Document ID: EPA-HQ-OPP-2002-0146-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-06-25T04:00Z

OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No:
0050572
March
20,
2002
Memorandum
SUBJECT:
TEBUTHIURON
(PC
Code:
105501)
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document
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:
Paula
Deschamp,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(7509C)

DP
Barcode:
D277101
Submission:
S596544
Action
Requested:
Review
toxicology
studies
submitted
by
the
registrant
and
prepare
the
toxicology
chapter
to
support
Tolerance
Reassessment
Eligibility
Decision
(TRED)
for
tebuthiuron.

Attached
is
the
updated
toxicology
chapter
summarizing
the
findings
of
the
toxicology
studies.
TEBUTHIURON
PC
Code:
105501
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
Document
February
20,
2002
Prepared
by:
Robert
F.
Fricke,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
Mail
Code
7509C
Peer
reviewed
by:
Yung
Yang,
Ph.
D.
Toxicology
Branch
Health
Effects
Division
Mail
Code
7509C
Robert
F.
Fricke,
Toxicologist
Yung
Yang,
Toxicologist
TABLE
OF
CONTENTS
1
HAZARD
CHARACTERIZATION
........................................
1
2
REQUIREMENTS
....................................................
2
3
DATA
GAPS
.........................................................
3
4
HAZARD
ASSESSMENT
...............................................
3
4.1
Acute
Toxicity
....................................................
3
4.2
Subchronic
Toxicity
...............................................
3
4.2.1
870.3100
90­
Day
Oral
Toxicity
­
Rat
.........................
3
4.2.2
870.3150
90­
Day
Oral
Toxicity
­
Dog
........................
4
4.2.3
870.3200
21/
28­
Day
Dermal
Toxicity
­
Rabbit
..................
4
4.2.4
870.3250
90­
Day
Dermal
Toxicity
...........................
4
4.2.5
870.4365
90­
Day
Inhalation
Toxicity
.........................
5
4.3
Prenatal
Developmental
Toxicity
......................................
5
4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
...........
5
4.3.2
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
.........
6
4.4
Reproductive
Toxicity
..............................................
7
4.4.1
870.3800
Two­
Generation
Reproduction
and
Fertility
Effects
­
Rat
..
7
4.5
Chronic
Toxicity
..................................................
8
4.5.1
870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
StudyCD
SD)
BR
Rats
.................................
8
4.5.2
870.4100b
Chronic
Toxicity
­
Dog
............................
9
4.6
Carcinogenicity
..................................................
10
4.6.1
870.4200b
Carcinogenicity
Study
­
Crl:
CD­
1
(ICR)
BR
Mouse
.....
10
4.6.2
870.4300
Carcinogenicity
Study­
CD(
SD)
BR
Rats
..............
11
4.7
Mutagenicity
....................................................
11
4.8
Neurotoxicity
...................................................
13
4.8.1
870.6100
Delayed
Neurotoxicity
Study
­
Hen
..................
13
4.8.2
870.6200a
Acute
Neurotoxicity
Screening
Battery
...............
14
4.8.3
870.6200b
Subchronic
Neurotoxicity
Screening
Battery
...........
14
4.8.4
870.6300
Developmental
Neurotoxicity
Study
.................
14
4.9
Metabolism
.....................................................
14
4.9.1
870.7485
Metabolism
­
Rat
...............................
14
4.10
Special
Studies
..................................................
14
5
TOXICITY
ENDPOINT
SELECTION
....................................
14
5.1
Dermal
Absorption
...............................................
15
5.2
Classification
of
Carcinogenic
Potential
................................
15
5.2.1
Conclusions
and
Classification
of
Carcinogenic
Potential
...........
15
5.2.2
Quantification
of
Carcinogenic
Potential
........................
15
6
FQPA
CONSIDERATIONS
............................................
15
6.1
Special
Sensitivity
to
Infants
and
Children
..............................
15
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
................
15
7
OTHER
ISSUES
.....................................................
15
8
REFERENCES
......................................................
15
9
APPENDICES
.......................................................
19
9.1
Toxicity
Profile
Summary
Tables
.....................................
19
9.1.1
Acute
Toxicity
Table
.......................................
19
9.1.2
Subchronic,
Chronic,
and
Other
Toxicity
Table
...................
19
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Tebuthiuron
for
Use
in
Human
Risk
Assessment
.................................................
22
Tebuthiuron
(105501)
RED
Toxicology
Chapter
1
1
HAZARD
CHARACTERIZATION
The
toxicological
database
for
tebuthiuron
is
not
considered
adequate
for
hazard
characterization,
however
the
database
will
support
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
for
the
current
registered
uses.
Hazard
characterization
was
not
possible
because
of
datagaps
which
include
a
developmental
toxicity
study
in
rabbit,
a
chronic
feeding/
carcinogenicity
study
in
the
rat
and
oncogenicity
study
in
the
mouse;
all
of
these
studies
were
found
to
be
unacceptable.
The
requirement
for
a
developmental
neurotoxicity
study
is
being
held
in
reserve,
pending
submission
of
the
rabbit
developmental
toxicity
study.
Additionally,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(HIARC)
determined
that
a
28­
day
inhalation
is
required
to
provide
better
hazard
characterization.

The
acute
toxicity
studies
indicate
that
tebuthiuron,
technical,
is
more
toxic
for
oral
(Toxicity
Category
II)
exposure
than
for
either
dermal
(Toxicity
Category
IV)
or
inhalation
(Toxicity
Category
III).
Tebuthiuron
is
not
an
eye
or
skin
irritant
and
not
a
skin
sensitizer.

In
the
21­
day
dermal
toxicity
study
in
rabbits,
no
dermal
or
systemic
toxicity
was
observed
at
1000
mg/
kg/
day
(limit
dose).

Although
the
most
consistent
toxicological
effect
was
decreased
body
weight,
histopathological
changes
in
the
pancreas
were
observed
in
both
the
subchronic
and
chronic
toxicity
studies
in
the
rat.
Pancreatic
acinar
cells
of
both
sexes
showed
vacuolation,
which
was
described
as
generally
slight
or
affecting
only
a
few
cells;
males
also
had
increased
relative
spleen
and
prostate
gland
weights.
In
a
rat
developmental
study,
however,
pancreatic
tissue
appeared
normal.

Subchronic
and
chronic
toxicity
studies
were
available
for
the
dog.
In
a
subchronic
study,
anorexia,
with
resulting
weight
loss,
and
clinical
chemistry
effects
(increased
blood
urea
nitrogen
and
alkaline
phosphatase)
were
observed
at
50
mg/
kg/
day.
In
a
chronic
(1­
year)
study
clinical
signs
of
toxicity
(emesis
anorexia,
and
diarrhea
),
decreased
body
weight,
increased
ALT
and
ALP
(males
only),
increased
absolute
and
relative
liver
weights,
and
increased
relative
kidney
(females
only)
thyroid
(males
only)
weights.

At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms.
However,
the
HIARC
(TXR
No.
0050450,
dated
February
5,
2002)
concluded
that
the
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.

Tebuthiuron
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.

Results
from
the
rat
developmental
and
reproductive
toxicity
studies
indicated
that
there
was
no
evidence
(qualitative
or
quantitative)
for
increased
susceptibility
following
in
utero
and/
or
pre
post­
natal
exposure.
The
rabbit
developmental
toxicity
study
was
found
to
be
unacceptable;
susceptibility
can
not
be
evaluated
in
rabbits.

In
a
rat
metabolism
study
with
14
C­
tebuthiuron,
absorption
was
complete;
excretion
was
rapid
both
sexes,
but
was
delayed
during
the
first
12
hours
post­
dose,
indicating
saturation
of
Tebuthiuron
(105501)
RED
Toxicology
Chapter
2
biotransformation
or
excretion.
At
termination,
no
significant
amounts
of
residual
radioactivity
in
any
tissue
examined,
but
the
skin
showed
the
highest
amounts
relative
to
other
tissues.
Six
metabolites
of
tebuthiuron
were
identified.
The
major
urinary
metabolite
was
identified
as
hydroxylated
tebuthiuron
metabolites.

