Document ID: EPA-HQ-OPP-2002-0146-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2001-06-25T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
WASHINGTON,
D.
C.
20460
WASHINGTON,
D.
C.
20460
WASHINGTON,
D.
C.
20460
OFFICE
OF
OFFICE
OF
OFFICE
OF
OFFICE
OF
PREVENTION,
PESTICIDES
AND
PREVENTION,
PESTICIDES
AND
PREVENTION,
PESTICIDES
AND
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TOXIC
SUBSTANCES
TOXIC
SUBSTANCES
TOXIC
SUBSTANCES
22­
April­
2002
MEMORANDUM:

SUBJECT:
Tebuthiuron.
Preliminary
Human
Health
Risk
Assessment.
HED
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED).
Chemical
No.
105501.
DP
Barcode
D274580.

FROM:
Paula
A.
Deschamp,
M.
S.,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(7509C)

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

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

Attached
is
HED's
Preliminary
Human
Health
Risk
Assessment
for
the
Tebuthiuron
Tolerance
Reassessment
Eligibility
Decision
(TRED).
This
document
addresses
tolerances
subject
to
reassessment
in
accordance
with
Federal
Food
Drug
&
Cosmetic
Act
(FFDCA)
as
amended
by
the
Food
Quality
Protection
Act
of
1996
(FQPA).
The
FQPA
requires
EPA
to
re­
evaluate
existing
tolerances
to
ensure
that
children
and
other
sensitive
subpopulations
are
protected
from
pesticide
risks.
Because
FQPA
addresses
only
non­
occupational
(residential)
risk
concerns
for
food­
use
pesticides
with
established
tolerances
or
exemptions,
risks
to
workers
are
not
addressed
in
this
document.

The
human
health
risk
findings
summarized
in
this
assessment
incorporate
disciplinary
chapters
and
other
supporting
documentation
as
follows:

TRED
for
Tebuthiuron.
M.
Corbin
(11/
28/
01;
D279066)
Addendum
to
TRED
Drinking
Water
Assessment
for
Tebuthiuron.
M.
Corbin
(2/
22/
02;
D279066)
Product
Chemistry
Chapter
for
the
TRED.
K.
Dockter
(11/
15/
01;
D277104)
Residue
Chemistry
Chapter
for
the
TRED.
S.
Piper
(04/
09/
02;
D277103)
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
TRED.
S.
Piper
(04/
03/
02;
D281821)
Toxicology
Chapter
for
the
TRED.
R.
Fricke
(3/
20/
02;
D277101;
TXR
0050572)
2
Third
Report
of
the
HIARC
Committee.
R.
Fricke
(4/
16/
02;
TXR
0050672)
Report
of
the
FQPA
Safety
Factor
Committee.
Carol
Christensen
(2/
12/
02;
TXR
0050466)
The
Outcome
of
the
HED
MARC
Meeting
(2/
25/
02;
TXR
0050409)

RDI:
Team
(04/
03/
02),
BRSrSci:
Nielsen
(04/
22/
02),
RARC
(04/
03/
02)
P.
Deschamp
812D:
CM#
2:
(703)
305­
6227:
7509C:
RRB2
1.0
EXECUTIVE
SUMMARY
...................................................
1
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
.................
4
2.1
Chemical
Structure
and
Identification
of
Active
Ingredient
.................
4
2.2
Physical
Properties
..................................................
4
3.0
HAZARD
CHARACTERIZATION
............................................
4
3.1
Hazard
Profile
......................................................
4
3.2
FQPA
Considerations
..............................................
10
3.3
Dose
Response
Assessment
..........................................
10
3.4
Endocrine
Disruption
...............................................
13
4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
......................
14
4.1
Summary
of
Registered
Uses
.........................................
14
4.2
Dietary
Exposure/
Risk
Pathway
......................................
15
4.2.1
Residue
Profile
..........................................
15
4.2.2
Dietary
Exposure
........................................
19
4.2.2.1
Acute
Dietary
Exposure
Analysis
..........................
20
4.2.2.2
Chronic
Dietary
Exposure
Analysis
........................
20
4.2.2.3
Cancer
Dietary
Exposure/
Risk
............................
21
4.3
Water
Exposure/
Risk
Pathway
.......................................
21
4.4
Residential
Exposure/
Risk
Pathway
...................................
23
4.4.1
Other
Non­
Occupational
Exposure
..........................
23
5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATIONS
.......
24
5.1
Acute
Risk
........................................................
24
5.1.1
Aggregate
Acute
Risk
Assessment
...........................
24
5.1.2
Acute
DWLOC
Calculations
................................
24
5.2
Short­
and
Intermediate­
Term
Risk
...................................
25
5.3
Chronic
Risk
......................................................
25
5.3.1
Aggregate
Chronic
Risk
Assessment
.........................
25
5.3.2
Chronic
DWLOC
Calculations
..............................
25
6.0
CUMULATIVE
............................................................
26
7.0
OCCUPATIONAL
EXPOSURE
..............................................
27
8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
....................................
28
1
Tebuthiuron
(PC
Code
105501)
Preliminary
Human
Health
Risk
Assessment
HED
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)

1.0
EXECUTIVE
SUMMARY
The
following
human
health
risk
assessment
has
been
prepared
by
the
Health
Effects
Division
(HED)
for
Phase
1
(Registrant
Error
Correction)
of
the
tolerance
reassessment
eligibility
decision
(TRED)
process
for
tebuthiuron.
The
Tebuthiuron
Reregistration
Standard
Guidance
Document
was
issued
6/
94.

Tebuthiuron
is
a
non­
selective
substituted
urea
herbicide.
The
mechanism
of
herbicidal
action
is
the
inhibition
of
photosynthesis.
Unlike
other
substituted
ureas
such
as
fluometuron,
diuron,
and
linuron,
tebuthiuron
contains
a
dimethyl
thiadiazole
moiety
and
does
not
degrade
or
metabolize
to
3,4­
dichloroaniline.
Tebuthiuron
controls
broadleaf
and
grassy
weeds
and
woody
plants.
Use
sites
include
pastureland/
rangeland,
non­
crop
industrial
areas
such
as
highways,
fence
rows,
firebreaks,
utility
rights­
of­
ways,
railroad
rights­
of­
ways,
and
clearings
for
wildlife
habitat.
Pastureland/
rangeland
in
TX,
OK
and
NM
is
the
primary
use
site.
End­
use
formulations
include
granular,
pelleted/
tablets,
and
wettable
powder
products
which
are
applied
using
ground
and
aerial
equipment.

The
only
source
of
dietary
(food)
exposure
is
the
consumption
of
secondary
residues
in
meat
and
milk
from
livestock
fed
tebuthiuron­
treated
grass
forage
and
hay.
Tolerances
in
meat
and
milk
are
established
at
2
ppm
and
in
grass
forage
and
hay
at
10
ppm
for
residues
of
tebuthiuron
and
its
metabolites
containing
the
dimethyl
thiadiazole
moiety.
There
are
no
registered
residential
uses.

Hazard
Profile,
Dose/
Response
Analysis,
and
FQPA
Considerations
The
toxicology
database
for
tebuthiuron
is
not
complete,
but
provides
sufficient
information
to
adequately
identify
hazards
for
risk
assessment
purposes.
The
acute
toxicity
studies
indicate
that
tebuthiuron
is
more
toxic
for
oral
(Category
II)
exposure
than
for
either
dermal
(Category
IV)
or
inhalation
(Category
III)
exposure.
Tebuthiuron
is
not
an
eye
or
skin
irritant
and
not
a
skin
sensitizer.
In
a
21­
day
dermal
toxicity
study
in
rabbits,
no
dermal
or
systemic
toxicity
was
observed
at
the
limit
dose
of
1000
mg/
kg/
day.
In
subchronic
and
chronic
toxicity
studies
in
the
rat
the
most
consistent
toxicological
effect
was
decreased
body
weight;
however,
histopathological
changes
in
the
pancreas
were
also
observed.
In
subchronic
and
chronic
toxicity
studies
in
the
dog,
anorexia,
decreased
body
weight,
clinical
chemistry
effects,
and
increased
organ
weights
were
observed.
There
was
no
qualitative/
quantitative
evidence
of
increased
susceptibility
in
rat
developmental
and
reproduction
studies;
however
susceptibility
could
not
as
assessed
in
the
rabbit.

The
classification
of
tebuthiuron
as
a
Group
D,
not
classifiable
as
to
human
carcinogenicity,
was
reevaluated
by
HIARC.
At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms;
however,
the
HIARC
concluded
that
the
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.
Tebuthiuron
was
not
mutagenic
in
bacteria,
but
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
sells.
The
effect
in
mammalian
cells
was,
however,
confined
to
non­
activated
test
conditions.
There
was
also
some
2
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.
HED
has
requested
new
carcinogenicity
studies
in
rats
and
mice
and
an
in
vivo
mammalian
bone
marrow
chromosomal
aberration
test
as
confirmatory
data.

