Document ID: EPA-HQ-OPP-2004-0411-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-02-18T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
Date:
26­
JAN­
2005
MEMORANDUM
SUBJECT:
Revised
as
per
30­
day
Error
Only
Registrant
Comments.
Ametryn:
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED).
PC
Code:
080801,
Case
#:
2010,
DP
Barcode:
D307100.

Regulatory
Action:
Phase
1
Reregistration
Action
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
William
H.
Donovan,
Ph.
D.,
Chemist
Reregistration
Branch
3
(
RRB3)
Health
Effects
Division
(
HED)
(
7509C)

AND
John
Doherty,
Ph.
D,
Toxicologist
Robert
Travaglini,
Chemist
RRB3/
HED
(
7509C)

THROUGH:
Danette
Drew,
Branch
Senior
Scientist
RRB3/
HED
(
7509C)

TO:
Mark
T.
Howard,
CRM
Reregistration
Branch
3
Special
Review
and
Registration
Division
(
7508C)
2
Table
of
Contents
1.0
Executive
Summary
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1
2.0
Ingredient
Profile
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6
2.2
Structure
and
Nomenclature
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7
2.3
Physical
and
Chemical
Properties
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7
3.0
Metabolism
Assessment
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8
3.1
Comparative
Metabolic
Profile
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8
3.2
Nature
of
the
Residue
in
Foods
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8
3.2.1.
Description
of
Primary
Crop
Metabolism
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8
3.2.2
Description
of
Livestock
Metabolism
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9
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
.
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11
3.3
Environmental
Degradation
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11
3.4
Tabular
Summary
of
Metabolites
and
Degradates
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12
3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
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12
3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
.
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13
3.6.1
Tabular
Summary
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13
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
.
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13
4.0
Hazard
Characterization/
Assessment
.
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14
4.1
Hazard
Characterization
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14
4.2
FQPA
Hazard
Considerations
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19
4.2.1
Adequacy
of
the
Toxicity
Data
Base
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19
4.2.2
Evidence
of
Neurotoxicity
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19
4.2.3
Developmental
Toxicity
Studies
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19
4.2.4
Reproductive
Toxicity
Study
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20
4.2.5
Additional
Information
from
Literature
Sources
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21
4.2.6
Pre­
and/
or
Postnatal
Toxicity
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21
4.2.6.1
Determination
of
Susceptibility
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21
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
.
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22
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
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22
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
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22
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
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22
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
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22
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
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22
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
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22
4.4.3
Chronic
Reference
Dose
(
cRfD)
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22
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
.
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23
4.4.5
Dermal
Absorption
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24
4.4.6a
Dermal
Exposure
(
Short
and
Intermediate
Term)
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24
3
4.4.7a
Inhalation
Exposure
(
Short
and
Intermediate
Term)
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25
4.4.7b
Inhalation
Exposure
(
Long
Term).
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25
4.4.8
Margins
of
Exposure
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26
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
.
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26
4.4.10
Classification
of
Carcinogenic
Potential
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26
4.5
Special
FQPA
Safety
Factor
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29
4.6
Endocrine
disruption
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30
5.0
Public
Health
Data
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30
5.1
Incident
Reports
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30
6.0
Exposure
Characterization/
Assessment
.
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30
6.1
Dietary
Exposure/
Risk
Pathway
.
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30
6.1.1
Residue
Profile
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30
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
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32
6.2
Water
Exposure/
Risk
Pathway
.
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33
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
.
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34
6.3.1
Home
Uses
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34
6.3.2
Recreational
Uses
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34
6.3.3
Other
(
Spray
Drift,
etc.)
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34
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
.
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35
7.1
Acute
Aggregate
Risk
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35
7.2
Short­
Term
Aggregate
Risk
.
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35
7.3
Intermediate­
Term
Aggregate
Risk
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35
7.4
Long­
Term
Aggregate
Risk
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35
7.5
Cancer
Risk
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37
8.0
Cumulative
Risk
Characterization/
Assessment
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40
9.0
Occupational
Exposure/
Risk
Pathway
.
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40
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
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40
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
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55
10.0
Data
Needs
and
Label
Requirements
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55
10.1
Toxicology
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55
10.2
Residue
Chemistry
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55
10.3
Occupational
and
Residential
Exposure
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56
References:
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57
Appendices
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58
1
1.0
Executive
Summary
This
assessment
provides
information
to
support
the
issuance
of
a
risk
management
decision
document
known
as
a
Reregistration
Eligibility
Decision
(
RED)
Document
for
ametryn.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Use
Profile
Ametryn,
(
2­
ethylamino)­
4­(
isopropylamino)­
6­(
methylthio)­
s­
triazine,
is
a
selective
methylthiotriazine
herbicide
registered
for
the
control
of
broadleaf
and
grass
weeds
in
corn,
pineapple,
and
sugarcane.
Ametryn
has
no
residential
uses.
In
the
U.
S.,
ametryn
is
registered
to
Syngenta
Crop
Protection,
Inc.
(
the
basic
producer)
under
the
trade
name
EVIK
®
and
is
formulated
as
a
80%
water
dispersible
granule
(
DF).
Ametryn
can
be
applied
by
aerial
equipment
(
sugarcane
only)
and
by
ground
boom
sprayers.
For
corn
(
field,
pop,
and
sweet),
ametryn
is
used
as
a
directed
spray
for
soil
treatment
post­
emergence.
For
sugarcane,
ametryn
is
used
as
a
band
treatment
(
ratoon),
or
as
a
broadcast
spray
(
pre­
emergence,
ratoon,
and
post­
emergence).
For
pineapple,
ametryn
is
used
as
a
blanket
(
i.
e.,
broadcast)
spray.

Ametryn
is
a
FIFRA
List
B
pesticide
that
was
the
subject
of
a
Phase
4
Review,
dated
11/
19/
90,
and
a
Reregistration
Update,
dated
12/
9/
94.
Ametryn
will
not
be
included
in
the
cumulative
risk
assessment
for
atrazine,
simazine,
propazine,
and
their
degradates
(
desethyl­
satrazine
desisopropyl­
s­
atrazine,
and
diaminochlorotriazine)
as
determined
by
the
Office
of
Pesticide
Programs'
Health
Effects
Division
in
its
March
2002
report:
"
The
Grouping
of
a
Series
of
Triazine
Pesticides
Based
on
a
Common
Mechanism
of
Toxicity."
Ametryn
was
not
grouped
with
chloro­
s­
triazines
(
atrazine,
simazine,
propazine
and
their
chloro­
s­
triazine
metabolites)
because
it
has
a
different
functional
group
attached
to
the
triazene
ring,
i.
e.,
thiomethyl
versus
chloro.
Further,
ametryn
does
not
exhibit
the
same
toxicity
profile
as
the
chloro­
s­
triazines.
There
were
several
tumors
induced
by
ametryn
in
a
rat
bioassay,
but
only
at
an
excessive
dose
which
confounds
the
interpretation
of
this
response.
This
pattern
of
tumor
response
is
not
characteristic
of
the
chloro­
s­
triazines.
Tolerances
are
currently
established
for
the
residues
of
ametryn
per
se
[
40
CFR
§
180.258],
and
are
set
at
0.25
ppm
for
all
plant
commodities,
with
the
exceptions
of
corn
forage
and
stover,
each
at
0.5
ppm,
and
cassava
root
at
0.1
ppm.
There
are
currently
no
livestock
tolerances
for
ametryn.

Comprehensive
information
on
use
patterns
and
formulations
is
provided
in
the
ametryn
Master
Label
which
was
submitted
to
the
EPA
by
Syngenta
Crop
Protection,
Inc.
The
risk
assessments
for
ametryn
are
based
solely
on
the
Master
Label,
since
it
only
lists
supported
uses
(
M.
T.
Howard,
Use
Closure
Memo,
27­
FEB­
2004).

Hazard
Identification
and
Dose
Response
Assessment
2
The
toxicology
data
base
is
adequate
to
characterize
the
toxicity
of
ametryn.
Ametryn
is
placed
in
Toxicity
Category
IV
for
acute
inhalation
toxicity
and
dermal
irritation;
and
in
Toxicity
Category
III
for
acute
oral
and
dermal
toxicity
and
eye
irritation.
Ametryn
is
not
a
skin
sensitizer.

The
available
toxicity
database
indicates
that
the
liver
is
the
most
sensitive
organ
and
the
dog
the
is
the
most
sensitive
species
to
ametryn
exposure.
Other
toxic
effects
included
decreases
in
body
weight
and
gain
related
to
decreases
in
food
efficiency
across
species,
but
were
most
pronounced
in
the
rat.
Changes
in
body
weight
and
gain
were
the
main
effects
seen
in
the
developmental
and
reproductive
studies.
There
was
no
indication
of
increased
qualitative
or
quantitative
sensitivity
or
susceptibility
in
fetuses
or
offspring.
There
is
no
residual
uncertainty
for
pre
and/
or
post
natal
toxicity.
Therefore,
the
special
FQPA
uncertainty
factor
for
sensitivity
in
infants
and
children
was
reduced
to
1x.
There
were
no
signs
of
mutagenicity,
immunotoxicity,
or
direct
neurotoxocity
in
the
available
database.
In
the
rat,
ametryn
was
rapidly
absorbed,
metabolized
into
polar
constituents
and
excreted.

The
Cancer
Assessment
Review
Committee
(
CARC)
met
to
evaluate
the
carcinogenic
potential
of
ametryn
on
21­
JUL­
2004
and
concluded
that
the
"
data
are
inadequate
for
an
assessment
of
human
carcinogenic
potential".
The
carcinogenicity
study
in
rats
is
unacceptable
because
the
high
dose
was
considered
to
be
excessive.
The
CARC
requested
that
the
carcinogenicity
study
in
rats
be
repeated
at
a
dose
that
is
adequate
to
assess
carcinogenicity.
However,
the
available
data
allow
for
a
determination
of
a
provisional
Q
1*
value
of
0.0066
(
mg/
kg/
day)­
1,
based
on
observations
of
combined
mammary
tumors
in
female
rats.
The
ametryn
risk
assessment
team
believes
that
using
the
estimated
provisional
Q
1*
based
on
existing
data
will
reasonably
approximate
cancer
risk
to
humans
and
considers
it
unlikely
that
the
requested
new
cancer
study
will
result
in
a
higher
risk
for
ametryn.
Support
for
this
conclusion
comes
from
the
observation
that
there
were
no
tumors
in
the
rat
study
at
500
ppm,
a
dose
resulting
in
minimal
body
weight
decrease
and
the
fact
that
there
were
no
compound
related
tumors
in
the
mouse
study
at
dose
levels
up
to
and
including
2000
ppm.

Dietary,
drinking
water,
and
occupational
exposure
scenarios
are
relevant
for
ametryn.
No
acute
dietary
assessment
was
conducted
as
an
appropriate
endpoint
for
single
dose
effects
was
not
identified
in
the
available
toxicity
datatbase.
The
chronic
dietary
endpoint
was
selected
based
on
a
chronic
feeding
study
in
dogs,
where
degenerative
and
inflammatory
liver
effects
were
observed
at
a
dose
of
70
mg/
kg/
day.
This
study
was
also
used
to
establish
the
long­
term
inhalation
and
dermal
endpoints.
The
short­
and
intermediate­
term
oral
and
inhalation
endpoints
were
selected
from
a
developmental
toxicity
study
in
rabbits,
where
increased
liver
weights
and
decreased
feed
consumption
were
noted
at
60
mg/
kg/
day.
The
short­
and
intermediate­
term
dermal
endpoints
were
based
on
a
21­
day
dermal
toxicity
study
in
rabbits,
where
a
body
weight
gain
decrease
occurred
at
a
dose
of
1000
mg/
kg/
day.
Endpoints
used
in
the
assessment
are
provided
in
Table
1.
A
standard
uncertainty
factor
(
UF)
of
100x
was
applied
to
all
oral,
dermal,
and
inhalation
risk
assessments
(
10x
due
to
intraspecies
variation
and
10x
due
to
interspecies
extrapolation).
Overall,
available
data
indicate
that
ametryn
is
a
relatively
low
toxicity
compound.
3
Table
1.
Endpoints
Used
for
Ametryn
Risk
Assessment
Dietary
NOAEL
mg/
kg/
day
RfD
mg/
kg/
day
PAD
mg/
kg/
day
chronic
­
all
populations
7.2
0.072
(
UF=
100;
FQPA
=
1)
0.072
Occupational/
Residential
NOAEL
mg/
kg/
day
MOE
dermal
­
short
term
and
intermediate
term
100
100
incidental
oral
­
short
term
and
intermediate
term
10
100
inhalation
­
short
term
and
intermediate
term
10
100
dermal
and
inhalation
­
long
term
7.2
100
Exposure
Assessment
Analysis
of
dietary,
drinking
water,
cancer,
and
occupational
exposure
pathways
were
included
in
the
ametryn
risk
assessment.
Sources
of
dietary
exposure
include
food
from
treated
crops
of
corn,
sugarcane,
and
pineapple.
The
anticipated
dietary
exposure
to
ametryn
is
expected
to
be
low
due
to
the
long
PHIs,
the
susceptibility
of
crops
to
damage
from
ametryn,
and
the
limited
number
of
crop
uses.
Drinking
water
exposure
may
occur
due
to
run­
off
from
the
agricultural
uses
of
ametryn.
Occupational
exposure
may
occur
through
use
of
ametryn
during
mixing,
loading,
and
application
procedures.
For
the
occupational
exposures,
short­
and
intermediate­
term
dermal
and
inhalation
pathways
were
assessed
based
on
label
directed
use
patterns.
Long­
term
exposures
to
ametryn
are
not
expected
for
the
current
registered
uses.
Residential
exposures
were
not
assessed
as
there
were
no
residential
uses.

Risk
Assessment
and
Risk
Characterization
Risk
assessments
were
conducted
for
dietary,
drinking
water,
cancer,
and
occupational
exposure
pathways.
An
aggregate
assessment
of
risk
from
the
combined
food
and
drinking
water
pathways
was
also
conducted
(
both
cancer
and
non­
cancer).
A
cumulative
risk
assessment
considering
risks
from
other
pesticides
or
chemical
compounds
having
a
common
mechanism
of
toxicity
has
not
been
conducted
for
this
RED.
Although
HED
has
determined
that
ametryn
does
not
share
a
common
mechanism
of
toxicity
with
chlorinated
triazines
(
atrazine,
simazine,
propazine,
and
their
chlorinated
metabolites),
HED
has
not
yet
determined
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
in
common
with
that
of
ametryn.

Food
Pathway
Exposure
and
Risk
HED
conducted
refined
chronic
and
cancer
dietary
exposure
analyses
using
the
Dietary
Exposure
Evaluation
Model
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
)
and
the
Lifeline
model.
The
chronic
dietary
analyses
were
conducted
for
the
general
U.
S.
population
and
all
population
subgroups,
while
the
cancer
dietary
analysis
was
conducted
for
the
US
population
only.
For
the
purpose
of
estimating
dietary
risk
in
this
document
and
use
in
the
aggregate
risk
assessments,
the
higher
of
the
estimated
exposure
levels
predicted
by
DEEMFCID
 
and
Lifeline
were
selected
for
each
population
subgroup.
4
Chronic
dietary
risks
are
expressed
as
a
percentage
of
the
chronic
Population
Adjusted
Dose
(
cPAD).
A
dietary
risk
of
100%
of
the
PAD
is
the
level
of
exposure
that
should
not
be
exceeded,
(
i.
e.,
estimated
risk
less
than
100%
of
PAD
is
not
of
concern).
The
PAD
is
the
chronic
reference
dose
(
cRfD)
modified
by
the
special
FQPA
Safety
Factor.
The
special
FQPA
safety
factor
for
sensitivity
in
infants
and
children
for
the
chronic
dietary
assessment
is
1X.
Based
on
these
analyses,
chronic
dietary
risk
from
existing
and
proposed
uses
of
ametryn
are
below
HED's
level
of
concern
for
the
general
US
population
and
all
population
subgroups.
Chronic
exposure
estimates
were
<
100%
of
the
cPAD,
with
the
highest
chronic
exposure
(
0.000018
mg/
kg/
day)
occurring
in
children
1­
2
years
old
(<
0.1%
cPAD).

For
cancer
exposures,
HED
is
generally
concerned
when
estimated
cancer
risks
exceed
one
in
one
million
(
i.
e.,
the
risk
exceeds
1
x
10­
6).
The
lifetime
cancer
risk
calculated
in
Lifeline
 
for
the
US
population
is
2.7
x
10­
8
and
is
therefore
less
than
HED's
level
of
concern.

Drinking
Water
Pathway
Exposure
and
Risk
The
Environmental
Fate
and
Effects
Division
(
EFED)
performed
a
drinking
water
assessment
for
ametryn
in
surface
water
and
ground
water
(
D307105,
K.
Costello,
16­
NOV­
2004).
EFED
used
the
PRZM­
EXAMS
model
for
estimating
the
upper
bound
on
the
concentrations
that
could
occur
in
surface­
water­
source
drinking
water,
and
SCIGROW2
(
Screening
Concentration
in
Ground
Water)
to
estimate
the
concentrations
in
ground
water
used
for
drinking
water.
The
chronic
and
cancer
estimated
drinking
water
concentrations
(
EDWCs)
of
ametryn
in
surface
water
are
92
and
73
ppb,
respectively.
The
chronic
and
cancer
groundwater
EDWCs
are
15.6
ppb.

Aggregate
Exposures
and
Risks
Since
there
is
potential
for
concurrent
exposure
via
food
and
water,
the
combined
exposures
are
estimated
for
the
aggregate
assessment.
To
assess
aggregate
risk,
drinking
water
levels
of
comparison
(
DWLOCs)
are
compared
with
model­
based
EDWCs
determined
by
EFED.
The
DWLOC
is
the
concentration
of
a
chemical
in
drinking
water
that
would
be
acceptable
as
an
upper
limit
in
light
of
total
aggregate
exposure
to
that
chemical
from
food,
water,
and
residential
sources.
Aggregate
risk
for
ametryn
exposure
is
calculated
for
chronic
and
cancer
exposures.
Chronic
and
cancer
DWLOCs
include
aggregate
exposure
from
food
and
drinking
water
only.

The
ametryn
chronic
DWLOCs
are
>
720
ppb,
based
on
the
most
highly
exposed
subgroup
(
children
1­
2
years
old).
EFED's
model­
based
estimates
for
chronic
concentrations
of
ametryn
in
surface
and
ground
water
are
92
and
15.6
ppb,
respectively.
Since
the
model­
based
estimates
for
concentrations
in
surface
water
and
groundwater
are
below
the
calculated
chronic
DWLOCs,
HED
concludes
that
aggregate
exposure
to
food
and
drinking
water
will
not
result
in
estimates
that
exceed
HED's
level
of
concern
for
chronic
exposure
scenarios.

The
ametryn
provisional
cancer
DWLOC
for
the
general
US
population
is
5.2
ppb.
EFED's
model­
based
estimates
for
cancer
comparisons
of
ametryn
in
surface
and
ground
water
are
73
and
15.6
ppb,
respectively.
In
this
case,
since
the
EDWCs
for
ground
and
surface
water
exceed
HED's
provisional
cancer
DWLOC
for
the
U.
S.
population,
the
cancer
assessment
fails
this
screening
analysis
and
indicates
a
need
for
additional
data
in
the
form
of
a
new
rat
cancer
5
study.

Occupational
Pathway
Exposure
and
Risk
Based
on
product
labeling
and
information
provided
for
the
completion
of
the
RED
process
for
this
pesticide,
HED
has
identified
14
occupational
handler
scenarios
for
which
shortand
intermediate­
term
exposure
to
ametryn
may
occur.
Exposure
estimates
were
conducted
using
the
maximum
application
rates
for
each
of
the
crops.
MOEs
for
11
of
the
14
handler
scenarios
are
>
100
at
either
baseline
or
minimum
PPE
protection
levels
and
are
not
of
concern.
The
following
scenario
does
not
exceed
an
MOE
of
100
at
baseline
or
minimum
PPE
levels:
Mixing/
loading
liquids
for
aerial
application
to
sugarcane
at
the
application
rate
of
7.2
lbs
ai/
acre,
where
the
MOE
=
79.
The
two
other
scenarios,
aerial
application
of
liquid
sprays
to
sugarcane
at
8.0
and
2.0
lbs
ai/
acre,
have
indeterminable
MOEs
at
these
protection
levels.
All
occupational
exposure
scenarios
have
MOEs
which
exceed
100
when
engineering
controls
are
added.
6
2.0
Ingredient
Profile
Ametryn
(
2­
ethylamino)­
4­(
isopropylamino)­
6­(
methylthio)­
s­
triazine
is
a
methylthiotriazine
herbicide
registered
for
the
preemergent
control
of
weeds
in
corn,
pineapples,
and
sugarcane.
Ametryn
is
registered
in
the
U.
S.
to
Syngenta
Crop
Protection,
Inc.
under
the
trade
name
EVIK
®
and
is
formulated
as
an
80%
water
dispersible
granule
(
DF),
which
is
typically
applied
as
a
broadcast
preemergence
and/
or
a
directed
postemergence
application
using
ground
or
aerial
equipment.

