OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No:
0050429
30
Jan
2002
Memorandum
SUBJECT:
LINURON
(PC
Code:
035506)
REVISED
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document,
(Replaces
TXR
No.
0050415)

FROM:
Robert
Fricke,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
(7509C)

THRU:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
2
Health
Effects
Division
(7509C)

TO:
Carol
Christensen,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(7509C)

DP
Barcodes:
D272367
Submission:
S590997
Action
Requested:
Review
toxicology
studies
submitted
by
the
registrant
and
prepare
the
toxicology
chapter
to
support
reregistration
eligibility
decision
for
linuron
Attached
is
the
updated
toxicology
chapter
summarizing
the
findings
of
the
toxicology
studies.
LINURON
PC
Code:
035506
REVISED
(Replaces
Previous
Document
TXR
No.
0050415)

Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
(or
Registration
Support)
Document
Date
completed:
January
30,
2002
Prepared
by:
Robert
F.
Fricke,
Ph.
D
Reregistration
Branch
2
Health
Effects
Division
Mail
Code
7509C
Peer
reviewed
by:
Yung
Yang,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
Mail
Code
7509C
Robert
F.
Fricke,
Toxicologist
Yung
Yang,
Toxicologist
TABLE
OF
CONTENTS
1
HAZARD
CHARACTERIZATION
...........................................
5
2
REQUIREMENTS
........................................................
6
3
DATA
GAPS
............................................................
7
4
HAZARD
ASSESSMENT..................................................
7
4.
1
Acute
Toxicity
.......................................................
7
4.
2
Subchronic
Toxicity...................................................
8
4.2.1
870.3100
90­
Day
Oral
Toxicity
­
Rat
..............................
8
4.2.2
870.3150
90­
Day
Oral
Toxicity
­
Dog
..............................
8
4.2.3
870.3200
21/
28­
Day
Dermal
Toxicity
­
Rabbit
.......................
8
4.2.4
870.3250
90­
Day
Dermal
Toxicity
................................
8
4.2.5
870.4365
90­
Day
Inhalation
Toxicity
..............................
9
4.
3
Prenatal
Developmental
Toxicity
........................................
9
4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
................
9
4.3.2
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
............
10
4.4
Reproductive
Toxicity
................................................
11
4.4.1
870.3800
Three­
Generation
Reproduction
and
Fertility
Effects
­
Rat
....
11
4.4.2
870.3800
Two­
Generation
Reproduction
Study
in
the
Rat
.............
13
4.
5
Chronic
Toxicity
....................................................
15
4.5.1
870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
Study­
CD(
SD)
BR
Rats
...............................................
15
4.5.2
870.4100b
Chronic
Toxicity
­
Dog
................................
17
4.5.3
870.4100b
Chronic
Toxicity
­
Dog
................................
18
4.6
Carcinogenicity
.....................................................
19
4.6.1
870.4200b
Carcinogenicity
Study
­
Crl:
CD­
1
(ICR)
BR
Mouse
.........
19
4.6.2
870.4300
Carcinogenicity
Study­
CD(
SD)
BR
Rats
...................
20
4.
7
Mutagenicity
.......................................................
20
4.
8
Neurotoxicity.......................................................
22
4.8.1
870.6100
Delayed
Neurotoxicity
Study
­
Hen
.......................
22
4.8.2
870.6200a
Acute
Neurotoxicity
Screening
Battery
....................
22
4.8.3
870.6200b
Subchronic
Neurotoxicity
Screening
Battery
...............
22
4.8.4
870.6300
Developmental
Neurotoxicity
Study
......................
22
4.
9
Metabolism
........................................................
22
4.9.1
870.7485
Metabolism
­
Rat
.....................................
22
4.9.2
870.7600
Dermal
Absorption
­
Rat
...............................
23
4.10
Special
Studies
......................................................
23
4.10.1
Biochemical
and
Histopathological
Effects
in
Rats
...................
23
4.10.2
Leydig
Cell
Tumorigenisis
in
Rat
.................................
25
4.10.3
Special
Reproduction
Study
­
Cross­
mating
­
Rat
.....................
27
5
TOXICITY
ENDPOINT
SELECTION
.......................................
28
5.1
See
Section
9.2
for
Endpoint
Selection
Table
..............................
28
5.
2
Dermal
Absorption
...................................................
28
5.3
Classification
of
Carcinogenic
Potential
..................................
28
5.3.1
Conclusions
..................................................
28
5.3.2
Classification
of
Carcinogenic
Potential
............................
28
5.3.3
Quantification
of
Carcinogenic
Potential
...........................
28
6
FQPA
CONSIDERATIONS................................................
28
6.1
Special
Sensitivity
to
Infants
and
Children
................................
28
6.
2
Recommendation
for
a
Developmental
Neurotoxicity
Study
..................
29
7
OTHER
ISSUES.........................................................
29
8
REFERENCES
..........................................................
29
9
APPENDICES
.........................................................
33
9.
1
Toxicity
Profile
Summary
Tables
.......................................
34
9.1.1
Acute
Toxicity
Table
...........................................
34
9.1.2
Subchronic,
Chronic,
and
Other
Toxicity
Table
......................
34
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Linuron
for
Use
in
Human
Risk
Assessment.........................................................
41
5
1
HAZARD
CHARACTERIZATION
The
toxicological
database
for
linuron
is
adequate
to
assess
the
potential
hazard
to
humans,
including
special
sensitivity
of
infants
and
children.
The
database
will
support
the
reregistration
eligibility
decision
(RED)
for
the
current
registered
uses.
However,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(HIARC)
determined
that
a
developmental
neurotoxicity
study
and
a
28­
day
inhalation
study
are
required
to
provide
better
hazard
characterization..