A
dose
level
of
25
mg/
kg/
day
was
selected
for
acute
dietary
risk
assessment
based
on
increased
post­
implantation
loss
and
fetal/
litter
resorptions
observed
at
50
mg/
kg/
day
in
the
rabbit
developmental
study.
A
dose
level
of
14
mg/
kg/
day
was
selected
for
chronic
dietary
risk
assessment
based
on
decreased
body
weight
and
feed
consumption
observed
at
30
mg/
kg/
day
in
F1
females
in
a
2­
generation
rat
reproduction
study.
An
uncertainty
factor
(UF)
of
100
was
applied
to
all
doses
selected
for
risk
assessment
purposes
to
account
for
interspecies
extrapolation
(10x)
and
intraspecies
variability
(10x).

The
FQPA
Safety
Factor
Committee
recommended
that
the
FQPA
Safety
Factor
be
reduced
to
3x
when
assessing
acute
dietary
exposure
to
females
13­
50
years
old
because
there
is
a
data
gap
for
the
susceptibility
of
fetuses
following
in
utero
exposure
to
tebuthiuron.
The
Committee
also
recommended
that
the
safety
factor
be
removed
(1x)
when
assessing
chronic
dietary
exposure
to
the
general
U.
S.
population
and
all
population
subgroups.

Exposure
and
Risk
Contributions
from
the
Food
Pathway
HED
did
not
identify
any
risk
concerns
from
exposure
to
tebuthiuron
in
food.
The
acute
and
chronic
dietary
risk
estimates
associated
with
the
use
of
tebuthiuron
do
not
exceed
HED's
level
of
concern
(!100%)
for
any
population
subgroup.
A
Tier
2
deterministic
chronic
dietary
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
Inputs
to
the
dietary
analysis
included
anticipated
residues
(ARs)
from
field
trials
and
livestock
feeding
studies.
Maximum
and
weighted
average
estimates
of
percent
crop
treated
were
incorporated
into
the
acute
and
chronic
assessments,
respectively.
The
calculated
chronic
dietary
exposure
(residue
x
consumption)
was
compared
to
a
chronic
population
adjusted
dose
(cPAD)
of
0.14
mg/
kg/
day,
which
reflects
a
FQPA
factor
of
1x
for
the
general
U.
S.
population
and
all
population
subgroups.
The
chronic
dietary
exposure
estimate
for
the
general
U.
S.
population
and
all
subgroups
was
<1%
of
the
cPAD.
The
acute
dietary
exposure
was
compared
to
an
acute
population
adjusted
dose
(aPAD)
of
0.083
mg/
kg/
day.
The
acute
dietary
risk
estimates
associated
with
the
use
of
tebuthiuron
do
not
exceed
HED's
level
of
concern
for
females
13­
50
years
old.
The
acute
dietary
risk
estimate
for
this
population
subgroup
is
<1%
of
the
aPAD.

Exposure
and
Risk
Contributions
from
the
Water
Pathway
HED
did
not
identify
any
acute
or
chronic
risk
concerns
from
exposure
to
tebuthiuron
in
drinking
water.
Tebuthiuron
and
its
dimethyl
thiadiazole­
containing
degradate
(Compound
104)
are
persistent
and
mobile.
The
Environmental
Fate
and
Effects
Division
(EFED)
Tier
II
(PRZM/
EXAMS)
surface
water
modeling
for
residues
of
tebuthiuron
and
its
degradate
104
using
the
index
reservoir
with
the
percent
cropped
area,
predicts
the
1
in
10
year
peak
(acute)
3
concentration
of
tebuthiuron
is
not
likely
to
exceed
15.5
!g/
L.
The
1
in
10
year
annual
average
concentration
(non­
cancer
chronic)
of
tebuthiuron
is
not
likely
to
exceed
4.3
!g/
L.
The
SCIGROW
predicted
concentration
of
tebuthiuron
and
its
degradate
104
in
ground
water
is
not
expected
to
exceed
245
µg/
L.

Aggregate
Risk
Assessments
HED
did
not
identify
any
aggregate
risk
concerns.
The
aggregate
acute
and
aggregate
chronic
dietary
risk
estimates
include
exposure
to
residues
of
tebuthiuron
in
food
and
water.
No
short­,
intermediate­
or
long­
term
residential
use
scenarios
were
identified.
Acute
dietary
(food)
exposure
is
<1%
of
the
aPAD
for
females
13­
50.
Chronic
dietary
(food)
exposure
is
<1%
of
the
chronic
PAD
for
the
general
U.
S.
population
and
all
population
subgroups.
The
estimated
acute
and
chronic
EECs
in
ground
and
surface
water
are
less
than
the
drinking
water
levels
of
comparison
indicating
that
acute
and
chronic
aggregate
exposures
to
tebuthiuron
do
not
exceed
HED's
level
of
concern.

Data
Gaps
and
Uncertainties
Toxicology
data
gaps
include
a
developmental
toxicity
study
in
rabbit,
as
well
as
the
chronic
feeding/
carcinogenicity
study
in
the
rat
and
oncogenicity
study
in
the
mouse;
all
of
these
studies
were
found
to
be
unacceptable.
Although
tebuthiuron
was
not
mutagenic
in
bacteria,
it
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells,
but
only
under
non­
activated
test
conditions.
An
in
vivo
bone
marrow
cytogenetic
assay
is
needed
to
fully
evaluate
the
mutagenic
potential
of
tebuthiuron.
Further,
a
28­
day
inhalation
study
in
the
rat
is
required
to
characterize
the
effects
of
tebuthiuron
via
the
inhalation
route,
and
the
requirement
for
a
developmental
neurotoxicity
study
is
being
held
in
reserve,
pending
submission
of
the
rabbit
developmental
toxicity
study.

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
other
long­
term
toxicity
studies,
doses
of
50
mg/
kg/
day
(1­
year
dog)
and
80
mg/
kg/
day
(2­
year
rat)
were
identified
as
LOAELs;
a
LOAEL
was
not
established
in
the
78­
week
mouse
oncogenicity
study
at
the
highest
dose
tested
(240
mg/
kg/
day).
Based
on
this
weight­
of­
evidence,
the
HIARC
inferred
that
a
repeat
study
in
rats
at
higher
dose
would
provide
hazard
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.

Although
there
are
some
uncertainties
regarding
the
carcinogenic
potential
of
tebuthiuron,
HED
has
elected
not
to
quantify
cancer
risk
at
this
time
because
the
dose
levels
used
in
the
available
carcinogenicity
studies
were
sufficient
to
decrease
any
cancer
risk
concerns.
HED
has
requested
new
carcinogenicity
studies
in
rats
and
mice
and
an
in
vivo
mammalian
bone
marrow
chromosomal
aberration
test
as
confirmatory
data.
4
N
N
S
N
CH
3
CH
3
C
H
3
O
NH
2
OH
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
2.1
Chemical
Structure
and
Identification
of
Active
Ingredient
Chemical
Name:
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N,
N'­
dimethylurea
Common
Name:
Tebuthiuron
PC
Code
Number:
105501
CAS
Registry
No.:
34014­
18­
1
Chemical
Class:
Phenylurea
Chemical
Type:
Herbicide
Trade
Names:
Spike
Mode
of
Action:
Photosynthetic
inhibitor
which
causes
disruption
of
cell
membranes
Empirical
formula:
C9H16N4OS
Molecular
weight:
228.3
2.2
Physical
Properties
Tebuthiuron
is
a
solid
at
room
temperature
with
a
low
vapor
pressure;
thus,
any
losses
due
to
volatilization/
sublimation
are
expected
to
be
minimal.
Preliminary
analysis
data
indicate
there
are
no
impurities
of
toxicological
concern
in
tebuthiuron
technical
material.
A
detailed
list
of
the
physical
properties
of
tebuthiuron
technical
is
provided
below:

Color:
off­
white
Physical
state:
crystalline
solid
Odor:
pungent
MP:
161.5­
164C
Bulk
Density:
0.
579
g/
cc
Water
solubility:
2.
5
mg/
mL
@25C
Vapor
Pressure:
2
x
10
­6
mm
Hg
@
25C
log
Pow:
1.
79
Stability:
Stable
for
3
yrs
at
normal
temperatures.

3.0
HAZARD
CHARACTERIZATION
3.1
Hazard
Profile
The
toxicology
database
for
tebuthiuron
is
not
complete,
but
provides
sufficient
information
to
adequately
identify
hazards
for
risk
assessment
purposes.
Toxicology
data
gaps
include
a
developmental
toxicity
study
in
rabbit,
as
well
as
the
chronic
feeding/
carcinogenicity
study
in
the
rat
and
oncogenicity
study
in
the
mouse;
all
of
these
studies
were
found
to
be
unacceptable.
Although
5
tebuthiuron
was
not
mutagenic
in
bacteria,
it
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells,
but
only
under
non­
activated
test
conditions.
An
in
vivo
bone
marrow
cytogenetic
assay
is
needed
to
evaluate
the
mutagenic
potential
of
tebuthiuron.
A
28­
day
inhalation
study
in
the
rat
is
required
to
characterize
the
effects
of
tebuthiuron
via
the
inhalation
route.
Further,
the
requirement
for
a
developmental
neurotoxicity
study
is
being
held
in
reserve,
pending
submission
of
the
rabbit
developmental
toxicity
study.

