Document ID: EPA-HQ-OPP-2005-0309-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-01T05:00Z

FILE
NAME:
Gowan
Hexythiazox
Corn.
wpt
(
6/
24/
2005)
(
xml)
Template
Number
P25
ATTENTION:

All
commodity
terms
must
comply
with
the
Food
and
Feed
Commodity
Vocabulary
database
(
http://
www.
epa.
gov/
pesticides/
foodfeed/).

All
text
in
blue
font
(
instructions
for
preparing
the
document),
should
be
removed
prior
to
sending
the
document
to
the
Federal
Register
Staff.
Instructional
text
and
prompts
in
green
font
should
also
be
removed.

COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
1/
1/
2005)

EPA
Registration
Division
contact:
George
LaRocca,
PM
#
13,
telephone
(
703)
305­
6100
INSTRUCTIONS:
Please
utilize
this
outline
in
preparing
tolerance
petition
documents.
In
cases
where
the
outline
element
does
not
apply
please
insert
"
NA­
Remove"
and
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the
outline.
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notes
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Simply
replace
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appear
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italics
and
brackets,
i.
e.,
"[
insert
company
name],"
with
the
information
specific
to
your
action.

TEMPLATE:

Gowan
Company
(
number
not
currently
available)

EPA
has
received
a
pesticide
petition
(
number
not
currently
available)
from
Gowan
Company,
370
South
Main
Street,
Yuma
AZ
85364
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180
by
establishing
tolerances
for
residues
of
hexythiazox
(
trans­
5­(
4­
chlorophenyl)­
N­
cyclohexyl­
4­
methyl­
2­
oxothiazolidine­
3­
carboxamide)
and
2
its
metabolites
containing
the
(
4­
chlorophenyl)­
4­
methyl­
2­
oxo­
3­
thiazolidine
moiety
in
or
on
the
raw
agricultural
commodities
corn,
field
grain
at
0.05
parts
per
million
(
ppm)
(
regional
tolerance),
corn,
field,
forage
at
2.0
parts
per
million
(
ppm)
(
regional
tolerance)
and
corn,
field,
stover
at
2.0
parts
per
million
(
ppm)
(
regional
tolerance).
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
The
metabolism
of
hexythiazox
as
well
as
the
nature
of
the
residues
in
plants
is
adequately
understood
for
purposes
of
this
petition.
Metabolism
studies
were
conducted
in
four
crops;
viz.,
pears,
grapes,
oranges
and
apples.
The
major
residue
component
is
unmetabolized
parent.
The
metabolites
are
hydroxylcyclohexyl
and
ketocyclohexyl
analogs
of
hexythiazox
and
the
amide
formed
by
loss
of
the
cyclohexyl
ring.
Parent
hexythiazox
and
its
thiazolidine
metabolites
are
converted
to
a
common
moiety
for
residue
analysis.

2.
Analytical
method.
A
practical
analytical
method,
high
pressure
liquid
chromatography
with
an
ultraviolet
detector,
which
detects
and
measures
residues
of
hexythiazox
and
its
metabolites
as
a
common
moiety,
is
available
for
enforcement
purposes
with
a
limit
of
detection
that
allows
monitoring
of
food
with
residues
at
or
above
the
levels
set
in
these
tolerances.

3.
Magnitude
of
residues.
Three
field
trials
were
conducted
in
Texas
and
Kansas.
These
trials
are
sufficient
to
support
regional
tolerances
in
the
Western
United
States.
Samples
of
corn
grain,
forage
and
stover
were
analyzed.
A
processing
study
was
not
conducted
because
residues
were
not
detected
in
corn
grain
from
plots
treated
at
5
times
the
proposed
application
rate.
Residues
in
corn
forage
sampled
45
±
1
day
after
treatment
averaged
0.57
ppm
and
ranged
up
to
1.38
ppm.,
while
residues
in
corn
stover
averaged
0.36
ppm
and
ranged
up
to
0.83
ppm.

B.
Toxicological
Profile
1.
Acute
toxicity.
A
battery
of
acute
toxicity
studies
places
technical
grade
hexythiazox
in
Toxicity
Category
IV
for
acute
oral
lethal
dose
(
LD
50
)
>
5,000
milligrams
per
kilogram
(
mg/
kg),
Category
III
for
dermal
LD
50
>
5,000
mg/
kg,
Category
III
for
inhalation
lethal
concentration
(
LC
50
)
>
2.0
milligrams
per
liter
(
mg/
L),
Category
III
for
primary
eye
irritation
(
mild
irritation,
reddened
conjunctiva),
and
Category
IV
for
dermal
irritation
(
non­
irritant).
Hexythiazox
is
a
non­
sensitizer.

