Document ID: EPA-HQ-OPP-2002-0146-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-06-25T04:00Z

1
THIS
VERSION
INCLUDES
REVISIONS
IN
THE
MUTACGENICITY
AND
DATAGAP
SECTIONS
TXR
No:
0050672
DATE:
April
16,
2002
MEMORANDUM
SUBJECT:
TEBUTHIURON
­
THIRD
Report
of
the
Hazard
identification
Assessment
Review
Committee
FROM:
Robert
F.
Fricke,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
(7509C)

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

TO:
Wilhelmena
Livingston,
Chemical
Review
Manager
Special
Review
and
Registration
Division
(7508C)

PC
CODE:
105501
On
December
13,
2001,
January
17,
2002
and
February
12,
2002,
the
Hazard
Identification
assessment
Review
Committee
(HIARC)
reviewed
the
toxicology
data
base
of
tebuthiuron
and
selected
endpoints/
doses
the
acute
and
chronic
reference
doses.
The
HIARC
also
evaluated
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
tebuthiuron
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
The
conclusions
drawn
at
these
meetings
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
in
attendance:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Paula
Deschamp
Elizabeth
Doyle
(Co­
Chair)
Pamela
Hurley,
John
Liccione,
Elizabeth
Mendez,
David
Nixon
Members
in
absentia:.
Jess
Rowland
(Co­
Chair)

Also
in
attendance:
Susan
Makris,
and
Pauline
Wagner
Data
evaluation
/
presentation:
Robert
F.
Fricke
Reregistration
Branch
2
3
N
N
S
N
CH
3
CH
3
C
H
3
C
H
3
O
N
H
CH
3
Tebuthiuron
(105501)
1
INTRODUCTION
On
December
13,
2001
and
January
17,
2002
the
Health
Effects
Division's
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
tebuthiuron
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfD).
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
tebuthiuron
was
also
evaluated.
The
HIARC
met
again
on
February
12,
2002
to
discuss
the
need
for
an
additional
uncertainty
factor
due
to
the
lack
of
an
acceptable
chronic
toxicity/
carcinogenicity
study
in
rats.
The
conclusions
drawn
at
these
meeting
are
presented
in
this
report.

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

Study
Selected:
Rabbit
Developmental
Toxicity
Guideline
No.:
870.3700
(83­
4b)
Main
and
Range­
Finding
studies
MRID
No.:
00020644,
40776301
Executive
Summary:
In
a
developmental
toxicity
study,
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.
Doses
were
selected
on
the
basis
of
preliminary
studies
summarized
in
MRID
40776301.
Details
of
the
purity
and
composition
of
the
test
article
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
were
selected
on
the
basis
of
preliminary
studies
which
were
summarized
in
MRID
40776301.
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.
4
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.
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
of
the
high­
dose
group
were
83%
of
the
control
level,
the
decrease
was
due
to
a
statistically
significant
(p
#
0.01)
negative
correlation
[increased
litter
size
results
in
a
significant
decrease
in
fetal
body
weight]
between
litter
size
and
fetal
body
weight.

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.

From
the
range­
finding
study,
the
percentage
of
early
resorptions
in
the
25,
50,
and
100
mg/
kg/
day
groups
was
68.8,
66.7,
and
100%.

Dose
and
Endpoint
for
Establishing
RfD:
25
mg/
kg/
day,
based
on
increased
number
of
early
resorptions.

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

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
HIARC
considered
the
data
of
the
main
study
and
the
range­
finding
study
to
establish
this
endpoint.
In
the
main
study,
no
maternal
or
developmental
toxicity
was
seen
at
the
highest
dose;
the
NOAEL
was
25
mg/
kg/
day
(HDT).
In
the
range­
finding
study,
early
resorptions
were
observed
at
25
(69%),
50
(67%),
and
100
(100%)
mg/
kg/
day.
Although
the
range­
finding
study
indicates
that
25
mg/
kg/
day
is
an
effect
level,
this
dose
(25
mg/
kg/
day)
was
selected
for
risk
assessment,
since
there
was
no
dose
response
in
the
observed
early
resorptions
and
because
there
was
greater
confidence
in
the
results
of
the
main
study
where
no
toxicity
was
seen
at
this
dose
(25
mg/
kg/
day)
and
thus
was
deemed
to
be
an
appropriate
dose
for
risk
assessment.