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)
dog
study,
clinical
signs
of
toxicity
(emesis
anorexia,
and
diarrhea
),
decreased
body
weight,
increased
alanine
aminotransferase
(ALT)
and
alkaline
phosphatase
(ALP)
(males
only),
increased
absolute
and
relative
liver
weights,
and
increased
relative
kidney
(females
only)
and
thyroid
(males
only)
weights.
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.
At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms.
However,
the
HIARC
(TXR
No.
0050672,
April
16,
2002)
concluded
that
the
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.
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.

In
a
rat
metabolism
study
with
14
C­
tebuthiuron,
absorption
was
complete;
excretion
was
rapid
in
both
sexes,
but
was
delayed
during
the
first
12
hours
post­
dose,
indicating
saturation
of
biotransformation
or
excretion.
At
termination,
no
significant
amounts
of
residual
radioactivity
remained
in
any
tissue
examined,
but
the
skin
showed
the
highest
amounts
relative
to
other
tissues.
Six
metabolites
of
tebuthiuron
were
identified.
The
major
urinary
metabolites
were
identified
as
hydroxylated
tebuthiuron
metabolites.
A
summary
of
the
findings
from
acute
toxicity
tests
is
presented
in
Table
1
and
a
summary
of
the
findings
from
the
subchronic,
chronic,
mutagenicity
and
other
toxicity
studies
is
presented
in
Table
6
2.

Table
1.
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
–
7
Table
2.
Subchronic,
Chronic,
and
Other
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicity­
rat
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
toxicity­
dog
00020663
(1972)
Acceptable/
Guideline
0,
12.5,
25,
50
mg/
kg/
day
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)

870.4100
[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.

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)
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
Table
2.
Subchronic,
Chronic,
and
Other
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
8
870.3700
[83­
3(
b)]
Developmental
Toxicity
­
Rabbit
(Range­
finding)
40776301
(1988)

5,
10,
20,
25,
50,
100
mg/
kg/
day
Mated
rabbits
(4/
group).
Three
animals
in
the
100
mg/
kg/
day
group
died
or
were
killed
moribund
on
GD
8­
10.
The
percentage
of
early
resorptions
in
the
25,
50,
and
100
mg/
kg/
day
groups
was
68.8,
66.7
and
100%,
respectively.

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
870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00141691
(1984)
Acceptable/
Guideline
There
was
no
increase
in
mutant
frequency
in
tested
bacterial
strains
exposed
up
to
the
limit
dose
(5000
!g/
plate)
with
or
without
S9
activation.

870.5100
Bacterial
reverse
gene
mutation
assay
MRID
00141690
(1984)
Acceptable/
Non­
Guideline
There
was
no
increase
in
mutant
frequency
in
any
S.
typhimurium
or
E.
coli
tested
strain
exposed
to
tebuthiuron
(98.0%,)
with
or
without
metabolic
activation.
There
was
no
evidence
of
induced
mutant
colonies
over
background
in
tested
S.
typhimurium
strains
and
E.
coli
strains
with
or
without
S9
activation.

870.5300
In
vitro
mammalian
cell
gene
mutation
MRID
00145041
(1984)
Acceptable/
Guideline
In
a
mammalian
cell
gene
mutation
assay
in
vitro,
cultures
of
mouse
lymphoma
were
exposed
to
Tebuthiuron
(98.0%)
technical
at
concentrations
limited
by
cytotoxicity.
Mutations
were
not
induced
at
any
concentration
with
activation.
Tebuthiuron
was
considered
weakly
mutagenic
but
only
in
the
absence
of
metabolic
activation.
No
evidence
of
an
increased
mutant
frequency
was
observed
in
the
presence
of
metabolic
activation.

870.5550
Unscheduled
DNA
synthesis
in
mammalian
cell
culture
MRID
40750901
Acceptable/
Guideline
MRID
40750901
(1988)
Acceptable/
Guideline
In
an
unscheduled
DNA
synthesis
assay,
primary
rat
hepatocyte
cultures
were
exposed
to
Tebuthiuron
(99.1%
)
to
the
limit
of
cytotoxicity
(
!900
!g/
mL).
UDS
activity
was
evaluated
at
concentrations
up
to
800
!g/
mL
and
there
was
no
evidence
of
induction
of
UDS.
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[nuclear
silver
grain
counts]
was
induced.

870.5375
In
vitro
mammalian
cell
chromosome
aberration
MRID
41134101
(1989)
Acceptable/
Guideline
In
a
mammalian
chromosome
aberration
assay,
Chinese
Hamster
Ovary
(CHO)
cell
cultures
were
exposed
to
Tebuthiuron
(99.08%)
at
concen
trations
limited
by
cytotoxicity.
A
significant
increase
in
the
percent
of
cells
with
aberrations
was
noted
in
nonactivated
and
activated
cultures
at
cytotoxic
doses.
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
at
cytotoxic
doses.
Table
2.
Subchronic,
Chronic,
and
Other
Toxicity
Table
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
9
870.5915
In
vivo
sister
chromatid
exchange
MRID
40750902
(1988)
Acceptable/
Guideline
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.

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.
10
3.2
FQPA
Considerations
The
HED
FQPA
Safety
Factor
Committee
met
on
February
4,
2002
to
evaluate
the
hazard
and
exposure
data
for
tebuthiuron.
The
Committee
recommended
that
the
FQPA
safety
factor
(as
required
by
the
Food
Quality
Protection
Act
of
August
3,
1996)
be
reduced
to
3x
when
assessing
the
risk
posed
by
this
chemical
for
the
following
reasons:

"
there
is
no
indication
of
quantitative
or
qualitative
increased
susceptibility
of
rats
to
in
utero
exposure;

"
there
is
no
indication
of
quantitative
or
qualitative
increased
susceptibility
of
rat
offspring
seen
in
the
two­
generation
reproductive
toxicity
study;

"
the
dietary
(food
and
drinking
water)
exposure
assessments
will
not
underestimate
the
potential
exposures
for
infants
and
children;
and
"
there
is
a
data
gap
for
a
developmental
toxicity
study
in
the
rabbit.

The
reduced
FQPA
safety
factor
of
3x
is
required
when
assessing
acute
dietary
exposure
to
females
13­
50.
This
is
because
there
is
a
data
gap
for
assessing
susceptibility
of
fetuses
following
in
utero
exposure
to
tebuthiuron.
When
assessing
chronic
dietary
exposure
to
the
general
population,
the
FQPA
safety
factor
will
be
removed
(1x).
This
is
because
there
was
no
susceptibility
identified
in
the
2­
generation
rat
reproduction
study
(a
long­
term
study).

3.3
Dose
Response
Assessment
On
December
13,
2001,
January
17,
2002,
and
February
12,
2002
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
toxicology
database
of
tebuthiuron
and
selected
the
doses
and
toxicological
endpoints
summarized
in
Table
3
for
use
in
risk
assessments.
Also
included
in
this
table
is
the
FQPA
safety
factor
selected
by
the
FQPA
Safety
Factor
Committee
on
February
4,
2002.
This
table
is
followed
by
rationales
for
the
selection
of
endpoints
and
doses.
11
aRfD
FQPA
SF
aPAD=

cRfD
FQPA
SF
cPAD=
Table
3.
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).
12
Acute
Reference
Dose
(RfD)
Females
13­
50
years
old
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
UC
77179
decreased
body
weight
gain,
lethality
and
early
resorption
were
observed.

Acute
Reference
Dose
(RfD)
General
U.
S.
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.

It
should
be
noted
that
HED
considers
the
finding
of
a
lower
acute
RfD
than
the
chronic
RfD
to
be
an
artifact
of
the
available
data.
The
lower
acute
RfD
is
due
to
the
use
of
an
additional
3x
uncertainty
factor
for
the
acute
assessment
(due
to
the
lack
of
an
acceptable
rabbit
developmental
study).
HED
considered
the
results
from
the
chronic
study
with
those
of
the
acute
studies
and
determined
that
the
cPAD
at
the
higher
dose
level
is
adequately
protective
of
females
13­
50
for
both
the
chronic
toxic
effect
(decreased
body
weight
and
feed
consumption)
and
the
acute
toxic
effect
(increased
early
resorptions).

Chronic
Reference
Dose
(RfD)
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
a
repeat
study
in
rats
at
higher
dose
would
provide
hazard
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.
13
Classification
of
Carcinogenic
Potential
The
classification
of
tebuthiuron
as
a
Group
D,
not
classifiable
as
to
human
carcinogenicity,
was
reevaluated
by
HIARC.
At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms;
however,
the
HIARC
concluded
that
the
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.