2.1
Summary
of
Supported
Uses
Table
2.1.
Overall
Use
Patterns
for
Ametryn1
Crop
Max
Single
Rate
(
Lbs/
ai/
A)
Applications/
Yr
Maximum
Lbs
/
A/
Yr
Lbs
ai
/
year
Percent
Crop
Treated
Corn
(
Field,
Sweet,
Pop)
2.0
1
2.0
200,000
<
2.5
Pineapple
7.2
NS
7.2
58,000
100
Sugarcane
(
state
dependent)
8.0
5
16.0
90,000
30
State
Use
Programs:
FL
1.2
3
3.6
66,000
NA
LA
2/
2.4/
2.4/
2.4/
2.4
5
11.6
824
0.1
TX
2/
2/
2
3
6.0
8,600
10
HI
7.2/
2.4/
2.4
3
12.0
58,000
90
PR
8/
4/
4
3
16.0
NA
NA
1
Information
taken
from
Ametryn
Use
Closure
Memo,
M.
Howard,
27­
FEB­
2004.
7
N
N
N
N
H
S
C
H
3
NH
CH
3
CH
3
CH
3
2.2
Structure
and
Nomenclature
Table
2.2.
Chemical
Structure
and
Nomenclature
for
Ametryn.

Chemical
structure
Common
name
Ametryn
Molecular
Formula
C9H17N5S
Molecular
Weight
227.35
IUPAC
name
N2­
ethyl­
N4­
isopropyl­
6­
methylthio­
1,3,5­
triazine­
2,4­
diamine
CAS
name
N­
ethyl­
N

­
(
1­
methylethyl)­
6­(
methylthio)­
1,3,5­
triazine­
2,4­
diamine
CAS
#
834­
12­
8
PC
Code
080801
Food/
Feed
Site
Registration
Corn,
Pineapple,
and
Sugarcane
2.3
Physical
and
Chemical
Properties
Ametryn
is
a
non­
volatile
solid
with
moderate
water
solubility.

Table
2.3
Physicochemical
Properties
of
Ametryn
Parameter
Value
Reference
Melting
point
84.5­
86

C
MRID
40877301;
Ametryn
PC
RED
Chapter
pH
8­
9
at
20

C
(
1%
solution
in
water)

Density,
bulk
density,
or
specific
gravity
0.373
g/
mL
at
20

C
Water
solubility
0.020
g/
100
mL
at
20

C
Solvent
solubility
56.9
g/
100
mL
in
acetone
61.4
g/
100/
mL
in
methylene
chloride
51.6
g/
100
mL
in
methanol
46.0
g/
100
mL
in
toluene
24.2
g/
100
mL
in
n­
octanol
1.4
g/
100mL
in
n­
hexane
Vapor
pressure
2.74
x
10­
6
mm
Hg
at
25

C
Dissociation
constant,
pKa
4.02
at
20

C
Octanol/
water
partition
coefficient
KOW
=
423
(
log
P
=
2.63)

UV/
visible
absorption
spectrum
 
max
=
223
nm
8
3.0
Metabolism
Assessment
3.1
Comparative
Metabolic
Profile
Rat
metabolism:
Ametryn
is
readily
absorbed
by
rats
after
a
single
or
multiple
oral
doses
of
0.5
or
200
mg/
kg.
Ametryn
is
widely
distributed,
being
found
in
all
tissues
and
organs
tested.
It
is
metabolized
to
polar
products,
13
of
which
were
identified.
Ametryn
is
excreted
in
urine
(
50­
61%)
within
48
hours,
with
the
remainder
in
the
feces
(
30­
42%).
No
significant
differences
in
pharmacokinetic
parameters
were
seen
among
dosing
groups
(
singular
oral,
high
or
low,
multiple
low,
single
intravenous)
or
between
sexes.

Plant
metabolism:
In
general,
ametryn
is
extensively
metabolized
in
plants
primarily
by
Ndealkylation
and
desulfation
(
oxidation/
hydroxylation)
to
a
variety
of
triazine
ring
containing
metabolites,
each
accounting
for
<
10%
of
the
TRR
in
edible
plant
parts.
In
corn
stalks
and
foilage,
metabolite
GS­
11354
was
also
found
(
see
Table
3.4).

Livestock
metabolism:
The
metabolism
of
ametryn
in
livestock
involves
N­
dealkylation
of
the
isopropyl
and
ethyl
side
chains,
as
well
as
modification
at
the
6­
position,
followed
by
conjugation,
possibly
to
proteins,
with
the
triazine
ring
structure
remaining
intact.
Metabolites
found
in
excess
of
10%
TRR
include
GS­
11354,
GS­
11355,
and
GS­
26831
(
see
Table
3.4).

Water
degradates:
Since
ametryn
is
persistent,
degradates
were
not
observed
at
high
concentrations
in
laboratory
tests.
Only
one
degradate
was
observed
at
greater
than
10%
of
applied
parent
(
GS­
11355
in
the
aerobic
soil
metabolism
study).
Nonetheless,
since
degradates
GS­
11354
and
GS­
11355
are
significantly
similar
in
structure
to
parent
ametryn,
they
were
included
in
the
drinking
water
exposure
assessment
as
possible
degradates
of
concern.

Qualitatively,
the
metabolism
of
ametryn
is
similar
across
the
various
matrices
studied.
The
major
metabolites
and
degradates
found
in
the
plant,
livestock
and
water
studies
were
also
found
in
the
rat
metabolism
study.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
qualitative
nature
of
ametryn
residues
in
corn,
pineapple,
and
sugarcane
is
understood
based
on
the
adequate
corn,
sugarcane,
and
banana
metabolism
studies.

In
the
corn
metabolism
study,
[
U­
14C­
triazine]
ametryn
was
applied
postemergence
as
a
basal/
soil
directed
spray
to
greenhouse­
grown
corn
at
4
lb
ai/
A
(
2x
the
maximum
label
rate)
when
plants
were
12­
18
inches
in
height.
Total
radioactive
residues
(
TRR)
were
2.47
ppm
in
forage
at
56
days
after
treatment
(
DAT),
and
4.56
ppm
in
fodder
and
0.16
ppm
in
grain
at
maturity
(
111
DAT).
Organosoluble
14C­
residues
in
immature
forage
declined
from
100%
of
the
TRR
on
the
day
of
application
to
11%
of
the
TRR
in
mature
fodder.
Radioactive
residues
in
immature
forage
were
not
further
analyzed.
At
maturity,
organosoluble
residues
in
fodder
consisted
primarily
of
ametryn
(
1.8%
TRR)
and
GS­
11354
(
0.2%
TRR).
In
mature
tissues,
the
majority
of
14C­
residues
consisted
of
aqueous
soluble
(
45­
58%
TRR)
and
insoluble
(
31­
57%
TRR)
residues.
Cation
9
exchange
chromatography
separated
aqueous
soluble
14C­
residues
from
mature
tissues
into
numerous
distinct
components
most
of
which
accounted
for
<
10%
of
the
TRR.
The
cation
exchange
elution
profiles
were
qualitatively
similar
for
14C­
residues
from
stalks,
cobs,
and
grain.
Aqueous
soluble
14C­
residues
(
60.5%
TRR)
in
stalks
with
foliage
were
separated
by
cation
exchange
chromatography
into
14
distinct
components,
with
each
one
accounting
for
0.7­
12.7%
of
the
TRR.
Insoluble
14C­
residues
in
stalks/
foliage
were
solubilized
by
refluxing
in
aqueous
MeOH
and
by
enzymatic
and
acid
hydrolyses,
and
were
polar
in
nature.

In
the
sugarcane
metabolism
study,
[
U­
14C­
triazine]
ametryn
was
applied
to
greenhousegrown
sugarcane
as
a
preemergence
application
at
8
lb
ai/
A
and
again
as
soil/
basal
directed
sprays
at
4
lb
ai/
A/
application
at
29
and
50
days
after
planting,
for
a
total
of
16
lb
ai/
A
(
1x
maximum
use
rate).
TRR
in
forage
were
0.12
and
1.57
ppm
in
forage
collected
29
and
50
days
after
the
first
application.
In
separated
stalks
and
foliage,
TRR
were
0.40
and
2.17
ppm,
respectively,
at
84
DAT
and
0.42
and
3.06
ppm
at
202
DAT.
Organosoluble
14C­
residues
in
immature
sugarcane
declined
from
55.2%
of
the
TRR
on
Day­
29
to
28­
32%
of
the
TRR
in
Day­
84
stalks
and
foliage
and
3.4­
7.2%
of
the
TRR
in
mature
(
Day­
202)
stalks
and
foliage.
Organosoluble
residues
were
not
further
analyzed.
Cation
exchange
chromatography
separated
aqueous
soluble
14C­
residues
from
mature
tissues
into
14
distinct
components.
Each
of
these
fractions
accounted
for
<
10%
of
the
TRR,
with
the
exception
of
one
fraction
(
12.6%
TRR)
in
foliage.
Insoluble
14C­
residues
from
mature
tissues
were
released
by
refluxing
in
aqueous
MeOH
and
by
enzymatic
and
acid
hydrolyses.

In
the
banana
metabolism
study,
[
U­
14C­
triazine]
ametryn
was
applied
three
times
as
a
directed
soil
application
to
greenhouse­
grown
banana
plants
at
112­
120
days
retreatment
intervals,
beginning
when
plants
were
3.5
feet
in
height.
TRR
were
0.579
in
immature
leaves
collected
31
days
after
the
second
application
and
1.59
ppm
in
mature
leaves
collected
at
fruit
maturity,
69
days
after
the
second
application.
TRR
in
mature
fruit
(
0.087
ppm)
were
substantially
lower
than
in
leaves
and
were
equally
distributed
between
the
peel
(
0.098
ppm)
and
pulp
(
0.076
ppm).
Methanolic
extraction
of
leaf
and
fruit
samples
released
61.4­
90.9%
of
the
TRR,
and
subsequent
analyses
of
organic
and
aqueous
soluble
14C­
residues
identified
40.6­
61.6%
of
the
TRR
in
leaves
and
58.7­
75.6%
of
the
TRR
in
whole
fruit,
peel
and
pulp
samples.
Including
ametryn,
a
total
of
10
triazine­
ring
containing
compounds
were
identified
in
leaves
and
fruit.

In
general,
ametryn
is
extensively
metabolized
in
plants
primarily
by
N­
dealkylation
and
desulfation
(
oxidation/
hydroxylation)
to
a
variety
of
triazine
ring
containing
metabolites,
each
accounting
for
<
10%
of
the
TRR
in
edible
plant
parts.
Therefore,
ametryn
per
se
is
recommended
for
inclusion
in
the
risk
assessment
and
for
the
tolerance
expression.

3.2.2
Description
of
Livestock
Metabolism
The
qualitative
nature
of
ametryn
residues
in
poultry
and
ruminants
is
understood
based
on
the
adequate
goat
and
hen
metabolism
studies.

The
ametryn
risk
assessment
team
has
determined
that,
if
new
ametryn
uses
are
added
so
that
tolerances
are
needed
for
livestock
commodities,
the
regulated
residues
in
livestock
commodities
should
include
parent
and
its
three
thiomethyl
metabolites
(
GS­
11354,
GS­
11355,
and
GS­
26831)
for
the
purpose
of
tolerance
enforcement
and
risk
assessment.
The
basis
for
this
10
decision
is
as
follows:

°
Metabolism
studies
in
goats
and
hens
demonstrate
that
ametryn
and
the
thiomethyl
metabolites
comprise
>
10%
TRR
in
several
edible
livestock
matrices.
°
An
adequate
data
collection
method
is
available
(
Method
AG­
649)
for
determination
of
ametryn
and
its
three
thiomethyl
metabolites.
If
necessary,
this
method
could
be
validated
for
tolerance
enforcement
purposes.

In
the
goat
metabolism
study,
two
goats
were
dosed
orally
for
3
days
with
[
U­
14C­
triazine]
ametryn
at
a
level
equivalent
to
50
ppm
in
the
diet,
which
is
280x
the
maximum
theoretical
dietary
burden
(
MTDB)
for
dairy
cattle.
Maximum
14C­
residues
were
attained
in
milk
on
Day
2
at
0.686
or
1.277
ppm.
At
sacrifice,
TRR
were
2.71­
2.89
ppm
in
liver,
3.0­
3.05
ppm
in
kidney,
0.092­
0.137
ppm
in
muscle,
and
0.084­
0.088
ppm
in
fat.
Solvent
extraction
released
84%
of
the
TRR
from
fat,
42­
53%
of
the
TRR
from
milk,
muscle,
and
kidney,
and
29%
of
the
TRR
from
liver.
Subsequent
acid
hydrolyses
released
the
remaining
radioactivity
from
each
matrix,
and
HPLC
and
TLC
analyses
identified
>
80%
of
the
TRR
in
each
matrix.

The
principal
organosoluble
residues
in
goats
milk
and
tissues
were
ametryn,
GS­
11354,
and
GS­
26831.
Ametryn
accounted
for
40%
of
the
TRR
in
fat,
9.7%
TRR
in
muscle,
and
0.2­
2.3%
TRR
in
liver,
kidney,
and
milk,
and
GS­
11354
accounted
for
20.8%
TRR
in
fat,
11.5%
TRR
in
muscle,
and
1.9­
2.4%
TRR
in
liver,
kidney,
and
milk.
Metabolite
GS­
26831
accounted
for
13.5%
TRR
in
muscle,
7.0­
9.6%
TRR
in
milk
and
kidney,
and
3.3­
4.7%
TRR
in
liver
and
fat.
The
organosoluble
metabolite
GS­
11355
was
also
identified
in
milk
and
all
tissues
at
0.9­
4.6%
of
the
TRR.
The
combined
residues
of
ametryn
its
three
thiomethyl
metabolites
(
GS­
11354,
GS­
11355,
and
GS­
26831)
accounted
for
16.4%
TRR
in
milk,
9.1%
TRR
in
liver,
12.5%
TRR
in
kidney,
37.1%
TRR
in
muscle,
and
71.2%
TRR
in
fat;
actual
levels
of
these
combined
residues
ranged
from
0.03
ppm
in
muscle
to
0.37
ppm
in
kidney.
Other
minor
solvent
extracted
metabolites
containing
the
triazine­
ring
were
detected
in
various
tissues
or
milk
at
0.3­
9.8%
TRR.

In
the
poultry
metabolism
study,
10
hens
were
dosed
orally
for
3
days
with
[
U­
14Ctriazine
ametryn
at
levels
equivalent
to
50
ppm
in
the
diet
(
1,250x
MTDB).
Maximum
14C­
residues
in
eggs
were
attained
on
Day
3
at
0.099
ppm
in
egg
whites
and
0.268
ppm
in
egg
yolks.
At
sacrifice,
TRR
were
4.98
ppm
in
liver,
0.379­
0.558
in
muscle,
0.618
ppm
in
skin,
and
0.240
ppm
in
fat.
Solvent
extraction
released
72
and
58%
of
the
TRR
from
egg
whites
and
fat,
respectively,
and
16­
25%
of
the
TRR
from
the
remaining
matrices.
Subsequent
protease
and
acid
hydrolyses
released
essentially
all
of
the
remaining
radioactivity
from
each
matrix.

The
principal
organosoluble
residues
in
poultry
were
ametryn,
accounting
for
40%
of
the
TRR
in
fat
and
0.3­
2.7%
of
the
TRR
in
skin,
yolks,
and
muscle,
and
GS­
26831,
accounting
for
52%
TRR
in
egg
whites,
10.4%
TRR
in
yolks,
5.7­
8.7%
TRR
in
muscle,
and
1.2­
1.6%
TRR
in
fat
and
liver.
Other
minor
organosoluble
residues
in
eggs
and
tissues
were
detected
at
0.1­
5.2%
TRR.
The
combined
residues
of
ametryn
its
three
thiomethyl
metabolites
(
GS­
11354,
GS­
11355,
and
GS­
26831)
accounted
for
63.7%
TRR
in
egg
white,
14.3%
TRR
in
yolks,
14­
24%
TRR
in
muscle,
51.7%
TRR
in
fat,
and
7.4%
TRR
in
liver;
actual
levels
of
the
combined
residues
ranged
11
from
0.03
ppm
in
yolks
to
0.42
ppm
in
liver.

The
metabolism
of
ametryn
in
livestock
involves
N­
dealkylation
of
the
isopropyl
and
ethyl
side
chains,
as
well
as
modification
at
the
6­
position,
followed
by
conjugation,
possibly
to
proteins,
with
the
triazine
ring
structure
remaining
intact.
Based
on
the
metabolic
profile
and
metabolism
study
results,
the
ametryn
risk
assessment
team
has
classified
ametryn
residues
under
40
CFR
§
180.6(
a)(
3),
"
no
reasonable
expectation
of
finite
residues
for
meat,
milk,
poultry,
and
eggs."

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
The
results
of
the
confined
rotational
crop
study
were
similar
to
the
metabolism
of
ametryn
in
primary
crops.
Ametryn
is
metabolized
in
soil
and
plants
by
N­
dealkylation
and
desulfation
(
oxidation/
hydroxylation)
to
a
variety
of
metabolites
containing
a
hydroxylated
triazine
ring.

3.3
Environmental
Degradation
Ametryn
is
a
moderately
persistent
herbicide.
A
single
aerobic
soil
metabolism
study
suggests
that
this
is
an
important
route
of
dissipation
in
the
environment,
with
an
observed
halflife
of
84
days.
Ametryn
is
stable
to
hydrolysis,
and
degrades
slowly
by
aquatic
photolysis
(
368
days).

Since
ametryn
is
persistent,
degradates
were
not
observed
at
high
concentrations
in
laboratory
tests.
Only
one
degradate
was
observed
at
greater
than
10%
of
applied
parent
(
GS­
11355
in
the
aerobic
soil
metabolism
study).
Nonetheless,
since
degradates
2­
amino­
4­
isopropylamino­
6­
methylthio­
s­
triazine
(
GS­
11354)
and
2­
ethylamino­
4­
amino­
6­
methylthio­
striazine
(
GS­
11355)
are
significantly
similar
in
structure
to
parent
ametryn,
they
were
included
in
the
drinking
water
exposure
assessment
as
possible
degradates
of
concern.

