumed
to
occur
following
a
single
exposure
of
females
of
child­
bearing
age
and,
therefore,
are
appropriate
for
this
risk
assessment.

Acute
RfD
=
12
mg/
kg/
day
=
0.12
mg/
kg/
day
100(
UF)

3.3.2
Chronic
Reference
Dose
(RfD)

For
the
chronic
reference
dose,
the
study
selected
to
define
the
dose­
response
relationship
for
risk
assessment
is
a
chronic
toxicity
(1­
Year)
study
in
the
dog
(MRID
40952601).
In
this
study,
linuron
(96.2%
a.
i.,
Batch
No.
6,569)
was
administered
to
groups
of
4
male
and
4
female
dogs
in
the
diet
at
concentrations
of
0,
10,
25,
125,
or
625
ppm.
No
treatment­
related
clinical
signs
of
toxicity
or
mortalities
were
observed
at
any
dose
level.
However,
red
blood
cell
counts,
hemoglobin,
and
hematocrit
were
slightly
decreased
throughout
the
study
in
high­
dose
males
and
females
as
compared
with
those
of
the
controls.
White
blood
cell
and
platelet
counts
were
significantly
(p
#
0.05)
increased
in
high­
dose
females
at
3,
6,
and
9
months
and
platelet
counts
were
increased
(p
#
0.05)
in
high­
dose
males
at
3
months.
Met­
and
sulf­
hemoglobin
levels
were
significantly
(p
#
0.05)
increased
in
the
625
ppm
males
and
females
at
all
time
points
as
compared
with
those
of
the
controls.
In
addition,
for
the
125
ppm
groups
methemoglobin
levels
were
increased
(p
#
0.05)
in
males
and
females
at
3
and
6
months
while
sulfhemoglobin
levels
were
(p
#
0.05)
increased
at
9
months
in
males
and
at
3,
9,
and
12
months
in
females.
Increased
hematopoiesis
was
observed
in
the
bone
marrow
in
3/
4
high­
dose
males
and
4/
4
high­
dose
females,
compared
with
none
of
the
control
males
and
only
1/
4
control
females.

The
LOAEL
for
linuron
in
male
and
female
beagle
dogs
was
established
at
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
abnormal
hematology
findings
(increased
met­
and
sulfhemoglobin
levels).
The
NOAEL
was
established
at
25
ppm
(0.79
mg/
kg/
day,
males
and
0.77
mg/
kg/
day,
females).
An
uncertainty
factor
of
100x
(10x
intraspecies
variability,
10x
interspecies
extrapolation)
was
recommended.

Chronic
RfD
=
0.77
mg/
kg/
day
=
0.0077
mg/
kg/
day
100
(UF)

3.4
Endocrine
Disruption
From
special
studies
(non­
guideline)
and
open
literature
publications,
linuron
was
shown
to
be
an
26
endocrine
disruptor.
Key
findings
include
(See
HIARC
Report,
HED
Doc.
No.
0050286,
Robert
Fricke
November
20,
2001
for
more
details):

(1)
Linuron
and
some
of
its
metabolites
are
androgen
receptor
antagonists;

(2)
Rats
treated
with
linuron
had
reduced
anogenital
distance,
retention
of
nipples,
and
a
low
incidence
of
hypospadias;

(3)
The
responsiveness
of
Leydig
cells
to
luteinizing
hormone
was
decreased
in
both
immature
(22
days)
and
mature
(11
months)
male
rats
treated
with
linuron.
Mature
rats
were
less
responsive
that
immature
ones;

(4)
F0
and
F1
males
had
significantly
increased
levels
of
estradiol
and
luteinizing
hormone;

(5)
Linuron
inhibits
activities
of
steroidogenic
enzymes;
and,

(6)
A
dose­
dependent
increase
in
areola/
nipple
retention
in
male
rats.

The
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC)
is
the
Agency's
body
that
is
asked
to
develop
a
screening
program
to
determine
whether
certain
substances
"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."
However,
in
the
case
of
linuron,
the
toxicological
database
includes
compelling
evidence
that
the
chemical
is
an
endocrine
disruptor.
The
Agency
believes
that
this
assessment
is
protective
of
these
effects.
The
endpoints
selected
for
regulation
of
linuron
are
below
the
doses
at
which
endocrine
effects
(areola/
nipple
retention,
hypoplastic
testes
and
epididymides,
and
partial
agenesis
of
the
epididymides)
were
seen
(HIARC
Report,
HED
Doc.
No.
0050286,
Robert
Fricke
November
20,
2001).
When
additional
testing
protocol
are
developed,
linuron
may
be
subjected
to
further
study
to
better
characterize
effects
related
to
endocrine
disruption.

3.5
Potential
Tetrachloroazobenzene
Contamination
This
section
has
been
derived
from
the
Diuron
Risk
Assessment
(DP
Barcode
D272130).
Diuron,
propanil
and
linuron
have
all
been
reported
to
contain
trace
amounts
of
a
manufacturing
impurity,
3,3',
4,4'­
tetrachloroazobenzene,
a.
k.
a.
TCAB,
which
has
been
shown
to
be
a
cytochrome
P450
enzyme
inducer.
A
summary
of
short­
term
bioassays
compiled
by
the
National
Toxicology
Program
states
that,

"3,3',
4,4'­
tetrachloroazobenzene
caused
typical
dioxin­
like
effects,
such
as
thymic
atrophy,
an
increase
in
liver
weights,
induction
of
hepatic
cytochrome
P4501A,
and
decreased
mean
body
weight
gains.
Furthermore,
in
the
13­
week
studies,
a
sharp
decrease
in
circulating
thyroxine
27
concentrations
was
observed
even
at
the
lowest
dose
(0.1
mg/
kg)
tested
in
rats.
Other
effects
included
a
decrease
in
epididymal
spermatozoal
concentration
in
mice,
major
effects
on
the
hematopoietic
system,
and
increased
incidences
of
hyperplasia
of
the
forestomach
in
3
and
30
mg/
kg
males
and
30
mg/
kg
females.
A
NOAEL
was
not
reached
in
rats.
The
NOAEL
in
mice
was
0.1
mg/
kg.
Comparison
of
various
dioxin­
like
effects
in
these
studies
with
those
reported
in
the
literature
indicate
that
3,3',
4,4'­
tetrachloroazobenzene
is
six
to
two
orders
of
magnitude
less
potent
than
2,3,7,8­
tetrachlorodibenzo­
p­
dioxin."

Chronic
toxicity/
carcinogenicity
studies
are
not
available
for
TCAB.
The
specific
endpoint(
s)
and
related
dose
levels
that
may
be
observed
in
chronic
toxicity
studies,
or
the
specific
carcinogenic
potential
of
this
compound
is
not
known.
However,
since
it
is
assumed
that
TCAB
may
have
been
present
in
all
linuron
toxicological
test
materials,
including
the
test
material
for
the
chronic
toxicity/
carcinogenicity
studies,
the
Agency
believes
that
the
risks
from
exposure
to
linuron
(including
carcinogenic
potential)
have
not
been
underestimated.

4.0
Exposure
Assessment
and
Characterization
4.1
Summary
of
Registered
Use
Patterns
Linuron
[3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea]
is
a
substituted
urea
compound
and
controls
a
variety
of
weed
species
including
annual
morning
glory,
rye
grass,
and
barnyard
grass.
Linuron
is
a
systemic,
selective
herbicide
that
works
as
a
photosynthesis
inhibitor
(Hill
reaction).
Linuron
may
be
applied
pre­
plant,
pre­
emergence,
post­
emergence
or
post­
transplant
and
is
registered
for
use
on
asparagus,
carrots,
celery,
field
and
sweet
corn,
cotton,
parsley,
potatoes,
sorghum,
soybeans,
and
wheat.
Linuron
can
be
applied
using
ground
equipment
including
band
sprayer,
boom
sprayer,
sprinkler
irrigation,
and
tractor
mounted
sprayer
as
well
as
using
aerial
application
methods.

Linuron
is
formulated
as
an
emulsifiable
concentrate,
flowable
concentrate,
water
dispersible
granules,
and
a
wettable
powder.
The
range
of
percentage
of
active
ingredient
in
the
product
formulations
is
40­
50%.
The
application
rates
range
from
0.5­
4.0
lbs
ai/
acre/
year
and
1
or
2
applications
are
allowed
per
year.
Linuron
is
mainly
an
early
season
use,
but
a
few
crops
have
relatively
short
PHIs,
notably
asparagus
(1
day)
and
carrot
(14
days).
Pre­
harvest
intervals
are
currently
not
often
specified
on
the
label
and
are
necessary.
This
is
one
of
the
recommendations
made
in
this
tolerance
reassessment.

