UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
August
22,
2002
SUBJECT:
REVISED:
HED
Chapter
for
the
Hexazinone
Tolerance
Reassessment
Eligibility
Decision
PC
Code
107201.
Case
0266.
DP
Barcode
D275621.

FROM:
Carol
Christensen,
MPH
Reregistration
Branch
II
Health
Effects
Division
(7509C)

THRU:
Al
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(7509C)

TO:
Dirk
Helder
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(7508C)

The
following
human
health
risk
assessment
has
been
prepared
by
the
Health
Effects
Division
(HED)
for
the
Phase
III
Public
Comment
Period
of
the
tolerance
reassessment
process
for
hexazinone
[3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)­
dione].
The
HED
chapter
reflects
the
Agency's
current
guidelines
concerning
the
retention
of
the
Food
Quality
Protection
Act
(FQPA)
safety
factor
and
risk
assessment.
The
chapter
is
based
upon
the
product
chemistry
review
by
Ken
Dockter,
the
toxicology
review
by
David
Anderson,
the
residue
chemistry
and
dietary
exposure
and
risk
analysis
by
John
Punzi,
the
drinking
water
exposure
assessment
by
Larry
Liu
of
the
Environmental
Fate
and
Effects
Division
(EFED),
and
the
incident
review
by
Jerry
Blondell
and
Monica
Spann.
Table
of
Contents
1.0
Executive
Summary
.........................................................
3
2.0
Physical
and
Chemical
Properties
..............................................
5
3.0
Hazard
Characterization
......................................................
7
3.1
Hazard
Profile
.......................................................
7
3.2
FQPA
Considerations
................................................
16
3.3
Dose
Response
Assessment
............................................
16
3.3.1
Acute
Reference
Dose
(RfD)
­
Females
13­
50
......................
17
3.3.2
Chronic
Reference
Dose
(RfD)
..................................
18
3.4
Endocrine
Disruption
.................................................
19
4.0
Exposure
Assessment
and
Characterization
.....................................
20
4.1
Summary
of
Registered
Use
Patterns
....................................
20
4.2
Dietary
(Food)
Exposure/
Risk
Pathway
..................................
21
4.2.1
Residue
Profile
.............................................
21
4.2.2
Acute
Dietary
Exposure
(Females
13­
50)
..........................
28
4.2.3
Chronic
Dietary
..............................................
29
4.3
Water
Exposure/
Risk
Pathway
.........................................
31
4.3.1
Environmental
Fate
...........................................
33
4.3.2
Drinking
Water
Exposure
Estimates
..............................
34
4.4
Residential
Exposure/
Risk
Pathway
.....................................
38
4.4.1
Other
Non­
Occupational
Exposures
..............................
38
5.0
Aggregate
Risk
Assessment
and
Characterization
................................
39
5.1
Acute
Aggregate
Risk
Assessment
......................................
40
5.2
Chronic
Aggregate
Risk
Assessment
.....................................
41
6.0
Cumulative
Risk
...........................................................
42
7.0
Incident
Data
.............................................................
43
8.0
Data
Needs
...............................................................
44
References
..................................................................
45
3
1.0
Executive
Summary
Hexazinone
[3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)
dione
is
a
triazine­
dione
herbicide
registered
for
use
on
alfalfa,
blueberries,
pasture
and
range
grasses,
pineapple,
and
sugarcane.
It
is
also
registered
for
use
on
ornamental
plants,
forest
trees,
and
noncrop
areas.
There
are
no
residential
uses
of
the
chemical.
Hexazinone
is
used
to
control
a
variety
of
weed
species
and
works
through
inhibition
of
photosynthesis.
Hexazinone
may
be
applied
for
pre­
or
post­
emergence
weed
control
by
layby,
directed
spray,
broadcast
spray,
or
basal
soil
treatments
and
can
be
applied
using
either
ground
or
aerial
equipment.
It
is
formulated
as
a
dry
flowable
(DF),
emulsifiable
concentrate
(EC),
granular
(G),
and
soluble
concentrate
(SC)
and
these
formulations
are
registered
for
food/
feed
uses.
The
range
of
percentage
of
active
ingredient
in
product
formulations
is
10­
90%.
The
application
rates
range
from
1­
4
lbs.
active
ingredient
per
acre
and
the
number
of
applications
typically
limited
to
one
per
year
or
per
crop
cycle.
Hexazinone
is
mainly
an
early
season
use,
pre­
harvest
intervals
(PHIs)
of
180­
234
days,
but
there
are
PHIs
of
30
days
for
some
uses.
There
are
approximately
400,000
pounds
of
active
ingredient
used
per
year.

Hexazinone
has
low
acute
toxicity
by
the
oral
(Category
III),
dermal
(Category
IV)
and
inhalation
routes
(Category
III).
It
has
low
acute
dermal
toxicity
(Category
IV)
and
causes
mild
skin
irritation
(Category
IV).
Hexazinone
is
not
a
skin
sensitizer.
However,
the
chemical
causes
severe
primary
eye
irritation
(Category
I).
In
chronic
studies
of
hexazinone's
toxicity,
body
weight
decrement
and
liver
toxicity,
including
changes
in
liver
related
clinical
chemistry
values,
and
microscopic
lesions
are
noted.
Hexazinone
is
classified
as
a
group
D
for
carcinogenic
potential,
not
classifiable
as
to
human
carcinogenicity.
Hexazinone
is
not
known
to
be
an
endocrine
disruptor
nor
is
there
evidence
of
neurotoxicity
in
the
toxicological
database.
The
hexazinone
rat
metabolism
study
indicated
that
the
chemical
is
rapidly
absorbed
and
excreted
and
there
is
essentially
no
difference
in
the
metabolism
between
males
and
females
at
high
or
low
doses.
A
small
amount
of
hexazinone
parent
and
two
major
metabolites,
metabolites
A
(3­(
4­
hydroxycyclohexyl)­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione)
and
C
(3­(
4­
hydroxycyclohexyl)­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione)
were
recovered.
(Chemical
structures
begin
on
p.
24.)

There
is
no
evidence
of
qualitative
or
quantitative
susceptibility
in
prenatal
developmental
studies
in
the
rat
or
rabbit
or
in
post­
natal
reproduction
studies
in
the
rat.
A
recently
submitted
rabbit
developmental
study
showed
fetal
weight
decrement
at
the
same
dose
as
maternal
weight
decrement.
A
developmental
neurotoxicity
study
for
hexazinone
is
not
required.
There
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
in
any
of
the
available
studies
with
hexazinone.
Therefore,
the
FQPA
Safety
Factor
Committee
recommended
that
OPP
depart
from
the
default
10X
additional
safety
factor
and
instead
use
a
different
additional
safety
factor
of
1X
when
assessing
the
risk
of
hexazinone
to
human
health.
There
is
no
"special"
FQPA
safety
factor
necessary
to
protect
the
safety
of
infants
and
children
(no
enhanced
susceptibility
of
fetuses/
offspring).
4
Hexazinone
exhibits
systemic
and
liver
toxicity
in
studies
of
chronic
exposure.
Toxicological
endpoints
were
established
for
acute
and
chronic
dietary
exposure
scenarios
as
well
as
dermal
(intermediate­
and
long­
term)
and
inhalation
(short­,
intermediate­,
and
long­
term)
exposure
scenarios.
Incidental
oral
endpoints
were
not
selected
because
there
are
no
residential
uses
for
hexazinone
and
a
short­
term
dermal
endpoint
was
not
selected
because
no
hazard
was
identified.
No
adverse
effects
attributed
to
a
single
exposure
were
identified
for
the
general
population.
For
the
purposes
of
this
tolerance
reassessment
eligibility
decision
(TRED),
only
the
acute
and
chronic
dietary
exposure
scenarios
will
be
addressed.
Occupational
exposure
and
risk
were
considered
in
the
previous
reregistration
eligibility
decision
(RED,
1994).

An
acute
dietary
endpoint
was
identified
for
females
13­
50
years
of
age.
The
endpoints
of
decreased
male
and
female
fetal
weight,
increased
incidence
of
kidneys
with
no
papilla
and
an
increased
incidence
of
misaligned
sternebrae
in
the
fetuses
were
identified
from
a
developmental
toxicity
study
in
rats.
Because
the
toxic
endpoint
for
acute
dietary
exposure
concerns
in
utero
exposure,
the
risk
assessment
is
performed
for
females
of
childbearing
age
(females
13­
50),
since
only
members
of
this
group
are
at
risk
for
being
pregnant
at
the
time
of
exposure.
The
dose
selected
for
establishing
the
acute
reference
dose
(RfD)
is
the
developmental
No
Observed
Adverse
Effect
Level
(NOAEL)
of
400
mg/
kg/
day.
The
chronic
dietary
endpoint
was
identified
in
an
oral
toxicity
study
in
the
dog
and
is
based
upon
severe
body
weight
decrement,
clinical
chemistry
changes
in
the
liver
and
microscopic
lesions
in
the
liver
[NOAEL=
5.0
mg/
kg­
bw/
day].

Tolerances
for
residues
of
hexazinone
in/
on
plant,
livestock,
and
processed
commodities
are
currently
expressed
in
terms
of
the
combined
residues
of
hexazinone
and
its
metabolites
(calculated
as
hexazinone).
The
tolerance
expression
should
be
modified
to
include
the
specific
metabolites
(A,
B,
C,
C­
2,
D,
E,
and
F)
by
the
appropriate
chemical
name
(See
Table
4,
p.
23).
Reassessed
tolerances
range
from
0.1
ppm
to
4.0
ppm.
Tolerances
are
reassessed
for
alfalfa
(hay
and
forage),
blueberry,
pineapple,
and
sugarcane
as
well
as
for
secondary
residues
in
cattle,
goat,
horse,
sheep,
and
milk.
HED
is
recommending
that
tolerances
be
revoked
for
livestock
fat,
hog
meat
and
meat
by­
products
based
on
the
results
of
the
metabolism
and
feeding
studies.
HED
is
also
recommending
that
tolerances
for
pasture/
rangeland
grasses
be
revoked
due
to
a
lack
of
adequate
field
trial
data.
Tolerance
reassessment
for
secondary
residues
in
meat
and
milk
when
grass
is
a
significant
feed
item
could
not
be
completed.
However,
HED
has
determined
that
a
potential
diet
can
be
constructed
for
other
registered
feed
items,
and
subsequently
tolerances
for
meats
and
milk
can
be
reassessed.
It
is
important
to
note
that
the
tolerance
reassessment
and
risk
assessment
performed
in
this
document
assumes
the
tolerances
for
pasture/
rangeland
grasses
are
revoked
and
the
uses
withdrawn
from
the
label.
In
addition,
a
tolerance
is
proposed
for
alfalfa
seed
in
this
TRED.

Estimated
acute
dietary
(food
only)
risk
for
females
age
13­
50
associated
with
the
use
of
hexazinone
does
not
exceed
the
Agency's
level
of
concern.
The
acute
dietary
risk
for
females
13­
50
years
of
age
is
approximately
1%
of
the
acute
population
adjusted
dose
(aPAD).
The
chronic
dietary
(food
only)
risk
estimate
does
not
exceed
the
Agency's
level
of
concern
for
any
population
subgroups
examined
including
the
most
highly
exposed
sub­
group,
children
1­
6
years
5
N
N
N
N
O
O
of
age.
The
chronic
dietary
risk
for
this
subgroup
is
approximately
15%
of
the
chronic
PAD
and
approximately
4%
for
the
general
U.
S.
population.
Since
the
acute
and
chronic
dietary
exposure
assessments
utilized
tolerance
level
residue
values
and
assumed
100%
of
the
crops
are
treated,
risk
estimates
are
considered
upper­
end.

Aggregate
acute
and
chronic
exposure
and
risk
estimates
include
the
contribution
of
risk
from
all
dietary
(food+
water)
sources.
Short­
and
intermediate­
term
aggregate
exposure
and
risk
assessments
were
not
performed
since
there
are
no
residential
uses
for
hexazinone.
Drinking
water
estimated
environmental
concentrations
(EECs)
were
derived
from
both
model
and
monitoring
results.
The
chemical
is
persistent
and
mobile
in
the
environment.
Hexazinone
parent,
drinking
water
degradate
G3170,
and
all
metabolites
with
conjoined
cyclohexyl
and
triazine
rings
were
included
in
the
drinking
water
exposure
and
risk
assessment.
(Chemical
structures
on
p.
23
and
31.)
The
FIRST
model
was
used
to
estimate
concentrations
of
hexazinone
and
its
metabolites
in
surface
water
using
model
parameters
for
alfalfa.
The
results
of
a
prospective
water
monitoring
study
were
used
to
estimate
concentration
of
the
chemical
in
groundwater.
Neither
acute
nor
chronic
aggregate
risk
exceed
the
Agency's
level
of
concern.
Therefore,
the
Agency
can
conclude
with
reasonable
certainty
that
residues
of
hexazinone
plus
its
metabolites
of
concern
would
not
likely
result
in
an
aggregate
risk
to
infants
and
children.
The
Agency
based
this
determination
on
a
comparison
of
estimated
concentration
of
hexazinone
and
its
metabolites
to
calculated
drinking
water
levels
of
comparison
or
"DWLOCs."

The
database
for
hexazinone
is
considered
adequate
for
risk
assessment,
however,
data
deficiencies
have
been
identified.
The
Agency
requires
a
28­
day
inhalation
study.
Residue
chemistry
data
requirements
include
outstanding
label
amendments
(new
labels
should
reflect
cancelled
use
on
pasture/
rangeland
grasses)
and
a
field
rotational
crop
study
for
corn
and
wheat.

