
Page
1
of
28
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
Date:
15­
February­
2006
Subject:
Terbacil.
Section
3
Registration
for
Application
to
Watermelon.
HED
Risk
Assessment.

Registration:
3E6640
DP
#:
D327041
Decision
#:
354086
PC
Code:
012701
From:
Tom
Bloem,
Chemist
Lisa
Austin,
Ph.
D.,
Toxicologist
Mark
Dow,
Ph.
D.,
Biologist
Registration
Action
Branch
1
(
RAB1)
Health
Effects
Division
(
HED;
7509C)

Through:
PV
Shah,
Ph.
D.,
Branch
Senior
Scientist
RAB1/
HED
(
7509C)

To:
Dan
Rosenblatt
(
RM
05)
Registration
Division
(
RD;
7505C)

The
HED
of
the
Office
of
Pesticide
Programs
(
OPP)
is
charged
with
estimating
the
risk
to
human
health
from
exposure
to
pesticides.
The
RD
of
OPP
requested
that
HED
evaluate
hazard
and
exposure
data
and
conduct
dietary,
occupational,
residential,
and
aggregate
exposure
assessments,
as
needed,
to
estimate
the
risk
to
human
health
that
will
result
from
all
registered
and
proposed
uses
of
terbacil.
A
summary
of
these
findings
is
provided
in
this
document.
The
risk
assessment,
residue
chemistry
review,
and
dietary
exposure
assessment
were
provided
by
Tom
Bloem
of
RAB1;
the
hazard
characterization
was
provided
by
Lisa
Austin
of
RAB1;
the
occupational/
residential
exposure
and
risk
assessment
was
provided
by
Mark
Dow
of
RAB1;
and
the
drinking
water
assessment
was
provided
by
Ibrahim
Abdel­
Shaib
of
the
Environmental
Fate
and
Effects
Division
(
EFED).
Page
2
of
28
Table
of
Contents
1.0
Executive
Summary
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3
2.0
Ingredient
Profile
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6
2.1
Summary
of
Registered/
Proposed
Uses
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6
2.2
Structure
and
Nomenclature
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7
2.3
Physical
and
Chemical
Properties
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7
3.0
Hazard
Characterization/
Assessment
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8
3.1
Hazard
and
Dose
Response
Characterization
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8
3.2
Absorption,
Distribution,
Metabolism
Excretion
(
ADME)
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11
3.3
FQPA
Considerations
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11
3.4
FQPA
Safety
Factor
for
Infants
and
Children
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15
3.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
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15
3.6
Endocrine
Disruption
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16
4.0
Public
Health
and
Pesticide
Epidemiology
Data
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17
5.0
Dietary
Exposure/
Risk
Characterization
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17
5.1
Metabolism
and
Environmental
Degradation
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17
5.2
Watermelon,
Rotational
Crop,
and
Drinking
Water
Residue
Profile
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19
5.3
Dietary
Exposure
and
Risk
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22
6.0
Residential
(
non­
occupational)
Exposure/
Risk
Characterization
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22
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
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23
8.0
Cumulative
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23
9.0
Occupational
Exposure/
Risk
Pathway
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23
9.1
Handler
Risk
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23
9.1
Postapplication
Risk
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25
10.0
Data
Needs
and
Label
Requirements
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25
10.1
Toxicology
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25
10.2
Residue
Chemistry
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25
10.3
Occupational/
Residential
Exposure
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25
Page
3
of
28
1.0
Executive
Summary
Background:
Terbacil
provides
control
of
annual
grasses
and
broadleaf
weeds
via
photosynthesis
inhibition
(
inhibition
of
photosystem
II).
Terbacil
is
readily
absorbed
by
roots
and
translocated
upward;
when
absorbed
by
leaves,
translocation
is
minimal.

Tolerances
are
currently­
established
for
the
combined
residues
of
terbacil
and
its
metabolites
3­
tert­
butyl­
5­
chloro­
6­
hydroxymethyluracil
(
metabolite
A),
6­
chloro­
2,3­
dihydro­
7­
hydroxymethyl
3,3­
dimethyl­
5H­
oxazolo
(
3,2­
a)
pyrimidin­
5­
one
(
metabolite
B),
and
6­
chloro­
2,3­
dihydro­
3,3,7­
trimethyl­
5H­
oxazolo
(
3,2­
a)
pyrimidin­
5­
one
(
metabolite
C),
calculated
as
terbacil,
in/
on
alfalfa,
apple,
asparagus,
blueberry,
caneberry,
peach,
peppermint,
spearmint,
strawberry,
and
sugarcane
ranging
from
0.1­
2.0
ppm
(
40
CFR180.209;
see
attachment
1
for
structures).
A
time­
limited
tolerance
in/
on
watermelon
is
also
established
at
0.4
ppm
(
expires
30­
Jun­
2007;
Section
18
registration).

The
Interregional
Research
Project
Number
4
(
IR­
4)
proposed
a
Section
3
registration
for
application
of
terbacil
to
watermelon
and
establishment
of
a
1
ppm
tolerance
in/
on
watermelon
for
the
combined
residues
of
terbacil
and
its
metabolites
A,
B,
and
C.

Hazard
Assessment:
Terbacil
was
minimally
toxic
by
the
oral,
dermal,
and
inhalation
routes
(
Toxicity
Category
IV)
in
acute
studies.
It
was
mildly
irritating
to
the
eye
(
Toxicity
Category
III).
It
is
neither
a
dermal
irritant
nor
sensitizer.
The
acute
dermal
and
primary
skin
irritation
studies
submitted
to
the
EPA
were
performed
with
an
80%
wettable­
powder
(
WP)
formulation
of
terbacil.

The
critical
effects
were
increased
liver
weight
(
relative
and
absolute),
vacuolation,
focal
necrosis,
triaditis,
hepatocyte
hypertrophy,
decreased
body
weight
and
body
weight
gain.
In
general,
these
effects
were
observed
in
both
sexes
in
rats
and
mice.
However,
in
the
dog
(
both
sexes),
the
critical
effect
was
thymic
involution.
The
dog
was
also
the
most
sensitive
species
to
terbacil
toxicity.
Terbacil
was
negative
in
a
variety
of
genotoxicity
screening
assays.
Thus,
it
appears
that
terbacil
is
not
a
genotoxic
chemical.
This
chemical
was
previously
classified
by
the
HED
RfD/
Peer
Review
Committee
as
Group
E,
evidence
of
non­
carcinogenicity
for
humans
(
TXR
No.
011277,
30­
Sep­
1994).
In
accordance
with
current
guidelines,
terbacil
is
classified
as
not
likely
to
be
carcinogenic
to
humans
based
on
the
lack
of
evidence
of
carcinogenicity
in
a
carcinogenicity
study
in
mice
and
two
combined
chronic
toxicity/
carcinogenicity
studies
in
rats.

There
is
no
evidence
of
increased
fetal
susceptibility
in
rats
or
rabbits
based
on
developmental
studies
in
the
rat
and
rabbit
and
the
multi­
generation
reproduction
study
in
the
rat.
Terbacil
induced
a
decrease
in
the
number
of
live
fetuses/
litter
in
rats
at
a
dose
higher
than
the
dose
which
caused
maternal
toxicity
(
decreased
body
weight
gain).
In
rabbits,
the
developmental
effects
were
decreased
body
weight,
increased
incidence
of
skeletal
malformations
(
fused
ribs)
and
increased
frequency
of
skeletal
variations.
These
effects
occurred
at
the
same
dose
that
induced
maternal
toxicity
(
mortality,
anorexia,
discharge,
decreased
body
weight
and
body
weight
gain).
Reproductive
performance
was
not
affected
at
the
highest
dose
(
250
ppm)
tested
in
the
3­
generation
reproduction
study
in
rats.
Page
4
of
28
Dose
Response:
Based
on
HED's
review
of
the
toxicological
data,
the
following
endpoints
were
used
to
assess
dietary
and
occupational
exposure
to
terbacil.
HED
reduced
the
Food
Quality
Protection
Act
Safety
Factor
(
FQPA
SF)
to
1x
based
on
toxicological
considerations
and
residue
assumptions
used
in
the
dietary
analyses.

Table
1:
Summary
of
Toxicological
Endpoints
used
in
this
Assessment
acute
dietary
(
all
population
subgroups)
An
endpoint
of
concern
attributable
to
a
single
dose
for
the
general
population
and
females
13+
was
not
identified.

chronic
dietary
NOAEL
=
1.4
mg/
kg/
day
chronic
RfD
and
cPAD1
=
0.014
mg/
kg/
day
dermal
(
all
durations)
Quantification
of
dermal
risk
is
not
required;
the
lack
of
dermal
or
systemic
toxicity
at
5000
mg/
kg
(
5X
the
limit
dose)
in
a
21
day
dermal
toxicity
study
in
rats
which
indicates
poor
dermal
absorption.

short­
term
inhalation
(
1­
30
days)
oral
NOAEL
=
2.0
mg/
kg/
day
Target
MOE2
$
100
(
occupational)

cancer
Classification:
Not
likely
to
be
carcinogenic
to
humans;
cancer
risk
assessment
is
not
required.

1
cPAD
=
chronic
population
adjusted
dose
=
cRfD
÷
FQPA
SF
2
MOE
=
margin
of
exposure
=
NOAEL
÷
estimated
exposure
Occupational
Exposure
and
Risk
Assessment:
Based
upon
the
proposed
use
pattern
and
the
lack
of
dermal
endpoints
(
see
previous
section),
HED
anticipates
only
short­
term
(
1
­
30
days)
inhalation
exposures
to
non­
commercial
handlers.
Post­
application
inhalation
exposures
are
not
anticipated
as
it
is
expected
that
the
spray
solution
will
have
dried
after
the
labeled
specified
12­
hour
restricted
reentry
interval
(
REI).
Since
no
chemical­
specific
data
were
available
with
which
to
assess
pesticide
handler
exposure,
the
surrogate
data
from
studies
in
the
Pesticide
Handler
Exposure
Database
Version
1.1
(
August
1998)
PHED
SURROGATE
EXPOSURE
GUIDE
were
used
to
estimate
mixer/
loader
and
applicator
exposure.
It
is
HED
policy
to
assess
handler
exposure
and
risk
using
"
baseline"
personal
protective
equipment
(
PPE)
which
is
comprised
of
long­
sleeved
shirt,
long
pants,
and
shoes
plus
socks
and
if
necessary
to
assess
"
baseline"
plus
the
use
of
protective
gloves
or
other
PPE
as
might
be
necessary
or
appropriate.
The
resulting
MOEs
were
108
for
the
mixer/
loader
and
6300
for
the
applicator
and
are
therefore
less
than
HED's
level
of
concern.