Ametryn
was
observed
to
be
highly
mobile
in
3
of
4
soils
in
laboratory
tests
(
Kd
=
1.07
to
1.21
in
loam,
sandy
loam
and
sand
soils,
26.2
in
a
clay
soil).
Given
its
persistence
and
mobility,
transport
of
ametryn
to
ground
water
and
surface
water
is
expected
from
normal
agricultural
use.
Monitoring
of
ametryn
concentrations
in
ground
water
and
surface
water
is
limited,
however.
Ametryn
was
not
included
among
analytes
in
the
NAWQA
program,
for
instance.
Monitoring
in
Hawaii
of
ground
water
in
pineapple
use
areas
in
the
mid­
1990'
s
resulted
in
a
maximum
concentration
similar
in
magnitude
to
that
predicted
with
the
ground­
water
screening
model
SCIGROW
(
Screening
Concentration
in
Ground
Water).
Quarterly
surface­
water
monitoring
on
the
borders
of
the
Everglades
Agricultural
Area
(
EAA)
has
resulted
in
surface
water
concentrations
well
below
those
estimated
for
maximum
application
rates
by
the
PRZM/
EXAMS
models,
resulting
in
greater
uncertainty
in
these
estimates.
12
3.4
Tabular
Summary
of
Metabolites
and
Degradates
Chemical
Name
(
Code)
Chemical
Structure
Matrices/
MRIDs
Ametryn
2­
ethylamino­
4­
isopropylamino­
6­
methylthio­
s­
triazine
(
G­
34162;
CG­
1)
Corn
stalks/
foliage
41662302
Goat
41662305
(
milk,
liver,
muscle,
kidney,
fat)

Water
Putative:
Hen
41662303
(
eggs,
muscle,
skin,
fat)

N­
De­
ethyl­
ametryn
2­
amino­
4­
isopropylamino­
6­
methylthio­
s­
triazine
(
GS­
11354;
CG­
3)
Corn
stalks/
foliage
41662302
Goat
41662305
(
milk,
liver,
muscle,
kidney,
fat)

Water
Putative:
Hen
41662303
(
eggs,
muscle,
skin,
fat)

N­
De­
propyl­
ametryn
2­
ethylamino­
4­
amino­
6­
methylthio­
s­
triazine
(
GS­
11355;
CG­
4)
Goat
41662305
(
milk,
liver,
muscle,
kidney,
fat)

Water
Putative:
Hen
41662303
(
eggs,
muscle,
liver,
skin,
fat)

2,4­
diamino­
6­
methylthio­
striazine
(
GS­
26831;
CG­
2)
Goat
41662305
(
milk,
liver,
muscle,
kidney,
fat)

Putative:
Hen
41662303
(
eggs,
muscle,
liver,
skin,
fat)

3.5
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Toxicity
data
are
not
available
on
the
metabolites
and
degradates
of
ametryn.
In
the
absence
of
toxicity
data,
metabolites
are
assumed
to
have
the
same
toxicity
as
parent
ametryn.
Accordingly,
decisions
to
regulate
metabolites/
degradates
were
based
on
the
abundance
of
the
13
compounds
found
in
the
various
matrices
studied
and
the
availability
of
analytical
methods
to
detect
these
compounds.

3.6
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.6.1
Tabular
Summary
Table
3.6.
Summary
of
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plants
Primary
Crop
ametryn
per
se
ametryn
per
se
Rotational
Crop
ametryn
per
se
ametryn
per
se
Livestock
Ruminant
Not
Applicable
­
no
residues
expected
Not
Applicable
­
no
tolerances
required
Poultry
Not
Applicable
­
no
residues
expected
Not
Applicable
­
no
tolerances
required
Drinking
Water
ametryn,
GS­
11354,
GS­
11354
Not
Applicable
3.6.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
The
ametryn
risk
assessment
team
has
determined
that
the
regulated
residues
in
corn,
sugarcane,
and
pineapple
will
include
parent
only
for
the
purpose
of
tolerance
enforcement
and
risk
assessment.
The
basis
for
this
decision
is
as
follows:

°
Residue
levels
of
ametryn
and
its
three
thiomethyl
metabolites
are
very
low
in
the
edible
parts
of
crops
that
will
be
treated
with
ametryn.
In
corn
grain,
residue
levels
of
ametryn
and
its
three
thiomethyl
metabolites
were
each
<
0.02
ppm
(
LOQ)
in
29
field
trials
conducted
at
1x,
9
trials
at
2x,
4
trials
at
3x,
and
4
trials
at
5x.
In
pineapple,
residue
levels
of
the
three
thiomethyl
metabolites
were
each
<
0.02
ppm
(
LOQ)
in
8
field
trials
conducted
at
1x,
3
trials
at
2x,
and
2
trials
at
3x.
Ametryn
residue
levels
were
0.05
ppm
in
the
same
trials.
In
sugarcane,
residue
levels
of
ametryn
and
its
three
thiomethyl
metabolites
were
each
<
0.02
ppm
(
LOQ)
in
17
field
trials
conducted
at
a
nominal
rate
of
1x.
°
Corn,
sugarcane,
and
banana
metabolism
studies
show
that
the
thiomethyl
metabolites
each
comprise
<
10%
TRR
in
the
edible
parts
of
the
crops
studied.
°
The
toxicological
database
does
not
indicate
a
special
concern
regarding
the
toxicity
of
14
three
thiomethyl
metabolites.

Because
there
is
no
reasonable
expectation
of
quantifiable
residues
of
ametryn
occurring
in
livestock
commodities
[
40
CFR
§
180.6(
a)(
3)],
no
tolerances
are
appropriate
for
livestock
commodities.
In
the
case
of
drinking
water,
the
levels
of
two
of
the
three
thiomethyl
metabolites
(
GS­
11354
and
GS­
11355)
were
found
to
be
present
in
sufficient
abundance
in
some
studies
to
warrant
inclusion
as
residues
of
concern
in
the
risk
assessment.

4.0
Hazard
Characterization/
Assessment
4.1
Hazard
Characterization
Acute
toxicity.
Ametryn
is
of
low
acute
toxicity
with
the
acute
oral
and
dermal
being
Toxicity
Category
III
and
the
acute
inhalation
toxicity
being
Category
IV.
Ametryn
is
also
nonirritating
to
the
eye
(
Category
III)
or
skin
(
Category
IV)
and
did
not
demonstrate
sensitization.

Subchronic
Dermal
and
Inhalation
Toxicity.
In
a
21­
day
dermal
toxicity
study
the
only
effects
noted
were
decreased
body
weight
and
food
consumption.
There
is
no
subchronic
inhalation
toxicity
study.

Subchronic
and
Chronic
Oral
Toxicity.
The
liver
is
the
most
sensitive
target
organ
for
ametryn
and
the
dog
was
demonstrated
to
be
the
most
sensitive
species
for
signs
of
degeneration.
Body
weight
and
gain
were
affected
at
higher
doses.
In
rats,
body
weight
effects
are
the
most
pronounced
effect
but
at
higher
doses
resulted
in
some
evidence
of
histological
changes
in
the
testes,
kidney
and
pituitary
in
males
and
in
the
liver
and
mammary
gland
in
females.

Carcinogenicity
Evaluation.
There
were
no
indications
of
increased
neoplasms
in
mice.
The
rat
study
demonstrated
increases
in
testicular,
thyroid
and
epididymis
in
males
and
liver
and
mammary
gland
in
females
neoplasms.
However,
there
were
no
statistically
significant
pair­
wise
comparisons
for
the
testicular,
epididymal
or
liver
tumors.
Also,
in
rats
these
increases
occurred
at
dose
levels
where
there
was
an
initial
large
decrease
in
body
weight
gain
and
decreased
body
weight
was
sustained
throughout
the
study
rendering
the
significance
of
these
increased
incidents
of
neoplasms
not
interpretable.
A
second
study
in
rats
is
being
requested
to
further
characterize
the
potential
for
ametryn
to
induce
neoplasms
in
rats.

Developmental
Toxicity.
Neither
the
rat
or
rabbit
developmental
toxicity
studies
demonstrated
effects
on
the
fetuses
at
the
highest
doses
tested
and
at
dose
levels
showing
maternal
toxicity.

Reproductive
Toxicity.
Reproductive
performance
of
neither
the
males
or
the
females
was
affected
by
ametryn.
Systemic
toxicity
to
the
parental
groups
consisted
of
decreased
body
weight
and
gain
and
decreased
feed
efficiency.
Offspring
toxicity
was
indicated
by
decreased
pup
weight
and
weight
gains
during
lactation.
These
results
indicate
no
increased
sensitivity
or
susceptibility
15
in
pups.

Mutagenicity.
There
is
no
mutagenicity
concern
for
ametryn
and
the
existing
mutagenicity
data
base
does
not
indicate
positive
effects.

Immunotoxicity
and
Neurotoxicity.
Although
there
were
no
special
studies
on
immunotoxicity
or
direct
neurotoxicity,
there
were
no
indications
of
immunotoxicity
or
direct
neurotoxicity
in
the
studies
with
rats,
dogs,
mice
or
rabbits.

Metabolism.
Ametryn
is
readily
absorbed
by
rats
after
a
single
or
multiple
oral
doses
of
0.5
or
200
mg/
kg.
It
is
widely
distributed,
being
found
in
all
tissues
and
organs
tested
although
in
low
levels.
It
is
metabolized
to
several
polar
products,
13
of
which
were
identified.
It
is
excreted
mainly
through
the
urine
(
50­
61%)
within
48
hours
with
the
feces
being
the
other
major
route
(
30­
42%).
No
significant
differences
in
pharmacokinetic
parameters
were
seen
among
dosing
groups
(
singular
oral
high
and
low,
multiple
low)
or
between
sexes.

Table
4.1a
Acute
Toxicity
Profile
­
Ametryn
(
PC
Code
080801)

Guideline
Study
Type
MRID(
s)
Results
Tox
Cat
870.1100
Acute
oral­
rat
40995814
(
1988)
LD50
=
1356
(
1164­
1581mg/
kg

"
=
1009
(
829­
1229)
mg/
kg

III
870.1200
Acute
dermal­
rabbit
40995815
(
1988)
LD50
>
2020
mg/
kg
III
870.1300
Acute
inhalation­
rat
42470902
(
1991)
LC50
>
5.03
mg/
L
IV
870.2400
Acute
eye
irritation­
rabbit
40995817
(
1988)
No
corneal
involvement,
mild
conjunctiva
irritation
(
redness,
chemosis
and
discharge)
reversed
by
72
hours
in
washed
eyes.
III
870.2500
Acute
dermal
irritation­
rabbit
40995818
(
1988)
Essentially
non­
irritating.
IV
870.2600
Skin
sensitization
­
guinea
pig
40995819
(
1988)
Not
a
sensitizer
[
]

All
studies
classified
as
"
ACCEPTABLE"
16
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
­
rat
Old
study
.
Refer
to
chronic
dosing.

870.3150
90­
Day
oral
toxicity
­
dog
Old
study.
Refer
to
chronic
dosing.

870.3200
21­
Day
dermal
toxicity
­
rabbit
41067902
(
1989),
Acceptable/
Non­
Guideline
0,
10,
100
or
1000
mg/
kg/
day
NOAEL
=
100
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day
based
primarily
on
body
weight
gain
effects
and
decreased
food
consumption.

Note:
Study
is
non­
guideline
because
on
5/
sex/
dose
group
were
used.

870.3250
90­
Day
dermal
toxicity
(
species)
No
study.

870.3465
90­
Day
inhalation
toxicity
(
species)
No
study.

870.3700a
Prenatal
developmental
in
rats.
00153215
(
1985)
Acceptable/
Guideline
0,
5,
50
or
250
mg/
kg/
day
Maternal
NOAEL
=
5
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day
based
on
ptosis
and
salivation.
Developmental
NOAEL
and
LOAEL
>
250
mg/
kg/
day.
No
effects
at
highest
dose
tested.

870.3700b
Prenatal
developmental
in
rabbits
00153214
(
1985)
Acceptable/
Guideline
0,
1,
10
or
60
mg/
kg/
day
Maternal
NOAEL
=
10
mg/
kg/
day
LOAEL
=
60
mg/
kg/
day
based
on
body
weight
loss,
deceased
feed
consumption
and
increased
liver
weight.
Developmental
NOAEL
and
LOAEL
>
60
mg/
kg/
day.
No
effects
at
highest
dose
tested.

870.3800
Reproduction
and
fertility
effects
(
species)
40349905
(
1987)
Acceptable/
Guideline
0,
1.3,
13
or
131
mg/
kg/
day
in
males
(
approximately)*.
0,
1.2,
12
or
117
mg/
kg/
day
in
females
(
approximately).
*
based
on
the
mean
for
both
generations.
**
based
on
the
lowest
set
for
premating
and
gestation
for
both
generations.
Parental/
Systemic
NOAEL
=
13
mg/
kg/
day
LOAEL
=
131
mg/
kg/
day
based
on
decreased
body
weight
and
weight
gain
and
decreased
feed
efficiency.
Reproductive
NOAEL
and
LOAEL
>
131
mg/
kg/
day.
No
effects
at
highest
dose
tested.
Offspring
NOAEL
=
13
mg/
kg/
day
LOAEL
=
131
mg/
kg/
day
based
on
decreased
pup
weights
and
weight
gain
in
the
F2
generation.
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
17
870.4100a
Chronic
toxicity
Refer
to
870.4200
combined
chronic
feeding/
carcinogenicity
study
in
rats
below.

870.4100b
Chronic
toxicity
(
dog)
40349902
(
1987)
Acceptable/
Guideline
0,
0.71,
7.2,
70,
103
and
83
mg/
kg/
day
in
males
and
0,
0.84,
8.1,
74,
112
and
92
mg/
kg/
day
in
females.
NOAEL
=
7.2
mg/
kg/
day
LOAEL
=
70
mg/
kg/
day
based
on
degenerative
liver
lesions.

870.4200.
Chronic
Feeding/
Carcinogenicity
(
rat)
40349906
(
1987),
41184201
(
1987)
and
403
82001
(
1987)
Acceptable/
Guideline
0,
2,
21
or
145
mg/
kg/
day
for
males
and
0,
2.5,
26
or
176
mg/
kg/
day
for
females.
NOAEL
=
21
mg/
kg/
day
LOAEL
=
145
mg/
kg/
day
based
on
body
weight
and
gain
effects
and
histological
changes
in
the
testes,
kidney
and
pituitary
in
males
and
in
the
liver
and
pancreas
in
females.

The
CARC
(
refer
to
CARC
report
dated
9/
17/
04
in
TXR
#
0052862)
determined
that
the
data
in
the
high
dose
group
are
not
interpretable
because
of
weight
decreases
and
also
the
mid
dose
group,
although
showing
about
4
to
7%
weight
decrease,
was
not
considered
high
enough
to
meet
criteria
for
adequate
dosing.
An
additional
carcinogenicity
evaluation
in
rats
was
requested
by
the
CARC.

870.4300
Carcinogenicity
(
mouse)
40349904
(
1981)
"
CORE
MINIMUM"
0,
1.5,
150
or
300
mg/
kg/
day.
NOAEL
and
LOAEL
>
300
mg/
kg/
day.
No
effects
at
highest
dose
tested.
No
evidence
of
carcinogenicity.

Note:
Marked
decreases
in
body
weight
at
3000
ppm
justify
selection
of
2000
ppm
as
an
acceptable
dose.

Gene
Mutation
870.5100.
Ames
test,
bacterial
mutation.
40995829
and
41189701
(
1984)
Acceptable/
Guideline
0,
20,
80,
320,
1280
or
5120

g/
mL.
No
evidence
of
mutagenicity
in
Salmonella
strains
TA98,
TA
100,
TA
1535
and
TA
1537
up
to
levels
causing
cytotoxicity.

Cytogenetics
870.5395.
Mouse
micronucleus
test.
41067903
(
1989)
Acceptable/
Guideline
1.
800
mg/
kg,
harvest
at
16,
24,
and
48
hours.
2.
200,
400
or
800
mg/
kg:
harvest
at
24
hours.
Negative
for
increased
MPCEs
up
to
clinical
toxicity
(
death).
Table
4.1b
Subchronic,
Chronic
and
Other
Toxicity
Profile
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
18
Other
Effects
870.5550.
Unscheduled
DNA
synthesis
in
rat
hepatocytes.
41067904
(
1989)
Acceptable/
Guideline.
1.
0.1
to
100

g/
mL
2.
0.137
to
33.3

g/
mL
Negative
for
increases
UDS
up
to
cytotoxicity.

870.6200a
Acute
neurotoxicity
screening
battery
No
study.

870.6200b
Subchronic
neurotoxicity
screening
battery
No
study.

870.6300
Developmental
neurotoxicity
No
study.

870.7485
Metabolism
and
pharmacokinetics
(
species)
41463301,
41463302,
41463303
(
all
1990)
Acceptable.
Ametryn
is
readily
absorbed
by
rats
after
a
single
or
multiple
oral
doses
of
0.5
or
200
mg/
kg.
It
is
widely
distributed,
being
found
in
all
tissues
and
organs
tested
although
in
low
levels.
It
is
metabolized
to
several
polar
products,
13
of
which
were
identified.
It
is
excreted
mainly
through
the
urine
(
50­
61%)
within
48
hours
with
the
feces
being
the
other
major
route
(
30­
42%).
No
significant
differences
in
pharmacokinetic
parameters
were
seen
among
dosing
groups
(
singular
oral
high
and
low,
multiple
low)
or
between
sexes.

870.7600
Dermal
penetration
(
species)
No
study.

Special
studies
No
studies.
19
4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
for
ametryn
is
complete
for
FQPA
assessment.

4.2.2
Evidence
of
Neurotoxicity
There
is
not
a
concern
for
neurotoxicity
resulting
from
exposure
to
ametryn
based
on
lack
of
evidence
of
neurotoxicity
from
the
available
studies.

4.2.3
Developmental
Toxicity
Studies
a.
Rat
study.

Executive
Summary:
In
a
developmental
toxicity
study
(
1985,
MRID
00153215
and
92002024),
Ametryn
Technical
(
batch/
lot
#
FL­
840991,
purity
96.8%)
was
administered
to
24
female
Charles
River
rats/
dose
by
gavage
at
dose
levels
of
0,
5,
50,
or
250
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.
On
gestation
day
(
GD)
20,
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
were
examined
externally.
The
total
numbers
of
fetuses
examined
(
number
of
litters)
was
281(
20),
271(
22),
325(
23),
and
305(
22)
for
the
0,
5,
50,
and
250
mg/
kg
bw/
day
groups,
respectively.
Approximately
one­
third
of
the
fetuses
were
examined
viscerally,
and
the
other
twothirds
of
the
fetuses
were
examined
for
skeletal
malformations/
variations.
Maternal
toxicity.
Dams
treated
with
50
mg/
kg
bw/
day
had
statistically
increased
(
p

0.05)
incidences
of
ptosis
(
3/
24
affected)
and
salivation
(
3/
24,
compared
with
0/
24
for
both
signs
in
controls).
Treatment
with
250
mg/
kg
bw/
day
resulted
in
maternal
toxicity
as
evidenced
by
mortality
(
2/
24);
statistically
increased
(
p

0.01)
incidences
of
ptosis
(
19/
24),
salivation
(
24/
24),
and
hypoactivity
(
8/
24);
and
decreased
feed
consumption
(

12
to
32%,
starting
on
GD
6
and
continuing
through
GD
15,
p

0.05;
0.01)
accompanied
by
decreased
maternal
body
weight
(

5
to
9%,
p

0.05;
0.01,
starting
on
GD
8
and
continuing
to
study
termination).
Body
weight
gain
was
statistically
decreased
at
all
measured
dosing
intervals
(

26
to
32%,
p

0.05;
0.01),
with
the
corrected
(
final
body
weight
minus
uterine
weight)
body
weight
gain
for
GD
0­
20
being
decreased
by
28%
(
p

0.01).
The
maternal
toxicity
LOAEL
=
50
mg/
kg/
day
based
on
clinical
signs
of
toxicity
(
ptosis
and
salivation).
The
maternal
toxicity
NOAEL
is
5
mg/
kg
bw/
day.
Developmental
Toxicity.
No
treatment­
related,
statistically
significant
effects
on
pregnancy
rate,
number
of
corpora
lutea,
pre­
or
postimplantation
losses,
resorptions/
dam,
fetuses/
litter,
fetal
body
weight,
or
fetal
sex
ratio
were
noted
No
dams
had
complete
litter
resorptions.
No
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed.
The
fetal
incidence
of
unossified
metacarpals
was
apparently
increased
in
the
mid
and
high
dose
group
but
other
structures
did
not
have
this
condition
and
it
was
not
considered
a
definite
developmental
effect
but
possible
related
to
the
weight
effect
in
the
dams.
The
developmental
toxicity
NOAEL
is

250
mg/
kg
bw/
day.
The
developmental
toxicity
LOAEL
could
not
be
established.
This
study
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.

b.
Rabbit
study.