NA
­
Remove
2.
Genotoxicty.
The
following
genotoxicity
studies
were
all
negative:
Ames
gene
mutation,
CHO
chromosome
aberration,
mouse
micronucleus
and
rat
hepatocyte
unscheduled
DNA
synthesis.
3
NA
­
Remove
3.
Reproductive
and
developmental
toxicity.
In
a
developmental
toxicity
study
in
rats,
the
maternal
No­
Observed­
Adverse­
Effect­
Level
(
NOAEL)
was
240
mg/
kg/
day
and
the
maternal
Lowest­
Observed­
Adverse­
Effect­
Level
(
LOAEL)
was
720
mg/
kg/
day
based
on
increased
ovarian
weights
and
decreased
bone
ossification.
In
a
developmental
toxicity
study
in
rabbits,
the
maternal
NOAEL
was
1,080
mg/
kg/
day
,
the
highest
dose
tested
(
HDT).
The
developmental
LOAEL
was
not
determined
in
a
2­
generation
reproduction
study
in
rats;
the
parental
NOAEL
was
35
mg/
kg/
day
and
the
parental
LOAEL
was
200
mg/
kg/
day
based
on
decreased
body
weight
gain,
decreased
food
consumption
and
efficiency,
and
increased
liver,
kidney
and
ovarian
weights.
The
reproductive
NOAEL
was
35
mg/
kg/
day
and
the
reproductive
LOAEL
based
on
decreased
pup
body
weight
(
bwt)
during
lactation,
delayed
hair
growth
and
eye
opening.
NA
­
Remove
4.
Subchronic
toxicity.
In
a
1­
month
feeding
study
in
dogs,
the
NOAEL
was
1.75
mg/
kg/
day
and
the
LOAEL
was
12.5
mg/
kg/
day,
based
on
increased
liver
and
adrenal
weights.
NA
­
Remove
5.
Chronic
toxicity.
In
a
1­
year
feeding
study
in
dogs,
the
NOAEL
was
2.5
mg/
kg/
day
and
the
LOAEL
was
12.5
mg/
kg/
day,
based
on
increased
alkaline
phosphatase,
increased
adrenal
and
liver
weights,
and
liver
and
adrenal
lesions.
In
a
carcinogenicity
study
in
mice,
the
NOAEL
was
36
mg/
kg/
day
and
the
LOAEL
was
215
mg/
kg/
day.
Effects
were
decreased
bwt
in
males
and
increased
hepatocellular
carcinomas
and
combined
adenoma/
carcinomas.
In
a
chronic
feeding/
carcinogenicity
study
in
rats,
the
NOAEL
(
systemic)
was
26
mg/
kg/
day
and
the
LOAEL
(
systemic)
was
180
mg/
kg/
day
based
on
decreased
bwt
gain
and
increased
liver
weights
in
both
sexes.
The
chronic
reference
dose
(
RfD)
for
hexythiazox
is
based
on
the
1­
year
dog
feeding
study
with
a
NOAEL
of
2.5
mg/
kg/
day
and
an
uncertainty
factor
of
100.
The
Agency
has
classified
hexythiazox
as
a
category
C
(
possible
human)
carcinogen
based
on
an
increased
incidence
of
hepatocellular
carcinomas
(
p
=
0.028)
and
combined
adenomas/
carcinomas
(
p
=
0.024)
in
female
mice
at
the
highest
dose
tested
(
1,500
ppm)
when
compared
to
the
controls
as
well
as
a
significantly
increased
(
p<
0.001)
incidence
of
pre­
neoplastic
hepatic
nodules
in
both
males
and
females
at
the
HDT.
The
decision
supporting
a
category
C
classification
was
based
primarily
on
the
fact
that
only
one
species
was
affected
and
mutagenicity
studies
were
negative.
In
classifying
hexythiazox
as
a
category
C
carcinogen,
the
Agency
concluded
that
a
quantitative
estimate
of
the
carcinogenic
potential
for
humans
should
be
calculated
because
of
the
increased
incidence
of
liver
tumors
in
the
female
mouse.
A
Q1*
of
0.022
mg/
kg/
day­
1
in
human
equivalents
was
published
in
the
Federal
Register
of
October
16,
1998
(
63
FR
55430)
(
FRL­
6035­
2).