Aggregate
Exposure
and
Risk
Assessment:
Since
there
are
no
registered/
proposed
uses
which
result
in
residential
exposures,
only
a
chronic
aggregate
risk
assessment,
considering
exposure
from
food
and
water,
is
necessary
(
acute
endpoint
was
not
identified
and
terbacil
is
classified
as
not
likely
to
be
carcinogenic
to
humans).
The
chronic
dietary
exposure
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
­
Food
Consumption
Intake
Database
(
DEEM­
FCID
 
,
ver.
2.03)
model
which
incorporates
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII;
1994­
1996
and
1998).
The
chronic
dietary
analysis
assumed
tolerance
level
residues,
100%
crop
treated,
and
DEEM
(
ver
7.81)
default
processing
factors
for
all
registered/
proposed
crops.
The
SCI­
GROW
(
Screening
Concentration
in
Ground
Water)
modeled
water
estimate
was
assumed
for
all
water
sources
(
direct
and
indirect).
Although
rotational
crop
tolerances
are
not
currently
established,
based
on
the
available
field
rotational
crop
data
and
the
application
rates,
residues
in/
on
crops
rotated
into
alfalfa,
sugarcane,
and
mint
fields
which
were
treated
with
terbacil
are
possible
(
alfalfa,
sugarcane,
and
mint
are
registered
crops).
Page
5
of
28
Therefore,
the
analysis
incorporated
a
conservative
residue
estimates
for
cereal
grains
and
soybean
(
these
crops
are
commonly
rotated
with
alfalfa,
sugarcane,
and
mint).
The
chronic
dietary
exposure
estimates
were
#
99%
the
cPAD
and
are
therefore
less
than
HED's
level
of
concern
(
all
infants
<
1­
year
were
the
most
highly­
exposed
population
subgroup).

HED
notes
that
the
assessment
assumes,
based
on
cultural
practices,
that
only
cereal
grains
and
soybean
are
rotated
into
alfalfa,
sugar
cane,
and
mint
fields
while
the
registered
application
scenario
for
these
crops
permits
the
rotation
of
any
crop.
When
the
residue
estimates
used
to
generate
the
dietary
exposure
estimates
are
taken
in
total
(
SCI­
GROW
drinking
water
estimates;
tolerance
level
residue
and
100%
crop
treated
for
all
registered/
proposed
crops),
HED
concludes
that
exposure
to
terbacil
is
likely
to
be
significantly
lower
than
the
estimates
provided
in
this
document.

Recommendations
for
Tolerances/
Registration:
Provided
the
petitioner
submits
a
revised
Section
F
and
the
Analytical
Chemistry
Laboratory
(
ACL)
of
the
Biological
and
Economic
Analysis
Division
(
BEAD)
is
able
to
validate
the
proposed
plant
enforcement
method,
HED
concludes
that
the
toxicological,
residue
chemistry,
and
occupational/
residential
databases
support
a
conditional
registration
and
establishment
of
1.0
ppm
tolerance
for
the
residues
of
terbacil
and
its
metabolites
A,
B,
and
C
in/
on
watermelon.

Unconditional
registration
may
be
established
upon
submission
of
data
which
adequately
address
the
following
deficiencies:

CFood
and
Drug
Administration
(
FDA)
multiresidue
testing
of
terbacil
and
its
metabolites
A,
B,
and
C
through
protocol
D
Cadditional
watermelon
field
trials,
conducted
with
application
after
crop
emergence,
in
Regions
3
(
n=
1),
5
(
n=
1),
and
6
(
n=
1)
Page
6
of
28
2.0
Ingredient
Profile
2.1
Summary
of
Registered/
Proposed
Uses
Registered:
Terbacil
is
currently
registered
for
application
to
alfalfa,
apple,
asparagus,
blueberry,
caneberry,
peach,
peppermint,
spearmint,
strawberry,
and
sugarcane
with
tolerances
for
the
combined
residues
of
terbacil
and
metabolites
A,
B,
and
C,
expressed
as
terbacil,
ranging
from
0.1­
2.0
ppm
(
40
CFR180.209).
A
section
18
registration
for
application
of
terbacil
to
watermelon
is
currently
established
with
a
time­
limited
tolerance
of
0.4
ppm
(
expires
30­
Jun­
2007).
Based
on
the
HED
Reregistration
Eligibility
Document
(
RED;
D.
Miller,
18­
Dec­
1996)
and
the
Section
18
watermelon
risk
assessment
(
D231995
and
D231994,
G.
Herndon,
29­
Jan­
1997),
terbacil
application
rates
for
the
currently­
registered
crops
range
from
0.1­
4.8
lbs
ai/
acre/
season.

Proposed:
The
petitioner
provided
a
supplemental
Dupont
 
Sinbar
®
Herbicide
(
WP;
80%
terbacil
by
weight;
EPA
Reg.
No.
352­
317)
label
which
includes
instructions
for
application
to
watermelon.
Table
2
is
a
summary
of
the
proposed
application
scenario.

The
supplemental
label
indicates
that
for
seeded
watermelon,
applications
are
to
be
made
after
planting
but
before
the
crop
emerges;
however,
application
to
emerged
crops
is
also
permitted
since
the
supplemental
label
cautions
that
the
spray
solution
should
not
be
allowed
to
contact
the
crop
(
over­
the­
top
applications
are
prohibited).
No
rotational
crop
restrictions
are
included
on
the
supplemental
label;
however,
the
supplemental
label
states
that
all
applicable
directions,
restrictions,
and
precautions
on
the
main
label
must
be
followed.
The
main
label
indicates
that
no
crops
may
be
planted
within
2
years
of
application
as
injury
to
the
subsequent
crops
may
result.
The
main
label
also
indicates
that
application
through
irrigation
equipment
is
prohibited
and
that
unless
otherwise
directed,
the
product
is
to
be
applied
with
a
fixed­
boom
power
sprayer.

The
Sinbar
®
label
directs
applicators
and
other
handlers
to
wear
long­
sleeved
shirt,
long
pants,
chemical­
resistant
gloves
(
such
as
butyl,
natural,
neoprene
or
nitrile
rubber)
$
14
mils
and
shoes
plus
socks.
A
REI
of
12
hours
is
specified.

HED
concludes
that
the
proposed
application
instructions
are
adequate.

Table
2:
Summary
of
Proposed
Application
Scenario
for
Terbacil
Application
Equipment
Max.
Single
Applic.
Rate
(
lb
ai/
acre)
Max.
No.
Applic.
per
Season
PHI1
(
days)
Comments
Watermelon
ground
equipment;
fixed­
boom
power
sprayer
0.10­
0.15
1
70
lower
rate
is
for
coarse
texture
soils
lower
in
organic
matter;
20­
40
gallon/
acre
1
PHI
=
preharvest
interval
Page
7
of
28
N
HN
O
C(
CH3)
3
O
Cl
H3C
2.2
Structure
and
Nomenclature
Table
3:
Test
Compound
Nomenclature.

Chemical
structure
Common
name
terbacil
Company
experimental
name
DPX­
D0732
IUPAC
name
3­
tert­
butyl­
5­
chloro­
6­
methyluracil
CAS
name
5­
chloro­
3­(
1,1­
dimethylethyl)­
6­
methyl­
2,4(
1H,
3H)­
pyrimidinedione
CAS
registry
number
5902­
51­
2
End­
use
product
(
EP)
Sinbar
®
80WP
(
80%
terbacil)

2.3
Physical
and
Chemical
Properties
Table
4:
Physicochemical
Properties
of
the
Technical
Grade
Test
Compound.

Parameter
Value
Reference
Melting
point/
range
175­
177
°
C
Terbacil
Reregistration
Standard
(
8­
Mar­
1989,
R.
Schmitt)
pH
not
available
Density
1.34
g/
cm3
(
25
/

C)

Water
solubility
(
mg/
L
(
25
°
C))
710
Solvent
solubility
(
mg/
mL
(
25
°
C))
dimethylformamide
33.7
cyclohexane
22
methyl
isobutyl
ketone
13.8
butyl
acetate
9.7
Xylene
6.5
Vapor
pressure
4.7
x
10­
7
mm
Hg
(
29.5
/

C)

Dissociation
constant,
pKa
not
available
Octanol/
water
partition
coefficient
(
KOW)
81.9
UV/
visible
absorption
spectrum
not
available
Page
8
of
28
3.0
Hazard
Characterization/
Assessment
3.1
Hazard
and
Dose
Response
Characterization
Terbacil
was
minimally
toxic
by
the
oral,
dermal
and
inhalation
routes
(
Toxicity
Category
IV)
in
acute
studies.
It
was
mildly
irritating
to
the
eye
(
Toxicity
Category
III).
It
is
neither
a
dermal
irritant
nor
sensitizer.
The
acute
dermal
and
primary
skin
irritation
studies
submitted
to
the
EPA
were
performed
with
an
80%
WP
formulation
of
terbacil.
Table
4
is
a
summary
of
the
acute
toxicity
profile
for
terbacil.

The
critical
effects
were
increased
liver
weight
(
relative
and
absolute),
vacuolation,
focal
necrosis,
triaditis,
hepatocyte
hypertrophy,
decreased
body
weight
and
body
weight
gain.
In
general,
these
effects
were
observed
in
both
sexes
in
rats
and
mice.
However,
in
the
dog
(
both
sexes),
the
critical
effect
was
thymic
involution.
The
dog
was
also
the
most
sensitive
species
to
terbacil
toxicity.
Terbacil
was
negative
in
a
variety
of
genotoxicity
screening
assays.
Thus,
it
appears
that
terbacil
is
not
a
genotoxic
chemical.
This
chemical
was
previously
classified
by
the
HED
RfD/
Peer
Review
Committee
as
Group
E,
evidence
of
non­
carcinogenicity
for
humans
(
TXR
No.
011277,
30­
Sep­
1994).
In
accordance
with
current
guidelines,
terbacil
is
classified
as
not
likely
to
be
carcinogenic
to
humans
based
on
the
lack
of
evidence
of
carcinogenicity
in
a
carcinogenicity
study
in
mice
and
two
combined
chronic
toxicity/
carcinogenicity
studies
in
rats.

There
is
no
evidence
of
increased
fetal
susceptibility
in
rats
or
rabbits
based
on
developmental
studies
in
the
rat
and
rabbit
and
the
multi­
generation
reproduction
study
in
the
rat.
Terbacil
induced
a
decrease
in
the
number
of
live
fetuses/
litter
in
rats
at
a
dose
higher
than
the
dose
which
caused
maternal
toxicity
(
decreased
body
weight
gain).
In
rabbits,
the
developmental
effects
were
decreased
body
weight,
increased
incidence
of
skeletal
malformations
(
fused
ribs)
and
increased
frequency
of
skeletal
variations.
These
effects
occurred
at
the
same
dose
that
induced
maternal
toxicity
(
mortality,
anorexia,
discharge,
decreased
body
weight
and
body
weight
gain).
Reproductive
performance
was
not
affected
at
the
highest
dose
(
250
ppm)
tested
in
the
3­
generation
reproduction
study
in
rats.

There
was
no
appreciable
difference
in
the
absorption,
distribution,
and
metabolism
of
radioactivity
in
rats
with
regard
to
dose
and
sex.
Terbacil
was
rapidly
absorbed,
metabolized
and
eliminated.
The
total
excretion
of
terbacil
was
91
to
103%
of
radioactivity
within
5
days
following
dosing.
The
primary
routes
of
elimination
were
the
urine
(
55
­
68%,
66­
81%)
and
feces
(
2­
14%,
10­
25%)
within
24
and
48
hours
of
dosing,
respectively.
Radioactivity
recovered
in
tissues
accounted
for
less
than
0.3%
of
the
administered
dose.
The
highest
residue
levels
were
found
in
the
gastrointestinal
tract
(
0.04­
0.23%
of
the
dose)
and
whole
blood
(
0.04­
0.06%
of
the
dose).
Excretion
in
expired
air
accounted
for
less
than
0.5%
of
the
dose.