2.0
Physical
and
Chemical
Properties
Hexazinone
[3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H
dione]
is
a
contact
and
residual
herbicide
used
to
control
a
broad
spectrum
of
weeds
including
woody
plants
found
in
alfalfa,
rangeland,
pastures,
woodlands,
pineapple,
sugarcane
and
blueberries.
Non­
crop
areas
include
ornamental
plants
and
forests.
Hexazinone
interferes
with
electron
transport
in
chloroplast
membranes
which
allows
oxidation
of
plant
lipids
and
proteins.
Upon
exposure
to
the
chemical,
damaged
cell
membranes
leak,
causing
the
cells
to
dry
and
disintegrate.
Hexazinone
is
registered
for
pre­
emergent,
post­
emergence,
directed
spray
and
soil
applications.
Chemical
end­
use
products
are
formulated
as
a
granular,
water
dispersible
granules,
emulsifiable
concentrates,
ready­
to­
use
liquids,
and
soluble
concentrates/
solids.
Products
are
applied
by
aerial,
broadcast,
and
directed
spray.
There
are
no
reported
impurities
of
toxicological
concern
in
hexazinone.
There
is
a
single
hexazinone
technical
[T]
product
registered
under
PC
Code
107201,
the
Dupont
98.7
%
T;
EPA
Reg.
No.
352­
399.
(K.
Dockter,
Product
Chemistry
Chapter
for
the
Tolerance
6
Reassessment
Eligibility
Decision,
April
23,
2002.)

Identity:
3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)
dione
Class:
Triazine
Empirical
formula:
C12
H20
N4
O2
Molecular
weight:
252.3
CAS
Registry
No.:
51235­
04­
2
Color:
White
Physical
state:
crystalline
solid
Odor:
mildly
pungent
MP:
113.5
C
Bulk
density:
0.61
g/
mL
Water
solubility:
2.98
g/
100g@
25
C
vapor
pressure:
1.9
x
10
­7
mm
Hg@
25
C
log
Pow
:
2.76
Stability:
stable
in
slightly
acidic
or
alkaline
media
at
elevated
temperatures,
slowly
degrades
under
artificial
sunlight.
Approximately
1%
decomposition
when
stored
2
years
under
ambient
conditions.

There
is
the
potential
for
exposure
to
the
chemical
via
all
routes,
oral,
dermal
and
inhalation.
Hexazinone
has
low
vapor
pressure
but
high
water
solubility,
indicating
a
strong
potential
to
enter
and
remain
in
water
systems.
There
is
low
potential
for
bioaccumulation
based
on
this
chemical's
properties.
This
tolerance
reassessment
eligibility
decision
document
will
assess
the
exposure
and
risks
via
the
oral
route
(food
and
water
pathways)
only.
There
are
no
residential
uses
for
hexazinone.
Occupational
exposures
and
risk
were
considered
at
the
time
of
the
Reregistration
Eligibility
Document
(RED,
1994)
and
risk
mitigation
recommendations
were
made
at
that
time.
The
purpose
of
this
document
is
to
reassess
the
hexazinone
tolerances
in
accordance
with
FQPA.
7
3.0
Hazard
Characterization
3.1
Hazard
Profile
The
acute
toxicity
of
hexazinone
is
presented
in
Table
1.
All
studies
were
performed
using
hexazinone
technical
as
the
test
substance.

Table
1:
Acute
Toxicity
of
Hexazinone
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
41235004
LD50
=
1200
mg/
kg
III
870.1200
Acute
dermal
toxicity
00104974
LD50
>
5278
mg/
kg
IV
870.1300
Acute
inhalation
toxicity
41756701
(1990)
LC50
>
3.94
mg/
L(
4
hour)
III
870.2400
Acute
eye
irritation
00106003
Irreversible
corneal
opacity
I
870.2500
Acute
dermal
irritation
00106004
Mild
IV
870.2600
Skin
sensitization
41235005
Not
a
dermal
sensitizer
in
the
Buehler
test
in
Guinea
pigs
NA
The
toxicity
profile
for
hexazinone
is
shown
in
Table
2.
8
Table
2:
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicity
rats
0010977
(1973)
Dose:
0,
200,
1000
or
5000
ppm
(equivalent
to
0,
16.0/
16.4,
81.0/
87.3,
440/
451
mg/
kg/
day,
male/
female)
Acceptable
NOAEL
=
1000
ppm
(81.0/
87.3
mg/
kg/
day
male/
female)
LOAEL
=
5000
ppm
(440/
451
mg/
kg/
day
male/
female)
based
on
decreased
body
weight
and
food
efficiency.

870.3150
90­
Day
oral
toxicity
in
non­
rodents
00114484
(1973)
Doses
of
0,
200,
1000,
or
5000
ppm
(equivalent
to
0/
0,
5.1/
7.0,
25.9/
31.6,
122.5/
137.3
mg/
kg/
day,
males/
females)

Acceptable
NOAEL
=
1000
ppm
(equivalent
to
25.9/
31.6
mg/
kg/
day
for
males/
females).
LOAEL
=
5000
ppm
(equivalent
to
122.5/
137.3
mg/
kg/
day
in
males/
females)
based
on
decreased
body
weight
gains,
increased
relative
liver
weights,
and
increased
alkaline
phosphatase
levels
in
both
sexes
and
transiently
decreased
food
consumption
in
the
females.

870.3200
21/
28­
Day
dermal
toxicity
in
rabbits
41309005
(1989)
Doses:
0,
50,
400,
or
1000
mg/
kg/
day
Acceptable
NOAEL
=
1000
mg/
kg/
day.
LOAEL
=
was
not
identified
for
systemic
and
dermal
toxicity.

870.3250
90­
Day
dermal
toxicity
Not
required
870.3465
90­
Day
inhalation
toxicity
The
90­
day
inhalation
study
is
not
required,
however
a
28­
Day
inhalation
study
is
required
­
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
9
870.3700a
Prenatal
developmental
in
rats
40397501
(1980)
Doses:
0,
40,
100,
400,
or
900
mg/
kg
Acceptable
Maternal
NOAEL
=
100
mg/
kg/
day
LOAEL
=
400
mg/
kg/
day
based
on
decreased
food
consumption
during
dosing
and
nominal
decreases
in
body
weight
gain
from
day
7
to
day
17
and
at
all
measured
intervals
between
and
at
900
mg/
kg/
day
mortality
and
decreased
body
weight
gains
and
food
consumption.
Developmental
NOAEL
=
400
mg/
kg/
day
LOAEL
=
900
mg/
kg/
day
and
at
900
mg/
kg/
day
an
increased
incidence
of
kidneys
with
no
papilla
(malformation),
and
an
increased
incidence
of
misaligned
sternebrae
(variation).

870.3700a
Prenatal
developmental
in
rats
00114486
(1974)
Doses:
0,
18.9,
94.5,
and
482.0
mg/
kg/
day
Unacceptable/
Upgradable
Maternal:
NOAEL
is
1000
ppm
(equivalent
to
94.5
mg/
kg/
day).
LOAEL
=
5000
ppm
(equivalent
to
482.0
mg/
kg/
day)
based
on
decreased
body
weights,
body
weight
gains,
and
food
efficiency.
Developmental:
NOAEL
=
5000
ppm
(equivalent
to
482.0
mg/
kg/
day).
LOAEL
was
not
observed.

870.3700b
Prenatal
developmental
in
rabbits
45677801
(2002)
Doses:
0,
50,
125,
175
mg/
kg/
day
Acceptable
Maternal:
NOAEL=
50
mg/
kg/
day.
LOAEL=
125
mg/
kg/
day
based
on
body
weight
gain
decrement,
decreased
food
consumption,
abortions,
death
and
clinical
signs
including
abnormal
gait
at
175
mg/
kg/
day.

Developmental:
NOAEL
=
50
mg/
kg/
day.
LOAEL=
125
mg/
kg/
day
based
on
mean
male
and
female
fetal
weight
decrement
and
female
fetal
weight
decrement.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
10
870.3700b
Prenatal
developmental
in
rabbits
00028863
(1980)
Doses:
0,
20,
50,
or
125
mg/
kg/
day
Unacceptable/
Upgradable
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
125
mg/
kg/
day
based
on
transient
decreases
in
food
consumption
and
body
weight
gains.
Developmental
NOAEL
=
50
mg/
kg/
day
LOAEL
=
125
mg/
kg/
day
based
on
possible
skeletal
abnormalities
and
total
abnormalies.

870.3800
Reproduction
and
fertility
effects
in
rats
42066501
(1991)
Acceptable
0,
200,
2000
or
5000
ppm
M:
0,
11.8,
117
or
294
mg/
kg/
day
F:
0,
14.3,
143
or
383
mg/
kg/
day
Parental/
Systemic
NOAEL
=
14.3
mg/
kg/
day
LOAEL
=
143
mg/
kg/
day
based
on
male
body
weight
decrement.
Reproductive
NOAEL
=
383
mg/
kg/
day
LOAEL
=
None
based
on
no
effects
on
or
organs
of
reproduction.
Offspring
NOAEL
=
14.3
mg/
kg/
day
LOAEL
=
143
mg/
kg/
day
based
on
reduced
female
pup
weight
at
birth
and
during
lactation.

870.4100a
Chronic
toxicity
in
rats
See
870.4300
870.4100b
Chronic
toxicity
dogs
42162301
(1991)
Doses:
0,
200,
1500,
or
6000
ppm
(equivalent
to
5.00/
4.97,
41.24/
37.6
and
161/
167
mg/
kg/
day,
male/
female.

Acceptable
NOAEL
=
200
ppm
(5.0/
4.97
mg/
kg/
day,
male/
female)
LOAEL
=
1500
ppm
(41.24
and
37.6
mg/
kg/
day,
respectively)
based
on
thinness
in
one
male
and
hepatotoxicity
as
evidenced
by
changes
in
clinical
chemistry
parameters
and
microscopic
lesions.

870.4200
Carcinogenicity
rats
See
below
870.4300
No
evidence
of
carcinogenicity
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
11
870.4200
Carcinogenicity
mice
00079203
(1981),
41359301
(1984),
42509301
(1992)
and
43202901
(1994)
Doses:
0,
0,
200,
2500
or
10,000
ppm
(equivalent
to
28/
34,
366/
450
and
1635/
1915
mg/
kg/
day,
male/
female)

Acceptable
NOAEL
=
200
ppm
(28/
450
mg/
kg/
day,
male/
female,
respectively)
LOAEL
=
2500
ppm
for
males
(equivalent
to
366
mg/
kg/
day)
based
on
gross
liver
nodules/
masses,
hyperplastic
nodules
in
the
liver
and
centrilobular
hepatocyte
hypertrophy
and
10,000
ppm
for
females
(equivalent
to
1915
mg/
kg/
day
[limit
dose])
based
on
decreased
body
weights,
increased
relative
liver/
gall
bladder
weights,
hyperplastic
nodules
and
centrilobular
hepatocyte
hypertrophy.
Insufficient
evidence
for
carcinogenicity
in
mice.

870.4300
Combined
chronic/
carcinogenicity/
rats
00108638
(1977)
Doses:
0,
200,
1000,
or
2500
ppm
(equivalent
to
0,
10.2/
12.5,
53.4/
67.5,
or
138/
179
mg/
kg/
day,
male/
female)

Acceptable
NOAEL
=
200
ppm
for
males
and
females
(10.2/
12.5
mg/
kg/
day,
male/
female).
LOAEL
=
1000
ppm
for
males
and
females
(equivalent
to
53.3/
67.5
mg/
kg/
day,
male/
female)
based
on
decreased
body
weight
and
food
efficiency
in
males
and
females.
In
males
at
2500
ppm
the
body
weight
decrement
and
food
efficiency
decrement
occurred
only
for
the
first
6
months
of
the
study.
The
carcinogenic
potential
of
hexazinone
is
considered
negative
in
rats.

Gene
mutation
870.5100;
Reverse
mutation
in
Salmonella
strains
40826201
(1977)
200,
400,
600,
800
and
1000
:
g/
plate
­S9
and
400,
800,
1200,
1600
and
2000
:
g/
mL
+
S9­
mix.

Unacceptable
No
mutagenic
potential
was
seen,
but
doses
insufficient
to
cause
cell
toxicity.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
12
Gene
mutation
870.5300;
hamster
CHO
cells/
HPRT
assay
00076956
(1980)
Trial
1
were
2.0,
11.1,
13.1,
13.9
and
14.3
mM
­S9
and
2.0,
7.9,
8.9,
9.3
and
9.9
mM
+S9.
Trial
2
were
2.0,
5.9,
11.1,
13.1
and
13.9
mM
­S9
and
2.0,
7.9,
8.9,
9.3
and
9.9
mM
+
S9.

Acceptable
No
evidence
of
mutagenic
potential
at
cytotoxic
doses.

Cytogenics
870.5375;
Chromosomal
aberrations
in
hamster
CHO
cells
00130709
(1982)
In
Trial
1,
1.58,
3.94,
15.85
and
19.82
mM
­S9
and
0.32,
3.17,
7.93
and
15.85
mM
+
S9.
In
Trial
2,
1.58,
3.94,
7.93
and
15.85
S9
0.32,
3.17,
7.93
and
15.85
mM
+
S9
Acceptable
Positive
for
structural
chromosomal
aberrations
with
and
without
S9.

Other
Effects
870.5385,
In
vivo
Rat
bone
marrow
cytogenics
assay
00131355
(1982)
Rat
doses:
1000,
2000
or
3000
mg/
kg
Unacceptable
No
evidence
of
mutagenic
potential,
but
insufficient
animals
and
cells
were
tested.

Other
Effects
870.5395
Mouse
bone
marrow
micronucleus
test
45124401
(2000)
Mouse
doses:
1000,
2000
and
3000
mg/
kg
Acceptable
No
evidence
of
clastogenic
or
aneugenic
effect
in
bone
marrow
at
toxic
doses.
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
13
Other
Effects
870.5550,
UDS
in
rat
hepatocytes
00130708
(1983)
Trial
1:
1
x
10
­5
,
1
x
10
­4
,
1
x
10
­3
,
1
x
10
­2
,
0.1,
1.0,
10.0
and
30.0
mM
and
Trial
2:
1
x
10
­5
,
1
x
10
­4
,
1
x
10
­3
,
1
x
10
­2
,
0.1,
1.0,
5.0,
10.0
and
30.0
mM.
Acceptable
No
evidence
of
mutagenic
potential
at
precipitating
dose
levels.

870.6200a
Acute
neurotoxicity
screening
battery
Not
required
870.6200b
Subchronic
neurotoxicity
screening
battery
Not
required.