A
profile
of
linuron
usage
has
been
developed
by
the
OPP
Biological
and
Economic
Analysis
Division
(F.
Hernandez,
August
18,
2000).
The
use
profile
is
based
on
data
from
EPA,
USDA,
and
the
National
Center
for
Food
and
Agricultural
Policy.
Based
on
data
from
1988
through
1997,
an
annual
estimate
of
linuron
total
domestic
usage
averaged
1.2
million
pounds
of
active
ingredient
for
over
two
million
acres
treated.
The
largest
market
interms
of
total
pounds
of
active
ingredient
is
allocated
to
soybean
(75%),
carrots
(9%),
and
potatoes
(7%).
Most
of
the
usage
is
in
the
Midwestern
states
of
28
Illinois,
Indiana,
Ohio,
and
Michigan
and
also
Maryland
and
Washington
states.
Crops
with
the
highest
percent
of
crop
treated
include
carrots
(100%),
asparagus
(33%)
and
celery
(22%).
This
information
has
been
used
in
the
food
exposure
analysis.

There
are
no
registered
uses
for
this
chemical
at
residential
sites.
The
populations
of
concern
for
this
assessment
are
those
who
may
be
exposed
through
consuming
crops
treated
with
linuron
or
consuming
water
contaminated
with
linuron.

4.2
Dietary
(Food)
Exposure/
Risk
Pathway
4.2.1
Residue
Profile
The
qualitative
nature
of
the
residue
in
plants
and
animals
is
adequately
understood.
Plant
metabolism
studies
show
the
major
plant
metabolites
to
be
3,4­
dichlorophenylurea
or
DCPU
(a.
k.
a.
norlinuron)
and
desmethoxy­
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methylurea,
DCPMU).
There
was
a
significant
amount
of
unidentified
polar
components
in
both
plant
metabolism
studies,
however,
it
was
concluded
that
the
components
in
plants
are
hydrolyzable
to
3,4­
dichloroaniline
(3,4­
DCA).

In
animals,
linuron
is
metabolized
to
DCPU
and
hydroxy­
norlinuron
through
desmethoxy­
linuron
and
demethyl­
linuron
intermediates.
Small
amounts
of
3,4­
dichloroaniline
were
detected
in
both
the
corn
and
poultry
studies.
The
registrant
analyzed
poultry
tissues,
excreta,
and
eggs
for
TCAB
and
TCAOB
residues
and
none
were
detected.
The
chemical
structures
of
the
metabolites
of
concern
are
listed
in
Figure
1.

Tolerances
are
currently
established
for
the
use
of
linuron
on
asparagus,
carrots,
celery,
field
and
sweet
corn,
cotton,
parsley,
potatoes,
sorghum,
soybeans,
and
winter
wheat.
The
tolerance
for
asparagus
is
7.0
ppm
and
the
tolerance
for
field
corn
is
6.0
ppm,
all
other
tolerances
range
from
0.05­
2.0
ppm.
They
are
listed
at
40
CFR
180.184.
During
the
Phase
II
Response
to
Error­
Only
Comment
time
period,
two
new
uses
supported
by
the
Inter­
regional
Research
Project
number
4
(IR­
4)
were
added
to
the
list
of
crops
on
which
linuron
may
be
used,
rhubarb
(0.5
ppm)
and
celeriac
(1.0
ppm).
These
additional
uses
are
incorporated
into
this
risk
assessment.

Tolerances
for
residues
of
linuron
are
currently
expressed
in
terms
of
linuron
per
se.
However,
the
HED
Metabolism
Assessment
and
Review
Committee
(MARC)
determined
that
the
tolerance
expression
under
40
CFR
§180.184(
a)
and
(c)
should
be
revised
as
follows:
"Tolerances
are
established
for
the
combined
residues
of
the
herbicide
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea)
and
its
metabolites
convertible
to
3,4­
dichloroaniline,
calculated
as
linuron."
It
should
be
noted
that
the
analytical
method
for
quantifying
residues
of
concern
from
application
of
linuron
converts
all
residues
to
3,4­
DCA
as
a
technical
convenience.
(Linuron
Plant
and
Animal
Metabolism:
Results
of
the
HED
Metabolism
Committee
Meetings
held
October
21
and
October
29,
1993.
Dennis
McNeilly.
November
17,
1993.)

The
MARC
concluded
that
residues
of
3,4­
DCA
are
not
of
regulatory
concern
in
connection
with
the
29
N
H
Cl
Cl
O
N
O
CH
3
CH
3
N
H
N
H
O
Cl
Cl
CH
3
N
H
NH
2
O
Cl
Cl
N
H
Cl
Cl
O
N
H
O
CH
3
N
H
Cl
Cl
O
NH
2
OH
NH
2
Cl
Cl
registered
use
of
linuron.
Tolerances
for
linuron
residues
of
concern
in
milk
are
being
recommended
in
this
action.
There
are
established
tolerances
for
linuron
residues
of
concern
in
the
meat,
fat,
and
meat
byproducts
of
cattle,
goat,
swine,
horse,
and
sheep.
Tolerances
are
being
recommended
for
the
liver
and
kidney
of
certain
animal
commodities
and
a
reduction
in
tolerance
is
recommended
for
certain
animal
tissues.
Metabolism
studies
with
corn,
soybeans,
and
potatoes
indicate
that
linuron
is
absorbed
from
the
soil
and
translocated
(i.
e.,
systemic).
Poultry
and
ruminant
feeding
studies
were
also
performed.
These
studies
show
that
the
metabolic
pathways
for
plants
and
animals
are
similar.

Figure
1.
Chemical
names
and
structures
of
linuron
and
its
metabolites
identified
in
plant
and
animal
commodities.

Linuron:
3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea
DCPMU;
IN­
15654;
Desmethoxy
linuron:
3­(
3,4­
dichlorophenyl)­
1­
methylurea
DCPU;
Norlinuron;
IN­
R915:
3,4­
dichlorophenylurea
Desmethyl
linuron:
3­(
3,4­
dichlorophenyl)­
1­
methoxyurea
Hydroxy­
norlinuron:
(4,5­
dichloro
2­
hydroxyphenyl)
urea
3,4­
DCA:
3,4­
dichloroaniline
Metabolism
studies
also
illustrate
the
distribution
of
residues
of
linuron
within
plant
and
animals.
Radiolabeled
14
C­
linuron
equivalents
were
found
in
corn
forage
and
potato
and
soybean
foliage.
Detectable
residues
were
also
found
in
the
potato
plant
itself,
however.
In
animals,
the
highest
levels
of
14
C­
linuron
equivalents
were
found
in
the
liver
of
both
goat
and
poultry.
No
intact
linuron
(<
0.001
ppm)
was
detected
in
the
milk,
tissues,
or
urine
of
the
test
animals.
About
95%
of
the
radioactivity
in
milk
was
identified
as
polar
metabolites
based
on
polar
solvents
used
in
the
analytical
procedure.
No
attempts
were
made
to
identify
these
polar
metabolites.
The
residues
listed
in
the
tolerance
expression
are
the
same
that
will
be
included
in
the
dietary
risk
assessment,
linuron
and
metabolites
convertible
to
3,4­
DCA.

On
November
17,
1993,
the
HED
Metabolism
Assessment
and
Review
Committee
(MARC)
met
to
discuss
the
plant
and
animal
metabolism
of
linuron.
Plant
metabolism
studies
in
corn,
potato,
and
soybean
as
well
as
animal
metabolism
studies
in
poultry
and
for
ruminant
consumption,
were
considered
by
the
committee.
The
terminal
residues
of
concern
in
plants
and
animals
are
linuron
(parent)
and
30
metabolites
convertible
to
3,4­
DCA
including
desmethoxy­
linuron,
norlinuron,
desmethyl
linuron,
and
hydroxy­
norlinuron.
The
committee
also
decided
that
3,4­
DCA
was
not
of
regulatory
concern
in
connection
with
the
registered
use
of
linuron
due
to
the
very
low
levels
at
which
the
chemical
is
detected
in
plants
and
animals
(<
0.01ppm).
The
MARC
concluded
that
with
the
possible
exception
of
3,4­
DCA
itself,
metabolites
convertible
to
3,4­
DCA
are
not
likely
to
be
more
toxic
than
the
parent
compound.
Linuron
can
therefore,
be
regulated
by
using
the
enforcement
analytical
method
in
which
unidentified
polar
components
in
plants
and
bound
residues
in
animal
tissues
are
hydrolyzed
to
3,4­
DCA.
The
total
residue
convertible
to
3,4­
DCA
will
be
compared
to
the
reference
dose
for
parent
linuron
for
purposes
of
dietary
risk
assessment.
The
MARC
did
not
review
linuron
as
part
of
the
TRED
process
because
no
new
metabolism
information
was
provided
since
the
time
of
the
RED
(EPA
738­
R­
95­
003,
March
1995).