In
addition,
the
selection
of
the
25
mg/
kg/
day
dose
for
risk
assessment
is
supported
by
the
NOAEL
of
50
mg/
kg/
day
in
a
rabbit
developmental
range­
finding
study
with
a
structurally
related
urea
(UC
77179).
This
chemical
had
a
toxicity
profile
similar
to
that
of
tebuthiuron.
At
200
mg/
kg/
day
decreased
body
weight
gain,
lethality
and
early
resorption
were
observed.
5
2.2
Acute
Reference
Dose
(RfD)
­
General
Population
An
appropriate
end
point
attributable
to
a
single­
dose
was
not
available
in
the
database.
The
slight
decrease
(7%)
in
body
weight
gain
seen
on
gestation
day
16
in
the
rabbit
study
is
not
attributable
to
a
single
dose
and
no
maternal
toxicity
was
seen
in
the
rabbit
study.

2.3
Chronic
Reference
Dose
(RfD)

Proposed
Study:
Two­
Gen
Repro
­
Rat
Guideline
No.:
OPPTS
870.3800
(83.4)

MRID
No.:
00090108
Executive
Summary:
In
a
two­
generation
reproduction
study,
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
generations
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%
(p
#
.05,
not
biologically
significant)
and
8­
13%
(p
#
0.05),
respectively,
less
than
the
control
group
throughout
the
premating
period
starting
with
day
14
(10%,
NS)
for
the
200
ppm
group
and
day
7
(12%,
p
#
0.05)
for
the
400
ppm
group.
Weight
gain
over
the
entire
premating
period
was
7%
(not
significant)
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
for
tebuthiuron
is
400
ppm
(30
mg/
kg/
day)
based
on
deceases
in
body
weight,
body
weight
gain
and
food
consumption
of
F1
females;
the
NOAEL
is
200
ppm
(14
mg/
kg/
day).
Parental
effect
levels
were
not
established
for
adult
male
rats
in
this
study.

No
effects
were
observed
on
reproductive
parameters
as
measured
by
sperm
morphology,
fertility
index
for
females,
and
the
number
of
litters
produced.
6
Chronic
R
D
14
mg
/
kg
/day(
NOAEL)
100
(UF)
0.14
mg
/
kg
/
day
f
=
=
The
reproductive
LOAEL
for
tebuthiuron
could
not
be
established
for
this
study.
The
NOAEL
is
$
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.
Pups
in
the
400
ppm
group
weighed
about
5­
14%
less
than
the
controls
and
gained
slightly
less
weight
than
controls
throughout
lactation.
Mean
litter
sizes
in
the
400
ppm
group
were
larger
than
those
for
the
control
group
and
probably
contributed
to
the
lower
body
weights.
Dosing
was
considered
to
be
barely
adequate
for
assessing
reproductive
and
offspring
toxicity.

The
offspring
LOAEL
could
not
be
established
for
this
study.
The
NOAEL
is
$
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.

Dose
and
Endpoint
for
Establishing
RfD:
Parental
systemic
NOAEL
of
14
mg/
kg/
day
based
on
decreased
body
weight,
body
weight
gain
and
food
consumption
in
F1
females
at
30
mg/
kg/
day.