2
REQUIREMENTS
The
requirements
(CFR
§158.340,
revised
as
of
July
1,
1999)
for
Food
and
Non­
Food
Use
for
tebuthiuron,
technical,
are
summarized
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(1998)
guideline
protocols
were
used.

Study
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
Yes
No
Yes
No
Yes
Yes
Yes

No
a

870.3700a
Developmental
Toxicity
(Rodent)
.............
870.3700b
Developmental
Toxicity(
Non­
rodent)
.........
870.3800
Reproduction
............................
Yes
Yes
Yes
Yes
No
a
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
No
a
Yes
No
a
No
a
No
a
870.5100
Mutagenicity—
Gene
Mutation
­
bacterial
.......
870.5300
Mutagenicity—
Gene
Mutation
­
mammalian
.....
870.5375
Mutagenicity–
in
vitro
cytogenicity
870.5385
Mutagenicity—
Mammalian
bone
marrow
chromosomal
aberration
test
.................
870.5550
Mutagenicity—
UDS
in
Mammalian
cells
in
vitro
870.5900
In
vitro
sister
chromatid
exchange
assay
........
Yes
Yes
Yes
No
Yes
Yes
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
b

No
a
870.7485
General
Metabolism
........................
870.7600
Dermal
Penetration
........................
Yes
No
Yes
Yes
a
The
HIARC
determined
that
these
studies
must
be
repeated
b
The
HIARC
determined
that
this
study
is
held
in
reserve
pending
submission
of
a
rabbit
developmental
toxicity
study
Tebuthiuron
(105501)
RED
Toxicology
Chapter
3
3
DATA
GAPS
28­
day
inhalation
study
in
the
rat
(870.3465)
Developmental
toxicity
study
in
the
rabbit
(870.3700b)
Chronic
feeding/
oncogenicity
study
in
the
rat
(870.4300)
Oncogenicity
study
in
the
mouse
(870.4200)
Developmental
neurotoxicity
study
(870.6300)
(held
in
reserve)

4
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
database
for
acute
toxicity
is
considered
adequate.
The
acute
toxicity
studies
indicate
that
tebuthiuron,
technical,
is
more
toxic
for
oral
(Toxicity
Category
II)
exposure
than
for
either
dermal
(Toxicity
Category
IV)
or
inhalation
(Toxicity
Category
III).
The
primary
eye
and
skin
irritation
studies
were
both
Toxicity
Category
IV;
no
dermal
sensitization
occurred
with
tebuthiuron
in
guinea
pigs.

Acute
Toxicity
of
Tebuthiuron,
Technical
Guideline
No.
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
Oral
(Rat)
40583901
LD50
=477.5
mg/
kg
(%%)
387.5
mg/
kg
(&&)
II
870.1200
Acute
Dermal
(Rabbit)
40583902
LD50
=>
5000
mg/
kg
(%%and
&&)
IV
870.1300
Acute
Inhalation
(Rat)
00155730
LC50
=
3.696
mg/
L
III
870.2400
Primary
Eye
Irritation
40583903
Slight
irritation
IV
870.2500
Primary
Skin
Irritation
40583902
Non­
irritating
IV
870.2600
Dermal
Sensitization
40583904
Non­
sensitizer

4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
With
the
exception
of
the
28­
day
inhalation
study,
the
database
for
subchronic
toxicity
is
considered
adequate.
Subchronic
studies
in
both
the
rat
and
dog,
as
well
as
a
28­
dy
dermal
toxicity
study,
were
considered
to
be
acceptable.

4.2.1
870.3100
90­
Day
Oral
Toxicity
­
Rat
Executive
Summary:
In
a
subchronic
toxicity
study
(MRID
00020662),
Harlan
SpragueDawley
rats
(10/
sex/
dose)
were
fed
diets
containing
tebuthiuron
(purity
not
given)
at
0,
400,
1000
or
2500
ppm
(0,
20,
50
or
125
mg/
kg/
day)
for
three
months.
High
dose
males
and
females
showed
decreased
body
weights,
increased
relative
liver,
kidney,
gonad
Tebuthiuron
(105501)
RED
Toxicology
Chapter
4
weights;
males
also
had
increased
relative
weights
for
spleen,
prostate
gland
and
moderate
vacuolization
of
the
pancreatic
acinar
cells.

The
LOAEL
was
established
at
125
mg/
kg/
day,
based
on
increased
relative
organ
weights
and
increased
incidence
of
vacuolization
of
the
pancreatic
acinar
cells;
the
NOAEL
was
established
at
50
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
subchronic
toxicity
study
[870.3100
(§
82­
1a)]
in
rats.

4.2.2
870.3150
90­
Day
Oral
Toxicity
­
Dog
Executive
Summary:
In
a
subchronic
toxicity
study
(MRID
00020663),
beagle
dogs
(2/
sex/
dose)
were
dosed
(capsule)
with
tebuthiuron
(purity
not
given)
at
0,
12.5,
25
or
50
mg/
kg/
day
for
90
days.
Clinical
signs
were
limited
to
high
dose
dogs,
which
had
anorexia;
all
animals
survived
to
terminal
sacrifice.
High­
dose
females
had
body
weight
losses
of
5%.
Transient
increases
(up
to
4­
fold)
in
alkaline
phosphatase
activity
were
observed
in
high­
dose
animals;
other
clinical
chemistry
parameters
were
unaffected
by
treatment.
Relative
liver
weights
were
slightly
increased
in
one
male
and
female
in
the
high­
dose
group,
however,
gross
and
histopathological
observations
did
not
show
any
treatmentrelated
effects
in
these
animals.

The
LOAEL
was
established
at
50
mg/
kg/
day,
based
on
decreased
body
weight
and
increased
alkaline
phosphatase
activity;
the
NOAEL
was
established
at
25
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
subchronic
toxicity
study
[870.3150
(§
82­
1b)]
in
dogs.

4.2.3
870.3200
21/
28­
Day
Dermal
Toxicity
­
Rabbit
Executive
Summary:
In
a
dermal
toxicity
study
(MRID
00149733,
00160796)
New
Zealand
White
rabbits
were
treated
for
21
days
with
tebuthiuron
(purity
not
given)
at
0
or
1000
(limit
dose)
mg/
kg/
day.
No
treatment­
related
toxicity
was
observed.

The
LOAEL
was
not
established;
the
NOAEL
was
established
at
1000
mg/
kg/
day
(limit
dose)

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
21­
day
dermal
toxicity
study
[870.3200
(§
82­
2)]
in
rabbits.

4.2.4
870.3250
90­
Day
Dermal
Toxicity
No
study
available,
not
required
4.2.5
870.4365
90­
Day
Inhalation
Toxicity
Tebuthiuron
(105501)
RED
Toxicology
Chapter
5
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
not
complete.
The
developmental
toxicity
study
in
the
rabbit
was
found
to
be
unacceptable;
the
requirement
for
a
developmental
neurotoxicity
study
is
being
held
in
reserve
pending
submission
of
this
study.
In
the
rat
developmental
toxicity
study,
no
qualitative/
quantitative
evidence
of
increased
susceptibility
was
observed.

4.3.1
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
00020803,
40485801),
25
presumed
pregnant
Harlan
rats
per
group
were
administered
tebuthiuron
(purity
not
given;
Lot
No.
1093­
316A­
259)
at
dietary
concentrations
of
0,
600,
1200,
or
1800
ppm
(0,
37,
72,
or
110
mg/
kg/
day,
respectively)
on
gestation
days
(GD)
6­
15,
inclusive.
On
GD
20,
dams
were
sacrificed
and
subjected
to
gross
necropsy;
pancreatic
tissue
was
saved
from
10
females/
group
for
histopathological
examination.
Fetal
sex,
weight,
and
viability
were
determined
and
each
fetus
was
examined
for
external
abnormalities.
Approximately
onethird
of
all
fetuses
were
fixed
in
Bouin's
solution
for
subsequent
visceral
examination
and
the
remainder
were
cleared
for
skeletal
examination.