Linuron
has
low
acute
toxicity
by
the
oral
(LD50
=
2600
mg/
kg),
dermal
(LD50
>
2000
mg/
kg),
and
inhalation
(LC50
>
218
mg/
L)
routes
of
exposure.
Linuron
is
not
an
eye
or
skin
irritant,
and
not
a
skin
sensitizer.

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.
In
the
rat
study,
linuron,
at
a
dietary
dose
125
ppm
(5.1
mg/
kg/
day
in
males
and
7.8
mg/
kg/
day
in
females)
caused
an
increase
in
the
incidence
of
hemolysis.
Microscopic
observations
revealed
increased
incidence
of
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
and
increased
incidences
of
microscopic
changes
in
the
epididymides
(perivasculitis/
vasculitis)
and
renal
pelvis
(transitional
cell
hyperplasia
and
mineralization/
calculi)
of
males
and
in
the
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
the
combined
chronic
toxicity/
oncogenicity
study
in
rats,
common
neoplasms,
included
pituitary
adenomas
of
the
pars
anterior
in
both
male
and
female
rats
and
mammary
fibroadenomas
in
female
rats.
Testicular
adenomas
were
observed
in
6,
28
and
54%,
respectively
for
control,
125
and
625
ppm
dose
groups.
Decreased
incidences
of
both
these
tumor
types
were
noted
in
the
high­
dose
female
group.
In
the
mouse
oncogenicity
study,
treatment
of
up
to
104
weeks
with
1500
ppm
resulted
in
a
significant
increase
in
the
incidence
of
hepatocellular
adenomas
(control,
6%;
1500
ppm,
25%,
p
<
0.05)
in
females.
Linuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells.
There
was
also
no
indication
of
a
clastogenic
effect
up
to
toxic
doses
in
vivo.
Based
on
the
results
of
these
studies,
linuron
was
classified
as
an
unquantifiable
Group
C
carcinogen
(a
possible
human
carcinogen
for
which
there
is
limited
animal
evidence)
requiring
no
quantification
of
human
cancer
risk..

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.
6
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.
While
the
F0
males
were
not
affected,
testicular
lesions
and
reduced
fertility
were
seen
in
the
F1
males.
This
effect
in
the
F1
males
is
an
indication
of
qualitative
evidence
of
susceptibility.

In
a
metabolism
study
linuron
(single
doses
at
24
mg/
kg
and
400
mg/
kg)
was
administered
by
gavage
to
male
and
female
rats.
The
biological
half­
lives
ranged
from
21
hr
in
the
low
dose
males
to
56
hr
in
the
high
dose
females.
Total
recovery
of
radioactivity
was
96%
in
males
and
97%
in
females,
the
majority
of
the
administered
14
C­
linuron
was
eliminated
in
the
urine
(>
80%)
and,
to
a
lesser
extent,
in
the
feces
(~
15%).
Tissue
and
organ
residues
were
very
low
(<
l%)
at
both
dose
levels,
and
there
was
no
indication
of
accumulation
or
retention
of
linuron
or
its
metabolites.
The
major
metabolites
identified
in
the
urine
were
hydroxy­
norlinuron,
desmethoxy
linuron
and
norlinuron,
and
in
feces,
hydroxy­
norlinuron,
and
norlinuron.
Neither
hydroxy­
3,4­
dichloroanaline
nor
3,4­
dichloroanaline
were
present
in
any
of
the
samples.
Exposure
to
linuron
appeared
to
induce
mixed­
function
oxidative
enzymes.

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

2
REQUIREMENTS
The
requirements
(CFR
§158.340,
revised
as
of
July
1,
1999)
for
Food
and
Non­
Food
Use
for
linuron
are
summarized
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(1998)
guideline
protocols
were
used.
7
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.........................
870.1200
Acute
Dermal
Toxicity
.......................
870.1300
Acute
Inhalation
Toxicity
....................
870.2400
Primary
Eye
Irritation
.......................
870.2500
Primary
Dermal
Irritation
.....................
870.2600
Dermal
Sensitization
........................
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.3100
Oral
Subchronic
(Rodent)
....................
870.3150
Oral
Subchronic
(Non­
Rodent)
................
870.3200
21­
Day
Dermal
.............................
870.3250
90­
Day
Dermal
.............................
870.3465
28­
Day
inhalation
870.3465
90­
Day
Inhalation
..........................
Yes
Yes
No
No
Yes
No
Yes
a
Yes
a

No
870.3700a
Developmental
Toxicity
(Rodent)
..............
870.3700b
Developmental
Toxicity(
Non­
rodent)
...........
870.3800
Reproduction
..............................
Yes
Yes
Yes
Yes
Yes
Yes
870.4100a
Chronic
Toxicity
(Rodent)
.....................
870.4100b
Chronic
Toxicity
(Non­
rodent)
.................
870.4200a
Oncogenicity
(Rat)
...........................
870.4200b
Oncogenicity
(Mouse)
........................
870.4300
Chronic/
Oncogenicity
........................
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.5100
Mutagenicity—
Gene
Mutation
­
bacterial
.........
870.5300
Mutagenicity—
Gene
Mutation
­
mammalian
......
870.5385
Mutagenicity—
Mammalian
bone
marrow
chromosomal
aberration
test
...................
870.5395
Mutagenicity—
in
vivo
mammalian
cytogenetics
870.5550
Mutagenicity—
USD
in
Mammalian
cells
in
vitro
...
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
870.6100a
Acute
Delayed
Neurotox.
(Hen)
................
870.6100b
90­
Day
Neurotoxicity
(Hen)
...................
870.6200a
Acute
Neurotox.
Screening
Battery
(Rat)
.........
870.6200b
90
Day
Neuro.
Screening
Battery
(Rat)
...........
870.6300
Developmental
Neurotoxicity
..................
No
No
No
No
Yes