Eight
metabolites
were
detected
in
the
urine,
a
6­
hydroxymethyl
derivative
(
metabolite
A),
glucuronide
(
DF1),
sulfate
(
EF2),
and
sulfate/
N­
acetylcysteine
(
EF1/
EF3)
conjugates
and
3
unidentified
metabolites.
The
major
metabolites
were
DF1,
EF2
and
EF1/
EF3.
These
same
metabolites,
with
the
exception
of
EF2,
were
identified
in
the
feces.
There
were
five
unidentified
metabolites
detected
in
the
feces.
The
primary
metabolic
pathway
is
hydroxylation
of
the
6­
methyl
group
to
form
an
alcohol
which
is
conjugated
to
form
the
glucuronide
(
35%
of
the
dose)
and
the
sulfate
derivatives
(
11%).
Terbacil
is
also
metabolized
to
the
5­
hydroxy
intermediate,
which
is
further
conjugated
to
form
a
sulfate
derivative
(
17%).
Page
9
of
28
Table
4:
Acute
Toxicity
of
Terbacil
Guideline
No.
Study
Type
MRID
#
Results
Toxicity
Category
870.1100
(
81­
1)
Acute
Oral
(
rat)
12235
LD50
>
5000
mg/
kg
IV
870.1200
(
81­
2)
Acute
Dermal
(
rabbit)*
00114963
LD50
>
5000
mg/
kg
IV
870.1300
(
81­
3)
Acute
Inhalation
(
rat)
00125700
LC50
>
4.4
mg/
L
IV
870.2400
(
81­
4)
Primary
Eye
Irritation
(
rabbit)
00157179
Mild
irritant
III
870.2500
(
81­
5
)
Primary
Skin
Irritation1
(
rabbit)
125785
Not
a
dermal
irritant
IV2
87.2600
(
81­
6)
Dermal
Sensitization
(
guinea
pig)
00157180
Not
a
dermal
sensitizer
N/
A
1
Studies
conducted
with
a
80WP
formulation.
2
Based
on
a
21­
day
dermal
toxicity
study
in
rabbits.

Table
5:
Toxicity
Profile
of
Terbacil
Guideline
No./
Study
type
MRID
No.(
year)/
classification/
Doses
Results
870.3100
90­
Day
Oral
[
rat]
00068035
(
1965)
0,
100,
500
and
5000
ppm(
equivalent
to0,
8,
20,
200
mg/
kg/
day)
acceptable/
guideline
NOAEL
=
500
ppm
(
20
mg/
kg/
day)
LOAEL
=
5000
ppm
(
200
mg/
kg/
day),
based
on
focal
necrosis
and
triaditis
in
females,
vacuolization
in
males
and
increased
relative
liver
weight
and
hypertrophy
of
hepatocytes
in
both
sexes.

870.3200
21­
Day
Dermal
[
rabbit]
125785
(
1965)
0
and
5000
mg/
kg/
day
acceptable/
non­
guideline
NOAEL
=
5000
mg/
kg/
day
LOAEL
was
not
established
There
were
no
clinical
signs
of
toxicity,
gross
or
histopathologic
changes.

870.4100
Chronic
Oral
[
2
years­
dog]
00060851(
1966)
0,
50,
250,
2500/
10000
ppm
(
equivalent
to
0,
1.0,
5.0,
50/
200)
mg/
kg/
day
mg/
kg/
day
acceptable/
guideline
NOAEL
=
250
ppm
(
equivalent
to
5.0
mg/
kg/
day)
LOAEL
=
2500
ppm
(
equivalent
to
50
mg/
kg/
day),
based
on
increased
relative
thyroid
weights
and
thymic
involution
in
both
sexes.

870.4200
Carcinogenicity
[
mouse]
00126770
(
1981)
M/
F:
0/
0,
6.5/
8.0,
162/
199,
746/
895
mg/
kg/
day
acceptable/
guideline
NOAEL
=
162
mg/
kg/
day
LOAEL
=
746
mg/
kg/
day,
based
on
increased
liver
weights,
hyperplastic
nodules,
necrosis,
and
vacuolation
in
the
liver
in
males.
There
was
no
oncogenic
potential
at
the
doses
tested.

870.3700
Developmental
Toxicity
[
rat]
00050467
(
1980)
0,
24,
104
and
392
mg/
kg/
day
acceptable/
guideline
Maternal
NOAEL
was
not
established
Maternal
LOAEL
=
24
mg/
kg/
day
based
on
decreased
body
weight
gain.
Developmental
NOAEL
=
24
mg/
kg/
day
Developmental
LOAEL
=
104
mg/
kg/
day,
based
on
decreased
number
of
live
fetuses/
litter.

870.3700
Developmental
Toxicity
[
rabbit]
00150945
(
1984)
0,
30,
200,
and
600
mg/
kg/
day
acceptable/
non­
guideline
Maternal
NOAEL
=
200
mg/
kg/
day
Maternal
LOAEL
=
600
mg/
kg/
day,
based
on
mortality,
clinical
findings
(
anorexia,
discharge),
decreased
body
weight
and
body
weight
gain.
Developmental
NOAEL=
200
mg/
kg/
day
Developmental
LOAEL
=
600
mg/
kg/
day,
based
on
decreased
body
weight,
increased
incidence
of
skeletal
malformations
(
fused
ribs)
and
increase
frequency
of
skeletal
variations.
Table
5:
Toxicity
Profile
of
Terbacil
Guideline
No./
Study
type
MRID
No.(
year)/
classification/
Doses
Results
Page
10
of
28
870.3800
3­
generation
reproduction­
[
rat]
0060852
(
1967)
0,
50,
and
250
ppm
(
equivalent
to
0,
2.0,
and
10
mg/
kg/
day)
acceptable/
non­
guideline
Parental
NOAEL
=
50
ppm
(
equivalent
to2.0
mg/
kg/
day)
Parental
LOAEL
=
250
ppm
(
equivalent
to
10
mg/
kg/
day)
based
on
decreased
body
weight,
Reproductive
NOAEL
=
250
ppm
(
equivalent
to
10
mg/
kg/
day)
Reproductive
LOAEL
was
not
established
Offspring
NOAEL
=
250
ppm
(
equivalent
to
10
mg/
kg/
day)
Offspring
LOAEL
was
not
established
870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
[
rat]
42987601
(
1993)
M/
F:
0/
0,
0.9/
1.4,
58/
83,
308/
484
mg/
kg/
day
acceptable/
guideline
NOAEL
(
M/
F)=
58/
1.4
mg/
kg/
day
LOAEL
(
M/
F)=
308/
83
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
and
increased
absolute
and
relative
liver
weights
in
males
and
females.
There
was
no
oncogenic
potential
at
the
doses
tested.

870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
[
rat]
00060850
(
1966)
0,
50,
250,
and
2500/
10000
ppm
(
equivalent
to
0,
2.0,
10
and
100/
400
mg/
kg/
day)
acceptable/
guideline
Systemic
NOAEL
=
250
ppm
(
equivalent
to
10
mg/
kg/
day)
Systemic
LOAEL
=
2500/
10000
ppm
(
equivalent
to
100/
400
mg/
kg/
day)
based
on
increased
mean
relative
liver
weights,
hepatocyte
centrilobular
hypertrophy
in
males
and
females
and
vacuolation
in
females.
There
was
no
oncogenic
potential
at
the
doses
tested.

870.5300
Mutagenic­
(
HGPRT)
00150943
(
1984)
unacceptable
Pages
missing
in
report.

870.5300
Mutagenic­
(
HGPRT)
00260460
(
1984)
0,
2,
3,
5
and
6
mM
(­
S9);
0,
1,
2,
2.5,
2.75,
3.25
and
3.50
mM
(+
S9)
acceptable/
guideline
Did
not
induce
mutation
in
chinese
hamster
ovary
cells
with
or
without
metabolic
activation.

870.5375
in
vitro
chromosome
aberration
assay
[
CHO
cells]
00150944
(
1984)
0,
20,
100
and
500
mg/
kg
acceptable/
guideline
Negative
for
clastogenic
activity
in
the
rat
bone
marrow
cytogenetic
assay.

870.5500
unscheduled
DNA
synthesis
assay
rat
primary
hepatocyte
00150939
(
1984)
0,
0.010,
0.033,
0.10,
0.33,
1.0,
2.5,
5.0,
7.5,
and
10
mM
acceptable/
guideline
Did
not
induce
unscheduled
DNA
synthesis
in
primary
rat
hepatocytes.

870.5100
Mutagenicity
Study
(
bacteriophage
assay)
12178
(
1965)
acceptable/
non­
guideline
Did
not
show
the
suspected
(
5­
bromo­
uracil
metabolite)
mutagenic
action.

870.7485
Metabolism
Study
in
Rats
40104702
(
1986)
single
doses
of
6.5
or
500
mg/
kg
acceptable/
guideline
Approximately
57­
82%
of
the
administered
dose
was
absorbed
in
24
hours.
Ninety
one
to
103%
of
radioactivity
was
recovered
within
5
days;
with
70
to
86%
in
urine
and
14­
28%
in
feces.
The
major
metabolites
were
glucuronide,
sulfate
and
sulfate/
Nacetylcysteine
conjugates.
The
primary
metabolic
pathway
is
hydroxylation
of
the
6­
methyl
group
to
form
the
alcohol
which
is
conjugated
to
form
the
glucuronide
(
35%
of
the
dose)
and
the
sulfate
derivatives
(
11%).
Terbacil
is
also
metabolized
to
the
5­
hydroxy
intermediate,
which
is
further
conjugated
to
form
a
sulfate
derivative
(
17%).
There
was
no
evidence
suggestive
of
bioaccumulation.

M
­
Male;
F
­
Female
Page
11
of
28
3.2
Absorption,
Distribution,
Metabolism
Excretion
(
ADME)

In
rats,
terbacil
was
well
absorbed,
distributed,
metabolized
and
excreted.
Urine
and
feces
were
found
to
be
major
routes
of
excretion
for
terbacil.
There
were
no
significant
gender
differences.
At
24
hours
post
exposure,
55­
68%
of
the
radioactivity
was
eliminated
in
the
urine;
2­
14%
was
eliminated
in
the
feces.
At
48
hours,
66­
81%
was
eliminated
in
the
urine;
10­
25%
in
the
feces.
At
120
hours
(
5
days)
post­
exposure,
for
all
dose
groups,
70
to
86%
of
the
dose
was
excreted
in
the
urine
and
14
to
28%
was
excreted
in
the
feces.
Based
on
excretion,
approximately
57­
82%
of
the
administered
dose
was
absorbed
in
24
hours.
Tissues
collected
and
analyzed
for
radioactivity
accounted
for
less
than
0.3%
of
the
administered
dose.
The
highest
residue
levels
were
found
in
the
gastrointestinal
tract
(
0.04­
0.23%
of
the
dose)
and
whole
blood
(
0.04­
0.06%
of
the
dose).
Excretion
in
expired
air
accounted
for
less
than
0.5%
of
the
dose.

The
unmetabolized
parent
compound
was
not
identified
in
urine
or
feces;
however,
8
metabolites
were
detected
in
the
urine
and
feces.
The
major
metabolites
identified
in
the
urine
were
glucuronide
(
DF1,
20­
39%),
sulfate
(
EF2,
13­
17.9%)
and
sulfate/
N­
acetylcysteine
(
EF1/
EF3,
8.5­
14
%)
conjugates.
The
major
metabolites
in
the
feces
were
DF1
(
1­
2%),
EF1/
EF3
(
0.7­
2%)
and
6­
hydroxydervative,
DF4
(
2%).

The
proposed
metabolic
pathway
for
terbacil
in
rats
involved
the
hydroxylation
of
the
6­
methyl
group
to
form
an
alcohol
which
is
extensively
conjugated
to
form
the
glucouronide
and
sulfate
derivatives.
Terbacil
is
also
metabolized
to
the
5­
hydroxy
intermediate,
which
is
further
conjugated
to
form
a
sulfate
derivative.