870.6300
Developmental
neurotoxicity
Not
required.

870.7485
Metabolism
and
pharmacokinetics
00140162
&
00109237
(1980
&1982)
Acceptable
No
parent
was
seen
in
urine
or
feces,
which
was
rapidly
absorbed
and
excreted.
Two
identified
metabolites
resulted
from
hydroxylation
of
the
cyclohexyl
ring
and
differed
only
by
the
metabolic
conversion
of
the
6­
dimethyl
amine
to
a
secondary
methyl
amine.
No
sex­,
or
dose­
related
differences
in
the
formation
and
excretion
of
these
metabolites
were
found.

870.7600
Dermal
penetration
Not
required
Special
studies
None
submitted
The
toxicological
database
for
hexazinone
is
considered
complete
for
hazard
characterization.
The
toxicity
profile
of
hexazinone
can
be
characterized
for
potential
reproductive,
developmental
and
neurological
effects.
Primary
effects
of
hexazinone
toxicity
include
body
weight
decrement
and
liver
toxicity.
There
is
no
evidence
of
developmental
or
14
reproductive
susceptibility
in
the
studies
for
the
chemical.
Hexazinone
is
considered
a
Group
D
carcinogen,
not
classifiable
as
to
carcinogenicity.
There
is
an
adequate
metabolism
study
in
the
rat.
However,
the
Agency
requires
a
28­
day
inhalation
study
for
hexazinone
because
of
concern
for
potential
inhalation
exposure
based
on
the
use
pattern.
(D.
Anderson,
Toxicology
Disciplinary
Chapter,
May
30,
2002.)

Hexazinone
has
low
acute
toxicity
by
the
oral
(Category
III),
dermal
(Category
IV
)
and
inhalation
routes
(Category
III).
However,
primary
eye
irritation
is
severe,
causing
corneal
opacity
and
moderate
irritation
in
unwashed
eyes
(Category
I).
It
causes
mild
skin
irritation
(Category
IV)
and
is
not
a
skin
sensitizer
in
the
Guinea
pig.
The
21­
day
dermal
study
in
the
rabbit
showed
no
systemic
toxicity
and
mild
dermal
irritation
at
the
limit
dose.

Body
weight
decrement,
decreased
food
consumption,
and
kidney
and
liver
effects
were
seen
in
acute
and
chronic
studies
with
hexazinone.
The
chronic
dog
and
mouse
studies
resulted
in
liver
toxicity.
Both
chronic
rat
studies
and
the
rat
reproduction
study
show
body
weight
decrement.
The
chronic
study
in
dogs
showed
severe
body
weight
decrement
in
addition
to
changes
in
liver
related
clinical
chemistry
values
and
microscopic
lesions
in
the
liver.

In
a
rat
reproduction
study,
pup
weight
decrement
occurred
at
the
same
dose
as
parental
body
weight
decrement.
No
other
reproductive
effects
were
seen
in
the
study.
The
rat
prenatal
developmental
toxicity
study
showed
fetal
weight
decrement
and
renal
malformations,
but
no
increased
susceptibility.
The
rabbit
prenatal
developmental
toxicity
study
developmental
effects
were
seen
at
the
same
dose
showing
maternal
toxicity;
no
susceptibility
was
identified
in
this
study.

Body
weight
decrement
was
seen
in
both
the
chronic
carcinogenicity
study
in
rats
and
mice.
The
mouse
carcinogenicity
study
showed
an
increased
trend
for
liver
carcinomas,
but
no
pair
wise
significant
increases
were
identified.
The
rat
study
showed
no
carcinogenic
potential.
Because
there
is
no
evidence
of
carcinogenicity
in
rats
and
insufficient
evidence
of
carcinogenicity
in
the
mouse,
the
RfD/
Peer
Review
Committee
classified
hexazinone
as
a
group
D
chemical,
not
classifiable
as
to
human
carcinogenicity.

Rat
metabolism
studies
showed
that
hexazinone
was
rapidly
absorbed
and
excreted
with
essentially
no
difference
in
the
metabolism
of
males
and
females
at
high
or
low
dose
levels.
Almost
no
parent
hexazinone
was
recovered
in
urine
or
feces.
Metabolites
A
(66%)
[3­(
4­
hydroxycyclohexyl)­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione]
and
C
(28%)
[3­(
4­
hydroxycyclohexyl)­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione]
were
recovered
from
feces
and
urine,
in
addition
to
lesser
amounts
of
metabolite
B
(9%)
[(
3­
(cyclohexyl)­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione]
and
small
amounts
of
conjugated
products
in
urine
(<
5%).
These
metabolites
are
also
present
in
plant
and
animal
commodities
as
well
as
in
environmental
studies.
For
the
purposes
of
risk
assessment,
the
toxicity
of
the
metabolites
and/
or
degradates
were
assumed
to
be
equal
to
the
parent
hexazinone
due
to
similarity
in
structure.
However,
hexazinone
is
not
likely
to
be
toxicologically
related
to
15
other
triazine
pesticides.

The
Hazard
Identification
and
Review
Committee
(HIARC)
requested
a
28­
day
inhalation
toxicity
study
with
hexazinone
because
of
the
concern
for
potential
inhalation
exposure
based
on
the
use
pattern.

3.2
FQPA
Considerations
The
toxicology
database
for
hexazinone
contains
acceptable
developmental
and
reproduction
studies
in
the
rat
and
in
the
rabbit;
there
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
in
the
fetuses
or
offspring
in
these
studies.
The
HIARC
concluded
that
a
developmental
neurotoxicity
study
with
hexazinone
is
not
required
because
there
is
no
evidence
of
neurotoxicity
in
the
database.

There
are
no
residual
uncertainties
identified
in
the
exposure
databases.
The
dietary
food
exposure
assessment
is
Tier
1,
screening
level,
which
is
based
on
tolerance
level
residues
and
assumed
100%
of
all
crops
are
treated
with
hexazinone.
The
dietary
drinking
water
assessment
uses
monitoring
data
(groundwater)
and
modeling
results
(surface
water)
based
on
chemicalspecific
data
and
includes
extrapolated
estimates
for
all
degradates
of
concern.
These
assessments
will
not
underestimate
the
exposure
and
risks
posed
by
hexazinone.
The
safety
factor
recommendation
is
based
on
the
assumption
that
the
use
of
hexazinone
on
pasture
and
rangeland
grasses
is
withdrawn
(due
to
lack
of
field
trial
residue
data
for
forage
and
hay)
and
that
all
established
tolerances
associated
with
this
use
are
revoked.
The
FQPA
SFC
recommends
OPP
depart
from
the
default
10X
additional
safety
factor
and
instead
use
a
different
additional
safety
factor
of
1X
to
assessing
exposure
and
risk
associated
with
the
use
of
hexazinone;
no
additional
traditional
safety
factors
are
needed
with
regard
to
the
completeness
of
the
hexazinone
toxicity
database
and
no
Special
FQPA
Safety
Factor
is
necessary
to
protect
the
safety
of
infants
and
children.
(B.
Tarplee,
Hexazinone
­
2
nd
Report
of
the
FQPA
Safety
Factor
Committee,
August
8,
2002.)

3.3
Dose
Response
Assessment
Toxicological
endpoints
were
established
for
exposure
scenarios
of
interest
to
this
risk
assessment.
For
this
tolerance
reassessment
eligibility
decision
for
hexazinone,
only
the
acute
and
chronic
dietary
exposure
scenarios
will
be
assessed.
Acute
dietary
exposure
to
the
general
population
is
not
included
in
this
assessment
since
there
was
no
appropriate
endpoint
attributable
to
a
single­
dose
identified
in
the
database.
Three
toxicological
studies
determined
endpoint
doses
for
the
relevant
exposure
scenarios:
a
developmental
toxicity
study
in
the
rat
and
in
the
rabbit
and
a
chronic
feeding
study
in
the
dog.
The
HIARC
also
selected
endpoints
for
the
dermal
and
inhalation
routes
of
exposure.
However,
as
there
are
no
exposure
scenarios
pertaining
to
these
routes
of
exposure
assessed
in
this
action,
these
endpoints
are
not
listed
in
Table
3.
A
discussion
16
of
the
dose­
response
relationships
for
acute
and
chronic
dietary
endpoints
follows
presentation
of
Table
3.
(Hexazinone­
3
rd
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(HIARC),
TXR
0051033,
August
12,
2002.)
17
Table
3:
Hazard
Endpoint
Selection
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
and
Exposure
Based
Special
FQPA
Safety
Factor
Study
and
Endpoint
for
Risk
Assessment
Dietary
Risk
Assessments
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
400
UF
=
100
Acute
RfD
=
4.0
mg/
kg/
day
1x
aPAD=
4.0
mg/
kg/
day
Developmental
Toxicity
­
Rat
Decreased
male
and
female
fetal
weight,
kidneys
with
no
papilla
(malformation)
and
misaligned
sternebrae
(variation)

Acute
Dietary
general
population
including
infants
and
children
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified
in
the
oral
studies.

Chronic
Dietary
all
populations
NOAEL=
5.0
UF
=
100
Chronic
RfD
=
0.05
mg/
kg/
day
1x
cPAD=
0.05
mg/
kg/
day
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.

Cancer
Group
D
­
Not
Classifiable
as
to
human
carcinogenicity
3.3.1
Acute
Reference
Dose
(RfD)
­
Females
13­
50
The
study
selected
to
define
the
dose­
response
relationship
for
risk
assessment
of
acute
dietary
exposure
to
females
13­
50
is
a
developmental
toxicity
study
in
the
rat
(MRID
40397501).
In
this
study,
hexazinone
was
administered
orally
to
female
rats
at
dose
levels
of
0,
40,
100,
400,
or
900
mg/
kg
on
gestation
day
7
through
16.
There
were
no
treatment­
related
changes
in
clinical
signs,
gross
pathology,
pregnancy
rate,
live
fetuses,
resorption,
pre­
or
post­
implantation
loss,
corpora
lutea,
or
implantations
noted
at
any
dose
level
tested
in
the
dams.
At
the
highest
dose
tested,
one
treatment
related
death,
alopecia
and
enlarged
stomach,
decreased
body
weight
gain
and
decreased
food
consumption
occurred.
The
maternal
LOAEL
is
400
mg/
kg/
day
based
on
decreased
food
consumption
during
dosing
and
nominal
decreases
in
body
weight
gain
from
day
7
to
day
17
and
at
all
measured
intervals
in
the
dosing
regimen.
The
maternal
NOAEL
is
100
18
mg/
kg/
day.

In
the
fetuses
at
the
highest
dose
tested
male
and
female
fetal
weights
were
decreased
and
there
was
an
increased
incidence
of
misaligned
sternebrae.
Furthermore,
an
increased
incidence
of
kidneys
with
no
papilla
was
observed.
Although
the
incidence
was
not
statistically
significant,
a
dose­
related
trend
was
observed.
The
developmental
toxicity
LOAEL
is
900
mg/
kg/
day,
based
on
decreased
male
and
female
fetal
weight
and
increased
incidence
of
kidneys
with
no
papilla
(malformation),
and
an
increased
incidence
of
misaligned
sternebrae
(variation).
The
malformations
are
presumed
to
occur
after
a
single
dose
and
thus
appropriate
for
acute
risk
assessment.
The
dose
selected
for
establishing
the
acute
reference
dose
(aRfD)
for
females
13­
50
is
the
developmental
NOAEL
of
400
mg/
kg/
day.
Because
the
toxic
endpoint
for
acute
dietary
exposure
concern
in
utero
exposure,
the
risk
assessment
is
performed
for
females
of
childbearing
age
(females
13­
50),
since
only
members
of
this
group
are
at
risk
of
being
pregnant
at
the
time
of
exposure.
Traditional
uncertainty
factors
(UFs)
of
10X
(10X
intraspecies
variation;
10X
interspecies
extrapolation)
are
applied
to
the
RfD.
There
are
no
additional
traditional
or
"special"
uncertainty
factors
applied
to
the
RfD
(1X)
because
there
is
no
susceptibility
identified
in
the
hazard
database.

3.3.2
Chronic
Reference
Dose
(RfD)

The
study
selected
to
define
the
dose­
response
relationship
for
risk
assessment
is
a
oneyear
chronic
dog
study
(MRID
42162301).
Hexazinone
was
administered
to
beagle
dogs
in
the
diet.
Time­
weighted
average
doses
for
the
treated
groups
were
5.00,
41.24,
and
161.48
mg/
kg/
day,
respectively,
for
males
and
4.97,
37.57,
and
166.99
mg/
kg/
day,
respectively,
for
females.
All
animals
survived
to
scheduled
necropsy.
Treatment­
related
clinical
signs
of
toxicity
included
the
observation
of
thinness,
decreased
body
weight,
and
decreased
food
consumption.
Clinical
chemistry
changes
such
as
moderate
macrocytic
anemia,
decreases
in
RBC
counts,
hemoglobin,
and
hematocrit
and
increases
in
MCV
and
MCH
in
one
or
both
sexes
throughout
the
study.
For
the
high­
dose
animals,
decreases
in
absolute
testes
weights
in
males
and
kidney,
heart,
and
brain
weights
in
females
(­
12%)
and
increases
in
relative
liver
weights
in
males
and
females
were
considered
due
to
lower
final
body
weights
of
these
animals
as
compared
with
controls.
Liver
effects
were
seen
in
the
high
dose
animal
group.
This
group
had
aspartate
aminotransferase
levels
140­
203%
(p
#
0.05)
of
the
control
values
and
alanine
aminotransferase
levels
206­
276%
(p
#
0.05)
of
the
control
values.
Alkaline
phosphatase
levels
were
also
significantly
(p
#
0.05)
increased
in
the
mid­
dose
males
(259­
409%
of
controls)
and
females
(163­
194%
of
controls)
beginning
at
week
26
and
in
the
high­
dose
males
(346­
1363%
of
Acute
RfD
(Females
13­
50)
=
400
mg/
kg/
day
=
4.0
mg/
kg/
day
100
(UF)
19
controls)
and
females
(307­
559%
of
controls)
beginning
at
week
13.
Microscopic
lesions
in
the
liver
of
high­
dose
animals
included
concentric
membranous
bodies
in
4
males
and
5
females,
centrilobular
single
cell
necrosis
in
3
males
and
3
females,
hepatocellular
pigment
in
3
males
and
3
females,
and
vacuolation
in
3
males
and
4
females.
In
addition
vacuolation
was
observed
in
one
mid­
dose
male
and
pigment
and
membranous
bodies
were
each
observed
in
one
mid­
dose
female.
These
lesions
were
not
seen
in
control
or
low­
dose
animals.