While
there
is
evidence
that
other
registered
substituted
urea
compounds
are
mutagenic
and
show
carcinogenic
potential,
a
conclusive
SAR
analogy
between
these
compounds
and
tebuthiuron
cannot
be
drawn
because
tebuthiuron
contains
a
thiadiazole
moiety
and
the
other
substituted
ureas
do
not.
An
unregistered
sulfonamide
compound
(UC77179),
shown
to
induce
thyroid
adenomas
in
rats,
also
bears
some
structural
similarities
to
tebuthiuron.
However,
comparison
of
tebuthiuron
and
UC77179
genotoxicity
data
does
not
support
a
strong
SAR
analogy.
Compound
UC77179
caused
gene
mutation
is
an
Ames
assay,
produced
chromosomal
damage
in
cultured
Chinese
Hamster
Ovary
(CHO)
cells,
and
was
negative
in
other
mutagenicity
tests.
Tebuthiuron
was
not
mutagenic
in
bacteria,
but
was
weakly
positive
for
gene
mutations
in
cultured
mouse
lymphoma
cells.
There
was
also
some
evidence
of
a
clastogenic
response
at
cytotoxic
doses
both
with
and
without
S9
activation.

Although
there
are
some
uncertainties
regarding
the
carcinogenic
potential
of
tebuthiuron,
HED
has
elected
not
to
quantify
cancer
risk
at
this
time
because
the
dose
levels
used
in
the
available
carcinogenicity
studies
were
sufficient
to
decrease
any
cancer
risk
concerns.
HED
has
requested
new
carcinogenicity
studies
in
rats
and
mice
and
an
in
vivo
mammalian
bone
marrow
chromosomal
aberration
test
as
confirmatory
data.

3.4
Endocrine
Disruption
EPA
is
required
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(including
all
pesticide
active
and
other
ingredients)
"may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(EDSP).

In
the
available
toxicity
studies
on
tebuthiuron,
there
was
no
evidence
of
endocrine
disruptor
effects.
When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
tebuthiuron
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.
14
4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
4.1
Summary
of
Registered
Uses
Tebuthiuron
is
a
non­
selective
substituted
urea
herbicide
that
provides
long­
term
control
of
annual
and
perennial
grasses,
herbaceous
plants
and
woody
brush.
Use
sites
include
pastureland/
rangeland,
non­
crop
industrial
areas
such
as
highways,
fence
rows
firebreaks,
utility
rights­
of­
ways,
railroad
rights­
of­
ways,
and
clearings
for
wildlife
habitat;
there
is
no
agricultural
crop
use
of
tebuthiuron
except
for
range
and
pasture
land
uses.
The
primary
use
site
is
pastureland/
rangeland
in
TX,
OK
and
NM.
Based
on
a
search
of
OPP's
REFS
conducted
on
22­
March­
2002,
there
are
eight
active
Section
3
registrations
for
end­
use
products
containing
tebuthiuron.
End­
use
formulations
include
granular,
pelleted/
tablets,
and
wettable
powder
products
which
are
applied
using
ground
and
aerial
equipment.

In
a
SMART
meeting
on
2­
May­
2001,
Dow
AgroSciences
expressed
their
intention
to
support
all
currently
registered
uses
and
products
of
tebuthiuron.
A
summary
of
the
currently
registered
enduse
products
and
use
sites
is
given
in
the
table
below:

Company
EPA
Reg.
No.
Formulation
Class
%
ai
Use
Sites
Rainbow
Technology
Corp.
13283­
18
Granular
2
Industrial
areas
(outdoor)
Nonag
rights­
of­
way/
fencerows/
hedgerows
13283­
21
Granular
1
Industrial
areas
(outdoor)
Nonag
rights­
of­
way/
fencerows/
hedgerows
SSI
Maxim
Company,
Inc.
34913­
10
Granular
5
Drainage
systems
Nonag
uncultivated
areas/
soils
34913­
15
Granular
1
Nonag
uncultivated
areas/
soils
34913­
16
Granular
2
Nonag
uncultivated
areas/
soils
Dow
AgroSciences
LLC
62719­
107
Wettable
Powder
80
Drainage
systems
Nonag
uncultivated
areas/
soils
62719­
121
Pelleted/
Tableted
20
Pasture/
rangeland
Nonag
uncultivated
areas/
soils
62719­
122
Pelleted/
Tableted
40
Pasture/
rangeland
Nonag
uncultivated
areas/
soils
15
The
20%
and
40%
P/
T
formulations
are
registered
for
a
single
broadcast
application
to
rangeland
and
forage
grasses
by
aerial
or
ground
equipment
at
0.5­
4.00
lb
ai/
A.
Tebuthiuron
may
be
applied
anytime
but
the
recommended
timing
of
application
is
prior
to
the
resumption
of
active
seasonal
growth
in
the
spring
or
before
expected
seasonal
rainfall.
The
maximum
recommended
rate
is
4.0
lb
ai/
A
for
areas
receiving
>20
inches
average
annual
rainfall,
or
2.0
lb
ai/
A
for
areas
receiving
<20
inches
average
annual
rainfall.
Application
to
ditches
used
to
transport
irrigation
or
potable
water
is
prohibited.
Treated
grasses
may
not
be
cut
for
hay
for
livestock
feed
for
one
year
after
treatment.

4.2
Dietary
Exposure/
Risk
Pathway
A
refined
acute
and
chronic
dietary
exposure
assessment
was
conducted
for
tebuthiuron
registered
for
foliar
application
to
pastures
and
rangeland
(secondary
transfer
to
livestock
commodities).
Anticipated
residues
from
livestock
feeding
studies,
residue
field
trials,
and
percent
crop
treated
data
were
utilized
to
estimate
the
dietary
exposure
to
tebuthiuron
in
the
diets
of
the
U.
S.
Population
(chronic)
and
females
13­
50
years
old
(acute
only).

4.2.1
Residue
Profile
Tolerances
for
residues
of
tebuthiuron
have
been
established
for
grasses
and
animal
commodities
[40
CFR
§180.390].
These
tolerances
are
expressed
in
terms
of
the
combined
residues
of
N­[
5
1,1diemthylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N,
N'­
dimethylurea
and
its
metabolites
containing
the
dimethylethyl
thiadiazole
moiety.

No
Codex
MRLs
have
been
established
or
proposed
for
residues
of
tebuthiuron.
Therefore,
issues
of
compatibility
with
respect
to
U.
S.
tolerances
and
Codex
MRLs
do
not
exist.

For
dietary
risk
assessment,
the
Metabolism
Committee
concluded
that
the
residue
of
concern
in
plants
are
the
parent
compound
and
its
metabolites
103,
103(
OH),
104,
and
109.
The
residue
of
concern
in
livestock
commodities
(fat,
meat,
kidney,
and
liver)
are
tebuthiuron
and
its
metabolites
104,
106,
108,
and
109;
the
terminal
residues
of
concern
in
milk
are
tebuthiuron
and
metabolites
104,
104(
OH),
106,
109,
and
109(
OH).
MARC
revisited
N.
Dodd's
memo,
"Nature
of
the
Residue
in
Milk
and
Bovine
Tissues,"
dated
6/
22/
89
and
determined
the
parent
compound
and
its
metabolites
103
(OH),
104,
and
109
should
also
be
included
in
the
risk
assessment
(3/
28/
02;
MARC
members
C.
Olinger,
L.
Cheng,
R.
Loranger
and
D.
Nixon).

GLN
860.1300:
Nature
of
the
Residue­
Plants
The
qualitative
nature
of
the
residue
in
grasses
is
adequately
understood.
The
registrant
(1976;
MRID
00020756)
submitted
a
"revised"
metabolism
study
in
which
a
[
14
C]
tebuthiuron
solution
(labeled
in
the
5­
position
of
the
thiadiazole
ring;
specific
activity
of
16.9
uCi/
mg)
was
applied
to
the
surface
of
the
soil
in
which
10­
week
old
tall
fescue
(0.374
lb
ai/
A),
little
bluestem
and
indiangrass
(0.75
lb
ai/
A.)
were
grown.
The
residues
of
concern
are
the
parent
compound
and
its
metabolites
103
(OH),
104,
and
109
(N.
Dodd,
12/
10/
87).
16
Tebuthiuron
was
the
most
abundant
14
C­
residue
recovered
in
the
organosoluble
fraction
of
the
grass
extract.
Other
metabolites
identified
in
the
organosoluble
fraction
from
all
three
grass
species
were
103(
OH),
104,
and
109.
Approximately
39­
86%
of
the
total
14
C­
activity
of
all
grasses
was
identified
from
the
organosoluble
fraction.
The
metabolites
which
were
recovered
and
identified
by
acid
hydrolysis
of
the
aqueous
fraction
were
103(
OH),
104,
and
l04(
0H).
The
predominant
conjugate
in
little
bluestem
was
103(
OH)
while
104
was
the
major
conjugate
in
indiangrass.
One
additional
metabolite,
isopropyl
103,
was
found
in
the
hydrolysates
of
the
aqueous
fraction
of
little
bluestem.
Based
on
the
14
C­
residues
identified
in
the
organosoluble
and
aqueous
fractions,
approximately
81­
89,
58­
70,
and
78­
80%
of
the
total
14
C­
activity
found
in
tall
fescue,
little
bluestem,
and
indiangrass,
respectively,
was
identified.
In
summary,
two
major
metabolic
pathways
are
involved:
N­
demethylation
of
tebuthiuron
to
form
104
and
alkyl
hydroxylation
of
the
dimethylethyl
side
chain
to
form
103(
OH).
The
molecular
structures
of
the
metabolites
of
concern
are
presented
in
Table
4.

