Document ID: EPA-HQ-OPP-2002-0079-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-06-19T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICID
ES
AND
TOXIC
SUBSTANCES
HED
DOC.
NO.
0050286
DATE:
November
20,
2001
MEMORANDUM
SUBJECT:
LINURON
­
Report
of
the
Hazard
identification
Assessment
Review
Committee
FROM:
Robert
F.
Fricke,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
(7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(7509C)

TO:
Carmen
Rodia
Chemical
Review
Manager
Special
Review
and
Registration
Division
(7508C)

CC:
Tom
Meyers
(SRRD,
7508C)
Carol
Christensen
(HED,
RRB2,
7509C)

PC
CODE:
035506
On
September
13
and
27,
2001
the
Hazard
Identification
assessment
Review
Committee
(HIARC)
reviewed
the
toxicology
data
base
of
linuron
and
selected
endpoints/
doses
for
various
exposure
assessments.
The
HIARC
also
evaluated
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
linuron
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
The
conclusions
drawn
at
these
meetings
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
in
attendance:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Paula
Deschamp
Pamela
Hurley,
John
Liccione,
David
Nixon,
Jess
Rowland
(Co­
Chair),
and
Brenda
Tarplee
Members
in
absentia:.
Elizabeth
Doyle
(Co­
Chair)
and
Elizabeth
Mendez
Also
in
attendance:
Susan
Makris,
Carol
Christensen,
Ken
Doctor,
and
Pauline
Wagner
Data
evaluation
/
presentation:
Robert
F.
Fricke
Reregistration
Branch
2
3
N
H
Cl
Cl
O
N
CH
3
O
CH
3
Linuron
(035506)
1
INTRODUCTION
On
September
13
and
27,
2001
the
Health
Effects
Division's
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
Linuron
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfD),
the
toxicological
endpoints
for
short
(1­
30
days)­
and
intermediate
(1­
6
months)­
term
dermal
occupational
exposure,
and
the
endpoints
for
short­,
intermediate­
and
long­
term
(greater
than
6
months)
inhalation
occupational
exposure.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Linuron
was
also
evaluated.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.

2
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(RfD)
­
Females
13+

Study
Selected:
Prenatal
Oral
Developmental/
Rat
OPPTS
870.3700
MRID
No.:
00018167
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
00018167),
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.
Average
doses
to
the
treated
dams
were
5.0,
12.1,
and
50
mg/
kg/
day,
respectively.
The
day
evidence
of
mating
was
found
was
designated
GD
1.
Maternal
body
weights
and
food
consumption
were
recorded
on
GD
6,
10,
16,
and
21.
On
GD
21,
all
surviving
dams
were
sacrificed
and
all
fetuses
were
weighed
and
examined
for
external
malformations/
variations.
Crown­
rump
length
was
measured
on
each
fetus.
Approximately
one­
half
of
the
fetuses
in
each
litter
were
fixed
in
Bouin's
solution
for
visceral
examination
and
the
remaining
one­
half
were
processed
for
skeletal
examination.

All
animals
survived
to
scheduled
termination
without
the
appearance
of
any
treatmentrelated
clinical
signs
of
toxicity.
Gross
necropsy
was
unremarkable.
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
Body
weight
gains
and
food
consumption
by
the
low­
and
mid­
dose
groups
were
similar
to
the
controls
throughout
the
study.
Body
weights
of
the
high­
dose
group
were
significantly
(p
#
0.05)
less
than
the
control
group
on
GD
10,
16,
and
21.
Food
consumption
by
the
high­
dose
group
was
significantly
(p
#
0.05)
less
than
that
of
the
controls
for
the
intervals
of
GD
6­
10
and
10­
16.
4
Therefore,
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
control,
low­,
mid­,
and
high­
dose
groups
post­
implantation
loss
was
5.8,
3.5,
4.4,
and
14.0%,
respectively,
and
the
number
of
resorptions
per
litter
with
resorption
was
1.6,
1.6,
1.2,
and
2.1,
respectively.

No
treatment­
related
external
or
visceral
malformations/
variations
were
noted.
In
the
highdose
group
bipartite
thoracic
vetebral
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
625
ppm
(50
mg/
kg/
day)
based
on
increases
in
post­
implantation
loss
and
in
litter/
fetal
resorptions.
The
developmental
toxicity
NOAEL
is
125
ppm
(12
mg/
kg/
day).

This
study
is
classified
as
Acceptable/
Guideline
and
does
satisfy
the
guidelines
for
a
developmental
toxicity
study
[OPPTS
870.3700
(83­
3a)]
in
rats.

AcuteR
D
mg
kg
day
UF
mg
kg
day
f
=
=
12
100
012
//
()
.//

Dose
and
Endpoint
for
Establishing
Acute
RfD:
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).

Uncertainty
Factor(
s):
100x
(10x
intraspecies
variability,
10x
interspecies
extrapolation).

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
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.

2.2
Acute
Reference
Dose
(RfD)
­
General
Population
An
appropriate
end
point
attributable
to
a
single­
dosesment
for
this
population
subgroup
was
not
available
in
the
database.
5
2.3
Chronic
Reference
Dose
(RfD)

Study
Selected:
Chronic
Toxicity
(1­
Year)/
Dog
870.4100
(§
83­
1b)

MRID
No.:
40952601
Executive
Summary:
In
a
one­
year
chronic
toxicity
study,
linuron
(96.2%
a.
i.,
Batch
No.
6,569)
was
administered
to
groups
of
4
male
and
4
female
beagle
dogs
in
the
diet
at
concentrations
of
0,
10,
25,
125,
or
625
ppm
(MRID
40952601).
Time­
weighted
average
doses
for
the
treated
groups
were
0.29,
0.79,
4.2,
and19
mg/
kg/
day,
respectively,
for
males
and
0.30,
0.77,
3.5,
and
16
mg/
kg/
day,
respectively,
for
females.

No
treatment­
related
clinical
signs
of
toxicity
or
mortalities
were
observed
at
any
dose
level.
Body
weights,
body
weight
gains,
and
food
consumption
were
not
affected
by
treatment.
No
treatment­
related
ophthalmological
lesions
or
changes
in
urinalysis
parameters
were
noted
and
gross
necropsy
was
unremarkable.

RBC
counts,
hemoglobin,
and
hematocrit
were
slightly
(n.
s.)
decreased
throughout
the
study
in
high­
dose
males
and
females
as
compared
with
those
of
the
controls.
WBC
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
sulfhemoglobin
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
from
3/
4
high­
dose
males
and
4/
4
high­
dose
females,
compared
with
none
of
the
control
males
and
only
1/
4
control
females.

Cholesterol
levels
were
increased
in
the
high­
dose
groups
at
all
time
points
as
compared
with
control
levels
with
statistical
significance
(p
#
0.05)
attained
at
3,
6,
9,
and
12
months
for
males
and
3
months
for
females.

Absolute
liver
weights
were
slightly
(n.
s.)
increased
in
the
625
ppm
males
and
relative
liver
weights
were
significantly
(p
#
0.05)
increased
in
the
125
and
625
ppm
males.
No
effects
on
liver
weights
were
noted
in
females.

Increases
in
the
incidence
and/
or
severity
of
brown
pigment
(hemosiderin)
deposition
in
the
liver
were
observed
microscopically
in
high­
dose
males
and
females.

The
LOAEL
for
linuron
in
male
and
female
beagle
dogs
was
established
at
125
ppm
(4.17
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).
6
This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
chronic
toxicity
study
[OPPTS
870.4100
(83­
1b)]
in
dogs.

Dose
and
Endpoint
for
Establishing
Chronic
RfD:
NOAEL
=
0.77
mg/
kg/
day,
based
on
increased
met­
and
sulfhemoglobin
levels
at
the
LOAEL
(4.17
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females).

Uncertainty
Factor(
s):
100x
(10x
intraspecies
variability,
10x
interspecies
extrapolation).

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
route
of
administration
and
duration
of
exposure
are
appropriate
for
establishing
a
chronic
RfD.

ChronicR
D
mg
kg
day
UF
mg
kg
day
f
=
=
077
100
0
0077
.//
()
.//

2.4
Occupational
Exposure
2.4.1
Oral
Exposure
2.4.1.1
Short­
Term
(1­
30
days)
Incidental
Oral
Exposure
Study
Selected:
Reproduction
and
Fertility
Effects/
Rat
870.3800
(§
83­
4)

MRID
No.:
41463401,
41864701
Executive
Summary:
In
a
two­
generation
reproduction
study,
linuron
(96.2%
a.
i.)
was
administered
to
groups
of
30
male
and
30
female
Crl:
CDBR
rats
in
the
diet
at
concentrations
of
0,
12.5,
100,
or
625
ppm
(MRID
Nos:
41463401,
41864701).
One
litter
was
produced
by
each
generation.
Average
premating
doses
for
the
treated
F0
groups
were
0.74,
5.8,
and
36
mg/
kg/
day,
respectively,
for
males
and
0.92,
7.33,
and
45.1
mg/
kg/
day,
respectively,
for
females.
Average
premating
doses
for
the
treated
F1
groups
were
0.948,
7.77,
and
54.0
mg/
kg/
day,
respectively,
for
males
and
1.12,
9.24,
and
63.0
mg/
kg/
day,
respectively,
for
females.
F0
and
F1
parental
animals
were
administered
test
or
control
diet
for
72
or
75
days,
respectively,
prior
to
mating
and
throughout
mating,
gestation,
and
lactation,
and
until
necropsy.

No
treatment­
related
clinical
signs
of
toxicity
or
mortalities
were
observed
in
the
adult
animals
of
either
generation.

Body
weights,
body
weight
gains,
and
food
consumption
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
beginning
on
day
7
for
the
high­
dose
F0
animals
(19%,
males;
14%,
females)
and
throughout
premating
for
the
mid­
(6%,
males;
8%,
females)
7
and
high­
(24%,
males;
25%,
females)
dose
F1
animals.
At
the
high­
dose,
overall
weight
gains
in
F0
males
and
females
were
decreased
59%
and
55%,
respectively,
and
for
highdose
F1
males
and
females,
76%
and
75%,
respectively.
Mean
daily
food
consumption
levels
for
the
high­
dose
groups
during
the
premating
interval
were
80­
85%
of
the
control
levels.
Absolute
body
weights
of
the
mid­
dose
F0
males
were
occasionally
significantly
(p
#
0.05)
less
than
the
controls
with
premating
weight
gains
and
food
consumption
88%
and
94%
(both,
p
#
0.05),
respectively,
of
the
control
levels.
For
the
mid­
dose
F1
males
and
females,
final
premating
body
weights,
body
weight
gains,
and
food
consumption
were
92­
94%
of
the
control
levels.
For
the
mid­
and
high­
dose
dams
of
both
generations,
lower
body
weights
during
gestation
and
lactation
were
considered
a
continuation
of
premating
effects.

No
treatment­
related
lesions
were
noted
at
necropsy
of
the
F0
males
or
females.
In
highdose
F1
males,
gross
lesions
of
the
testes
included
reduced
in
size
(9/
30),
abnormally
large
(3/
30),
soft
(5/
30),
small
epididymides
(8/
30),
and
unspecified
deformities
of
the
epididymides
(5/
30);
these
were
noted
as
significant
incidences,
but
control
rates
were
not
given
in
the
original
DER.
Microscopically,
increased
incidences
(p
#
0.05)
of
testicular
and
epididymal
lesions
were
found
in
high­
dose
F1
males
as
compared
with
the
controls:
atrophy
(14/
30),
fibrosis
(8/
30),
and
hyperplasia
(7/
30)
in
the
testes
and
arteritis
(6/
30),
inflammation
(5/
30),
and
oligospermia
(12/
30)
in
the
epididymides.
Only
one
incidence
each
of
atrophy
and
oligospermia
were
observed
in
control
animals.
Absolute
testes
weights
of
the
high­
dose
F1
males
were
significantly
(p
#
0.05;
80%
of
control)
less
than
the
controls.
In
high­
dose
F1
females,
gross
findings
(n.
s.)
included
cystic
ovaries
(4/
30),
dilatation
(3/
30),
and
fluid
filled
uterine
horns
(2/
30),
none
of
which
were
observed
in
control
animals.

In
addition,
lesions
of
the
eye
were
noted
in
high­
dose
F1
males
and
females
and
were
reviewed
in
MRID
41864701.
A
significant
(p
#
0.05)
increase
was
seen
in
the
number
of
high­
dose
F1
males
with
any
type
of
corneal
or
conjunctival
change
(14/
30
vs
4/
30
controls).
The
lesions
included
corneal
degeneration/
basophilia
and
conjunctival
inflammation/
basophilia.
Degeneration
of
the
lens
was
observed
in
3/
30
high­
dose
males
and
3/
29
high­
dose
females
compared
with
only
1/
30
control
male.
However,
a
clear
treatment­
related
effect
in
females
was
not
considered
to
be
definitive.