No
870.7485
General
Metabolism
..........................
870.7600
Dermal
Penetration
..........................
Yes
No
Yes
Yes
a
These
data
requirements
are
satisfied
by
the
corresponding
chronic
studies
3
DATA
GAPS
28­
Day
inhalation
study
(OPPTS
870.3465)
Developmental
neurotoxicity
study
(OPPTS
870.6300)

4
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
Linuron
has
low
acute
toxicity,
with
toxicity
8
categories
of
III
for
oral
(LD50
=
2600
mg/
kg),
dermal
(LD50
>
2000
mg/
kg)
and
toxicity
category
IV
for
inhalation
(
LC50
>
218
mg/
L).
Primary
eye
and
skin
irritation
studies
were
category
III
and
IV,
respectively;
no
dermal
sensitization
was
observed
in
guinea
pigs.
The
acute
toxicity
data
for
linuron
are
summarized
below
in
Table
2.

Table
2:
Acute
Toxicity
of
Linuron,
Technical
Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(Rat)
00027625
LD50
=
2600
mg/
kg
III
870.1200
Acute
Dermal
(Rabbit)
00027625
LD50>
2000
mg/
kg
III
870.1300
Acute
Inhalation
(Rat)
00053769
LC50
>
218
mg/
L
IV
870.2400
Primary
Eye
Irritation
42849001
Slight
conjunctival
redness
at
24
hrs;
clear
at
72
hrs
III
870.2500
Primary
Skin
Irritation
42849002
Not
an
irritant
IV
870.2600
Dermal
Sensitization
00146868
Not
a
sensitizer
N/
A
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
No
subchronic
toxicity
studies
were
available;
the
respective
chronic
toxicity
studies
satisfies
the
data
requirements.
A
28­
day
inhalation
study
is
required
at
this
time
to
address
the
concern
for
inhalation
exposure.

4.2.1
870.3100
90­
Day
Oral
Toxicity
­
Rat
The
chronic
rat
study
presented
later
in
section
4.5.1
(870.4100a)
satisfies
the
data
requirements
for
870.3100.

4.2.2
870.3150
90­
Day
Oral
Toxicity
­
Dog
The
chronic
dog
study
presented
later
in
section
4.5.2
(870.4100b)
satisfies
the
data
requirements
for
870.3150.

4.2.3
870.3200
21/
28­
Day
Dermal
Toxicity
­
Rabbit
No
study
available
4.2.4
870.3250
90­
Day
Dermal
Toxicity
No
study
available
4.2.5
870.4365
90­
Day
Inhalation
Toxicity
9
No
study
available.
A
28­
day
inhalation
study
has
been
identified
as
a
data
gap
by
the
HIARC.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete
and
no
additional
studies
are
required
at
this
time.
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
observed
in
the
rat
and
rabbit
developmental
toxicity
studies
4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
No:
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,
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.
10
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.
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.
These
deficiencies
were
considered
to
be
minor.

4.3.2
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
Nos:
00153867
and
40437201),
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%
hydroxypropyl­
methylcellulose.
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.
11
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.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete
and
no
additional
studies
are
required
at
this
time.

4.4.1
870.3800
Three­
Generation
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
three­
generation
reproduction
study
(MRID
No.:
00146071
&
00155168),
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
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
12
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
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
13
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.

4.4.2
870.3800
Two­
Generation
Reproduction
Study
in
the
Rat
Executive
Summary:
In
a
two­
generation
reproduction
study
(MRID
No:
41463401),
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
mg/
kg/
day,
respectively,
for
females.
Average
premating
doses
for
the
treated
F1
groups
were
0.95,
7.8,
and
54
mg/
kg/
day,
respectively,
for
males
and
1.1,
9.2,
and
63
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
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
14
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).
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
9.2
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
1.1
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.
15
The
reproductive
toxicity
NOAEL
was
greater
than
or
equal
to
625
ppm
(average
premating
doses
36­
63
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
9.2
mg/
kg/
day)
based
on
reduced
F1a,
b
and
F2a,
b
pup
body
weights.
The
offspring
toxicity
NOAEL
was
established
at
12.5
ppm
(average
premating
doses
0.74­
1.1
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.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete
and
no
additional
studies
are
required
at
this
time.

4.5.1
870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
Study­
CD(
SD)
BR
Rats
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
CD1
rats/
sex/
dose
at
concentrations
of
0,
50,
125,
and
625
ppm
(0,
2.1,
5.1,
and
27
mg/
kg/
day
for
males
and
0,
3.1,
7.8,
and
48
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
00
164117)
due
to
inappropriate
statistical
methods
used
in
the
original
study
report.

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.
16
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
epididyinides
at
the
mid­
and
highdose
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
(5.1
mg/
kg/
day
for
males
and
7.8
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
(2.1
mg/
kg/
day
for
males
and
3.1
mg/
kg/
day
for
females).

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
highdose
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
4.5.2
870.4100b
Chronic
Toxicity
­
Dog
17
Executive
Summary:
In
a
one­
year
chronic
toxicity
study,
linuron
(96.2%
a.
i.,
Batch
No.
16,569)
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,
and
19
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.
Methemoglobin
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
highdose
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
(4.2
mg/
kg/
day,
males
and
3.5
mg/
kg/
day,
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).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
chronic
toxicity
study
[OPPTS
870.4100
(83­
1b)]
in
dogs.

4.5.3
870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
a
2­
year
chronic
toxicity
study
(MRID
00018374),
H­
326
(Lot
no.
not
given,
purity
not
given)
was
administered
in
the
diet
to
three
dogs/
sex
at
doses
of
18
0,
25,
125,
or
625
ppm.
Average
doses
to
animals
were
not
measured
or
calculated.