Executive
Summary:
In
a
developmental
toxicity
study
(
1985,
MRID
00153214
and
92002025),
Ametryn
Technical
(
96.8%
a.
i.;
batch/
lot
#
FL­
840991)
was
administered
by
gavage
to
19
female
New
Zealand
White
rabbits/
group
at
dose
levels
of
0,
1,
10,
or
60
mg/
kg
bw/
day
from
days
7
through
19
of
gestation.
On
gestation
day
(
GD)
29,
does
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
examined
for
external,
visceral,
and
20
skeletal
abnormalities.
The
total
numbers
of
fetuses
examined
(
number
of
litters)
were
145(
16),
121(
14),
142(
16),
and
100(
13)
for
the
0,
1,
10,
and
60
mg/
kg
bw/
day
groups,
respectively.
Maternal
Toxicity.
Treatment
with
60
mg/
kg
bw/
day
of
Ametryn
Technical
resulted
in
maternal
toxicity
as
evidenced
by
reduced
body
weight
gain,
decreased
feed
consumption,
and
increased
liver
weights.
The
high­
dose
group
had
reduced
body
weight
gain
manifested
as
a
weight
loss
over
GDs
7­
10
(­
7
g
loss
vs.
37
g
gain
for
controls;
p

0.05),
10­
14
(­
2
g.
loss
vs.
54
g;
gain,
n.
s.),
and
14­
20
(­
4
g
loss
vs.
148
g
gain;
p

0.05).
The
loss
in
body
weight
was
accompanied
by
decreased
daily
feed
consumption
starting
on
GD
7,
with
the
decreases
attaining
statistical
significance
on
all
days
between
GDs
13­
19
(

31
to
41%;
p

0.05;
0.01).
Feed
consumption
then
slowly
increased
starting
on
GD
20,
with
the
increases
attaining
statistical
significance
on
GDs
24­
28
(

43­
104%;
p

0.05;
0.01),
accompanied
by
statistically
increased
body
weight
gain
over
GDs
24­
29
(
151
g
gain
vs.
28
g
gain
for
controls;
p

0.01).
Treatment
with
60
mg/
kg
bw/
day
also
resulted
in
statistically
increased
mean
absolute
liver
weight
(

18%;
p

0.01)
and
liver
weight
as
a
percentage
of
final
body
weight
corrected
for
uterine
weight
(

16%;
p

0.05).
Th
maternal
toxicity
LOAEL
is
60
mg/
kg
bw/
day
based
on
maternal
body
weight
loss,
decreased
feed
consumption,
and
increased
liver
weights.
The
maternal
toxicity
NOAEL
is
10
mg/
kg
bw/
day.
Developmental
toxicity.
No
treatment­
related,
statistically
significant
effects
on
pregnancy
rates,
number
of
corpora
lutea,
pre­
or
postimplantation
losses,
resorptions/
dam,
fetuses/
litter,
fetal
body
weights,
or
fetal
sex
ratios
were
observed.
No
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed
in
any
group.
The
developmental
toxicity
NOAEL
is

250
mg/
kg
bw/
day.
The
developmental
toxicity
LOAEL
could
not
be
established.
This
developmental
toxicity
study
in
the
rabbit
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700b;
OECD
414)
in
the
rabbit.

4.2.4
Reproductive
Toxicity
Study
Executive
Summary:
In
a
two­
generation
reproduction
study
(
1987,
MRID
40349905),
ametryn
technical
(
96.8%
a.
i.,
Batch
No.
FL
840991)
was
administered
in
the
feed
to
groups
of
30/
sex
Charles
River
(
CRCD)
VAF/
PLUS
rats
at
concentrations
of
0,
20,
200,
or
2000
ppm.
The
dietary
levels
corresponded
with
doses
of
0,
1.4,
14,
132
mg/
kg/
day,
respectively,
for
F0
males;
0,
1.3,
13,
and
131
mg/
kg/
day,
respectively,
for
F1
males;
0,
1.5,
26,
134
mg/
kg/
day,
respectively,
for
F0
females;
and
0,
1.4,
14,
and
138
mg/
kg/
day,
respectively,
for
F1
females.
The
premating
period
was
70
days
for
the
F0
generation
and
84
days
for
the
F1
generation.
Both
males
and
females
received
the
test
material
during
the
premating,
mating,
gestation,
and
lactation
periods.
Parental
Systemic
Toxicity.
No
treatment­
related
deaths
or
clinical
signs
were
observed
in
adult
rats
of
either
generation.
High­
dose
F0
and
F1
males
and
females
had
significantly
(
p

0.05)
reduced
body
weight
throughout
the
study.
High­
dose
F0
males
weighed
9­
20%
less
than
controls
and
high­
dose
F1
males
weighed
24­
31%
less
than
controls
and
both
generations
gained
30%
and
21%
less
weight,
respectively,
over
the
entire
study.
High­
dose
F0
females
weighed
5­
12%
less
during
premating
and
high­
dose
F1
females
weighed
14­
17%
during
premating
and
both
generations
gained
24%
and
10%
less
weight,
respectively,
than
controls
over
the
premating
period.
Mid
dose
F1
males
also
showed
slightly
lower
(
5­
6%
body
weight)
differences
during
the
premating
period.

High­
dose
F0
and
F1
males
consumed
14­
20%
and
20­
24%
less
food,
respectively,
than
controls
for
each
weekly
interval
during
the
study
and
consumed
17%
and
22%
less,
respectively,
for
the
entire
study.
High­
dose
F0
and
F1
females
consumed
7­
13%
and
12­
17%
less
food,
respectively,
than
controls
for
each
weekly
interval
during
premating
and
8%
and
16%
less
food,
during
the
entire
premating
period.
The
food
efficiency
values
for
high­
dose
F0
male
and
female
rats
were
reduced
by
14%
and
18%,
respectively,
compared
with
controls
during
the
premating
period;
the
food
efficiency
values
for
high­
dose
F1
male
and
female
rats
slightly
exceeded
those
of
controls.
21
Therefore,
reduced
weight
gain
for
F0
rats
was
not
due
entirely
to
reduced
food
consumption
but
to
toxicity
of
the
test
material.
The
significantly
lower
body
weights
for
high­
dose
females
during
the
premating
period
continued
through
gestation
and
lactation.
High­
dose
F0
and
F1
females
weighed
11­
12%
and
16­
18%
less,
respectively,
than
controls
during
gestation
and
gained
11%
and
16%
less
weight,
respectively.
During
lactation,
they
weighed
9­
13%
and
14­
23%
less,
respectively,
and
gained
markedly
more
weight
than
the
controls.
Food
consumption
was
reduced
during
gestation,
but
was
not
measured
during
lactation.
The
systemic
LOAEL
is
2000
ppm
(
131
mg/
kg/
day
for
males
and
134
­
138
mg/
kg/
day
for
females)
based
on
decreased
body
weight
and
weight
gain
in
both
generations.
The
NOAEL
is
200
ppm
(
14
mg/
kg/
day
for
males
and
14­
26
mg/
kg/
day
for
females).
Reproductive
Toxicity.
Mating,
fertility,
and
gestation
indices,
gestation
interval,
and
the
number
of
viable
litters
born
were
not
affected
by
treatment
with
the
test
material
for
either
the
Fo
or
F1
parental
generations.
The
absolute
weight
of
the
testes
and
ovaries
were
similar
to
those
of
controls
at
all
dose
levels.
The
significantly
increased
relative
testes
weight
was
due
to
the
decreased
terminal
body
weight.
No
treatment­
related
lesions
were
observed
during
macroscopic
or
microscopic
examination
of
the
reproductive
organs.
The
reproductive
LOAEL
could
not
be
established
and
the
reproductive
NOAEL
is

2000
ppm
(
131
mg/
kg/
day
for
males
and
134­
138
mg/
kg/
day
for
females).
Offspring
Toxicity.
Litter
size
and
viability
of
pups
during
lactation
were
not
affected
by
treatment
with
the
test
material.
High­
dose
F1
and
F2
male
and
female
pups
weighed
significantly
less
than
controls
throughout
lactation.
In
particular,
the
high­
dose
F1
pups
weighed
7­
10%
less
from
PND
0­
7
and
15­
19%
less
from
PND
14­
21,
and
the
high­
dose
F2
pups
weighed
12­
17%
less
from
PND
0­
7
and
10­
21%
less
from
PND
14­
21.
High­
dose
male
and
female
F1
and
F2
pups
gained
13­
25%,
7­
12%
(
except
for
F2
females),
7­
19%,
and
19­
39%
less
weight
during
PND
0­
4,
4­
7,
7­
14,
and
14­
21,
respectively.
There
appeared
to
be
a
transient
weight
effect
in
the
mid­
dose
F2
male
and
female
pups
since
they
weighed
9%
less
than
controls
on
PND
4
and
gained
16­
18%
less
weight
from
PND
0­
4
and
14­
17%
less
from
PND
14­
21.
However,
the
apparent
transient
weight
affect
was
considered
to
be
related
to
there
being
more
pups/
litter
in
the
mid
dose
group
than
in
the
control
group
rather
than
a
definite
response
to
treatment.
No
treatment­
related
gross
lesions
were
observed
in
either
sex
or
generation.
The
LOAEL
for
offspring
is
2000
ppm
(
131
mg/
kg/
day
for
males
and
134­
38
mg/
kg/
day
for
females)
based
on
decreased
pup
weights
and
weight
gain
in
both
the
F1
and
F2
generations.
The
NOAEL
is
200
ppm
(
13
mg/
kg/
day
for
males
and
14­
26
mg/
kg/
day
for
females).
This
two­
generation
study
in
rats
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
2­
generation
reproductive
toxicity
study
[(
OPPTS
870.3800);
OECD
416]
in
rats.
The
mid­
dose
female
group
mistakenly
received
the
high­
dose
diet
and
the
high­
dose
group
mistakenly
received
the
mid­
dose
diet
during
one
7­
day
interval.
The
overall
mean
dose
for
mid­
dose
F0
females
was
almost
twice
that
of
the
F1
females.

4.2.5
Additional
Information
from
Literature
Sources
No
relevant
studies
on
ametryn
to
indicate
a
concern
for
developmental
toxicity
were
available
from
the
open
literature.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
There
is
not
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
ametryn.

4.2.6.1
Determination
of
Susceptibility
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
following
in
utero
exposure
of
ametryn
to
rats
and
rabbits.
The
offspring
in
the
rat
reproduction
study
demonstrated
NOAELs
and
22
LOAELs
at
the
same
dose
levels
as
the
adults.
The
possibility
that
the
pups
in
the
low
dose
group
in
the
second
generation
in
the
reproduction
study
had
an
initial
lower
body
weight
than
controls
was
considered
but
this
lower
body
weight
could
not
be
definitely
associated
with
treatment
because
the
low
and
mid
dose
groups
had
a
higher
mean
number
of
pups
per
litter
than
the
controls,
and
the
pups
regained
weight
after
culling
and
no
similar
effect
was
noted
in
the
first
generation.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
There
is
no
concern
for
increased
susceptibility
based
on
the
animal
studies.

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
ametryn;
thus,
a
developmental
neurotoxicity
study
is
not
required.

4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
None.
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
There
was
no
evidence
of
neurotoxicity
or
neuropathology
due
to
ametryn
in
any
of
the
available
toxicity
studies.
Ametryn
does
not
belong
to
a
class
of
chemicals
known
to
induce
neurotoxicity.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
No
appropriate
endpoint
for
females
age
13
­
49
attributable
to
a
single
exposure
was
available
from
oral
studies
including
the
developmental
toxicity
studies.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
No
appropriate
endpoint
for
the
general
population
attributable
to
a
single
exposure
was
available
from
oral
studies
including
the
developmental
toxicity
studies.

4.4.3
Chronic
Reference
Dose
(
cRfD)
Study
Selected:
Dog
chronic
dosing
study
(
1987,
MRID:
40349902)
­
dogs.

Executive
Summary:
In
a
52­
week
oral
toxicity
study
(
1987,
MRID
40349902),
Ametryn
(
96.8%
purity,
batch
#
FL­
840012
and
FL­
840991)
was
administered
to
6­
8
dogs/
sex/
dose
in
the
diet
at
concentrations
of
0,
20,
200,
2000,
4000

2500
or
8000

6000

3000
ppm
(
equivalent
to
0,
0.71,
7.2,
70.,
103,
and
83
mg/
kg
bw/
day
in
males
and
0,
0.84,
8.1,
74,
112
and
92
mg/
kg
bw/
day
in
females).
The
initial
doses
in
ths
high
dose
groups
were
adjusted
downward
at
week
29
for
and
weeks
4
and
8
respectively,
due
to
reduced
body
weight
gains.
One
male
and
one
female
in
the
2500
group
and
three
males
in
the
3000
ppm
group
were
found
dead
during
the
study
due
to
poor
physical
condition
secondary
to
treatment.
Clinical
signs
occurring
primarily
in
the
2500
and
3000
ppm
groups
included
ataxia,
cachexia,
coma,
23
convulsions,
hypersensitivity
to
touch,
hypoactivity,
hypotonia,
pallor,
tremors,
and
unkempt
appearance.
Food
consumption
was
decreased
the
2500
and
3000
ppm
groups
early
in
the
study
when
the
initial
doses
for
those
groups
were
4000
and
8000

6000
ppm,
respectively,
and
remained
49%
and
20%
lower
in
the
3000
ppm
males
and
females,
respectively,
at
52
weeks.
Body
weight
of
the
2500
and
3000
ppm
groups
was
significantly
reduced
for
most
weeks,
and
at
study
end
body
weight
of
the
females
in
those
groups
was
approximately
25%
lower.
Body
weight
gain
was
significantly
lower
in
the
2500
and
3000
ppm
groups
throughout
most
of
the
study,
and
in
the
3000
ppm
group
was
only
20%
of
the
control
gain
at
52
weeks.
Alterations
in
red
blood
cell
parameters
and
absolute
and
relative
organ
weights
in
the
2500
and
3000
ppm
groups
seen
at
study
end
were
attributed
to
the
decreased
body
weights.
Increases
in
SGOT
(
up
to
96%),
SGPT
(
up
to
154%),
alkaline
phosphatase
(
up
to
176%),
and
gamma­
GT
(
up
to
358%)
in
groups
receiving

2000
ppm
Ametryn
were
correlated
with
inflammatory
and
degenerative
liver
lesions
seen
at
histopathologic
examination.
These
lesions
included
granulomatous,
purulent,
and
lymphocytic
inflammation;
isolated
cellular
necrosis;
endogenous
pigment
deposition;
vacuolar
degeneration;
bile
duct
hyperplasia;
and
necrosis.
The
incidence
and
severity
of
lesions
generally
increased
with
increasing
dose
at
2000
ppm
and
above.
During
a
four­
week
recovery
period,
the
incidence
and
severity
of
most
of
these
lesions
decreased,
suggesting
they
may
be
reversible.
The
LOAEL
=
2000
ppm
(
70.0
mg/
kg/
day
for
males
and
74
mg/
kg/
day
for
females),
based
on
degenerative
of
liver
lesions.
The
NOAEL
is
200
ppm
(
7.2
mg/
kg/
day
for
males,
and
8.1
mg/
kg/
day
for
females).
This
52­
week
oral
toxicity
study
in
the
dog
is
Acceptable/
Guideline,
and
satisfies
the
guideline
requirement
for
a
chronic
oral
toxicity
study
(
OPPTS
870.4100;
OECD
452)
in
dogs.

Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
=
7.2
mg/
kg/
day
and
a
LOAEL
of
70
mg/
kg/
day
based
on
degenerative
liver
lesions.

Uncertainty
Factor(
s):
100.
This
includes
a
10
X
for
interspecies
extrapolation,
10
X
for
intraspecies
variation.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
study
with
dogs
represent
the
lowest
toxicologically
relevant
NOAEL.
The
chronic
study
with
rats
has
some
evidence
of
weight
decreases
at
500
ppm
(
21
mg/
kg/
day)
and
would
thus
have
a
NOAEL
of
20
ppm
(
2
mg/
kg/
day)
but
using
this
dose
as
a
NOAEL
is
not
considered
appropriate
since
the
weight
effects
at
21
mg/
kg/
day
were
marginal.

4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Study
Selected:
Rabbit
Developmental
Toxicity
study
(
1985,
MRID
Nos:
00153214
and
02992025).

Dose
and
Endpoint
Selected
for
Risk
Assessment:
Maternal
toxicity
NOAEL
of
10
mg/
kg/
day
with
a
LOAEL
of
60
mg/
kg/
day
based
on
decreased
body
weight
and
food
consumption
and
increased
liver
weight.
Chronic
RfD
=
7.2
mg/
kg/
day
(
NOAEL)
=
0.072
mg/
kg/
day
100
(
UF)
24
Comments
about
Study/
Endpoint.
The
rabbit
developmental
toxicity
study
was
selected
to
set
doses
and
endpoints
for
both
the
short
and
intermediate
term
incidental
oral
exposures.
Since
the
study
demonstrates
a
clear
NOAEL,
a
MOE
of
100
is
considered
appropriate.

4.4.5
Dermal
Absorption
There
are
no
laboratory
animal
studies
conducted
to
assess
for
dermal
absorption.
A
dermal
absorption
factor
of
6%
has
been
estimated
by
comparing
the
results
of
the
rabbit
developmental
toxicity
study
that
has
a
NOAEL
and
LOAEL
of
10
and
60
mg/
kg/
day,
respectively,
based
on
signs
of
reduced
body
weight
and
food
consumption
and
increased
liver
weight
to
the
rabbit
dermal
toxicity
study
with
a
NOAEL
and
LOAEL
of
100
and
1000
mg/
kg/
day,
respectively,
based
on
signs
of
decreased
body
weight
gain
and
decreased
food
consumption
at
1000
mg/
kg/
day.
In
particular,
60
mg/
kg/
day/
1000
mg/
kg/
day
X
100
=
6%.

4.4.6a
Dermal
Exposure
(
Short
and
Intermediate
Term)
Study
Selected:
Rabbit
21­
day
dermal
toxicity
study
(
1989,
MRID
No.:
41067902).

Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
1989,
MRID
41067902),
Ametryn
®
(
97.4%
a.
i.,
batch/
lot
#
FL
840991)
was
applied
to
the
shaved
skin
of
5
New
Zealand
white
rabbits/
sex/
dose
at
dose
levels
of
0,
10,
100,
or
1000
mg/
kg
bw/
day,
6
hours/
day
for
21­
24
days.
Total
body
weight
gains
(
days
0­
21)
were
apparently
reduced
in
the
mid
(

17%,
gain
of
0.20
kg)
and
high
(

32%,
gain
of
only
0.16
kg)
­
dose
males,
and
in
the
high­
dose
females
(

39%,
gain
of
only
0.18
kg).
However,
there
were
no
statistically
significant
differences
in
body
weight
and
weight
gains
for
the
control
males
were
0.24
and
females
were
0.29
kg.
There
was
also
noted
an
apparent
increase
in
body
weight
gain
of
19%
(
0.286
kg)
in
the
low
dose
group.
Total
food
consumption
values
(
Days
0­
21)
ranged
from
92­
112%
for
treated
females
and
from
81­
100%
of
the
control
value
for
treated
males.
Although,
food
efficiency
(
FE)
differences
might
also
be
consistent
with
a
possible
adverse
effect
(
as
opposed
to
a
palatability
problem),
with
decreases
in
the
mid
(

10%)­
and
high
(

18%)­
dose
males,
and
the
high­
dose
female
(

32%).
However,
there
was
also
an
increase
in
food
efficiency
of
7%
in
the
low
dose
group
males.
Overall,
the
apparent
decrease
in
weight
gain
in
the
mid
dose
group
males
is
considered
to
be
of
too
small
a
magnitude
and
the
difference
in
food
efficiency
within
normal
variation
to
include
the
mid
dose
group
in
a
LOAEL
based
on
weight
gain.
The
consistency
of
dose­
related,
minimal
decreases
in
the
indicators
of
circulating
red
cell
mass
(
RBCs,
HGB,
and
HCT)
among
treated
groups
suggested
a
mild
effect.
Dose­
related
increases
in
cholesterol,
triglycerides,
and
GGT
(
statistically
significant)
were
suggestive
of
an
hepatic
effect
of
Ametryn
®
in
high­
dose
males.
Increases
in
cholesterol
and
triglyceride
levels
in
females
were
less
pronounced
than
in
males,
and
not
dose­
related.
Absolute
hepatic
weights
were
statistically
increased
in
the
low­
and
high­
dose
females,
but
a
dose­
response
and
histopathological
correlates
were
absent.
Apparent
increases
in
absolute
spleen
weights
in
males
(
1
to
6%)
and
in
relative
(
to
body
weight)
spleen
weights
(
2
to
14%)
in
females
suggested
a
possible
mild
effect
of
treatment
on
the
spleen.
Mild,
dose­
related
increases
in
absolute
cardiac
weights
in
males
(
2
to
8%)
suggested
a
possible
effect
on
the
heart.
Apparent
decreases
in
absolute
and
relative
prostate
weights
(
20
to
22%)
at
all
dose
levels,
and
reductions
in
testicular
weights
in
the
mid
(
12%,
absolute
and
5%
relative)­
and
high
(
20%,
both
absolute
and
relative)­
dose
males
were
suggestive
of
treatment
effects.
None
of
the
organ
weight
differences
were
associated
with
gross
lesions
and
at
the
mid
dose
group
are
small
and
are
considered
not
definitely
related
to
treatment..
The
systemic
LOAEL
is
1000
mg/
kg/
day
based
on
reductions
in
total
body
weight
gain
(

32%
in
males,
39%
in
25
females),
and
reduced
food
efficiency
(

18%
in
males
and
32%
in
females).
The
systemic
NOAEL
is
100
mg/
kg/
day.
The
dermal
LOAEL
>
1000
mg/
kg/
day.
This
21­
day
dermal
toxicity
study
in
the
rabbit
is
Acceptable/
Non­
Guideline
and
does
not
satisfy
the
guideline
requirement
(
OPPTS
870.3200;
OECD
410).
The
limiting
factor
is
that
there
were
only
5
rabbits/
sex/
dose
limiting
the
interpretation
of
the
body
weight
and
organ
weight
differences
and
histopathology
was
limited
and
incomplete.
However,
the
study
is
useful
for
risk
assessment.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
of
100
mg/
kg/
day
with
a
LOAEL
of
1000
mg/
kg/
day
based
on
decreased
body
weight
gain
and
decreased
food
consumption.