Samples
for
the
plant
and
animal
metabolism
studies
were
analyzed
using
the
extraction
procedures
of
the
enforcement
methods
(colorimetric
method
and
modifications
thereof
and
the
GC/
ECD
method).
These
methods
demonstrate
that
the
identified
metabolites
plus
a
large
portion
of
the
unidentified
polar
metabolites
were
converted
to
3,4­
DCA
and
would
therefore
be
determined
using
the
enforcement
method.
(Linuron
TRED
Residue
Chemistry
Consideration,
D272368,
John
Punzi,
November
26,
2001)

HED
has
confidence
in
the
magnitude
of
the
residue
data
used
to
determine
reassessed
tolerances
for
linuron
in/
on
plant
and
animal
commodities.
Adequate
and
representative
field
trial
studies
are
available
to
assess
the
degree
of
chemical
in
food
commodities.
Field
trial
studies
showed
detectable
residues
of
linuron
on
plants,
and,
ruminant
feeding
studies
and
animal
metabolism
studies
indicate
transfer
of
residues
to
meat
and
milk.
The
tolerance
for
asparagus
is
7.0
ppm
and
the
tolerance
for
field
corn
is
6.0
ppm,
all
other
tolerances
range
from
0.05­
2.0
ppm.

However,
there
are
some
aspects
of
the
residue
chemistry
database
that
are
incomplete
for
linuron.
There
are
a
number
of
label
amendments
required.
The
amendments
relate
to
the
use
of
linuron
in
tank
mixes,
impractical
grazing/
feeding
restrictions
which
should
be
removed
from
the
label,
and
the
specification
of
PHIs
for
several
crops
and
use
directions.
Use
directions
on
product
labels
for
asparagus
and
soybean
need
to
be
clarified.
The
re­
registeration
requirements
for
residue
analytical
methods
are
not
fulfilled
as
the
registrants
must
proposed
a
new
enforcement
method.
In
addition,
storage
stability
requirements
are
not
fulfilled
for
some
crops.
Information
about
cotton,
sweet
corn
and
parsnips
must
be
submitted.
The
re­
registration
requirements
for
magnitude
of
the
residue
in
plants
are
not
fulfilled
for
a
number
of
crops.
The
unsatisfied
data
requirements
for
crops
are
generally
either
storage
stability
information
or
additional
geographic
representation.

The
re­
registration
requirements
for
the
magnitude
of
the
residue
in
processed
food/
feed
are
fulfilled
for
field
corn,
cotton,
soybeans,
and
wheat.
Previous
actions
by
the
Agency
concluded
that
additional
data
were
required
to
upgrade
an
existing
potato
processing
study.
These
data
are
not
available,
but
are
considered
confirmatory.
There
are
sufficient
data
available
to
reassess
tolerances
and
estimate
dietary
exposure
for
potato
processed
products.
Generally,
residues
of
linuron
and
metabolites
do
not
31
appear
to
concentrate
in
processed
commodities.
There
are,
however,
two
exceptions.
The
potato
processing
data
indicate
that
linuron
residues
of
concern
concentrate
in
wet
peel
waste
(processing
factor
of
5.5x),
chips
(2.0x),
dehydrated
granules
(3.4x),
and
oven­
baked
potatoes
(2.1x),
but
do
not
concentrate
in
peeled
potato
(0.82x)
or
mashed
potato
(0.61x).
The
available
soybean
processing
data
indicate
that
residues
were
found
to
concentrate
in
soybean
isolate
(1.6x)
and
lecithin
(2.3x).
Cooking
studies
were
available
in
asparagus,
carrot
and
potato.
These
studies
generally
show
a
significant
reduction
in
residues
through
cooking.

Monitoring
data
are
available
from
both
the
U.
S.
Department
of
Agriculture
(USDA)
and
the
Food
and
Drug
Administration
(FDA).
However,
both
monitoring
programs
report
levels
of
linuron
parent
only.
USDA
and
FDA
do
not
look
for
residues
of
linuron
metabolites
convertible
to
3,4
dichloroaniline,
namely
DCPU
(3,4­
dichlorophenylurea)
and
DCPMU
(3­(
3,4­
dichlorophenyl)­
1­
methylurea).
In
USDA
Pesticide
Data
Program
information,
the
detection
rate
for
linuron
parent
on
carrots
is
approximately
35%
and
residues
were
frequently
found
as
high
as
0.2
and
0.3
ppm.
However,
these
data
cannot
be
used
in
dietary
exposure
assessment
as
they
may
underestimate
the
amount
of
residues
of
concern.
The
assessment
will
use
field
trial
data,
refined
by
percent
of
crop
treated
data,
processing
studies
and
residue
reduction
studies.

Currently,
the
Pesticide
Analytical
Manual
(PAM)
Vol.
II
lists
a
colorimetric
method
(Method
I)
and
a
paper
chromatographic
method
for
the
enforcement
of
tolerances
for
linuron
residues.
Both
these
methods
determine
linuron
and
all
metabolites
hydrolyzable
to
3,4­
DCA
and
have
limits
of
detection
of
0.05
ppm.
However,
the
registrants
must
propose
a
more
updated
data
collection
method
as
an
enforcement
method
for
plant
and
animal
commodities.
The
current
enforcement
method,
GC/
ECD,
involves
conversion
to
residues
of
3,4­
DCA
and
therefore
will
detect
residues
of
linuron
and
its
metabolites.
The
LOQ
is
0.01
ppm.
This
method
is
the
same
method
used
for
data
collection
purposes
for
residues
of
diuron
in/
on
plant
and
animal
commodities.
Therefore,
the
reregistration
requirements
for
residue
analytical
methods
are
not
fulfilled.
Residue
data
for
linuron
in/
on
plant
and
animal
commodities
were
collected
using
Method
I
(or
modifications
thereof)
or
a
GC­
ECD
method
similar
to
Method
I.
The
multi­
residue
testing
method
is
inadequate
for
detection
of
linuron
and
its
metabolites
in/
on
plant
and
animal
commodities
it
is
able
to
identify
linuron
parent
only
and
some
of
the
metabolites
of
concern.

No
maximum
residue
limits
(MRLs)
for
linuron
have
been
established
by
Codex
for
any
agricultural
commodity.
In
addition,
no
Canadian
or
Mexican
MRLs
have
been
established
for
linuron.
Therefore,
no
compatibility
questions
exist
with
respect
to
U.
S.
tolerances.

4.2.2
Acute
Dietary
­
Females
13­
50
Acute
dietary
(food)
risk
estimates
associated
with
the
use
of
linuron
do
not
exceed
the
Agency's
level
of
concern
(>
100%
of
aPAD)
for
females
13­
50
years
of
age.
The
acute
dietary
risk
estimate
for
females
13­
50
is
approximately
10%
of
the
aPAD.
(Linuron
Anticipated
Residues
and
Dietary
Exposure
Assessment,
DP
Barcode
D
279340,
John
Punzi,
November
26,
2001.)
32
The
acute
dietary
exposure
assessment
for
linuron
is
a
tier
III
probabilistic
(Monte
Carlo)
analysis.
Residue
levels
from
USDA
and
FDA
monitoring
programs
do
not
include
all
residues
of
concern
needed
for
this
assessment
(linuron
and
metabolites
converted
to
3,4­
DCA)
and
would
underestimate
residue
values.
Anticipated
residues
(ARs)
were
computed
from
field
trial
data
and
subsequently
utilized
to
estimate
the
acute
dietary
exposure
to
linuron
in
the
diets
of
females
13­
50.
Percent
crop
treated
(%
CT)
data,
residue
reduction
data
from
washing,
cooking
and
various
processing
studies
were
used
as
refinements
to
the
residue
data.
Residue
distribution
files
(RDFs)
were
generated
for
all
nonblended
commodities
in
the
linuron
dietary
risk
assessment
incorporating
the
maximum
percent
of
crop
treated
estimate
as
a
representative
number
of
`zeros'
in
the
RDF.