No
treatment­
related
mortality
occurred
and
no
clinical
signs
of
toxicity
were
reported
during
the
study.
One
mid­
dose
male
was
sacrificed
after
47
weeks
due
to
a
neurological
disorder
not
related
to
treatment.
Food
and
water
consumption
were
not
monitored.
There
were
no
statistically
significant
effects
on
absolute
or
relative
organ
weights.
Treatment
with
the
test
material
did
induce
a
slight
decrease
(8.5%)
in
the
body
weight
of
high­
dose
female
dogs,
as
well
as
a
slight
decrease
in
body
weight
gain.
These
effects
were
not
observed
in
male
dogs
and
were
not
considered
biologically
or
toxicologically
relevant
in
females.

At
necropsy,
no
significant
changes
in
gross
pathology
were
observed
at
any
treatment
level.
Hematocrit,
hemoglobin,
and
erythrocyte
counts
were
slightly
but
statistically
significantly
(p
#
0.05)
reduced
in
male
dogs
at
625
ppm
after
104
weeks
of
treatment.
Corroborating
microscopic
pathology
data
indicated
hemosiderin
deposition
in
liver
Kupffer
cells
of
6/
6
dogs
and
erythroid
hyperplasia
in
the
bone
marrow
of
3/
6
dogs
(1
male
and
2
females)
in
this
group.

Under
the
conditions
of
this
study,
the
LOAEL
for
the
systemic
toxicity
of
H­
326
in
male
and
female
beagles
is
625
ppm
based
on
mild
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.
The
NOAEL
is
125
ppm.

For
a
variety
of
reasons
discussed
in
the
study
deficiencies,
this
chronic
toxicity
study
is
classified
as
Unacceptable/
Guideline
and
does
not
satisfy
the
Subdivision
F
requirements
for
a
chronic
oral
toxicity
study
in
non­
rodents
[OPPTS
870.4100
(§
83­
1)].

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete
and
no
additional
studies
are
required
at
this
time.

4.6.1
870.4200b
Carcinogenicity
Study
­
Crl:
CD­
1
(ICR)
BR
Mouse
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
gains
of
high­
dose
males
were
8%
and
15%
lower
than
the
controls,
19
respectively,
and
high­
dose
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.

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).
The
chronic/
oncogenicity
study
presented
above
in
section
4.5
(870.4100a)
satisfies
the
data
requirements
for
870.4200a.
20
4.6.2
870.4300
Carcinogenicity
Study­
CD(
SD)
BR
Rats
The
executive
summary
for
the
chronic/
oncogenicity
study
is
presented
above
in
section
4.5.1
(870.4300)
satisfies
the
data
requirements
for
870.4300.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
submitted
test
battery
satisfies
the
Pre1991
mutagenicity
initial
testing
battery
guidelines.
No
further
testing
is
required
at
this
time.

Gene
Mutation
870.5100­
Bacterial
reverse
gene
mutation
assay
MRID
00131738
Acceptable
In
a
reverse
gene
mutation
assay
in
bacteri,
S.
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537
were
exposed
to
Linuron
(95­
97%,
lot
number
not
given)
in
dimethylsulfoxide
at
concentrations
of
0.5,
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.
There
was
no
evidence
of
induced
mutant
colonies
over
background
with
or
without
S9
activation.

870.5300
CHO/
HGPRT
cell
forward
gene
mutation
assay
MRID
00137152
Acceptable
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.

Cytogenetics
21
870.5385­
In
vivo
bone
marrow
chromosomal
aberration
assay
MRID
00137153
Acceptable
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
highdose
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.

Other
Genotoxicity
870.5550
­
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
00132583
Acceptable
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.
There
is
no
evidence
that
Linuron
induced
chromosomal
aberrations
in
bone
marrow
cells
of
rats
over
background
levels.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
No
acute
or
subchronic
neurotoxicity
studies
on
Linuron
are
available.
Evaluation
of
subchronic,
chronic
and
reproduction
toxicity,
did
not
reveal
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.
However,
the
HIARC
(Nov
20,
2001)
determined
that
a
developmental
neurotoxicity
study
in
the
rat
is
required
based
on
the
finding
that
linuron
is
an
endocrine
disruptor,
increased
testicular
lesions
and
decreased
fertility.

4.8.1
870.6100
Delayed
Neurotoxicity
Study
­
Hen
This
study
is
not
required.

4.8.2
870.6200a
Acute
Neurotoxicity
Screening
Battery
This
study
is
not
required.
22
4.8.3
870.6200b
Subchronic
Neurotoxicity
Screening
Battery
This
study
is
not
required.

4.8.4
870.6300
Developmental
Neurotoxicity
Study
This
study
is
required.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
complete
and
no
additional
studies
are
required
at
this
time.

4.9.1
870.7485
Metabolism
­
Rat
Executive
Summary:
In
a
metabolism
study
(00146489,
40142401,
41960001,
42006801),
linuron
was
administered
by
gavage
to
male
and
female
rats
at
single
doses
of
24
or
400
mg/
kg/
day,
Linuron
was
extensively
metabolized
by
male
and
female
rats
at
both
the
low
and
high­
dose
levels.
The
biological
half­
life
was
affected
by
sex
and
dose
level
and
ranged
from
21
hours
in
the
low
dose
males
to
56
hours
in
the
high
dose
females.
Total
recovery
of
radioactivity
was
96%
in
males
and
97%
in
females.
At
400
mg/
kg,
the
majority
of
the
administered
14
C­
linuron
was
eliminated
in
the
urine
(81%
in
males
and
72%
in
females)
and,
to
a
lesser
extent,
in
the
feces
(15%
in
males
and
20%
in
females).
In
general,
tissue
and
organ
residues
were
very
low
(<
l%)
at
both
dose
levels,
and
there
was
no
indication
of
accumulation
or
retention
of
linuron
or
its
metabolites.
The
major
metabolites
identified
in
the
urine
were
hydroxy­
norlinuron
(59%
in
males
and
64%
in
females),
desmethoxy
linuron
(11%
in
males
and
females)
and
norlinuron
(3%
in
males
and
2%
in
females),
and
in
feces,
hydroxy­
norlinuron,(
28%
in
males
and
32%
in
females)
and
norlinuron
(28%
in
males
and
23%
in
females).
Neither
hydroxy­
3,4­
dichloroanaline
nor
3,4­
dichloroanaline
were
present
in
any
of
the
samples.
Exposure
to
linuron
appeared
to
induce
mixed­
function
oxidative
enzymes.