The
systemic
toxicity
LOAEL
was
established
at
100
ppm
(average
premating
doses
5.8­
9.24
mg/
kg/
day)
based
on
reduced
body
weight
gains
in
males
and
females
during
both
generations.
The
systemic
toxicity
NOAEL
was
established
at
12.5
ppm
(average
premating
doses
0.74­
1.12
mg/
kg/
day).

No
treatment­
related
adverse
effects
were
found
on
the
reproductive
performance
of
either
generation.
For
the
control,
low­,
mid­,
and
high­
dose
group,
pup
viability
for
lactation
days
0­
4
was
99.4,
98.0,
99.8,
and
91.7%
(p
#
0.05),
respectively,
for
the
F1
generation
and
96.8,
92.7,
99.5,
and
76.2%
(p
#
0.05),
respectively,
for
the
F2
generation.
The
mean
number
of
pups
per
litter
in
the
high­
dose
F2
group
was
significantly
(p
#
0.05)
less
than
the
control
throughout
lactation.
The
number
of
litters
8
with
pups
showing
clinical
signs
was
significantly
(p
#
0.05)
increased
in
both
generations.
Body
weights
of
the
mid­
and
high­
dose
F1
male
and
female
pups
and
of
the
high­
dose
F2
male
and
female
pups
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
throughout
lactation.
These
data
were
not
considered
for
setting
the
reproductive
toxicity
NOAEL
in
the
original
DER.

The
reproductive
toxicity
NOAEL
was
greater
than
or
equal
to
625
ppm
(average
premating
doses
36­
63.0
mg/
kg/
day)
and
the
reproductive
toxicity
LOAEL
was
not
established.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
reproductive
toxicity
study
[OPPTS
870.3800
(83­
4)]
in
rats.

Dose
and
Endpoint
Selected:
5.8
mg/
kg
(maternal
NOAEL)
based
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
systemic
toxicity
(body
weight
decrease)
is
relevant
for
the
populations
(infants
and
children)
and
duration
(1
­
30
days)
of
concern.
The
NOAEL
of
5.8
mg/
kg/
day
used
for
this
exposure
period
is
based
on
the
decrease
in
body
weight
seen
during
days
1
through
30
at
36
mg/
kg/
day
and
is
used
only
for
this
risk
assessment.
This
NOAEL/
LOAEL
differs
from
the
overall
NOAEL/
LOAEL
(0.7/
5.8)
established
for
the
study.
In
an
open
literature
publication
[McIntyre,
B.
S.
et
al.,
Toxicol
Appl
Pharmacol
167(
2):
87­
99
(2000)]
the
effects
observed
(retention
of
areolae/
nipples
in
male
rats)
at
12.5
mg/
kg/
day
were
not
considered
to
be
biologically
significant
for
risk
assessment
since
the
findings
were
not
replicated
in
any
other
studies.
.

2.4.2
Intermediate­
Term
(1
to
6
Months)
Incidental
Oral
Exposure
Study
Selected:
One­
year
chronic
study
­
Dog
870.4100
(§
83­
1b)

MRID
No.:
40952601
Executive
Summary:
See
Chronic
RfD
(2.3)

Dose
and
Endpoint
Selected:
0.77
mg/
kg/
day,
based
on
increased
met­
and
sulfhemoglobin
concentrations
at
3.5
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
effects
seen
in
this
study
after
3
and
6
months
treatment
were
within
the
time
frame
for
intermediate­
term
exposure.

2.5
Dermal
Absorption
9
Study
Selected:
Dermal
penetration
870.7600
(§
85­
2)

MRID
No.:
163837
Executive
Summary:
In
this
dermal
absorption
study,
four
groups
of
20
rats
(one
female
group
and
three
male
groups)
were
dosed
with
14
C
(2.35
:
Ci/
mg)
linuron
at
0.12,
1.00,
or
7.4
mg/
2
in
2
(2.82,
23.5,
or
17.4
:
Ci,
respectively).

Based
on
the
results
of
this
study,
a
dermal
absorption
factor
of
16%
was
observed
for
an
exposure
of
8
to
10
hr
(2%/
hr).

Percentage
(%)
Dermal
Absorption:
16%
for
8
to
10
hour
exposure
(2%
per
hour)

2.6
Dermal
Exposure
2.6.1
Short­
Term
(1­
30
days)
Dermal
Exposure
Study
Selected:
Reproduction
and
Fertility
Effects/
Rat
870.3800
(§
83­
4)

MRID
No.:
41463401,
41864701
Executive
Summary:
See
short­
term
oral
exposure
(2.4.1.1)

Dose
and
Endpoint
Selected:
Parental
NOAEL
of
5.8
mg/
kg
based
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day.

Comments
about
Study/
Endpoint:
No
repeat
dose
dermal
toxicity
study
is
available.
Therefore,
an
oral
NOAEL
of
5.8
mg/
kg/
day
was
selected
for
this
exposure
period.
The
NOAEL
used
for
this
exposure
period
is
based
on
the
decrease
in
body
weight
seen
during
days
1
through
30
at
36
mg/
kg/
day
and
is
used
only
for
this
risk
assessment.
This
NOAEL/
LOAEL
differs
from
the
overall
NOAEL/
LOAEL
(0.7/
5.8)
established
for
the
study.
A
dermal
absorption
factor
of
16%
should
be
used
for
route
to
route
extrapolation.

2.6.2
Intermediate
(1
to
6
Months)
Term
Dermal
Exposure
Study
Selected:
One­
year
chronic
study
­
Dog
870.4100
(§
83­
1b)

MRID
No.:
40952601
Executive
Summary:
See
Chronic
RfD
(2.3)

Dose
and
Endpoint
Selected:
0.77
mg/
kg/
day,
based
on
increased
met­
and
sulfhemoglobin
concentrations
after
3
and
6
months
treatment
at
3.5
mg/
kg/
day.
10
Comments
about
Study/
Endpoint:
No
repeat
dose
dermal
toxicity
study
is
available.
The
systemic
toxicity
(increased
met­
and
sulfhemoglobin
concentrations)
is
relevant
for
this
duration
(seen
after
3
and
6
months).
A
dermal
absorption
factor
of
16%
should
be
used
for
route
to
route
extrapolation.

2.6.3
Long­
term
(greater
than
6
months)
Dermal
Exposure
Study
Selected:
One­
year
chronic
study
­
Dog
870.4100
(§
83­
1b)

MRID
No.:
40952601
Executive
Summary:
See
Chronic
RfD
(2.3)

Dose
and
Endpoint
Selected:
0.77
mg/
kg/
day;
based
on
increased
met­
and
sulfhemoglobin
concentrations
after
9
and
12
months
treatment
at
3.5
mg/
kg/
day.
A
dermal
absorption
factor
of
16%
should
be
used
for
route
to
route
extrapolation.

Comments
about
Study/
Endpoint:
This
dose
and
endpoint
were
selected
to
establish
the
chronic
RfD.
A
dermal
absorption
factor
of
16%
should
be
used
for
route
to
route
extrapolation.

2.7
Inhalation
Exposure
2.7.1
Short­
Term
(1­
30
days)
Inhalation
Exposure
Study
Selected:
Reproduction
and
Fertility
Effects/
Rat
870.3800
(§
83­
4)

MRID
No.:
41463401,
41864701
Executive
Summary:
See
short­
term
oral
exposure
(2.4.1.1)

Dose
and
Endpoint
Selected:
Parental
NOAEL
of
5.8
mg/
kg
based
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day.

Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.
The
NOAEL
used
for
this
exposure
period
is
based
on
the
decrease
in
body
weight
seen
during
days
1
through
30
at
36
mg/
kg/
day
and
is
used
only
for
this
risk
assessment.
This
NOAEL/
LOAEL
differs
from
the
overall
NOAEL/
LOAEL
(0.7/
5.8)
established
for
the
study.

2.7.2
Intermediate­
Term
(1
to
6
Months)
Incidental
Inhalation
Exposure
Study
Selected:
One­
year
chronic
study
­
Dog
870.4100
(§
83­
1b)
11
MRID
No.:
See
Chronic
RfD
(2.3)

Executive
Summary:
See
Chronic
RfD
(2.3)

Dose
and
Endpoint
Selected
0.77
mg/
kg/
day,
based
on
increased
met­
and
sulfhemoglobin
concentrations
after
3
and
6
months
treatment
at
3.5
mg/
kg/
day.

Comments
about
Study/
Endpoint:
In
the
absence
of
an
inhalation
study,
an
oral
study
was
selected.

2.7.3
Long­
term
(greater
than
6
months)
Inhalation
Exposure
Study
Selected:
One­
year
chronic
study
­
Dog
870.4100
(§
83­
1b)

MRID
No.:
See
Chronic
RfD
(2.3)

Executive
Summary:
See
Chronic
RfD
(2.3)

Dose
and
Endpoint
Selected:
0.77
mg/
kg/
day,
based
on
increased
sulfhemoglobin
concentrations
after
9
and
12
months
treatment
at
3.5
mg/
kg/
day.

Comments
about
Study/
Endpoint:
See
Chronic
RfD
(2.3)

2.8
Margins
of
Exposure
for
Occupational
Risk
Assessments
Margin
of
exposure
of
100
is
adequate
for
occupational
dermal
and
inhalation
exposure
risk
assessments.
The
MOEs
for
residential
use
will
be
determined
by
the
FQPA
Safety
Factor
Committee.

3
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
00029680,
00029679
Executive
Summary:
In
a
chronic
toxicity/
oncogenicity
study
(MRID
00029680
and
MRID
00029679),
INZ­
326
(Linuron;
96.9­
97.2%
a.
i.;
Lot
No.
20427,
Batch
No.
90,
E
6110­
29B)
was
administered
in
the
diet
to
groups
of
70
ChR­
CD®
rats/
sex/
dose
at
concentrations
of
0,
50,
125,
and
625
ppm
(0,
2.09,
5.11,
and
27.1
mg/
kg/
day
for
males
and
0,
3.13,
7.75,
and
48.3
mg/
kg/
day
for
females)
for
up
to
2
years.
Additional
groups
of
10
rats/
sex/
dose
were
administered
the
same
diets
for
12
months
for
interim
evaluation.
All
clinical
pathology
data
were
reanalyzed
(MRID
00164117)
due
to
inappropriate
statistical
methods
used
in
the
original
study
report.
12
Linuron
had
no
effect
on
mortality
at
any
dose,
and
there
were
no
treatment­
related
clinical
signs
reported.
Absolute
body
weights
of
the
high­
dose
male
group
were
decreased
to
88­
91%
of
controls
during
weeks
1­
19,
with
decreased
body
weight
gain
during
weeks
0­
13
and
52­
104
resulting
in
body
weight
gain
for
the
entire
study
being
89%
of
controls.
Absolute
body
weights
of
the
high­
dose
female
group
were
decreased
throughout
the
study,
with
the
magnitude
of
the
decrease
generally
increasing
throughout
the
course
of
the
study.
The
body
weight
gain
of
this
group
for
the
entire
study
was
57%
of
controls.
Body
weight
gain
by
mid­
dose
males
was
decreased
to
64%
of
controls
during
the
week
52­
76
interval,
with
body
weight
loss
during
the
week
76­
104
interval
being
increased
to
148%
of
controls.
Body
weight
gain
by
the
mid­
dose
female
group
was
decreased
to
75%
of
controls
during
the
week
52­
76
interval.
There
were
no
toxicologically
significant
treatment­
related
effects
on
food
consumption;
however,
food
efficiency
values
of
high­
dose
females
were
decreased
to
74­
88%
of
controls
during
weeks
1­
4
and
to
58%
of
controls
for
the
entire
study
period.

Histopathology
observations
consistent
with
hemolysis
were
observed
at
increased
incidences
in
high­
and
mid­
dose
males
and
females
from
the
main
study
and
interim
sacrifice
groups,
including
hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes,
and
transient
decreases
in
the
erythrocyte
count,
hemoglobin
concentration,
and
hematocrit
of
the
high­
dose
female
group
were
noted
at
6
and/
or
12
months.