GLN
860.1300:
Nature
of
the
Residue­
Animals
The
qualitative
nature
of
the
residue
in
milk
and
ruminant
tissues
is
adequately
understood.
The
terminal
residues
of
concern
in
fat,
meat,
kidney,
and
liver
are
tebuthiuron
and
its
metabolites
104,
106,
108,
and
109;
the
terminal
residues
of
concern
in
milk
are
tebuthiuron
and
metabolites
104,
104
(OH),
106,
109,
and
A
[109
(OH)]
(N.
Dodd,
MRIDs
40985001
and
40985002,
6/
22/
89).
A
poultry
metabolism
study
is
not
required
since
grasses
are
not
considered
to
be
poultry
feed
items.

A
metabolism
study
was
conducted
on
one
cow
dosed
by
capsule
containing
[
14
C]
tebuthiuron
labeled
in
the
5­
position
of
the
thiadiazole
ring
at
a
calculated
feeding
level
of
50
ppm.
Doses
were
administered
every
12
hours
(morning
and
evening)
for
3
consecutive
days.
The
cow
was
sacrificed
12
hours
after
the
final
dose.
The
percentage
of
the
total
radioactivity
which
was
identified
was
82.7
percent
in
fat,
87.2
percent
in
lean,
83.2
percent
in
liver,
and
91.0
percent
in
kidney.
The
predominant
residues
in
milk
(days
1,
2,
and
3)
as
a
percentage
of
TRR
were
metabolites
104
(21%),
106
(21­
26%),
104(
OH)
(10­
16%),
109
(10­
12%),
and
109
(OH)
(8­
12%).
Parent
tebuthiuron
was
present
at
about
1%
of
the
TRR.
17
N
N
S
N
CH
3
CH
3
C
H
3
O
N
H
CH
3
OH
N
N
S
NH
2
CH
3
C
H
3
C
H
3
N
N
S
N
CH
3
CH
3
C
H
3
C
H
3
O
NH
2
N
N
S
N
CH
3
CH
3
C
H
3
C
H
3
O
N
H
OH
N
N
S
N
CH
3
CH
3
C
H
3
O
NH
2
OH
N
N
S
N
CH
3
CH
3
C
H
3
O
N
H
OH
OH
N
N
S
N
H
CH
3
C
H
3
C
H
3
O
NH
2
Table
4.
The
chemical
structures
of
the
metabolites
of
concern
of
tebuthiuron.
Structure
Metabolite:
Chemical
name
Structure
Metabolite:
Chemical
name
103
(OH):
N­[
5­(
2­
hydroxy­
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N,
N
dimethylurea
108:
2­
dimethylethyl­
5­
amino­
1,3,4­
thiadiazole
104:
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol
2­
yl]­
N­
methylurea
109:
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol
2­
yl]­
N'­
hydroxymethyl­
N­
methylurea
104
(OH):
N­[
5­(
2­
hydroxy­
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N
methylurea
A
[109
(OH)]:
N­[
5­(
2­
hydroxy­
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N
hydroxymethyl­
N­
methylurea
106:
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol
2­
yl]
urea
18
GLN
860.1340:
Residue
Analytical
Methods
­
Plants
and
Animals
An
adequate
method
is
available
for
the
enforcement
of
plant
commodity
tolerances.
A
GLC
method
with
flame
photometric
detection
is
designated
as
Method
II
in
PAM
Vol.
II.
Tebuthiuron
and
metabolites
104
and
109
are
thermally
degraded
on
the
GLC
column
and
are
determined
as
5­
(1,1­
dimethylethyl)­
N­
methyl­
1,3,4­
thiadiazol­
2­
amine;
metabolite
103
(OH)
is
determined
as
5­(
2­
hydroxy­
1,1­
dimethylethyl)­
N­
methyl­
1,3,4­
thiadiazol­
2­
amine.
The
stated
detection
limits
are
0.1
ppm
for
tebuthiuron
and
metabolites
104
and
109,
and
0.2
ppm
for
metabolite
103
(OH).
A
revised
enforcement
method
for
milk,
to
include
hydrolysis
steps
and
the
determination
of
metabolites
104
(OH)
and
A
[109
(OH)],
and
a
revised
enforcement
method
for
animal
tissues,
to
include
hydrolysis
steps
and
the
determination
of
metabolite
108,
have
been
submitted.

GLN
860.1480:
Magnitude
of
the
Residue
in
Meat,
Milk,
Poultry
and
Eggs
The
reregistration
requirements
for
data
depicting
magnitude
of
the
residue
in
milk,
eggs,
and
livestock
tissues
are
fulfilled
and
the
data
demonstrate
a
transfer
of
tebuthiuron
residues
to
animal
tissue
(meat,
meat
by­
products,
etc.).
An
acceptable
ruminant
feeding
study
(S.
Funk,
D217379,
12/
05/
95)
has
been
submitted.
The
results
of
the
ruminant
feeding
study
conducted
at
a
nominal
45
ppm
tebuthiuron
feeding
level
(1.5x)
for
28
days
show
that
the
existing
tolerances
for
milk
and
meat
are
inadequate
and
that
they
should
be
revised.
The
tolerances
for
meat
and
fat
may
be
lowered,
but
the
tolerances
for
milk
and
meat
byproducts
must
be
increased.
For
details,
refer
to
Appendix
A
Table
1:
Tolerance
Reassessment
Summary
for
Tebuthiuron.

No
poultry
of
swine
feed
items
are
associated
with
the
registered
uses
on
grass;
therefore,
there
is
no
reasonable
expectation
of
detectable
residues
of
tebuthiuron
and
its
metabolites
in
poultry,
swine,
and
eggs
resulting
from
the
use
patterns
being
considered
for
reregistration.
These
uses
for
poultry,
swine,
and
eggs
can
be
classified
under
Category
3
(no
reasonable
expectation
of
finite
residues)
of
40
CFR§
180.6(
a).

GLN
860.1500:
Magnitude
of
the
Residue
in
Plants
All
data
requirements
for
the
magnitude
of
the
residue
in
plants
have
been
evaluated
and
deemed
acceptable.

GLN
860.1520:
Processed
Food/
Feed
No
processed
food/
feed
studies
were
submitted
by
the
registrant
and
none
are
required
to
support
the
existing
use
pattern.

GLNs
860.1850/
1900:
Confined/
Field
Rotational
Crops
Grasses
in
rangeland
are
not
rotated.
Pastures
on
the
other
hand
can
vary
from
permanent
(>
8
years),
short
term
(2­
4
years),
long
term
(5­
8
years),
as
well
as
temporary
(<
1
year).
A
rotational
pasture
is
one
used
for
a
few
seasons
and
then
plowed
and
planted
to
another
crop.
19
The
Quantitative
Usage
Analysis
for
Tebuthiuron
indicates
that
the
states
with
the
most
acres
treated
are
in
the
Southwest
U.
S.
(TX,
OK,
NM,
and
AZ).
The
grassland
areas
covered
by
these
states
include
the
Southern
Plains
and
the
Southwest
Grasslands.
These
grassland
areas
are
predominately
rangeland
that
contains
perennial
native
or
introduced
grasses,
that
have
been
invaded
by
woody
perennial
weedy
shrubs
which
are
very
difficult
to
control.
Pastures
are
mostly
perennial
grasses
or
legumes;
however,
we
do
not
know
if
there
are
any
significant
pasture
acreage
planted
to
annual
forages
in
this
region.

Therefore,
confined
field
rotational
crop
studies
will
be
conditionally
required
unless
the
registrant
can
provide
information
that
pastureland
in
this
area
is
either
insignificant
in
acreage
or
is
predominantly
perennial
grasses
that
are
not
rotated
annually.