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

Co
mments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
HIARC
noted
that
the
chronic
toxicity/
carcinogenicity
study
in
rats
is
unacceptable
since
at
the
doses
tested
(0,
20,
40
or
80
mg/
kg/
day)
no
treatment­
related
effects
were
seen
for
mortality,
clinical
signs
or
clinical
pathology.
Treatment
had
no
effects
on
absolute
body
weight
or
body
weight
gains
in
males
and
there
were
minimal
(15%
reduction)
changes
in
absolute
body
weights
in
females
at
termination.
There
were
no
effects
on
neoplastic
and
non­
neoplastic
lesions
in
either
sex.
Because
of
the
lack
of
systemic
toxicity,
the
HIARC
determined
that
the
doses
tested
were
inadequate
to
assess
the
chronic
toxicity
or
the
carcinogenic
potential
of
tebuthiuron.

The
NOAEL
of
14
mg/
kg/
day
from
the
two­
generation
reproduction
study
used
for
derivation
of
the
chronic
RfD
is
the
lowest
NOAEL
in
the
database.
In
the
1­
year
chronic
study
in
dog,
the
NOAEL
was
25
mg/
kg/
day
and
the
LOAEL
was
50
mg/
kg/
day.
In
the
78­
week
carcinogenicity
study
in
mice,
the
NOAEL
was
240
mg/
kg/
day
(HDT).
The
HIARC
inferred
that
although
a
repeat
study
in
rats
at
higher
dose
would
provide
hazard
7
characterization
and
evaluate
the
carcinogenic
potential
of
this
pesticide,
but
would
not
yield
a
dose
that
is
lower
than
the
dose
that
is
used
for
derivation
of
the
RfD.
The
chronic
RfD
is
adequate
to
protect
any
adverse
toxicity
effects
following
exposure
to
tebuthiuron.
The
Committee
therefore
concluded
that
an
additional
uncertainty
factor
(for
data
gap)
is
not
needed.
The
HIARC,
however,
determined
that
a
repeat
study
is
required
to
assess
the
carcinogenic
potential
of
tebuthiuron
and
recommended
that
the
request
for
this
study
should
come
as
a
Data
Call
In
notice.

2.4
Occupational/
Residential
Exposure
Toxicological
endpoints
for
occupational/
residential
exposure
risk
assessments
were
not
selected
since
tebuthiuron
is
scheduled
for
a
Tolerance
Reassessment
Eligibility
Decision
(TRED)

3
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
0020714
Executive
Summary:
In
a
chronic
toxicity/
carcinogenicity
study,
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
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
8
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.
The
NOAEL
was
established
at
40
mg/
kg/
day
in
females.
A
LOAEL
was
not
established
in
males;
the
NOAEL
was
established
at
80
mg/
k/
day.

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.

Adequacy
of
Dose
Levels:
The
HIARC
disagreed
with
the
1993
RfD
conclusions
that
the
doses
tested
approached
an
adequate
dose
because
of
the
minimal
change
in
female
body
weight.
No
decrease
in
body
weight
was
observed
in
males,
further,
there
was
no
systemic
toxicity.
The
dose
levels
were
selected
from
a
90­
day
feeding
study,
where
decreased
body
weight,
organ
weight
changes
and
slight
to
moderate
vacuolization
of
the
pancreatic
cells
was
seen
at
2500
ppm.
Based
on
the
results
of
this
study,
animals
could
have
been
tested
at
higher
doses.

Discussion
of
Tumor
Data:
No
treatment­
related
neoplasms
were
reported
at
the
doses
tested.

3.2
Carcinogenicity
Study
in
Mice
MRID
No.
00020717
Executive
Summary:
In
a
carcinogenicity
study,
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
(equivalent
to
60,
120,
or
240
mg/
kg
bw/
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
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.
9
The
LOAEL
for
systemic
toxicity
was
not
established
in
this
study.
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
the
mouse
is
unacceptable/
guideline
and
does
not
satisfy
guideline
requirements
for
a
carcinogenicity
study
[OPPTS
870.4200;
OECD
451]
in
mice.