The
linuron
acute
dietary
exposure
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
software
Version
7.73,
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
The
1989­
92
data
are
based
on
the
reported
consumption
of
more
than
10,000
individuals
over
three
consecutive
days,
and
therefore
represent
more
than
30,000
unique
person
days
of
data.
Foods
as
consumed
(e.
g.,
apple
pie)
are
linked
to
raw
agricultural
commodities
and
their
food
forms
(e.
g.,
apples­
cooked/
canned
or
wheat­
flour)
by
recipe
translation
files
internal
to
the
DEEM
software.
Consumption
data
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

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
(Tier
3/
4)
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(i.
e.,
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.
In
accordance
with
HED
policy,
per
capita
exposure
and
risk
are
reported
for
all
tiers
of
analysis.
The
acute
population
adjusted
dose
(aPAD)
is
calculated
as
the
acute
RfD
divided
by
the
FQPA
safety
factor.
The
calculated
acute
exposure
(residue
x
consumption)
was
compared
to
an
aPAD
of
0.0403
mg/
kg­
bw/
day,
which
reflects
an
FQPA
factor
of
3x.
The
results
are
presented
in
Table
4.

Table
4:
Summary
of
Acute
Dietary
Exposure
and
Risk
for
Linuron
Percentile
of
Exposure
Population
Subgroup:
Females
13­
50
Dietary
Exposure
(mg/
kg/
day)
%
aPAD
95th
0.000605
1.5
99th
0.001177
2.9
33
99.9th
0.003839
9.5
Uncertainties
associated
with
this
assessment
include
accuracy
of
the
percent
of
crop
treated
estimates;
the
translation
of
the
cooking/
processing
factors
across
crops;
and,
the
representativeness
of
the
Continuing
Survey
of
Food
Intake
by
Individuals
(CSFII)
consumption
survey.
The
Agency
is
confident,
however,
that
the
dietary
exposures
and
risks
anticipated
through
use
of
linuron
in/
on
plant
and
animals
are
not
under­
estimated.

4.2.3
Chronic
Dietary
Chronic
dietary
(food)
risk
estimates
associated
with
the
use
of
linuron
do
not
exceed
the
Agency's
level
of
concern
(>
100%
cPAD)
for
any
population
subgroup
including
the
most
highly
exposed
subgroup,
children
1­
6
years.
The
chronic
dietary
risk
for
children
ages
1­
6
years
is
approximately
35%
of
the
cPAD
and
approximately
15%
for
the
general
population.
(Linuron
Anticipated
Residues
and
Dietary
Exposure
Assessment,
DP
Barcode
D
279340,
John
Punzi
January
15,
2002.)

A
refined
(tier
3)
analysis
was
done
for
the
chronic
dietary
risk
assessment.
Residue
levels
from
USDA
and
FDA
monitoring
programs
do
not
include
all
residues
of
concern
needed
for
this
assessment
(linuron
and
metabolites
converted
to
3,4­
dichloroanaline)
and
would
underestimate
residue
values.
Anticipated
residues
were
computed
from
field
trial
data
and
subsequently
utilized
to
estimate
the
dietary
exposure
to
linuron
of
the
general
U.
S.
population,
as
well
as
certain
population
subgroups.
Percent
crop
treated
data,
residue
reduction
data
from
washing,
cooking
and
various
processing
studies
were
used
as
refinements
to
the
residue
data.

Linuron
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
software
Version
7.73,
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
dietary
exposure
assessment.

For
chronic
exposure
and
risk
assessment,
an
estimate
of
the
residue
level
in
each
food
or
foodform
(e.
g.,
orange
or
orange­
juice)
on
the
commodity
residue
list
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form.
The
resulting
residue
consumption
estimate
for
each
food/
food
form
is
summed
with
the
residue
consumption
estimates
for
all
other
food/
food
forms
on
the
commodity
residue
list
to
arrive
at
the
total
estimated
exposure.
Exposure
estimates
are
expressed
in
mg/
kg
body
weight/
day
and
as
a
percent
of
the
cPAD.
The
chronic
population
adjusted
dose
(cPAD)
is
the
chronic
RfD
divided
by
the
FQPA
safety
factor.
The
calculated
chronic
exposure
(residue
x
consumption)
was
compared
to
an
cPAD
of
0.00077
mg/
kg­
bw/
day,
which
reflects
an
FQPA
factor
of
10x.
This
procedure
is
performed
for
each
population
subgroup.
34
This
assessment
is
a
refined
tier
III
analysis
employing
a
number
of
residue
correction
factors
to
reflect
realistic
exposure
levels
in
the
diet.
These
include
the
application
of
percent
of
crop
treated
information
and
residue
reduction
studies.
Uncertainties
associated
with
this
assessment
include
accuracy
of
the
percent
of
crop
treated
estimates;
the
application
of
the
cooking/
processing
factors
across
crops;
and,
the
representativeness
of
the
CSFII
consumption
survey.
The
Agency
is
confident,
however,
that
the
exposures
and
risks
anticipated
through
use
of
linuron
on
plant
and
animals
is
not
under­
estimated.
The
chronic
exposure
estimates
were
less
than
100%
of
the
cPAD
with
the
highest
chronic
exposure
(0.00027
mg/
kg/
day)
occurring
in
children
1­
6
years
old
(35%
of
the
cPAD).
These
results
are
presented
in
Table
5.

Table
5:
Chronic
Dietary
Exposure
and
Risk
Values
Population
Subgroup
Dietary
Exposure
(mg/
kg/
day)
%
cPAD
U.
S.
Population
0.000114
14.8
All
Infants
(<
1
year)
0.000179
22.3
Children
1­
6
years
0.000268
34.7
Children
7­
12
years
0.000173
22.4
Females
13­
50
years
0.000083
10.8
Males
13­
19
years
0.000102
13.2
Males
20+
years
0.000088
11.4
Seniors
55+
years
0.000094
12.2
4.3
Water
Exposure/
Risk
Pathway
The
linuron
drinking
water
exposure
assessment
is
based
upon
review
of
environmental
fate
studies
for
parent
linuron,
modeling
and
monitoring
results
for
parent
linuron,
and
modeling
results
for
the
degradates
of
linuron
based
upon
parent
linuron
model
input
parameters.
Parent
linuron
appears
to
be
moderately
persistent
and
relatively
immobile.
Water
degradates
identified
in
the
linuron
aerobic
soil
metabolism
study
are
desmethyl
linuron,
3,4­
dichlorophenylurea
or
DCPU
(norlinuron)
and
desmethoxy­
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methylurea,
DCPMU.
The
degradate
3,4­
dichloroaniline
was
not
included
in
the
water
assessment
as
it
was
not
detected
in
the
aerobic
soil
metabolism
study
(0.01
ppm
detection
limit).
According
to
acceptable
fate
studies,
3,4­
DCA
is
formed
under
anaerobic
aquatic
conditions
rarely
found
in
the
environment
and
is
not
relevant
to
drinking
water
assessment.
The
environmental
fate
assessment
for
linuron
is
incomplete
and
tentative
because
information
on
the
persistence,
mobility
and
dissipation
pathways
of
several
degradates
of
linuron
is
not
35
available.
However,
none
of
the
linuron
water
degradates
are
present
at
levels
greater
than
10%
of
the
applied
parent,
and
therefore
not
considered
major
water
metabolites.
With
the
information
available,
EFED
believes
linuron
and
its
degradates
have
the
potential
to
impact
drinking
water
quality.
(Drinking
Water
Assessment
for
Linuron
metabolites
on
Carrots
in
California.
Ibrahim
Abdel­
Saheb.
Environmental
Fate
and
Effects
Division.
January
14,
2002.)

4.3.1
Environmental
Fate
There
is
a
reasonable
expectation
that
linuron
parent
and
its
metabolites
would
be
found
in
drinking
water.
Increased
mobility
may
occur
under
specific
environmental
conditions
such
as
in
coarse
textured
soils
and
soils
with
low
levels
of
organic
matter.
Linuron
dissipates
principally
by
biotic
processes
such
as
microbial
degradation.
In
surface
soils
with
adequate
organic
matter,
the
combined
processes
of
adsorption
and
microbial
degradation
would
limit
linuron's
potential
to
migrate
to
groundwater.
Linuron
could
runoff
to
surface
water
bodies.
In
that
case,
it
would
degrade
fairly
rapidly
to
desmethyl
linuron,
3,4­
dichlorophenylurea
(DCPU
or
norlinuron),
and,
desmethoxy­
linuron
(3­(
3,4­
dichlorophenyl)­
1­
methylurea
(DCPMU).
None
of
these
water
degradates
is
present
in
amounts
greater
than
10%
of
the
applied
radioactivity
in
the
aerobic
soil
metabolism
study.
The
available
data
on
the
major
degradates
of
linuron
are
insufficient
to
assess
their
runoff
potential
or
persistence
in
water.