This
metabolism
study
in
the
rat
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
metabolism
study
[OPPTS
870.7485
(§
85­
1)]
in
the
rat.

4.9.2
870.7600
Dermal
Absorption
­
Rat
Executive
Summary:
In
this
dermal
absorption
study
(MRID
163837),
four
grous
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).

4.10
Special
Studies
4.10.1
Biochemical
and
Histopathological
Effects
in
Rats
23
Executive
Summary:
A
special
study
(MRID
No:
00164093)
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
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
24
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,
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.

4.10.2
Leydig
Cell
Tumorigenisis
in
Rat
Executive
Summary:
A
special
mechanism
study
(MRID
No:
41630101)
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
25
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
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.
26
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
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.

4.10.3
Special
Reproduction
Study
­
Cross­
mating
­
Rat
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
27
with
those
for
groups
in
which
the
females
were
treated
(90­
86%
for
males
and
85­
85%
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
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table
5.2
Dermal
Absorption
For
Executive
Summary
see
section
4.9.2
The
dermal
absorption
factor
=
16%

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Conclusions
Linuron
was
placed
in
special
review
for
carcinogenic
effects
in
1982.
Linuron
was
later
classified
as
a
group
C
carcinogen
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
again
classified
linuron
as
a
Group
C
carcinogen
requiring
no
quantification
of
human
cancer
risk
[Federal
Register
53(
159):
31262].

5.3.2
Classification
of
Carcinogenic
Potential
Group
C
carcinogen
5.3.3
Quantification
of
Carcinogenic
Potential
28
Not
quantification
of
human
cancer
risk
is
required
6
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
seen
in
the
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
postimplantation
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.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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.

7
OTHER
ISSUES
None
8
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33­
79.
(Unpublished
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1979
under
352­
270;
CDL:
240982­
B)

00018374
Hodge,
H.
C.
and
W.
L.
Downs
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Chronic
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Department
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29
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1977
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11;
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a.,
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CDL:
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A)

00029679
Everett,
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ChR­
CD
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I.
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80,
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4,
1980,
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00029680
Kaplan,
A.,
L.,
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al.
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Long­
term
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study
in
rats
with
3­(
3,4­
dichlorophenyl)­
l­
methoxy­
l­
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linuron:
INZ­
326).
Haskell
Laboratory
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I.
du
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DE
19711.
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full
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date
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Unpublished.

00053769
Kapp,
R.
W.
(1975)
Final
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Acute
Inhalation
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Study
in
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Project
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M915­
103.
(Unpublished
study
received
Dec
19,
1977
under
33660­
11;
prepared
by
Hazleton
Laboratories
America,
Inc.,
submitted
by
Industria
Prodotti
Chimici,
s.
p.
a.,
Novate
Milanese,
Italy;
CDL:
232505­
E)

00124195
Wood,
C.;
et
al.
(1982)
Long­
term
Feeding
Study
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...
Lorox,
Linuron,
Inz­
326
in
Mice:
Haskell
Laboratory
Report
No.
758­
82.
Final
rept.
(Unpublished
study
received
Jan
13,
1983
under
352­
326;
submitted
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E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE;
CDL:
249255­
A;
249256)

00131738
Russell,
J.
(1983)
Mutagenicity
Evaluation
in
Salmonella
typhimurium:
Haskell
Laboratory
Report
No.
106­
83;
MR
No.
4581­
067.
(Unpublished
study
received
Oct
26,
1983
under
352­
326;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE;
CDL:
251571­
A)

00132583
Chromey,
N.;
Horst,
A.;
McCooey,
K.
(1983)
Unscheduled
DNA
Synthesis/
Rat
Hepatocytes
in
vitro:
Haskell
Laboratory
Report
No.
190­
83;
MR
No.
4581­
067.
(Unpublished
study
received
Oct
26,
1983
under
352­
326;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE;
CDL:
251571­
B)

00137152
McCooey,
K.
(1983)
CHO/
HGPRT
Assay
for
Gene
Mutation:
[Linuron]:
Haskell
Laboratory
Report
No.
540­
83;
MR
No.
4581­
067.
(Unpublished
study
received
Jan
12,
1984
under
352­
326;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE;
CDL:
252172­
A)

00137153
Farrow,
M.,
et
al.
(1983)
In
vivo
Bone
Marrow
Chromosome
Study
in
Rats:
[H#
14,703]:
HLA
Project
Number
201­
584.
Final
rept.
(Unpublished
study
received
30
Jan
12,
1984
under
352­
326;
prepared
by
Hazleton
Laboratories
America,
Inc.,
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE;
CDL:
252172­
B)

00146071
Pastoor,
T.
(1984)
Multigeneration
Reproduction
Study
in
Rats
with
3­(
3,4­
Dichlorophenyl)­
1­
methoxy­
1­
methylurea
(Lorox,
Linuron,
INZ­
326):
Haskell
Laboratory
Report
No.
436­
84.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
347
p.

00146489
Carter,
L.
(1985)
Metabolism
of
Phenyl­[
Carbon
14
(UL)]
Linuron
by
Male
and
Female
Rats:
Document
No.
AMR­
250­
84.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
C0.,
Inc.
110
p.