Male
rats
of
the
main
study
group
had
significantly
increased
incidences
of
mineralization/
calculi
in
the
renal
pelvis,
transitional
cell
hyperplasia
in
the
renal
pelvis,
and
subacute
perivasculitis
and/
or
vasculitis
in
the
epididymides
at
the
mid­
and
high­
dose
treatment
levels.
Female
rats
of
the
main
study
group
had
significantly
increased
incidences
of
calculi
in
renal
tubules
at
the
mid­
and
high­
dose
treatment
levels
and
significantly
increased
incidences
of
hepatic
sinusoidal
ectasia
and
collecting
duct
ectasia
in
the
kidney
at
the
high­
dose
treatment
level.
The
high­
dose
female
group
also
had
a
non­
statistically
significantly
increased
incidence
of
transitional
cell
hyperplasia
in
the
renal
pelvis
compared
to
controls.
Hepatocellular
megalocytosis/
syncytium
formation
with
fibroplasia
radiating
between
hepatic
cords,
and
occasional
increased
hepatocellular
intracytoplasmic
basophilia
was
only
observed
in
the
main
study
high­
dose
female
group
(15/
68
animals
examined
at
that
site)
and
may
have
been
related
to
induction
of
hepatocellular
protein
synthesis.
The
significance
of
this
finding
is
unknown
but
considered
adverse.

The
lowest­
observed­
adverse­
effect
level
(LOAEL)
for
Linuron
in
ChR­
CD®
rats
is
125
ppm
(5.11
mg/
kg/
day
for
males
and
7.75
mg/
kg/
day
for
females),
based
on
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),
and
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.
The
corresponding
no­
observed­
adverse­
effect
level
is
50
ppm
(2.09
mg/
kg/
day
for
males
and
3.13
mg/
kg/
day
for
females).
13
There
was
a
treatment­
related
increase
in
the
incidence
of
testicular
interstitial
adenomas
at
the
125
and
625
ppm
treatment
levels
(5.7,
27.5,
and
53.6%
for
control,
mid­,
and
high­
dose
males,
respectively;
p<
0.01).
Common
neoplasms,
included
pituitary
adenomas
of
the
pars
anterior
in
both
male
and
female
rats
and
mammary
fibroadenomas
in
female
rats.
Decreased
incidences
of
both
these
tumor
types
were
noted
in
the
high­
dose
female
group.
Dosing
was
considered
adequate
based
on
the
decreases
in
body
weight
and
body
weight
gain
of
high­
dose
females.

This
chronic
toxicity/
oncogenicity
study
in
the
rat
is
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirement
for
a
chronic
toxicity/
oncogenicity
oral
study
[OPPTS
870.4300
(§
83­
5)]
in
the
rat;
however,
it
must
be
noted
that
results
from
concentration
and
stability
analyses
indicate
potential
variation
between
nominal
and
actual
diet
concentrations
which
make
the
exact
doses
to
the
animals
questionable.

Discussion
of
Tumor
Data:
In
a
chronic
toxicity/
oncogenicity
study,
INZ­
326
(linuron;
96.9­
97.2%
a.
i.)
was
administered
in
the
diet
to
groups
of
70
ChR­
CD'
rats/
sex/
dose
at
concentrations
of
0,
50,
125,
and
625
ppm
(0,
2.09,
5.11,
and
27.1
mg/
kg/
day
for
males
and
0,
3.13,
7.75,
and
48.3
mg/
kg/
day
for
females)
for
up
to
2
years.

There
was
a
treatment­
related
increase
in
the
incidence
of
testicular
interstitial
adenomas
at
the
125
and
625
ppm
treatment
levels
(5.7,
27.5,
and
53.6%
for
control,
mid­,
and
high­
dose
males,
respectively;
p<
0.01).
Common
neoplasms,
included
pituitary
adenomas
of
the
pars
anterior
in
both
male
and
female
rats
and
mammary
fibroadenomas
in
female
rats.
Decreased
incidences
of
both
these
tumor
types
were
noted
in
the
high­
dose
female
group.

Adequacy
of
Dose
Levels:
Dosing
was
considered
adequate
based
on
the
decreases
in
body
weight
and
body
weight
gain
of
high­
dose
females.

3.2
Carcinogenicity
Study
in
Mice
MRID
No.
00124195
Executive
Summary:
In
an
oncogenicity
study
(MRID
00124195),
INZ­
326
(97.0%
a.
i.,
Haskell
Laboratory
identification
no.
10720)
was
administered
to
groups
of
80
male
and
80
female
Charles
River
CD®­
1
mice
in
the
diet
at
concentrations
of
0,
50,
150,
or
1500
ppm.
The
test
diets
were
given
for
24
months.
The
concentrations
of
50,
150,
and
1500
ppm
resulted
in
mean
daily
compound
intakes
for
males
of
8,
23,
and
261
mg/
kg/
day;
and
for
females
of
12,
35,
and
455
mg/
kg/
day,
respectively,
calculated
from
food
intake
and
body
weight
measurements.

No
significant
treatment­
related
effects
were
seen
in
clinical
signs
or
survival.
Body
weights
were
consistently
and
significantly
lower
in
males
and
females
at
1500
ppm
than
in
the
control
groups
throughout
the
study.
At
52
weeks,
the
group
mean
body
weights
and
weight
14
gains
of
high­
dose
males
were
8%
and
15%
lower
than
the
controls,
respectively,
and
highdose
females
were
decreased
by
11%
and
21%.
At
104
weeks,
the
body
weights
and
weight
gains
of
high­
dose
males
were
10%
and
20%
less
than
the
controls,
and
in
high­
dose
females
were
8%
and
14%
less
than
the
controls,
respectively.
The
overall
food
intake
for
high­
dose
males
was
decreased
by
about
14%
and
by
10%
for
high­
dose
females
compared
to
the
controls.
Food
efficiency
for
the
2­
year
study
was
not
significantly
affected
in
treated
animals.

Increases
of
9­
18%
in
group
mean
erythrocyte
cell
volume
and
mean
cell
hemoglobin
were
seen
in
males
and
females
after
6
months
of
treatment
at
1500
ppm.
Erythrocyte
counts
were
decreased
by
9%
and
14%
in
high­
dose
males
and
females,
respectively,
compared
to
the
controls
at
6
months.
These
hematology
values
returned
to
near
control
levels
later
in
the
study.
A
significant
increased
incidence
of
hemosiderin
deposits
in
the
spleens
of
both
sexes
at
1500
ppm
is
suggestive
of
a
compensated
hemolytic
anemia
in
high­
dose
animals.
Methemoglobin
levels
were
increased
in
high­
dose
females
by
117%
compared
to
the
control
group,
and
were
increased
in
high­
dose
males
by
613%
compared
to
the
50
ppm
group
(the
male
control
value
was
not
available).
Differential
white
cell
counts
were
within
normal
parameters
for
both
sexes
at
all
doses.

The
absolute
and
relative
(to
body)
liver
weights
were
increased
by
20%
and
24%,
respectively
in
high­
dose
males
and
by
65%
in
high
dose
females
compared
to
the
controls.
Microscopic
evidence
of
liver
toxicity
at
1500
ppm
included
increased
incidences
of
focal
hepatocellular
cytoplasmic
alteration,
focal
centrilobular
peliosis,
and
centrilobular
hepatocytomegaly
in
both
sexes,
and
increased
incidence
of
hepatocellular
cytoplasmic
vacuolation
in
females.

The
LOAEL
for
INZ­
326
in
mice
is
1500
ppm
in
the
diet
for
males
(261
mg/
kg/
day)
and
females
(455
mg/
kg/
day),
based
on
microscopic
liver
changes,
methemoglobinemia,
and
decreased
body
weight
and
weight
gain
in
both
sexes.
The
NOAEL
was
150
ppm
for
males
(23
mg/
kg/
day)
and
females
(35
mg/
kg/
day).

Treatment
of
up
to
104
weeks
with
1500
ppm
INZ­
326
resulted
in
a
significant
increase
in
the
incidence
of
hepatocellular
adenomas
(control,
6%;
1500
ppm,
25%,
p
<
0.05)
in
female
Charles
River
CD®­
1
mice
under
the
conditions
of
this
study.
Dosing
was
considered
adequate
based
on
the
liver
changes,
methemoglobinemia,
and
decreased
body
weights.

This
oncogenicity
study
in
the
mouse
is
Acceptable
(Guideline)
and
does
satisfy
the
guideline
requirement
for
an
oncogenicity
study
[OPPTS
870.4200
(§
83­
2)]
in
mice.
There
were
a
number
of
deficiencies
in
this
study,
but
none
that
would
alter
the
conclusions
reached
through
the
available
data.

Discussion
of
Tumor
Data:
Treatment
of
up
to
104
weeks
with
1500
ppm
INZ­
326
resulted
in
a
significant
increase
in
the
incidence
of
hepatocellular
adenomas
(control,
6%;
1500
ppm,
25%,
p
<
0.05)
in
female
Charles
River
CD®­
1
mice
under
the
conditions
of
this
study.
15
Adequacy
of
the
Dose
Levels:
Tested:
Dosing
was
considered
adequate
based
on
the
decreases
in
body
weights,
body
weight
gains
and
other
systemic
effects
(microscopic
liver
changes,
methemoglobinemia)
in
high­
dose
males
(261
mg/
kg/
day)
and
females
(455
mg/
kg/
day).

3.3
Special
Oncogenicity
Study
­
Aged
Male
Rats
MRID
No.:
45506501
Executive
Summary:
A
special
study
(MRID
45506501)
was
conducted
to
determine
whether
linuron
(94.5%
a.
i.)
administered
in
the
diet
to
aged
male
Crl:
CD(
SD)
BR
rats
would
induce
testicular
interstitial
cell
(Leydig
cell)
hyperplasia
and
adenomas.
Two
groups
of
25
rats
each
were
given
625
ppm
linuron
beginning
at
12
or
18
months
of
age
and
continuing
for
6
and
12
months;
terminal
sacrifice
was
carried
out
at
24
months
of
age.
Another
group
of
25
rats
was
given
basal
diet
and
served
as
controls.
Compound
intake
for
both
treated
groups
was
22­
23
mg/
kg/
day
for
the
treatment
interval.

Treatment­
related
clinical
signs
of
toxicity
were
limited
to
swollen
testes
observed
in
2,
4,
and
5
rats
in
the
control,
6­,
and
12­
month
groups.
A
total
of
6,
4,
and
4
rats,
respectively,
were
found
dead
or
were
sacrificed
in
extremis
prior
to
scheduled
termination;
further
details
were
not
included.

Body
weights
of
both
treated
groups
were
significantly
reduced
as
compared
with
the
control
group
within
two
weeks
after
the
initiation
of
feeding
the
test
article.
Final
body
weights
for
the
control,
6­,
and
12­
month
groups
were
848.5,
670.1,
and
668.5
g,
respectively
(additional
data
not
given
in
original
DER).
Weight
gains
during
the
treatment
intervals
were
significantly
(p
#
0.05)
less
than
the
controls
with
a
weight
loss
for
animals
treated
for
6
months
(­
107.8
g
vs
45.6
g
for
control)
and
a
weight
gain
2.1%
of
the
control
level
by
the
animals
treated
for
12
months.
Food
consumption
and
food
efficiency
values
were
slightly
reduced
for
both
treated
groups
as
compared
with
the
controls
throughout
the
treatment
intervals,
but
statistical
significance
was
not
attained.

At
necropsy
discoloration
of
the
testes
was
observed
in
2/
25,
4/
25,
and
6/
25
rats
in
the
control,
6­
and
12­
month
groups,
respectively.
However
the
observation
did
not
correlate
with
either
interstitial
cell
adenoma
or
hyperplasia.

For
rats
sacrificed
at
study
termination,
a
dose­
related
increases
in
the
incidence
of
testicular
adenoma
were
observed.
The
incidences
in
the
control,
6­,
and
12­
month
groups
were
0/
19,
2/
21,
and
6/
21
(p
#
0.05),
respectively.
In
addition,
testicular
hyperplasia
was
observed
in
6/
19,
7/
21,
and
14/
21
(p
#
0.05)
rats,
respectively.
No
increased
incidences
of
hyperplasia
or
adenoma
in
the
adrenal
cortex,
adrenal
medulla,
or
the
pituitary
gland
were
observed
in
the
treated
groups
as
compared
with
the
control
group.
16
In
conclusion,
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,
in
fact
linuron
may
be
more
potent
as
an
oncogen
than
previously
estimated
from
the
two­
year
study.

This
study
is
classified
as
Acceptable/
Nonguideline
as
a
special
feeding
study
in
aged
rats.