3.3
FQPA
Considerations
Adequacy
of
the
Toxicity
Data
Base:
The
toxicology
database
for
terbacil
is
adequate.
The
following
acceptable
studies
are
available:
Developmental
toxicity
in
rats
and
rabbits
and
threegeneration
reproduction
study
in
rats.

Evidence
of
Neurotoxicity:
There
is
not
a
concern
for
neurotoxicity
resulting
from
exposure
to
terbacil.
Acute
and
subchronic
neurotoxicity
studies
were
not
performed.
No
clinical
signs
of
neurotoxicity
or
neuropathology
were
observed
in
the
subchronic
and
chronic
studies;
therefore,
the
chemical
is
not
considered
neurotoxic.

Developmental
Toxicity
Studies:
The
registrant
has
submitted
rat
and
rabbit
developmental
studies
and
a
rat
multigenration
study.
The
following
paragraphs
are
summaries
of
these
data.

Rat
Developmental
Study
(
MRID
00050467):
Terbacil
(
96.6
%
a.
i.,
Lot#:
T­
811115­
D)
was
administered
to
pregnant
ChR­
CD
©
rats
(
27/
dose)
at
dose
levels
of
0,
250,
1250,
or
5000
ppm
(
0,
24,
104.
and
392
mg/
kg/
day)
by
diet
on
gestation
days
(
GDs)
6
through
15.
No
premature
deaths
occurred
during
the
study.
All
dams
were
sacrificed
on
GD
21.

There
were
no
effects
of
treatment
on
mortality,
clinical
signs,
or
gross
pathology.
A
significant
(
p<
0.05)
decrease
in
average
body
weight
gain
was
observed
in
the
mid
(
38%)
and
high
(
68%)
dose
groups
on
GD
6­
10,
and
in
all
treatment
groups
on
GD
10­
16
(
15%,
21%,
18%
at
250,
1250
and
5000
ppm,
respectively).
This
was
accompanied
by
a
dose­
dependent
decrease
in
mean
Page
12
of
28
body
weight
that
reached
significant
levels
(
p<
0.05)
at
1250
(
5%,
8%,
6%)
and
5000
ppm
(
10%,
10%,
8%)
on
GD
10,
16,
and
21,
respectively,
relative
to
controls.
Food
consumption
was
significantly
decreased
relative
to
controls
in
the
mid
(
21%,
34%)
and
high
(
13%,
14%)
dose
groups
on
GD
6­
10
and
10­
16,
respectively.

The
maternal
LOAEL
was
250
ppm
(
24
mg/
kg/
day)
based
on
decreased
body
weight
gain.
The
maternal
NOAEL
was
not
observed.

There
was
no
significant
difference
between
the
control
and
treated
groups
in
pregnancy
rate
or
number
of
abortions,
resorptions,
or
dead
fetuses.
The
mean
number
of
implantations
per
litter
was
significantly
lower
(
p<
0.05)
relative
to
controls
(
11.4
+
2.3)
at
5000
ppm
(
9.3
+
3.1)
and
the
effect
was
dose­
dependent.
The
mean
number
of
live
fetuses
per
litter
decreased
in
a
dosedependent
manner
and
was
significant
(
p<
0.05)
at
1250
(
9.1
+
3.2)
and
5000
ppm
(
8.6
+
2.9)
relative
to
controls
(
10.9
+
2.0).
A
dose­
dependent
increase
relative
to
controls
in
litters
with
early
resorption
(
24%,
24%
and
48%)
and
litters
partially
resorbed
(
19%,
19%,
and
29%)
was
observed
at
250,
1250
and
5000
ppm,
respectively.
However,
the
differences
were
not
statistically
significant
and
the
mean
number
of
resorption/
litter
and
resorptions
was
similar
across
treatment
group.
There
was
a
significant
increase
of
fetuses
with
dilation
of
the
renal
pelvis
and/
or
hydroureter
observed
in
all
treated
groups
(
4/
22,
6/
22,
4/
22)
relative
to
control
(
0/
19);
these
effects
were
not
dose
dependent.
Additionally,
the
recorded
incidences
were
within
range
of
historical
control
values
as
reported
by
DuPont
in
a
response
to
concerns
regarding
the
increase
in
dilation
of
the
renal
pelvis
and/
or
hydrourteter
during
the
1982
Registration
Standard.
The
response
was
accepted
(
Tox.
Doc.
No.
003401).
No
statistically­
or
biologically­
significant
increases
in
gross
and
skeletal
malformations
were
detected.

The
developmental
LOAEL
is
1250
ppm
(
104
mg/
kg)
based
on
decreased
number
of
live
fetuses/
litter.
The
developmental
NOAEL
is
250
ppm
(
24
mg/
kg).

The
developmental
toxicity
study
in
rats
is
classified
Acceptable/
Non­
guideline
(
§
83­
3[
a]),
and
does
not
satisfy
the
guideline
requirements
for
a
developmental
toxicity
study
in
the
rat
because
of
the
following
deficiencies:
treatment
occurred
during
GD
6­
15
instead
of
GD
6­
21,
individual
data
on
fetal
sex
and
body
weight,
gravid
uterine
weight,
body
weight
adjusted
for
gravid
uterine
weight.
However,
this
study
is
adequate
to
evaluate
the
teratogenic
susceptibility
of
rats
to
terbacil.

Rabbit
Developmental
Study
(
MRID
00150945):
Terbacil
[
96.1%
a.
i.
in
0.5%
methyl
cellulose
vehicle]
was
administered
to
18
artificially
inseminated
New
Zealand
White
female
rabbits/
group
via
gavage
at
dose
levels
of
0
(
0.5%
methyl
cellulose
vehicle),
30,
200,
and
600
mg/
kg
body
weight/
day
from
days
7
through
19
of
gestation.
Surviving
does
were
sacrificed
on
GD
29
and
their
fetuses
were
removed
by
cesarean
and
examined.

Maternal
mortality
was
significantly
(
p<
0.05)
increased
among
does
in
the
600
mg/
kg
group.
4/
18
does
died
and
1/
18
was
sacrificed
in
extremis
during
the
treatment
period.
During
posttreatment
1/
18
doe
died
and
1/
18
was
sacrificed
in
extremis.
There
was
a
significant
(
p<
0.05)
decrease
in
body
weight
gain
in
the
high
dose
group
(­
0.19
kg
vs
0.06
kg
in
controls).
There
were
also
significant
incidences
of
anorexia
(
15/
18)
and
semi­
solid
and
watery
yellow
(
7/
18),
Page
13
of
28
orange
or
red
discharges
(
from
GD
day
19).
Trichobezoars
filled
the
stomachs
completely
in
11/
18
does
at
dose
levels
of
600
mg/
kg/
day
versus
5/
18
in
the
control
group.
Mild
gastric
lesions
were
observed
microscopically
in
the
control
and
high
dose
groups
but
were
considered
secondary
to
the
formation
of
trichobezoars.
The
incidences
of
these
lesions
were
not
significantly
different
between
the
two
groups.

The
maternal
toxicity
LOAEL
is
600
mg/
kg/
day
based
on
mortality,
clinical
finding
(
anorexia,
discharge)
and
decreased
bodyweight
gain.
The
maternal
NOAEL
was
200
mg/
kg/
day.

There
was
no
significant
difference
between
the
control
and
treated
groups
in
pregnancy
rate
or
in
the
number
of
nidations,
abortions,
resorptions,
live
and
dead
fetuses.
Fetal
toxicity
at
600
mg/
kg/
day
was
demonstrated
by
a
significant
decrease
in
fetal
body
weight
(
17%).
There
was
a
184%
increase
relative
to
controls,
in
the
percentage
of
malformed
fetuses/
litter
and
a
significantly
higher
incidence
of
fused
ribs
in
the
600
mg/
kg
group
relative
to
controls
(
7%
pups
in
50%
litters
vs
0%
in
controls).
Also,
a
significant
increase
in
the
frequencies
of
extra
ribs
(
2.8X
controls)
and
partially
ossified
or
unossified
phalanges
(
30%
vs
3%)
and
pubes
(
48%
vs
18%)
was
observed
relative
to
controls.

The
developmental
toxicity
LOAEL
is
600
mg/
kg/
day
based
on
decreased
body
weight,
increased
incidence
of
skeletal
malformations
(
fused
ribs)
and
an
increased
frequency
of
skeletal
variations
(
extra
ribs
and
partially
ossified
or
unossified
phalanges
and
pubes).
The
developmental
NOAEL
was
200
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable/
Non­
guideline.
This
study
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
[
OPPTS
870.3700;
§
83­
3(
b)]
in
the
rabbit,
because
of
inadequate
study
duration.
Other
deficiencies
noted
included
no
measurement
of
food
consumption,
gravid
uterine
weights,
body
weights
adjusted
for
gravid
uterine
weights,
and
no
historical
control
data.
In
addition,
dead
fetuses
were
not
examined
for
external
or
visceral
anomalies.
However,
this
study
is
considered
adequate
to
evaluate
the
teratogenic
potential
of
terbacil
in
developing
rabbits
during
the
period
of
organogenesis.

Rat
Multigeneration
Reproduction
Study
(
MRID
0060852):
Terbacil
technical
(
Batch
#
1,
80%)
was
administered
in
the
diet
continuously
to
3
generations
of
albino
CD
rats
(
10
males/
20
females/
dose)
at
dose
levels
of
0,
50
and
250
ppm
(
0,
2.0
and
10
mg/
kg/
day).
Parental
animals
from
every
generation
underwent
2
breeding
cycles.
Two
females
were
mated
with
one
male;
each
cycle
with
a
different
male.
Pups
from
the
1st
litter
(
1st
breeding
cycle)
of
all
matings
were
examined
for
abnormalities
and
sacrificed.
Representative
pups
(
10
males/
20
females/
dose)
from
the
2nd
litter
(
2nd
breeding
cycle)
of
all
matings
were
selected
as
parental
rats
for
the
succeeding
generation.
Observations
were
recorded
for
10
mice/
sex/
dose
of
the
2nd
breeding
cycle
in
each
generation.

There
were
no
treatment­
related
clinical
signs
or
mortalities.
Mean
body
weight
was
decreased
in
a
dose­
dependent
manner
in
P
1
(
9%,
10%),
P
2
(
4%,
17%),
and
P
3
(
5%,
9%)
males
and
P
2
females
(
8%,
10%)
at
50
and
250
ppm,
respectively,
relative
to
controls
after
33,
33
and
26/
33
weeks,
respectively.
Weekly
mean
food
consumption
per
rat
was
increased
in
P
1
males
(
3%,
14%)
and
Page
14
of
28
decreased
in
P
2
males
(
4%,
4%)
and
females
(
8%,
13%)
and
P
3
males
(
9%,
10%)
at
50
and
250
ppm,
respectively,
relative
to
controls.
P
3
males
exhibited
a
10­
13%
decrease
in
body
weight
gain
in
the
last
12
weeks
of
treatment.

There
was
a
dose­
dependent
increase
in
relative
adrenal
weights
in
P
3
females
(
15%,
21%)
relative
to
controls
at
50
and
250
ppm,
respectively.
Relative
and/
or
absolute
weights
were
increased
in
various
organs
in
females
at
both
doses.
However,
in
the
absence
of
histopathological
changes,
changes
in
organ
weights
were
not
regarded
as
toxicologically
significant.