Discussion
of
Tumor
Data:
No
treatment­
related
neoplasms
were
reported.

Adequacy
of
the
Dose
Levels
Tested:
The
HIARC
disagreed
with
the
1993
RfD
conclusions
that
the
tumor
profile
would
not
change
if
the
dose
was
increased.
At
1600
ppm
there
was
a
12%
decrease
in
female
body
weight;
males
were
unaffected
by
treatment.

The
dose
levels
were
not
considered
adequate
due
to
lack
of
significant
toxicity
at
the
highest
dose
tested.

3.3
Classification
of
Carcinogenic
Potential
The
HIARC
reevaluated
the
classification
and
concluded
that
the
carcinogenic
potential
of
tebuthiuron
can
not
be
determined
due
to
inadequate
carcinogenicity
studies.
The
RfD
Committee
classified
tebuthiuron
as
a
"Group
D"
Carcinogen
­
Not
classifiable
as
to
human
carcinogenicity
(Second
RfD/
Peer
Review
Report
of
Tebuthiuron,
March
1,
1993).

4
MUTAGENICITY
4.1
Salmonella
typhimurium/
Escherichia
coli
reverse
gene
mutation
assay
[OPPTS
870.5100
(§
84­
2)]

MRID
No:
00141691
Executive
Summary:
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.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
rat
liver.

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
(DMSO)
and
positive
control
(2­
aminoanthracene,
2­
nitrofluorene,
9­
aminoacridine,
N­
methyl­
N'nitro­
N­
nitroso
guanidine
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.
10
This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5100
(§
84­
2)]
for
in
vitro
mutagenicity
(bacterial
reverse
gene
mutation)
assay.

4.2
Reverse
Gene
Mutation
Assay
in
Bacteria
[OPPTS
870.5100
(§
84­
2)]

MRID
No.:
00141690
Executive
Summary:
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).
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
rat
liver.

No
increase
in
mutant
frequency
was
noted
in
any
S.
typhimurium
or
E.
coli
tester
strain
with
or
without
metabolic
activation.
The
solvent
(DMSO)
and
positive
control
(2­
aminoanthracene,
N­
methyl­
N'nitro­
N­
nitrosoguanidine)
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.

This
study
is
classified
as
Acceptable/
Nonguideline.

4.3
Mutagenicity­
in
vitro
Cytogenetic
Assay
[OPPTS
870.5375]

MRID
No.:
41134101
Executive
Summary:
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).
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Fischer
344
rat
liver.
Tebuthiuron
was
tested
up
to
concentrations
limited
by
cytotoxicity.
A
preliminary
cytotoxicity
under
nonactivated
conditions
showed
survival
of
15%
at
2285
:
g/
mL,
39%
at
1750
:
g/
mL,
55%
at
1500
:
g/
mL,
and
115%
at
1000
:
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.
Cyclophosphamide
and
mitomycin
C
positive
11
control
values
were
acceptable.
There
was
evidence
of
an
increase
in
structural
chromosomal
aberrations
over
background
in
the
presence
and
absence
of
metabolic
activation
but
only
at
cytotoxic
concentrations.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
OPPTS
870.5375
(84­
2)
for
in
vitro
cytogenetic
mutagenicity
assay.

4.4
In
vitro
Bone
Marrow
Cytogenetic
Assay
[OPPTS
870.5300
(§
84­
2)]

MRID
No.:
00145041
Executive
Summary:
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.
The
S9­
fraction
was
obtained
from
Aroclor
1254­
induced
rats.

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.

This
study
is
classified
as
Acceptable/
Guideline.
It
does
satisfy
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5300
(§
84­
2)]
for
in
vitro
mutagenicity
(mammalian
forward
gene
mutation)
data.

4.5
UDS
Assay
­
Primary
Rat
Hepatocytes
[OPPTS
870.5550
(§
84­
2)]

MRID
No.:
40750901
Executive
Summary:
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
12
:
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.