Discussion
of
Tumor
Data:
A
special
study
was
conducted
to
determine
whether
linuron
(94.5%
a.
i.)
administered
in
the
diet
to
aged
male
Crl:
CD(
SD)
BR
rats
would
induce
testicular
interstitial
cell
(Leydig
cell)
hyperplasia
and
adenomas.
Two
groups
of
25
rats
each
were
given
625
ppm
linuron
beginning
at
12
or
18
months
of
age
and
continuing
until
sacrifice
at
24
months
of
age;
another
group
of
25
rats
was
given
basal
diet
and
served
as
controls.
Compound
intake
for
both
treated
groups
was
22­
23
mg/
kg/
day
for
the
treatment
interval.

For
rats
sacrificed
at
study
termination,
a
dose­
related
increased
incidence
of
testicular
adenoma
was
observed.
The
incidence
rates
in
the
control,
6­,
and
12­
month
groups
were
0/
19,
2/
21,
and
6/
21
(p
#
0.05),
respectively.
In
addition,
testicular
hyperplasia
was
observed
in
6/
19,
7/
21,
and
14/
21
(p
#
0.05)
rats,
respectively.
No
increased
incidences
of
hyperplasia
or
adenoma
in
the
adrenal
cortex,
adrenal
medulla,
or
the
pituitary
gland
were
observed
in
the
treated
groups
as
compared
with
the
control
group.

In
conclusion,
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,
in
fact,
linuron
may
be
a
more
potent
oncogen
than
previously
estimated
from
the
2
year
study.

Adequacy
of
Dose
Levels:
Dose
levels
were
the
same
as
the
previously
conducted
oncogenicity
study
in
the
rat.

3.4
Classification
of
Carcinogenic
Potential
Linuron
was
placed
in
special
review
for
carcinogenic
effects
in
1982.
Linuron
was
later
classified
as
a
group
C
carcinogen
with
a
Q1*
of
2
x
10
­5
on
the
basis
of
a
dose­
related
increase
in
interstitial
cell
hyperplasia
and
adenomas
in
a
two­
year
rat
feeding
study
(00029680)
and
hepatocellular
tumors
that
appeared
in
low­
dose
male
and
high­
dose
female
mice
in
a
two­
year
feeding
study
(00124195).
Subsequent
review
by
the
HED
peer
review
committee
and
the
Science
Advisory
Panel
resulted
in
the
removal
of
the
Q1*
for
quantification
of
risk.
At
present,
Linuron
is
classified
as
a
Group
C
carcinogen
requiring
no
quantification
of
human
cancer
risk
[Federal
Register
54(
17):
4072].

4
MUTAGENICITY
4.1
Gene
Mutations
4.1.1
Salmonella
typhimurium/
Escherichia
coli
reverse
gene
mutation
assay
MRID
No.:
00131738
17
Executive
Summary:
In
a
reverse
gene
mutation
assay
in
bacteria,
S.
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537
were
exposed
to
Linuron
(95­
97%)
in
dimethylsulfoxide
(DMSO)
at
concentrations
of
0.5,
0.75,
1.0,
2.5,
and
5.0
:
g/
plate
in
the
absence
of
mammalian
metabolic
activation
(S9­
mix)
and
1,
5,
10,
50,
and
100
:
g/
plate
in
the
presence
of
S­
9
mix.
Duplicate
plates
were
utilized
for
each
test
concentration,
and
two
independent
assays
were
performed.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
Charles
River
CD
rat
liver.

Linuron
was
cytotoxic
at
$
5
:
g/
plate
without
S­
9
mix;
and
was
cytotoxic
at
$
50
:
g/
plate
with
S­
9
mix.
No
treatment­
related
increase
in
mutant
frequency
was
noted
in
any
strain
tested
with
or
without
exogenous
metabolic
activation.
The
solvent
(DMSO)
and
positive
control
(N­
methyl­
N'­
nitro­
N­
nitrosoguanidine,
2­
nitrofluorene,
9­
aminoacridine,
and
2­

aminoacridene)
values
were
appropriate
in
the
respective
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background
with
or
without
S9
activation.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
[OPPTS
870.5100
(§
84­
2)]
for
in
vitro
mutagenicity
(bacterial
reverse
gene
mutation)
data.

4.1.2
Chinese
Hamster
Ovary
(CHO)/
HGPRT
cell
forward
gene
mutation
assay
MRID
No.:
00137152
Executive
Summary:
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
at
concentrations
of
0.05,
0.25,
0.35,
0.40,
0.45,
and
0.50
mM
in
the
absence
of
mammalian
metabolic
activation
(S9­
mix),
and
at
0.25,
0.50,
0.75,
0.90,
and
1.0
mM
in
the
presence
of
Charles
River
S9­
mix.
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.
18
This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
[OPPTS
870.5300
(§
84­
2)]
for
in
vitro
mutagenicity
(mammalian
forward
gene
mutation)
data.

4.2
Chromosome
Aberrations
4.2.1
In
vivo
bone
marrow
cytogenetic
assay
MRID
No.:
00137153
Executive
Summary:
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
of
0,
100,
300,
or
1000
mg/
kg.
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.
Low­
and
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.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
OPPTS
[870.5385
(§
84­
2)]
for
in
vivo
cytogenetic
mutagenicity
data.

4.3
Other
Mutagenic
Mechanisms
4.3.1
Unscheduled
DNA
synthesis
(UDS)
in
WI­
38
human
fibroblasts
assay
MRID
No.:
00132583
Executive
Summary:
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)
at
concentrations
of
0.00001,
0.0001,
0.001,
0.01,
0.1,
1.0,
10,
and
50.0
mM
(trial
1)
or
0.01,
0.1,
1.0,
10,
and
50.0
mM
(trial
2)
for
18
hours.

Linuron
was
cytotoxic
in
one
of
2
cultures
at
1.0
mM
in
trial
1;
no
other
cytotoxicity
data
19
were
provided.
The
mean
net
nuclear
grain
counts
were
calculated
from
25
randomly
selected
nuclei
per
slide.
There
was
no
increase
in
mean
net
nuclear
grain
counts
in
treated
cells
compared
to
the
solvent
control,
indicating
no
induction
of
UDS
activity.
The
solvent
(DMSO)
and
positive
control
(1.0
mM
dimethylbenzanthracene)
values
were
appropriate.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[nuclear
silver
grain
counts]
was
induced.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirements
for
FIFRA
Test
Guideline
[OPPTS
870.5550
(§
84­
2)]
for
other
genotoxic
mutagenicity
data.

4.4
Conclusions:
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.

The
submitted
test
battery
satisfies
the
Pre­
1991
mutagenicity
initial
testing
battery
guidelines.
No
further
testing
is
required
at
this
time.

5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
toxicology
data
base
is
complete
but
is
inadequate
for
an
FQPA
assessment.
The
required
developmental
toxicity
studies
in
the
rat
and
rabbit
and
reproduction
studies
in
the
rat
meet
guideline
requirements.

5.2
Neurotoxicity
Data
No
acute
or
subchronic
neurotoxicity
studies
on
Linuron
are
available.
Evaluation
of
subchronic,
chronic
and
reproduction
toxicity,
did
not
indicate
any
treatment­
related
effects
on
the
central
or
peripheral
nervous
system
of
mice,
rats,
or
rabbits.
No
changes
in
clinical
signs,
brain
weights,
gross
necropsy
results
or
histopathological
results
suggested
any
part
of
the
nervous
system
as
a
target
organ.
20
5.3
Developmental
Toxicity
5.3.1
Prenatal
Developmental
Study
­
Rat
MRID
No:
00018167
Executive
Summary:
In
a
developmental
toxicity
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.
Average
doses
to
the
treated
dams
were
5.0,
12,
and
50
mg/
kg/
day,
respectively.
The
day
evidence
of
mating
was
found
was
designated
GD
1.
Maternal
body
weights
and
food
consumption
were
recorded
on
GD
6,
10,
16,
and
21.
On
GD
21,
all
surviving
dams
were
sacrificed
and
all
fetuses
were
weighed
and
examined
for
external
malformations/
variations.
Crown­
rump
length
was
measured
on
each
fetus.
Approximately
one­
half
of
the
fetuses
in
each
litter
were
fixed
in
Bouin's
solution
for
visceral
examination
and
the
remaining
one­
half
were
processed
for
skeletal
examination.

All
animals
survived
to
scheduled
termination
without
the
appearance
of
any
treatmentrelated
clinical
signs
of
toxicity.
Gross
necropsy
was
unremarkable.
No
treatmentrelated
clinical
signs
of
toxicity
were
observed.
Body
weight
gains
and
food
consumption
by
the
low­
and
mid­
dose
groups
were
similar
to
the
controls
throughout
the
study.
Body
weights
of
the
high­
dose
group
were
significantly
(p
#
0.05)
less
than
the
control
group
on
GD
10,
16,
and
21.
Food
consumption
by
the
high­
dose
group
was
significantly
(p
#
0.05)
less
than
that
of
the
controls
for
the
intervals
of
GD
6­
10
and
10­
16.

The
maternal
toxicity
LOAEL
is
625
ppm
(50
mg/
kg/
day)
based
on
reduced
body
weight
gain
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
control,
low­,
mid­,
and
high­
dose
groups
post­
implantation
loss
was
5.8,
3.5,
4.4,
and
14.0%,
respectively,
and
the
number
of
resorptions
per
litter
with
resorption
was
1.6,
1.6,
1.2,
and
2.1,
respectively.

No
treatment­
related
external
or
visceral
malformations/
variations
were
noted.
In
the
high­
dose
group
bipartite
thoracic
vetebral
centra
was
observed
in
7
fetuses
from
7
litters
and
unapposed
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.

The
developmental
toxicity
LOAEL
is
625
ppm
(50
mg/
kg/
day)
based
on
increases
in
post­
implantation
loss
and
in
litter/
fetal
resorptions.
The
developmental
toxicity
NOAEL
is
125
ppm
(12
mg/
kg/
day).
21
This
study
is
classified
as
Acceptable/
Guideline
and
does
satisfy
the
guidelines
for
a
developmental
toxicity
study
[OPPTS
870.3700
(83­
3a)]
in
rats.
Deficiencies
included
no
information
on
dietary
formulation
preparation
or
analyses,
the
treatment
period
should
have
been
GD
7­
16,
body
weight
on
GD
0
were
not
collected,
fetal
anomalies
were
not
classified
as
malformations
or
variations,
and
fetuses
were
not
individually
identified.

5.3.2
Developmental
Toxicity
Study
in
the
Rabbit
MRID
Nos:
00153867
and
40437201
Executive
Summary:
In
a
developmental
toxicity
study,
25
presumed
pregnant
New
Zealand
white
rabbits
per
group
were
administered
0,
5,
25,
or
100
mg/
kg/
day
of
linuron
(96.2%
a.
i.)
by
gavage
on
gestation
days
(GD)
7­
19,
inclusive.
Doses
were
chosen
based
on
the
results
of
a
range­
finding
study.
The
vehicle
was
0.5%
hydroxypropylmethylcellulose
On
GD
29,
all
surviving
does
were
sacrificed
and
the
livers
weighed.
All
fetuses
were
weighed
and
examined
for
external
and
visceral
malformations/
variations
including
free­
hand
sectioning
of
the
brain.
All
fetuses
were
eviscerated
and
processed
for
skeletal
examination.

No
dose­
or
treatment­
related
clinical
signs
of
toxicity,
maternal
deaths,
or
necropsy
findings
were
observed
in
any
group.
Absolute
body
weights
and
food
consumption
for
the
low­
and
mid­
dose
groups
and
body
weight
gain
by
the
low­
dose
group
were
not
affected
by
treatment.

Body
weight
of
the
high­
dose
group
was
significantly
(p
#
0.05)
less
than
that
of
the
controls
on
GD
19.
Body
weight
gains
during
GD
13­
16
were
slightly
less
for
the
middose
group
(50%,
n.
s.)
and
significantly
less
for
the
high­
dose
group
(­
0.01
g
vs
0.08
g
for
the
controls;
p
#
0.05)
as
compared
with
the
controls.
Similarly,
during
GD
16­
20
body
weight
gains
were
slightly
less
for
the
mid­
dose
group
and
significantly
(p
#
0.01)
less
for
the
high­
dose
group
(0.00
g
for
mid­
dose
and
­0.12
g
for
high­
dose
vs
0.02
g
for
the
controls)
as
compared
with
the
controls.
Both
mid­
and
high­
dose
groups
had
significantly
(p
#
0.05)
greater
body
weight
gains
as
compared
with
the
controls
during
GD
20­
24.
Food
consumption
by
the
high­
dose
group
was
significantly
(p
#
0.05)
less
than
that
of
the
controls
on
GD
13­
16
and
16­
20.

In
the
high­
dose
group,
absolute
and
relative
liver
weights
were
increased
to
129%
(p
#
0.01)
and
135%
(n.
s.),
respectively
of
controls.