The
study
selected
for
the
chronic
dietary
endpoint
is
of
the
appropriate
duration
for
assessing
long­
term
exposure.
The
RfD/
peer
Review
Committee
chose
the
same
dose
and
endpoint
in
1994,
which
formed
the
basis
of
the
Chronic
RfD
for
the
1994
RED.
The
dose
selected
for
establishing
the
chronic
dietary
endpoint
is
the
NOAEL
of
5.0
mg/
kg/
day.
The
LOAEL
is
38
mg/
kg/
day
based
on
elevated
clinical
chemistry
values
(serum
alkaline
phosphatase,
serum
aspartate
aminotransferase),
other
changes
in
clinical
chemistry
values,
liver
microscopic
findings
and
body
weight
decrement
and
clinical
observation
of
thinness
in
one
male
(4
of
10
males
and
females
at
the
next
higher
dose).
An
uncertainty
factor
of
100
(10x
interspecies
and
10x
intra­
species)
is
applied
to
the
endpoint.

3.4
Endocrine
Disruption
EPA
is
required
under
the
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
hexazinone,
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,
hexazinone
may
be
subject
to
additional
screening
and/
or
testing
to
further
characterize
effects
related
to
endocrine
disruption.
Chronic
RfD
=
5.0
mg/
kg/
day
(NOAEL)
=
0.05
mg/
kg/
day
100
(UF)
20
4.0
Exposure
Assessment
and
Characterization
4.1
Summary
of
Registered
Use
Patterns
Hexazinone
[3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)
dione
is
a
triazine­
dione
herbicide
registered
for
use
on
alfalfa,
blueberries,
pasture
and
range
grasses,
pineapple,
and
sugarcane.
It
is
also
registered
for
use
on
ornamental
plants,
forest
trees,
and
non­
crop
areas.
Hexazinone
is
used
to
control
a
variety
of
weed
species
including
geratum,
alder,
and
alexander
grass
and
works
through
inhibition
of
photosynthesis.
Hexazinone
is
a
proprietary
chemical
of
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.
which
is
the
sole
producer
and
primary
registrant
of
this
broad
spectrum
herbicide.
Hexazinone
formulations,
sold
under
the
trade
name
Velpar®,
may
be
applied
pre­
or
post­
emergence
by
layby,
broadcast,
directed
spray,
or
basal
soil
treatments
using
ground
or
aerial
equipment.
(J.
Punzi,
Hexazinone
Tolerance
Reassessment
Eligibility
Decision
Residue
Chemistry
Chapter,
DP
Barcode
D279899,
May
20,
2002.)

Hexazinone
is
formulated
as
a
dry
flowable
(DF),
emulsifiable
concentrate
(EC),
soluble
concentrate
(SC)
and
as
a
granular
(G)
and
these
end­
use
products
are
registered
to
DuPont
for
food/
feed
uses.
The
range
of
percentage
of
active
ingredient
in
the
product
formulations
is
10­
90%.
The
application
rates
range
from
1­
4
lbs.
active
ingredient
per
acre.
The
number
of
applications
per
year
(or
season)
are
typically
limited
to
one
per
year.
Hexazinone
is
mainly
an
early
season
use,
PHIs
range
from
180­
234
days,
but
PHIs
are
30­
60
days
for
alfalfa
and
blueberry,
respectively.

A
profile
of
hexazinone
usage
has
been
developed
by
the
OPP
Biological
and
Economic
Analysis
Division
(BEAD).
The
use
profile
is
based
on
data
from
US
EPA,
USDA
and
the
National
Center
for
Food
and
Agricultural
Policy.
From
1991
through
2000,
the
total
annual
domestic
usage
of
hexazinone
averaged
approximately
400,000
pounds
of
active
ingredient
for
over
700,000
acres
treated.
Hexazinone's
largest
markets
in
terms
of
total
pounds
active
ingredient
includes
alfalfa,
woodland,
and
pasture
and
rangeland.
Alfalfa
is
the
crop
with
the
highest
percent
of
crop
treated.
Crops
with
less
than
1
percent
treated
include
blueberries,
other
hay,
and
sugarcane.
(F.
Hernandez,
Quantitative
Usage
Analysis
for
Hexazinone,
September
10,
2001.)

There
are
no
registered
uses
for
this
chemical
at
residential
sites.
Occupational
exposures
are
not
considered
in
this
tolerance
reassessment
action.
The
populations
of
concern
for
this
assessment
are
those
who
may
be
exposed
through
consuming
crops
treated
with
hexazinone
or
consuming
water
containing
hexazinone
residues.

4.2
Dietary
(Food)
Exposure/
Risk
Pathway
Tolerance
reassessment
and
dietary
risk
assessment
for
hexazinone
is
based
on
the
residue
data
summarized
in
this
section.
Tolerances
for
residues
of
hexazinone
in/
on
plant,
21
animal,
and
processed
commodities
are
currently
expressed
in
terms
of
the
combined
residues
of
hexazinone
and
its
metabolites
(calculated
as
hexazinone).
Permanent
tolerances
are
established
for
plant
and
animal
commodities
under
40
CFR
§180.396(
a).
Hexazinone
tolerances
with
regional
(Florida
sugarcane)
registrations
are
established
under
40
CFR
§180.396(
c).
Tolerances
exist
for
blueberry,
pineapple,
sugarcane,
alfalfa
and
grasses
as
well
and
meats
and
milk.
Current
tolerances
range
from
0.02
to
0.5
ppm
on
raw
agricultural
commodities,
8.0­
10.0
ppm
on
agricultural
feed
items,
and
are
0.1
ppm
for
secondary
residues
in
meats
and
milk.
HED
is
requesting
the
registrant
to
propose
a
tolerance
for
hexazinone
residues
of
concern
in/
on
alfalfa
seed
of
2.0
ppm
based
upon
a
residue
field
trial
study
at
1.5x
the
maximum
registered
rate
on
alfalfa
grown
for
seed.
Reassessed
tolerances
range
from
0.1
to
4.0
ppm.
(J.
Punzi,
Hexazinone
Tolerance
Reassessment
Eligibility
Decision
Residue
Chemistry
Chapter,
DP
Barcode
D279899,
May
20,
2002.)

4.2.1
Residue
Profile
The
HED
Metabolism
Assessment
Review
Committee
(MARC)
has
reviewed
the
hexazinone
toxicology
and
metabolism
data
(meeting
dates
1/
29/
02
and
3/
12/
02)
and
recommends
that
the
tolerance
expression
for
plant
material
should
include
hexazinone
(parent)
and
metabolites
A,
B,
C,
D,
and
E.
The
tolerance
expression
for
milk
should
include
hexazinone
(parent)
and
metabolites
B,
C,
C­
2,
and
F,
and
the
tolerance
expression
for
ruminant
tissue
should
include
hexazinone
(parent)
and
metabolites
B
and
F.
The
tolerance
expression
should
be
modified
to
include
the
specific
metabolites
(A,
B,
C,
C­
2,
D,
E
and
F)
by
the
appropriate
chemical
name
(See
Table
4).
The
Agency
has
determined
that
tolerances
for
hexazinone
residues
in
eggs
and
poultry
tissue
are
not
required
based
on
the
results
of
the
respective
poultry
metabolism
and
feeding
studies
(CFR
§180.6(
a)(
3)).
(S.
Kinard,
The
Outcome
of
the
HED
Metabolism
Review
Committee
for
Water,
April
25,
2002.)

Adequate
residue
data
have
been
submitted
to
reassess
the
tolerances
for
alfalfa
(seed,
forage,
hay),
blueberries,
pineapple,
sugarcane,
and
associated
livestock
commodities
(meat,
milk).
Residue
data
are
not
adequate
to
reassess
tolerances
for
pasture
and
rangeland
grass
(forage
and
hay)
and
a
recommendation
has
been
made
to
revoke
those
tolerances
and
to
withdraw
this
use
from
the
product
labels.
Data
depicting
magnitude
of
the
residues
of
hexazinone
and
metabolites
A,
B,
C,
D,
and
E
in/
on
grass
forage
and
hay
harvested
the
day
following
a
single
broadcast
application
of
representative
formulations
at
1.125
lb
ai/
A
are
listed
as
data
requirements
in
the
Residue
Chemistry
chapter.
However,
these
data
are
not
listed
as
required
in
this
action
because
the
tolerance
reassessment
and
risk
assessment
will
assume
that
the
tolerances
are
revoked
and
the
uses
withdrawn
from
the
label
due
to
the
lack
of
field
trial
data.

The
MARC
also
recommended
that
for
the
purposes
of
risk
assessment
estimates
of
dietary
exposure
and
risk
should
be
based
on
residue
estimates
of
hexazinone
(parent)
and
metabolites
B,
C,
C­
1,
C­
2,
and
F
for
ruminant
commodities
and
metabolites
A,
B,
C,
D,
and
E
for
plant
commodities.
The
metabolites
and
parent
hexazinone
are
assumed
to
have
equal
22
toxicity
based
upon
similarity
in
chemical
structure.

Metabolism
in
Plants
and
Animals
The
qualitative
nature
of
hexazinone
residue
in
plants
and
animals
is
adequately
understood
based
on
submitted
metabolism
studies
in
alfalfa,
pineapple,
sugarcane,
ruminants,
and
poultry.

Plants:
Plant
metabolism
studies
indicate
that
root
uptake
is
the
principal
mechanism
for
the
absorption
of
hexazinone
by
plants
from
soils.
Hexazinone
is
translocated
through
the
xylem
to
the
foliage
where
it
blocks
the
photosynthetic
process.
Hexazinone
is
metabolized
by
hydroxylation
to
metabolite
A
which
is
then
metabolized
to
metabolite
C
by
demethylation,
and
to
metabolite
E
after
oxidation.
In
an
alfalfa
metabolism
study,
alfalfa
was
sprayed
with
[
14
C]
hexazinone
dissolved
in
water
at
an
application
rate
equivalent
to
1.0
lb
ai/
100
gal/
A.
Alfalfa
samples
were
collected
at
two,
three,
and
six
months
after
treatment.
Total
radioactive
residues
(TRR),
calculated
as
hexazinone,
declined
at
each
sampling
interval,
and
were
0.6,
0.5,
and
0.1
ppm
(95,
84,
and
80%
respectively).
Analysis
of
the
two­
month
alfalfa
cutting
identified
hexazinone
(2.7%
TRR),
free
metabolite
A
(7.1%
TRR),
free
metabolite
B
(0.7%
TRR),
and
conjugated
metabolites
A,
B,
and
C
(4.5%
TRR).
The
remaining
radioactive
residues
were
found
in
water­
soluble,
polar
materials
comprised
of
amino
acids,
sugars,
polybasic
acids,
and
smaller
amounts
of
natural
products.
In
a
pineapple
metabolism
study,
94­
99%
of
TRR
was
extractable
with
the
following
components
identified
in
the
pulp:
hexazinone
(0.8­
1.8%
TRR),
metabolite
A
(23­
28%
TRR),
metabolite
C
(13­
15%
TRR),
metabolite
D
(16­
21%
TRR),
and
metabolite
F
(1­
2%
TRR).
The
following
components
were
identified
in
sugarcane:
metabolite
E
(30%
TRR),
metabolite
C
(23%
TRR),
metabolite
A
(14%
TRR),
metabolite
B
(1%
TRR),
metabolite
D
(3%
TRR),
and
hexazinone
(<
1%
TRR).

Animals:
A
lactating
goat
was
dosed
orally
with
[
14
C]
hexazinone
radiolabeled
in
the
triazine
ring
at
a
dose
rate
of
136.4
mg/
day,
equivalent
to
2.2
mg/
kg/
body
weight
for
five
consecutive
days.
TRRs,
expressed
as
hexazinone
equivalents,
were
6.74
ppm
in
milk,
3.03
ppm
in
liver,
2.54
ppm
in
kidney,
0.27
ppm
in
muscle,
and
0.03
ppm
in
fat.
Residues
were
adequately
extracted,
characterized,
and
identified,
and
on
this
basis
the
MARC
concluded
that
the
hexazinone
tolerance
expression
for
milk
should
include
hexazinone
plus
metabolites
B,
C,
C­
2.
The
MARC
also
concluded
that
the
hexazinone
tolerance
expression
for
ruminant
tissue
should
include
hexazinone
plus
metabolites
B
and
F
and
that
residues
of
hexazinone
and
metabolites
B,
C,
C­
1,
C­
2,
and
F
should
be
taken
into
account
for
risk
assessment.

In
a
poultry
metabolism
study
five
laying
hens
were
dosed
orally
at
6.9
mg/
day
with
carbonyl­
labeled
[
14
C]
hexazinone
for
six
consecutive
days.
The
daily
dose
rate
was
equivalent
to
57
ppm
in
the
feed,
which
is
38x
the
maximum
theoretical
dietary
burden.
No
single
metabolite
in
edible
poultry
tissue
was
greater
than
0.04
ppm,
and
unidentified
metabolites
represented
less
than
0.05
ppm
in
all
edible
tissues.
For
these
reasons,
poultry
tolerances
are
not
necessary.
23
N
N
N
O
O
CH
3
N
CH
3
CH
3
N
N
N
O
O
CH
3
N
CH
3
CH
3
HO
N
N
N
O
O
CH
3
N
H
CH
3
Table
4:
Chemical
Structures
of
Hexazinone
and
its
Regulated
Metabolites
(Metabolites
A
through
F)

Common
Name/
Code
Chemical
name
Structure
Hexazinone
3­
cyclohexyl­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H
dione
Metabolite
A
3­(
4­
hydroxycyclohexyl)­
6­
(dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)­
dione
Metabolite
A­
1
is
hydroxylated
at
the
2­
position
of
the
cyclohexyl
ring;
Metabolite
A­
2
is
hydroxylated
at
the
3­
position
of
the
cyclohexyl
ring.