The
fertility
index
for
F
2B
females
decreased
to
45%
at
250
ppm;
however,
this
effect
was
not
dose­
dependent
and
fell
within
the
historical
control
range
(
14­
90%).
The
number
of
litters
per
group,
total
number
of
stillbirths,
live
births,
percent
survival,
mean
body
weight
at
weaning
and
the
reproductive
capabilities
of
rats
fed
terbacil
in
the
diet
were
comparable
to
those
of
control
rats
in
each
generation.

The
LOAEL
for
systemic
parental
toxicity
was
250
ppm
(
equivalent
to
10
mg/
kg/
day)
based
on
decreased
body
weight
in
both
sexes.
The
NOAEL
was
50
ppm
(
equivalent
to2.0
mg/
kg/
day).
The
LOAEL
for
systemic
offspring
toxicity
was
not
established.
The
offspring
NOAEL
is
250
ppm
(
equivalent
to
10
mg/
kg/
day).
The
LOAEL
for
reproductive
toxicity
was
not
established.
The
reproductive
NOAEL
is
250
ppm
(
equivalent
to
10
mg/
kg/
day).

The
study
was
done
prior
to
implementation
of
Good
Laboratory
Practices
(
GLP)
Guidelines,
therefore,
does
not
fall
under
the
purview
of
either
GLP
Guidelines
or
Quality
Assurance
requirements.
It
was
reviewed
for
the
1982
Registration
Standard,
and
graded
coresupplementary
based
on
testing
only
2
dose
levels
and
the
use
of
antibiotics
on
the
test
animals
during
the
study.
The
study
was
upgraded
to
core­
minimum
(
Tox.
Doc.
003401)
after
the
registrant
addressed
concerns
(
Acc.
No.
249455)
regarding
unavailable
necropsy
records
for
the
first
litters
and
incomplete
breeding
records.
The
study
is
classified
as
Acceptable/
Non­
guideline
and
satisfies
the
regulatory
requirements
(
§
83­
4[
a])
for
a
multigenerational
reproductive
toxicity
study
in
rats.

Pre­
and/
or
Postnatal
Toxicity:
There
is
no
evidence
of
increased
susceptibility
in
rat
and
rabbit
fetuses
to
in
utero
exposure
to
terbacil.
There
is
no
evidence
of
increased
susceptibility
to
terbacil
following
prenatal
exposure
in
a
3­
generation
reproduction
study
in
rats.

Degree
of
Concern
Analysis
and
Residual
Uncertainties:
There
are
no
residual
uncertainties
or
concerns
for
increased
susceptibility;
there
are
well
established
NOAELs
and
LOAELs
in
the
developmental
and
reproduction
studies.

Recommendation
for
a
Developmental
Neurotoxicity
Study:
There
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
terbacil.
There
is
no
indication
of
neurotoxicity
observed
in
any
other
subchronic
or
chronic
toxicity
studies.
Based
on
the
available
data
from
multiple
studies,
the
chemical
is
not
considered
neurotoxic,
thus,
a
developmental
neurotoxicity
study
is
not
required
for
terbacil.
Page
15
of
28
3.4
FQPA
SF
for
Infants
and
Children
HED
concludes
that
the
FQPA
SF
can
be
reduced
to
1x
for
the
following
reasons:
(
1)
there
is
no
evidence
of
increased
susceptibility
in
rat
and
rabbit
fetuses
to
in
utero
exposure
to
terbacil;
(
2)
there
is
no
evidence
of
increased
susceptibility
to
terbacil
following
prenatal
exposure
in
a
3­
generation
reproduction
study
in
rats;
(
3)
there
are
no
residual
toxicological
uncertainties
or
concerns
for
increased
susceptibility;
(
4)
there
are
well
established
NOAELs
and
LOAELs
in
the
developmental
and
reproduction
studies;
(
5)
the
environmental
fate
database
is
adequate
to
access
the
nature
and
magnitude
of
the
residue
in
drinking
water;
(
6)
the
dietary
exposure
analysis
assumed
tolerance­
level
residues
and
100%
crop
treated.

3.5
Hazard
Identification
and
Toxicity
Endpoint
Selection
The
following
text
and
Table
6
are
summaries
of
the
endpoints
chosen
by
HED
for
oral,
dermal,
and
inhalation
risk
assessment.

Acute
Dietary
Endpoint:
Acute
dietary
endpoints
for
child
bearing
females
(
Females
13+)
and
the
general
population
including
infants
and
children,
were
not
established
since
an
endpoint
of
concern
attributable
to
a
single
dose
was
not
identified.

Chronic
Dietary
Endpoint:
The
cRfD
of
0.014
mg/
kg/
day
was
determined
on
the
basis
of
the
Combined
Chronic
Toxicity/
Carcinogenicity
study
in
rats.
This
study
provided
the
lowest
NOAEL
in
the
database
(
most
sensitive
endpoint)
and
that
will
also
provide
the
most
protective
limits
for
human
effects.
An
uncertainty
factor
(
UF)
of
100X
(
10­
fold
for
interspecies
extrapolation
and
10­
fold
for
intra
species
variability)
was
applied
to
the
NOAEL
of
1.4
mg/
kg/
day
to
derive
the
cRfD.
The
LOAEL
of
83
mg/
kg/
day
was
based
on
decreased
body
weight
and
body
weight
gain
in
females.
The
FQPA
SF
of
1X
is
applicable
for
chronic
dietary
risk
assessment.
Therefore,
the
cPAD
is
0.014
mg/
kg/
day.

Short­
and
Intermediate­
Term
Incidental
Oral
and
inhalation
Endpoints:
Short­
and
intermediate­
term
incidental
oral
and
inhalation
endpoints
are
based
on
a
3­
generation
reproduction
study
in
the
rat.
The
LOAEL
of
10
mg/
kg/
day
was
based
on
decreased
body
weight
(
NOAEL
=
2.0
mg/
kg/
day).
A
3­
generation
reproduction
study
in
the
rat
is
selected
for
these
scenarios
because
it
is
appropriate
for
the
duration
of
exposures
and
population
of
concern.
The
level
of
concern
for
residential
and
occupational
exposures
is
for
MOEs
<
100.

Long­
Term
Inhalation
Endpoints:
Long­
term
inhalation
endpoints
are
based
on
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats.
The
LOAEL
was
83
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
females
(
NOAEL
1.4
mg/
kg/
day).
Since
an
oral
NOAEL
was
selected
for
the
inhalation
exposure
assessment,
an
inhalation
absorption
factor
of
100%
oral
equivalent
should
be
used.
The
level
of
concern
for
residential
and
occupational
exposures
is
for
MOEs
<
100.

Dermal:
Short­,
intermediate­,
and
long­
term
dermal
risk
assessments
are
not
required
for
the
following
reason:
the
lack
of
dermal
or
systemic
toxicity
at
5000
mg/
kg
(
5X
the
limit
dose)
in
a
21­
day
dermal
toxicity
study
in
rats
which
indicates
poor
dermal
absorption.
Page
16
of
28
Carcinogenicity:
This
chemical
was
previously
classified
by
the
HED
RfD/
Peer
Review
Committee
as
Group
E,
evidence
of
non­
carcinogenicity
for
humans
(
TXR
No.
011277,
9/
30/
94).
In
accordance
with
current
guidelines,
terbacil
is
classified
as
not
likely
to
be
carcinogenic
to
humans
based
on
the
lack
of
evidence
of
carcinogenicity
in
a
carcinogenicity
study
in
mice
and
two
combined
chronic
toxicity/
carcinogenicity
studies
in
rats.

Table
6:
Summary
of
Toxicological
Dose
and
Endpoints
for
Terbacil
Used
in
Human
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
population
and
Females
13+)
An
endpoint
of
concern
attributable
to
a
single
dose
for
the
general
population
and
females
13+
was
not
identified.

Chronic
Dietary
(
All
populations)
NOAEL
=
1.4
mg/
kg/
day
UF
=
100X
cRfD
=
0.014
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
cRfD
÷
FQOA
SF
=
0.014
mg/
kg/
day
Combined
Chronic
Toxicity/
Carcinogenicity­
rat;
LOAEL
=
83
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
in
females.

Short
(
1­
30
days)
and
Intermediate
(
1­
6
months)
Term
Incidental
Oral
NOAEL
=
2.0
mg/
kg/
day
level
of
concern
(
LOC)
for
MOEs
<
100
(
occupational
and
residential)
3­
Gen
Repro
­
rat;
LOAEL
=
10
mg/
kg/
day,
based
on
decreased
body
weight
Dermal
(
Any
Time
Period)
Quantification
of
dermal
risk
is
not
required;
the
lack
of
dermal
or
systemic
toxicity
at
5000
mg/
kg
(
5X
the
limit
dose)
in
a
21
day
dermal
toxicity
study
in
rats
which
indicates
poor
dermal
absorption.

Short
(
1­
30
days)
and
Intermediate
(
1­
6
months)
Term
Inhalation
oral
NOAEL
=
2.0
mg/
kg/
day
(
inhalation
absorption
rate
=
100%
oral
equivalent)
LOC
for
MOEs
<
100
(
occupational
and
residential)
3­
Gen
Repro
­
rat;
LOAEL
=
10
mg/
kg/
day,
based
on
decreased
body
weight
Long­
Term
Inhalation
(>
6
months)
oral
NOAEL
=
1.4
mg/
kg/
day
(
inhalation
absorption
rate
=
100%
oral
equivalent)
LOC
for
MOEs
<
100
(
occupational
and
residential)
Combined
Chronic
Toxicity/
Carcinogenicity­
rat;
LOAEL
=
83
mg/
kg/
day,
based
on
decreased
body
weight
and
body
weight
gain
in
females.

Cancer
Classification:
Not
likely
to
be
carcinogenic
to
humans;
cancer
risk
assessment
is
not
required.

3.6
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
has
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
terbacil,
there
was
no
evidence
of
potential
estrogen,
androgen
and/
or
thyroid
hormone
mediated
toxicity.
Page
17
of
28
4.0
Public
Health
and
Pesticide
Epidemiology
Data
National
Health
and
Nutrition
Examination
Survey
(
NHANES):
Terbacil
was
not
measured
in
NHANES
III
(
1988­
1994)
or
in
NHANES
99+
(
1999­
2002).

Agricultural
Health
Study:
Terbacil
was
not
among
the
top
50
chemicals
assessed
in
Phase
1
of
the
Agricultural
Health
Study
(
AHS).
Terbacil
had
a
low
frequency
of
use
in
AHS
Phase
2
with
13
subjects
(
6
NC
and
7
Iowa)
among
35,000
private
applicators
surveyed.
Terbacil
was
reported
as
used
on
bluebeeries,
strawberries
and
weed
and
brush
control.
It
is
not
among
the
the
top
83
chemical
indicator
variables
developed
in
AHS
Phase
2,
due
to
the
low
frequency
of
use,
so
no
additional
information
is
available.

Other
Pesticide
Epidemiology
Published
Literature:
There
were
no
health­
related
Pub
Med
citations
for
Terbacil.

5.0
Dietary
Exposure/
Risk
Characterization
5.1
Metabolism
and
Environmental
Degradation
Nature
of
the
Residue
­
Plants:
The
petitioner
has
previously
submitted
and
HED
has
reviewed
alfalfa,
blueberry,
and
sugarcane
metabolism
studies.
Based
on
these
data,
HED
concluded
that
the
nature
of
the
residue
in
plants
is
adequately
understood
and
the
residues
of
concern,
for
risk
assessment
and
tolerance
enforcement,
are
terbacil
and
metabolites
A,
B,
and
C
(
Terbacil
Reregistration
Standard,
8­
Mar­
1989,
R.
Schmitt;
D222891,
D.
Miller,
5­
Dec­
1996;
HED
RED,
D.
Miller,
18­
Dec­
1996).