The
maternal
toxicity
LOAEL
was
established
at
25
mg/
kg/
day
based
on
reduced
body
weight
gain.
The
maternal
toxicity
NOAEL
was
established
at
5
mg/
kg/
day.

The
number
of
fetuses(
litters)
available
for
evaluation
in
the
control,
low­,
mid­,
and
high­
dose
groups
was
135(
20),
135(
20),
121(
17),
and
79(
13),
respectively.
22
Five
high­
dose
does
aborted
between
days
20­
25
compared
with
one
control
doe
on
GD
22.
The
mean
number
and
percentage
of
resorptions
and
number
of
dead
fetuses
were
similar
between
the
treated
and
control
groups.
In
the
high­
dose
group,
slight
(n.
s.)
decreases
in
the
mean
number
of
live
fetuses/
litter
(6.1
vs
6.8
for
controls)
and
mean
fetal
body
weight
(41.99
g
vs
45.8
g
for
controls)
were
observed.

No
treatment­
related
external
or
visceral
fetal
malformations/
variations
were
noted.
In
the
control,
low­,
mid­,
and
high­
dose
groups,
skull
alterations
(irregularly
shaped
fontanelle,
hole
in
parietals,
parietals
contain
intraparietals,
and
unossified)
were
observed
in
1(
1),
9(
5),
5(
3),
and
19(
6)
fetuses(
litters),
respectively.
The
litter
incidence
for
the
high­
dose
group
was
significantly
(p
#
0.05)
greater
than
that
of
the
control
group.
It
should
be
noted
that
6
fetuses
from
5
low­
dose
litters
also
had
a
variety
of
external
malformations
of
the
head
and
body.

The
developmental
toxicity
LOAEL
was
established
at
100
mg/
kg/
day
based
on
alterations
of
the
bones
of
the
skull.
The
developmental
toxicity
NOAEL
was
established
at
25
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
Guideline
and
does
satisfy
the
guidelines
for
a
developmental
toxicity
study
[OPPTS
870.3700
(83­
3b)]
in
rabbits.

5.4
Reproductive
Toxicity
5.4.1
Three­
Generation
Reproduction
­
Rat
MRID
No.:
00146071
&
00155168
Executive
Summary:
In
a
three­
generation
reproduction
study,
Linuron
(94.5%
a.
i.)
was
administered
to
groups
of
20
male
and
20
female
Crl:
CD®
rats
in
the
diet
at
concentrations
of
0,
25,
125,
or
625
ppm.
Two
litters
were
produced
by
the
F0
and
F1
generations
and
one
litter
was
produced
by
the
F2
generation.
Average
premating
doses
were
0,
2,
9,
and
44
mg/
kg/
day,
respectively,
for
F0
males;
0,
2,
10,
and
50
mg/
kg/
day,
respectively,
for
F0
females;
0,
2,
9,
and
50
mg/
kg/
day,
respectively,
for
F1
males;
0,
2,
11,
and
59
mg/
kg/
day,
respectively,
for
F1
females;
0,
2,
9,
and
48
mg/
kg/
day,
respectively,
for
F2
males;
and
0,
2,
11,
and
67
mg/
kg/
day,
respectively,
for
F2
females.
F1
and
F2
adults
were
chosen
from
the
F1b
and
F2b
litters,
respectively.
F0,
F1,
and
F2
male
and
female
parental
animals
were
administered
test
or
control
diet
for
at
least
90
days
prior
to
mating,
throughout
mating,
gestation,
and
lactation,
and
until
necropsy.
At
weaning
10
F2b
pups/
sex/
group
were
subjected
to
gross
necropsy
with
microscopic
examination
of
selected
tissues.
Following
the
reproductive
toxicity
evaluations,
F1
and
F2
adults
were
maintained
on
their
respective
diets,
for
up
to
a
total
of
22
months
on
study,
for
hematological
evaluations
(MRID
00155168).

Premature
deaths
of
several
adults
in
each
generation
were
considered
incidental
to
23
treatment.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
males
or
females
during
premating
in
any
generation.
Necropsy
findings
were
not
reported
for
adults.
No
effects
on
body
weights
or
body
weight
gains
were
seen
in
the
low­
dose
groups
of
any
generation;
food
consumption
and
food
efficiency
were
not
affected
by
treatment.

Body
weights
of
the
high­
dose
parental
animals
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
beginning
on
day
7
for
the
F0
adults
and
throughout
premating
for
the
F1
and
F2
adults.
Compared
with
their
control
levels,
body
weights
for
the
high­
dose
males
and
females
were
83­
90%
and
88­
93%,
respectively,
for
the
F0
adults,
77­
81%
and
74­
87%,
respectively,
for
the
F1
adults,
and
72­
79%
and
74­
81%,
respectively,
for
the
F2
adults.
Premating
weight
gains
for
the
high­
dose
males
and
females
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
in
all
generations.
Body
weights
of
the
mid­
dose
males
were
less
than
those
of
the
controls
during
each
generation,
but
statistical
significance
was
reached
only
occasionally.
Body
weights
of
the
mid­
dose
females
from
all
generations
were
88­
94%
of
the
control
levels
with
statistical
significance
(p
#
0.05)
attained
at
most
time
points.
Lower
body
weights
of
the
mid­
and/
or
high­
dose
dams
after
weaning
of
their
litters
were
considered
a
continuation
of
the
premating
effects
on
body
weights.

Hematology
results
for
the
F1
rats
were
inconclusive.
No
treatment­
related
hematological
effects
were
noted
in
F2
males
after
continuous
feeding
for
20
months.
However,
for
F2
females
a
mild
anemia
was
observed
in
the
mid­
and
high­
dose
groups
at
20
and
22
months.
In
mid­
and
high­
dose
females,
RBC
counts
were
decreased
to
90­
91%
of
the
controls,
hemoglobin
was
decreased
to
89­
93%
of
controls,
and
the
percent
of
reticuloytes
was
increased
to
147­
213%
of
the
control
levels.
Although
statistical
significance
was
not
attained
for
all
endpoints
at
both
sampling
intervals,
the
changes
in
red
cell
parameters
are
considered
to
be
biologically
significant.

Treatment­
related
lesions
observed
in
the
liver
of
high­
dose
F2b
weanlings
are
considered
systemic
toxicity.
In
the
control,
low­,
mid­,
and
high­
dose
groups,
the
incidence
(average
severity)
of
hepatocellular
atrophy
was
1/
10
(2.0),
0/
10
(0),
2/
10
(1.5),
and
8/
10
(2.1),
respectively,
for
males
and
2/
10
(3.0),
1/
10
(3.0),
2/
10
(2.0),
and
10/
10
(2.5),
respectively,
for
females.
The
incidence
and
severity
of
decreased
cytoplasmic
vesiculation
was
the
same
as
that
of
hepatocellular
atrophy
for
all
groups
except
the
high­
dose
males
in
which
10/
10
were
affected
with
an
average
severity
score
of
2.0.

The
LOAEL
for
systemic
toxicity
was
established
at
125
ppm
(average
premating
dose
9
mg/
kg/
day,
males
and
10
mg/
kg/
day,
females)
based
on
reduced
body
weights
of
males
and
females
and
anemia
in
females.
The
systemic
toxicity
NOAEL
is
25
ppm
(premating
dose
2
mg/
kg/
day
in
males
and
females).

Fertility,
pup
survival,
and
pup
body
weights
were
not
affected
in
the
low­
or
mid­
dose
24
groups
in
any
generation.
In
the
high­
dose
groups,
fertility
was
decreased
with
each
successive
litter
and
generation.
The
fertility
indices
for
production
of
the
F1a,
F1b,
F2a,
F2b,
and
F3
litters
were
100,
89.5,
63.2,
61.1,
and
52.6%,
respectively.
Mean
live
litter
size
at
birth
and
pup
viability
during
lactation
days
0­
4
were
significantly
(p
#
0.05)
or
slightly
reduced
for
all
litters
produced
by
the
high­
dose
groups.
Both
of
these
parameters
generally
declined
with
each
successive
litter
and
generation.
Mean
live
litter
sizes
were
6.2­
9.3
pups
for
the
high­
dose
groups
compared
with
11.7­
13.3
pups
for
the
control
groups.
Viability
indices
for
lactation
days
0­
4
were
58.8­
92.0%
for
the
highdose
litters
compared
with
92.1­
100%
for
the
control
litters.

The
reproductive
toxicity
LOAEL
was
established
at
625
ppm
(premating
dose
44
mg/
kg/
day
in
males
and
48
mg/
kg/
day
in
females)
based
on
reduced
fertility.
The
reproductive
toxicity
NOAEL
is
125
ppm
(average
premating
dose
9
mg/
kg/
day
in
males
and
10
mg/
kg/
day
in
females).

Body
weights
of
the
high­
dose
pups
from
all
generations
were
consistently
reduced
throughout
lactation
as
compared
to
those
of
the
controls
with
statistical
significance
(p
#
0.05)
attained
at
most
time
points.
Body
weights
of
the
high­
dose
pups
from
both
litters
of
the
F1
and
F2
generations
were
approximately
82­
94%
of
the
control
levels
one
day
after
birth
and
declined
to
approximately
66­
80%
of
the
control
levels
at
weaning.
In
contrast
body
weights
of
the
high­
dose
F3
pups
were
84­
89%
of
the
controls
throughout
lactation.
Differences
in
absolute
and/
or
relative
organ
weights
in
high­
dose
F2b
weanlings
were
considered
to
be
due
to
lower
final
body
weights.

The
offspring
toxicity
LOAEL
was
established
at
625
ppm
(premating
dose
44
mg/
kg/
day,
males
and
48
mg/
kg/
day,
females)
based
on
decreased
pup
survival,
and
lower
pup
body
weights.
The
offspring
toxicity
NOAEL
is
125
ppm
(average
premating
dose
9
mg/
kg/
day
in
males
and
10
mg/
kg/
day
in
females).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
reproduction
study
(870.3800
[83­
4])
in
rats.

5.4.2
Two­
Generation
Reproduction
­
Rat
MRID
No:
41463401
Executive
Summary:
In
a
two­
generation
reproduction
study,
linuron
(96.2%
a.
i.)
was
administered
to
groups
of
30
male
and
30
female
Crl:
CDBR
rats
in
the
diet
at
concentrations
of
0,
12.5,
100,
or
625
ppm.
One
litter
was
produced
by
each
generation.
Average
premating
doses
for
the
treated
F0
groups
were
0.74,
5.8,
and
36
mg/
kg/
day,
respectively,
for
males
and
0.92,
7.3,
and
45.1
mg/
kg/
day,
respectively,
for
females.
Average
premating
doses
for
the
treated
F1
groups
were
0.95,
7.77,
and
54.0
mg/
kg/
day,
respectively,
for
males
and
1.12,
9.24,
and
63.0
mg/
kg/
day,
respectively,
for
females.
F0
and
F1
parental
animals
were
administered
test
or
control
diet
for
72
or
75
days,
respectively,
prior
to
mating
and
throughout
mating,
gestation,
and
lactation,
and
until
25
necropsy.

No
treatment­
related
clinical
signs
of
toxicity
or
mortalities
were
observed
in
the
adult
animals
of
either
generation.

Body
weights,
body
weight
gains,
and
food
consumption
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
beginning
on
day
7
for
the
high­
dose
F0
animals
and
throughout
premating
for
the
mid­
and
high­
dose
F1
animals.
At
the
end
of
premating,
body
weights
of
the
high­
dose
F0
males
and
females
were
81%
and
86%,
respectively,
of
the
controls
with
overall
weight
gains
59%
and
55%,
respectively,
of
the
control
values.
For
the
high­
dose
F1
males
and
females
final
premating
body
weights
were
76%
and
75%,
respectively,
with
weight
gains
77%
and
77%,
respectively,
of
the
control
levels.
Mean
daily
food
consumption
levels
for
the
high­
dose
groups
during
the
premating
interval
were
80­
85%
of
the
control
levels.
Absolute
body
weights
of
the
mid­
dose
F0
males
were
occasionally
significantly
(p
#
0.05)
less
than
the
controls
with
premating
weight
gains
and
food
consumption
88%
and
94%
(both,
p
#
0.05),
respectively,
of
the
control
levels.
For
the
mid­
dose
F1
males
and
females,
final
premating
body
weights,
body
weight
gains,
and
food
consumption
were
92­
94%
of
the
control
levels.
For
the
mid­
and
high­
dose
dams
of
both
generations,
lower
body
weights
during
gestation
and
lactation
were
considered
a
continuation
of
premating
effects.