00146868
Schulz,
M.
(1985)
Guinea
Pig
Maxinization
Test
Using
Linuron
Technical:
Intox
Sample
No.
584:
Project
NO.
GRF­
AT­
008.
Unpublished
study
prepared
by
Intox
Laboratories.
19
p.

00153867
Hoberman,
A.
(1985)
Developmental
Toxicity
Study
of
INZ­
326
Administered
Via
Gavage
to
New
Zealand
White
Rabbits:
Final
Report:
Protocol
104­
009.
Unpublished
study
prepared
by
Argus
Research
Laboratories,
Inc.
214
p.

00155168
Holt,
D.;
Carakostas,
M.
(1985)
Hematologic
Values
in
Rats
Fed
for
20,
22
or
26
Months
with
0,25,125
or
625
ppm
INZ­
326:
Haskell
Lab.
Rep.
No.
760­
85;
Clinical
Pathology
Rep.
No.
21­
85.
Unpublished
study
prepared
by
Haskell
Laboratory.
68
p.

00159846
Pastoor,
T.
(1985)
Cross­
mating
Study
in
Rats
with
INZ­
326:
Report
No.
413­
85:
MR
No.
4580­
001.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
and
Co.
70
p.

00163837
Anderson,
J.
(1984)
Dermal
Absorption
of
Carbon
14
Linuron
in
the
Lorox
L
Formulation
by
the
Rat:
Document
No.
AMR­
259­
84.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
29
p.

00164093
Pastoor,
T.
(1986)
Biomedical
and
Pathological
Effects
of
Linuron
on
Selected
Tissues
of
Male
and
Female
Rats:
Report
No.
643­
86:
MR
No.
4580­
001.
Unpublished
study
prepared
by
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine
in
cooperation
with
E.
I.
du
Pont
de
Nemours
and
Co.
468
p.

00164117
Carakostas,
M.
(1986)
Evaluation
of
clinical
laboratory
data
from
two­
year
rat
study
with
INZ­
326.
Central
Research
and
Development
Department,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine.
Re­
evaluation
of
data
from
Haskell
Laboratory
Report
number
100­
80,
with
no
new
laboratory
or
registrant
report
or
study
number
provided,
August
13,
1986,
Unpublished.

40142401
Cater,
L.
(1985)
Metabolism
of
Phenyl­
Carbon
14(
UL)
Linuron
by
Male
and
Female
Rats:
?Supplement
to
F
:
Report
No.
AMR­
250­
84.
Unpublished
study
31
prepared
by
E.
I.
du
Pont
de
Nemours
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62
p.

40437201
Christian,
M.
and
Hoberman,
A.
(1985)
Supplement
to:
Developmental
Toxicity
Study
of
INZ­
326
Administered
via
Gavage
to
New
Zealand
White
Rabbits:
Laboratory
Project
ID:
MR
7560­
001;
HLO
609­
85.
Unpublished
study
prepared
by
Argus
Research
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76
p.

40952601
Malley,
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(1988)
Chronic
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with
IN
Z326­
118:
One­
Year
Feeding
Study
in
Dogs:
Report
No.
181­
88;
Medical
Research
Project
No.
8031­
001.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
and
Co.,
Inc.
660
p
41463401
Mullin,
L.
(1990)
Reproductive
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with
INZ326­
118
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Multigeneration
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Medical
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511­
001:
Haskell
Laboratory
Report
20­
90.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
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1104
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41630101
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Leydig
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Linuron
in
Rats:
Lab
Project
Number:
494/
90.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
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Inc.
173
p.

41864701
Stula,
E.
(1990)
Reproductive
and
Fertility
Effects
with
IN
Z326­
118
MultiGeneration
Reproduction
Study
in
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Project
Number:
8511­
001:
20­
90.
Unpublished
study
prepared
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I.
du
Pont
de
Nemours
and
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41960001
Hundley,
S.
(1991)
Metabolism
of
[Phenyl­
Carbon­
14(
U)]
Linuron
by
the
Laboratory
Rat:
Lab
Project
Number:
HLR
351­
91:
1448­
89.
Unpublished
study
prepared
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E.
I.
du
Pont
de
Nemours
and
Co.
7
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42006801
Brown,
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(1991)
Supplement
No.
1
to:
Metabolism
of
[Phenyl­
14­
Carbon
(U)]
Linuron
by
the
Laboratory
Rat:
Lab
Project
Number:
HLR
351­
91:
1448­
89.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
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67
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42849001
Shibata,
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(1992)
A
Primary
Eye
Irritation
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the
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Lab
Project
Number:
BOZO/
B­
2177:
B­
2177.
Unpublished
study
prepared
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24
p.

42849002
Allen,
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(1993)
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Primary
Skin
Irritation
Test
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Rabbit:
Lab
Project
Number:
498/
21.
Unpublished
study
prepared
by
Safepharm
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Ltd.
13
p.

Fed
Reg
Linuron;
Preliminary
determination
to
Conclude
the
Special
Review
Notice
53(
159):
31262
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17,
1988)

U.
S.
EPA
LINURON
­
Report
of
the
Hazard
identification
Assessment
Review
Committee
HED
Doc
No:
0050286
(November
20,
2001)
32
U.
S.
EPA
LINURON:
Report
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the
FQPA
Safety
Factor
Committee,
TXR
NO.
0050322
(December
6,
2001)
33
9
APPENDICES
Tables
for
Use
in
Risk
Assessment
34
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic,
and
Other
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicity­
rat
Requirement
fulfilled
by
Chronic
rat
study870.4100a
N/
A
870.3150
90­
Day
oral
toxicity­
dog
Requirement
fulfilled
by
Chronic
dog
study870.4100b
N/
A
870.3200
21/
28­
Day
dermal
toxicity­
rabbit
No
study
available
N/
A
870.3250
90­
Day
dermal
toxicity
No
study
available
N/
A
870.3465
90­
Day
inhalation
toxicity
No
study
available
N/
A
870.4100
[83­
1(
b)]
1­
Year
Feeding
Study
­
Dog
40952601
(1988)