All
dams
survived
to
terminal
sacrifice.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
any
group.
Body
weights,
body
weight
gains,
and
food
consumption
by
the
low­
and
mid­
dose
groups
were
similar
to
the
controls
throughout
the
study.
No
treatment­
related
lesions
were
observed
in
any
dam
at
necropsy.
Pancreatic
tissue,
as
evaluated
by
both
gross
and
microscopic
examination,
appeared
normal.

For
the
high­
dose
group,
absolute
body
weights
were
slightly
reduced
on
GD
16
to
93%
of
the
control
level
due
to
reduced
body
weight
gains
during
the
entire
treatment
interval.
Body
weight
gains
by
the
high­
dose
dams
were
21%
of
the
control
level
during
GD
6­
10
and
57%
of
the
control
level
during
GD
11­
15.
During
the
treatment
interval,
food
consumption
by
the
high­
dose
group
was
71%
of
the
control
amount
for
GD
6­
10
and
95%
of
the
control
amount
for
GD
11­
15.
Compensatory
weight
gain
and
food
consumption
was
observed
in
the
high­
dose
group
during
the
post­
treatment
interval.

The
maternal
toxicity
LOAEL
is
1800
ppm
(110
mg/
kg/
day)
based
on
decreased
body
weight
gains
and
food
consumption.
The
maternal
toxicity
NOAEL
is
1200
ppm
(72
mg/
kg/
day).

No
differences
were
observed
between
the
treated
and
control
groups
for
pregnancy
rate,
number
of
corpora
lutea/
dam,
number
of
implantation
sites/
dam,
pre­
or
post­
implantation
losses,
number
of
fetuses/
litter,
fetal
body
weights,
or
fetal
sex
ratios.
No
dead
fetuses
were
observed.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
6
The
total
number
of
fetuses(
litters)
available
for
examination
for
malformations/
variations
in
the
control,
low­,
mid­,
and
high­
dose
groups
was
259(
23),
263(
21),
300(
23),
and
258(
21),
respectively.
No
treatment­
related
abnormalities
were
found
in
any
fetus.
In
the
control,
low­,
mid­,
and
high­
dose
groups,
the
total
number
of
fetuses(
litters)
with
external,
visceral,
or
skeletal
malformations/
variations
was
3(
2),
4(
4),
11(
7),
and
4(
3),
respectively.
Hydronephrosis
was
a
common
finding
in
fetuses
from
control
and
treated
groups.

The
developmental
toxicity
NOAEL
is
$
$1800
ppm
(110
mg/
kg/
day)
and
the
developmental
toxicity
LOAEL
was
not
identified.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirements
for
a
developmental
toxicity
study
[870.3700
(§
83­
3a)]
in
rats.

4.3.2
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
00020644),
15
presumed
pregnant
Dutch
belted
rabbits
per
group
were
administered
tebuthiuron
(96.5%
a.
i.;
Lot
No.:
B30­
23­
149)
by
gavage
at
doses
of
0,
10,
or
25
mg/
kg/
day
on
gestation
days
(GD)
6­
18,
inclusive.
Details
of
the
purity
and
composition
and
of
the
insemination
procedure
were
given
in
MRID
41122401.
On
GD
28,
all
surviving
does
were
sacrificed
and
examined
grossly.
Litters
were
weighed
and
each
fetus
examined
for
viability,
sex,
and
external
malformations/
variations.
The
fetuses
were
killed,
examined
viscerally
by
fresh
dissection
(including
the
brain),
and
the
carcasses
processed
for
skeletal
examination.

Doses
for
the
study
were
selected
on
the
basis
of
a
preliminary
range­
finding
study
(MRID
40776301).
In
this
study,
mated
rabbits
(4/
group)
were
administered
5,
10,
20,
25,
50,
or
100
mg/
kg/
day
on
GD
6­
18.
Three
animals
in
the
100
mg/
kg/
day
group
died
or
were
killed
moribund
on
GD
8­
10.
Overall
body
weight
changes
for
the
treated
groups
were
140,
5,
­37,
­72,
­103,
and
­480
g,
respectively.
From
the
range­
finding
study,
the
percentage
of
resorptions
in
the
25,
50,
and
100
mg/
kg/
day
groups
was
68.8,
66.7,
and
100%..

In
the
main
study,
premature
deaths
of
several
animals
were
considered
incidental
to
treatment.
No
clinical
signs
of
toxicity
were
observed
in
any
animal.
No
effects
on
body
weights,
body
weight
changes,
or
food
consumption
were
noted
for
the
treated
groups
as
compared
with
the
controls.
No
treatment­
related
lesions
were
found
at
gross
necropsy.

The
maternal
toxicity
NOAEL
was
established
at
25
mg/
kg/
day;
the
LOAEL
for
maternal
toxicity
was
not
established.

No
differences
between
the
treated
and
control
groups
were
noted
for
pregnancy
rate
or
numbers
of
corpora
lutea,
implantations,
fetuses/
litter,
or
resorptions.
Although
the
mean
fetal
body
weights
in
the
high­
dose
group
were
significantly
lower
than
the
control
value,
the
decreases
were
attributed
to
increased
liter
size.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
7
The
total
number
of
fetuses(
litters)
examined
in
the
control,
low­,
and
high­
dose
groups
was
48(
11),
58(
11),
and
68(
12),
respectively.
No
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed
in
this
study.

The
developmental
toxicity
NOAEL
is
established
at
25
mg/
kg/
day;
the
LOAEL
was
not
established.

This
study
is
classified
as
Unacceptable/
Guideline
and
does
not
satisfy
the
guideline
requirements
for
a
developmental
toxicity
study
[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
Two­
Generation
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
two­
generation
reproduction
study
(MRID
00090108),
tebuthiuron
(Lot
No.
00880­
1L­
1,
X­
35920,
98.0%
a.
i.)
was
fed
to
groups
of
25
male
and
25
female
Wistar
rats
per
dose
at
dietary
concentrations
of
0,
100,
200,
and
400
ppm.
The
dietary
levels
corresponded
to
doses
of
6­
7,
13­
14,
and
26­
28
mg/
kg/
day,
respectively,
for
F0
and
F1
males
and
7­
8,
14­
15,
and
30­
31
mg/
kg/
day,
respectively,
for
F0
and
F1
females
averaged
over
the
premating
period
only.
Adult
rats
of
both
generation
were
fed
the
treated
or
control
diets
during
the
premating
period
(98
days
for
F0
and
124
days
for
F1
rats)
and
during
mating,
gestation,
and
lactation
of
two
litters
per
generation.
Pups
from
the
F1a
litters
were
selected
to
parent
the
F2
generation.

No
treatment­
related
deaths,
clinical
signs
of
toxicity,
gross
lesions,
or
microscopic
lesions
were
observed
in
adult
rats
of
either
generation.
No
treatment­
related
effects
were
observed
on
body
weight,
body
weight
gain,
food
consumption,
or
food
efficiency
in
F0
male
rats,
F1
male
rats,
or
F0
female
rats
fed
any
dose
at
any
time
during
the
study
including
the
premating,
mating,
gestation,
and
lactation
periods.
F1
females
in
the
200
and
400
ppm
groups
had
mean
weekly
body
weights
7­
9%
(not
biologically
significant)
and
8­
13%
(p<
0.01
or
<0.05),
respectively,
less
than
the
control
group
throughout
the
premating
period
starting
with
day
21
for
the
200
ppm
group
and
day
7
for
the
400
ppm
group.
Weight
gain
over
the
entire
premating
period
was
7%
(N.
S.)
less
than
controls
for
200
ppm
group
F1
females
and
14%
(p<
0.05)
less
for
the
400
ppm
group.
Cumulative
food
consumption
was
not
significantly
affected,
but
food
efficiency
was
reduced
by
13%
(p<
0.01)
for
400
ppm
group
F1
females.
The
decreased
body
weights
and
weight
gain
did
not
extend
into
the
gestation
or
lactation
period
for
F2a
litters.