Nature
of
the
Residue
­
Livestock:
The
petitioner
has
previously
submitted
and
HED
has
reviewed
acceptable
ruminant
(
D190213,
D.
Miller,
9­
Sep­
1993)
and
poultry
(
D192398,
D.
Miller,
28­
Jul­
1993)
metabolism
studies.
Based
on
these
data,
HED
concluded
that
the
nature
of
the
residues
in
livestock
is
adequately
understood
and
the
residues
of
concern,
for
risk
assessment
and
tolerance
enforcement,
are
terbacil
and
metabolites
A,
B,
and
C
(
HED
RED,
D.
Miller,
18­
Dec­
1996).

Nature
of
the
Residue
in
Rotational
Crops:
A
confined
rotational
crop
study
is
not
currently
available.
The
HED
RED
(
D.
Miller,
18­
Dec­
1996)
stated
that
if
the
aerobic
soil
metabolism
study
(
MRID
42369901),
which
was
being
reviewed
by
the
EFED,
revealed
no
new
metabolites
other
than
those
regulated
in
the
primary
crops,
then
a
confined
rotational
crop
study
may
not
be
required.
The
following
information
was
gathered
from
the
EFED
RED
(
D229773,
J.
Hetrick,
26­
Jun­
1997):

Terbacil
is
persistent
under
aerobic
and
anaerobic
soil
conditions
(
t1/
2=
235
to
653
days).
Minor
nonvolatile
transformation
products
(<
10%
of
applied)
are
t­
butylurea
and
3­
t­
butyl­
6­
methyluracil.
The
major
volatile
transformation
product
is
CO2.
The
reported
laboratory
degradation
data
indicate
terbacil
is
persistent
in
terrestrial
environments.
Marginally
acceptable
field
dissipation
studies
indicate
terbacil,
at
5
lbs
ai/
acre,
is
persistent
and
mobile
under
actual
use
conditions.
Field
dissipation
half­
lives
in
Delaware,
Illinois,
and
California
ranged
from
204
to
252
days.
The
maximum
depth
of
terbacil
detection
was
45
to
50
cm.
Metabolites
A
(
maximum
concentration
15
days
after
application
(
0.14
ppm))
and
B
(
maximum
concentration
60
days
after
application
(
0.07
ppm))
were
detected
in
the
Page
18
of
28
field
dissipation
studies.
The
Chemistry
Science
Advisory
Council
(
ChemSAC)
was
consulted
concerning
the
need
for
an
additional
confined
rotational
crop
study.
Based
on
the
demonstrated
persistence
of
terbacil
in
the
aerobic
and
anaerobic
soil
metabolism
studies
(
half­
life
=
235­
653
days;
EFED
RED,
D229773,
J.
Hetrick,
26­
Jun­
1997),
the
ChemSAC
concluded
that
a
confined
rotational
crop
study
is
not
necessary
(
see
ChemSAC
minutes
for
1­
Feb­
2006).
Therefore,
HED
concludes
that
the
residues
of
concern
in
rotational
crops
are
terbacil,
metabolite
A,
metabolite
B,
metabolite
C,
and
3­
t­
butyl­
6­
methyluracil.
Metabolites
A,
B,
and
C
were
included
as
these
are
residues
of
concern
in
the
primary
crops
and
may
form
in
rotational
crops
via
uptake
and
metabolism
of
parent.
3­
t­
butyl­
6­
methyluracil
was
included
as
it
was
identified
in
the
aerobic
soil
metabolism
study.
HED
notes
that
3­
t­
butyl­
6­
methyluracil
was
identified
at
<
10%
TRR;
however,
the
aerobic
soil
metabolism
study
was
conducted
for
only
1
year
and
the
proposed
registered
plant
back
intervals
(
PBIs)
are
2
years
(
i.
e.,
concentration
of
3­
t­
butyl­
6­
methyluracil
may
be
significant
after
2
years;
t­
butylurea
was
not
included
based
on
concentration
and
toxicological
considerations).

Residues
of
concern
in
Drinking
Water:
The
following
information
concerning
the
environmental
fate
of
terbacil
was
taken
from
the
EFED
RED
(
D229773,
J.
Hetrick,
June­
1997).
Based
on
acceptable,
supplemental,
and
ancillary
environmental
fate
data,
terbacil
dissipation
appears
to
be
dependent
on
microbial­
mediated
degradation,
photodegradation
in
water,
and
movement
into
ground
and
surface
waters.
The
relative
importance
of
degradation
and
mobility
in
controlling
terbacil
dissipation
under
actual
use
conditions
cannot
be
fully
evaluated
from
the
existing
environmental
fate
data.
However,
the
data
indicate
that
terbacil
is
very
persistent
and
potentially
very
mobile
in
terrestrial
environments.
Compounds
with
similar
environmental
fate
behavior
(
e.
g.,
bromacil)
have
been
detected
in
ground
and
surface
waters.

Terbacil
is
stable
to
abiotic
hydrolysis
and
slowly
degrades
through
photolysis
in
natural
and
reference
laboratory
water
samples
(
t
1/
2
=
29
to
54
days)
and
soil
(
t
1/
2
=
122
days).
The
photodegradation
rate
appears
to
be
dramatically
enhanced
by
the
presence
of
some
photosenitizers
(
riboflavin
and
methylene
blue).
Major
photodegradation
transformation
products
(>
10%
of
applied)
are
(
1)
chloro­
6­
methyluracil,
(
2)
3­
tert­
butyl­
6­
methyluracil,
(
3)
6­
chloro­
2,3­
dihydro­
3,3,
7­
trimetyl­
5H
oxazolo
(
3,2­
a)­
pyrimidine­
5­
one,
(
4)
tert­
butyl­
5­
acetyl­
5­
hydroxyhydantoin,
(
5)
3­
tert­
butyl­
5­
hydroxyhydantoin,
and
(
6)
5­
chloro­
6­
methyl­(
3',
5')­
5'­
chloro­
6'­
methyl­
5',
6'­
dihydro­
6',
2­
anhydro­
3'­
tert­
butyluracilyluracil.
Terbacil
is
persistent
under
aerobic
and
anaerobic
soil
conditions
(
t
1/
2
=
235
to
653
days).
Minor
nonvolatile
transformation
products
are
t­
butylurea
(
aerobic
and
anaerobic
soil
metabolism),
3­
t­
butyl­
5­
chloro­
6­
hydroxymethyuracil
(
anaerobic
soil
metabolism),
and
3­
t­
butyl­
6­
methyuracil
(
aerobic
soil
metabolism).
The
major
volatile
transformation
product
is
CO
2
.
The
reported
laboratory
degradation
data
indicate
terbacil
is
persistent
in
terrestrial
environments.

Terbacil
has
a
low
sorption
affinity
to
soil
(
K
ad
=
0.39
to
1.3
ml/
g;
K
oc
=
44
to
61
ml/
g).
Therefore,
terbacil
is
expected
to
be
very
mobile
in
soil.
Soil
column
studies
also
indicate
that
terbacil
and
its
transformation
products
can
move
through
soil
columns.
Laboratory
mobility
studies
indicate
terbacil
and
its
transformation
products
are
potentially
mobile
in
terrestrial
environments.

Marginally­
acceptable
field
dissipation
studies
indicate
terbacil,
at
5
lbs
ai/
acre,
is
persistent
and
Page
19
of
28
mobile
under
actual
use
conditions.
Field
dissipation
half­
lives
in
Delaware,
Illinois,
and
California
ranged
from
204
to
252
days.
The
maximum
depth
of
terbacil
detection
was
45
to
50
cm.
Ancillary
field
studies
using
plants
as
biological
indicators
also
suggest
that
phytotoxic
"
terbacil
residues"
are
persistent
and
mobile.
Field
dissipation
studies
confirm
that
terbacil
is
persistent
and
potentially
mobile
under
actual
use
conditions.

Based
on
these
data
HED
concluded
that
the
residues
of
concern
in
drinking
water
are
terbacil
and
the
following
photodegradates:
(
1)
5­
chloro­
6­
methyluracil;
(
2)
3­
tert­
butyl­
6­
methyluracil;
and
(
3)
6­
chloro­
2,3­
dihydro­
3,3,7­
trimethyl­
5H
oxazolo
(
3,2­
a)­
pyrimidine­
5­
one.

Pesticide
Metabolites
and
Degradates
of
Concern:
Table
7
is
a
summary
of
the
residues
of
concern
in
plants,
livestock,
rotational
crops,
and
drinking
water
(
see
preceding
paragraphs
for
rationale):

Table
7:
Residues
for
Tolerance
Expression
and
Risk
Assessment
Matrix
Residues
included
for
Risk
Assessment
Residues
included
in
the
Tolerance
Expression
Plants1
terbacil
and
metabolites
A,
B,
and
C
terbacil
and
metabolites
A,
B,
and
C
Livestock
terbacil
and
metabolites
A,
B,
and
C
terbacil
and
metabolites
A,
B,
and
C
Rotational
Crops
terbacil;
metabolites
A,
B,
and
C;
and
3­
tert­
butyl­
6­
methyluracil
terbacil;
metabolites
A,
B,
and
C;
and
3­
tert­
butyl­
6­
methyluracil
Drinking
Water
terbacil
and
the
following
photodegradates:
(
1)
5­
chloro­
6­
methyluracil;
(
2)
3­
tert­
butyl­
6­
methyluracil,
and
(
3)
6­
chloro­
2,3­
dihydro­
3,3,7­
trimethyl­
5H
oxazolo
(
3,2­
a)­
pyrimidine­
5­
one
not
applicable
Comparative
Metabolic
Profile:
The
proposed
metabolic
pathway
for
terbacil
in
rats
involves
the
hydroxylation
of
the
6­
methyl
group
to
form
metabolite
A
which
is
extensively
conjugated
to
form
the
glucouronide
and
sulfate
derivatives.
Terbacil
is
also
metabolized
to
the
5­
hydroxy
intermediate,
which
is
further
conjugated
to
form
a
sulfate
derivative.
The
rat
metabolism
studies
did
not
involve
the
formation
of
the
oxazolo
metabolites,
5­
chloro­
6­
methyluracil,
or
3­
tert­
butyl­
6­
methyluracil
(
residues
of
concern
identified
in
plants,
livestock,
and/
or
water).
Based
on
the
structure
activity
relationships,
HED
concludes
that
these
compounds
are
not
likely
to
be
more
toxic
than
parent
(
see
attachment
1
for
structures).

5.2
Watermelon,
Rotational
Crop,
and
Drinking
Water
Residue
Profile
Watermelon
Residue
Profile:
In
support
of
the
proposed
application
of
terbacil
to
watermelon,
the
petitioner
submitted
a
field
trial
study
which
presented
the
magnitude
of
terbacil
(
limit
of
quantitation
(
LOQ)
=
0.50
ppm),
metabolite
A
(
LOQ
=
0.30
ppm),
metabolite
B
(
LOQ
=
0.10
ppm),
and
metabolite
C
(
LOQ
=
0.10
ppm)
residues
in/
on
watermelon
following
a
single
application
at
0.248­
0.297
lb
ai/
acre
(
1.6­
2.0x;
PHI
=
69­
94
days).
Combined
residues
of
terbacil
and
metabolites
A,
B,
and
C
in/
on
the
treated
samples
were
<
LOQ
(<
1.0
ppm).
Terbacil
residues,
per
se,
which
were
<
LOQ
were
found
in/
on
many
of
the
treated
samples
and
ranged
from
<
0.001­
0.091
(
n=
11)
with
one
sample
at
0.230
ppm
(
no
residues
of
metabolites
A,
B,
or
C
were
found
in/
on
any
sample).