NA
­
Remove
6.
Animal
metabolism.
The
metabolism
of
hexythiazox
has
been
studied
in
goats,
hens
and
4
rats.
Metabolic
pathways
in
the
animal
are
similar
to
those
in
plants.
NA
­
Remove
7.
Metabolite
toxicology.
There
are
no
metabolites
of
toxicological
concern
based
on
a
differential
metabolism
between
plants
and
animals.
NA
­
Remove
8.
Endocrine
disruption.
No
specific
tests
have
been
conducted
with
hexythiazox
to
determine
whether
the
chemical
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen
or
if
it
has
other
endocrine
effects.
However,
there
were
no
significant
findings
in
other
relevant
toxicity
tests;
i.
e.,
the
teratology
and
multigeneration
studies,
that
would
suggest
that
hexythiazox
produces
effects
characteristic
of
the
disruption
of
the
estrogenic
hormone.
NA
­
Remove
C.
Aggregate
Exposure
1.
Dietary
exposure.
Tolerances
have
been
established
(
40
CFR
180.448)
for
residues
of
hexythiazox
and
its
metabolites
containing
the
(
4­
chlorophenyl)­
4­
methyl­
2­
oxo­
3­
thiazolidine
moiety
in
or
on
almond
hulls,
apples,
wet
apple
pomace,
the
caneberry
crop
subgroup,
cotton
seed,
cotton
gin
byproducts,
dates,
the
stone
fruit
crop
group,
the
tree
nut
crop
group,
pears,
peppermint,
pistachios,
strawberries,
milk
and
the
meat,
fat
and
meat
byproducts
of
cattle,
goats,
horses,
sheep
and
swine.
Time­
limited
tolerances
for
field
corn
grain,
forage
and
stover,
equal
to
the
tolerance
levels
proposed
here,
already
exist.
EPA
has
estimated
the
following
dietary
exposures
from
hexythiazox
in
food
(
Federal
Register
of
September
29,
2000
(
65
FR
58437)
(
FRL­
6746­
5).
NA
­
Remove
i.
Food.
i.
Acute
exposure.
For
acute
dietary
exposure
of
the
general
population
including
infants
and
children,
a
dose
and
endpoint
attributable
to
a
single
exposure
were
not
identified
by
the
Agency
from
the
available
oral
toxicity
studies.
An
acute
RfD
of
2.4
mg/
kg/
day
for
females
13­
50
years
of
age
was
identified
from
the
rat
developmental
toxicology
based
on
delayed
ossification.
A
conservative
analysis
was
performed
by
the
Agency
using
existing
and
recommended
tolerance
level
residues
and
100%
crop
treated
(
CT)
information
for
all
commodities.
The
acute
dietary
exposure
estimate
for
the
female
13­
50
year­
old
subgroup
was
0.002617
mg/
kg/
day
at
the
95th
percentile.
The
registrant
has
concluded
that
the
proposed
use
on
corn
will
not
contribute
to
a
significant
incremental
increase
to
this
dietary
exposure.

ii.
Chronic
exposure.
A
partially
refined
deterministic
analysis
was
performed
by
the
Agency
using
anticipated
residue
(
AR)
levels
for
mos
crops
and
%
CT
or
anticipated
market
share
information
for
all
crops.
Dietary
exposure
estimates
for
the
U.
S.
population
were
and
other
representative
subgroups
were
<
0.00003
mg/
kg/
day.
The
registrant
has
concluded
that
the
proposed
use
on
corn
will
not
contribute
to
a
significant
incremental
increase
to
this
dietary
exposure.
5
iii.
Cancer.
A
partially
refined
deterministic
analysis
was
performed
by
the
Agency
using
AR
levels
and
%
CT
or
anticipated
market
share
information
for
all
crops.
The
chronic
dietary
exposure
estimate
for
the
U.
S.
population
was
0.000011
mg/
kg/
day.
The
registrant
has
concluded
that
the
proposed
use
on
corn
will
not
contribute
to
a
significant
incremental
increase
in
oncogenic
risk.

NA
­
Remove
ii.
Drinking
water.
Using
the
Generic
Expected
Environmental
Concentration
(
GENEEC)
and
Screening
Concentration
in
Ground
Water
(
SCI­
GROW)
models,
the
Agency
has
calculated
the
estimated
environmental
concentrations
(
EECs)
of
hexythiazox
to
be
910.32
nanograms
per
liter
(
ng/
L)
for
surface
water
and
1.47
ng/
L
for
ground
water.
These
estimates
are
based
on
a
maximum
application
rate
of
0.1875
lb
active
ingredient
per
acre.

NA
­
Remove
2.
Non­
dietary
exposure.
The
term
"
residential
exposure"
is
used
by
the
Agency
to
refer
to
non­
occupational,
non­
dietary
exposure;
e.
g.,
for
lawn
and
garden
pest
control,
indoor
pest
control,
termiticides,
and
flea
and
tick
control
on
pets.
Hexythiazox
is
not
registered
for
use
on
any
sites
that
would
result
in
residential
exposure.