The
parental
systemic
LOAEL
was
established
at
400
ppm
(30
mg/
kg/
day)
for
female
rats
based
on
deceases
in
body
weight
and
weight
gain;
NOAEL
was
established
at
200
ppm
(14
mg/
kg/
day).
Parental
effect
levels
were
not
established
for
adult
male
rats
in
this
study.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
8
No
effects
were
observed
on
reproductive
parameters
as
measured
by
sperm
morphology,
fertility
index
for
females,
and
the
number
of
litters
produced.

A
reproductive
LOAEL
was
not
established;
the
NOAEL
was
established
at
400
ppm
(30
mg/
kg/
day).

The
F1a
,
F1b
,
F2a
,
or
F2b
offspring/
litters
were
not
affected
by
treatment
with
tebuthiuron
in
the
diet.
The
mean
litter
size
at
birth,
litter
size
throughout
lactation,
survival
indices
(live
birth,
viability,
and
lactation),
and
pup
weights
and
pup
weight
gain
throughout
lactation
were
not
statistically
different
between
treated
and
control
groups.
Dosing
was
considered
to
be
barely
adequate
for
assessing
reproductive
and
offspring
toxicity.

The
offspring
LOAEL
was
not
established;
the
NOAEL
was
established
at
400
ppm
(30
mg/
kg/
day).

This
study
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
two­
generation
reproductive
study
(OPPTS
870.3800,
§83­
4)
in
the
rat.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
not
complete;
datagaps
include
a
chronic
feeding/
carcinogenicity
study
in
the
rat.

It
should
be
noted
that
initial
review
of
the
carcinogenicity
studies
in
the
rat
and
mouse
by
the
RfD
Committee
on
August
28,
1992
did
not
consider
the
doses
to
be
adequate
based
on
the
absence
of
systemic
effects.
On
February
25,
1993,
however,
the
RfD
Committee
(Second
RfD/
Peer
review
report
of
Tebuthiuron,
memo
dated
March
1,
1993)
reconvened
and
found
the
rat
carcinogenicity
study
to
be
acceptable;
the
committee
felt
that
the
doses
were
considered
adequate,
or
at
least
approaching
an
adequate
dose,
for
carcinogenicity
testing
in
rats
based
on
body
weight
gain
decrease.
Even
though
the
Committee
found
the
mouse
carcinogenicity
study
to
be
unacceptable
(inadequate
dose
levels),
they
concluded
that
treatment
did
not
seem
to
alter
the
tumor
profile
for
this
strain
of
mouse
and
indicated
that
there
would
be
no
need
for
another
study.

4.5.1
870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
Study­
CD(
SD)
BR
Rats
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
study
(MRID
00020714),
tebuthiuron
(>
97%
a.
i.,
lot
number,
6SG43
and
B30­
23­
149)
was
administered
to
male
and
female
Wistar
rats
(40/
group/
sex)
at
dietary
concentrations
of
400,
800,
or
1600
ppm
(20,
40,
and
80
mg/
kg/
day,
based
on
the
default
food
factor
of
0.05).
Two
control
groups
of
60
male
and
60
female
Wistar
rats
administered
untreated
basal
diet.
No
interim
sacrifice
was
conducted
for
this
study.
Two
replicate
studies
were
carried
out.

No
treatment­
related
effects
were
reported
for
clinical
signs,
mortality,
or
clinical
pathology
in
male
or
female
rats
receiving
any
dose
of
the
test
material.
The
mortality
rates
for
all
groups
was
high.
During
the
first
year
of
treatment,
10­
19%
of
males
died
Tebuthiuron
(105501)
RED
Toxicology
Chapter
9
while
at
the
end
on
the
study,
only
26%
of
all
rats
remained
alive.
Pneumonia
affected
the
majority
of
animals
in
all
groups
at
various
times
during
the
study;
antibiotic
treatment
was
required
during
one
episode.
Absolute
body
weights
presented
graphically
indicated
that
high­
dose
males
and
females
weighed
less
than
controls
throughout
most
of
the
study.
The
magnitude
of
the
reduction
in
absolute
body
weight
could
not
be
determined
for
assessment
of
statistical
or
toxicologic
significance.
A
15%
reductions
in
body
weight
in
high­
dose
females
was
observed
at
study
termination.
Food
consumption
was
measured
but
not
reported.

Relative
kidney
weights
were
depressed
in
high­
dose
male
rats,
but
no
histopathological
correlates
were
observed.
Each
animal
was
necropsied,
but
gross
findings
were
not
tabulated.
Vacuolization
of
pancreatic
acinar
cells
(generally
slight
or
affecting
only
a
few
cells)
was
observed
in
11
males
and
13
females
receiving
the
high­
dose
and
in
none
of
the
controls
of
either
sex.
Only
selected
histopathological
data
were
presented
in
the
summary
tables
of
the
study
report;
therefore,
a
complete
assessment
of
histopathological
findings
could
not
be
conducted.
No
treatment­
related
neoplasms
were
reported;
common
neoplasms
included
pituitary
adenomas
and
mammary
fibroadenomas
in
female
rats.
The
microscopic
findings
in
the
pancreatic
acinar
cells
were
generally
slight,
affected
only
a
few
cells,
and
caused
no
physiological
effect
on
glucose
levels.

Based
on
the
results
of
this
study
(decreased
terminal
body
weight
in
females),
the
LOAEL
for
systemic
toxicity
was
established
at
80
mg/
kg/
day;
a
LOAEL
was
not
established
im
males.
The
NOAEL
was
established
at
40
mg/
kg/
day
in
females
at
80
mg/
k/
day
in
females.

The
HIARC
(TXR
No.
0050450,
dated
February
5,
2002)
determined
that
doses
used
in
this
study
were
not
considered
to
be
adequate
for
the
evaluation
of
the
carcinogenic
potential
of
tebuthiuron.

This
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
Unacceptable/
Guideline
and
does
not
satisfy
the
guideline
requirement
for
a
chronic
toxicity/
carcinogenicity
oral
study
[OPPTS
870.4300
(§
83­
5)]
in
the
rat.

4.5.2
870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
a
one­
year
chronic
toxicity
study,
tebuthiuron
(98.9%
a.
i.,
Batch
No.
X­
35920)
was
administered
daily
by
capsule
to
groups
of
4
male
and
4
female
beagle
dogs
at
doses
of
0,
12.5,
25.0,
or
50.0
mg/
kg/
day
(MRID
00146801).

All
animals
survived
to
scheduled
termination.
Clinical
signs
of
toxicity
in
high­
dose
animals
included
anorexia,
emesis,
and
diarrhea.
Absolute
body
weights
for
females
and
food
consumption
for
males
and
females
were
not
affected
by
treatment.
Body
weights
of
the
high­
dose
males
were
less
than
those
of
the
controls
throughout
most
of
the
study
with
statistical
significance
attained
occasionally.
Overall
weight
gains
by
the
high­
dose
males
and
females
were
67%
and
82%,
respectively,
of
the
control
levels.
No
treatment­
related
ophthalmological
lesions,
changes
in
urinalysis
parameters,
or
microscopic
lesions
were
Tebuthiuron
(105501)
RED
Toxicology
Chapter
10
noted
and
gross
necropsy
was
unremarkable.