Linuron
exhibits
some
of
the
properties
and
characteristics
of
chemicals
that
have
been
detected
in
ground
water,
and
linuron
itself
has
been
detected
in
ground
water
in
four
states
(Georgia,
Missouri,
Virginia
and
Wisconsin).
Linuron
is
moderately
persistent
with
an
aerobic
soil
metabolism
half­
life
ranging
from
57
to
100
days.
Because
parent
linuron
is
sufficiently
persistent
and
may
be
mobile
under
certain
environmental
conditions,
it
has
the
potential
to
impact
ground
water
quality.

Linuron
can
be
applied
aerially
or
by
ground
spray
and
therefore
could
contaminate
surface
waters
through
spray
drift.
It
has
the
potential
to
be
somewhat
persistent
in
surface
waters,
particularly
those
with
low
microbiological
activity
and
long
hydrological
residence
times.
Linuron
degraded
with
a
half­
life
of
less
than
3
weeks
in
non­
sterile
anaerobic
silt
loam
and
sand
soil:
water
(1:
1)
systems.
It
may
be
less
persistent
in
water
and
sediment
under
anaerobic
conditions
than
under
aerobic
conditions.
Its
bioconcentration
potential
is
relatively
low.

Linuron
is
not
currently
regulated
under
the
Safe
Drinking
Water
Act,
and
water
supply
systems
are
not
required
to
sample
and
analyze
for
it.
The
primary
treatment
processes
employed
by
most
water
systems
may
not
always
be
completely
effective
in
removing
linuron
and
its
degradates.
As
a
result,
the
Agency
does
have
some
moderate
concerns
regarding
potential
risks
of
linuron
and
these
degradates
to
surface
water
source
supply
systems.

4.3.2
Drinking
Water
Exposure
Estimates
The
Agency
currently
lacks
sufficient
water­
related
exposure
data
from
monitoring
to
complete
36
a
quantitative
drinking
water
exposure
analysis
and
risk
assessment
for
linuron
and
its
degradates.
Therefore,
the
Agency
is
presently
relying
on
computer­
generated
estimated
environmental
concentrations
(EECs).
The
tier
II
screening
model
PRZM/
EXAMS
is
used
to
generate
expected
environmental
concentrations
(EECs)
for
surface
water
and
SCI­
GROW
(an
empirical
model
based
upon
actual
monitoring
data
collected
for
a
number
of
pesticides
that
serve
as
benchmarks)
predicts
EECs
in
groundwater.
These
models
take
into
account
the
use
patterns
and
the
environmental
profile
of
a
pesticide,
but
do
not
include
consideration
of
the
impact
that
processing
raw
water
for
distribution
as
drinking
water
could
have
on
the
removal
or
metabolism
of
pesticides
from
the
source
water.

For
any
given
pesticide,
the
SCI­
GROW
model
generates
a
single
EEC
value
of
pesticide
concentration
in
ground
water.
That
EEC
is
used
in
assessments
of
both
acute
and
chronic
dietary
risk.
It
is
not
unusual
for
the
ground
water
EEC
to
be
significantly
lower
than
the
surface
water
EECs.
PRZM/
EXAMS
provides
surface
water
annual
daily
maximum,
an
annual
mean
as
well
as
36­
year
overall
mean
value
of
pesticide
concentration
in
surface
water
and
is
used
when
a
refined
surface
water
EEC
is
needed.

Surface
Water
The
use
of
linuron
on
carrots
in
California
was
modeled
for
the
purpose
of
assessing
surface
drinking
water
exposure
to
the
chemical
and
its
degradates.
This
use
represents
the
greatest
potential
drinking
water
exposure.
The
Tier
II
screening
models
PRZM
and
EXAMS
with
the
Index
Reservoir
and
Percent
Crop
Area
adjustment
(IR­
PCA)
were
used
to
determine
estimated
surface
water
concentrations
of
linuron
and
linuron
degradates.
The
IR­
PCA
modeling
results
indicate
that
linuron
and
its
degradates
have
the
potential
to
contaminate
surface
waters
by
spray
drift,
and
runoff
in
areas
with
large
amounts
of
annual
rainfall.
Modeling
results
are
higher
than
those
from
existing
surface
water
monitoring
data
for
linuron.

EFED
has
limited
monitoring
data
on
the
concentrations
of
linuron
(parent
only)
in
surface
water
and
has
no
monitoring
data
on
the
concentrations
of
desmethyl
linuron,
desmethoxy
linuron
or
nor
linuron
in
surface
water.
EFED
has
limited
fate
and
mobility
data
on
these
metabolites;
thus,
a
combined
residue
approach
was
used
to
calculate
their
aerobic
soil
metabolism
half­
lives
(assuming
equal
toxicity)
by
the
summation
of
the
concentrations
of
the
parent
and
its
metabolites.
The
index
reservoir
represents
a
potentially
vulnerable
drinking
water
source
based
on
the
geometry
of
an
actual
reservoir
and
its
watershed
in
a
specific
area
(Illinois),
using
regional
screening
specific
cropping
patterns,
weather,
soils,
and
other
factors.
The
PCA
is
a
generic
watershed­
based
adjustment
factor
which
represent
the
portion
of
a
watershed
planted
to
a
crop
or
crops
and
will
be
applied
to
pesticide
concentrations
estimated
for
the
surface
water
component
of
the
drinking
water
exposure
assessment
using
PRZM/
EXAMS
with
the
index
reservoir
scenario.
The
IR­
PCA
PRZM/
EXAMS
inputs
included
modeling
the
use
of
linuron
on
carrots
(greatest
percent
of
crop
treated
estimate),
a
14­
day
interval
between
applications,
and
ground
boom
application,
among
other
things.
("
Drinking
Water
Assessment
for
Linuron
on
Carrots
in
California."

Ibrahim
Abdel­
Sahed,
EFED,
October
14,
2001.)
37
There
are
a
number
of
inherent
limitations
with
the
water
model
used
to
estimate
concentrations
on
linuron
in
surface
water.
Because
the
index
reservoir
represents
a
fairly
vulnerable
watershed,
the
estimated
exposure
may
not
reflect
actual
exposure
for
most
drinking
water
sources.
A
single
steady
flow
has
been
used
to
represent
the
flow
through
the
reservoir
and
this
assumption
can
underestimate
or
overestimate
the
concentration
in
the
pond
depending
upon
the
annual
precipitation
pattern
at
the
site.
In
addition,
soils
can
vary
substantially
across
even
small
areas,
affecting
residue
concentrations
in
water,
and
this
variation
is
not
reflected
in
these
simulations.
Tile
drainage
is
not
specifically
considered
in
the
index­
reservoir
of
PRZM­
EXAMS.
Tile
drainage
may
cause
either
an
increase
or
decrease
in
the
pesticide
concentration
in
the
reservoir.
Turnover
occurs
when
the
temperature
drops
in
the
fall
and
the
thermal
stratification
of
the
reservoir
is
removed
and
EXAMS
is
unable
to
easily
model
spring
and
fall
turnover.
EFED
assumes
that
the
field
scale
processes
simulated
by
the
coupled
PRZM
and
EXAMS
models
are
a
reasonable
approximation
of
pesticide
fate
and
transport
within
a
watershed
that
contains
a
drinking
water
reservoir.
However,
available
monitoring
data
suggest
uneven
model
results.
In
addition,
the
use
of
input
parameter
values
for
the
parent
when
assessing
the
linuron
degradates
increases
the
uncertainties
in
the
assessment.
All
these
limitations
should
be
noted
when
evaluating
exposure
to
linuron
through
surface
water.

Groundwater
The
Screening
Concentration
in
Groundwater
(SCI­
GROW)
model
was
used
to
estimate
groundwater
concentrations
for
linuron
and
its
degradates.
The
SCI­
GROW
groundwater
modeling
result
is
lower
than
historical
monitoring
data
for
linuron
presence
in
groundwater.
The
maximum
observed
concentration
was
5.0
µg/
l
as
compared
to
the
SCI­
GROW
EEC
of
0.78
µg/
l
(combined
residues).
The
recommended
groundwater
drinking
water
EECs
is
5.0
µg/
l
and
is
based
upon
monitoring
data.