The
high
terbacil
LOQ
was
due
to
residues
at
0.134
ppm
and
0.182
ppm
in/
on
two
of
the
control
Page
20
of
28
samples
collected
from
the
field
trials.
The
study
indicated
that
these
may
be
treated
samples
mislabeled
as
untreated
samples;
however,
no
evidence
supporting
this
claim
was
provided.
Terbacil
residues
were
found
in/
on
many
of
the
remaining
control
samples
at
<
0.001­
0.074
ppm
(<
0.001
ppm
(
n=
2)
and
0.047­
0.078
ppm
(
n=
8)).
If
the
0.134
ppm
and
0.182
ppm
control
samples
are
excluded
and
based
on
the
residues
in/
on
the
remaining
control
samples,
a
terbacil
LOQ
of
at
least
0.20
ppm
would
be
established
(
assumes
LOQ
=
3x
the
background).
Assuming
a
terbacil
LOQ
of
0.20
ppm,
terbacil
residues
in/
on
the
treated
samples
would
be
<
LOQ
for
all
excluding
one,
0.230
ppm.

Based
on
the
discussion
from
the
previous
paragraph,
HED
concludes
that
the
data
submitted
in
the
watermelon
field
trial
study
are
acceptable
despite
the
exaggerated
rate
due
to
residues
less
than
or
slightly
greater
than
the
LOQ.
HED
generally
allows
for
a
25%
reduction
in
the
suggested
number
of
field
trials
when
residues
are
<
LOQ
(
Table
5,
OPPTS
860.1500).
However,
since
the
terbacil
and
metabolite
A
LOQs
are
high
and
since
the
label
indicates
that
application
after
crop
emergence
is
permitted
(
all
the
currently­
available
field
trials
were
conducted
post
planting
and
prior
to
crop
emergence),
HED
concludes
this
reduction
is
not
appropriate
and
requests
additional
watermelon
field
trial,
conducted
with
application
after
crop
emergence,
in
Regions
3
(
n=
1),
5
(
n=
1),
and
6
(
n=
1).
Provided
the
petitioner
agrees
to
submit
these
data
and
based
on
the
currently­
available
data,
HED
concludes
that
a
tolerance
of
1.0
ppm
for
the
combined
residues
of
terbacil
and
metaoblites
A,
B,
and
C
in/
on
watermelon
is
appropriate.
A
revised
Section
F
is
requested.

Rotational
Crops
Residue
Profile:
The
residues
of
concern
in
rotational
crops
are
terbacil;
metabolites
A,
B,
and
C;
and
3­
tert­
butyl­
6­
methyluracil.
Two
field
rotational
crop
studies
and
have
been
submitted
and
reviewed
(
MRID
00011948
­
see
EFED
review,
23­
July­
1981;
MRID
43221501
­
D206093,
D.
Miller,
31­
Aug­
1994).
MRID
43221501
presented
data
concerning
the
magnitude
of
terbacil
and
metabolites
A,
B,
and
C
in/
on
beet
(
root
and
tops),
wheat,
and
lettuce
following
a
bare
soil
application
at
5.0
lb
ai/
acre
(
33x
the
watermelon
rate)
and
a
2­
year
plantback
interval
(
PBI).
Due
to
phytotoxicity,
neither
immature
nor
mature
wheat
and
lettuce
plants
could
be
harvested
for
residue
analysis.
Phytotoxicity
was
also
observed
for
beets
with
severe
reduction
in
harvest
yield
noted
and
only
small
samples
of
immature
and
mature
beets
harvested.
Terbacil
residues
were
0.19
ppm
in/
on
immature
beet
(
whole
plant),
0.07
ppm
in/
on
mature
beet
top,
and
<
0.05
ppm
in/
on
mature
beet
root.
Metabolites
A,
B,
and
C
were
<
0.05
ppm
in/
on
all
mature
and
immature
beet
samples.
MRID
00011948
presented
data
concerning
the
magnitude
of
terbacil
and
metabolite
A
in/
on
beet
(
root
and
tops),
sunflower
(
seed),
and
cabbage
following
ten
annual
applications
of
terbacil
at
1.0
lb
ai/
acre
(
10­
month
PBI;
silt
loam
soil;
6.7x
the
watermelon
rate)
and
three
annual
applications
of
terbacil
at
1.0­
2.0
lb
ai/
acre
(
2­
year
PBI;
muck
soil;
13.3x
the
watermelon
rate;
2.0
lb
ai/
acre
the
1st
year
and
1.0
lb
ai/
acre
for
the
2nd
and
3rd
years).
Residues
of
terbacil
and
metabolite
A
were
<
LOQ
in/
on
all
samples
excluding
cabbage
grown
in
muck
(
2­
year
PBI)
where
terbacil
residues
of
0.18
ppm
were
found.

Based
on
the
watermelon
application
rate
and
the
results
of
the
currently­
available
field
trial
studies
(
6.7­
33x
the
watermelon
application
rate;
terbacil
and
metabolite
A
residues
of
#
0.19
ppm),
HED
concludes
that
residues
in/
on
crops
rotated
into
watermelon
fields
which
were
treated
with
terbacil
is
unlikely.
Therefore,
additional
field
rotational
crop
studies
conducted
at
the
maximum
proposed/
registered
application
rate
and
monitoring
for
the
residues
of
concern
in
rotational
crops
are
unnecessary
for
the
current
petition.
However,
HED
notes
that
future
Page
21
of
28
petitions
may
require
additional
field
rotational
crop
studies
(
see
ChemSAC
minutes
for
1­
Feb­
2006).
Currently,
there
are
no
rotational
crop
tolerances;
however,
based
on
the
available
field
rotational
crop
data
and
the
application
rates
for
the
currently­
registered
crops,
residues
in/
on
crops
rotated
into
alfalfa
(
2
x
1.2
lb
ai/
acre),
mint
(
2
x
1.2
lb
ai/
acre),
and
sugar
cane
(
1
x
3.2
lb
ai/
acre)
fields
which
were
treated
with
terbacil
are
possible.
Based
on
the
available
field
rotational
crop
data,
the
dietary
analysis
assumed
a
residue
of
1.0
ppm
for
cereal
grains
and
soybean
(
these
crops
are
commonly
rotated
into
alfalfa,
mint,
and
sugarcane
fields;
D212427,
D.
Miller,
12­
Dec­
1996
and
communication
from
B.
Schneider).
Based
on
the
tolerances
for
the
primary
crops
(
0.1­
2.0
ppm),
HED
anticipates
that
the
1.0
ppm
residue
estimate
is
conservative.
HED
notes
that
the
assessment
assumes
that
only
cereal
grains
and
soybean
are
rotated
into
alfalfa,
sugar
cane,
and
mint
fields
while
the
registered
application
scenario
for
these
crops
permits
the
rotation
of
any
crop.

Analytical
Methodology:
There
are
currently
two
terbacil
enforcement
methods
in
the
Pesticide
Analytical
Manual
(
PAM;
Vol.
II).
The
HED
RED
(
D.
Miller,
18­
Dec­
1996)
concluded
that
Method
I
is
unacceptable
as
it
does
not
include
instructions
for
the
quantitation
of
metabolites
A,
B,
and
C
and
Method
II
is
unacceptable
as
it
uses
a
microcoulometric
detector.
The
HED
RED
went
on
to
say
that
an
adequate
gas
chromatograph/
nitrogen­
phosphorus
detector
(
GC/
NPD)
method,
which
is
a
modification
of
Method
II
in
PAM
(
Vol.
II),
may
be
an
appropriate
enforcement
method
and
requested
that
the
petitioner
submit
this
procedure
to
HED
for
a
petition
method
validation
(
PMV;
since
the
procedure
is
similar
to
Method
II,
an
independent
laboratory
validation
(
ILV)
was
deemed
unnecessary).
The
petitioner
did
not
submit
a
separate
study
with
the
analytical
procedure
for
this
method.
However,
the
watermelon
field
trial
study
employed
the
method
in
question
and
this
study
included
a
copy
of
the
analytical
procedure
as
an
attachment.
This
information
was
forwarded
to
the
ACL
of
BEAD
for
PMV
(
D324601,
T.
Bloem,
21­
Dec­
2005).
A
successful
PMV
is
needed
before
this
method
may
be
used
for
enforcement.

Multiresidue
Methods:
Data
have
been
submitted
pertaining
to
the
analytical
behavior
of
terbacil
and
its
regulated
metabolites
through
FDA
Multiresidue
Protocols
and
these
data
have
been
forwarded
to
FDA
for
inclusion
in
PAM
(
Vol.
I,
Appendix
I).
The
registrant
has
submitted
the
results
of
FDA
Multiresidue
Protocol
C
to
the
Agency
(
Protocols
A,
B,
and
E
are
not
applicable)
which
demonstrates
that
terbacil
and
its
metabolites
yield
acceptable
results
when
tested
under
the
specified
GLC
conditions.
Results
from
Protocol
D,
however,
were
not
submitted,
and
the
registrant
is
required
to
use
this
method
to
test
an
appropriate
commodity
and
submit
the
results
for
terbacil
and
its
regulated
metabolites
for
inclusion
in
PAM
(
HED
RED,
D.
Miller,
18­
Dec­
1996).
These
data
have
not
been
submitted.

International
Residue
Limits:
There
are
no
Codex,
Canadian,
or
Mexican
maximum
residue
limits
(
MRLs)
in/
on
the
requested
crops.
Page
22
of
28
Drinking
Water
Residue
Profile:
EFED
provided
surface
(
PRZM/
EXAMS)
and
ground
water
(
SCI­
GROW)
EECs
for
terbacil
and
its
metabolites
of
concern
(
D313755,
I.
Abdel­
Saheb,
20­
Dec­
2005).
Several
scenarios
were
run
with
sugarcane
(
1
x
3.0
lb
ai/
acre;
highest
registered/
proposed
application
rate)
yielding
the
highest
EECs.
The
PRZM/
EXAMS
model
assumed
that
a
percent
cropped
area
of
87%.
Table
8
is
a
summary
the
drinking
water
estimates.

Table
8:
Estimated
concentrations
of
Terbacil
and
Degradates
of
Concern
in
Surface
and
Ground
Water
Crop
EECs
(:
g/
L)

Acute
One­
in­
10­
year
annual
mean
Surface
water
123
25.4
Ground
Water
111
5.3
Dietary
Exposure
and
Risk
Chronic
dietary
risk
assessments
were
conducted
using
the
DEEM­
FCID
 
(
ver.
2.03)
model
which
incorporates
consumption
data
from
the
USDA
CSFII
(
1994­
1996
and
1998).
The
chronic
dietary
analysis
incorporated
tolerance
level
residues,
100%
crop
treated,
and
DEEM
(
ver
7.81)
default
processing
factors
for
all
registered/
proposed
crops.
The
SCI­
GROW
modeled
water
estimate
was
assumed
for
all
water
sources
(
direct
and
indirect).
Although
rotational
crop
tolerances
are
not
currently
established,
based
on
the
available
field
rotational
crop
data
and
the
application
rates,
residues
in/
on
crops
rotated
into
alfalfa,
sugarcane,
and
mint
fields
which
were
treated
with
terbacil
are
possible
(
alfalfa,
sugarcane,
and
mint
are
registered
crops).
Therefore,
the
analysis
incorporated
a
conservative
residue
estimates
for
cereal
grains
and
soybean
(
crops
which
are
commonly
rotated
with
alfalfa,
sugarcane,
and
mint).
The
chronic
dietary
exposure
estimates
were
#
99%
the
cPAD
and
are
therefore
less
than
HED's
level
of
concern
(
all
infants
<
1­
year
were
the
most
highly­
exposed
population
subgroup).
Table
9
is
a
summary
of
the
chronic
dietary
exposure
analyses
(
acute
and
cancer
exposure
assessments
are
unnecessary).