Thrombocyte
counts
were
significantly
(p
#
0.05)
increased
in
high­
dose
males
at
6
and
12
months
as
compared
with
the
controls.
Alanine
aminotransferase
(ALT)
levels
were
increased
in
males
after
1
month
and
in
females
after
3
months
to
186­
529%
and
228­
407%,
respectively,
of
the
control
group
levels.
In
addition,
alkaline
phosphatase
(AP)
levels
in
males
were
increased
to
283­
408%
of
the
control
levels
at
6
and
12
months.
Statistical
significance
was
not
attained
at
all
timepoints
for
the
increases
in
enzyme
levels
due
to
large
variability
between
individual
animals.

Absolute
liver
weights
were
significantly
(p
#
0.05)
increased
in
the
high­
dose
males
and
females.
No
other
differences
in
absolute
organ
weights
were
found.
Also
for
the
highdose
groups,
significant
(p
#
0.05)
differences
in
organ
weights
relative
to
final
body
weight
included
increased
relative
liver
weights
in
males
and
females,
increased
relative
kidney
weights
in
females,
and
increased
relative
thyroid
weights
in
males.

The
LOAEL
was
established
at
50
mg/
kg/
day
based
on
clinical
signs
(anorexia,
emesis,
and
diarrhea),
decreased
body
weight
gains,
increased
alanine
aminotransferase
and
alkaline
phosphatase
(males
only)
levels,
increased
absolute
and
relative
liver
weights,
increased
relative
kidney
weights
(females
only),
and
increased
relative
thyroid
weights
(males
only).
The
NOAEL
was
established
at
25
mg/
kg/
day.

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

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
database
for
carcinogenicity
is
considered
inadequate.
The
HIARC
(TXR
No.
0050450,
dated
February
5,
2002)
reevaluated
the
classification
and
concluded
that
the
carcinogenic
potential
of
tebuthiuron
can
not
be
determined
due
to
inadequate
carcinogenicity
studies.

4.6.1
870.4200b
Carcinogenicity
Study
­
Crl:
CD­
1
(ICR)
BR
Mouse
Executive
Summary:
In
a
carcinogenicity
study
(MRID
00020717)
Tebuthiuron
(>
97%
a.
i.,
lot
#
B30­
23­
149)
was
administered
to
groups
of
80
Harlan
ICR
mice/
sex/
dose
in
pelleted
diet
at
dose
levels
of
400,
800,
or
1600
ppm
(60,
120,
or
240
mg/
kg
/day
based
on
the
default
food
factor
of
0.15)
for
2
years.
The
control
group,
consisting
of
120
males
and
120
females
was
fed
untreated
pelleted
diet.
Animals
were
equally
subdivided
by
dose
and
sex
into
two
substudies;
the
second
substudy
was
started
1
week
after
the
first.
It
should
be
noted
that
animals
were
not
assigned
by
body
weight.

Although
there
was
a
statistically
significant
decrease
(32.4
g,
12%)
in
the
terminal
body
weights
of
high­
dose
females
in
one
of
the
substudies
(M9153),
this
is
likely
due
to
the
higher
body
weight
(36.7
g)
of
the
control
females
in
this
substudy.
The
terminal
body
Tebuthiuron
(105501)
RED
Toxicology
Chapter
11
weight
of
the
control
females
in
the
other
substudy
was
34.1
g.

There
were
no
compound
related
effects
on
mortality,
clinical
signs,
hematology
or
clinical
chemistry,
organ
weights,
or
gross
or
microscopic
pathology.

The
LOAEL
for
systemic
toxicity
was
not
established.
The
NOAEL
was
established
at
1600
ppm
(240
mg/
kg/
day).

At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
that
of
controls.
Dosing
was
not
considered
adequate
based
on
the
absence
of
systemic
effects.

This
carcinogenicity
study
in
Unacceptable/
Guideline
and
does
not
satisfy
guideline
requirements
for
a
carcinogenicity
study
in
the
rat.

4.6.2
870.4300
Carcinogenicity
Study­
CD(
SD)
BR
Rats
Executive
Summary:
See
section
4.5.1
(870.4300).

Adequacy
of
the
Dose
Levels
Tested:
At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
that
of
controls.
Dosing
was
not
considered
adequate
based
on
the
absence
of
systemic
effects.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
database
for
mutagenicity
is
considered
adequate.
The
submitted
test
battery
satisfies
the
Pre­
1991
mutagenicity
initial
testing
battery
guidelines.
There
is
no
evidence
of
gene
mutations
in
bacteria
or
mammalian
cells,
chromosome
aberrations
in
mammalian
cells
or
unscheduled
DNA
syntheses
in
cultured
rat
hepatocytes.
No
further
testing
is
required
at
this
time.

Gene
Mutation
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00141691
Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria,
S.
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537,
and
TA1538
were
exposed
to
Tebuthiuron
(98.0%,
lot
number
X­
35920)
in
dimethylsulfoxide
(DMSO)
at
concentrations
of
100,
500,
1000,
2500,
or
5000
:g/
plate
in
the
presence
and
absence
of
mammalian
metabolic
activation
(S9­
mix).
Triplicate
plates
were
utilized
for
each
test
concentration.
Tebuthiuron
was
tested
up
to
the
limit
dose.
No
increase
in
mutant
frequency
was
noted
in
any
strain
with
or
without
metabolic
activation.
The
solvent
and
positive
control
values
were
appropriate
in
the
respective
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
with
or
without
S9
activation.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
12
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00141690
Acceptable/
Guideline
In
a
reverse
gene
mutation
assay
in
bacteria,
S.
typhimurium
strains
G46,
TA1535,
TA100,
C3076,
TA1537,
D3052,
TA1538,
and
TA98
and
E.
coli
strains
WP2
and
WP2
uvrA­
were
exposed
to
tebuthiuron
(98.0%,
lot
number
X­
35920)
in
dimethylsulfoxide
(DMSO)
over
a
concentration
range
of
0.1
to
1000
:g/
mL,
in
a
gradient
plate
assay,
in
the
presence
and
absence
of
mammalian
metabolic
activation
(S9­
mix).
No
increase
in
mutant
frequency
was
noted
in
any
S.
typhimurium
or
E.
coli
tester
strain
with
or
without
metabolic
activation.
The
solvent
and
positive
control
values
were
appropriate
in
the
respective
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
S.
typhimurium
strains
G46,
TA1535,
TA100,
C3076,
TA1537,
D3052,
TA1538,
and
TA98
and
E.
coli
strains
WP2
and
WP2
uvrA­
with
or
without
S9
activation.