No
treatment­
related
lesions
were
noted
at
necropsy
of
the
F0
males
or
females.
In
highdose
F1
males,
gross
lesions
of
the
testes
included
reduced
in
size
(9/
30),
abnormally
large
(3/
30),
soft
(5/
30),
small
epididymides
(8/
30),
and
unspecified
deformities
of
the
epididymides
(5/
30);
these
were
noted
as
significant
incidences,
but
control
rates
were
not
given
in
the
original
DER.
Microscopically,
increased
incidences
(p
#
0.05)
of
testicular
and
epididymal
lesions
were
found
in
high­
dose
F1
males
as
compared
with
the
controls:
atrophy
(14/
30),
fibrosis
(8/
30),
and
hyperplasia
(7/
30)
in
the
testes
and
arteritis
(6/
30),
inflammation
(5/
30),
and
oligospermia
(12/
30)
in
the
epididymides.
Only
one
incidence
each
of
atrophy
and
oligospermia
were
observed
in
control
animals.
Absolute
testes
weights
of
the
high­
dose
F1
males
were
significantly
(p
#
0.05;
80%
of
control)
less
than
the
controls.
In
high­
dose
F1
females,
gross
findings
(n.
s.)
included
cystic
ovaries
(4/
30),
dilatation
(3/
30),
and
fluid
filled
uterine
horns
(2/
30),
none
of
which
were
observed
in
control
animals.

In
addition,
lesions
of
the
eye
were
noted
in
high­
dose
F1
males
and
females
and
were
reviewed
in
MRID
41864701.
A
significant
(p
#
0.05)
increase
was
seen
in
the
number
of
high­
dose
F1
males
with
any
type
of
corneal
or
conjunctival
change
(14/
30
vs
4/
30
controls).
The
lesions
included
corneal
degeneration/
basophilia
and
conjunctival
inflammation/
basophilia.
Degeneration
of
the
lens
was
observed
in
3/
30
high­
dose
males
and
3/
29
high­
dose
females
compared
with
only
1/
30
control
male.
However,
a
clear
treatment­
related
effect
in
females
was
not
considered
to
be
definitive.

The
systemic
toxicity
LOAEL
was
established
at
100
ppm
(average
premating
doses
5.8­
9.24
mg/
kg/
day)
based
on
reduced
body
weight
gains
in
males
and
females
26
during
both
generations.
The
systemic
toxicity
NOAEL
was
established
at
12.5
ppm
(average
premating
doses
0.74­
1.12
mg/
kg/
day).

No
treatment­
related
adverse
effects
were
found
on
the
reproductive
performance
of
either
generation.
For
the
control,
low­,
mid­,
and
high­
dose
group,
pup
viability
for
lactation
days
0­
4
was
99.4,
98.0,
99.8,
and
91.7%
(p
#
0.05),
respectively,
for
the
F1
generation
and
96.8,
92.7,
99.5,
and
76.2%
(p
#
0.05),
respectively,
for
the
F2
generation.
The
mean
number
of
pups
per
litter
in
the
high­
dose
F2
group
was
significantly
(p
#
0.05)
less
than
the
control
throughout
lactation.
The
number
of
litters
with
pups
showing
clinical
signs
was
significantly
(p
#
0.05)
increased
in
both
generations.

The
reproductive
toxicity
NOAEL
was
greater
than
or
equal
to
625
ppm
(average
premating
doses
36­
63.0
mg/
kg/
day)
and
the
reproductive
toxicity
LOAEL
was
not
established.

Body
weights
of
the
mid­
and
high­
dose
F1
male
and
female
pups
and
of
the
high­
dose
F2
male
and
female
pups
were
significantly
(p
#
0.05)
less
than
those
of
the
controls
throughout
lactation
LOAEL
for
offspring
toxicity
was
established
at
100
ppm
(average
premating
doses
5.8­
9.24
mg/
kg/
day)
based
on
reduced
F1
pup
body
weights.
The
offspring
toxicity
NOAEL
was
established
at
12.5
ppm
(average
premating
doses
0.74­
1.12
mg/
kg/
day).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
reproductive
toxicity
study
[OPPTS
870.3800
(83­
4)]
in
rats.

5.5
Special
Studies
5.5.1
Biochemical
and
Histopathological
Effects
in
Rats
MRID
No:
00164093
Executive
Summary:
A
special
study
was
conducted
to
determine
the
biochemical
and
histopathological
effects
under
a
variety
of
conditions
of
linuron
(94.5%
a.
i.)
administration
to
Crl:
CD®
BR
rats.
The
rats
utilized
for
various
parts
of
this
study
were
young
adult
males
approximately
22
days
old
(young),
retired
breeder
males
approximately
11
months
old
(old),
and
male
and
female
F1b
and
F2b
rats
from
a
multigeneration
study
(MRID
41463401)
maintained
on
diets
of
0,
12.5,
100,
or
625
ppm
(0,
0.75,
4.1,
and
22
mg/
kg/
day,
respectively,
for
males
and
0,
1.1,
6.1,
and
37
mg/
kg/
day,
respectively,
for
females).
Additionally,
Leydig
cell
enzyme
analyses
were
conducted
in
vitro.

The
activities
of
five
testicular
steroidogenic
enzymes
were
assayed
in
vitro
using
horse
27
testicular
microsomal
preparations
in
the
presence
of
0,
0.5,
5,
50,
500,
or
5000
:
M
linuron
or
linuron
metabolites.
Enzyme
activities
measured
included
aromatase,
17­
20
desmolase
(desmolase),
3­
$
­hydroxysteriod
dehydrogenase/
isomerase
(isomerase),
17­
hydroxylase
(hydroxylase),
and
17­
ketosteriod
reductase
(reductase).
Linuron
concentrations
of
500
and
5000
:
M
resulted
in
significantly
decreased
aromatase
and
desmolase
and
increased
reductase
activities.
At
50
:
M
the
activities
of
aromatase,
desmolase,
isomerase,
and
hydroxylase
were
decreased
by
10­
20%
and
reductase
was
increased
by
20%
as
compared
with
the
controls.
Effects
of
linuron
metabolites
on
enzyme
activities
were
highly
variable
and
generally
only
seen
at
5000
:
M.

The
testosterone
metabolic
clearance
rate
was
measured
in
young
male
rats.
Groups
of
5
animals
were
administered
0
or
200
mg/
kg/
day
for
eight
days,
castrated,
and
then
infused
with
testosterone
at
3
or
6
:
g/
hour.
Blood
samples
were
taken
every
30
minutes
for
180
minutes
after
the
start
of
infusion.
No
differences
between
the
treated
and
control
groups
were
noted
at
the
lower
infusion
rate.
At
the
higher
infusion
rate,
the
mean
plateau
concentrations
(60­
180
minutes)
in
the
control
and
treated
rats
were
769±
344
and
605±
67.4
:
g/
dL,
respectively,
resulting
in
calculated
metabolic
clearance
rates
of
780
and
992
mL/
h,
respectively.
Due
to
the
large
variability
between
individual
animals
it
was
concluded
that
linuron
does
not
affect
testosterone
clearance
in
young,
castrated
rats.

Two
trials
evaluated
the
response
of
Leydig
cells
to
luteinizing
hormone
(LH).
In
trial
1,
the
groups
consisted
of
five
young
or
five
old
males
treated
with
0
or
200
mg/
kg/
day
for
three
days,
and
five
0­
ppm
and
five
625­
ppm
F2b
males
which
were
approximately
11
months
old.
In
trial
2,
the
groups
consisted
of
five
young
or
five
old
males
treated
with
0
or
200
mg/
kg/
day
for
seven
days,
and
five
each
of
the
0,
12.5,
100,
and
625
ppm
F2b
males
which
were
approximately
19
months
old.
Leydig
cells
were
isolated
from
the
testes
and
incubated
with
up
to
1000
ng
LH/
tube.
Results
from
trial
1
showed
no
differences
in
the
response
between
the
treated
and
control
young
rats.
However
in
old
rats,
Leydig
cells
from
the
treated
animals
were
less
responsive
than
the
controls
both
in
maximum
response
and
potency.
In
contrast,
Leydig
cells
from
the
chronically
treated
F2b
males
were
significantly
more
responsive
to
LH
stimulation
as
compared
with
their
controls.
In
trial
2,
Leydig
cells
from
treated
young
and
old
rats
had
decreased
maximum
responses
and
potency
as
compared
with
controls,
with
old
rats
more
affected
than
young
rats.
From
the
chronically
exposed
rats,
Ledig
cells
were
moderately
responsive
from
the
control
and
low­
dose
groups,
minimally
responsive
from
the
mid­
dose
group,
but
significantly
greater
in
response
from
the
high­
dose
group.
Taken
together,
the
two
trials
were
reasonably
consistent
with
a
preliminary
conclusion
that
there
are
dose­
and
timerelated
effects
of
linuron
upon
the
sensitivity
of
rat
Leydig
cells
to
stimulation
by
LH.

F1b
and
F2b
rats
were
sacrificed
at
two
years
of
age
for
histopathological
evaluation
of
selected
tissues.
The
number
of
high­
dose
males
of
both
generations
with
small
or
discolored
testes
was
increased
as
compared
with
the
controls
(stated
in
text
of
DER;
incidence
rates
not
readable).
No
other
gross
observations
were
noted.
Microscopically,
mid­
and
high­
dose
males
had
increased
incidences
of
interstitial
cell
adenomas
and
hyperplasia.
Combining
data
from
both
generations,
adenomas
were
observed
in
1/
19,
28
0/
25,
6/
25,
and
2/
16
animals
and
hyperplasia
was
observed
in
2/
19,
0/
25,
7/
25,
and
3/
19
animals
from
the
control,
low­,
mid­,
and
high­
dose
groups,
respectively.
The
lower
incidences
in
the
high­
dose
group
were
probably
due
to
fewer
animals
available
for
examination.
In
females
the
combined
incidence
rate
for
cervical
endometrial
hyperplasia
was
0/
28,
6/
30,
9/
29,
and
13/
29,
respectively,
and
of
cervical
cystic
hyperkeratosis
was
0/
28,
1/
30,
1/
29,
and
7/
29,
respectively.
These
lesions
in
both
males
and
females
are
consistent
with
findings
in
a
2­
year
chronic
study.

In
conclusion,
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.

This
study
is
classified
as
Acceptable/
Nonguideline
as
a
special
mechanistic
study
in
rats.

5.5.2
Special
Reproduction
Study
­
Leydig
Cell
Tumorigenisis
in
Rat
MRID
No:
41630101
Executive
Summary:
A
special
mechanism
study
was
conducted
in
male
Crl:
CD(
SD)
BR
rats.
Linuron
(96.2%
a.
i)
was
administered
at
200
mg/
kg/
day
by
gavage
for
14
days
to
groups
of
10
growing
(32­
33
days
of
age)
and
adult
(93
days
of
age)
rats.
Additional
groups
of
10
rats
each
were
used
as
negative
control,
pair­
fed
control,
and
positive
control
(flutamide,
10
mg/
kg/
day).
All
rats
were
observed
daily
and
body
weights
and
food
consumption
were
recorded.
At
termination,
blood
was
collected
for
serum
hormone
analyses
and
the
organs
of
the
reproductive
tract
were
weighed.
In
addition,
blood
was
collected
from
the
F0
and
F1
males
and
organ
weights
were
recorded
from
the
F0
males
from
a
multigeneration
study
(MRID
41463401).
Premating
doses
for
the
multigeneration
study
were
0.74­
0.95,
5.8­
7.8,
and
36­
54
mg/
kg/
day.
Finally,
linuron
and
four
of
its
metabolites
were
evaluated
in
vitro
for
their
ability
to
compete
for
binding
to
the
androgen
receptor.

No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
the
growing
rats,
the
positive
controls,
or
the
F0
and
F1
rats.
Adult
rats
treated
with
the
test
article
for
14
days
had
significantly
(p
#
0.05)
increased
incidences
of
discharge
and/
or
stains
in
the
perioral,
perinasal,
and
or
periocular
regions
(9/
10),
eye
discharge
(5/
10),
and
weak
appearance
(9/
10)
as
compared
with
both
the
negative
and
pair­
fed
control
groups.
These
signs
were
not
observed
in
the
control
groups
with
the
exception
of
one
pair­
fed
animal
with
discharge
and/
or
stains.