HED
notes
that
the
assessment
assumes
that
only
cereal
grains
and
soybean
are
rotated
into
alfalfa,
sugar
cane,
and
mint
fields
while
the
registered
application
scenario
for
these
crops
permits
the
rotation
of
any
crop
(
this
assumption
is
based
on
cultural
practices).
When
the
residue
estimates
used
to
generate
the
dietary
exposure
estimates
are
taken
in
total
(
SCI­
GROW
drinking
water
estimates;
tolerance
level
residue
and
100%
crop
treated
for
all
registered/
proposed
crops),
HED
concludes
that
exposure
to
terbacil
is
likely
to
be
significantly
lower
than
the
estimates
provided
in
this
document.

Table
9:
Summary
of
Chronic
Dietary
Exposure
and
Risk
for
Terbacil
(
drinking
water
included)

Population
Subgroup
Chronic
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
aPAD
General
U.
S.
Population
0.01
0.005584
40
All
Infants
(<
1
year
old)
0.013823
99
Children
1­
2
years
old
0.013161
94
Children
3­
5
years
old
0.011751
84
Children
6­
12
years
old
0.007500
54
Youth
13­
19
years
old
0.004892
35
Adults
20­
49
years
old
0.004650
33
Adults
50+
years
old
0.004184
30
Table
9:
Summary
of
Chronic
Dietary
Exposure
and
Risk
for
Terbacil
(
drinking
water
included)

Population
Subgroup
Chronic
cPAD
(
mg/
kg/
day)
Exposure
(
mg/
kg/
day)
%
aPAD
Page
23
of
28
Females
13­
49
years
old
0.004510
32
6.0
Residential
(
non­
occupational
Exposure/
Risk
Characterization
There
are
no
registered/
proposed
application
scenarios
that
are
expected
to
result
in
residential
exposure.
HED
notes
that
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
the
ground
application.
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.

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
Since
there
are
no
registered/
proposed
uses
which
result
in
residential
exposures,
only
chronic
aggregate
exposure
assessments,
considering
exposure
from
food
and
water,
is
required
(
acute
and
cancer
assessments
are
unnecessary).
Since
the
dietary
exposure
analysis
included
the
drinking
water
estimates,
the
discussion
and
exposure
estimates
presented
in
Section
5.3
represent
aggregate
chronic
risk
assessment.

8.0
Cumulative
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
terbacil
and
any
other
substances
and
terbacil
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
terbacil
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
Office
of
Pesticide
Programs
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
pesticides/
cumulative/.
Page
24
of
28
9.0
Occupational
Exposure/
Risk
Pathway
The
petitioner
is
proposing
application
of
Dupont
 
Sinbar
®
Herbicide
(
80WP;
EPA
Reg.
No.
352­
317)
to
watermelon.
Table
2
is
a
summary
of
the
proposed
application
scenario.

9.1
Handler
Risk
Based
upon
the
proposed
use
pattern
and
the
lack
of
dermal
endpoints
(
see
previous
section),
HED
believes
occupational
pesticide
handlers
(
i.
e.,
mixers,
loaders
and
applicators)
will
be
exposed
to
only
short­
term
(
1
­
30
days)
inhalation
exposures.
Treatment
blocks
(
number
of
acres)
are
relatively
small
compared
to
typical
field
crops
such
as
cotton,
corn,
soybeans
or
wheat.
Due
to
the
methods
of
application,
it
is
likely
that
handlers
will
be
private,
grower
(
noncommercial
handlers.
The
most
highly­
exposed
handlers
are
expected
to
be
a
mixer/
loader
using
open
pour
of
WPs
and
an
applicator
using
ground­
boom
equipment.

Chemical­
specific
data
were
not
available
with
which
to
assess
pesticide
handler
exposure.
Therefore
surrogate
data
from
studies
in
the
Pesticide
Handler
Exposure
Database
Version
1.1
(
August
1998)
PHED
SURROGATE
EXPOSURE
GUIDE
were
used
to
estimate
mixer/
loader
and
applicator
exposure.
It
is
HED
policy
to
assess
handler
exposure
and
risk
using
"
baseline"
PPE
which
is
comprised
of
long­
sleeved
shirt,
long
pants,
and
shoes
plus
socks
and
if
necessary
to
assess
"
baseline"
plus
the
use
of
protective
gloves
or
other
PPE
as
might
be
necessary
or
appropriate.

In
some
cases,
HED
recognizes
that
the
same
individual
may
perform
all
three
tasks,
i.
e.,
mix,
load
and
apply
a
pesticide
material.
The
available
exposure
data
for
combined
mixer/
loader/
applicator
scenarios
are
limited
in
comparison
to
the
monitoring
of
these
two
activities
separately.
These
exposure
scenarios
are
outlined
in
the
PHED
Surrogate
Exposure
Guide
(
August
1998).
HED
has
adopted
a
methodology
to
present
the
exposure
and
risk
estimates
separately
for
the
job
functions
in
some
scenarios
and
to
present
them
as
combined
in
other
cases.
Most
exposure
scenarios
for
hand­
held
equipment
(
such
as
hand
wands,
backpack
sprayers,
and
push­
type
granular
spreaders)
are
assessed
as
a
combined
job
function.
With
these
types
of
hand
held
operations,
all
handling
activities
are
assumed
to
be
effected
by
the
same
individual.
The
available
monitoring
data
support
this
and
HED
presents
them
in
this
way.
Conversely,
for
equipment
types
such
as
fixed­
wing
aircraft,
groundboom
tractors,
or
air­
blast
sprayers,
the
applicator
exposures
are
assessed
and
presented
separately
from
those
of
the
mixers
and
loaders.
By
separating
the
two
job
functions,
HED
determines
the
most
appropriate
levels
of
PPE
for
each
aspect
of
the
job
without
requiring
the
applicator
to
wear
unnecessary
PPE
that
may
be
required
for
a
mixer/
loader
(
e.
g.,
chemical­
resistant
gloves
may
only
be
necessary
during
the
pouring
of
a
liquid
formulation).

A
MOE
of
100
is
adequate
to
protect
occupational
pesticide
handlers.
Since
the
MOE's
are
>
100,
the
proposed
use
does
not
exceed
HED's
level
of
concern.
Table
10
is
a
summary
of
exposures
and
risks
to
occupational
pesticide
handlers.
Page
25
of
28
Table
10:
Estimated
Handler
Exposure
and
Risk
from
the
Use
of
Terbacil
on
Watermelon
Unit
Exposure1
(
mg
ai/
lb
handled)
Applic.
Rate2
Units
Treated3
Per
Day
Average
Daily
Dose4
mg
ai/
kg
bw/
day
MOE5
Mixer/
Loader
­
WP
­
Open
Pour
Inhal
0.0434
HC
0.15
lb
ai/
acre
200
A
Inhal
0.019
108
Applicator
­
Ground­
boom
­
Open
Cab
Inhal
0.00074
HC
0.15
lb
ai/
acre
200
A
Inhal
0.00032
6,300
1
Unit
Exposures
are
taken
from
"
PHED
SURROGATE
EXPOSURE
GUIDE",
Estimates
of
Worker
Exposure
from
The
Pesticide
Handler
Exposure
Database
Version
1.1,
August
1998.
Inhal.
=
Inhalation.
Units
=
mg
a.
i./
pound
of
active
ingredient
handled.
Data
Confidence:
LC
=
Low
Confidence,
MC
=
Medium
Confidence,
HC
=
High
Confidence.
2
Applic.
Rate.
=
Taken
from
supplemental
label
and
IR­
4
submission..
3
Units
Treated
are
taken
from
"
Standard
Values
for
Daily
Acres
Treated
in
Agriculture";
SOP
No.
9.1.
Science
Advisory
Council
for
Exposure;
Revised
5
July
2000;
4
Average
Daily
Dose
=
Unit
Exposure
x
Applic.
Rate
x
Units
Treated
÷
Body
Weight
(
70
kg).
5
MOE
=
NOAEL
÷
ADD;
NOAEL
=
2.0
mg
ai/
kg
bw/
day
9.1
Postapplication
Risk
Typically,
it
is
possible
for
agricultural
workers
to
experience
post­
application
exposures
to
dislodgeable
pesticide
residues.
In
this
case,
there
are
no
dermal
toxicological
endpoints
identified.
HED
believes
that
post­
application
inhalation
exposures
are
negligible.
There
is
a
12
hour
restricted
entry
interval
(
REI)
for
this
product.
It
is
expected
that
there
is
no
volatility
as
the
spray
is
essentially
dry
after
12
hours.
The
product
is
a
WP
versus
a
liquid
formulation
thereby
further
reducing
the
possibility
of
significant
inhalation
exposure.
The
proposed
use
does
not
exceed
HED's
level
of
concern.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
Cnone
10.2
Residue
Chemistry
CRevised
Section
F
CPMV
of
the
plant
and
livestock
enforcement
methods
CFDA
multiresidue
testing
of
terbacil
and
its
metabolites
A,
B,
and
C
through
protocol
D
Cadditional
watermelon
field
trial,
conducted
with
application
after
crop
emergence,
in
Regions
3
(
n=
1),
5
(
n=
1),
and
6
(
n=
1)

10.3
Occupational/
Residential
Exposure
Cnone
RDI:
RAB1
(
15­
Feb­
2006)
T.
Bloem:
806R:
CM#
2:(
703)
605­
0217:
7590C
Page
26
of
28
Attachment
1:
Chemical
Structures
Page
27
of
28
N
HN
O
C(
CH3)
3
O
Cl
H3C
N
HN
O
C(
CH3)
3
O
Cl
HOH2C
N
N
O
Cl
HOH2C
O
H3C
CH3
N
N
O
Cl
H3C
O
H3C
CH3
N
HN
O
C(
CH3)
3
O
H
H3C
(
H3C)
C
N
NH2
H
O
N
HN
O
C(
CH3)
3
O
Cl
OH2C
gluc
Attachment
1:
Chemical
Structures
Name
Structure
terbacil
3­
tert­
butyl­
5­
chloro­
6­
methyluracil
5­
chloro­
3­(
1,1­
dimethylethyl)­
6­
methyl­
2,4(
1H,
3H)­
pyrimidinedi
one
metabolite
A
(
also
called
DF4)

3­
tert­
butyl­
5­
chloro­
6­
hydroxymethyluracil
metabolite
B
6­
chloro­
2,3­
dihydro­
7­
hydroxymethyl­
3,3­
dimethyl­
5Hoxazolo
(
3,2­
a)
pyrimidin­
5­
one
metabolite
C
6­
chloro­
2,3­
dihydro­
3,3,7­
trimethyl­
5H­
oxazolo
(
3,2­
a)
pyrimidin­
5­
one
3­
t­
butyl­
6­
methyluracil
t­
butylurea
DF1
Name
Structure
Page
28
of
28
N
HN
O
C(
CH3)
3
O
HO3SO
H3C
N
HN
O
C(
CH3)
3
O
Cl
HO3SOH2C
EF2
EF1/
EF3