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

4.6
Sister
Chromatid
Exchange
[OPPTS
870.5900
(§
84­
2)]

MRID
No.:
40750902
Executive
Summary:
In
an
in
vivo
cytogenetic
assay
measuring
sister
chromatid
exchange
(SCE)
frequency
in
Chinese
hamster
bone
marrow
cells
female
Chinese
hamsters
(3/
group)
were
administered
single
oral
doses
of
tebuthiuron
(99.1%,
Lot
No.
729AS7)
in
10%
aqueous
acacia
at
3000,
4000,
or
5000
mg/
kg.

Tebuthiuron
was
tested
up
to
cytotoxic
concentrations.
Hypoactivity
was
noted
in
all
treatment
groups
and
bone
marrow
cytotoxicity
(as
evidenced
by
an
increase
in
the
percent
division
metaphases)
was
observed
at
5000
mg/
kg.
There
was
no
increase
in
the
number
of
cells
containing
SCEs
compared
to
controls
at
any
concentration
of
tebuthiuron
tested.
Cyclophosphamide
(50
mg/
kg)
and
vehicle
control
values
were
acceptable.
There
was
no
evidence
of
an
increase
in
SCEs
over
background.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5915
(§
84­
2)]
for
in
vivo
cytogenetic
mutagenicity
data.

4.7
Conclusions:

The
submitted
test
battery
satisfies
the
Pre­
1991
mutagenicity
initial
testing
battery
guidelines.
Tebuthiuron
was
not
mutagenic
in
bacteria,
but
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells.
The
effect
in
mammalian
cells
was,
however,
confined
to
non­
activated
test
conditions.
There
was
also
some
evidence
of
a
clastogenic
response
at
cytotoxic
doses
both
with
and
without
S9­
activation.
Since
an
acceptable
in
vivo
bone
marrow
cytogenetic
assay
is
not
available,
final
conclusions
regarding
the
mutagenic
potential
of
tebuthiuron
can
not
be
made
at
this
time.
13
5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
toxicology
data
base
is
adequate
for
an
FQPA
assessment.
The
required
developmental
toxicity
study
in
the
rabbit
does
not
meet
guideline
requirements.

6
FQPA
CONSIDERATIONS
6.1
Neurotoxicity
Data
No
acute
or
subchronic
neurotoxicity
studies
on
tebuthiuron
are
available.
Evaluation
of
subchronic,
chronic
and
reproduction
toxicity,
did
not
indicate
any
treatment­
related
effects
on
the
central
or
peripheral
nervous
system
of
mice,
rats,
or
rabbits.
No
changes
in
clinical
signs,
brain
weights,
gross
necropsy
results
or
histopathological
results
suggested
that
any
part
of
the
nervous
system
as
a
target
organ.

6.2
Developmental
Toxicity
6.2.1
Prenatal
Developmental
Study
­
Rat
MRID
No:
00020803,
40485801
Executive
Summary:
In
a
developmental
toxicity
study,
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
on
gestation
days
(GD)
6­
15,
inclusive.
Doses
to
the
animals
were
0,
37,
72,
or
110
mg/
kg/
day
(calculated
from
body
weight
and
feed
consumption
data),
respectively.
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
one­
third
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
14
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
postimplantation
losses,
number
of
fetuses/
litter,
fetal
body
weights,
or
fetal
sex
ratios.
No
dead
fetuses
were
observed.

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.

6.2.2
Developmental
Toxicity
Study
in
the
Rabbit
MRID
No.:
00020644
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
main
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
15
groups
were
140,
5,
­37,
­72,
­103,
and
­480
g,
respectively.
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.

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.