Metabolite
B
3­
cyclohexyl­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H
dione
Common
Name/
Code
Chemical
name
Structure
24
N
N
N
O
O
CH
3
N
H
CH
3
HO
N
N
NH
O
O
CH
3
O
N
N
NH
O
O
CH
3
O
HO
N
N
N
O
O
CH
3
NH
2
Metabolite
C
3­(
4­
hydroxycyclohexyl)­
6­
methylamino
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H
dione
Metabolite
C­
1
is
hydroxylated
at
the
2­
position
of
the
cyclohexyl
ring;
Metabolite
C­
2
is
hydroxylated
at
the
3­
position
of
the
cyclohexyl
ring.

Metabolite
D
3­
cyclohexyl­
1­
methyl­
1,3,5­
triazine
2,4,6­(
1H,
3H,
5H)­
trione
Metabolite
E
3­(
4­
hydroxycyclohexyl)­
1­
methyl
1,3,5­
triazine­
2,4,6­(
1H,
3H,
5H)­
trione
Metabolite
F
3­
cyclohexyl­
6­
amino­
1­
methyl
1,3,5­
triazine­
2,4­(
1H,
3H)­
dione
25
Residue
Analytical
Methods
Plant
Matrices:
Adequate
methods
are
available
for
purposes
of
enforcement
of
tolerances
and
data
collection
for
residues
of
hexazinone
and
metabolites
A,
B,
C,
D,
and
E
in/
on
plant
commodities.
For
tolerance
enforcement,
the
Pesticide
Analytical
Manual
(PAM)
Volume
II
lists
Method
I
as
available
for
the
determination
of
hexazinone
residues
of
concern
in/
on
plant
commodities.
The
combined
limit
of
quantitation
(LOQ)
for
hexazinone
residues
(parent
and
metabolites)
by
Method
I
in
PAM
Volume
II,
is
0.55
ppm.

For
data
collection,
the
registrant
utilized
Methods
92013­
V2
and
92013­
V3
during
analyses
of
samples
collected
from
a
recent
field
residue
study
submission
on
alfalfa.
Methods
92013­
V2
and
92013­
V3
have
been
deemed
adequate
for
data
collection
based
on
acceptable
method
validation
and
concurrent
recovery
data.

Animal
Tissue
/
Milk:
The
registrant
has
proposed
a
liquid
chromotography/
mass
spectroscopy
(LC/
MS)
method
(AMR
3783­
96)
as
an
enforcement
method
for
livestock
commodities.
The
proposed
method
would
determine
residues
of
parent
hexazinone,
metabolite
B,
metabolite
C
and
its
isomer
(C­
2),
and
metabolite
F
in
milk.
In
livestock
tissues,
Method
AMR
3783­
96
would
determine
residues
of
parent
hexazinone,
metabolite
B,
and
metabolite
F.
The
reported
limits
of
quantitation
(LOQ)
s
were
0.02
ppm
for
hexazinone
and
metabolite
B
and
0.05
ppm
for
metabolites
C,
C­
2,
and
F.
This
method
has
been
subjected
to
a
successful
independent
laboratory
validation
(ILV)
and
a
radiovalidation
study
and,
if
method
validation
by
the
Agency
is
successful,
the
method
will
be
proposed
for
inclusion
in
PAM
Volume
II
(no
additional
data
concerning
this
guideline
topic
will
be
required
for
reregistration).

Multi­
Residue
Methods
The
reregistration
requirements
for
multiresidue
methods
data
are
fulfilled.
However,
the
10/
99
FDA
PESTDATA
database
(PAM
Volume
I,
Appendix
I)
indicates
that
hexazinone
(and
metabolites
A,
B,
C,
D,
and
E)
are
only
partially
recovered
(50­
80%)
using
Multiresidue
Method
Sections
302
(Luke
Method;
Protocol
D)
and
are
not
recovered
using
Sections
303
(Mills,
Onley,
Gaither;
Protocol
E
­
nonfatty
foods)
and
304
(Mills;
Protocol
E
­
fatty
foods).

Field
Trial
Data
Reassessed
tolerances
and
the
dietary
risk
assessment
are
based
on
field
trail
data
conducted
on
blueberries,
alfalfa,
pineapple,
and
sugarcane.
Pending
label
revisions
for
certain
crops,
the
reregistration
requirements
for
data
depicting
"magnitude
of
the
residue"
in/
on
the
following
raw
agricultural
commodities
(RACs)
are
satisfied:
alfalfa
forage,
alfalfa
hay,
alfalfa
seed,
blueberries,
pineapple,
and
sugarcane.
An
adequate
number
of
field
trials
have
been
conducted
for
these
RACs,
and
the
trials
were
conducted
using
registered
hexazinone
formulation(
s)
at
the
maximum
registered
rate.
However,
the
reregistration
requirements
for
data
depicting
magnitude
of
the
residue
in/
on
grass
forage
and
grass
hay
are
not
satisfied.
The
lack
of
26
these
data
prevent
calculation
of
a
maximum
theoretical
dietary
burden
(MTDB)
for
livestock
which
includes
these
feed
items.

The
Health
Effects
Division
(HED)
is
recommending
that
in
order
to
reassess
the
established
hexazinone
tolerances
for
milk
and
the
fat,
meat,
and
meat
byproducts
of
livestock
and
to
compute
a
maximum
theoretical
dietary
burden
(MTDB)
of
hexazinone
to
livestock,
uses
on
pasture
and
rangeland
grasses
must
be
revoked
and
the
uses
withdrawn.
A
MTDB
could
not
be
calculated
including
grass
and
grass
hay
since
additional
residue
data
are
required
for
use
patterns
in
which
significant
residues
are
expected
in/
on
the
RACs.
HED
recognizes
that
the
estimated
100,000
acres
of
pasture
and
rangeland
treated
with
hexazinone
is
relatively
low.
However,
since
grass
and
grass
hay
are
considered
major
components
of
ruminant
diets
(up
to
60%
of
the
diet
per
current
OPPTS
GLN)
a
MTDB
for
livestock
could
not
be
developed
when
grasses
are
included
in
the
registered
uses.
Therefore,
it
is
important
to
note
that
the
tolerance
reassessment
and
risk
assessment
presented
in
this
document
does
not
include
the
use
of
hexazinone
on
pasture/
rangeland
grasses;
it
assumes
that
these
tolerances
are
revoked
and
the
uses
withdrawn
from
the
label.
However,
HED
has
determined
that
a
MTDB
could
be
constructed
from
other
potential
feed
items
for
livestock
and
subsequently
tolerances
for
meats
and
milk
can
be
reassessed.
Reassessed
tolerances
range
from
0.1
ppm
to
4.0
ppm.
Tolerances
are
not
currently
needed
for
livestock
fat,
hog
meat,
and
hogmeat
by­
products
due
to
the
results
of
metabolism
and
feeding
studies.

Blueberries:
Data
indicate
that
the
combined
residues
of
hexazinone
and
its
regulated
metabolites,
as
measured
by
the
data­
collection
method
were
less
than
the
detection
level
(<
0.05
ppm
for
each
compound/
metabolite)
in/
on:
(1)
12
samples
of
lowbush
blueberries
harvested
433­
446
days
following
a
single
application
of
the
2
lb/
gal
EC
or
90%
SC
formulation
at
3
or
6
lb
ai/
A
(1.5
or
3.0x
the
maximum
registered
rate)
using
ground
or
aerial
equipment;
and
(2)
12
samples
of
highbush
blueberries
harvested
68­
97
days
following
a
single
application
of
the
2
lb/
gal
EC
or
90%
SC
formulation
at
2
or
4
lb
ai/
A
(0.8
or
1.3x
the
maximum
registered
rate).
Based
on
the
combined
LOQs
(0.55
ppm)
of
the
enforcement
method,
HED
is
now
recommending
that
the
RAC
tolerance
be
reassessed
from
0.2
ppm
to
0.6
ppm.

Pineapple:
Data
indicate
that
the
combined
residues
of
hexazinone
and
its
regulated
metabolites,
as
measured
by
the
data­
collection
method,
were
less
than
the
detection
level
(<
0.05
ppm
for
each
compound/
metabolite)
in/
on
pineapple
fruits
harvested
at
a
minimum
PHI
of
181
days
following
five
ground
applications
of
a
representative
hexazinone
formulation
at
0.45­
0.9
lb
ai/
A
for
a
total
rate
of
3.6
lb
ai/
A.
Based
on
the
combined
LOQs
(0.55
ppm)
of
the
enforcement
method,
HED
is
now
recommending
that
the
RAC
tolerance
be
reassessed
from
0.5
ppm
to
0.6
ppm.

Sugarcane:
Data
indicate
that
the
combined
residues
of
hexazinone
and
its
regulated
metabolites,
as
measured
by
the
data­
collection
method,
were
less
than
the
detection
level
(<
0.05
ppm
for
each
compound/
metabolite)
in/
on
samples
of
sugarcane
treated
with
the
90%
SC
formulation
of
hexazinone.
In
Hawaii,
sugarcane
was
harvested
179­
181
days
following
a
total
27
of
four
applications
(one
pre­
emergence
application
at
1.35
or
1.47
lb
ai/
A,
a
post­
emergence
application
at
0.45
lb
ai/
A
per
application,
followed
by
two
post­
emergence
applications
at
1.8
lb
ai/
A
per
application)
for
a
total
rate
of
5.4­
5.5
lb
ai/
A
per
season
(1.5x
the
maximum
seasonal
rate
in
HI).
Similar
results
were
found
in
field
trials
in
Texas
and
Puerto
Rico.
Based
on
the
combined
LOQs
(0.55
ppm)
of
the
enforcement
method,
HED
is
now
recommending
that
the
RAC
tolerance
be
reassessed
from
0.2
ppm
to
0.6
ppm.

Alfalfa:
Data
indicate
that
the
combined
residues
of
hexazinone
and
its
regulated
metabolites
did
not
exceed
the
established
tolerances
of
2.0
ppm
in/
on
alfalfa
forage
and
8.0
ppm
in/
on
alfalfa
hay
harvested
29­
31
days
following
a
single
broadcast
dormant
or
non­
dormant
application
of
the
2
lb/
gal
EC
or
90%
SC
formulation
at
1.5
lb
ai/
A
(~
1x).
The
maximum
combined
residues
in/
on
treated
samples
were
<1.87
ppm
and
<3.33
ppm
for
alfalfa
forage
and
hay,
respectively.
Based
on
these
data,
the
established
tolerance
for
alfalfa
forage
is
reassessed
at
its
existing
level
of
2.0
ppm;
however,
the
tolerance
for
alfalfa
hay
should
be
lowered
from
8.0
ppm
to
4.0
ppm.
Data
indicate
that
the
combined
residues
of
hexazinone
and
its
regulated
metabolites
ranged
from
<1.30
ppm
(sum
of
the
LOQs)
to
<1.46
ppm
in/
on
alfalfa
seed
following
a
single
broadcast
dormant
application
of
the
2
lb/
gal
EC
or
90%
SC
formulation
at
0.75
lb
ai/
A
(1.5x
the
maximum
registered
rate
on
alfalfa
grown
for
seed).

Processing
Data
Pineapple:
Residues
of
hexazinone
and
its
regulated
metabolites
did
not
concentrate
in
pineapple
juice.
Metabolite
B
concentrated
(3x)
in
process
residue,
based
on
quantified
residues
of
0.06
ppm
in
pineapple
process
residue
and
0.02
ppm
in/
on
pineapple
RAC
after
treatment
with
hexazinone
at
a
1x
rate.

Sugarcane:
Residues
declined
in
raw
sugar
(reduction
factor
of
0.2x)
and
processed
sugar
(reduction
factor
of
0.2x).
The
maximum
average
combined
residue
of
hexazinone
and
its
regulated
metabolites
was
1.92
ppm
for
"A
molasses."

Secondary
Residue
/
Livestock
Commodities
Poultry:
Based
on
the
results
of
a
poultry
metabolism
study,
the
Agency
has
determined
that
tolerances
(and
dietary
risk
assessment)
for
hexazinone
residues
in
eggs
and
poultry
tissues
are
not
required
under
the
provision
of
Category
3,
40
CFR
§180.6(
a)(
3)
In
the
poultry
study,
liver
tissue
contained
the
highest
TRR
(0.19
ppm).
Considering
that
the
feeding
level
was
38x
of
the
maximum
theoretical
dietary
burden,
the
maximum
residue
in
poultry
tissue
would
be
0.005
ppm,
an
order
of
magnitude
below
the
limit
of
detection
for
hexazinone
metabolites.

Ruminants:
The
results
of
a
ruminant
(goat)
metabolism
study
suggested
a
very
significant
transfer
of
hexazinone
residues
of
concern
to
meat
and
milk.
Hexazinone
residues
of
concern
may
transfer
to
milk
and
edible
tissues
of
livestock
animals
as
a
result
of
ingestion
of
treated
feed
items
such
as:
alfalfa
forage,
hay,
meal,
and
silage;
pineapple
process
residue;
and
28
sugarcane
molasses.
Tolerances
and
risk
assessment
for
hexazinone
and
metabolites
in
milk,
meat
and
meat
byproducts
are
based
on
an
estimate
of
exposure
or
"dietary
burden"
to
livestock
from
the
above
feed
items
and
an
estimate
of
the
level
of
residue
"transfer"
to
milk
and
meat
that
may
occur.
The
rate
of
transfer
of
hexazinone
and
metabolites
is
based
on
the
results
of
a
feeding
study
in
dairy
cattle.

Based
on
residue
estimates
for
alfalfa
forage,
alfalfa
hay,
and
sugarcane
molasses
(and
excluding
the
current
registration
for
grass
and
grass
hay)
a
maximum
dietary
burden
of
4.64
ppm
estimated
for
ruminants
forms
the
basis
for
tolerances
in
milk
(0.2
ppm),
meat
(0.1
ppm)
and
meat
byproducts
(0.1
ppm).
Residues
in
ruminant
fat
and
hog
commodities
are
not
expected
and
a
revocation
of
tolerance
is
recommended
under
the
provision
of
Category
3,
40
CFR
§180.6(
a)(
3).