Groundwater
monitoring
data
were
compiled
from
the
1992
USEPA
Pesticide
in
Groundwater
Database.
Validated
monitoring
data
for
linuron
sampled
in
Georgia,
Missouri,
Virginia,
and
Wisconsin
were
considered
when
selecting
the
EEC
for
groundwater.
The
highest
concentration
of
linuron
in
groundwater
is
from
a
study
in
Georgia
in
which
67
out
of
70
well
results
detected
the
presence
of
linuron.
Monitoring
data
were
also
available
from
the
USGS
National
Water
Quality
Assessment
Program
(NAWQA),
however,
the
frequency
and
duration
of
sampling
were
not
sufficient
to
represent
an
adequate
monitoring
data
set
for
exclusive
use
in
drinking
water
exposure
determination.
SCIGROW
model
results
are
substantially
less
than
both
surface
water
modeling
and
groundwater
monitoring
data
indicate.
Therefore,
for
drinking
water
concentrations
from
groundwater,
EFED
recommends
an
EEC
value
of
5.0
µg/
l
derived
from
the
results
of
groundwater
monitoring
studies
for
linuron
parent.

EFED
also
reviewed
potential
groundwater
contamination
by
linuron
degradates.
EFED
has
no
monitoring
data
on
the
concentrations
of
desmethyl
linuron,
desmethoxy
linuron
or
nor
linuron
in
groundwater
at
the
present
time.
There
is
a
possibility
that
those
metabolites
were
not
included
in
the
38
sampling,
or
they
might
have
been
present
at
concentrations
lower
than
that
of
the
instruments
used
for
the
water
samples
collected.
The
SCI­
GROW
model
was
used
to
estimate
potential
groundwater
concentrations
of
linuron
water
degradates.
Groundwater
EECs
predicted
using
the
SCI­
GROW
screening
model
are
substantially
less
than
those
estimated
for
surface
water
using
PRZM
and
EXAMS.
However,
generally,
persistence
of
linuron
water
degradates
in
groundwater
should
be
longer.
The
values
listed
in
Table
6
will
be
used
in
comparison
to
a
drinking
water
level
of
comparison
(DWLOC).

Table
6.
Estimated
environmental
concentrations
in
surface
and
groundwater
for
linuron
use
on
carrots.

model/
monitoring
EECs
(µg/
L)

Linuron
Desmethyl
linuron
Desmethoxy
linuron
Norlinuron
Surface
water/
peak
(90
th
percentile
annual
daily
max.)
31.3
1.69
3.26
1.26
Surface
water/
90
th
percentile
annual
mean)
12.5
1.60
3.10
1.20
Surface
water/
36­
year
overall
mean
7.31
1.17
2.28
0.88
Groundwater/
peak
and
long
term
average
0.54
0.047
0.094
0.035
Groundwater
monitoring
result
5.0*
N/
A
N/
A
N/
A
Use(
s)
modeled
two
applications
on
carrots
@
1.0
lb
ai/
acre,
ground
application
two
applications
on
carrots
@
0.04
lb
ai/
acre,
ground
application
two
applications
on
carrots
@
0.08
lb
ai/
acre,
ground
application
two
applications
on
carrots
@
0.03
lb
ai/
acre,
ground
application
Percent
Crop
Area
(PCA)
Default
PCA
(0.87)

*
USEPA
Pesticide
in
Groundwater
Database,
1992
4.4
Residential
Exposure/
Risk
Pathway
39
There
are
currently
no
registered
uses
for
linuron
in
the
residential
environment.
However,
the
linuron
label
does
include
use
of
the
chemical
in
rights­
of­
way
areas
and
spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
this
type
of
spraying
operation.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
groundboom
application
methods.
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.
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
and
risks
associated
with
the
application
of
linuron
by
aerial
as
well
as
other
application
types
where
appropriate.

5.0
Aggregate
Risk
Assessment
and
Risk
Characterization
The
Food
Quality
Protection
Act
(FQPA)
amendments
to
the
Federal
Food,
Drug
and
Cosmetic
Act
requires
for
establishing
or
reassessing
a
pesticide
tolerance
"that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
the
pesticide
chemical
residue,
including
all
anticipated
dietary
exposures
and
all
other
exposure
for
which
there
is
reliable
information."
The
November
20
th
,
2001
HIARC
meeting
resulted
in
endpoint
selection
for
all
exposure
durations
and
routes,
including
the
residential
pathway.
However,
exposure
is
only
expected
to
occur
via
the
food
and
water
pathways
of
exposure.
If
new
uses
are
added
to
the
label
in
the
future
which
include
possible
exposure
to
persons
in
the
residential
environment,
EPA
will
conduct
this
analysis.
The
toxicological
endpoints
appropriate
for
the
dietary
(oral)
route
of
exposure
are,
therefore,
the
only
hazard
endpoints
considered
in
this
analysis.

Acute
and
chronic
aggregate
risk
is
comprised
of
the
combined
exposures
from
food
and
water.
Risk
estimates
are
aggregated
because
it
is
assumed
exposure
may
occur
over
the
same
time
period.
The
HIARC
selected
an
acute
dietary
endpoint
for
females
13­
50
based
upon
increased
postimplantation
loss
and
fetal/
litter
resorptions
at
the
LOAEL
seen
in
a
developmental
rat
study.
However,
no
appropriate
effect
attributed
to
a
single
exposure
was
identified
in
the
toxicology
database
for
the
general
population.
The
chronic
dietary
aggregate
assessment
will
utilize
an
endpoint
based
on
a
chronic
oral
study
in
the
dog
which
demonstrated
an
increased
met­
and
sulfhemoglobin
level
at
the
LOAEL.

DWLOCs
are
used
to
estimate
aggregate
risk
from
drinking
water
sources.
DWLOCs
are
theoretical
upper
limits
of
a
pesticide's
concentration
in
drinking
water
in
light
of
total
aggregate
exposure
to
a
pesticide
in
food
and
drinking
water.
A
DWLOC
will
vary
depending
on
the
toxic
endpoint,
drinking
water
consumption,
and
body
weight.
HED
uses
DWLOC's
internally
in
the
risk
assessment
process
as
a
surrogate
measure
of
potential
exposure
associated
with
pesticide
exposure
40
through
drinking
water.
In
the
absence
of
reliable
monitoring
data
for
pesticides
which
can
be
used
directly
and
quantitatively
in
the
risk
assessment,
it
is
used
as
a
point
of
comparison
against
conservative
model
estimates
of
a
pesticide's
concentration
in
water.
DWLOC
values
are
not
a
regulatory
standard
for
drinking
water.
However,
they
do
have
an
indirect
regulatory
impact
through
aggregate
exposure
and
risk
assessments.

Risk
estimates
for
food
and
water
are
summarized
in
Tables
7
and
8.
The
estimates
of
food
exposure
are
considered
to
be
highly
refined
since
anticipated
residues
were
generated
for
both
the
acute
and
chronic
dietary
exposure
scenarios
which
includes
incorporation
of
percent
of
crop
treated
values,
processing
factors,
and
reduction
of
residue
information
such
as
cooking
and
washing
factors.
In
addition,
for
the
acute
dietary
exposure
assessment,
a
probabilistic
approach
was
used.

On
March
13,
2002,
the
Registration
Division
informed
the
Health
Effects
Division
of
an
Interregional
Research
Project
number
4
(IR­
4)
request
for
additional
tolerances
for
linuron.
The
two
new
uses
are
on
rhubarb
(0.5
ppm)
and
celeriac
(1.0
ppm).
When
these
two
new
uses
are
added
to
the
dietary
exposure
assessment,
there
are
no
changes
to
the
total
exposure
and,
therefore,
total
dietary
risk
estimates
for
this
chemical.
Similarly,
there
are
no
changes
expected
to
the
total
aggregate
exposure
and
risk
estimate.
Therefore,
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
linuron
when
the
new
uses
for
rhubarb
and
celeriac
are
added
to
the
list
of
crops
on
which
the
chemical
may
be
used.

5.1
Acute
Risk
5.1.1
Acute
Aggregate
Risk
Assessment
(Females
13­
50)

The
acute
aggregate
exposure
from
residues
of
linuron
and
its
metabolites
in
food
and
drinking
water
and
do
not
exceed
the
Agency's
level
of
concern.
The
calculated
DWLOCs
exceed
the
estimated
drinking
water
concentrations.
HED
calculates
DWLOCs
by
a
two­
step
process:
exposure
is
subtracted
from
the
PAD
to
obtain
the
maximum
exposure
allowed
in
drinking
water;
DWLOCs
are
then
calculated
using
that
value
and
HED
default
body
weight
and
drinking
water
consumption
figures.
In
assessing
human
health
risk,
DWLOCs
are
compared
to
EECs.
When
EECs
are
less
than
DWLOCs,
HED
considers
the
aggregate
risk
[from
food
+
water
exposures]
to
be
acceptable.