6.3
Reproductive
Toxicity
6.3.1
Two­
Generation
Reproduction
­
Rat
MRID
No:
90108
Executive
Summary:
In
a
two­
generation
reproduction
study,
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.
16
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
2
00
and
400
ppm
groups
had
mean
weekly
body
weights
7­
9%
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
for
tebuthiuron
is
400
ppm
(30
mg/
kg/
day)
for
female
rats
based
on
deceases
in
body
weight
and
weight
gain;
the
corresponding
NOAEL
is
200
ppm
(14
mg/
kg/
day).
Parental
effect
levels
were
not
established
for
adult
male
rats
in
this
study.

No
effects
were
observed
on
reproductive
parameters
as
measured
by
sperm
morphology,
fertility
index
for
females,
and
the
number
of
litters
produced.

The
reproductive
LOAEL
for
tebuthiuron
could
not
be
established
for
this
study.
The
NOAEL
is
$
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.
Mean
litter
size
in
400
ppm
group
was
larger
than
those
for
the
control
group
and
probably
contributed
to
the
lower
body
weights.
Dosing
was
considered
to
be
barely
adequate
for
assessing
reproductive
and
offspring
toxicity.

The
offspring
LOAEL
could
not
be
established
for
this
study.
The
NOAEL
is
$
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.

6.4
Additional
Information
from
Literature
Sources
No
studies
available
17
6.5
Determination
of
Susceptibility
There
is
no
qualitative/
quantitative
evidence
of
increased
susceptibility
following
in
utero
exposure
to
rats
or
following
pre/
post
natal
exposure
to
rats
in
the
2­
generation
reproduction
study.
Susceptibility
could
not
be
assessed
due
to
the
lack
of
maternal
or
developmental
toxicity
at
the
highest
dose
tested..

6.6
Evidence
That
Suggest
Study
Requiring
a
Developmental
Neurotoxicity
Study
The
need
for
a
developmental
neurotoxicity
study
is
being
held
in
reserve,
pending
submission
of
developmental
toxicity
studies
in
the
rabbit
(data
gap).

6.7
Evidence
That
Do
Not
Suggest
Requiring
a
Developmental
Neurotoxicity
Study:

(1)
No
neurological
signs
or
neuropathy
were
observed
in
any
of
the
studies.

(2)
No
increased
susceptibility
in
rat
developmental
study.

(3)
No
increased
susceptibility
the
2­
generation
reproduction
study
in
the
rat.

7
HAZARD
CHARACTERIZATION
The
toxicological
database
for
tebuthiuron
is
not
considered
adequate
for
hazard
characterization.
The
developmental
toxicity
studies
in
the
rat
and
rabbit
as
well
as
the
chronic
feeding
study
in
the
rat
and
oncogenicity
studies
in
the
rat
and
mouse
were
found
to
be
unacceptable.
Further,
because
tebuthiuron
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells,
an
in
vivo
mammalian
bone
marrow
chromosomal
aberration
assay
is
also
required.

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.

Although
the
most
consistent
toxicological
effect
was
decreased
body
weight,
histopathological
changes
in
the
pancreas
were
observed
in
the
rat.
Vacuolation
of
pancreatic
acinar
cells
was
observed
in
both
the
subchronic
and
chronic
feeding
studies.
Vacuolation
was
described
as
slight
or
affecting
only
a
few
cells.

Subchronic
feeding
studies
are
available
in
the
rat
and
dog,
as
well
as
a
21­
day
dermal
toxicity
study
in
the
rabbit.
In
the
rat
study,
reduced
body
weight,
increases
in
relative
liver,
kidney
and
gonad
weights,
and
slight
vacuolation
of
pancreatic
acinar
cells
were
observed
in
both
sexes;
males
also
had
increased
relative
spleen
and
prostate
gland
weights.
In
the
dog
study,
anorexia,
18
weight
loss,
increases
in
blood
urea
nitrogen
and
alkaline
phosphatase,
and
increases
in
spleen
and
thyroid
gland
weights
were
observed.
In
the
21­
day
dermal
toxicity
study
in
rabbits,
no
dermal
or
systemic
toxicity
was
observed
at
1000
mg/
kg/
day
(limit
dose).