Comments
about
Study/
Endpoint:
The
21­
day
dermal
toxicity
study
is
route
specific
and
is
thus
the
most
appropriate
endpoint
for
dermal
exposure
scenarios.
Although
non­
guideline,
the
study
is
acceptable
and
considered
useful
for
risk
assessment.

4.4.6b
Dermal
Exposure
(
Long
Term)

Study
Selected:
Same
as
for
chronic
dietary
(
see
above).

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
of
7.2
mg/
kg/
day
with
a
LOAEL
of
70
mg/
kg/
day
based
on
degenerative
lesions
in
the
liver.

Comments
about
Study/
Endpoint:
Since
an
oral
endpoint
was
used,
a
route
to
route
extrapolation
factor
of
6%
needs
to
be
used
to
adjust
for
using
an
endpoint
from
as
oral
study
for
a
dermal
risk
assessment.

4.4.7a
Inhalation
Exposure
(
Short
and
Intermediate
Term)
Study
Selected
Same
as
for
incidental
oral
short
and
intermediate
term
exposures.

Executive
Summary:
See
above.

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
=
10
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
and
increased
liver
weight
at
60
mg/
kg/
day.

Comments
about
Study/
Endpoint:
Since
an
oral
endpoint
was
used,
it
must
be
assumed
that
there
is
100%
absorption
from
inhaled
ametryn.

4.4.7b
Inhalation
Exposure
(
Long
Term).

Study
Selected
Same
as
for
chronic
dietary
RfD.

Executive
Summary:
See
above.

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
=
7.2
mg/
kg/
day
based
on
degenerative
liver
lesions
at
70
mg/
kg/
day.
26
Comments
about
Study/
Endpoint:
Since
an
oral
endpoint
was
used,
it
must
be
assumed
that
there
is
100%
absorption
from
inhaled
ametryn.

4.4.8
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
100
100
100
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
interspecies
extrapolation
and
10X
for
intraspecies
variation).

Ametryn
has
no
residential
uses;
therefore
no
residential
MOEs
are
applicable.

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
this
case,
since
ametryn
is
registered
only
for
agricultural
uses,
no
residential
exposures
are
anticipated.
Therefore,
the
aggregate
exposure
risk
assessment
for
ametryn
considers
only
exposures
and
risks
from
residues
of
ametryn
in
food
and
drinking
water.

4.4.10
Classification
of
Carcinogenic
Potential
The
ametryn
team
in
consultation
with
the
HED
Hazard
Assessment
Science
Policy
Council
(
HASPC)
determined
that
it
would
be
appropriate
to
estimate
the
cancer
risk
to
humans
associated
with
the
various
uses
of
ametryn
by
using
a
Q1*
based
on
the
mammary
tumors
in
a
rat
carcinogenicity
study
on
a
trial
basis.
The
mammary
tumors
were
the
most
sensitive
tumor,
i.
e.,
result
in
the
highest
estimated
Q1*
value.
The
team
recognizes
that
the
HED
CARC
found
that
the
rat
cancer
study
developed
tumors
at
dose
levels
also
associated
with
excess
weight
loss
to
confound
the
interpretation
of
the
significance
of
these
tumors.
Consequently,
the
CARC
recommended
that
a
new
cancer
study
in
rats
be
provided.
27
However,
the
ametryn
team
believes
that
using
the
Q1*
based
on
existing
data
will
reasonably
approximate
cancer
risk
to
humans
and
considers
it
unlikely
that
the
new
cancer
study
will
result
in
a
higher
risk
for
ametryn.
Support
for
this
conclusion
comes
from
the
observation
that
there
were
no
tumors
in
the
rat
study
at
500
ppm,
a
dose
resulting
in
minimal
body
weight
decrease
and
the
fact
that
there
were
no
compound
related
tumors
in
the
mouse
study
at
dose
levels
up
to
and
including
2000
ppm.

Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
females
13­
49)
&
(
general
population)
No
selection.

Chronic
Dietary
(
all
populations)
NOAEL
=
7.2
mg/
kg/
day
UF
=
100
1X
Dog
chronic
feeding
study
with
indications
of
degenerative
and
inflammatory
liver
effects
at
70
mg/
kg/
day.

Incidental
Oral
Short­
Term
(
1
­
30
days)
&
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
10
mg/
kg/
day
MOE
=
100
1X
Rabbit
developmental
toxicity.
Body
weight
and
deceased
feed
consumption
and
increased
liver
weight
at
60
mg/
kg/
day.

Dermal
Short­
Term
(
1
­
30
days)
&
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
100
mg/
kg/
day
MOE
=
100
1X
Rabbit
21day
dermal
toxicity
study.
Body
weight
gain
decrease
at
1000
mg/
kg/
day.

Dermal
Long­
Term
(>
6
months)
Same
as
for
Chronic
RFD.
MOE
=
100.
Dermal
absorption
factor
of
6%
recommended.

Inhalation
Short­
Term
(
1
­
30
days)
&
Intermediate­
Term
(
1
­
6
months)
Same
as
for
incidental
oral.
MOE
=
100.
Assume
100%
absorption
following
inhalation.

Inhalation
Long­
Term
(>
6
months)
Same
as
for
Chronic
RFD.
MOE
=
100.
Assume
100%
absorption
following
inhalation.
Table
4.4.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
28
Cancer
(
oral,
dermal,
inhalation)
The
Cancer
Assessment
Review
Committee
(
CARC)
met
to
evaluate
the
carcinogenic
potential
of
ametryn
on
21­
JUL­
2004
and
concluded
that
the
"
data
are
inadequate
for
an
assessment
of
human
carcinogenic
potential".
The
carcinogenicity
study
in
rats
is
unacceptable
because
the
high
dose
was
considered
to
be
excessive.
The
CARC
requested
that
the
carcinogenicity
study
in
rats
be
repeated
at
a
dose
that
is
adequate
to
assess
carcinogenicity.
However,
the
available
data
allow
for
a
determination
of
a
Q1*
value
of
0.0066
(
mg/
kg/
day)­
1,
based
on
observations
of
combined
mammary
tumors
in
female
rats.
The
ametryn
risk
assessment
team
believes
that
using
the
estimated
Q1*
based
on
existing
data
will
reasonably
approximate
cancer
risk
to
humans
and
considers
it
unlikely
that
the
requested
new
cancer
study
will
result
in
a
higher
risk
for
ametryn.
Support
for
this
conclusion
comes
from
the
observation
that
there
were
no
tumors
in
the
rat
study
at
500
ppm,
a
dose
resulting
in
minimal
body
weight
decrease
and
the
fact
that
there
were
no
compound
related
tumors
in
the
mouse
study
at
dose
levels
up
to
and
including
2000
ppm.

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
*
Refer
to
Section
4.5
29
4.5
Special
FQPA
Safety
Factor
Based
on
the
hazard
data,
the
ametryn
risk
assessment
team
recommended
the
special
FQPA
SF
be
reduced
to
1x
because
there
are
no
concerns
and
no
residual
uncertainties
with
regard
to
preand
post­
natal
toxicity
based
on
the
rat
and
rabbit
developmental
toxicity
studies
and
the
rat
reproduction
study
of
from
studies
in
the
open
literature.
There
were
no
indications
of
immunotoxicity
or
direct
neurotoxicity
in
the
standard
studies
with
rats,
dogs,
mice
or
rabbits.
The
ametryn
risk
assessment
team
evaluated
the
quality
of
the
exposure
data
and,
based
on
these
data,
recommended
that
the
special
FQPA
SF
be
reduced
to
1x.
The
recommendations
are
based
on
the
following:

°
Crop
field
trial
data
demonstrate
that
ametryn
use
at
the
highest
rates
permitted
on
the
label
results
in
residue
levels
0.05
ppm
in/
on
the
edible
parts
of
corn,
pineapple,
and
sugarcane.

°
The
dietary
drinking
water
assessment
utilizes
values
generated
by
models
and
associated
modeling
parameters
which
are
designed
to
provide
conservative,
health
protective,
high­
end
estimates
of
water
concentrations.
30
4.6
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
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
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
ametryn,
there
was
no
estrogen,
androgen,
and/
or
thyroid
mediated
toxicity.
When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
ametryn
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
Public
Health
Data
5.1
Incident
Reports
Relatively
few
incidents
of
illness
have
been
reported
due
to
ametryn.
Four
exposures
to
ametryn
products
were
reported
to
Poison
Control
Center
from
1993
through
2001.
Two
of
the
four
cases,
all
adults
involved
minor
symptoms.
One
of
the
cases
was
seen
in
a
health
care
facility
and
was
not
hospitalized
and
another
case
reported
diarrhea
and
drowsiness/
lethargy.
On
the
list
of
the
200
chemicals
for
which
NPIC
received
calls
from
1984­
1991
inclusively,
ametryn
was
not
reported
to
be
involved
in
human
incidents.
No
scientific
literature
was
located
concerning
acute
poisoning
due
to
exposure
to
ametryn.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
Reference:
Ametryn.
Residue
Chemistry
Considerations
for
Reregistration
Eligibility
Decision,
DP
Barcode:
D307104,
William
Donovan,
03­
NOV­
2004.

6.1.1
Residue
Profile
31
The
nature
of
the
residue
in
plants
and
animals
is
adequately
understood
based
on
the
available
corn,
sugarcane,
banana,
goat
and
hen
metabolism
studies.
In
plants,
ametryn
is
extensively
metabolized
by
N­
dealkylation
and
desulfation
(
oxidation/
hydroxylation)
to
a
variety
of
triazine
ring
containing
metabolites.
The
metabolism
of
ametryn
in
animals
also
involves
N­
dealkylation
of
the
isopropyl
and
ethyl
side
chains,
as
well
as
modification
at
the
6­
position,
followed
by
conjugation,
with
the
triazine
ring
structure
remaining
intact.
The
regulated
residues
in
plant
commodities
consist
of
ametryn
per
se.

Permanent
tolerances
are
established
for
residues
of
ametryn
per
se
in/
on
various
plant
commodities
at
0.25
ppm,
with
the
exceptions
of
corn
forage
and
stover,
each
at
0.5
ppm,
and
cassava
root
at
0.1
ppm
[
40
CFR
§
180.258].
There
are
currently
no
tolerances
for
ametryn
residues
in
livestock
commodities
or
for
inadvertent
residues
in
rotational
crops.

Adequate
methods
are
available
for
enforcing
tolerances
and/
or
collecting
data
on
ametryn
residues
in/
on
plant
and
livestock
commodities.
Two
GC
methods
are
available
for
enforcing
tolerances
of
ametryn
in
plant
commodities
and
are
listed
as
Methods
I
and
A
in
PAM
Vol.
II
(
section
180.258).
Method
I
is
a
GC/
microcoulometric
(
MC)
detection
method
for
determining
ametryn
per
se,
with
a
limit
of
quantitation
(
LOQ)
of
0.05
ppm.
Method
A
is
a
GC/
flame
photometric
detection
(
sulfur
mode,
FPDS
method
for
determining
residues
of
ametryn
and
its
three
thiomethyl
metabolites
(
GS­
11354,
GS­
11355,
and
GS­
26831),
with
a
LOQ
of
0.05
ppm
for
parent
and
0.1
ppm
for
each
metabolite.

Considering
the
data
from
the
available
animal
metabolism
and
feeding
studies
and
the
calculated
maximum
theoretical
dietary
burdens
(
MTDBs)
of
0.15­
0.18
ppm
for
cattle
and
0.04
ppm
for
poultry
and
swine,
HED
concludes
that
there
is
no
reasonable
expectation
of
quantifiable
residues
of
ametryn
occurring
in
livestock
commodities
[
40
CFR
§
180.6(
a)(
3)].
Therefore,
tolerances
for
livestock
commodities
are
not
required
at
the
present
time.

Adequate
field
trial
data
are
available
to
support
the
use
of
ametryn
on
corn
(
field,
pop,
and
seed),
pineapples,
and
sugarcane
provided
the
appropriate
label
amendments
are
made.
An
adequate
number
of
tests
were
conducted
in
the
appropriate
geographical
regions
using
the
appropriate
formulation
applied
at
the
maximum
use
rate.
These
studies
are
also
supported
by
adequate
storage
stability
data.
Although
Syngenta
has
deleted
the
uses
on
bananas
and
plantains
from
its
80%
DF
label,
adequate
field
trial
data
are
available
that
would
support
the
use
of
up
to
three
directed
applications
of
ametryn
(
WP,
FLC
or
DF)
to
bananas
or
plantains
at
3.2
lb
ai/
A/
application
at
30­
day
intervals,
using
ground
equipment,
for
a
maximum
use
rate
of
9.6
lb
ai/
A/
crop
cycle
with
a
7­
day
PHI.

The
available
processing
studies
for
corn
(
5x
rate)
and
pineapple
(
3x
rate)
are
adequate
and
indicate
that
residues
of
ametryn
and
its
three
thiomethyl
metabolites
are
not
likely
to
be
quantifiable
(
0.02
ppm)
in
corn
and
pineapple
processed
fractions
derived
from
crops
treated
at
the
maximum
labeled
rates.
However,
the
available
sugarcane
processing
study
is
not
adequate
because
residues
were
<
LOQ
in
cane
(
RAC)
following
applications
at
only
1x
the
maximum
rate.
A
new
sugarcane
processing
study
should
be
submitted.
32
An
adequate
confined
rotational
crop
study
is
available
and
indicates
that
the
metabolism
in
rotational
crops
is
similar
to
the
primary
crops.
Provided
that
the
required
label
amendments
are
made
to
corn
and
sugarcane
use
directions,
adequate
field
rotational
crop
studies
are
also
available
and
indicate
that
rotational
crop
tolerances
are
not
required.

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Reference:
Ametryn.
Chronic
and
Cancer
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D307103,
William
Donovan,
06­
OCT­
2004.

Chronic
and
cancer
dietary
risk
assessments
were
conducted
using
Lifeline
 
(
ver.
2.0)
and
the
Dietary
Exposure
Evaluation
Model
­
Food
Consumption
Intake
Database
(
DEEM­
FCID
 
,
Version
2.0)
models.
Both
of
these
models
use
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
The
analyses
were
performed
to
support
the
reregistration
eligibility
decision
for
ametryn.

The
chronic
and
cancer
analyses
were
conducted
using
average
residue
levels
from
applicable
field
trials,
percent
crop
treated
information
and
DEEM
(
ver.
7.76)
default
processing
factors.
The
Lifeline
 
chronic
exposure
estimates
were
<
0.1%
cPAD
for
all
population
subgroups
and
are
therefore
less
than
HED's
level
of
concern.
Table
6.1.2a
summarizes
the
results
of
the
chronic
dietary
analyses.
The
lifetime
cancer
risk
calculated
in
Lifeline
 
for
the
US
population
is
2.7
x
10­
8
and
is
therefore
less
than
HED's
level
of
concern
(
HED
performs
cancer
assessments
for
only
the
general
US
population).
Table
6.1.2b
summarizes
the
results
of
the
cancer
dietary
analyses.
DEEM­
FCID
 
resulted
in
chronic
and
cancer
exposure
estimates
nearly
identical
to
those
from
Lifeline
 
.
The
present
assessment
is
refined
as
it
makes
use
of
average
residue
levels
from
field
trial
results,
default
processing
factors,
and
percent
crop
treated
information.

Table
6.1.2a
Summary
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Ametryn.

Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
1
DEEM­
FCID
 
Lifeline
 
DEEM­
FCID
 
Lifeline
 
Chronic
Assessment
General
U.
S.
Population
0.000004
0.000004
<
0.1
<
0.1
All
Infants
(<
1
year
old)
0.000008
0.000008
<
0.1
<
0.1
Children
1­
2
years
old
0.000018
0.000018
<
0.1
<
0.1
Children
3­
5
years
old
0.000013
0.000014
<
0.1
<
0.1
Table
6.1.2a
Summary
of
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Ametryn.

Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
1
DEEM­
FCID
 
Lifeline
 
DEEM­
FCID
 
Lifeline
 
33
Children
6­
12
years
old
0.000008
0.000008
<
0.1
<
0.1
Youth
13­
19
years
old
0.000003
0.000004
<
0.1
<
0.1
Adults
20­
49
years
old
0.000003
0.000003
<
0.1
<
0.1
Adults
50+
years
old
0.000002
0.000003
<
0.1
<
0.1
Females
13­
49
years
old
0.000003
0.000003
<
0.1
<
0.1
Table
6.1.2b.
Summary
of
Provisional
Cancer
Dietary
Exposure
and
Risk
Estimates
for
Ametryn.

Population
Subgroup
Provisional
Q1*
(
mg/
kg/
day)­
1
Exposure
(
mg/
kg/
day)
Lifetime
risk
Lifeline
 
DEEM­
FCID
 
Lifeline
 
DEEM­
FCID
 
General
US
Population
0.0066
0.000004
0.000004
2.72
x
10­
8
2.74
x
10­
8
6.2
Water
Exposure/
Risk
Pathway
Reference:
Drinking
Water
Exposure
Assessment
for
Proposed
Reregistration
of
Ametryn
Use
on
Corn,
Pineapple
and
Sugarcane
(
Revised),
DP
Barcode:
D307105,
Kevin
Costello,
16­
NOV­
2004.

Water
models
were
used
to
assess
potential
exposure
to
ametryn
from
consumption
of
contaminated
drinking
water.
Estimated
Drinking
Water
Concentrations
(
EDWCs)
for
ametryn
were
generated
using
PRZM/
EXAMS
for
surface
water
and
SCI­
GROW2
for
groundwater.
The
EDWCs
for
surface
water
bodies
were
determined
using
the
Tier
II
screening­
level
simulation
models
PRZM
(
v.
3.12;
input
generated
by
PE4VO1.
pl,
dated
8/
8/
03)
and
EXAMS
(
2.98.04).
Potential
contaminants
of
concern
considered
in
the
drinking
water
exposure
assessment
are
parent
ametryn
and
the
degradates
2­
amino­
4­
isopropylamino­
6­
methylthio­
s­
triazine
(
GS­
11354)
and
2­
ethylamino­
4­
amino­
6­
methylthio­
s­
triazine
(
GS­
11355).
SCI­
GROW2
is
based
on
a
regression
approach
which
relates
ground­
water
concentrations
measured
in
prospective
ground­
water
monitoring
studies
to
the
aerobic
soil
metabolism
rate
and
soilwater
partitioning
properties
of
the
chemical.
The
model
provides
a
groundwater
exposure
value
to
be
used
in
determining
the
potential
risk
to
human
health
from
drinking
water
contaminated
with
the
pesticide.
SCI­
GROW2
estimates
likely
groundwater
concentrations
if
the
pesticide
is
used
at
the
maximum
allowable
rate
in
areas
where
groundwater
is
vulnerable
to
contamination.
Characteristics
of
34
such
vulnerable
areas
include
high
rainfall,
rapidly
permeable
soil,
and
a
shallow
aquifer.
In
most
cases,
a
large
majority
of
the
use
area
will
have
groundwater
that
is
less
vulnerable
to
contamination
than
the
areas
used
to
derive
the
SCI­
GROW2
estimate.

The
EDWCs
for
ametryn
in
ground
and
surface
water
are
summarized
in
Table
6.2.