Estimated
environmental
concentrations
for
linuron
and
its
water
degradates
were
compared
to
the
acute
DWLOCs
since
adequate
monitoring
data
were
not
available.
EFED
provided
Tier
II
PRZM­
EXAMS
with
Index
Reservoir
and
Percent
Crop
Area
adjustment
(IR­
PCA
PRZM­
EXAMS)
estimates
to
determine
acute
dietary
aggregate
exposure
and
risk
values.
This
model
simulated
linuron
drinking
water
concentrations
(for
the
carrot
use)
of
38
µg/
L
for
the
surface
water
peak
annual
daily
maximum
for
linuron
and
its
degradates
in
water.
The
SCI­
GROW
model
was
used
to
estimate
concentrations
of
linuron
and
its
degradates
in
groundwater
(0.76
µg/
L),
however,
EFED
recommended
that
the
groundwater
drinking
water
EEC
of
5.0
µg/
L
determined
through
groundwater
monitoring
41
studies
be
used.
This
is
because
the
model
estimate
is
an
order
of
magnitude
below
the
monitoring
estimate.

The
DWLOC
calculated
for
acute
aggregate
risk
for
females
13­
50
is
1085
µg/
L.
These
results
are
presented
in
Table
7.
Therefore,
HED
concludes
with
reasonable
certainty
that
residues
of
linuron
and
its
metabolites
in
drinking
water
will
not
contribute
significantly
to
the
acute
human
health
risk
and
that
the
acute
aggregate
exposure
from
residues
of
linuron
and
its
metabolites
in
food
and
drinking
water
and
will
not
exceed
the
Agency's
level
of
concern
for
acute
aggregate
exposure
for
females
13­
50.

5.1.2
Acute
DWLOC
Calculations
Table
7.
Acute
DWLOC
Calculations
Population
Subgroup
1
Acute
Scenario
aPAD
mg/
kg/
day
Acute
Food
Exp
mg/
kg/
day
Max
Acute
Water
Exp
mg/
kg/
day
1
Ground
Water
EEC
(ppb)
2
Surface
Water
EEC
(µg/
l)
2
Acute
DWLOC
(µg/
L)
3
Females
13­
50
0.0403
0.003839
4
0.036461
5
38
1085
1
Maximum
acute
water
exposure
(mg/
kg/
day)
=
[(
acute
PAD
(mg/
kg/
day)
­
acute
food
exposure
(mg/
kg/
day)]
2
The
crop
producing
the
highest
level
was
used
for
the
surface
water
EEC
and
groundwater
monitoring
results
are
used
for
the
groundwater
EEC.
3
Acute
DWLOC(
µg/
L)
=
[maximum
acute
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]
4
Acute
food
exposure
is
exposure
estimate
at
the
99.9th
percentile
from
the
Monte
Carlo
assessment
performed.
Assumptions:
Body
weights
(60
kg
adult
female);
water
consumption
2
liters/
day
adult.

5.2
Chronic
Risk
5.2.1
Chronic
Aggregate
Risk
Assessment
Chronic
aggregate
exposure
from
residues
of
linuron
and
its
metabolites
in
food
and
drinking
water
from
surface
water
sources
exceeds
the
Agency's
level
of
concern
for
chronic
aggregate
exposure
for
infants
and
children.
Calculated
DWLOCs
are
below
the
drinking
water
exposure
estimates.
EFED
provided
Tier
II
PRZM­
EXAMS
with
Index
Reservoir
and
Percent
Crop
Area
adjustment
(IR­
PCA
PRZM­
EXAMS)
to
determine
chronic
dietary
aggregate
exposure
and
risk
values.
This
model
simulated
drinking
water
concentrations
of
linuron
and
its
degradates
(for
the
carrot
use)
of
18.4
µg/
L
for
the
surface
water
annual
mean.
The
SCI­
GROW
model
was
used
to
estimate
concentrations
of
linuron
in
groundwater
(0.76
µg/
L),
however,
EFED
recommended
that
the
groundwater
drinking
water
EEC
of
5.0
µg/
L
determined
through
groundwater
monitoring
studies
be
used.
Because
the
model
estimate
is
an
order
of
magnitude
below
the
monitoring
estimate,
the
Agency
is
using
the
results
of
the
monitoring
data
assure
exposure
and
risks
are
conservatively
assessed.

As
shown
in
Table
8,
the
DWLOCs
calculated
for
chronic
aggregate
risk
range
from
6
µg/
L
for
infants
and
children
to
23
µg/
L
for
the
general
population
and
females
13­
50.
The
chronic
aggregate
42
risk
calculations
show
that
the
EEC
of
linuron
in
surface
drinking
water
exceed
the
allowable
levels
of
linuron
in
drinking
water
based
upon
the
DWLOC
value
for
the
infants
and
children
sub­
groups.
Therefore,
residues
of
linuron
and
its
metabolites
in
drinking
water
may
represent
a
chronic
human
health
risk
and
that
the
chronic
aggregate
exposure
from
residues
of
linuron
and
its
metabolites
in
food
and
drinking
water
exceeds
the
Agency's
level
of
concern
for
chronic
aggregate
exposure
for
infants
and
children.
The
degree
to
which
the
EEC
exceeds
the
calculated
DWLOC
is
slight,
but
it
does
represent
the
best
information
HED
has
to
assess
chronic
aggregate
exposure
and
risk
to
linuron.
An
immediate
conclusion
of
safety
cannot
be
made
for
the
population
subgroups
of
infants
and
children
1­
6
since
the
DWLOC
is
less
than
the
estimated
EECs.
However,
since
the
EEC
estimates
are
based
on
upper­
end
input
parameters
such
as
the
maximum
application
rate,
the
assessment
indicates
a
need
to
refine
the
drinking
water
exposure
estimates
by
attaining
additional
information
about
the
persistence
and
mobility
of
linuron
water
degradates.
The
issues
will
be
considered
by
the
Agency
as
part
of
linuron
tolerance
reassessment.

5.2.2
Chronic
DWLOC
Calculations
Table
8.
Chronic
DWLOC
Calculations
Population
Subgroup
1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day
2
Ground
Water
EEC
(ppb)
3
Surface
Water
EEC
(µg/
L)
3
Chronic
DWLOC
(µg/
L)

U.
S.
Population
0.00077
0.00011
0.00066
5
18
23
Females
13­
50
0.00077
0.000083
0.00069
5
18
23
Infants
(<
1
year)
0.00077
0.00018
0.00059
5
18
6
Children
1­
6
0.00077
0.00027
0.0005
5
18
6
1
Children
1­
6
are
the
most
highly
exposed
sub­
group.
2
Maximum
Chronic
Water
Exposure
(mg/
kg/
day)
=
[Chronic
PAD
(mg/
kg/
day)
­
Chronic
Dietary
Exposure
(mg/
kg/
day)]
3
The
use
of
linuron
on
carrots
was
modeled
to
determine
surface
water
EEC's
and
the
results
of
groundwater
monitoring
study
was
used
to
determined
groundwater
EEC.
4
Chronic
DWLOC(
µg/
L)
=
[maximum
chronic
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]
Assumptions:
Body
weights
(70
kg
adult
male;
60
kg
adult
female;
10
kg
child);
water
consumption
2
liters/
day
adult
and
1
liter/
day
infants
and
children.

6.0
Cumulative
Risk
The
Food
Quality
Protection
Act
(1996)
stipulates
that
when
determining
the
safety
of
a
pesticide
chemical,
EPA
shall
base
its
assessment
of
the
risk
posed
by
the
chemical
on,
among
other
things,
available
information
concerning
the
cumulative
effects
to
human
health
that
may
result
from
43
dietary,
residential,
or
other
non­
occupational
exposure
to
other
substances
that
have
a
common
mechanism
of
toxicity.
The
reason
for
consideration
of
other
substances
is
due
to
the
possibility
that
low­
level
exposures
to
multiple
chemical
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
could
lead
to
the
same
adverse
health
effect
as
would
a
higher
level
of
exposure
to
any
of
the
other
substances
individually.
A
person
exposed
to
a
pesticide
at
a
level
that
is
considered
safe
may
in
fact
experience
harm
if
that
person
is
also
exposed
to
other
substances
that
cause
a
common
toxic
effect
by
a
mechanism
common
with
that
of
the
subject
pesticide,
even
if
the
individual
exposure
levels
to
the
other
substances
are
also
considered
safe.