Final
body
weights,
body
weight
changes,
and
food
consumption
of
the
14­
day
treated
groups,
of
the
pair­
fed
control
groups,
and
of
the
mid­
and
high­
dose
F0
and
F1
groups
29
were
significantly
(p
#
0.05)
less
than
that
of
their
concurrent
negative
control
group
values.
Final
body
weight
and
weight
change
for
the
14­
day
adult
group
were
also
significantly
(p
#
0.05)
less
than
those
of
their
pair­
fed
control.
Body
weights
and
body
weight
changes
were
significantly
(p
#
0.05)
reduced
only
in
the
adult
positive
control
group
as
compared
with
their
negative
controls
(food
consumption
not
measured
in
positive
controls).

For
growing
rats,
absolute
and
relative
accessory
sex
organ
unit,
prostate,
ventral
prostate,
and
seminal
vesicle
weights
were
significantly
(p
#
0.05)
reduced
as
compared
with
both
negative
and
pair­
fed
control
groups.
Absolute
and
relative
dorsal
lateral
prostate
and
levator
ani
muscle
weights
and
absolute
testes
weights
were
significantly
(p
#
0.05)
reduced
and
relative
testes
weights
were
significantly
increased
(p
#
0.05)
as
compared
with
the
negative
controls.
Significant
(p
#
0.05)
differences
in
the
pair­
fed
control
group
as
compared
with
the
negative
control
group
included
decreased
absolute
accessory
sex
organ
unit,
ventral
prostate,
dorsal
lateral
prostate,
seminal
vesicles,
and
levator
ani
muscle
weights
and
relative
testes
and
levator
ani
muscle
weights.
In
the
positive
control
rats,
absolute
and
relative
testes
weights
were
not
affected,
but
all
other
absolute
and
relative
organ
weights
were
significantly
(p
#
0.05)
less
than
their
negative
controls.

For
adult
rats,
absolute
and
relative
accessory
sex
organ
unit,
prostate,
and
ventral
prostate
weights
were
significantly
(p
#
0.05)
reduced
as
compared
with
both
negative
and
pair­
fed
control
groups.
Absolute
epididymides,
seminal
vesicle,
coagulating
gland,
and
levator
ani
muscle
weights
significantly
(p
#
0.05)
reduced
as
compared
with
the
negative
controls.
Significant
(p
#
0.05)
differences
in
the
pair­
fed
control
group
as
compared
with
the
negative
control
group
included
decreased
absolute
accessory
sex
organ
unit,
coagulating
gland,
and
levator
ani
muscle
weights.
In
the
positive
control
rats,
testes
weights
were
not
affected,
but
all
other
absolute
and
relative
organ
weights
were
significantly
(p
#
0.05)
or
slightly
(n.
s.)
less
than
their
negative
controls.

Significant
differences
(p
#
0.05)
in
organ
weights
for
the
high­
dose
F0
males
as
compared
with
the
controls
included
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.

Serum
testosterone,
estradiol,
and
luteinizing
hormone
levels
in
both
growing
and
adult
rats
were
similar
to
the
control
levels.
However,
F0
and
F1
males
had
significantly
(p
#
0.05)
increased
levels
of
estradiol
(155
and
115%,
respectively)
and
luteinizing
hormone
(175
and
168%,
respectively).
In
the
positive
control
groups,
testosterone,
estradiol,
and
luteinizing
hormone
levels
were
increased
(p
#
0.05)
304,
123,
and
304%,
respectively,
in
growing
rats
and
915,
100
(n.
s.),
and
346%,
respectively,
in
adult
rats.

Linuron
and
three
other
compounds
[1­
(3,4­
dichlorophenyl)­
3­
methoxyurea;
3,4­
dichloroanaline;
3,4­
dichlorophenylurea;
and
1­(
3,4­
dichlorophenyl)­
3­
methylurea]
appeared
to
compete
with
testosterone
for
binding
to
the
androgen
receptor
in
vitro,
although
the
results
were
highly
variable.
IC50
values
for
linuron
and
flutamide
were
30
approximately
18,000
±
3,500
and
64,000±
11,000
nM,
respectively.
3,4­
dichlorophenylurea
did
not
displace
testosterone
from
the
receptor,
therefore
an
IC50
value
could
not
be
determined.
The
remaining
metabolites
had
IC50
ranging
from
110,000
to
260,000
nM.

In
conclusion,
linuron
may
be
a
weak
androgen
receptor
antagonist
based
on
decreased
accessory
sex
organ
weights
for
growing
and
adult
rats,
increased
serum
luteinizing
hormone
levels
in
F0
and
F1
rats,
and
competitive
androgen
receptor
binding
in
vitro.
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.

This
study
is
classified
as
Acceptable/
Nonguideline
as
a
special
mechanistic
study
in
rats.

5.5.3
Special
Reproduction
Study
­
Cross­
mating
­
Rat
MRID
No:
00159846
Executive
Summary:
A
special
study
(MRID
00159846)
was
conducted
to
evaluate
the
effects
of
linuron
(94.5%
a.
i.)
on
the
reproduction
and
lactation
performance
of
crossmated
male
and
female
Crl:
CD®(
SD)
BR
rats.
The
rats
utilized
for
this
study
were
the
F2
adults
from
a
multigeneration
study
and
the
current
study
was
initiated
within
two
weeks
after
weaning
of
the
last
F3a
litter.
High­
dose
(625
ppm)
and
control
animals
were
cross­
mated
to
produce
F3b
and
F3c
litters;
different
pairings
were
made
for
production
of
each
litter.
The
data
from
the
original
F2
control
group
from
the
multigeneration
study
was
used
as
control
data
for
the
current
study,
but
the
animals
were
not
remated.
The
fertility
index
was
calculated
in
the
report
as
(no.
litters
delivered/
no.
females
mated)
x
100.
The
reviewer
calculated
the
following
indices:
male
fertility
index
=
(no.
males
impregnating
females/
no.
males
exposed
to
females)
x
100;
female
fertility
index
=
(no.
females
conceiving/
no.
females
exposed
to
males)
x
100;
and
fecundity
index
=
(no.
pregnancies/
no.
copulations)
x
100.

During
production
of
both
litters,
the
fertility
index
and
the
number
of
pups/
litter
at
birth
and
at
weaning
were
reduced
as
compared
with
the
control
values.
The
fertility
indices
for
control
females
crossed
with
treated
males
and
for
treated
females
crossed
with
control
males
were
11.8
and
47.4%,
respectively,
for
the
F3b
litters
and
41.2
and
42.1%,
respectively,
for
the
F3c
litters
as
compared
with
89.5%
for
the
controls.
The
number
of
pups/
litter
at
birth
was
4.0­
9.2
for
the
cross­
mated
groups
and
13.1
for
the
controls.
At
weaning
the
number
of
pups/
litter
was
4.0­
4.3
for
the
F3b
litters
and
the
F3c
litters
from
treated
females
crossed
with
control
males
compared
with
8.1
pups/
litter
for
both
the
control
group
and
the
F3c
litters
from
control
females
crossed
with
treated
males.

In
production
of
both
litters,
male
and
female
fertility
indices
for
the
groups
in
which
the
males
were
treated
were
reduced
(47­
71%
for
males
and
47­
60%
for
females)
compared
with
those
for
groups
in
which
the
females
were
treated
(90­
86%
for
males
and
85­
85%
31
for
females).
The
fecundity
index
was
reduced
only
for
treated
males
crossed
with
control
females
during
production
of
the
F3b
litters
(25%)
as
compared
with
the
other
groups
(56.2­
63.6%).

Pup
viability
was
decreased
in
litters
from
treated
dams
mated
with
control
males
as
compared
with
litters
from
control
dams
mated
with
treated
males.
Pup
viability
for
days
0­
4
was
77.5%
in
litters
from
treated
dams
and
98.5%
in
litters
from
control
dams
while
viability
for
days
1­
4
was
88.6%
and
98.7%,
respectively.
Litter
survival
was
75%
from
treated
dams
compared
with
100%
from
control
dams.
Mean
pup
body
weights
from
treated
dams
were
also
slightly
or
significantly
(p
#
0.05)
less
than
those
from
the
control
dams
throughout
lactation.

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.

This
study
is
classified
as
Acceptable/
Nonguideline
as
a
special
cross­
mating
study
in
rats.

5.6
Additional
Information
from
Literature
Sources
5.6.1
McIntyre
BS,
Barlow
NJ,
Wallace
DG,
Maness
SC,
Gaido
KW,
Foster
PM,
Effects
of
in
utero
exposure
to
linuron
on
androgen­
dependent
reproductive
development
in
the
male
Crl:
CD(
SD)
BR
rat.
Toxicol
Appl
Pharmacol
167(
2):
87­
99
(2000)

Pregnant
rats
were
administered
linuron
by
gavage
at
0,
12.5,
25,
or
50
mg/
kg/
day
(n
=
11/
group)
from
gestation
day
12
to
21.

Anogenital
distance
of
resulting
offspring
was
unaffected,
whereas
male
areola/
nipple
retention
per
rat
was
increased
at
12.5,
25,
and
59
mg/
kg/
day
(1.0,
1.6,
and
3.7,
respectively)
compared
to
the
control
(<
1.0).

Hypoplastic
testes
in
adult
offspring
were
seen
in
2/
56
rats
(2/
10
litters),
8/
69
rats
(4/
11
litters),
and
5/
44
rats
(3/
8
litters),
while
hypoplastic
epididymides
occurred
in
1/
56
rats
(1/
10
litters),
8/
69
rats
(4/
11
litters),
and
2/
44
rats
(1/
8
litters)
in
the
12.5,
25,
and
50
mg/
kg/
day
dose
groups,
respectively.

Partial
agenesis
of
the
epididymides
was
observed
in
3/
44
rats
(2/
8
litters)
only
in
the
50
mg/
kg/
day
group.
These
data
indicate
that
in
utero
exposure
to
linuron
preferentially
impairs
testosterone­
mediated,
rather
than
DHT­
mediated,
reproductive
development.
This
effect
is
distinctly
different
from
the
effects
induced
by
flutamide,
an
AR
antagonist
that
shares
structural
similarities
with
linuron.

5.6.2
Lambright
C,
Ostby
J,
Bobseine
K,
Wilson
V,
Hotchkiss
AK,
Mann
PC,
32
Gray
LE,
Cellular
and
molecular
mechanisms
of
action
of
linuron:
an
antiandrogenic
herbicide
that
produces
reproductive
malformations
in
male
rats.
Toxicol
Sci
56(
2):
389­
99
(2000)

In
vitro,
linuron
binds
human
AR
(hAR),
and
and
acts
as
an
hAR
antagonist.
Linuron
competed
with
an
androgen
for
rat
prostatic
AR
EC50
=
100­
300
microM)
and
human
AR
(hAR)
in
a
COS
cell­
binding
assay
EC50
=
20
microM).

Linuron
inhibited
dihydrotestosterone
(DHT)­
hAR
induced
gene
expression
in
CV­
1
and
MDA­
MB­
453­
KB2
cells
EC50
=
10
microM)
at
concentrations
that
were
not
cytotoxic.

Linuron
(oral
100
mg/
kg/
d
for
7
days)
treatment
reduced
testosterone­
and
DHT­
dependent
tissue
weights
in
the
Hershberger
assay
using
castrate­
immature­
testosterone
propionate­
treated
male
rats
and
altered
the
expression
of
androgen­
regulated
ventral
prostate
genes
(oral
100
mg/
kg/
d
for
4
days).
[The
Hershberger
assay
is
an
EDSTAC
Tier
1
assay
to
provide
in
vivo
screening
data
relevant
to
androgen
agonism
and
antagonism
for
preliminary
hazard
identification.]

Histological
effects
of
in
utero
exposure
to
linuron
(100
mg/
kg/
d,
day
14­
18)
or
DBP
(500
mg/
kg/
d,
day
14
to
postnatal
day
3)
on
the
testes
and
epididymides
also
are
shown
here.

These
results
support
the
hypothesis
that
linuron
is
an
AR
antagonist
both
in
vivo
and
in
vitro,
but
it
remains
to
be
determined
if
linuron
alters
sexual
differentiation
by
additional
mechanisms
of
action.

5.6.3
Gray
LE,
Wolf
C,
Lambright
C,
Mann
P,
Price
M,
Cooper
RL,
Ostby
J,
Administration
of
potentially
antiandrogenic
pesticides
(procymidone,
linuron,
iprodione,
chlozolinate,
p,
p'­
DDE,
and
ketoconazole)
and
toxic
substances
dibutyland
diethylhexyl
phthalate,
PCB
169,
and
ethane
dimethane
sulphonate)
during
sexual
differentiation
produces
diverse
profiles
of
reproductive
malformations
in
the
male
rat.
Toxicol
Ind
Health
15(
1­
2):
94­
118
(1999)

Linuron
(100
mg/
kg/
day)
treatment
induced
a
level
of
external
effects
consistent
with
its
low
affinity
for
AR
[reduced
anogenital
distance
(AGD),
retained
nipples,
and
a
low
incidence
of
hypospadias].