4.2.2
Dietary
Exposure
Tebuthiuron
acute
and
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM™)
software
Version
7.73,
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
The
1989­
92
data
are
based
on
the
reported
consumption
of
more
than
10,000
individuals
over
three
consecutive
days,
and
therefore
represent
more
than
30,000
unique
"person
days"
of
data.
Foods
"as
consumed"
(e.
g.,
apple
pie)
are
linked
to
raw
agricultural
commodities
and
their
food
forms
(e.
g.,
apples­
cooked/
canned
or
wheat­
flour)
by
recipe
translation
files
internal
to
the
DEEM
software.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
exposure
assessment,
but
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

For
chronic
exposure
and
risk
assessment,
an
estimate
of
the
residue
level
in
each
food
or
food­
form
(e.
g.,
orange
or
orange­
juice)
on
the
commodity
residue
list
is
multiplied
by
the
average
daily
consumption
estimate
for
that
food/
food
form.
The
resulting
residue
consumption
estimate
for
each
food/
food
form
is
summed
with
the
residue
consumption
estimates
for
all
other
food/
food
forms
on
the
commodity
residue
list
to
arrive
at
the
total
estimated
exposure.
Exposure
estimates
are
expressed
in
mg/
kg
body
weight/
day
and
as
a
percent
of
the
cPAD.
This
procedure
is
performed
for
each
population
subgroup.

For
acute
exposure
assessments,
individual
one­
day
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
deterministic
(Tier
1
or
Tier
2)
exposure
assessment,
or
"matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
(Tier
3/
4)
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(i.
e.,
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.
In
accordance
with
HED
policy,
per
capita
exposure
and
risk
are
reported
for
all
tiers
of
analysis.
However,
for
tiers
1
and
2,
significant
differences
in
user
vs.
per
capita
exposure
and
risk
are
identified
and
noted
in
the
risk
assessment.
HED
notes
that
there
is
a
degree
of
uncertainty
in
extrapolating
exposures
for
certain
population
20
subgroups
which
may
not
be
sufficiently
represented
in
the
consumption
surveys
(i.
e.,
nursing
infants).
Therefore,
risks
estimated
for
these
subpopulations
were
included
in
representative
populations
having
sufficient
numbers
of
survey
respondents
(i.
e.,
all
infants
or
females
13­
50
years
old).
Thus,
the
population
subgroups
listed
in
Table
5
include
those
subgroups
having
sufficient
numbers
of
survey
respondents
in
the
CSFII
food
consumption
survey.

4.2.2.1
Acute
Dietary
Exposure
Analysis
A
Tier
2
acute
dietary
exposure
assessment
was
conducted
for
females
13­
50
years
old
using
anticipated
residues
for
meat
and
milk
commodities
which
incorporated
an
estimated
maximum
2%
CT
for
rangeland/
pastureland
(2/
28/
02;
S.
Smearman,
BEAD).
No
acute
dietary
endpoint
was
selected
by
the
HIARC
for
the
general
U.
S.
population,
including
infants
and
children.
Therefore,
an
acute
dietary
exposure
assessment
was
not
performed
for
these
population
subgroups.
The
acute
dietary
exposure
estimates
are
below
HED's
level
of
concern
(!100%
aPAD)
at
the
95
th
exposure
percentile
for
females
13­
50
years
old
(<
1%
of
the
aPAD).

4.2.2.2
Chronic
Dietary
Exposure
Analysis
A
Tier
2
chronic
dietary
exposure
assessment
was
conducted
for
the
general
U.
S.
population
and
all
population
subgroups
(including
infants
and
children)
using
anticipated
residues
for
meat
and
milk
commodities
which
incorporated
an
average
weighted
1%
CT
for
rangeland/
pastureland
provided
by
BEAD.
The
chronic
dietary
exposure
estimates
are
below
HED's
level
of
concern
(!100%
cPAD)
for
the
general
U.
S.
population
(<
1%
of
the
cPAD)
and
all
population
subgroups.
21
Table
5.
Summary
of
Results
from
Acute
and
Chronic
DEEM
™
Analyses
of
Tebuthiuron.

Population
Subgroup
Acute
Dietary
1
Chronic
Dietary
2
Cancer
Risk
or
MOE
Dietary
Exposure
(mg/
kg/
day)
%
aPAD
Dietary
Exposure
(mg/
kg/
day)
%
cPAD
U.
S.
Population
(total)

NA
3
0.000023
<1
NA
All
Infants
(<
1
year)
0.
000036
<1
Children
1­
6
years
0.
000083
<1
Children
7­
12
years
0.
000043
<1
Females
13­
50
0.000078
<1
0.000013
<1
Males
13­
19
NA
0.000025
<1
Males
20+
years
0.
000012
<1
Seniors
55+
0.000012
<1
1.
Acute
dietary
endpoint
applies
to
females
13­
50
years
old
only.
No
acute
dietary
endpoint
was
chosen
by
the
HIARC
for
the
general
U.
S.
population
(including
infants
and
children).
2.
Chronic
dietary
endpoint
applies
to
general
U.
S.
population
and
all
population
subgroups.
3.
NA
­
Not
Applicable.

4.2.2.3
Cancer
Dietary
Exposure/
Risk
The
classification
of
tebuthiuron
as
a
Group
D,
not
classifiable
as
to
human
carcinogenicity,
was
reevaluated
by
HIARC.
At
the
doses
tested,
neither
the
rat
nor
mouse
showed
any
treatment­
related
increase
in
the
incidence
of
neoplasms;
however,
the
HIARC
concluded
that
the
dose
levels
were
too
low
to
assess
the
carcinogenic
potential
of
tebuthiuron.
Although
there
are
some
uncertainties
regarding
the
carcinogenic
potential
of
tebuthiuron,
HED
has
elected
not
to
quantify
cancer
risk
at
this
time
because
the
dose
levels
used
in
the
available
carcinogenicity
studies
were
sufficient
to
decrease
any
cancer
risk
concerns.
HED
has
requested
new
carcinogenicity
studies
in
rats
and
mice
and
an
in
vivo
mammalian
bone
marrow
chromosomal
aberration
test
as
confirmatory
data.

4.3
Water
Exposure/
Risk
Pathway
The
Agency
currently
lacks
sufficient
water­
related
exposure
data
from
monitoring
to
complete
a
quantitative
drinking
water
exposure
analysis
and
risk
assessment
for
tebuthiuron.
Therefore,
the
Agency
is
presently
relying
on
computer­
generated
estimated
environmental
concentrations
(EECs).
PRZM/
EXAMS
is
used
to
generate
EECs
for
surface
water
and
SCI­
GROW
(an
empirical
model
based
upon
actual
monitoring
data
collected
for
a
number
of
pesticides
that
serve
as
benchmarks)
predicts
EECs
in
ground
water.
These
models
take
into
account
the
use
patterns
and
the
environmental
profile
of
a
pesticide,
but
do
not
include
consideration
of
the
impact
that
processing
raw
water
for
distribution
as
drinking
water
would
likely
have
on
the
removal
of
pesticides
from
the
22
source
water.
The
primary
use
of
these
models
by
the
Agency
at
this
stage
is
to
provide
a
screen
for
determining
whether
pesticide
residues
(and
metabolites)
in
water
are
not
of
concern.

EFED
(M.
Corbin,
28­
November­
2001)
provided
a
drinking
water
assessment
for
residues
of
tebuthiuron
and
its
degradate104
that
included
analysis
of
surface
and
ground
water
monitoring
data
and
PRZM/
EXAMS
(Tier
II)
and
SCI­
GROW
modeling
results.
There
is
no
Maximum
Contaminant
Level
Goal
(MCLG)
or
Maximum
Contaminant
Level
(MCL)
established
by
the
Agency's
Office
of
Water
for
tebuthiuron.

Environmental
Profile:

The
environmental
fate
database
is
essentially
complete
for
parent
tebuthiuron.
Degradate
104
was
the
only
tebuthiuron
degradate
of
toxicological
concern
detected
in
the
available
environmental
fate
studies;
degradate
104
was
found
at
6.9%
of
applied
parent
and
rising
by
the
end
of
the
aerobic
soil
metabolism
study.
Based
on
the
available
data,
the
parent
and
degradate
104
are
persistent
and
mobile.
The
quickest
observed
route
of
tebuthiuron
degradation
in
laboratory
studies
was
soil
photolysis
(half­
life
39.7
days.)
Tebuthiuron
is
stable
in
laboratory
studies
to
hydrolysis,
aqueous
photolysis,
and
aerobic
aquatic
metabolism.
Tebuthiuron
was
also
stable
during
a
9­
month
aerobic
soil
metabolism
study,
with
a
calculated
half­
life
of
35.4
months.
Soil
partition
coefficients
(Kd)
from
adsorption/
desorption
studies
were
0.11,
0.62,
0.82
and
1.82,
indicating
that
Tebuthiuron
is
very
mobile
over
a
range
of
soil
types.
The
corresponding
Koc
values
relating
to
these
studies
ranged
from
31
to
151,
with
a
median
of
76
l/
kg.
The
soil
adsorption
of
Tebuthiuron
appears
to
be
related
to
the
amount
of
organic
carbon
in
the
soil.