NA
­
Remove
D.
Cumulative
Effects
.
EPA
has
not
determined
whether
hexythiazox
has
a
common
mechanism
of
toxicity
with
other
substances
or
how
to
include
this
pesticide
in
a
cumulative
risk
assessment.
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
hexythiazox
does
not
share
a
toxic
metabolite
with
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
the
registrant
has
not
assumed
that
hexythiazox
has
a
common
mechanism
of
toxicity
with
other
substances.
For
purposes
of
this
petition
the
potential
risks
of
hexythiazox
in
its
aggregate
exposure
only
will
be
considered.

E.
Safety
Determination
EPA
evaluated
aggregate
risks
and
made
a
determination
of
safety
in
Unit
IV.
D.
of
the
Federal
Register
of
November
10,
2004
(
69
FR
65073).
Field
corn
was
included
in
that
evaluation,
so
that
evaluation
remains
equally
valid
at
the
present
time.

1.
U.
S.
population.
i.
Acute
risk.
Aggregate
exposure
risk
includes
exposure
from
food
and
water.
For
acute
dietary
exposure
of
the
general
population,
a
dose
and
endpoint
attributable
to
a
single
exposure
were
not
identified
by
the
Agency
from
the
available
oral
toxicity
studies.
For
the
relevant
population
subgroup
of
females
13+
years,
the
risk
from
acute
"
food
only"
exposure
is
less
than
1%
of
the
RfD,
which
is
less
than
EPA's
level
of
concern.
The
acute
drinking
water
level
of
comparison
(
DWLOC)
6
calculated
for
the
relevant
population
subgroup
of
females
13+
years
is
72,000
parts
per
billion
(
ppb).
The
calculated
DWLOC
is
significantly
higher
than
the
drinking
water
EECs
for
ground
water
(
0.0015
ppb)
and
surface
water
(
0.910
ppb).
EPA
has
concluded
with
reasonable
certainty
that
residues
of
hexythiazox
in
drinking
water
do
not
contribute
to
the
acute
aggregate
health
risk.

ii.
Short­
and
intermediate­
term
risk.
Hexythiazox
is
not
registered
for
use
on
any
sites
that
would
result
in
residential
exposure.
Therefore
the
aggregate
risk
is
the
sum
of
the
risk
from
food
and
water,
which
do
not
exceed
the
Agency's
level
of
concern.

iii.
Chronic
risk.
Aggregate
chronic
risk
(
non­
cancer)
exposure
from
"
food
only"
exposure
utilizes
less
than
1%
of
the
RfD
for
all
population
subgroups.
The
chronic
DWLOC
for
hexythiazox
exposure
in
drinking
water
is
870
ppb
for
the
U.
S.
population
and
250
ppb
for
infants
and
children.
The
calculated
DWLOCs
are
significantly
higher
than
the
drinking
water
EECs
for
ground
water
(
0.0015
ppb)
and
surface
water
(
0.910
ppb).
EPA
has
concluded
with
reasonable
certainty
that
residues
of
hexythiazox
in
drinking
water
do
not
contribute
to
the
chronic
(
non­
cancer)
aggregate
health
risk.

iv.
Cancer
risk.
The
carcinogenic
risk
estimate
(
food
only)
for
the
general
U.
S.
population
is
<
5
x
10­
7.
Thus
the
carcinogenic
dietary
risk
associated
with
the
existing
and
proposed
uses
of
hexythiazox
does
not
exceed
the
level
of
concern
for
excess
lifetime
cancer
risk
(
1
x
10­
6).
The
surface
water
and
ground
water
EECs
were
used
to
compare
against
the
back­
calculated
DWLOC
for
aggregate
risk
assessments.
For
the
carcinogenic
risk
scenario,
EPA
calculated
a
DWLOC
of
1.2
ppb
for
the
U.
S.
population.
The
EECs
for
ground
water
and
surface
water
(
0.0015
ppb
and
0.910
ppb
respectively)
are
less
than
EPA's
calculated
DWLOC.
Therefore,
EPA
concluded
that
residues
of
hexythiazox
in
drinking
water
do
not
contribute
significantly
to
the
carcinogenic
aggregate
human
health
risk.

NA
­
Remove
2.
Infants
and
children.
For
acute
dietary
exposure
of
infants
and
children,
a
dose
and
endpoint
attributable
to
a
single
exposure
were
not
identified
by
the
Agency
from
the
available
oral
toxicity
studies.
The
Agency
has
determined
that
the
10x
safety
factor
to
protect
infants
and
children
should
be
removed
and
reduced
to
1x.
It
is
concluded
that
there
is
a
reasonable
certainty
of
no
harm
to
infants
and
children
from
aggregate
exposure
to
hexythiazox
residues.
NA
­
Remove
F.
International
Tolerances
There
are
no
international
maximum
residue
limits
for
hexythiazox
on
field
corn.