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Ametryn.

Exposure
Duration
Ametryn
Surface
Water
Conc.,
ppb
a
Ground
Water
Conc.,
ppb
b
Chronic
(
non­
cancer)
92
15.6
Chronic
(
cancer)
73
15.6
a
From
the
Tier
II
PRZM­
EXAMS
­
Index
Reservoir
model.
Input
parameters
are
based
on
the
physical
properties
of
ametryn,
and
assuming
5
separate
applications
of
ametryn
to
sugarcane
in
LA,
for
a
total
rate
of
11.6
lb
ai/
A/
year.
b
From
the
SCI­
GROW
model
assuming
a
maximum
seasonal
use
rate
of
12
lb
ai/
A
[
sugarcane
in
HI],
a
Koc
of
96
mL/
g,
and
a
half­
life
of
91
days.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
Ametryn
uses
are
being
supported
only
for
the
following
agricultural
crops:
corn,
sugarcane,
and
pineapple.
There
are
no
residential
uses
and,
therefore,
no
anticipated
exposures
in
or
around
homes
or
recreational
areas.

6.3.1
Home
Uses
­
Not
applicable.

6.3.2
Recreational
Uses
­
Not
applicable.

6.3.3
Other
(
Spray
Drift,
etc.)

Spray
drift
is
always
a
potential
source
of
exposure
to
residents
nearby
to
spraying
operations.
This
is
particularly
the
case
with
aerial
application,
but,
to
a
lesser
extent,
could
also
be
a
potential
source
of
exposure
from
the
ground
application
method
employed
for
ametryn.
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.
On
a
chemical
by
chemical
basis,
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
with
specific
products
with
significant
risks
associated
with
drift.
35
36
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
(
add)
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.

For
most
pesticide
active
ingredients,
water
monitoring
data
are
considered
inadequate
to
determine
surface
and
ground
water
drinking
water
exposure
estimates,
so
model
estimates
have
been
used
to
estimate
residues
in
drinking
water
(
EDWCs).
In
order
to
determine
if
aggregate
risks
are
of
concern,
HED
then
calculates
drinking
water
levels
of
comparison,
or
DWLOCs.
The
DWLOC
is
the
maximum
amount
of
a
pesticide
in
drinking
water
that
would
be
acceptable
in
light
of
combined
exposure
from
food
and
residential
pathways.
The
calculated
DWLOCs
are
then
compared
to
the
EDWCs
provided
by
EFED;
if
model­
derived
EDWCs
exceed
the
DWLOCs
for
surface
or
ground
water,
there
may
be
a
concern
for
dietary
exposure
to
residues
in
drinking
water,
and
monitoring
data
may
be
required.

7.1
Acute
Aggregate
Risk
An
acute
aggregate
risk
assessment
was
not
conducted
because
an
endpoint
of
concern
attributable
to
a
single
dose
was
not
identified.

7.2
Short­
Term
Aggregate
Risk
A
short­
term
aggregate
risk
assessment
was
not
conducted
because
there
are
no
existing
or
proposed
residential
uses
for
ametryn.

7.3
Intermediate­
Term
Aggregate
Risk
An
intermediate­
term
aggregate
risk
assessment
was
not
conducted
because
there
are
no
existing
or
proposed
residential
uses
for
ametryn.

7.4
Long­
Term
Aggregate
Risk
A
long­
term
(
chronic)
aggregate
risk
assessment
was
conducted
for
ametryn.
The
chronic
assessment
considered
exposures
from
food
and
water
only,
because
there
are
no
residential
uses
and
no
residential
exposures
anticipated
for
this
chemical.
Since
adequate
water
monitoring
data
are
not
available
to
estimate
levels
of
ametryn
in
drinking
water,
HED
calculated
DWLOCs
and
compared
them
to
the
modelled
EDWCs
for
surface
and
ground
water
to
determine
whether
aggregate
chronic
risks
are
of
concern.

The
results
of
the
deterministic
dietary
exposure
assessment
indicate
that
dietary
exposures
to
37
ametryn
in
food
are
very
low
and
well
below
HED's
level
of
concern
(
100%
of
the
cPAD).
Ametryn
food
exposure
is
estimated
at
0.000004
mg/
kg/
day
for
the
U.
S.
population
(<
0.1%
of
the
cPAD)
and
0.000018
mg/
kg/
day
(<
0.1%
of
the
cPAD)
for
the
most
highly
exposed
population
subgroup
(
children,
1­
2
years
old)
using
the
LifeLine
model.
DEEM­
FCID
yielded
nearly
identical
results.
HED
used
the
LifeLine
exposure
estimates
to
calculate
chronic
DWLOCs
for
the
U.
S.
population
and
various
population
subgroups.
The
calculated
DWLOCs
ranged
from
2520
ppb
for
adults
to
720
ppb
for
children.
The
chronic
surface
water
EDWC
(
92
ppb)
generated
by
EFED
is
below
HED's
calculated
DWLOCs
for
chronic
exposure
to
ametryn
for
the
U.
S.
population
and
each
population
subgroup.
The
ground
water
EDWC
(
15.6
ppb)
is
also
less
than
HED's
calculated
chronic
DWLOCs
for
the
U.
S.
population
and
all
population
subgroups.
All
EDWCs
are
less
than
HED's
calculated
chronic
DWLOCs.
Therefore,
chronic
aggregate
exposures
to
ametryn
in
food
and
drinking
water
are
not
of
concern
from
a
risk
perspective.

Table
7.4.
Aggregate
Risk
Assessment
for
Chronic
Exposure
to
Ametryn.

Population
Subgroup1
Chronic
Scenario
cPAD
mg/
kg/
day
Chronic
Food
Exp
mg/
kg/
day
Max
Chronic
Water
Exp
mg/
kg/
day2
Ground
Water
EDWC
(
ppb)
3
Surface
Water
EDWC
(
ppb)
3
Chronic
DWLOC
(
ppb)

U.
S.
Population
0.072
4.00e­
06
0.071996
15.6
92
2520
All
Infants
(<
1
year
old)
0.072
8.00e­
06
0.071992
720
Children
1­
2
years
0.072
1.80e­
05
0.071982
720
Children
3­
5
years
0.072
1.40e­
05
0.071986
720
Children
6­
12
0.072
8.00e­
06
0.071992
720
Youth
13­
19
0.072
4.00e­
06
0.071996
2160
Adults
20­
49
0.072
3.00e­
06
0.071997
2520
Females
13+
0.072
3.00e­
06
0.071997
2160
Adults
50+
years
0.072
3.00e­
06
0.071997
2520
1
This
footnote
should
indicate
the
selected
subgroups
and
provide
rationale
for
selection.
Indicate
body
weights
(
70
kg
adult
male;
60
kg
adult
female;
10
kg
child).
2Maximum
Chronic
Water
Exposure
(
mg/
kg/
day)
=
[
Chronic
PAD
(
mg/
kg/
day)
­
Chronic
Dietary
Exposure
(
mg/
kg/
day)]
3
The
use
pattern
producing
the
highest
EDWC
level
was
selected:
sugarcane
use
in
HI
for
ground
water
and
sugarcane
use
in
LA
for
surface
water.
4
Chronic
DWLOC(

g/
L)
=
[
maximum
chronic
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)]
[
water
consumption
(
L)
x
10­
3
mg/

g]
38
7.5
Cancer
Risk
A
cancer
aggregate
risk
assessment
was
conducted
for
ametryn.
The
cancer
assessment
considered
exposures
from
food
and
water
only,
because
there
are
no
residential
uses
and
no
residential
exposures
anticipated
for
this
chemical.
Since
adequate
water
monitoring
data
are
not
available
to
estimate
levels
of
ametryn
in
drinking
water,
HED
calculated
DWLOCs
and
compared
them
to
the
modelled
EDWCs
for
surface
and
ground
water.

The
CARC
met
to
evaluate
the
carcinogenic
potential
of
ametryn
on
21­
JUL­
2004
and
concluded
that
the
"
data
are
inadequate
for
an
assessment
of
human
carcinogenic
potential".
The
carcinogenicity
study
in
rats
is
unacceptable
because
the
high
dose
was
considered
to
be
excessive.
The
CARC
requested
that
the
carcinogenicity
study
in
rats
be
repeated
at
a
dose
that
is
adequate
to
assess
carcinogenicity.
However,
the
available
data
allow
for
a
determination
of
a
provisional
Q
1*
value
of
0.0066
(
mg/
kg/
day)­
1,
based
on
observations
of
combined
mammary
tumors
in
female
rats.
The
ametryn
risk
assessment
team
believes
that
using
the
estimated
provisional
Q
1*
based
on
existing
data
will
provide
a
screening
level
tool
for
examining
possible
cancer
risks
involving
ametryn.

Table
7.5
summarizes
the
cancer
risk
calculations
for
ametryn.
The
calculated
cancer
DWLOC
for
the
US
population
was
5.2
ppb.
The
cancer
surface
water
EDWC
(
73
ppb)
generated
by
EFED
exceeds
HED's
calculated
DWLOC
for
cancer
exposure
to
ametryn.
The
ground
water
EDWC
(
15.6
ppb)
also
exceeds
HED's
calculated
cancer
DWLOC
for
the
U.
S.
population.
Generally,
if
modelderived
EDWCs
for
surface
or
ground
water
exceed
the
DWLOCs,
there
may
be
a
concern
for
cancer
dietary
exposure
to
residues
in
drinking
water.
In
this
case,
since
the
EDWCs
for
ground
and
surface
water
exceed
HED's
provisional
cancer
DWLOC
for
the
U.
S.
population,
this
screening
analysis
supports
the
need
for
additional
data
in
the
form
of
a
new
rat
cancer
study.

The
ground
and
surface
water
EDWCs
provided
in
Table
7.5
reflect
the
highest
levels
estimated
for
ametryn
use
in/
on
corn,
sugarcane,
and
pineapple.
In
general,
the
highest
EDWCs
resulted
from
sugarcane
applications
in
LA
or
HI.
For
comparison
purposes,
additional
water
modeling
results
showing
the
corn
and
pineapple
data
together
with
the
sugarcane
values
are
listed
below.

Crop
Ground
Water
EDWC
(
ppb)
Surface
Water
EDWC
(
ppb)

Chronic
Scenario
Cancer
Scenario
Corn
2.6
7.6
5.4
Pineapple
9.4
NA*
NA*

Sugarcane
15.6
[
HI]
92
[
LA]
73
[
LA]

15.1
[
LA]

7.8
[
TX]
39
4.7
[
FL]
19
[
FL]
12
[
FL]

*
Not
calculated
since
most
drinking
water
in
Hawaii
is
derived
from
ground
water
supplies.
The
HI
ground
water
number
may
be
substituted.

These
additional
data
demonstrate
that
the
corn
and
pineapple
uses
result
in
surface
water
EDWC
levels
only
slightly
above
the
cancer
DWLOC,
while
the
sugarcane
use
results
in
significantly
higher
predicted
levels
of
ametryn
in
drinking
water.

It
is
worthwhile
to
note
that
Hawaiian
ground
water
monitoring
data
in
pineapple
use
areas
in
the
mid­
1990'
s
resulted
in
a
maximum
concentration
similar
in
magnitude
to
that
predicted
with
the
ground
water
screening
model
SCI­
GROW
(
Screening
Concentration
in
Ground
Water).
40
Table
7.5
Cancer
DWLOC
Calculations
Populatio
n
Q*
Negligible
Risk
Level1
Target
Max
Exposure2
mg/
kg/
day
Chronic
Food
Exposure
mg/
kg/
day
Residential
Exposure
(
LADD)

mg/
kg/
day
Aggregate
cancer
risk
(
food
and
residential)
Max
Water
Exposure3
mg/
kg/
day
Ground
Water
EDWC4
(
ppb)
Surface
Water4
EDWC
(
ppb)
Cancer
DWLOC5
(
ppb)

U.
S.
Pop
6.60e­
0
3
1.00e­
06
1.52e­
04
4.00e­
06
0.000000
4.00e­
06
1.48e­
04
15.6
73
5.16
1
Indicate
in
this
footnote
the
basis
for
the
negligible
risk
if
other
than
1
x
10­
6.

2
Target
Maximum
Exposure
(
mg/
kg/
day)
=
[
negligible
risk/
Q*]

3
Maximum
Water
Exposure
(
mg/
kg/
day)
=
[
Target
Maximum
Exposure
­
(
Chronic
Food
Exposure
+
Residential
Exposure
(
Lifetime
Average
Daily
Dose))]

4
The
use
pattern
producing
the
highest
EDWC
level
was
selected:
sugarcane
use
in
HI
for
ground
water
and
sugarcane
use
in
LA
for
surface
water.

5
Cancer
DWLOC(
ppb)
=
[
maximum
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)]

[
water
consumption
(
L)
x
10­
3
mg/

g]
41
8.0
Cumulative
Risk
Characterization/
Assessment
Ametryn
was
not
grouped
with
chloro­
s­
triazines
(
atrazine,
simazine,
propazine
and
their
chloros
triazine
metabolites)
because
it
has
a
different
functional
group
attached
to
the
triazene
ring,
i.
e.,
thiomethyl
versus
chloro.
Further,
ametryn
does
not
exhibit
the
same
toxicity
profile
as
the
chloro­
striazines
There
were
several
tumors
induced
by
ametryn
in
a
rat
bioassay,
but
only
at
an
excessive
dose
which
confounds
the
interpretation
of
this
response.
This
pattern
of
tumor
response
is
not
characteristic
of
the
chloro­
s­
triazines.

9.0
Occupational
Exposure/
Risk
Pathway
Reference:
Ametryn.
HED
Occupational
and
Residential
Exposure
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
Revised),
DP
Barcode:
D311600,
Robert
Travaglini,
22­
DEC­
2004.

9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
HED
determines
potential
exposures
to
pesticide
handlers
by
identifying
exposure
scenarios
from
various
types
of
application
equipment
that
are
recommended
on
ametryn
labeling.
Based
on
the
product
labeling,
agricultural
use
patterns
specific
to
ametryn
are
associated
with
the
following
types
of
equipment:
aerial
(
sugarcane)
and
groundboom
sprayer
for
sugarcane,
pineapples
and
corn.

Based
on
product
labeling
and
information
provided
for
the
completion
of
the
RED
process
for
this
pesticide,
HED
has
identified
14
occupational
handler
scenarios
for
which
short­
and
intermediateterm
exposure
to
ametryn
may
occur.
Exposure
estimates
were
conducted
using
the
maximum
application
rates
for
each
of
the
crops.

The
following
14
occupational
handler
scenarios
were
evaluated
for
short
and
intermediate
term
exposure
to
ametryn.
3.
Mix/
load:
Liquids
for
Groundboom
to
Support
Application
to
Corn;
4.
Mix/
load:
Liquids
for
Groundboom
to
Support
Application
to
Pineapples;
5.
Mix/
load:
Liquids
for
Groundboom
to
Support
Application
to
Sugarcane;
6.
Mix/
load:
Liquids
for
Aerial
to
Support
Application
Sugarcane;
7.
Mix/
load:
Liquids
to
Support
Groundboom
Application
on
Sugarcane*;
8.
Mix/
load:
Liquids
for
Aerial
Application
on
Sugarcane*;
9.
Application:
Groundboom
Spray
Application
on
Corn;
10.
Application:
Groundboom
Spray
Application
on
Pineapples;
11.
Application:
Groundboom
Spray
Application
on
Sugarcane;
12.
Application:
Aerial
Spray
Application
on
Sugarcane;
13.
Application:
Groundboom
Spray
Application
on
Sugarcane*;
14.
Application:
Aerial
Application
of
Sprays
on
Sugarcane*;
15.
Flagger:
Aerial
on
Sugarcane;
16.
Flagger:
Aerial
on
Sugarcane*.
42
(*
denotes
lower
application
rate
of
2.0
lbs
ai/
acre).

Because
no
chemical
specific
data
and/
or
studies
were
submitted
in
support
of
the
reregistration
process
for
this
chemical,
PHED
V1.1
has
been
used
to
assess
the
exposure
scenarios
for
ametryn.
PHED
was
designed
by
a
Task
Force
of
representatives
from
the
U.
S.
EPA,
Health
Canada,
the
California
Department
of
Pesticide
Regulation,
and
member
companies
of
the
American
Crop
Protection
Association.
PHED
is
a
software
system
consisting
of
two
parts
­­
a
database
of
measured
exposure
values
for
workers
involved
in
the
handling
of
pesticides
under
actual
field
conditions
and
a
set
of
computer
algorithms
used
to
subset
and
statistically
summarize
the
selected
data.
Currently,
the
database
contains
values
for
over
1,700
monitored
individuals
(
i.
e.,
replicates).
Users
select
criteria
to
subset
the
PHED
database
to
reflect
the
exposure
scenario
being
evaluated.
The
subsetting
algorithms
in
PHED
are
based
on
the
central
assumption
that
the
magnitude
of
handler
exposures
to
pesticides
are
primarily
a
function
of
activity
(
e.
g.,
mixing/
loading,
applying),
formulation
type
(
e.
g.,
wettable
powders,
granulars),
application
method
(
e.
g.,
aerial,
groundboom),
and
clothing
scenarios
(
e.
g.,
gloves,
double
layer
clothing).
Once
the
data
for
a
given
exposure
scenario
has
been
selected,
the
data
are
normalized
(
i.
e.,
divided
by)
by
the
amount
of
pesticide
handled
resulting
in
standard
unit
exposures
(
milligrams
of
exposure
per
pound
of
active
ingredient
handled).
Following
normalization,
the
data
are
statistically
summarized.
The
distribution
of
exposure
values
for
each
body
part
(
e.
g.,
chest,
upper
arm)
is
categorized
as
normal,
lognormal,
or
"
other"
(
i.
e.,
neither
normal
nor
lognormal).
A
central
tendency
value
is
then
selected
from
the
distribution
of
the
exposure
values
for
each
body
part.
These
values
are
the
arithmetic
mean
for
normal
distributions,
the
geometric
mean
for
lognormal
distributions,
and
the
median
for
all
"
other"
distributions.
Once
selected,
the
central
tendency
values
for
each
body
part
are
composited
into
a
"
best
fit"
exposure
value
representing
the
entire
body.
The
handler
assessments
encompass
all
of
the
major
uses
of
ametryn
being
supported
throughout
the
country.
The
assumptions
used
in
calculating
exposures
and
risks
are
listed
below:
Application
Rates:
The
application
rates
are
the
maximum
allowable
that
were
identified
on
the
available
product
labels
for
each
use
assessed
in
this
document.
Acres
Treated**:
The
daily
acres
treated
are
HED
standard
values
(
EXPO
SAC
policy
9.1).
However,
for
sugarcane
HED
used
350
acres
(
low
acreage)
rather
than
1200
acres
(
high
acreage)
in
the
aerial
assessment
for
this
crop
based
on
information
that
typically
ametryn
is
not
applied
to
sugarcane
aerially,
but
is
more
typically
applied
by
ground
boom
equipment,
and
is
as
such
considered
a
high
acreage
groundboom
crop
and
a
rather
low
acreage
aerial
crop.
Unit
Exposures:
The
unit
exposure
values
calculated
by
PHED
generally
range
from
the
geometric
mean
to
the
median
of
the
selected
data
set.
To
add
consistency
and
quality
control
to
the
values
produced
from
this
system,
the
PHED
Task
Force
has
evaluated
all
data
within
the
system
and
has
developed
a
set
of
grading
criteria
to
characterize
the
quality
of
the
original
study
data.
The
assessment
of
data
quality
is
based
on
the
number
of
observations
and
the
available
quality
control
data.
While
data
from
PHED
provides
the
best
available
information
on
handler
exposures,
it
should
be
noted
that
some
aspects
of
the
included
studies
(
e.
g.,
duration,
acres
treated,
pounds
of
active
ingredient
handled)
may
not
accurately
represent
labeled
uses
in
all
cases.