HED
did
not
perform
a
cumulative
risk
assessment
as
part
of
the
TRED
for
linuron
because
HED
has
not
yet
initiated
a
comprehensive
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
linuron.
For
purposes
of
this
TRED,
EPA
has
assumed
that
linuron
does
not
have
a
common
mechanism
of
toxicity
with
other
substances.

On
this
basis,
the
registrant
must
submit,
upon
EPA's
request
and
according
to
a
schedule
determined
by
the
Agency,
such
information
as
the
Agency
directs
to
be
submitted
in
order
to
evaluate
issues
related
to
whether
linuron
shares
a
common
mechanism
of
toxicity
with
any
other
substance
and,
if
so,
whether
any
tolerances
for
linuron
need
to
be
modified
or
revoked.
If
HED
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
linuron,
HED
will
perform
aggregate
exposure
assessments
on
each
chemical,
and
will
begin
to
conduct
a
cumulative
risk
assessment.

HED
has
developed
a
framework
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
was
issued
on
January
16,
2002
(67
FR
2210­
2214)
and
is
available
from
the
OPP
Website
at:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cumulative_
guidance.
pdf.
In
the
guidance,
it
is
stated
that
a
cumulative
risk
assessment
of
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
will
not
be
conducted
until
an
aggregate
exposure
assessment
of
each
substance
has
been
completed.

Before
undertaking
a
cumulative
risk
assessment,
HED
will
follow
procedures
for
identifying
chemicals
that
have
a
common
mechanism
of
toxicity
as
set
forth
in
the
"Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity"
(64
FR
5795­
5796,
February
5,
1999).

7.0
Incident
Data
The
Agency
searched
several
databases
for
reports
of
poisoning
incident
data
for
linuron.
These
databases
include
the
OPP
Incident
Data
System,
the
Poison
Control
Centers
database,
the
California
Department
of
Pesticide
Regulation,
and
the
National
Pesticide
Telecommunications
Network.
Relatively
few
incidents
of
illness
have
been
reported.
Three
cases
were
submitted
to
the
California
Pesticide
Illness
Surveillance
Program
(1982­
1999)
concerning
possible
linuron
poisoning.
Effects
reported
in
these
cases
include
chemical
conjuctivitis
when
linuron
was
splashed
into
the
eyes,
44
headache,
nausea,
swollen
tongue
and
blurred
vision,
and
itchy
hives.
According
to
the
fifth
edition
of
"Recognition
and
Management
of
Pesticide
Poisonings"
(EPA
1999),
systemic
toxicity
is
unlikely
unless
large
amounts
have
been
ingested.
No
recommendations
can
be
made
based
on
the
few
incident
reports
available
for
linuron.
("
Review
of
Linuron
Incident
Reports."
#
035506
Jerome
Blondell,
January
11,
2002.).

8.0
Data
Needs
Product
Chemistry
1.
The
product
chemistry
data
base
is
complete.

Toxicology
2.
A
developmental
neurotoxicity
study
is
required
for
linuron
due
to
concern
for
neuro­
endocrine
disruption.
And,
a
28­
day
inhalation
study
in
the
rat
is
required.

Residue
Chemistry
3.
A
review
of
the
product
labels
and
the
supporting
residue
data
indicate
that
the
following
label
amendments
are
required:

The
product
labels
include
directions
for
use
for
a
number
of
tank
mixes.
In
many
cases,
the
tank
mix
products
are
no
longer
registered
for
use
on
the
subject
crop.
Inappropriate
tank
mix
recommendations
are
noted
in
Table
2
of
"Linuron
Tolerance
Reassessment
Eligibility
Decision
Residue
Chemistry
Considerations."
(DP
Barcode
272368)

A
number
of
grazing/
feeding
restriction
are
considered
to
be
impractical
by
HED
and
must
be
removed
from
the
appropriate
product
labels.

Several
crops/
use
directions
require
PHIs
to
be
specified.

Product
labels
which
contain
use
directions
for
asparagus
must
be
modified
to
make
it
clear
that
the
maximum
combined
application
rate
is
4.0
lb
ai/
A/
season
when
more
than
one
type
of
application
(preemergence,
postemergence,
or
application
at
the
fern
stage)
is
made.

The
product
label
for
EPA
Reg.
No.
1812­
245
includes
two
tables
of
application
rates
at
the
end
of
the
soybean
use
directions
which
are
titled
"Soybeans:
Broadcast
Application
­
Linex
4L
and
Sencor
DF
and
Lasso"
and
"Soybeans:
Broadcast
45
Application
­
Linex
4L
and
Sencor
DF
and
Duel
8E."
The
label
should
be
modified
to
clarify
application
timing
for
these
tables;
it
is
not
clear
to
which
application
type
preemergence
or
post­
emergence)
these
application
rates
pertain.

4.
The
reregistration
requirements
for
residue
analytical
methods
are
not
fulfilled.
The
registrants
must
propose
the
current
data
collection
method,
a
GC/
ECD
method,
as
an
enforcement
method
for
plant
and
animal
commodities
to
replace
the
outdated
colorimetric
enforcement
method.

5.
The
reregistration
requirements
for
storage
stability
are
not
fulfilled.
The
final
reports
for
ongoing
storage
stability
studies
on
cotton
processed
commodities,
and
sweet
corn
commodities
must
be
submitted.
In
addition,
information
pertaining
to
sample
storage
intervals
and
conditions
for
samples
of
parsnips
and
for
the
animal
feeding
studies
are
required.

6.
The
reregistration
requirements
for
magnitude
of
the
residue
in
plants
are
not
fulfilled
for:
celery;
corn,
field,
aspirated
grain
fractions;
corn,
sweet
(K+
CWHR);
corn,
sweet,
forage;
corn,
sweet,
stover;
sorghum
forage
and
stover;
wheat
forage,
hay,
and
straw.
Additional
crop
field
trial
data
and/
or
information
is
required
for
these
commodities.

7.
Tolerances
for
linuron
residues
of
concern
in
milk
must
be
proposed.

Environmental
Fate
8.
Two
environmental
fate
data
requirements
are
not
fulfilled.
They
are
a
Leaching/
Adsorption/
Desorption
study
and
a
Terrestrial
Field
Dissipation
study.
46
References:

Linuron.
Product
Chemistry
Chapter
for
the
Tolerance
Renewal
Eligibility
Decision
(TRED)
Document.
DP
Barcode
D273274.
Ken
Dockter.
October
1,
2001.

LINURON
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
(HED
Doc.
No.
0050286)
Robert
Fricke.
November
20,
2001.

LINURON
(PC
code
035506)
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document.
Robert
Fricke.
DP
Barcode
D272367
January
30,
2002.

Linuron.
Anticipated
Residues
and
Dietary
Exposure
Assessment
(PC
Code
035506).
John
Punzi.
DP
Barcode
D279340.
January
15,
2002.

Linuron
Tolerance
Reassessment
Eligibility
Decision
Residue
Chemistry
Considerations.
(DP
Barcode
D272368)
John
Punzi.
November
26,
2001.

Linuron
Plant
and
Animal
Metabolism:
Results
of
the
HED
Metabolism
Committee
Meetings
held
October
21
and
October
29,
1993.
Dennis
McNeilly.
November
17,
1993.

Drinking
Water
Assessment
for
Linuron
on
Carrots
in
California.
Ibrahim
Abdel­
Saheb.
Environmental
Fate
and
Effects
Division.
October
14,
2001.

Drinking
Water
Assessment
for
Linuron
metabolites
on
Carrots
in
California.
Ibrahim
Abdel­
Saheb.
Environmental
Fate
and
Effects
Division.
January
14,
2002.

Quantitative
Usage
Analysis
for
Linuron.
Frank
Hernandez.
August
18,
2000.

Review
of
Linuron
Incident
Reports.
Chemical
035506.
Jerome
Blondell.
January
11,
2002.

Linuron
­
Report
of
the
FQPA
Safety
Factor
Committee.
Carol
Christensen.
December
6,
2001.

DIURON:
The
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(RED).
PC
Code:
035505.
Case
0046.
DP
Barcode
D272130.
Diana
Locke.
December
2002.

Reregistration
Eligibility
Decision:
Linuron.
EPA
No.
738­
R­
95­
003.
March
1995.