870.5300
In
vitro
mammalian
cell
gene
mutation
MRID
00145041
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
in
vitro,
cultures
of
mouse
lymphoma
L5178Y
TK+/­
cells
were
exposed
to
Tebuthiuron
(98.0%,
lot
No.
X­
35920)
in
dimethylsulfoxide
at
concentrations
of
100,
200,
300,
400,
500,
600,
700,
or
800
:g/
mL
in
an
initial
assay
the
absence
of
mammalian
metabolic
activation
(S9­
mix),
and
at
concentrations
of
10,
100,
200,
300,
400,
500,
750,
or
1000
:g/
mL
in
an
initial
assay
in
the
presence
of
S9
mix.
Due
to
cytotoxicity,
the
nonactivated
assay
was
repeated
at
concentrations
of
10,
100,
200,
400,
500,
600,
700,
and
800
:g/
mL,
and
the
activated
assay
was
repeated
at
concentrations
of
1,
10,
100,
200,
400,
500,
600,
or
700
:g/
mL.
Tebuthiuron
technical
was
tested
up
to
concentrations
limited
by
cytotoxicity.
Relative
growth
ranged
from
57%
to
13%
(at
100
to
800
:g/
mL)
in
the
absence
of
metabolic
activation
in
the
initial
assay
and
from
28%
to
6%
(at
10
to
750
:g/
mL)
in
the
presence
of
metabolic
activation
in
the
initial
assay.
In
the
initial
nonactivated
assay,
mutation
indices
of
2.0
and
2.4
were
detected
at
700
and
800
:g/
mL,
respectively.
In
a
repeat
nonactivated
assay,
mutation
indices
of
2.0,
2.0,
and
2.7
occurred
at
200,
400,
and
500
:g/
mL,
respectively.
Mutations
were
not
induced
at
any
concentration
with
activation.
The
ethyl
methane
sulfonate
(without
S9)
and
3­
methylcholanthrene
(with
S9­
mix)
positive
controls
responded
appropriately.
Tebuthiuron
was
considered
weakly
mutagenic
in
the
absence
of
metabolic
activation.
No
evidence
of
an
increased
mutant
frequency
was
observed
in
the
presence
of
metabolic
activation.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
13
Cytogenetics
870.5375
In
vitro
mammalian
cell
chromosome
aberration
MRID
41134101
Acceptable/
Guideline
In
a
mammalian
chromosome
aberration
assay,
Chinese
Hamster
Ovary
(CHO)
cell
cultures
were
exposed
to
Tebuthiuron
(99.08%,
lot
number
729AS7)
in
dimethylsulfoxide
at
concentrations
of
0,
1650,
1800,
or
1950
:g/
mL
for
4
hours
in
the
absence
of
exogenous
metabolic
activation
(S9­
mix)
or
to
1350,
1450,
or
1550
:g/
mL
for
4
hours
in
the
presence
of
activation
(followed
by
an
additional
19­
hour
incubation
in
fresh
medium).
Tebuthiuron
was
tested
up
to
concentrations
limited
by
cytotoxicity.
A
preliminary
cytotoxicity
test
showed
survival
ranging
from
15%
at
2285
:g/
mL
to
115%
at
1000
:g/
mL
under
nonactivated
conditions
and
39%
at
1750
:g/
mL
and
55%
at
1500
:g/
mL.
A
significant
(p<
0.01)
increase
in
the
percent
of
cells
with
aberrations
was
noted
in
nonactivated
cultures
at
1950
:g/
mL
(15
&19%
for
treated
duplicate
cultures
vs.
5%
for
vehicle
controls)
and
activated
cultures
at
1550
:g/
mL
(15
&18%
for
treated
duplicate
cultures
vs.
5­
6%
for
vehicle
controls).
The
predominant
types
of
aberrations
were
chromosome
and
chromatid
breaks.
No
significant
increases
were
observed
at
lower
concentrations;
however,
rare
complex
aberrations,
such
as
triradials,
quadriradials
and
complex
rearrangements
were
noted,
providing
further
support
for
clastogenicity.
Positive
control
values
were
acceptable.
There
was
evidence
of
an
increase
in
structural
chromosomal
aberrations
over
background
in
the
presence
and
absence
of
metabolic
activation.

Other
Genotoxicity
870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
40750901
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay,
primary
rat
hepatocyte
cultures
were
exposed
to
Tebuthiuron
(99.1%
a.
i.;
Lot
No.
729AS7)
in
dimethylsulfoxide
at
eight
concentrations
ranging
from
300
to
800
:g/
mL
for
20
hours.
Tebuthiuron
was
tested
to
the
limit
of
cytotoxicity
(cytotoxicity
was
observed
at
$900
:g/
mL).
UDS
activity
was
evaluated
at
concentrations
up
to
800
:g/
mL
and
there
was
no
evidence
of
induction
of
UDS.
The
solvent
(1%
DMSO)
and
positive
control
(N­
methyl­
N'­
nitrosoguanidine
1
:g/
mL
and
2­
acetoaminofluorene
0.05
:g/
mL)
values
were
appropriate.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[nuclear
silver
grain
counts]
was
induced.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
No
acute
or
subchronic
neurotoxicity
studies
on
Tebuthiuron
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
meeting
on
December
13,
2001
and
January
17,
2002
determined
that
a
developmental
neurotoxicity
study
should
be
held
in
reserve,
pending
submission
of
a
developmental
toxicity
study
in
the
rabbit
(TXR
No.
0050450,
dated
Tebuthiuron
(105501)
RED
Toxicology
Chapter
14
February
5,
2002).

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.

4.8.3
870.6200b
Subchronic
Neurotoxicity
Screening
Battery
This
study
is
not
required.

4.8.4
870.6300
Developmental
Neurotoxicity
Study
The
requirement
for
this
study
is
being
held
in
reserve.

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
(MRID
42711701,
43129701),
male
and
female
Fischer
344
rats
were
dose
with
14
C­
tebuthiuron
at
a
single
low
oral
dose
(10
mg/
kg),
a
repeated
low
oral
dose
(10
mg/
kg
x
14
days),
or
a
single
high
dose
(100
mg/
kg).
Absorption
was
complete
at
both
the
low
and
high
dose.
Terminal
distribution
data
showed
no
significant
amounts
of
residual
radioactivity
in
any
tissue
examined,
but
the
skin
showed
the
highest
amounts
relative
to
other
tissues.
Excretion
was
rapid
at
both
the
low
and
high
dose
levels
in
both
sexes,
but
was
delayed
during
the
first
12
hours
postdose
indicating
saturation
of
biotransformation
or
excretion.
From
HPLC
and
mass
spectral
analysis
of
urine
samples,
6
metabolites
of
tebuthiuron
were
identified.
The
major
metabolite
was
identified
as
109OH
and/
or
104­
OH,
both
hydroxylated
metabolites
of
tebuthiuron.
This
metabolite
composed
between
39.6­
60.3%
of
the
administered
dose
in
0­
24
hour
urine
of
male
and
female
rats.
The
second
most
abundant
metabolite
was
identified
as
metabolite
106
of
tebuthiuron.
This
comprised
between
9­
15%
of
the
administered
dose
in
0­
24
hour
urine
of
low
dose
rats,
and
between
55.6%
and
57.3%
of
the
administered
dose
for
male
and
female
rats,
respectively.
Two
other
metabolites
identified,
104/
109
and
103­
OH,
comprised
between
2­
10%
of
the
administered
dose
in
male
and
female
0­
24
hour
urine.
Feces
contained
minor
amounts
of
104­
OH
and
109­
OH,
accounting
for
an
average
of
3.5%
of
the
administered
dose.

4.10
Special
Studies
None
5
TOXICITY
ENDPOINT
SELECTION
Tebuthiuron
(105501)
RED
Toxicology
Chapter
15
See
Section
9.2
for
Endpoint
Selection
Table
5.1
Dermal
Absorption
No
study
available.

5.2
Classification
of
Carcinogenic
Potential
5.2.1
Conclusions
and
Classification
of
Carcinogenic
Potential
The
HIARC
(TXR
No.
0050450,
dated
February
5,
2002)
reevaluated
the
classification
and
concluded
that
the
carcinogenic
potential
of
tebuthiuron
can
not
be
determined
due
to
inadequate
carcinogenicity
studies.

5.2.2
Quantification
of
Carcinogenic
Potential
Not
applicable
6
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
The
toxicological
database
is
inadequate
for
FQPA
assessment.
The
developmental
toxicity
study
in
the
rabbit
is
unacceptable
for
the
determination
of
susceptibility
to
the
fetuses
due
to
in
utero
tebuthiuron
exposure.
However,
there
is
an
adequate
developmental
toxicity
study
in
the
rat
and
a
two­
generation
reproductive
toxicity
study
in
the
rat
to
assess
the
susceptibility
of
fetuses/
offspring
to
tebuthiuron.
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
in
2­
generation
reproduction
study
in
the
rat
or
the
developmental
toxicity
study
in
the
rat.
In
the
developmental
toxicity
study
in
the
rabbit,
no
maternal
or
developmental
toxicity
was
observed
at
the
highest
dose
tested.
Because
there
was
no
toxicity
observed
at
the
highest
dose
tested,
susceptibility
could
not
be
ascertained
and
the
HIARC
concluded
that
a
new
developmental
toxicity
in
the
rabbit
is
needed..