Linuron
treatment
also
induced
malformed
epididymides
and
testis
atrophy.

The
results
suggest
that
Linuron
may
display
several
mechanisms
of
endocrine
toxicity,
one
of
which
involves
AR
binding
5.6.4
Vinggaard,
AM,
Hnida,
C,
Breinholt,
V
and
Larsen,
JC,
Screening
of
33
Selected
Pesticides
for
Inhibition
of
CYP19
Aromatase
Activity
In
vitro,
Toxicol
in
Vitro
14:
227­
234
(2000)

Linuron
was
tested
for
its
ability
to
affect
CYP19
aromatase
activity
in
human
placental
microsomes
using
the
classical
[
3
H]
20
method.
Linuron
did
not
affect
CYP19
aromatase
activity
in
human
placental
microsomes.
The
positive
control,
4­
hydroxyandrostendione
(1
:
m),
caused
a
74%
inhibition
of
CYP19
aromatase
activity
and
a
94%
inhibition
of
aromatase
activity
in
JEG­
3
human
carcinoma
cells.

5.6.5
Vinggaard,
AM,
Breinholt,
V
and
Larsen,
JC,
Screening
of
selected
pesticides
for
oestrogen
receptor
activation
in
vitro,
Food
Addit
Contam
16
(12),
533­
542
(1999)

Linuron,
tested
in
the
oestrogen
receptor
in
vitro
using
an
MCF7
cell
proliferation
assay
and
a
Yeast
Oestrogen
screen,
did
not
effect
the
proliferation
response
after
6
days
of
exposure.

5.6.6
Cook,
J.
C.,
Mullin,
L.
S.,
Frame,
S.
R.,
Biegel,
L.
B.,
Investigation
of
a
Mechanism
for
Leydig
Cell
Tumorigenesis
by
Linuron
in
Rats,
Toxicol
Appl
Pharmacol
119(
2):
195­
204
(1993)

Serum
testosterone,
estradiol,
and
luteinizing
hormone
(LH)
concentrations
in
sexually
immature
rats
and
testosterone
and
LH
concentrations
in
sexually
mature
rats
were
significantly
increased.

Linuron
significantly
decreased
body
weight
and
relative
epididymides,
accessory
sex
organ,
prostate,
and
seminal
vesicle
weights
in
sexually
immature
rats
and
body
weight
and
relative
accessory
sex
organ
and
prostate
weights
in
mature
rats.

Serum
estradiol
and
LH
concentrations
were
significantly
increased
in
sexually
mature
rats.
Estradiol,
LH,
and
testosterone
concentrations
were
not
affected
in
immature
males.

Linuron
significantly
decreased
body
weights
and
increased
serum
LH
and
estradiol
concentrations
in
both
parental
and
F1rats.

Linuron
was
found
to
compete
with
testosterone
for
binding
to
the
androgen
receptor.

The
authors
conclude
that
linuron
apparently
induces
Leydig
tumors
by
disrupting
the
hypothalamic/
pituitary/
testicular
axis
which
leads
to
a
sustained
hypersecretion
of
LH.
34
5.7
Determination
of
Susceptibility
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
of
rabbit
developmental
study;
developmental
effects
were
seen
at
a
dose
higher
than
that
causing
maternal
toxicity.
In
the
rat
developmental
study,
increases
in
post­
implantation
losses
and
increases
in
fetal
resorptions/
litter
were
seen
as
a
dose
that
caused
decreases
in
maternal
body
weight
and
food
consumption.
The
HIARC
determined
that
the
developmental
effects
are
not
indicative
of
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
either
in
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
(
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.

5.8
Evidence
that
suggest
study
requiring
a
Developmental
Neurotoxicity
Study:

From
special
studies
and
open
literature
publications,
Linuron
was
shown
to
be
an
endocrine
disruptor.
Key
findings
include:

(1)
Linuron
and
some
of
its
metabolites
are
androgen
receptor
antagonists
[§
5.5.2]
(2)
Rats
treated
with
linuron
had
reduced
anogenital
distance,
retention
of
nipples,
and
a
low
incidence
of
hypospadias.
[§
5.5.3].
(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
[§
5.4.3]
(4)
F0
and
F1
males
had
significantly
increased
levels
of
estradiol
and
and
luteinizing
hormone
[§
5.4.4].
(5)
Linuron
inhibits
activities
of
steroidogenic
enzymes
[§
5.4.3]
(6)
A
dose­
dependent
increase
in
areola/
nipple
retention
in
male
rats
[§

Although
there
was
no
evidence
for
increased
susceptibility
in
rats,
based
on
the
findings
that
linuron
is
an
endocrine
disruptor,
increased
testicular
lesions
and
decreased
fertility,
the
HIARC
concluded
that
a
development
neurotoxicity
study
in
the
rat
is
required.

6
HAZARD
CHARACTERIZATION
35
The
toxicological
database
for
linuron
is
considered
adequate
for
hazard
characterization.
At
the
time
of
this
review,
there
are
no
toxicological
data
gaps
and
no
outstanding
toxicological
concerns.

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.

Chronic
toxicity
studies
in
the
dog,
rat
and
mouse
showed
altered
hematological
findings.
Beagle
dogs
fed
linuron
at
dietary
concentration
of
625
ppm,
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.
ChR­
CD
rats
fed
diets
containing
Linuron
at
125
ppm
(5.11
mg/
kg/
day
in
males
and
7.75
mg/
kg/
day
in
females),
microscopic
observations
consistent
with
hemolysis
(hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes).
Rats
also
showed
decreased
body
weight
gains
in
both
sexes
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.
Systemic
toxicity
observed
in
mice
included
increased
methemoglobin
formation
and
vacuolation
and
hemosiderosis
of
the
spleen.

Oncogenicity
studies
in
the
rat
and
mouse
did
not
show
consistent
tumor
profiles
between
sexes
and
species.
In
rats
there
was
a
significant
increase
in
the
incidence
of
testicular
interstitial
cell
adenomas
in
males,
while
no
treatment­
related
neoplasms
were
observed
in
females.
In
a
mouse
oncogenicity
study
a
statistically
significant
increase
in
liver
tumors
was
observed
in
females.
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).

In
a
developmental
toxicity
study
using
rats,
the
highest
dose
level
caused
maternal
toxic
effects
including
decreased
body
weight
gain
and
food
consumption,
as
well
as
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
more
abortions,
fewer
fetuses
per
litter,
decreased
fetal
body
weight,
and
an
increased
incidence
of
fetuses
with
skeletal
skull
variations.

In
a
2­
generation
reproductive
toxicity
study
using
rats,
linuron
caused
effects
on
the
parents
including
decreased
body
weight
gain
and
abnormalities
in
the
eyes
and
testes.
Rats
exposed
to
linuron
could
develop
cell
tumors
in
testicular
tissue.
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
chronic
toxicity
of
linuron
has
been
evaluated
in
two­
year
feeding
studies
in
both
the
rat
and
dog.
Body
weights
were
measured
weekly
during
the
entire
study.
In
the
rat
study,
after
one
36
week
of
treatment,
a
significant
decrease
in
body
weight
gain
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
a
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.

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.
In
oncogenicity
studies
in
the
rat
and
mouse
tumors
were
observed,
however,
no
sex
and
species
differences
were
noted.
In
the
mouse
oncogenicity
study,
a
significant
increase
in
malignant
lymphomas
were
observed
in
the
spleen
of
females.
In
the
combined
chronic
toxicity/
oncogenicity
study
in
rats,
testicular
adenomas
were
observed
in
16
and
58%
of
males
at
600
and
1800
ppm,
respectively,
compared
to
6%
in
both
control
and
low­
dose
groups.
In
female
rats,
the
incidence
of
endometrial
polyps
was
observed
at
600
(15%)
and
1800
(13%)
ppm,
compared
to
4%
for
control
and
8%
at
200
ppm.

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
[§
5.6.2];
but
not
an
estrogen
receptor
antagonist
[§
5.6.5];
(2)
competitive
inhibition
of
the
transcriptional
activity
of
dihydrotestosterone
(DHT)­
human
androgen
receptor
(hAR)
in
vitro
[§
5.6.1,
§5.6.3],
decreased
anogenital
distance
[§
5.6.3]
and/
or
an
increase
in
the
retention
of
areolae/
nipples
[§
5.6.1,
§5.6.3]
in
male
offspring
following
in
utero
exposure
to
linuron;
(3)
inhibition
of
steroidogenic
enzymes
[§
5.6.4],
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
ones
[§
5.5.1];
(5)
F0
and
F1
males
had
significantly
increased
levels
of
estradiol
and
luteinizing
hormone
[§
5.5.2].

7
DATAGAPS
Developmental
neurotoxicity
study
­Rat
28­
day
inhalation
study
­
Rat.
37
8
ACUTE
TOXICITY
Acute
Toxicity
of
Linuron,
Technical
Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
81­
1
Acute
Oral
(Rat)
00027625
2600
mg/
kg
III
81­
2
Acute
Dermal
(Rabbit)
00027625
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
(Rat)
00053769
>
218
mg/
L/
hr
IV
81­
4
Primary
Eye
Irritation
42849001
Slight
conjunctival
redness
at
24
hrs;
clear
at
72
hrs
III
81­
5
Primary
Skin
Irritation
42849002
Not
an
irritant
IV
81­
6
Dermal
Sensitization
00146868
Not
a
sensitizer
N/
A
38
9
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

EXPOSURE
SCENARIO
DOSE
(mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
(Females
13­
50)
NOAEL=
12
UF
=
100
Increased
post­
implantation
loss
and
fetal/
litter
resorptions
at
50
mg/
kg/
day
(LOAEL).
Rat
Prenatal
Developmental
Toxicity
(MRID
00018167)

Acute
RfD
(Females
13­
50
years
old)
=
0.12
mg/
kg
Acute
Dietary
(General
Population)
No
appropriate
effects
attributed
to
a
single
exposure
was
identified.

Chronic
Dietary
NOAEL
=
0.77
UF
=
100
Increased
met­
and
sulfhemoglobin
levels
at
LOAEL
(4.17
mg/
kg/
day,
males;
3.5
mg/
kg/
day,
females).
Chronic
Oral
/
Dog
Chronic
RfD
=
0.0077
mg/
kg/
day
Incidental
Oral
Short­
Term
NOAEL=
5.8
Statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day
(LOAEL).
2­
Generation
Reproduction
Study/
Rat
Incidental
Oral
Intermediate­
Term
NOAEL
=
0.77
Increased
met­
and
sulfhemoglobin
concentrations
after
3
and
6
months
exposure4.17
mg/
kg/
day
(males)
and
3.5
mg/
kg/
day
(females).
Chronic
Oral
/
Dog
Dermal
1
Short­
Term
NOAEL=
5.8
Statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day
(LOAEL).
2­
Generation
Reproduction
Study/
Rat
Dermal
1
Intermediate­
Term
NOAEL
=
0.77
Increased
met­
and
sulfhemoglobin
concentrations
after
3
and
6
months
exposure4.17
mg/
kg/
day
(males)
and
3.5
mg/
kg/
day
(females).
Chronic
Oral
/
Dog
Dermal
1
Long­
Term
NOAEL
=
0.77
Increased
met­
and
sulfhemoglobin
concentrations
after
9
and
12
months
exposure4.17
mg/
kg/
day
(males)
and
3.5
mg/
kg/
day
(females).
Chronic
Oral
/
Dog
Inhalation
2
Short­
Term
NOAEL=
5.8
Statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
observed
at
36
mg/
kg/
day
(LOAEL).
2­
Generation
Reproduction
Study/
Rat
Inhalation
2
Intermediate­
Term
NOAEL
=
0.77
Increased
met­
and
sulfhemoglobin
concentrations
after
3
and
6
months
exposure4.17
mg/
kg/
day
(males)
and
3.5
mg/
kg/
day
(females).
Chronic
Oral
/
Dog
Inhalation
2
Long­
Term
NOAEL
=
0.77
Increased
met­
and
sulfhemoglobin
concentrations
after
9
and
12
months
exposure4.17
mg/
kg/
day
(males)
and
3.5
mg/
kg/
day
(females).
Chronic
Oral
/
Dog
1
The
dermal
absorption
factor
of
16%
should
be
applied
to
extrapolate
from
the
oral
route
to
the
dermal
route.
2
100%
absorption
rate
(default
value)
should
be
used
to
extrapolate
from
the
oral
route
to
the
inhalation
route.