4.2.2
Acute
Dietary
Exposure
(Females
13­
50)

Acute
dietary
(food)
risk
estimates
associated
with
the
use
of
hexazinone
and
its
metabolites
do
not
exceed
the
Agency's
level
of
concern
(>
100%
of
the
aPAD)
for
females
13­
50
years
of
age.
The
acute
dietary
risk
estimate
for
females
13­
50
years
of
age
is
approximately
1%
of
the
acute
Population
Adjusted
Dose
(aPAD).
The
acute
dietary
exposure
assessment
for
hexazinone
is
a
tier
I
analysis.
This
is
the
most
conservative
type
of
analysis
assuming
that
residues
on
foods
as
consumed
are
equal
to
the
tolerance
levels
and
that
100%
of
each
crop
is
treated.
The
tolerance
values
for
hexazinone
in/
on
blueberry,
pineapple,
and
sugarcane
are
based
on
the
analytical
method's
limit
of
quantitation
(LOQ)
and
all
studies
resulted
in
non­
detectable
residues.
The
same
residue
data,
therefore,
are
used
in
both
the
acute
and
chronic
analysis.
(J.
Punzi,
Revised
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
TRED,
July
30,
2002.)

The
hexazinone
acute
dietary
exposure
assessment
was
conduced
using
the
Dietary
Exposure
Evaluation
Model
(DEEM
TM
)
software
Version
7.76,
which
incorporates
consumption
data
from
USDA's
Continuing
Survey
of
Food
Intake
by
Individuals
(CSFII),
1989­
92.
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
retained
as
individual
consumption
events
for
acute
exposure
assessment.

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
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
exposure
is
expressed
as
a
percentage
of
the
aPAD
in
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
29
policy,
per
capita
exposure
and
risk
are
reported
for
all
tiers
of
analysis.
The
acute
population
adjusted
dose
(aPAD)
is
calculated
as
the
acute
RfD
divided
by
the
chemical­
specific
FQPA
safety
factor
(1x).
The
calculated
acute
exposure
(residue
x
consumption)
was
compared
to
an
aPAD
of
4.0
mg/
kg/
day.
The
results
are
displayed
in
Table
5.

Table
5:
Summary
of
Acute
Dietary
Exposure
and
Risk
for
Hexazinone
Population
of
Concern
Dietary
Exposure
(mg/
kg­
bw/
day)
%
aPAD
Females
13­
50
years
of
age
0.003611
<1.0
4.2.3
Chronic
Dietary
Exposure
Chronic
dietary
(food)
risk
estimates
associated
with
the
use
of
hexazinone
do
not
exceed
the
Agency's
level
of
concern
(>
100%
cPAD)
for
any
population
subgroup,
including
the
most
highly
exposed
subgroup
children
1­
6.
The
chronic
dietary
risk
for
children
ages
1­
6
is
approximately
15%
of
the
chronic
population
adjusted
dose
(cPAD)
and
approximately
4%
for
the
general
population.
(J.
Punzi,
Acute
and
Chronic
Dietary
Exposure
Assessment
for
the
TRED,
July
30,
2002.)

A
tier
I
analysis
was
done
for
the
chronic
dietary
risk
assessment.
This
is
the
most
conservative
type
of
analysis
assuming
that
residues
on
foods
as
consumed
are
equal
to
the
tolerance
levels
and
that
100%
of
the
each
crop
is
treated.
Hexazinone
chronic
dietary
exposure
assessment
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(DEEM
TM
),
software
Version
7.76
which
incorporates
consumption
data
from
USDA's
Continuing
Survey
of
Food
Intake
by
Individuals
(CSFII),
1989­
1992.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
dietary
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
to
arrive
at
the
total
estimated
exposure.
Chronic
population
adjusted
dose
(cPAD)
is
the
chronic
RfD
divided
by
the
FQPA
safety
factor.
The
calculated
chronic
exposure
(residue
x
consumption)
was
compared
to
a
cPAD
of
0.05
mg/
kg/
day,
which
reflects
a
special
FQPA
factor
of
1x
for
hazard
and
exposure.
The
procedure
is
performed
for
each
population
subgroup.
Results
of
this
chronic
dietary
exposure
and
risk
assessment
are
shown
in
Table
6.
30
Table
6:
Summary
of
Chronic
Dietary
Exposure
and
Risk
Values
for
Hexazinone
Population
Subgroup
Dietary
Exposure
(Mg/
kg/
day
%
cPAD
U.
S.
Population
0.002167
4
All
Infants
(<
1
year)
0.003752
7
Children
1­
6
years
0.007449
15
Children
7­
12
years
0.003964
8
Females
13­
50
years
0.001308
3
Males
13­
19
years
0.002334
5
Males
20+
years
0.001208
2
Seniors
55+
years
0.001159
2
HED
notes
that
there
is
a
degree
of
uncertainty
in
extrapolating
exposures
for
certain
population
subgroups
which
may
not
be
sufficiently
represented
in
the
consumption
surveys,
(e.
g.,
nursing
and
non­
nursing
infants
or
Hispanic
females).
Therefore,
risk
estimates
provided
include
only
representative
sub­
populations
that
have
sufficient
numbers
of
survey
respondents
(e.
g.,
all
infants,
or
females
13­
50
years
of
age).
31
4.3
Water
Exposure/
Risk
Pathway
Environmental
fate
data
suggest
that
the
parent
and
degradates
are
likely
to
be
persistent
and
mobile
in
the
environment.
Leaching
and
runoff
are
expected
to
be
primary
dissipation
routes.
Metabolites
A,
B,
D,
1
(JS472),
and
2
(JT677)
are
major
metabolites
found
in
soil/
aquatic
studies.
Metabolites
A­
1,
C
and
G3170
are
detected
in
ground
water
analysis.
Due
to
lack
of
toxicity
data
for
these
metabolites,
MARC
assumes
they
have
similar
toxicity
as
the
parent
because
of
the
structure
similarities
(except
G3170).
Metabolite
G3170
was
detected
at
the
highest
level
in
the
California
prospective
groundwater
study
(PGW)
and
there
are
no
toxicity
information
available
to
indicated
that
it
is
of
less
toxicological
concern
than
the
parent.
Therefore,
MARC
concludes
that
parent,
G3170,
and
all
degradates
with
conjoined
cyclohexyl
and
triazine
rings
(specifically,
A,
A­
1,
B,
C,
D,
1
(JS472),
and
2
(JT677))
are
residues
of
concern
for
risk
assessment
in
water.
(S.
Kinard,
The
Outcome
of
the
HED
Metabolism
Assessment
Review
Committee
for
Water,
April
25,
2002.)
Drinking
water
degradates
A,
A­
1,
B,
C
and
D
are
shown
in
Table
4;
degradates
G3170,
1,
and
2
are
shown
in
Table
7
below.
32
N
N
N
O
O
H
C
H
3
N
(CH
3
)
2
N
N
N
O
O
CH
3
N(
CH
3
)
2
O
N
N
N
O
N
CH
3
O
CH
3
CH
3
O
Table
7:
Drinking
Water
Degradates
Common
Name
Chemical
Name
Structure
Metabolites
G3170
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­
(1H,
3H)
dione
Metabolite
1,
JS472
3­(
4­
ketocyclohexyl)­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4­(
1H,
3H)­
dione
Metabolite
2,
JT677
3­(
2­
ketocyclohexyl)­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)
dione
The
environmental
fate
data
suggest
that
the
parent
and
degradates
are
likely
to
be
persistent
and
mobile
in
the
environment.
Leaching
and
runoff
are
expected
to
be
primary
dissipation
routes.
Estimated
Environmental
Concentrations
(EECs)
in
surface
waters
were
estimated
using
the
Tier
I
model
FIRST.
The
EECs
in
groundwater
were
estimated
using
an
available
small­
scale
prospective
groundwater
monitoring
study.
In
addition,
there
are
monitoring
data
available
from
the
state
of
Maine,
but
these
data
are
used
for
comparison
purposes
only.

The
surface
water
concentrations,
for
hexazinone
residues
were
as
follows:
acute
(peak)
33
value,
130
ppb,
and
the
chronic
annual
average
value,
47
ppb,
based
on
the
application
of
hexazinone
on
alfalfa,
which
is
the
major
food/
feed
use
for
the
chemical.
These
values
represent
upper­
bound
estimates
of
the
concentrations
that
might
be
found
in
surface
water
due
to
the
use
of
hexazinone
on
a
representative
crop.
The
groundwater
screening
concentration
for
hexazinone
residues
is
41.8
ppb.
It
is
noted
that
the
groundwater
screening
concentration
for
hexazinone
residues,
based
on
the
groundwater
prospective
monitoring
study
is
of
the
same
order
of
magnitude
of
the
groundwater
concentration
estimated
from
the
Tier
I
model
SCIGROW
(i.
e.,
20.2
ppb).
(Tier
I
Estimated
Environmental
Concentrations
of
Hexazinone
for
Use
in
the
Human
Health
Risk
Assessment,
D215026,
May
2,
2002.)

4.3.1
Environmental
Fate
Based
on
the
available
information,
hexazinone
appears
to
be
persistent
and
mobile
in
soil
and
aquatic
environments.
Hexazinone
is
stable
to
hydrolysis
(pH
levels
5,7,
and
9)
and
stable
to
aqueous
photolysis
(pH
7).
Studies
of
the
chemical's
half­
life
in
aerobic
and
anaerobic
soil
and
aquatic
environments
show
that
hexazinone
half­
life
in
the
environment
range
from
60­
230
days.
Data
on
hexazinone
metabolites
of
concern
indicate
that
they
are
highly
mobile
in
the
environment.
Based
on
the
environmental
fate
properties
of
hexazinone
and
its
degradates,
it
can
be
concluded
they
may
be
of
concern
for
surface
water
and
groundwater
contamination.
Hexazinone
is
not
to
be
applied
under
the
following
conditions
to
limit
the
migration
of
hexazinone
to
drinking
water:
(1)
when
rainfall
is
expected
immediately
after
application;
(2)
to
the
field
where
the
water
table
is
shallow
or
the
water
body
is
nearby;
and
(3)
to
soils
containing
low
organic
matter
and/
or
high
sand
content.

Hexazinone
possesses
high
solubility
in
water
and
a
low
adsorption
coefficient
in
soil.
Therefore,
this
chemical
is
expected
to
be
very
mobile
in
the
environment,
especially
in
soils
with
low
organic
matter
and/
or
high
sand
content.
Results
from
aquatic
metabolism
studies
suggest
that
the
parent
compound
is
expected
to
be
relatively
persistent
when
it
reaches
surface
water.
Although
some
degradation
could
occur
in
the
surface
water,
the
chemical
structures
and
the
fate
properties
of
the
resulting
degradates
are
similar
to
the
parent.
According
to
the
aerobic
soil
metabolism,
19%
and
11%
of
the
applied
were
found
as
Degradates
A­
1
and
1,
respectively,
after
one
year
of
incubation.
Hexazinone
can
be
applied
aerially
and,
therefore,
there
is
a
potential
for
runoff
from
spray
drift.
Hexazinone
is
expected
to
be
less
persistent
in
the
upper
layer
of
the
water
body
than
the
deep
layer.
The
bioconcentration
potential
is
very
low
for
this
chemical.
There
is
no
Safe
Drinking
Water
Act
Maximum
Contaminate
Level
(MCL)
for
the
chemical.

There
are
many
degradates
included
in
the
hexazinone
drinking
water
exposure
assessment.
They
include
degradates
G3170,
A,
A­
1,
B,
C,
D,
1(
JS472),
2(
JT677).
It
is
noted
that
although
Degradate
C
was
not
found
in
any
of
the
laboratory
fate
studies,
the
field
dissipation
and
the
small­
scale
prospective
groundwater
monitoring
study
observed
this
degradate.
In
addition,
degradates
D
and
2
were
the
major
degradates
found
in
the
anaerobic
34
aquatic
metabolism
study;
however,
the
field
dissipation
and
the
small­
scale
prospective
groundwater
monitoring
studies
did
not
monitor
these
two
degradates.
Therefore,
the
fate
of
degradates
D
and
2
could
not
be
assessed
in
the
natural
environment.
The
registrant
believed
that
both
field
studies
were
mostly
aerobic
and
the
degradates
were
unlikely
to
be
observed.
The
field
dissipation
studies
did
not
monitor
the
fate
of
degradate
G­
3170,
which
was
the
degradate
detected
at
the
highest
concentrations
in
the
small­
scale
prospective
groundwater
monitoring
study.
This
degradate
was
not
observed
in
the
aerobic
soil
metabolism
study.

4.3.2
Drinking
Water
Exposure
Estimates
The
Agency
currently
lacks
sufficient
water­
related
exposure
data
from
monitoring
to
complete
a
quantitative
drinking
water
exposure
analysis
and
risk
assessment
for
hexazinone
and
its
degradates.
The
Agency
is
presently
relying
on
a
computer
model,
FIRST,
to
estimate
the
environmental
concentrations
(EECs)
in
surface
water.
This
model
takes
into
account
the
use
patterns
and
the
environmental
profile
of
the
pesticide,
but
does
not
include
consideration
of
the
impact
that
processing
raw
water
for
distribution
as
drinking
water
could
have
on
the
removal
or
metabolism
of
pesticides
from
the
source
water.

The
registrant
submitted
a
small­
scale
prospective
groundwater
monitoring
study
and
the
results
indicate
that
hexazinone
and
its
metabolites
are
very
mobile
and
persistent
in
the
environment.
The
results
of
this
monitoring
study
are
used
to
estimate
concentrations
of
hexazinone
and
its
degradates
in
groundwater.
The
State
of
Maine
Board
of
Pesticides
Control
in
the
Department
of
Agriculture,
Food
and
Rural
Resources
performed
a
statewide
assessment
to
determine
the
impact
of
highly
leachable
pesticides
including
hexazinone.
This
study
is
considered
informative
but
not
used
to
derive
estimated
environmental
concentrations
for
drinking
water
exposure
and
risk
assessment.
The
estimated
environmental
concentrations
of
hexazinone
and
degradates
in
groundwater
are
based
upon
the
prospective
groundwater
monitoring
study.