MARC
Decision:
The
HED
Metabolism
Assessment
Review
Committee
(MARC)
concluded
that
the
parent
compound
tebuthiuron
and
its
degradate
104
should
be
included
in
the
drinking
water
risk
assessment.
Although,
MARC
expressed
concern
about
the
toxicity
of
other
metabolites
of
tebuthiuron,
the
Committee
did
not
recommend
including
them
in
a
drinking
water
risk
assessment
because
they
are
not
likely
to
be
present
in
drinking
water.
Available
data
indicate
that
the
parent
and
degradate
104
are
persistent
and
mobile
in
the
environment.
Tebuthiuron
is
frequently
detected
in
ground
and
surface
water
monitoring
studies.
The
degradate
104
was
detected
in
a
retrospective
ground
water
monitoring
study
and
was
a
major
degradate
in
a
terrestrial
field
dissipation
study
accounting
for
up
to
23%
of
the
mass
applied.
The
degradate
104
was
also
found
in
aerobic
soil
metabolism
and
soil
photolysis
studies
comprising
close
to
7%
of
the
mass
applied.
In
addition,
due
to
the
structural
similarity
of
degradate
104
to
tebuthiuron
(104
lacks
an
N­
methyl
group)
and
lack
of
toxicity
information
on
degradate
104,
MARC
assumes
that
it
has
similar
toxicity
to
the
parent.

Estimated
Environmental
Concentrations:
Tier
II
(PRZM/
EXAMS)
surface
water
modeling
for
residues
of
tebuthiuron
and
its
degradate
104
using
the
index
reservoir
with
the
percent
cropped
area,
predicts
the
1
in
10
year
peak
(acute)
concentration
of
tebuthiuron
is
not
likely
to
exceed
15.5
!g/
L.
The
1
in
10
year
annual
average
concentration
(non­
cancer
chronic)
of
tebuthiuron
is
not
likely
to
exceed
4.3
!g/
L.
The
SCIGROW
predicted
concentration
of
tebuthiuron
in
ground
water
is
not
expected
to
exceed
245
µg/
L.

Assumptions/
Uncertainties
for
Water
Exposure
Pathway:
23
A
cumulative
residue
approach
was
employed
to
provide
conservative
estimated
concentrations
in
drinking
water
for
tebuthiuron
and
its
degradation
products.
In
this
approach,
the
fate
parameters
necessary
for
Tier
II
modeling
are
estimated
from
the
total
residue
data
in
the
available
environmental
fate
studies.
For
tebuthiuron,
total
residue
data
were
evaluated
for
the
aerobic
soil
metabolism
half
life,
aqueous
photolysis
half­
life,
aerobic
aquatic
half
life,
anaerobic
soil
metabolism
half
life,
and
hydrolysis
half
lives.
Degradate
104
was
used
as
a
reference
degradate
because
it
was
the
degradate
detected
at
the
highest
concentration
in
the
environmental
fate
studies,
is
expected
to
be
a
highly
mobile
tebuthiuron
residue
in
soil
and
aquatic
environments
based
on
its
chemical
structure
and
the
fact
that
it
was
the
only
degradate
detected
in
a
Small
Scale
Retrospective
Monitoring
study.

Surface
water
concentrations
of
tebuthiuron
were
modeled
using
the
PRZM/
EXAMS
(Tier
II)
programs
for
pasture/
rangeland
using
EFED's
standard
scenario
for
alfalfa
in
Texas.
The
alfalfa
scenario
was
chosen
because
its
hydrologic
and
agronomic
practices
are
expected
to
approximate
those
of
pasture/
rangeland.
Groundwater
concentrations
were
modeled
using
the
SCI­
GROW
program.

4.4
Residential
Exposure/
Risk
Pathway
An
assessment
of
residential
exposure/
risk
was
not
conducted
because
the
registered
use
sites
are
limited
to
pastureland/
rangeland,
non­
crop
areas,
railroad/
utility
rights­
of­
way.

4.4.1
Other
Non­
Occupational
Exposure
Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
groundboom
application
methods.
The
Agency
has
been
working
with
the
Spray
Drift
Task
Force,
EPA
Regional
Offices
and
State
Lead
Agencies
for
pesticide
regulation
and
other
parties
to
develop
the
best
spray
drift
management
practices.
The
Agency
is
now
requiring
interim
mitigation
measures
for
aerial
applications
that
must
be
placed
on
product
labels/
labeling.
The
Agency
has
completed
its
evaluation
of
the
new
data
base
submitted
by
the
Spray
Drift
Task
Force,
a
membership
of
U.
S.
pesticide
registrants,
and
is
developing
a
policy
on
how
to
appropriately
apply
the
data
and
the
AgDRIFT
computer
model
to
its
risk
assessments
for
pesticides
applied
by
air,
orchard
airblast
and
ground
hydraulic
methods.
After
the
policy
is
in
place,
the
Agency
may
impose
further
refinements
in
spray
drift
management
practices
to
reduce
off­
target
drift
and
risks
associated
with
aerial
as
well
as
other
application
types
where
appropriate.

5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATIONS
An
aggregate
exposure
risk
assessment
was
performed
for
acute
and
chronic
dietary
(food
+
drinking
water)
exposures.
Since
HED
does
not
have
ground
and
surface
water
monitoring
data
to
calculate
a
quantitative
aggregate
exposure,
DWLOCs
were
calculated.
A
DWLOC
is
a
theoretical
upper
limit
on
a
pesticide's
concentration
in
drinking
water
in
light
of
total
aggregate
exposure
to
a
24
pesticide
in
food,
drinking
water,
and
through
residential
uses.
A
DWLOC
will
vary
depending
on
the
toxic
endpoint,
drinking
water
consumption,
body
weights,
and
pesticide
uses.
Different
populations
will
have
different
DWLOCs.
HED
uses
DWLOCs
in
the
risk
assessment
process
to
assess
potential
concern
for
exposure
associated
with
pesticides
in
drinking
water.
DWLOC
values
are
not
regulatory
standards
for
drinking
water.

To
calculate
the
chronic
DWLOCs,
the
chronic
dietary
exposure
estimates
from
food
(from
DEEM
™
)
were
subtracted
from
the
cPAD
value
to
obtain
the
allowable
average
exposure
to
tebuthiuron
in
drinking
water.
DWLOCs
were
then
calculated
using
the
standard
body
weights
and
drinking
water
consumption
figures:
70kg/
2L
(adult
male
and
U.
S.
Population),
60
kg/
2L
(adult
female),
and
10kg/
1L
(infant
&
children).

DWLOCs
are
compared
to
EECs
for
a
pesticide
in
surface
water
and
ground
water.
If
the
DWLOCs
are
greater
than
the
EECs,
HED
concludes
with
reasonable
certainty
that
estimates
of
aggregate
risks
are
below
HED's
level
of
concern.

5.1
Acute
Risk
5.1.1
Aggregate
Acute
Risk
Assessment
Acute
aggregate
risk
estimates
for
tebuthiuron
do
not
exceed
HED's
level
of
concern.
This
acute
aggregate
risk
assessment
addresses
potential
exposure
from
the
combined
residues
of
tebuthiuron
and
its
metabolites
containing
the
dimethylethyl
thiadiazole
moiety
in
food
and
residues
of
tebuthiuron
and
degradate
104
in
drinking
water
(both
surface
and
ground
water).

5.1.2
Acute
DWLOC
Calculations
As
shown
in
Table
6
below,
EFED's
EECs
are
less
than
the
Agency's
back
calculated
DWLOC
values
for
tebuthiuron
and
its
degradate
104.

Table
6.
Acute
DWLOC
Calculations
Population
Subgroup
Acute
Scenario
aPAD
mg/
kg/
day
Acute
Food
Exp
mg/
kg/
day
Max
Acute
Water
Exp
mg/
kg/
day
1
Ground
Water
EEC
(ppb
)
2
Surface
Water
EEC
(ppb)
2
Acute
DWLOC
(µg/
L)
3
Females
13­
50
0.083
0.000078
0.082922
245
15.1
2500
1
Maximum
Acute
Water
Exposure
(mg/
kg/
day)
=
[aPAD
(mg/
kg/
day)
­
acute
food
exposure
(mg/
kg/
day)]
2
Texas­
grown
alfalfa
was
selected
to
represent
pasture/
rangeland
as
the
scenario
with
the
highest
runoff
potential.
3
Acute
DWLOC(
µg/
L)
=
[maximum
acute
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]
25
5.2
Short­
and
Intermediate­
Term
Risk
The
are
no
currently
registered
residential
uses
for
tebuthiuron.
Therefore,
aggregate
short­
and
intermediate­
term
risk
assessments
were
not
conducted.