Acceptable/
Guideline
0,
10,
25,
125,
625
ppm
%
%
:
0,
0.29,
0.79,
4.2,
19
mg/
kg/
day
&
&
:
0,
0.30,
0.77,
3.5,
16
mg/
kg/
day
NOAEL=
0.77
mg/
kg/
day
LOAEL
=
3.5
mg/
kg/
day,
based
on
hematological
effects
in
males
and
females
(increased
methemoglobin
and
sulfhemoglobin
levels)
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
35
870.4100
[83­
1(
b)]
2­
Year
Feeding
Study
­
Dog
00018374
(1963)

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

Oncogenicity
Study
­
Mouse
0124195
(1981)

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

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

Acceptable/
Guideline
0,
50,
125,
625
ppm
0,
2.1,
5.1,
27
mg/
kg/
day
in
males
and
0,
3.1,
7.8,
48
mg/
kg/
day
in
females
NOAEL=
2.1
mg/
kg/
day
LOAEL
=
5.1
mg/
kg/
day,
based
on
hematological
effects,
decreased
body
weight
gains
in
both
sexes,
microscopic
observations
consistent
with
hemolysis
(hemosiderin
in
Kupffer
cells
and
increased
hemosiderosis
in
bone
marrow,
spleen,
and/
or
mesenteric
lymph
nodes)

Histopathology:
Significant
(p
=
0.004)
increase
(27%,
5.7%
control)
in
incidence
of
benign
interstitial
cell
adenomas
in
testes.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
36
870.3700
[83­
3(
a)]

Developmental
Toxicity
Study
­
Rat
00018167
(1979)

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

Developmental
NOAEL:
12
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
litters
with
early
resorptions.

870.3700
[83­
3(
b)]

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

Acceptable/
Guideline
0,
5,
25,
100
mg/
kg/
day
Maternal
Systemic
NOAEL=
5
mg/
kg/
day
LOAEL
=
25
mg/
kg/
day,
based
on
decreased
maternal
body
weight
gain.

Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
alterations
of
the
bones
and
skull
(irregularly
shaped
fontanelle,
hole
in
parietals,
parietals
contain
intraparietals,
and
unossified).

870.3800
[83­
4]

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

Acceptable/
Guideline
0,
25,
125,
625
ppm
%
%
:
0,
2,
10­
11,
48­
50
mg/
kg/
day
&
&
:
0,
2,
9,
44­
50
mg/
kg/
day
Systemic
NOAEL=
2
mg/
kg/
day
LOAEL
=
9
mg/
kg/
day,
based
on
decreased
body
weight
gains
in
males
and
females
and
anemia
in
females.

Reproductive
NOAEL
=
10
mg/
kg/
day
LOAEL
=
44
mg/
kg/
day
based
on
reduced
fertility,
decreased
pup
survival
and
lower
pup
body
weights.

Offspring
NOAEL
=
9
mg/
kg/
day
LOAEL
=
44
mg/
kg/
day,
based
on
decreased
pup
survival,
and
lower
pup
body
weights.
The
offspring
toxicity
NOAEL
is
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
37
870.3800
[83­
4]
2­
Generation
Reproduction
­
Rat
41463401
(1990)
41864701
(1991)

Acceptable/
Guideline
0,
12.5,
100,
625
ppm
%
%
:
0,
0.74,
5.8,
36
mg/
kg/
day
&
&
:
0,
0.92,
7.3,
45
mg/
kg/
day,
Systemic
NOAEL=
0.74
mg/
kg/
day
LOAEL
=
5.8
mg/
kg/
day,
based
on
decreased
body
weight
gains
in
males
and
females
in
both
generations
Reproductive
NOAEL
=
36
mg/
kg/
day
LOAEL
=
not
established
Offspring
NOAEL=
0.74
mg/
kg/
day
LOAEL
=
5.8
mg/
kg/
day,
based
on
decreased
pup
survival
and
lower
pup
body
weights
of
F1a,
b
and
F2a,
b
litters
870.7600
(85­
2)
Dermal
Penetration
Rat
00163837
(1984)

Acceptable/
Guideline
14
C
(2.35
:
Ci/
mg)
0.12,
1.00,
or
7.4
mg/
2
in2
2.82,
23.5,
or
17.4
:
Ci
Dermal
absorption
factor
=
16%
over
8
to
10
hours.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
38
870.7485
(85­
1)
Metabolism
Study
Rat
00146489
(1985),
40142401
(1985)
41960001
(1991
42006801
(1991)
Linuron
(single
doses
at
24
mg/
kg
and
400
mg/
kg)
was
administered
by
gavage
to
male
and
female
rats.
The
biological
half­
lives
ranged
from
21
hr
in
the
low
dose
males
to
56
hr
in
the
high
dose
females.
Total
recovery
of
radioactivity
was
96%
in
males
and
97%
in
females,
the
majority
of
the
administered
Clinuron
was
eliminated
in
the
urine
(>
80%)
and,
to
a
lesser
extent,
in
the
feces
(~
15%).
Tissue
and
organ
residues
were
very
low
(<
l%)
at
both
dose
levels,
and
there
was
no
indication
of
accumulation
or
retention
of
linuron
or
its
metabolites.
The
major
metabolites
identified
in
the
urine
were
hydroxy­
norlinuron,
desmethoxy
linuron
and
norlinuron,
and
in
feces,
hydroxy­
norlinuron,
and
norlinuron.
Neither
hydroxy­
3,4­
dichloroanaline
nor
3,4­
dichloroanaline
were
present
in
any
of
the
samples.
Exposure
to
linuron
appeared
to
induce
mixed­
function
oxidative
enzymes.