Surface
Water
The
FIRST
model
is
a
new
screening
model
designed
to
estimate
the
pesticide
concentrations
found
in
water
for
use
in
drinking
water
assessments.
The
model
provides
highend
values
on
the
concentrations
that
might
be
found
in
a
small
drinking
water
reservoir
due
to
the
use
of
pesticide.
Similar
to
GENEEC,
the
model
previously
used
for
Tier
I
screening
level,
FIRST
is
a
single­
event
model
(one
run­
off
event),
but
can
account
for
spray
drift
from
multiple
applications.
FIRST
uses
a
drinking
water
reservoir
instead
of
a
pond
as
the
standard
scenario.
The
FIRST
scenario
includes
a
427
acres
field
immediately
adjacent
to
a
13
acres
reservoir,
9
feet
deep,
with
continuous
flow
(two
turnovers
per
year).
The
pond
receives
a
spray
drift
event
from
each
application,
plus
one
runoff
event.
The
runoff
event
moves
a
maximum
of
8%
of
the
applied
pesticide
into
the
pond.
This
amount
can
be
reduced
due
to
degradation
on
field
and
the
effect
of
binding
to
soil.
Spray
drift
is
equal
to
6.4%
of
the
applied
concentration
from
the
35
ground
spray
application
and
16%
for
aerial
applications.

Model
inputs
used
to
develop
the
surface
water
estimated
environmental
concentrations
using
the
FIRST
model
include
estimating
drinking
water
exposure
based
on
application
to
alfalfa,
the
food/
feed
item
with
the
greatest
percent
of
crop
treated
with
hexazinone.
In
addition,
the
model
assumes
aerial
application,
an
application
rate
of
1.5
lbs.
a.
i./
acre,
application
once
per
year,
and
no
soil
incorporation
after
application.
FIRST
also
makes
adjustments
for
the
percent
of
the
area
cropped.
While
FIRST
assumes
that
the
entire
watershed
would
not
be
treated,
the
use
of
a
PCA
is
still
a
screen
because
it
represents
the
highest
percentage
of
crop
cover
of
any
large
watershed
in
the
US,
and
it
assumes
that
the
entire
crop
is
being
treated.
Other
conservative
assumptions
of
FIRST
include
the
use
of
a
small
drinking
water
reservoir
surrounded
by
a
runoff­
prone
watershed,
the
use
of
the
maximum
use
rate,
assumption
of
no
buffer
zone,
and
a
single
large
rainfall.

Groundwater
The
registrant
submitted
a
small­
scale
prospective
groundwater
monitoring
study
for
hexazinone
(MRID45132801).
In
this
study,
hexazinone
was
broadcast
applied
once
at
0.75
lb
a.
i./
A
in
January
1996
onto
a
field
of
alfalfa
underlain
with
sandy
soil
in
Merced
County,
California.
Results
indicated
that
hexazinone
and
its
degradates
are
very
mobile
and
persistent.
As
indicated
earlier,
the
degradates
D
and
2
(which
were
the
major
degradates
found
in
the
anaerobic
aquatic
metabolism
study),
were
not
monitored
in
the
small­
scale
prospective
groundwater
monitoring
studies.
No
information
about
the
fate
of
degradates
D
and
2
under
natural
environment
is
currently
available.
Table
8
provides
a
summary
with
the
maximum
concentrations
of
the
parent
and
its
degradates,
detected
in
the
small­
scale
prospective
groundwater
monitoring
study.
These
concentrations
(see
column
2)
were
expressed
in
parent
equivalents
(see
Column
3).
The
maximum
total
residues
of
hexazinone
and
its
degradates
detected
in
the
groundwater
study
were
41.8
ppb
(expressed
as
parent
equivalents).
36
Table
8:
Summary
of
Small­
Scale
Prospective
Groundwater
Monitoring
Study
Chemical
Maximum
Concentration
in
Groundwater
(ppb)
Maximum
Concentration
in
Groundwater
(ppb,
expressed
as
parent
equivalent)

Parent
9.2
9.2
A­
1
(G3453)
3
2.8
B
(A3928)
7.2
7.6
C
(T3935)
1.2
1.1
1
((
JS472)
2.1
2.0
G3170
12.9
19.1
Total
Residues
(parent
equivalent)
Not
applicable
41.8
The
State
of
Maine
also
conducted
a
drinking
water
monitoring
study,
however
these
data
are
considered
for
informational
purposes
only
and
are
presented
here
as
a
point
of
comparison.
The
Board
of
Pesticides
Control
in
the
Department
of
Agriculture,
Food
and
Rural
Resources
in
the
State
of
Maine
conducted
a
statewide
assessment
to
determine
the
impact
of
highly
leachable
pesticides
(including
hexazinone,
an
herbicide
used
in
the
production
of
blueberries)
on
surface
water
and
ground
water
in
Maine.
This
assessment
crossed
a
variety
of
agricultural
and
nonagricultural
pesticide
use
sites.
Surface
water
samples
were
collected
in
Narraguagus
River
and
Pleasant
River
in
Maine.
Although
the
total
amounts
of
hexazinone
used
on
blueberry
in
Maine
is
very
low
(only
approximately
1%
of
the
total
sale
in
the
U.
S.),
the
chemical
was
detected
in
groundwater
and
surface
water
at
very
high
frequency
(43­
59%
of
ground
water
samples,
and
31­
90%
of
surface
water
samples).
Although
this
monitoring
study
is
inherently
different
than
the
ground
water
prospective
monitoring
study,
it
was
observed
that
the
maximum
concentrations
of
parent
hexazinone
observed
in
groundwater
in
1998
and
1999
(i.
e.
2.15
and
1.97
ppb,
respectively),
were
similar
to
the
maximum
concentration
observed
in
the
small
scale
ground
water
monitoring
study
(i.
e.,
9.2
ppb).
Results
are
summarized
in
Table
9.
37
Table
9:
Summary
of
Monitoring
Information
from
the
Board
of
Pesticides
Control
in
the
Department
of
Agriculture,
Food
and
Rural
Resources
in
the
State
of
Maine
Year
No.
of
Samples
Collected
No.
of
Samples
with
Hexazinone
Detected
(%
of
Frequency)
Range
of
Concentrations
(ppb)

Ground
Water
1998
42
18
(43%)
0.14­
2.15
1999
22
13
(59%)
0.22­
1.97
Surface
Water
1998
36
11
(31%)
0.22­
0.94
1999
21
19
(90%)
0.13­
3.80
2000
24
21
(88%)
0.13­
2.65
2001
50
44
(88%)
0.08­
2.45
Therefore,
estimated
environment
concentrations
in
surface
and
groundwater
were
derived
from
both
modeled
data
and
a
prospective
groundwater
monitoring
study.
Aggregate
exposure
and
risks
from
consumption
of
hexazinone
contaminated
surface
water
as
drinking
water
will
utilize
the
FIRST
peak
untreated
water
concentration
of
129.8
ppb
for
the
acute
scenario
and
the
annual
average
untreated
water
concentration
of
47.1
ppb
for
the
chronic
scenario.
The
FIRST
model
estimates
include
all
drinking
water
degradates
of
concern
in
the
risk
assessment
(calculated
as
hexazinone
parent
equivalents).
Aggregate
exposure
and
risk
from
consumption
of
hexazinone
contaminated
groundwater
as
drinking
water
will
use
the
results
of
the
prospective
groundwater
monitoring
study,
41.8
ppb.
Although
this
study
did
not
monitor
for
the
presence
of
degradates
D
and
2,
it
is
still
considered
to
be
a
conservative
estimate
of
groundwater
drinking
water
exposure
since
the
total
residues
detected
in
this
study
are
twice
the
residue
level
estimated
through
the
SCI­
GROW
model,
which
included
all
metabolites
in
the
model
estimate.
The
surface
and
groundwater
drinking
water
estimated
environmental
concentrations
are
listed
in
Table
10.
38
Table
10:
Estimated
Environmental
Concentrations
in
Surface
and
Groundwater
for
Hexazinone
use
on
Alfalfa
Model
Hexazinone
(Total
Residues)
Source
FIRST
1.0
Peak
Untreated
Water
Concentration
129.8
ppb
Output
FIRST
1.0
Annual
Average
Untreated
Water
Concentration
47.1
ppb
Output
Small­
Scale
Prospective
Groundwater
Monitoring
Study
41.8
ppb
Monitoring
Data
SCI­
GROW
Ground
Water
Concentration
20.2
ppb
Output
4.4
Residential
Exposure/
Risk
Pathway
There
are
currently
no
registered
uses
for
hexazinone
in
the
residential
environment.
However,
the
hexazinone
label
does
include
use
of
the
chemical
in
rights­
of­
way
areas
and
spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
this
type
of
spraying
operation.
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
the
application
of
hexazinone
by
aerial
as
well
as
other
application
types
where
appropriate.

4.4.1
Other
Non­
Occupational
Exposures
It
is
important
to
note
that
U.
S.
EPA,
Region
IX
is
working
with
the
California
Department
of
Pesticide
Regulation,
the
US
Forest
Service
and
Native
American
tribes
in
California
to
determine
the
potential
exposure
to
forestry
herbicides,
including
hexazinone,
that
may
be
occurring
to
Native
Americans
through
their
use
of
forest
plant
materials.
Native
Americans
use
these
plant
materials
in
their
diets,
in
the
making
of
traditional
basketry,
for
medicinal
purposes,
and
in
ceremonial
activities.
In
response
to
the
health
concerns
raised
by
the
Native
American
communities,
the
California
Department
of
Pesticide
Regulation
(DPR)
and
the
USEPA
(Region
IX)
launched
a
risk
assessment
effort
in
1997.
This
effort
includes
five
steps:
39
DPR
measured
plant
residue
and
surface
water
levels
following
herbicide
application;
DPR
agreed
to
assess
the
total
exposures
and
risks
involved
using,
where
appropriate,
the
monitoring
data
collected;
informing
tribal
physicians
of
state
regulations
requiring
pesticide
illness
reporting;
participation
in
mediated
meetings
with
Native
American
communities
to
determine
the
key
issues
surrounding
herbicide
use;
and,
video
production
about
inadvertent
exposure
to
herbicides.
The
Office
of
Pesticide
Programs
is
aware
of
this
ongoing
work
and
will
communicate
with
USEPA
Region
IX,
California
DPR
and
other
entities,
as
appropriate,
to
ensure
that
potential
exposures
and
risks
are
assessed.

5.0
Aggregate
Risk
Assessment
and
Characterization
The
Food
Quality
Protection
Act
(FQPA)
amendments
to
the
Federal
Food,
Drug,
and
Cosmetic
Act
(FFDCA)
requires
for
establishing
or
reassessing
a
pesticide
tolerance
"that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
the
pesticide
chemical
residue,
including
all
anticipated
dietary
exposures
and
all
other
exposure
for
which
there
is
reliable
information."
The
July
30,
3003
HIARC
meeting
resulted
in
endpoint
selection
for
multiple
exposure
durations
and
routes,
including
the
residential
pathway.
However,
exposure
is
only
expected
to
occur
via
the
food
and
water
pathways
of
exposure.
If
new
uses
are
added
to
the
label
in
the
future
which
include
possible
exposure
to
persons
in
the
residential
environment,
EPA
will
conduct
this
analysis.
The
toxicological
endpoints
appropriate
for
the
dietary
(oral)
route
of
exposure
are,
therefore,
the
only
hazard
endpoints
considered
in
this
analysis.

Acute
and
chronic
aggregate
risk
is
comprised
of
the
combined
exposures
from
food
and
water.
Risk
estimates
are
aggregated
because
it
is
assumed
exposure
may
occur
over
the
same
time
period
to
the
same
person.
The
HIARC
selected
an
acute
dietary
endpoint
for
females
13­
50
based
upon
decreased
male
and
female
fetal
weight,
kidneys
with
no
papilla
(malformation)
and
misaligned
sternebrae
(variation)
at
the
LOAEL
in
the
developmental
rat
study.
However,
no
appropriate
effect
attributed
to
a
single
exposure
was
identified
in
the
toxicology
database
for
the
general
population.
The
chronic
dietary
aggregate
assessment
utilizes
an
endpoint
based
on
a
chronic
oral
study
in
the
dog
which
demonstrated
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase
at
the
LOAEL.

Drinking
Water
Levels
of
Comparisons
(DWLOCs)
are
used
to
estimate
aggregate
risk
from
drinking
water
sources.
DWLOCs
are
theoretical
upper
limits
of
a
pesticide's
allowable
concentration
in
drinking
water
in
light
of
total
aggregate
exposure
to
a
pesticide
in
food
and
drinking
water.
A
DWLOC
will
vary
depending
on
the
toxic
endpoint,
drinking
water
consumption,
and
body
weight.
The
Agency
uses
DWLOCs
internally
in
the
risk
assessment
process
as
a
surrogate
measure
of
potential
exposure
associated
with
pesticide
exposure
through
drinking
water.
In
the
absence
of
reliable
monitoring
data
for
pesticides
which
can
be
used
directly
and
quantitatively
in
the
risk
assessment,
it
is
used
as
a
point
of
comparison
against
conservative
model
estimates
of
a
pesticide's
concentration
in
water.
DWLOC
values
are
not
a
40
regulatory
standard
for
drinking
water.
However,
they
do
have
an
indirect
regulatory
impact
through
aggregate
exposure
and
risk
assessments.
For
this
analysis,
groundwater
monitoring
conclusions
are
used
to
compare
with
calculated
DWLOC
for
groundwater
and
modeling
results
are
used
to
compare
with
calculated
DWLOCs
in
surface
water.
Aggregate
risk
estimates
for
food
and
water
are
summarized
in
Tables
11
and
12.
The
estimates
of
food
exposure
are
considered
to
be
conservative
since
tolerance
level
residue
values
and
100%
of
crop
treatment
is
assumed.