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
FQPA
Committee
reserved
the
requirement
of
a
developmental
neurotoxicity
study
pending
submission
of
a
developmental
toxicity
study
in
rabbits.

7
OTHER
ISSUES
None
8
REFERENCES
00020662
Todd,
G.
C.;
Gibson,
W.
R.;
Kiplinger,
G.
F.
(1972)
The
Toxicological
Evaluation
of
EL­
103
in
Rats
for
3
Months.
(Unpublished
study
received
Mar
13,
1973
under
1471­
97;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Tebuthiuron
(105501)
RED
Toxicology
Chapter
16
Indianapolis,
Ind.;
CDL:
006422­
G)

00020663
Todd,
G.
C.;
Gibson,
W.
R.;
Kiplinger,
G.
F.
(1972)
The
Toxicological
Evaluation
of
EL­
103
in
Dogs
for
3
Months.
(Unpublished
study
received
Mar
13,
1973
under
1471­
97;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
Ind.;
CDL:
006422­
H)

00020644
Todd,
G.
C.,
Markham,
J.
K.,
Adams,
E.
R.,
Owen,
N.
V.,
Gossett,
F.
O.,
and
Morton,
D.
M.
(1975)
A
teratology
study
with
EL­
103
in
the
rabbit.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
No.
B­
7014.
April
1975.
Unpublished.

00020714
Todd,
G.,
W.
Gibson,
D.
Hoffman,
et
al.
1976.
The
toxicological
evaluation
of
tebuthiuron
(EL­
103)
in
rats
for
two
years.
Studies
R­
603
and
R­
613.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN,
November,
1976.
Unpublished.

00020717
Todd,
G.
C.;
Gibson,
W.
R.;
Hoffman,
D.
G.;
et
al.
(1976)
The
Toxicological
Evaluation
of
Tebuthiuron
(EL­
103)
in
Mice
for
Two
Years:
Toxicology
Report
#
8.
(Unpublished
study
received
Dec
1,
1976
under
1471­
EX­
43;
submitted
by
Elanco
Products
Co.,
Div.
of
Eli
Lilly
and
Co.,
Indianapolis,
Ind.;
CDL:
230139­
D)

00020803
Todd,
G.
C.,
Markham,
J.
K.,
Adams,
E.
R.,
Owen,
N.
V.,
Gibson,
W.
R.,
and
Kiplinger,
G.
F.
(1972)
Rat
teratology
study
with
EL­
103.
The
Lilly
Toxicology
Laboratories,
Eli
Lilly
and
Company,
Greenfield,
IN.
Laboratory
Study
No.
R632
September,
1972.
Unpublished.

00090108
Adams,
E.
R.,
N.
Owen,
and
J.
Hoyt.
1981.
A
two­
generation
reproduction
study
with
tebuthiuron
(Compound
75503)
in
the
Wistar
rat.
Lilly
Research
Laboratories,
Greenfield,
IN.
November,
1981.
Study
numbers
R03780
and
R08780.
Unpublished
00141691
Rexroat,
M.
A.,
Todd,
G.
C.
(1984).
The
effect
of
Tebuthiuron
(Lilly
Compound
75503)
on
the
induction
of
reverse
mutations
in
Salmonella
typhimurium
using
the
Ames
test.
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
No.
840326AMS655.
April,
1984.
Unpublished
00145041
Oberly,
T.
J,
Bewsey,
B.
J.,
Todd,
G.
C.
(1984).
The
effect
of
Tebuthiuron
(Lilly
Compound
75503)
on
the
induction
of
forward
mutation
at
the
thymidine
kinase
locus
of
L5178Y
mouse
lymphoma
cells.
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
Nos.
840410
MLA655,
84060MLA655,
840612MLA655.
Unpublished.

00146801
Todd,
G.
(1985).
The
toxicity
evaluation
of
tebuthiuron
(Lilly
compound
75503)
to
Beagle
dogs
for
one
year.
Lilly
Research
Laboratories,
Greenfield,
IN.
Laboratory
Study
No.
D04283.
February
1985.
MRID.
Unpublished.

00149733
Brown,
G.
(1985)
Subchronic
(21­
Day)
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits
with
Technical
Tebuthiuron:
Study
B01484.
Unpublished
study
Tebuthiuron
(105501)
RED
Toxicology
Chapter
17
prepared
by
Lilly
Research
Laboratories.
211
p.

00160796
Negilski,
D.;
McGrath,
J.;
Young,
S.
(1986)
Reply
to
U.
S.
EPA
Recommendation
To
Upgrade
the
Current
21­
day
Dermal
Toxicity
Study
(BO1484)
of
Technical
Tebuthiuron
with
Additional
Doses
to
Establish
a
Systemic
No­
effect
Level.
Unpublished
study
prepared
by
Eli
Lilly
and
Co.
18
p.

40485801
Todd,
G.
C.
and
Higdon,
G.
L.
(1972)
A
supplementary
report
of
a
rat
teratology
study
with
tebuthiuron
(EL­
103,
compound
75503).
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Laboratory
Study
No.
R­
632.
September,
1972.
Unpublished.

40750901
Negilski.
D.
S,
Garriot,
M.
L.,
Yount,
D.
J.
(1988)
.
The
effect
of
Tebuthiuron
(EL­
103,
Compound
75503)
on
the
induction
of
DNA
synthesis
in
primary
cultures
of
adult
rat
hepatocytes.
Eli
Lilly
and
Company,
Greenfield,
IN.
Study
Nos.
880510UDS0655
and
880517
UDS0655.
Unpublished.

40776301
Negilski,
D.
S.
and
Higdon,
G.
L.
(1988)
A
supplementary
report
in
support
of
a
teratology
study
with
tebuthiuron
(EL­
103,
Compound
75503)
in
the
rabbit.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
No.
B7014
June
8,
1988.
Unpublished.

40870101
Negilski,
D.;
Todd,
G.
(1988)
A
Supplemental
Inventory
of
Selected
Tissues
from
Rats
Given
Diets
Containing
Tebuthiuron
(...)
for
Two
Years:
Project
ID:
R­
603
and
R­
613.
Unpublished
study
prepared
by
Lilly
Research
Laboratories.
10
p.

41122401
Megilski,
D.
S.,
Rutherford,
B.
S.,
and
Higdon,
G.
L.
(1989)
A
supplementary
report
for
a
rabbit
teratology
study
(B­
7014)
with
tebuthiuron
(EL­
103,
Compound
75503)
­
A
response
to
the
U.
S.
EPA's
request
for
certain
additional
information
to
upgrade
the
rabbit
teratology
study
from
core
supplementary
to
core
minimum.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
No.
B­
7014.
March
8,
1989.
Unpublished.

41134101
Negilski,
D.
S.,
Garriot,
M.
L.,
Kindig,
D.
E.
F.
(1989)
The
effect
of
tebuthiuron
(EL­
103,
Compound
075503)
on
the
in
vitro
induction
of
chromosomal
aberrations
in
Chinese
Hamster
Ovary
cells.
Lilly
Research
Laboratories,
Greenfield,
IN,
Study
Nos.
890111CTX655,
890125CTX655,
890201CAB655,
890228CAB655.
April
12,
1989.
Unpublished.

42711701
Eschbach,
J.;
Hackett,
D.
(1993)
Absorption,
Distribution
and
Elimination
of
(Carbon
14)­
Tebuthiuron
in
Rats:
Lab
Project
Number:
DR­
0189­
9383­
001.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
107
p.

43129701
Eschbach,
J.;
Hackett,
D.
(1994)
Absorption,
Distribution
and
Elimination
of
(carbon
14)
Tebuthiuron
in
Rats:
Addendum:
Lab
Project
Number:
DR/
0189/
9383/
001.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
10
p.