Tebuthiuron
toxicity
was
also
evaluated
in
a
combined
chronic
toxicity/
oncogenicity
study
in
the
rat
and
a
chronic
feeding
study
in
the
dog.
Decreased
body
weights
were
observed
in
both
the
rat
and
dog.
Vacuolization
of
pancreatic
acinar
cells
(generally
slight
or
affecting
only
a
few
cells)
was
observed
in
rats,
while
increased
liver
and
thyroid
weights
were
observed
in
the
dog.

At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms.
However,
these
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.

Rat
and
rabbit
developmental
toxicity
studies
were
carried
out
with
tebuthiuron.
In
the
rat,
no
compound­
related
developmental
effects
were
observed.
In
the
rabbit
susceptibility
could
not
be
evaluated
due
to
lack
of
maternal
and
developmental
toxicity
at
the
high
dose
tested.

In
a
two­
generation
study
in
the
rat,
the
only
toxicological
effect
observed
was
a
statistically
and
biologically
significant
decrease
in
the
mean
body
weight
of
throughout
the
premating
period;
no
offspring
toxicity
was
seen.

Tebuthiuron
was
not
mutagenic
in
bacteria,
but
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells.
The
effect
in
mammalian
cells
was,
however,
confined
to
nonactivated
test
conditions.
There
was
also
some
evidence
of
a
clastogenic
response
at
cytotoxic
doses
both
with
and
without
S9­
activation.
Since
an
acceptable
in
vivo
bone
marrow
cytogenetic
assay
is
not
available,
final
conclusions
regarding
the
mutagenic
potential
of
tebuthiuron
can
not
be
made
at
this
time.

8
DATAGAPS
The
HIARC
identified
the
following
data
gaps:

28­
day
inhalation
study
in
the
rat
­
due
to
potential
long­
term
inhalation
exposure
based
on
the
current
use
pattern..

Developmental
toxicity
study
in
the
rabbit
­
the
current
study
is
unacceptable
and
is
not
adequate
to
assess
susceptibility
for
FQPA.

Chronic
feeding/
oncogenicity
study
in
the
rat
­
doses
tested
were
not
adequate
to
assess
the
carcinogenic
potential.

Carcinogenicity
study
in
the
mouse
­
doses
tested
were
not
adequate
to
assess
the
carcinogenic
potential.

In
vivo
bone
marrow
chromosomal
aberration
test
­
Tier­
II
test,
required
to
verify
the
positive
response
in
the
in
vitro
chromosomal
assay.

Developmental
neurotoxicity
study
­
in
Reserve
pending
submission
of
developmental
19
toxicity
in
the
rabbit.

9
ACUTE
TOXICITY
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
sensitizing
–
20
10
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
Tebuthiuron
EXPOSURE
SCENARIO
DOSE
(mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
(Females
13­
50)
NOAEL=
25
UF
=
100
Increased
post­
implantation
loss
and
fetal/
litter
resorptions
at
50
mg/
kg/
day
(LOAEL).
Developmental
Toxicity
Study
in
the
Rabbit
Acute
RfD
(Females
13­
50
years
old)
=
0.25
mg/
kg
Acute
Dietary
(General
Population)
No
appropriate
effects
attributed
to
a
single
exposure
was
identified.

Chronic
Dietary
NOAEL
=
14
UF
=
100
Decreased
body
weight
and
feed
consumption
in
F1
females
at
30
mg/
kg/
day
(LOAEL)
2­
Generation
Reproduction
Study
in
the
Rat
Chronic
RfD
=
0.
14
mg/
kg/
day
Toxicological
endpoints
for
occupational/
residential
exposure
risk
assessments
were
not
selected
since
tebuthiuron
is
scheduled
for
a
Tolerance
Reassessment
Eligibility
Decision
(TRED)