Special
Study
Leydig
cell
tumorigenesis
in
rats
41630101
(1990)
Acceptable/
Nonguideline
0
or
200
mg/
kg/
day
for
14
days
to
32
to
33
and
93
day
old
rats
No
treatment­
related
clinical
signs
of
toxicity
were
observed.
Body
weight
and
body
weight
change
were
significantly
less
than
controls
and
decreased
accessory
sex
organ
weights
for
growing
and
adult
rats.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
39
0,
0.74,
5.8,
36
mg/
kg/
day
in
males
and
0,
0.92,
7.3,
45
mg/
kg/
day
in
females
F0
and
F1
animals
from
2­
generation
reproduction
study
(41463401),
Selected
animals
from
the
2­
generation
reproduction
study
were
used
to
evaluate
changes
in
serum
hormone
levels,
accessory
sex
organ
weights.
Increased
serum
luteinizing
hormone
and
estradiol
levels
were
observed
in
F0
and
F1
males.
High­
dose
F0
males
had
decreased
absolute
epididymides,
dorsal
lateral
prostate,
and
levator
ani
muscle
weights
and
increased
relative
testes,
epididymides,
and
ventral
prostate
weights.
Organ
weights
were
unaffected
in
the
two
lower
dose
groups.

These
data
support
the
hypothesis
that
rats
exposed
to
linuron
could
develop
interstitial
hyperplasia
and
subsequent
adenomas
(Leydig
cell
tumors)
via
a
mechanism
of
sustained
hypersecretion
of
luteinizing
hormone
induced
by
the
antiandrogenic
potential
of
linuron.

Special
Study
Cross
Mating
00159846
(1985)

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

Special
Study
Aged
male
rats
45506501
(1986)

Acceptable/
Nonguideline
0,
625
ppm
0,
22
mg/
kg/
day
Linuron
induced
hyperplasia
and
adenomas
of
the
testes
in
aged
rats.
In
addition,
life­
time
feeding
was
not
necessary
to
induce
oncogenic
responses
in
this
tissue.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
40
Special
Study
Biochemical
and
Histopathological
effects
164093
(1986)

Acceptable/
Nonguideline
0,
12.5,
100,
625
ppm
%
%
:
0,
0.75,
4.1,
22
mg/
kg/
day
&
&
:
0,
1.1,
6.1,
37
mg/
kg/
day
The
biochemical
and
histopathological
data
presented
in
this
report
suggest
that
linuron
may
affect
testosterone
metabolism
in
horse
testicular
microsomes
for
a
range
of
concentrations
which
overlap
the
dose
levels
given
rats
chronically.
However,
the
net
effect
of
these
enzyme
changes
and
the
relevance
to
the
rat
in
vivo
are
uncertain.
Evidence
in
young
and
old
rats
exposed
repeatedly
(3­
7x)
or
for
11
or
19
months
suggests
that
Leydig
cell
incubates
are
differentially
altered
in
their
sensitivity
to
LH.
Microscopic
lesions
in
the
testes
and
cervix
have
been
confirmed
in
other
studies.
41
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Linuron
for
Use
in
Human
Risk
Assessment
42
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
12
UF
=
100
Acute
RfD
=
0.12
mg/
kg/
day
FQPA
SF
=
3
aPAD
=
acute
RfD
FQPA
SF
=
0.04
mg/
kg/
day
Prenatal
Oral
Developmental
/
Rat
LOAEL
=
50
mg/
kg/
day
based
on
increased
post­
implantation
loss
and
fetal/
litter
resorptions.

Acute
Dietary
general
population
including
infants
and
children
N/
A
N/
A
No
appropriate
effects
attributed
to
a
single
exposure
was
identified.

Chronic
Dietary
all
populations
NOAEL=
0.77
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.0077
mg/
kg/
day
FQPA
SF
=
10
cPAD
=
chr
RfD
FQPA
SF
=
0.00077
mg/
kg/
day
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Oral
(1­
7
days)

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

(Residential)
NOAEL=
0.77
mg/
kg/
day
LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Dermal
(1­
30
days)

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

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
2­
Generation
Reproduction
Study/
Rat
LOAEL
=
36
mg/
kg/
day
based
on
statistically
and
biologically
significant
decrease
in
premating
body
weights
in
F0
and
F1
animals
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
43
IntermediateTerm
Dermal
(1
­
6
months)

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

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels
after
3
and
6
months
of
treatment
Long­
Term
Dermal
(Longer
than
6
months)
(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
dermal
absorption
rate
=
16%
LOC
for
MOE
=
100
(Occupational)

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Short­
Term
Inhalation
(1­
30
days)

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

(Occupational/
Residential)
Oral
NOAEL=
0.77
mg/
kg/
day
(inhalation
absorption
rate
=
100%
LOC
for
MOE
=1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.

Long­
Term
Inhalation
(Longer
than
6
months)

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

LOC
for
MOE
=
1000
(Residential,
includes
the
FQPA
SF)
Chronic
Feeding
Study
­
Dog
LOAEL
=
4.2
mg/
kg/
day
in
males
and
3.5
mg/
kg/
day
in
females
based
on
increased
met­
and
sulfhemoglobin
levels.
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
44
Cancer
(oral,
dermal,
inhalation)
Group
C
carcinogen
Does
not
require
quantification
of
human
cancer
risk
Based
on
a
dose­
related
increase
in
interstitial
cell
hyperplasia
and
adenomas
in
a
two­
year
rat
feeding
study
and
hepatocellular
tumors
that
appeared
in
low­
dose
male
and
high­
dose
female
mice
in
a
two­
year
feeding
study
1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