Amount
Handled:
Based
on
the
daily
acres
treated.
43

Personal
Protective
Equipment
(
PPE):
HED
calculated
MOEs
for
the
baseline,
minimum
PPE,
and
PPE
with
engineering
controls
for
each
occupational
exposure
scenario
under
the
following
assumptions:
All
Scenarios:
All
occupational
handlers
are
wearing
footwear
(
socks
plus
shoes
or
boots),
foot
exposure
is
not
traditionally
monitored,
and
therefore,
a
100
percent
protection
factor
is
implied.
Baseline
Attire:
All
handlers
are
wearing
long­
sleeved
shirts,
long
pants,
no
gloves,
and
no
respirator.
Minimum
PPE:
All
handlers
are
wearing
long­
sleeved
shirts,
long
pants,
gloves,
and
no
respirator.
Engineering
Controls:
Represents
the
use
of
an
appropriate
engineering
control
such
as
a
closed
tractor
cab
or
closed
loading
system
for
granulars
or
liquids.
Potential
daily
dermal
exposure
is
calculated
using
the
following
formula:
Daily
Dermal
Exposure
(
mg
ai/
day)
=
Dermal
Unit
Exposure
(
mg
ai/
lb
ai)
x
Application
Rate
(
lb
ai/
lb
of
seed
)
x
Daily
amount
Treated
(
lbs)

Potential
daily
inhalation
exposure
is
calculated
using
the
following
formula:
Daily
Inhalation
Exposure
(
mg
ai/
day)
=
Inhalation
Unit
Exposure
(
mg
ai/
lb
ai)
x
Application
Rate
(
lb
ai/
lb
of
seed)
x
Daily
amount
Treated
(
lbs)

The
inhalation
and
dermal
daily
doses
were
calculated
using
the
following
formulas:
Daily
dermal
dose
(
mg/
kg/
day)
=
daily
dermal
exposure(
mg
ai/
day)/
body
weight(
kg)
x
dermal
absorption
factor(
100%)
Daily
Inhalation
dose
(
mg/
kg/
day)
=
daily
Inhalation
exposure(
mg
ai/
day)/
body
weight(
kg)
x
100%
(
where
body
weight
=
70kg.)

Using
the
daily
dermal
exposure
scenarios
identified
in
the
exposure
section,
HED
calculated
the
potential
risk
to
persons
from
handler
exposures
using
MOEs.
The
MOEs
were
calculated
using
the
following
formulas:
Dermal
MOE
=
Dermal
NOAEL(
mg/
kg/
day)/
Daily
Dermal
Dose
(
mg/
kg/
day)

Inhalation
MOE
=
Inhalation
NOAEL(
mg/
kg/
day)/
Daily
Inhalation
Dose
(
mg/
kg/
day)

Margins
of
exposure
(
MOEs)
were
calculated
for
handlers
for
short­
term
(
up
to
1
month)
and
intermediate­
term
(
1
to
6
months)
durations.
The
results
of
the
dermal
and
inhalation
handler
risk
estimates
for
short
and
intermediate­
term
exposure
durations
to
ametryn
are
summarized
in
Tables
9.1a,
9.1b,
&
9.1c.
MOEs
for
11
of
the
14
handler
scenarios
are
greater
than
100
at
either
baseline
or
minimum
PPE
protection
levels
and
are
not
of
concern.
The
three
scenarios
with
MOEs
which
do
not
exceed
100
at
baseline
or
PPE1
protection
levels:
Scenario
4
­
mixing/
loading
liquids
for
aerial
application
to
sugarcane
at
the
application
rate
of
7.2
lbs
ai/
acre;
Scenario
10
­
applying
spray
for
aerial
application
to
sugarcane
at
8.0
lbs.
ai/
acre
and
Scenario
12
­
applying
spray
for
aerial
application
to
sugarcane
at
2.0
lbs
ai/
acre.
All
three
of
these
scenarios
attain
MOEs
>
100
with
engineering
controls.
In
the
case
of
Scenario
4
(
mixing/
loading
ametryn
for
aerial
application
to
sugarcane)
which
achieves
a
combined
MOE
of
79
under
the
PPE1
protection
level,
adding
coveralls
would
yield
a
combined
MOE
of
97.
Adding
a
PF5
respirator
would
reduce
inhalation
exposure
by
80.0%,
therefore
the
combined
MOE
would
increase
to
109
without
coveralls.
Using
a
PF10
respirator,
without
coveralls
would
increase
the
combined
MOE
to
793.
44
Table
9.1a
Short
&
Intermediate
­
Term
Ametryn
Baseline
Exposure
Estimates
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Mixing/
Loading
Liquids
for
Groundboom
application
(
1)
2.9
1.2
Corn
2.0
lb
ai
per
acre
200
Acres
per
day
17
6
0.0069
1500
6
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
2.9
1.2
Pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
12
8
0.0049
2000
8.3
Mixing/
Loading
Liquids
for
Groundboom
application
(
3)
2.9
1.2
Sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
27
4
0.011
910
3.8
Mixing/
Loading
Liquids
for
Aerial
application
(
4)
2.9
1.2
Sugarcane
7.2
lb
ai
per
acre
350
Acres
per
day
100
1
0.043
230
0.95
Mixing/
Loading
Liquids
for
Groundboom
application
(
5)
2.9
1.2
Sugarcane
2.0
lb
ai
per
acre
40
Acres
per
day
3.3
30
0.0014
7300
30
Mixing/
Loading
Liquids
for
Aerial
application
(
6)
2.9
1.2
Sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
29
3
0.012
830
3.4
Applicator
Sprays
for
Groundboom
application
(
7)
0.014
0.74
Corn
2.0
lb
ai
per
acre
200
Acres
per
day
0.08
1300
0.0042
2400
820
Sprays
for
Groundboom
application
(
8)
0.014
0.74
Pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
0.12
870
0.0061
1600
570
Table
9.1a
Short
&
Intermediate
­
Term
Ametryn
Baseline
Exposure
Estimates
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
45
Sprays
for
Groundboom
application
(
9)
0.014
0.74
Sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
0.13
780
0.0068
1500
510
Sprays
for
Aerial
application
(
10)
No
Data
No
Data
sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Groundboom
application
(
11)
0.014
0.74
Sugarcane
2.0
lb
ai
per
acre
80
Acres
per
day
0.032
3100
0.0017
5900
2000
Sprays
for
Aerial
application
(
12)
No
Data
No
Data
sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
No
Data
No
Data
No
Data
No
Data
No
Data
Flagger
Flagging
for
Sprays
application
(
13)
0.011
0.35
Sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
0.44
230
0.014
710
170
Flagging
for
Sprays
application
(
14)
0.011
0.35
Sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.11
910
0.0035
2900
690
1Baseline
dermal
unit
exposures
represent
long
pants,
long
sleeved
shirts,
shoes,
and
socks.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

2Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

3Crops
and
use
patterns
are
from
product
labeling.

4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
various
labels.
In
most
scenarios,
a
range
of
maximum
application
rates
is
used
to
represent
the
range
of
rates
for
different
crops/
sites/
uses.
Application
rates
upon
which
the
analysis
is
based
are
presented
as
lb
ai/
A.

5Amount
treated
is
based
on
the
area
or
gallons
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Dermal
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
Short
&
Intermediate­
term
dermal
NOAEL
(
100
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
Short
&
Intermediate­
term
developmental
NOAEL
(
10
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.

10Total
MOE
=
[
1/
(
1/
dermal
Moe
+
1/
inhalation
MOE)]
46
Table
9.1b.
Short
&
Intermediate
­
Term
PPE
1
(
Single
Layer
Protection,
Gloves,
No
Respirator)
Ametryn
Exposure
Estimates
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Mixing/
Loading
Liquids
for
Groundboom
application
(
1)
0.023
1.2
Corn
2.0
lb
ai
per
acre
200
Acres
per
day
0.13
760
0.0069
1500
500
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
0.023
1.2
Pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
0.095
1100
0.0049
2000
690
Mixing/
Loading
Liquids
for
Groundboom
application
(
3)
0.023
1.2
Sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
0.21
480
0.011
910
310
Mixing/
Loading
Liquids
for
Aerial
application
(
4)
0.023
1.2
Sugarcane
7.2
lb
ai
per
acre
350
Acres
per
day
0.83
120
0.043
230
79
Mixing/
Loading
Liquids
for
Groundboom
application
(
5)
0.023
1.2
Sugarcane
2.0
lb
ai
per
acre
40
Acres
per
day
0.026
3800
0.0014
7300
2500
Mixing/
Loading
Liquids
for
Aerial
application
(
6)
0.023
1.2
Sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.23
440
0.012
830
290
Applicator
Sprays
for
Groundboom
application
(
7)
0.014
0.74
Corn
2.0
lb
ai
per
acre
200
Acres
per
day
0.08
1300
0.0042
2400
820
Sprays
for
Groundboom
application
(
8)
0.014
0.74
Pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
0.12
870
0.0061
1600
570
Table
9.1b.
Short
&
Intermediate
­
Term
PPE
1
(
Single
Layer
Protection,
Gloves,
No
Respirator)
Ametryn
Exposure
Estimates
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
47
Sprays
for
Groundboom
application
(
9)
0.014
0.74
Sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
0.13
780
0.0068
1500
510
Sprays
for
Aerial
application
(
10)
No
Data
No
Data
sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
No
Data
No
Data
No
Data
No
Data
No
Data
Sprays
for
Groundboom
application
(
11)
0.014
0.74
Sugarcane
2.0
lb
ai
per
acre
80
Acres
per
day
0.032
3100
0.0017
5900
2000
Sprays
for
Aerial
application
(
12)
No
Data
No
Data
sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
No
Data
No
Data
No
Data
No
Data
No
Data
Flagger
Flagging
for
Sprays
application
(
13)
0.01
0.35
Sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
0.4
250
0.014
710
190
Flagging
for
Sprays
application
(
14)
0.01
0.35
Sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.1
1000
0.0035
2900
740
1
PPE1
dermal
unit
exposures
represent
long
pants,
long
sleeved
shirts,
and
chemical­
resistant
gloves.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

2PPE1
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

2Baseline
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

3Crops
and
use
patterns
are
from
product
labeling.

4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
various
labels.
In
most
scenarios,
a
range
of
maximum
application
rates
is
used
to
represent
the
range
of
rates
for
different
crops/
sites/
uses.
Application
rates
upon
which
the
analysis
is
based
are
presented
as
lb
ai/
A.

5Amount
treated
is
based
on
the
area
or
gallons
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Dermal
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
Short
&
Intermediate­
term
dermal
NOAEL
(
100
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
Short
&
Intermediate­
term
developmental
NOAEL
(
10
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.

10Total
MOE
=
[
1/
(
1/
dermal
Moe
+
1/
inhalation
MOE)]
48
Table
9.1c.
Short
&
intermediate
­
Term
Ametryn
Exposure
Estimates
with
Engineering
Controls
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
Mixer/
Loader
Mixing/
Loading
Liquids
for
Groundboom
application
(
1)
0.0086
0.083
corn
2.0
lb
ai
per
acre
200
Acres
per
day
0.049
2000
0.00047
21000
1900
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
0.0086
0.083
pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
0.035
2800
0.00034
29000
2600
Mixing/
Loading
Liquids
for
Groundboom
application
(
3)
0.0086
0.083
sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
0.079
1300
0.00076
13000
1200
Mixing/
Loading
Liquids
for
Aerial
application
(
4)
0.0086
0.083
sugarcane
7.2
lb
ai
per
acre
350
Acres
per
day
0.31
320
0.0030
3300
290
Mixing/
Loading
Liquids
for
Groundboom
application
(
5)
0.0086
0.083
sugarcane
2.0
lb
ai
per
acre
40
Acres
per
day
0.0098
10000
0.000095
110000
9300
Mixing/
Loading
Liquids
for
Aerial
application
(
6)
0.0086
0.083
sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.086
1200
0.00083
12000
1100
Applicator
Sprays
for
Groundboom
application
(
7)
0.005
0.043
corn
2.0
lb
ai
per
acre
200
Acres
per
day
0.029
3500
0.00025
41000
3200
Sprays
for
Groundboom
application
(
8)
0.005
0.043
pineapple
7.2
lb
ai
per
acre
80
Acres
per
day
0.041
2400
0.00035
28000
2200
Table
9.1c.
Short
&
intermediate
­
Term
Ametryn
Exposure
Estimates
with
Engineering
Controls
Exposure
Scenario
(
Scenario
#)
Dermal
Unit
Exposure
(
mg/
lb
ai)
1
Inhalation
Unit
Exposure
(
Ug/
lb
ai)
2
Crop3
Application
Rate4
Daily
Area
Treated5
Dermal
Dose
(
mg/
kg/
day)
6
Dermal
MOE
7
Inhalation
Dose
(
mg/
kg/
day)
8
Inhalation
MOE9
Total
MOE10
49
Sprays
for
Groundboom
application
(
9)
0.005
0.043
sugarcane
8.0
lb
ai
per
acre
80
Acres
per
day
0.046
2200
0.00039
25000
2000
Sprays
for
Aerial
application
(
10)
0.005
0.068
sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
0.2
500
0.0027
3700
440
Sprays
for
Groundboom
application
(
11)
0.005
0.043
sugarcane
2.0
lb
ai
per
acre
80
Acres
per
day
0.046
2200
0.00039
25000
2000
Sprays
for
Aerial
application
(
12)
0.005
0.068
sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.2
500
0.0027
3700
440
Flagger
Flagging
for
Sprays
application
(
13)
0.00022
0.007
sugarcane
8.0
lb
ai
per
acre
350
Acres
per
day
0.0088
11000
0.00028
36000
8600
Flagging
for
Sprays
application
(
14)
0.00022
0.007
sugarcane
2.0
lb
ai
per
acre
350
Acres
per
day
0.0022
45000
0.00007
140000
34000
1Engineering
controls
dermal
unit
exposures
represent
long
pants
and
long
sleeved
shirts.
For
mixers
and
loaders,
chemical­
resistant
gloves
are
also
included.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

2Engineering
controls
inhalation
unit
exposures
represent
no
respirator.
Values
are
reported
in
the
PHED
Surrogate
Exposure
Guide
dated
August
1998
or
are
from
data
submitted
by
the
Outdoor
Residential
Exposure
Task
Force
dated
May
2000.

3Crops
and
use
patterns
are
from
product
labeling.

4Application
rates
are
based
on
maximum
values
found
in
various
sources
including
LUIS
and
various
labels.
In
most
scenarios,
a
range
of
maximum
application
rates
is
used
to
represent
the
range
of
rates
for
different
crops/
sites/
uses.
Application
rates
upon
which
the
analysis
is
based
are
presented
as
lb
ai/
A.

5Amount
treated
is
based
on
the
area
or
gallons
that
can
be
reasonably
applied
in
a
single
day
for
each
exposure
scenario
of
concern
based
on
the
application
method
and
formulation/
packaging
type.
(
Standard
EPA/
OPP/
HED
values).

6Dermal
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
mg/
lb
ai)
*
Dermal
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

7Dermal
MOE
=
Short
&
Intermediate­
term
dermal
NOAEL
(
100
mg/
kg/
day)
/
Daily
Dermal
Dose.
Target
Dermal
MOE
is
100.

8Inhalation
dose
(
mg/
kg/
day)
=
[
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
g
unit
conversion
*
Inhalation
absorption
(
100%)
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Daily
area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

9Inhalation
MOE
=
Short
&
Intermediate­
term
developmental
NOAEL
(
10
mg/
kg/
day)
/
Daily
Inhalation
Dose.
Target
Inhalation
MOE
is
100.

10Total
MOE
=
[
1/
(
1/
dermal
Moe
+
1/
inhalation
MOE)]
50
Provisional
cancer
risk
estimates
for
occupational
exposures
to
ametryn
range
from
5
x
10­
8
to
6
x
10­
6.
The
cancer
risk
estimates
presented
here
are
based
on
the
provisional
Q
1*
that
was
described
earlier
in
this
document.
In
this
sense
the
cancer
risk
estimates
should
be
considered
provisional
until
adequate
data
are
available
to
reconsider
these
risk
estimates.
The
carcinogenic
risks
presented
here
should
be
considered
high­
end
as
they
are
based
on
conservative
assumptions
for
maximum
acreage
and
application
rates
used
for
30
days/
year
and
for
35
years
over
a
70
year
lifetime.
Table
9.1d
summarizes
the
provisional
occupational
cancer
risks
determined
for
likely
ametryn
exposure
scenarios.
51
Table
9.1d.
Cancer(
Q*)
Risk
Table
Exposure
Scenario
(
Scenario
#)
Crop1
Baseline
Total
Daily
Dose2,
3
Baseline
Daily
LADD2,
4
Baseline
Risk2,
5
Maximum
PPE
Total
Daily
Dose2,
6
Maximum
PPE
LADD3,
6
Maximum
PPE
Risk4,
6
Eng
Cont
Total
Daily
Dose2,
7
Eng
Cont
LADD3,
7
Eng
Cont
Risk4,
7
Mixer/
Loader
Mixing/
Loading
Liquids
for
Groundboom
application
(
1)
corn
1
4.11E­
2
2.72E­
4
0.0065
2.68E­
4
1.77E­
6
0.0034
1.41E­
4
9.31E­
7
Mixing/
Loading
Liquids
for
Groundboom
application
(
2)
pineapple
0.72
2.96E­
2
1.96E­
4
0.0047
1.93E­
4
1.28E­
6
0.0025
1.01E­
4
6.71E­
7
Mixing/
Loading
Liquids
for
Groundboom
application
(
3)
sugarcane
1.6
6.58E­
2
4.36E­
4
0.010
4.28E­
4
2.84E­
6
0.0055
2.25E­
4
1.49E­
6
Mixing/
Loading
Liquids
for
Aerial
application
(
4)
sugarcane
6.3
2.59E­
1
1.72E­
3
0.041
1.69E­
3
1.12E­
5
0.022
8.86E­
4
5.87E­
6
Mixing/
Loading
Liquids
for
Groundboom
application
(
5)
sugarcane
0.20
8.23E­
3
5.45E­
5
0.0013
5.35E­
5
3.54E­
7
0.00068
2.81E­
5
1.86E­
7
Mixing/
Loading
Liquids
for
Aerial
application
(
6)
sugarcane
1.8
7.20E­
2
4.77E­
4
0.011
4.68E­
4
3.10E­
6
0.0060
2.46E­
4
1.63E­
6
Applicator
Sprays
for
Groundboom
application
(
7)
corn
0.0090
3.71E­
4
2.46E­
6
0.0042
1.72E­
4
1.14E­
6
0.0020
8.05E­
5
5.33E­
7
Sprays
for
Groundboom
application
(
8)
pineapple
0.013
5.34E­
4
3.54E­
6
0.0060
2.48E­
4
1.64E­
6
0.0028
1.16E­
4
7.68E­
7
Table
9.1d.
Cancer(
Q*)
Risk
Table
Exposure
Scenario
(
Scenario
#)
Crop1
Baseline
Total
Daily
Dose2,
3
Baseline
Daily
LADD2,
4
Baseline
Risk2,
5
Maximum
PPE
Total
Daily
Dose2,
6
Maximum
PPE
LADD3,
6
Maximum
PPE
Risk4,
6
Eng
Cont
Total
Daily
Dose2,
7
Eng
Cont
LADD3,
7
Eng
Cont
Risk4,
7
52
Sprays
for
Groundboom
application
(
9)
sugarcane
0.014
5.94E­
4
3.93E­
6
0.0067
2.76E­
4
1.83E­
6
0.0031
1.29E­
4
8.53E­
7
Sprays
for
Aerial
application
(
10)
sugarcane
No
Data
No
Data
No
Data
No
Data
No
Data
No
Data
0.015
6.05E­
4
4.00E­
6
Sprays
for
Groundboom
application
(
11)
sugarcane
0.0036
1.48E­
4
9.83E­
7
0.0017
6.89E­
5
4.56E­
7
0.00078
3.22E­
5
2.13E­
7
Sprays
for
Aerial
application
(
12)
sugarcane
No
Data
No
Data
No
Data
No
Data
No
Data
No
Data
0.0037
1.51E­
4
1.00E­
6
Flagger
Flagging
for
Sprays
application
(
13)
sugarcane
0.040
1.66E­
3
1.10E­
5
0.025
1.04E­
3
6.91E­
6
0.00081
3.32E­
5
2.20E­
7
Flagging
for
Sprays
application
(
14)
sugarcane
0.010
4.15E­
4
2.75E­
6
0.0064
2.61E­
4
1.73E­
6
0.00020
8.30E­
6
5.50E­
8
1Crops
and
use
patterns
are
from
product
labeling.

2Baseline
represents
the
use
of
long
pants
and
long
sleeved
shirt
(
no
respirator),
while
using
equipment
and
systems
that
are
not
engineering
controls.