USEPA
Memorandum:
Tebuthiuron
oncogenicity
studies,
HED
Project
No.
9­
0927,
Tebuthiuron
(105501)
RED
Toxicology
Chapter
18
Caswell
No.
366AA.
From
Quang
Q.
Bui,
Head,
Review
Section
I,
Tox
BranchHFAS
HED
to
Robert
Taylor,
PM,
#
25,
Registration
Division,
November
30,
1988
(TXR
No.:
007374)

USEPA
Memorandum:
Tebuthiuron:
Report
of
the
Hazard
Identification
Assessment
Review
Committee,
February
5,
2002
(TXR
No
0050450)

USEPA
Memorandum:
Tebuthiuron:
Report
of
the
FQPA
Safety
Factor
Committee,
February
12,
2002
(TXR
No.
0050466)
Tebuthiuron
(105501)
RED
Toxicology
Chapter
19
9
APPENDICES
­
Tables
for
Use
in
Risk
Assessment
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
toxicityrat
00020662
(1972)
Acceptable/
Guideline
0,
20,
50,
125
mg/
kg/
day
NOAEL
=
50
mg/
kg/
day
LOAEL
=
125
mg/
kg/
day,
based
on
decreased
body
weight,
increased
relative
liver,
kidney,
gonads,
spleen
(males
only),
and
prostate
and
slight
vacuolization
of
pancreatic
acinar
cells.

870.3150
90­
Day
oral
toxicitydog
00020663
(1972)
Acceptable/
Guideline
0,
12.5,
25,
50
NOAEL
=
25
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
decrease
in
body
weight
and
increased
alkaline
phosphatase
activity.

870.3200
21/
28­
Day
dermal
toxicity­
rabbit
00149733
(1985)
00160796
(1986)
Acceptable/
Guideline
0,
1000
mg/
kg/
day
NOAEL
=
1000
mg/
kg/
day
(limit
dose)

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
00146801
(1985)
Acceptable/
Guideline
0,
12.5,
25,
50
mg/
kg/
day
NOAEL=
25
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day
based
on
clinical
signs,
decreased
body
wt,
increased
ALT
and
ALP
(males
only),
increased
absolute
and
relative
livers
and
relative
thyroid
wt,
(males
only)
wt,
and
increased
absolute
liver
wt.

870.4200
[83­
2
(b)]

Oncogenicity
Study
­
Mouse
00020717
(1986)

Unacceptable/
Guideline
0,
60,
120,
240
mg/
kg/
day
NOAEL=
240
mg/
kg/
day
LOAEL
=
Not
achieved
Histopathology:
None
observed
at
doses
tested,
doses
not
high
enough
to
assess
carcinogenicity.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
20
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.4300
[83­
5(
a)]

Combined
Chronic
Toxicity/
Carcinogenicity
Study
­
Rat
00020714
(1976)
00098190
(1981)
40870101
(1988)

Unacceptable/
Guideline
0,
20,
40,
80
mg/
kg/
day
NOAEL
=
40
mg/
kg/
day,
females
80
mg/
kg/
day
males
LOAEL
=
80
mg/
kg/
day,
based
on
decreased
terminal
body
weight
in
females
not
established
in
males
Histopathology:
None
observed
at
doses
tested,
doses
not
high
enough
to
assess
carcinogenicity.

870.3700
[83­
3(
a)]

Developmental
Toxicity
Study
­
Rat
00020803
(1972)
40485801
(1972)

Acceptable/
Guideline
0,
37,
72,
110
mg/
kg/
day
Maternal
Systemic
NOAEL=
72
mg/
kg/
day
LOAEL
=
110
mg/
kg/
day)
based
on
decreased
body
weight
gains
and
food
consumption.

Developmental
NOAEL
=
110
mg/
kg/
day
LOAEL
=
not
established
870.3700
[83­
3(
b)]

Developmental
Toxicity
­
Rabbit
00020644
(1975)
40776301
(1988)
41122401
(1989)

Unacceptable/
Guideline
0,
10,
or
25mg/
kg/
day
Maternal
Systemic
NOAEL=
25
mg/
kg/
day
LOAEL
=
not
established
Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
not
established
870.3800
[83­
4]
2­
Generation
Reproduction
­
Rat
00090108
(1981)

Acceptable/
Guideline
%%
0,
7,
14,
and
26
mg/
kg/
day
&&
7,
14,
and
30
mg/
kg/
day,
Systemic
NOAEL=
14
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day,
based
on
deceased
in
body
weight
and
weight
gain
in
F1
females.
Parental
effect
levels
were
not
established
for
adult
male
rats
in
this
study.

Reproductive
NOAEL
=
30
mg/
kg/
day
LOAEL
=
not
established
Offspring
NOAEL
=
30
mg/
kg/
day
LOAEL
=
not
established
870.7600
(85­
2)
Dermal
Penetration
Rat
No
study
available
N/
A
Tebuthiuron
(105501)
RED
Toxicology
Chapter
21
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.7485
(85­
1)
Metabolism
Study
Rat
42711701
(1993)
43129701
(1994)
Acceptable/
Guideline
10
or
100
mg/
kg,
1
day
10
mg/
kg/
day
for
14
days
Terminal
distribution
data
showed
no
significant
amounts
of
residual
radioactivity
in
any
tissue
examined,
but
the
skin
showed
the
highest
amounts
relative
to
other
tissues.
Excretion
was
rapid
at
both
the
low
and
high
dose
levels
in
both
sexes,
but
was
delayed
during
the
first
12
hours
post­
dose,
indicating
saturation
of
biotransformation
or
excretion.
Six
metabolites
of
tebuthiuron
were
identified.
The
major
metabolite
in
0­
24
hour
urine
of
male
(58.3%)
and
female
(62.1%)
rats
was
identified
as
hydroxylated
tebuthiuron
metabolites
(#
109­
OH
and
/or
#104­
OH).
The
second
most
abundant
metabolite
was
identified
as
metabolite
106
of
tebuthiuron.
This
comprised
between
9­
15%
of
the
administered
dose
in
0­
24
hour
urine
of
low
dose
rats,
and
between
1
­
10%
of
the
administered
dose
in
high
dose
rats.
Two
other
metabolites
identified,
104/
109
and
103­
OH,
.comprised
between
2­
10%
of
the
administered
dose
in
male
and
female
0­
24
hour
urine.
Feces
contained
minor
amounts
of
104­
OH
and
109­
OH,
accounting
for
an
average
of
3.5%
of
the
administered
dose.
Tebuthiuron
(105501)
RED
Toxicology
Chapter
22
aPAD
aRfD
FQPA
SF
=
cPAD
cRfD
FQPA
SF
=
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Tebuthiuron
for
Use
in
Human
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
1
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
25
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.25
mg/
kg/
day
FQPA
SF
2
=3
=
0.083
mg/
kg/
day
Developmental
Toxicity
Study
Rabbit
NOAEL
of
25
mg/
kg/
day.
LOAEL
not
established
A
range­
finding
study
showed
increased
early
resorptions
at
50
mg/
kg/
day
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=
14
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.14
mg/
kg/
day
FQPA
SF
3
=
1
=
0.14
mg/
kg/
day
Two­
generation
reproduction
study
in
the
rat
LOAEL
=
30
mg/
kg/
day,
based
on
decreased
body
weight
and
feed
consumption
in
F1
females
Toxicological
endpoints
for
occupational/
residential
exposure
risk
assessments
were
not
selected
since
tebuthiuron
is
scheduled
for
a
Tolerance
Reassessment
Eligibility
Decision
(TRED)

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
2
Because
there
is
a
data
gap
for
assessing
susceptibility
of
fetuses
following
in
utero
exposure
a
FQPA
safety
factor
of
3x
will
be
used.

3
Because
there
was
no
susceptibility
identified
in
the
2­
generation
rat
reproduction
study
(a
long­
term
study).
the
FQPA
safety
factor
will
be
removed
(1x).