5.3
Chronic
Risk
5.3.1
Aggregate
Chronic
Risk
Assessment
Chronic
aggregate
risk
estimates
do
not
exceed
HED's
level
of
concern.
The
aggregate
chronic
dietary
risk
estimates
include
exposure
to
residues
of
tebuthiuron
and
its
metabolites
containing
the
dimethylethyl
thiadiazole
moiety
in
food
and
residues
of
tebuthiuron
and
degradate
104
in
drinking
water
(both
surface
and
ground
water).
No
chronic
residential
use
scenarios
were
identified.
Exposure
(food
only)
to
residues
of
tebuthiuron,
based
on
a
Tier
3
refinement
using
average
residues
from
livestock
feeding
studies
and
percent
of
crop
treated
data,
represent
less
than
1%
of
the
chronic
PAD
for
the
general
U.
S.
population
and
all
population
subgroups.

5.3.2
Chronic
DWLOC
Calculations
The
EECs
generated
by
EFED
are
less
than
HED's
calculated
chronic
DWLOCs
for
chronic
exposure
to
tebuthiuron.
The
EEC
values
used
for
comparison
to
the
DWLOC
are
4.31
(surface
water)
and
245
ppb
(ground
water).
These
estimated
environmental
concentrations
are
less
than
1400
ppb
which
is
HED's
lowest
drinking
water
level
of
comparison
for
exposure
to
tebuthiuron
in
drinking
water
as
a
contribution
to
aggregate
chronic
dietary
risk.
Based
on
the
available
information,
HED
concludes
with
reasonable
certainty
that
no
harm
to
any
population
will
result
from
aggregate
chronic
dietary
exposure
to
tebuthiuron.
Details
are
presented
in
Table
7.

Table
7.
Chronic
DWLOC
Calculations
Population
Subgroup
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day
1
Ground
Water
EEC
(ppb
)
2
Surface
Water
EEC
(ppb)
2
Chronic
DWLOC
(µg/
L)
3
U.
S.
Population
0.
14
0.
000023
0.139977
245
4.31
4900
All
Infants
(<
1yr)
0.14
0.000036
0.139964
245
4.31
1400
Children
1­
6
years
0.
14
0.
000083
0.139917
245
4.31
1400
Children
7­
12
yrs
0.
14
0.
000043
0.139957
245
4.31
1400
Females
13+
0.14
0.000013
0.139987
245
4.31
4200
Males
13­
19
years
0.
14
0.
000025
0.139975
245
4.31
4900
Males
20+
years
0.
14
0.
000012
0.139988
245
4.31
4900
Table
7.
Chronic
DWLOC
Calculations
Population
Subgroup
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day
1
Ground
Water
EEC
(ppb
)
2
Surface
Water
EEC
(ppb)
2
Chronic
DWLOC
(µg/
L)
3
26
Seniors
55+
years
0.
14
0.
000012
0.139988
245
4.31
4900
1
Maximum
Chronic
Water
Exposure
(mg/
kg/
day)
=
[cPAD
(mg/
kg/
day)
­
chronic
food
exposure
(mg/
kg/
day)]
2
Texas­
grown
alfalfa
was
selected
to
represent
pasture/
rangeland
as
the
scenario
with
the
highest
runoff
potential.
3
Chronic
DWLOC(
µg/
L)
=
[maximum
chronic
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]

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

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

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

HED
has
recently
developed
a
framework
that
it
proposes
to
use
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
was
issued
for
public
comment
on
January
16,
2002
(67
FR
2210­
2214)
and
is
available
from
the
OPP
Website
27
at:

http://
www.
epa.
gov/
pesticides/
trac/
science/
cumulative_
guidance.
pdf
In
the
guidance,
it
is
stated
that
a
cumulative
risk
assessment
of
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
will
not
be
conducted
until
an
aggregate
exposure
assessment
of
each
substance
has
been
completed.

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

7.0
OCCUPATIONAL
EXPOSURE
Because
FQPA
addresses
only
non­
occupational
(residential)
risk
concerns,
risks
to
occupational
workers
are
not
addressed
in
this
document.
28
8.0
DATA
NEEDS/
LABEL
REQUIREMENTS
Toxicology
OPPTS
870.3465:
28­
Day
inhalation
toxicity
study
OPPTS
870.3700b:
Developmental
Toxicity
(non­
rodent)
OPPTS
870.4100a:
Chronic
Toxicity
(Rodent)
OPPTS
870.4200a:
Oncogenicity
(Rat)
OPPTS
870.4200b:
Oncogenicity
(Mouse)
OPPTS
870.4300:
Chronic/
Oncogenicity
OPPTS
870.5385:
Mutagenicity­
Mammalian
bone
marrow
chromosomal
aberration
test
OPPTS
870.6300:
Developmental
Neurotoxicity
(held
in
reserve
pending
submission
of
a
rabbit
developmental
toxicity
study)

Residue
Chemistry
OPPTS
860.1340
Residue
Analytical
Methods:
Enforcement
methods
for
milk
and
animal
tissues
have
been
proposed;
independent
laboratory
validation
is
required.

OPPTS
860.1850
Rotational
Crops
(Confined):
The
confined
rotational
crop
studies
are
required
unless
the
registrant
can
provide
information
that
pastureland
in
TX,
OK,
and
NM
is
either
insignificant
in
acreage
or
is
predominantly
perennial
grasses
that
are
not
rotated
annually.

OPPTS
860.1100
Directions
for
Use:
The
current
labels
indicate
that
treated
grasses
may
not
be
cut
for
hay
for
livestock
feed
for
one
year
after
treatment.
The
Agency
considers
restrictions
against
the
grazing
of
treated
rangeland
to
be
impractical.
Removal
of
this
label
restriction
is
required.

cc:
P.
Deschamp
(RRB2),
R.
Fricke
(RRB2),
K.
Dockter
(RRB2),
S.
Piper
(CEB)
RDI:
Team
(04/
03/
02),
A.
Nielsen
(04/
22/
02),
RARC
(04/
03/
02)
P.
Deschamp
812D:
CM#
2:
(703)
305­
6227:
7509C:
RRB2
29
Appendix
A
Table
1:
Tolerance
Reassessment
Summary
for
Tebuthiuron
Commodity
Current
Tolerance
(ppm)
Tolerance
Reassessment
(ppm)
Correct
Commodity
Definition
Cattle,
fat
2
1
Cattle,
mbyp
2
5
Cattle,
meat
2
1
Goats,
fat
2
1
Goats,
mbyp
2
5
Goats,
meat
2
1
Grass,
hay
20
10
Grass,
rangeland,
forage
20
10
Grass,
forage
Horses,
fat
2
1
Horses,
mbyp
2
5
Horses,
meat
2
1
Milk
0.
3
0.
8
Sheep,
fat
2
1
Sheep,
mbyp
2
5
Sheep,
meat
2
1
HED
recommends
that
the
40
CFR
tolerance
expression
under
§180.390
be
modified
as
follows:

§
180.390
Tebuthiuron;
tolerances
for
residues
(a)
Tolerances
are
established
for
the
combined
residues
of
the
herbicide
tebuthiuron
(N­[
5­
(1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl­
N,
N'­
dimethylurea)
and
its
metabolites
N­[
5­(
2­
hydroxy­
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N,
N'­
dimethylurea,
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N­
methylurea,
and
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N'­
hydroxymethyl­
N­
methylurea
in
or
on
the
following
agricultural
commodities:

Commodity
Parts
per
million
Grass,
hay
10
Grass,
forage
10
(b)
Tolerances
are
established
for
the
combined
residues
of
the
herbicide
tebuthiuron
(N­[
5­
(1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl­
N,
N'­
dimethylurea)
and
its
metabolites
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N­
methylurea,
–[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]
urea,
2­
dimethylethyl­
5­
amino­
1,3,4­
thiadiazole,
and
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N'­
hydroxymethyl­
N­
methylurea
in
or
on
the
following
raw
agricultural
commodities:
30
Commodity
Parts
per
million
Cattle,
fat
1
Cattle,
mbyp
5
Cattle,
meat
1
Goats,
fat
1
Goats,
mbyp
5
Goats,
meat
1
Horses,
fat
1
Horses,
mbyp
5
Horses,
meat
1
Sheep,
fat
1
Sheep,
mbyp
5
Sheep,
meat
1
(c)
A
tolerance
is
established
for
the
combined
residues
of
the
herbicide
tebuthiuron
(N­[
5­
(1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl­
N,
N'­
dimethylurea)
and
its
metabolites
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N­
methylurea,
N­[
5­(
2­
hydroxy­
1,1­
dimethylethyl)
1,3,4
thiadiazol­
2­
yl]­
N­
methylurea,
N­[
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]
urea,
N
5­(
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N'­
hydroxymethyl­
N­
dimethylurea,
and
N­[
5­
(2­
hydroxy­
1,1­
dimethylethyl)­
1,3,4­
thiadiazol­
2­
yl]­
N'­
hydroxymethyl­
N­
methylurea
in
or
on
the
following
raw
agricultural
commodity:

Commodity
Parts
per
million
Milk
0.
8