3Total
daily
absorbed
dose
(
mg/
kg/
day)
=
[((
dermal
unit
exposure
(
mg/
lb
ai)
*
6.0
%
dermal
absorption)
+
(
inhalation
unit
exposure
(
ug/
lb
ai)
*
0.001
mg/
ug
unit
conversion
*
100%

inhalation
absorption))
*
Application
rate
(
lb
ai/
acre
or
lb
ai/
gallon)
*
Area
treated
(
acres
or
gallons)]
/
Body
weight
(
70
kg).

4LADD
(
Lifetime
average
daily
dose)
mg/
kg/
day
=
Total
daily
absorbed
dose
(
mg/
kg/
day)
*
(
30
days
worked
per
year
days
worked
per
year/
365
days
per
year)
*
(
35
years
worked
years
worked/
70
year
lifetime).
Days
worked
per
year
are
estimates.

5Cancer
Risk
=
LADD
(
mg/
kg/
day)
*
Q1*
=
0.00662
(
mg/
kg/
day)­
1.

6Maximum
PPE
represents
the
use
of
coveralls
worn
over
long­
sleeved
shirt
and
long
pants,
plus
chemical
resistant
gloves
and
an
organic­
vapor­
removing
respirator
or
equivalent
(
10­

fold
PF),
while
using
equipment
and
systems
that
are
not
engineering
controls.

7Engineering
controls
represents
the
use
of
long
pants
and
long
sleeved
shirt
(
no
respirator),
plus
 
when
mixing/
loading
 
chemical­
resistant
gloves,
while
using
equipment
and
systems
that
are
engineering
controls
(
e.
g.,
closed
mixing/
loading,
enclosed
cockpits,
and/
or
enclosed
cabs).
Note
that
data
for
airblast
applicators
includes
the
use
of
chemical
resistant
gloves,
because
data
are
not
available
for
the
"
no
glove"
scenario.

9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk
53
Ametryn
product
labeling
specifies
application
as
either
a
directed
spray
at
weeds
or
as
a
preemergent
broadcast
spray,
and
includes
instructions
to
avoid
application
to
the
crop
foliage.
Additionally,
for
corn
and
pineapples,
the
label
specifies
last
ametryn
application
be
made
30
and
160
days
prior
to
harvesting
respectively.
For
sugarcane,
the
label
specifies
"
Avoid
wetting
sugarcane
foliage,
or
injury
may
occur"
and
also
recommends
against
application
after
"
close­
in"
­
when
the
sugarcane
grows
over
the
planting
beds
prior
to
harvesting.
For
these
reasons,
HED
does
not
anticipate
any
foliar
residues
on
the
ametryn
treated
crops.
Therefore,
HED
does
not
expect
there
to
be
any
postapplication
foliar
exposures
to
occur
and
postapplication
occupational
exposures
were
not
assessed.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
New
rat
cancer
study
(
Guideline
#
870.4200).
Forward
gene
mutation
assay
in
mammalian
cell
cultures
(
Guideline
#
870.5300).

10.2
Residue
Chemistry
The
following
label
amendments
for
uses
on
corn
and
sugarcane
should
be
submitted:
Corn
­
remove
sweet
corn
or
provide
residue
data.
Corn
­
rotational
crop
restrictions
­
minimum
plantback
intervals
(
PBIs)
of
3
months
for
small
grains,
10
months
for
spinach
and
potatoes,
and
11
months
for
all
other
crops
following
application
of
ametryn
to
corn.
Sugarcane
­
change
the
maximum
application
rate
to
12
lb
ai/
A/
crop
cycle
from
16
lb
ai/
A/
crop
cycle,
or
provide
additional
crop
field
trial
data
to
support
the
16
lb
use
rate.
Sugarcane
­
rotational
crop
restriction
­
restrict
rotation
to
soybean,
sorghum,
or
cotton
with
a
PBI
of
11
months
following
application
of
ametryn
to
sugarcane.
No
rotational
crop
restriction
is
needed
for
corn
since
it
is
labeled
as
a
primary
crop
for
ametryn
use.

°
Unless
uses
on
sweet
corn
are
deleted
from
all
end­
use
products
(
EPs),
data
are
required
depicting
residues
of
ametryn
and
its
three
thiomethyl
metabolites
in/
on
sweet
corn
ears
(
kernels
plus
cob
with
husks
removed)
following
treatment
at
the
maximum
labeled
rate.

°
A
new
sugarcane
processing
study
is
required
using
sugarcane
bearing
detectable
residues
or
sugarcane
from
plants
treated
at
5x
the
maximum
label
rate.

Additional
data
are
required
concerning
product
composition,
preliminary
analysis
(
analysis
for
HCB/
PCB),
certified
limits,
enforcement
analytical
method,
dissociation
constant,
and
solvent
solubility
for
the
Syngenta
90%
ametryn
T
(
EPA
Reg.
No.
100­
579).

10.3
Occupational
and
Residential
Exposure
54
None
55
References:

Ametryn.
HED
Occupational
and
Residential
Exposure
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
Revised),
DP
Barcode:
D311600,
Robert
Travaglini,
21­
DEC­
2004
Ametryn.
Chronic
and
Cancer
Dietary
Exposure
Assessment
for
the
Reregistration
Eligibility
Decision,
DP
Barcode:
D307103,
William
Donovan,
06­
OCT­
2004.

Ametryn.
Residue
Chemistry
Considerations
for
Reregistration
Eligibility
Decision,
DP
Barcode:
D307104,
William
Donovan,
03­
NOV­
2004.

Drinking
Water
Exposure
Assessment
for
Proposed
Reregistration
of
Ametryn
Use
on
Corn,
Pineapple
and
Sugarcane
(
Revised),
DP
Barcode:
D307105,
Kevin
Costello,
16­
NOV­
2004.
56
Appendices
1.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
40
CFR
158.340)
for
food
uses
for
ametryn
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
no
see
870.4100a
see
870.4100b
yes
 
 
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
no
yes
yes
no
yes
­­

870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
no
yes
yes
yes
 
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­­
­­
 
 
 
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
­­
Test
Technical
Required
Satisfied
57
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
 
 
 
2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
870.4300.
Combined
Chronic
Feeding/
Carcinogenicity
­
rats.
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
1987,
MRID
40349906),
Ametryn
(
98.6%
a.
i.,
FL
840991)
was
administered
to
groups
of
70
Sprague­
Dawley
[
Crl:
COBS
®
CD
®
(
SD)
BR]
rats/
sex
at
concentrations
of
0,
50,
or
500
ppm
for
104
weeks.
Groups
of
70
rats
per
sex
received
a
5000­
ppm
diet
that
was
reduced
to
4000
ppm
after
141
days
and
further
reduced
to
2000
ppm
after
239
days
because
of
reductions
in
weight
gain
at
the
higher
doses.
Ten
rats/
sex/
group
were
dosed
for
52
weeks
for
interim
evaluation,
and
ten
rats/
sex/
group
control
and
the
high­
dose
groups
were
dosed
for
56
weeks
followed
by
control
diet
for
4
weeks
to
assess
recovery.
Treatment
related
effects
were
noted
in
the
high
dose
(
5000/
4000/
2000
ppm)
group.
80%
of
males
and
69%
of
females
in
the
high­
dose
group
survived
to
study
termination
compared
with
only
43%
and
44%
of
controls.
The
only
treatment­
related
clinical
sign
was
loose
feces
observed
in
high­
dose
males
during
the
time
they
were
fed
the
5000­
ppm
diet.
High­
dose
males
weighed
29­
48%
less
than
controls
when
fed
the
5000­
ppm
diet
and
18­
26%
less
when
fed
the
4000­
ppm
diet
followed
by
the
2000­
ppm
diet.
High­
dose
females
weighed
20­
34%
less
than
controls
regardless
of
the
concentration
of
test
material
in
the
diet.
High­
dose
males
and
females
lost
weight
during
the
first
week
of
treatment
and
gained
38%
and
40%
less
weight,
respectively,
when
fed
the
5000­
ppm
diet,
20%
and
57%
less
weight,
respectively,
when
fed
the
4000­
ppm
diet,
and
29%
and
15%
more
weight,
respectively,
when
fed
the
2000­
ppm
diet
for
the
remainder
of
the
first
year.
During
the
second
year,
high­
dose
males
gained
two
times
more
weight
than
controls
and
high­
dose
females
gained
51%
less
weight
than.
High­
dose
males
and
females
consumed
18­
41%
and
30­
45%
less
food
when
fed
the
5000­
ppm
diet,
12­
17%
and
18­
22%
less
when
fed
the
4000­
ppm
diet,
and
6­
14%
and
7­
12%
less
when
fed
the
2000­
ppm
diet
up
to
day
560
and
532,
respectively.
Food
efficiency
for
the
first
91
days
was
reduced
by
22%
and
17%
for
high­
dose
males
and
females,
respectively.
Body
weight
and
gain
in
the
500
ppm
males
(
from
about
3%
to
6.3%,
p
<
0.05)
and
females
(
from
about
3%
to
6.9%,
p
<
0.05)
were
statistically
significantly
lower
(
from
about
3%
to
6.3%)
for
most
of
the
two
year
study
especially
for
males.
The
50
ppm
dose
groups
did
not
show
statistical
differences
from
the
control.
No
toxicologically
significant
effects
were
observed
on
hematology
or
clinical
chemistry
parameters
except
for
elevated
alkaline
phosphatase
(
68­
94%
increase)
in
high­
dose
females.
Males
had
significantly
increased
incidences
of
mineralization/
concretions
in
the
renal
pelvis
(
25/
70
vs
10/
70
for
controls),
pituitary
hyperplasia
(
26/
70
vs
13/
70
for
controls),
and
interstitial
cell
hyperplasia
in
the
testes
(
12/
70
vs
2/
70
for
controls).
Males
and
females
had
a
significant
increase
in
the
incidence
of
hepatocellular
hyperplasia
(
males:
34/
70
vs
22/
70;
females:
36/
70
vs
18/
70)
and
a
nonsignificant
increase
in
the
incidence
of
acinar
cell
metaplasia
(
hepatocyte­
like
cells)
in
the
pancreas
(
3/
70
for
males,
4/
69
for
females
vs
0/
70
for
controls
in
both
sexes).
Females
had
a
significantly
increased
58
incidence
of
"
hepatocellular
alterations"
(
49/
70
vs
19/
70
for
controls).
Acinar
metaplasia
in
both
sexes,
interstitial
cell
hyperplasia
in
the
testes,
and
hepatocellular
alterations
in
females
were
observed
in
the
high­
dose
groups
after
only
1
year
of
treatment.
The
incidences
of
lesions
after
1
year
were
reduced
after
the
4­
week
recovery
period.
The
LOAEL
is
5000/
4000/
2000
ppm
(
145.3
and
176.1
mg/
kg/
day
for
males
and
females,
respectively)
based
on
decreased
body
weight
and
weight
gain
in
both
sexes
and
histopathologic
lesions
in
the
kidney,
testes,
and
pituitary
in
male
rats
and
in
the
liver
and
pancreas
in
male
and
female
rats.
The
NOAEL
is
500
ppm
(
20.9
and
26.2
mg/
kg/
day,
for
males
and
females,
respectively).
The
decreased
weight
effects
were
not
considered
by
the
CARC
to
be
sufficient
to
meet
criteria
for
adequate
dosing
for
carcinogenicity
assessment.
The
incidences
of
interstitial
cell
tumors
in
the
testes
and
epididymal
mesothelioma
were
9/
70
(
12.9%,
p=
0.06)
and
3/
70
(
4.3%,
N.
S.)
in
high­
dose
male
rats
compared
with
3/
70
(
4.3%)
and
0/
70,
respectively,
for
controls.
The
incidence
of
both
lesions
exceeded
that
of
historical
controls
reported
in
the
concurrent
study
(
8.8%
and
0%,
respectively)
and
the
incidence
of
interstitial
cell
tumors
in
the
testes
exceeded
that
reported
in
2001
by
Charles
River
Laboratories
(
CRL)
for
Sprague­
Dawley
rats.
The
incidences
of
other
neoplasms
were
4/
70
(
5.7%,
p=
0.06)
for
thyroid
follicular
cell
adenocarcinoma
in
high­
dose
males
compared
with
0/
70
for
controls,
4/
70
(
5.7%,
N.
S.)
for
hepatocellular
adenoma
in
highdose
females
compared
with
1/
70
(
1.4%)
for
controls,
and
24/
70
(
34.3%,
p

0.01)
for
mammary
adenocarcinoma
in
high­
dose
females
compared
with
11/
70
(
15.7%)
for
controls;
these
incidences
in
the
treated
rats
were
above
the
historical
control
incidences
reported
in
the
current
study
but
were
less
than
the
range
for
spontaneous
incidences
reported
by
CRL.
The
increased
incidences
of
neoplasms
in
the
testes
and
epididymides
and
thyroid
in
males
and
in
the
liver
and
mammary
gland
in
females
was
evaluated
by
the
HED
CARC
and
it
was
determined
that
dosing
was
excessive
based
on
reduced
body
weight
and
weight
gain
in
both
sexes
and
the
interpretation
of
the
neoplastic
findings
compromised
at
the
high
dose.
The
next
lower
dose
level
of
500
ppm
was
determined
by
the
CARC
to
be
insufficiently
high
to
adequately
challenge
the
animals
for
carcinogenicity
evaluation.
This
chronic
toxicity
aspects
of
this
study
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity
study
[
OPPTS
870.4100a].
The
carcinogenicity
assessment
aspect
of
this
study
is
classified
as
Unacceptable/
Guideline
and
does
not
satisfy
the
requirement
for
a
carcinogenicity
study
(
OPPTS
870.4200)
in
rats.

870.4200.
Carcinogenicity
­
mouse.
In
this
carcinogenicity
study
(
1981,
MRID
No.:
40349904),
four
groups
of
60/
sex
Charles
River
CD­
1
strain
mice
were
dosed
as
control,
10,
1000
or
2000
ppm
of
ametryn
(
Batch
#
FL­
761356,
98.9%
purity)
for
102
weeks.
These
doses
convert
to
0,
1.5,
150
or
300
mg/
kg/
day
based
on
1
ppm
=
0.15mg/
kg/
day.
These
dose
levels
were
based
on
range
finding
studies
(
MRID
#
92002041)
that
demonstrated
that
at
1000
and
3000
ppm
there
was
significant
body
weight
decrease
and
at
3000
ppm
and
above
there
were
clinical
signs
(
hunched
posture,
labored
breathing,
thin
appearance
and
deaths
at
10000
ppm
and
above).
There
were
no
reactions
to
treatment
noted.
There
were
no
treatment
related
increases
in
neoplasms.
This
carcinogenicity
study
in
mice
was
classified
as
"
Minimum"
and
satisfies
the
guideline
requirement
for
a
series
870.4100
carcinogenicity
study
in
mice.
The
high
dose,
although
there
was
no
actual
toxicity
noted,
was
considered
close
enough
to
the
dose
levels
that
in
the
dose
range
finding
study
demonstrated
toxicity.
59
870.7485.
General
Metabolism.
There
are
three
studies
(
all
1990,
MRID
Nos.:
41463301,
41463302
and
41463303),
that
assess
the
general
metabolism
of
ametryn
in
rats.
In
this
series
of
studies,
ametryn,
either
radiolabelled
or
otherwise
was
administered
to
young
(<
8
weeks)
Sprague­
Dawley
strain
rats
(
5/
sex)
as
either
single
oral
low
(
0.5
mg/
kg),
multiple
low
(
0.5
mg/
kg/
day
for
14
days
or
signal
high
(
200
mg/
kg)
or
an
intravenous
dose
(
0.5
mg/
g).
In
general,
this
series
of
studies
demonstrated
that
ametryn
is
readily
absorbed
by
rats
after
a
single
dose
or
multiple
oral
dose(
s).
Ametryn
was
widely
distributed
with
low
(<
1%
)
residues
in
all
tissues
and
organs.
The
liver
(
0.312%
of
the
total
dose)
had
the
highest
concentration.
Excretion
was
mainly
through
the
urine
(
50­
61%)
within
48
hours
with
the
remainder
in
the
feces
(
30­
42%).
Thirty
six
mostly
polar
conjugated
and
unconjugated
metabolic
products
were
detected
and
13
were
identified
in
the
urine.
N­
dealkalation
of
the
parent
and
glutathione
conjugation
were
the
major
biotransformation
products.
No
significant
differences
in
pharmacokinetic
parameters
were
noted
among
the
dosing
groups
or
between
sexes.
60
3.0
TOLERANCE
REASSESSMENT
SUMMARY
Tolerance
Reassessments
for
Ametryn
The
tolerances
listed
in
40
CFR
§
180.258(
a
and
c)
are
currently
expressed
in
terms
of
ametryn
(
2­
ethylamino)­
4­(
isopropylamino)­
6­(
methylthio)­
s­
triazine
per
se.
The
ametryn
risk
assessment
team
has
determined
that
the
residues
of
concern
for
the
tolerance
expression
consists
of
ametryn
per
se.
A
summary
of
ametryn
tolerance
reassessments
is
presented
in
Table
A.
3.0.

Tolerances
Listed
Under
40
CFR
§
180.258
(
a
and
c):

Adequate
residue
data
are
available
to
reassess
the
established
tolerances
on
bananas,
corn
(
forage,
grain,
and
stover),
pineapples,
and
sugarcane.
However,
data
are
not
available
to
support
the
tolerance
on
sweet
corn,
kernels
plus
cobs
with
husks
removed.
If
no
registrant
intends
to
support
the
use
on
sweet
corn,
then
this
tolerance
should
be
revoked
once
use
directions
for
sweet
corn
are
deleted
from
all
EPs.

The
available
residue
data
indicate
that
tolerances
can
be
lowered
for
all
commodities
(
see
Table
A.
3.0).
Tolerances
on
corn
grain,
forage,
and
stover
should
be
split
to
include
field
and
pop
corn
(
e.
g.
Corn,
field,
grain
and
Corn,
pop,
grain)

Based
on
the
available
livestock
metabolism
and
feeding
studies,
there
is
no
reasonable
expectation
of
finite
residues
occurring
in
livestock
commodities.
Therefore,
tolerances
for
livestock
commodities
are
not
currently
required.

The
tolerances
on
forage
and
fodder
of
pineapples
and
sugarcane
should
be
revoked
as
these
commodities
are
no
longer
regulated,
and
the
tolerances
on
banana,
cassava,
tanier,
and
yams
should
be
revoked
as
uses
on
these
crops
are
not
being
supported.
61
Table
A.
3.0.
Tolerance
Reassessment
Summary
for
Ametryn.

Commodity
Current
Tolerance
(
ppm)
Range
of
Residues
1
(
ppm)
Tolerance
Reassessment
1
(
ppm)
Comment/[
Correct
Commodity
Definition]

Tolerances
Listed
Under
40
CFR
§
180.258(
a):

Banana
0.25
<
0.02­
0.04
Revoke
Use
is
not
being
supported.

Corn,
forage
0.5
<
0.02­
0.10
0.1
Tolerances
for
forage,
grain
and
stover
should
each
be
split
into
separate
tolerances
for
Corn,
field
and
Corn,
pop.
Corn,
grain
0.25
<
0.02
0.05
2
Corn,
stover
0.5
<
0.02
0.05
2
Corn,
sweet,
kernel
plus
cob
with
husks
removed
0.25
No
data
TBD
3
Residue
data
remain
outstanding.
If
uses
on
sweet
corn
are
deleted
from
EPs,
then
this
tolerance
should
be
revoked.

Pineapple
0.25
<
0.02­
0.05
0.05
2
Pineapple,
fodder
0.25
not
applicable
Revoke
These
commodities
are
no
longer
regulated
livestock
feed
items
Pineapple,
forage
0.25
not
applicable
Sugarcane,
cane
0.25
<
0.02
0.05
2
Sugarcane,
fodder
0.25
not
applicable
Revoke
These
commodities
are
no
longer
regulated
livestock
feed
items
Sugarcane,
forage
0.25
not
applicable
Tanier
0.25
no
data
Revoke
Uses
are
not
being
support
on
these
crops.
Yam,
true,
tuber
0.25
no
data
Tolerances
Listed
under
40
CFR
180.258(
c):

Cassava,
root
0.1
no
data
Revoke
Use
is
not
being
supported
1
The
range
of
residues
for
ametryn
per
se.
2
The
LOQ
for
the
current
enforcement
method
is
0.05
ppm
for
ametryn
per
se.
3
TBD
=
to
be
determined.