5.1
Acute
Aggregate
Risk
Assessment
Since
the
calculated
EECs
are
less
than
the
DWLOC,
the
acute
aggregate
exposure
from
residues
of
hexazinone
and
its
metabolites
in
food
and
drinking
water
do
not
exceed
the
Agency's
level
of
concern.
HED
calculates
DWLOCs
by
a
two­
step
process:
exposure
is
subtracted
from
the
aPAD
to
obtain
the
maximum
exposure
allowed
in
drinking
water;
DWLOCs
are
then
calculated
using
that
value
and
HED
default
body
weight
and
drinking
water
consumption
figures.
In
assessing
human
health
risk,
DWLOCs
are
compared
to
EECs.
When
EECs
are
less
than
DWLOCs,
HED
considers
the
aggregate
risk
[from
food
+
water
exposures]
to
be
acceptable.

Estimated
environmental
concentrations
for
hexazinone
and
its
water
degradates
were
compared
to
the
acute
DWLOCs
since
adequate
monitoring
data
were
not
available
to
directly
assess
aggregate
exposure
to
food
and
water.
The
Environmental
Fate
and
Effects
Division
(EFED)
provided
Tier
I
FIRST
estimates
to
determine
acute
dietary
aggregate
exposure
and
risk
values.
This
model
simulated
hexazinone
and
its
metabolites
in
drinking
water
concentrations
(for
the
alfalfa
use)
of
130
µg/
L
for
the
surface
water
peak
untreated
water
concentration.
The
results
of
the
Small­
Scale
Prospective
Groundwater
Monitoring
Study
were
used
to
estimate
concentrations
of
hexazinone
and
its
degradates
in
groundwater
(42
µg/
L).
Interestingly,
the
results
of
the
monitoring
study
and
the
results
of
the
SCI­
GROW
model
are
roughly
equivalent,
42
µg/
L
as
compared
to
20.2
µg/
L.

The
DWLOC
calculated
for
acute
aggregate
risk
for
females
13­
50
years
old
is
120,000
µg/
L.
These
results
are
presented
in
Table
11.
Therefore,
HED
concludes
with
reasonable
certainty
that
residues
of
hexazinone
and
its
metabolites
in
drinking
water
will
not
contribute
significantly
to
the
acute
human
health
risk
and
that
the
acute
aggregate
exposure
from
residues
of
hexazinone
and
its
metabolites
in
food
and
drinking
water
and
will
not
exceed
the
Agency's
level
of
concern
for
acute
aggregate
exposure
for
females
13­
50.
41
Table
11.
Acute
DWLOC
Calculation
Population
Subgroup
Acute
Scenario
aPAD
(mg/
kg/
day)
Acute
Food
Exposure
(mg/
kg/
day)
1
Max
Acute
Water
Exposure
(mg/
kg/
day)
2
Groundwater
EEC
(
:
g/
l)
3
Surface
Water
EEC
(
:
g/
l)
4
Acute
DWLOC
(
:
g/
l)
5
Females
13­
50
4.0
0.003611
3.996
42
130
120,000
1
Acute
food
exposure
is
exposure
estimate
at
the
95th
percentile
from
the
Tier
I
assessment
performed.
2
Maximum
acute
water
exposure
(mg/
kg/
day)
=
[(
acute
PAD
(mg/
kg/
day)
­
acute
food
exposure
(mg/
kg/
day)]

3
Results
of
Small­
Scale
Prospective
Groundwater
Monitoring
Study
are
used
for
groundwater
EEC.
4
The
crop
producing
the
highest
level
was
modeled
to
produce
the
surface
water
EEC
results,
alfalfa.
5
Acute
DWLOC(
µg/
L)
=
[maximum
acute
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]
Assumptions:
Body
weights
(60
kg
adult
female);
water
consumption
2
liters/
day
adult.

5.2
Chronic
Aggregate
Risk
Assessment
Since
the
calculated
DWLOCs
are
above
the
drinking
water
exposure
estimates,
chronic
aggregate
exposure
from
residues
of
hexazinone
and
its
metabolites
in
food
and
drinking
water
sources
do
not
exceed
the
Agency's
level
of
concern
for
chronic
aggregate
exposure
for
any
subpopulation
EFED
provided
Tier
I
FIRST
estimates
to
determine
chronic
dietary
aggregate
exposure
and
risk
values.
This
model
simulated
drinking
water
concentrations
of
hexazinone
and
its
degradates
(for
the
alfalfa
use)
of
47
µg/
L
for
the
surface
water
annual
average
untreated
water
concentration.
The
results
of
a
Small­
Scale
Prospective
Groundwater
monitoring
study
were
used
to
estimate
concentrations
of
hexazinone
in
groundwater
(42
µg/
L).

The
DWLOC
calculated
for
chronic
aggregate
risk
for
all
populations
range
from
425­
1700
:
g/
L.
These
results
are
presented
in
Table
12.
Because
the
EECs
are
less
than
the
calculated
DWLOC,
HED
concludes
with
reasonable
certainty
that
residues
of
hexazinone
and
its
metabolites
in
drinking
water
will
not
contribute
significantly
to
the
chronic
human
health
risk
and
that
the
chronic
aggregate
exposure
from
residues
of
hexazinone
and
its
metabolites
in
food
and
drinking
water
and
will
not
exceed
the
Agency's
level
of
concern
for
chronic
aggregate
exposure
for
any
sub­
population.
42
Table
12:
Chronic
DWLOC
Calculations
Population
Subgroup
1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exposure
mg/
kg/
day
Max
Chronic
Water
Exposure
mg/
kg/
day
2
Ground
Water
EEC
(µg/
L)
3
Surface
Water
EEC
(µg/
L)
3
Chronic
DWLOC
(µg/
L)
4
U.
S.
Population
0.05
0.002167
0.04783
42
47
1700
Females
13­
50
0.05
0.001308
0.04869
42
47
1500
Infants
(<
1
year)
0.05
0.003752
0.04625
42
47
460
Children
1­
6
0.05
0.007449
0.04255
42
47
425
1
Children
1­
6
are
the
most
highly
exposed
sub­
group.
2
Maximum
Chronic
Water
Exposure
(mg/
kg/
day)
=
[Chronic
PAD
(mg/
kg/
day)
­
Chronic
Dietary
Exposure
(mg/
kg/
day)]

3
The
use
of
hexazinone
on
alfalfa
was
modeled
to
determine
surface
water
EEC's
and
the
results
of
groundwater
monitoring
study
was
used
to
determined
groundwater
EEC.
4
Chronic
DWLOC(
µg/
L)
=
[maximum
chronic
water
exposure
(mg/
kg/
day)
x
body
weight
(kg)]
[water
consumption
(L)
x
10
­3
mg/
µg]
Assumptions:
Body
weights
(70
kg
adult
male;
60
kg
adult
female;
10
kg
child);
water
consumption
2
liters/
day
adult
and
1
liter/
day
infants
and
children.

6.0
Cumulative
Risk
The
FQPA
(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
43
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
the
TRED
for
hexazinone
because
HED
has
not
yet
initiated
a
comprehensive
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
hexazinone.
For
purposes
of
this
TRED,
the
Agency
has
assumed
that
hexazinone
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
hexazinone
shares
a
common
mechanism
of
toxicity
with
any
other
substance
and,
if
so,
whether
any
tolerances
for
hexazinone
need
to
be
modified
or
revoked.
If
HED
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
hexazinone,
HED
will
perform
aggregate
exposure
assessments
on
each
chemical,
and
will
begin
to
conduct
a
cumulative
risk
assessment.
HED
has
developed
a
framework
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
was
issued
on
January
16,
2002
(67
FR
2210­
2214)
and
is
available
from
the
OPP
Website
at:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cumulative_
guidance.
pdf.

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
Incident
Data
The
Agency
searched
several
databases
for
reports
of
poisoning
incident
data
for
hexazinone.
These
databases
include
the
Office
of
Pesticide
Programs
(OPP)
Incident
Data
System
(IDS),
the
Poison
Control
Center
data,
California
Department
of
Pesticide
Regulation,
and
the
National
Pesticide
Telecommunication
Network
(NPTN).
Relatively
few
incidents
have
been
reported.
Cases
listed
in
the
IDS
include
individuals
reporting
burning
and
red
welts
on
the
legs,
eye
irritation
and
peeling
on
their
hands
and
feet.
Other
databases
included
reports
of
eye
effects
and
breathing
difficulties
after
exposure.
Because
there
are
so
few
cases
available,
no
recommendations
can
be
made
based
on
the
few
incident
reports
available.
(J.
Blondell,
Review
of
Hexazinone
Incident
Reports,
May
1,
2002.)
44
8.0
Data
Needs
Product
Chemistry
1.
The
product
chemistry
data
base
is
complete.

Toxicology
2.
The
HIARC
requested
a
28­
day
inhalation
study
on
formulation
with
hexazinone
because
of
the
concern
for
potential
inhalation
exposure
based
on
the
use
pattern.

Residue
Chemistry
3.
Outstanding
label
amendments
to
reflect
cancellation
of
use
on
pasture/
rangeland
grasses.

4.
Field
rotational
crop
studies
for
corn
and
wheat.

Environmental
Fate
5.
The
environmental
fate
database
is
complete.
45
References
Anderson,
D.
Hexazinone
(PC
Code
107201).
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
Document.
August
12,
2002.
TXR
No.
0051040.
DP
Barcode
D275620.

Anderson,
D.
Hexazinone
­
3rd
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
August
12,
2002.
TXR
No.
0051003.

Blondell,
J.
and
M.
Spann.
Review
of
Hexazinone
Incident
Reports.
Chemical
107201.
May
1,
2002.

Dockter,
K.
Hexazinone.
Product
Chemistry
Chapter
for
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
Document.
April
23,
2002.
DP
Barcode
D279324.

Hernandez,
F.
Quantitative
Usage
Analysis
for
Hexazinone.
September
10,
2001.

Kinard,
S.
Hexazinone.
The
Outcome
of
the
HED
Metabolism
Assessment
Review
Committee
for
Water.
PC
code
107201,
April
25,
2002.
DP
Barcode
D282111.

Li,
L.
2002.
Data
Analysis
of
Forestry
Herbicides
in
Plants
of
Interest
of
California
Tribes.
Final
Report.
Retrieved
from
Http://
www.
cdpr.
ca.
gov/
docs/
empm/
pubs/
forest/
reprts.
htm.

Liu,
L.
Tier
I
Estimated
Environmental
Concentrations
of
Hexazinone,
for
use
in
Human
Health
Risk
Assessment
Water
Assessment.
Environmental
Fate
and
Effects
Division.
May
2,
2002.

Punzi,
J.
Hexazinone.
Acute
and
Chronic
Dietary
Exposure
Assessments
for
the
TRED.
(PC
Code
107201).
July
30,
2002.
DP
Barcode
D279898.

Punzi,
J.
Hexazinone
Tolerance
Reassessment
Eligibility
Decision
Residue
Chemistry
Considerations.
May
20,
2002.
(DP
Barcode
D279899).

Segawa,
R.,
C.
Ando,
A.
Bradley,
J.
Walters,
R.
Sava,
C.
Gana,
et
al.
(2001).
Dissipation
and
Off­
site
Movement
of
Forestry
Herbicides
in
Plants
of
Importance
to
California
Tribes.
Final
Report.
Retrieved
from
Http://
www.
cdpr.
ca.
gov/
docs/
empm/
pubs/
forest/
reprts.
htm.

Tarplee,
B.
Hexazinone
­
2
nd
Report
of
the
FQPA
Safety
factor
Committee.
August
8,
2002.
TXR.
No.
0051049.
Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
b
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
46
Blueberries
0.2
<0.3
ppm
(nondetectable;
<0.05
ppm
for
each
compound)
0.60
Tolerance
should
be
increased
based
on
the
combined
LOQ
(0.55
ppm)
of
the
enforcement
method.
Blueberry
Cattle,
fat
0.
1
Revoke
c
Cattle,
mbyp
0.1
0.
10
Cattle,
meat
0.1
0.
10
Goat,
fat
0.
1
Revoke
c
Goat,
mbyp
0.1
0.
10
Goats,
meat
0.1
0.
10
Grasses,
pasture
10
Revoke
d
Grass,
forage
Grass,
hay
Grasses,
rangeland
10
Revoke
d
Hog,
fat
0.
1
Revoke
c
Hog,
mbyp
0.1
Revoke
c
Hog,
meat
0.1
Revoke
c
Horses,
fat
0.
1
Revoke
c
Horses,
mbyp
0.1
0.
10
Horses,
meat
0.1
0.
10
Milk
0.5
0.
20
Pineapple
0.
5
<0.35
(or
<0.05
ppm
for
each
compound)
0.60
Tolerance
should
be
increased
based
on
the
combined
LOQ
(0.55
ppm)
of
the
enforcement
method.

Sheep,
fat
0.
1
Revoke
c
Sheep,
mbyp
0.1
0.
10
Sheep,
meat
0.1
0.
10
Tolerances
needed
under
40
CFR
§180.396(
a):

Alfalfa,
seed
­­
<1.30­<
1.46
2.
0
Table
C
(continued).

Commodity
Current
Tolerance
(ppm)
a
Range
of
residues
(ppm)
b
Tolerance
Reassessment
(ppm)
Comment/
Correct
Commodity
Definition
47
Tolerances
listed
under
40
CFR
§180.396(
c):

Sugarcane
0.
2
<0.05
ppm
(nondetectable)
each
for
hexazinone
and
its
metabolites
0.60
Tolerance
should
be
increased
based
on
the
combined
LOQ
(0.55
ppm)
of
the
enforcement
method.

Sugarcane
molasses
5
(1.915
x
4x)
÷
2x
=
3.83
4.0
a
Expressed
in
terms
of
the
combined
residues
of
hexazinone
and
its
metabolites
(calculated
as
hexazinone).
b
Refer
to
section
on
Magnitude
of
Residues
in
Crop
Plant
for
detailed
discussion
of
residues
in
crops.

c
Tolerances
for
fat
are
not
required
(Category
3,
40
CFR
§180.6).
d
HED
is
recommending
revocation
of
these
tolerances
and
cancellation
of
uses,
since
grasses
are
a
major
feed
item
and
required
data
are
not
available
for
reassessment.
