Document ID: EPA-HQ-OPP-2003-0077-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-04-10T04:00Z

Page
1
of
26
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
11/
22/
02
SUBJECT:
PP#
7F04850
­­
FQPA
Human
Health
Risk
Assessment
for
Safener
HOE
107892
(
Mefenpyr
diethyl)
­
Proposal
for
Tolerances
of
Residues
in/
on
Barley
and
Wheat.

DP
Barcode:
D262816
PRAT
Case:
288950
Submission
No.:
S529372
Caswell
No.:
811800
Chemical#:
811800
Class:
Safener
40
CFR:
§
180.509
TO:
K
Boyle/
R.
Forrest/
PM
Team
5
MUIERB/
RD
(
7505C)

FROM:
Yan
Donovan,
Chemist
Pamela
Hurley,
Toxicologist
Margarita
Collantes,
Biologist
RAB2/
HED
(
7509C)

THRU:
Douglas
Dotson,
Chemist
Ed
Budd,
Toxicologist
Shih­
Chi
Wang,
Biologist
RAB2/
HED
(
7509C)

THRU:
Richard
A.
Loranger,
Branch
Senior
Scientist
RAB2/
HED
(
7509C)
Page
2
of
26
Cl
N
N
Cl
COOCH
2
CH
3
C
H
3
COOCH
2
CH
3
1.0
EXECUTIVE
SUMMARY
General
Background:

AgrEvo
USA
Company
(
now
Bayer
CropScience)
has
submitted
a
petition
for
the
establishment
of
permanent
tolerances
for
residues
of
a
herbicide
safener,
HOE
107892
{[
1­(
2,4­
dichlorophenyl)­
4,5­
dihydro­
5­
methyl­
1H­
pyrazole­
3,5­
dicarboxylic
acid,
diethyl
ester]},
(
proposed
common
name:
mefenpyr­
diethyl),
in/
on
wheat
and
barley
commodities.

Safeners
are
added
to
herbicidal
active
ingredients
in
formulations
to
protect
crops
from
potential
adverse
effects
of
the
herbicides.
Although
safeners
are
not
considered
to
be
pesticidal
by
the
Agency,
they
are
often
similar
in
molecular
structure
to
active
pesticides.
Thus,
the
Agency
has
established
tolerances
for
safeners
(
e.
g.,
see
40
CFR
§
180.460,
§
180.469,
and
§
180.471).

The
formulation
is
proposed
for
a
single
seasonal
broadcast
application
to
wheat
in
the
2­
to
6­
leaf
stage
before
jointing.
Ground
application
may
be
made
in
a
minimum
of
10
gallons
of
spray
solution/
A.
Under
dense
weed
populations
or
adverse
growing
conditions,
high
spray
volumes
(
15­
20
gallon/
acre)
may
be
required.
Aerial
application
may
be
made
in
a
minimum
of
5
gallons
of
water
per
broadcast
acre.

The
petitioner
is
proposing
the
establishment
of
tolerances
for
residues
of
HOE
107892
and
its
2,4­
dichlorophenyl­
pyrazoline
containing
metabolites
in/
on
the
following
commodities:

Barley,
grain
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.05
ppm
Barley,
hay
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.5
ppm
Barley,
straw
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
1.0
ppm
Barley,
pearled
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.06
ppm
Barley,
flour
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.07
ppm
Barley,
bran
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.385
ppm
Wheat,
grain
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.05
ppm
Wheat,
forage
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.75
ppm
Wheat,
hay
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.5
ppm
Wheat,
straw
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.75
ppm
Wheat,
germ
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.415
ppm
Wheat,
bran
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.385
ppm
Wheat,
flour
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.07
ppm
Wheat,
shorts
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.415
ppm
HOE
107892
HOE
107892
is
a
member
of
a
new
chemical
class.
Page
3
of
26
Section
18
Emergency
Exemptions
were
approved
for
uses
on
durum
wheat
and
barley
in
1996
and
1998,
respectively,
and
as
a
result,
HOE
107892
has
temporary
tolerances
for
wheat
and
barley
raw
agricultural
commodities
(
40
CFR
180.509,
due
to
expire
12/
31/
03).
For
the
purposes
of
those
Section
18s
only,
it
was
assumed
that
there
would
be
no
quantifiable
residues
of
HOE­
107892
in
wheat
grain
or
straw
and
that
there
would
be
no
quantifiable
residues
in
meat,
milk,
poultry,
or
eggs
resulting
from
the
use.
HOE
107892
has
no
other
registered
uses;
PP#
7F04850
will
be
the
first
permanent
food
use.

HED
has
evaluated
the
toxicological,
residue
chemistry
and
exposure
databases
for
HOE
107892.

Hazard
Assessment
The
toxicology
data
base
is
complete,
and
the
quality
of
the
data
is
sufficient
to
characterize
the
toxicity
of
this
chemical.
There
is
a
fairly
high
confidence
in
the
hazard
and
dose­
response
assessments
conducted.

The
HED
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
met
on
10/
13/
98
to
evaluate
the
toxicology
data
base,
establish
Reference
Doses
(
RfDs)
and
select
toxicological
endpoints
for
dietary
and
occupational
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
enhanced
sensitivity
of
infants
and
children
from
exposure
to
HOE
107892,
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
toxicology
database
supports
the
requested
regulatory
action
and
there
is
a
fairly
high
degree
of
confidence
in
the
scientific
quality
of
the
data.
The
available
toxicology
data
are
considered
adequate
to
define
the
toxicity
of
the
chemical.
The
HIARC
classified
HOE
107892
as
"
not
likely
to
be
a
human
carcinogen"
based
on
negative
rat
and
mouse
carcinogenicity
studies
as
well
as
negative
mutagenicity
studies.
Although
HOE
107892
was
not
tested
at
sufficiently
high
dose
levels
for
an
adequate
rat
carcinogenicity
study,
based
on
the
overall
toxicology
database
and
weight
of
the
evidence
from
the
negative
mouse
carcinogenicity
and
mutagenicity
studies,
it
is
unlikely
that
repeating
the
study
at
higher
dose
levels
would
significantly
change
the
target
organs
or
the
effects
observed.
There
are
no
data
gaps
for
this
particular
use;
however,
a
new
rat
carcinogenicity
study
will
be
requested
if
new
uses
result
in
significantly
higher
residues
in
human
foods
and/
or
there
is
significantly
higher
occupational
(
or
future
residential)
exposure
due
to
changes
in
parameters
such
as
the
method
of
application.

In
general,
HOE
107892
has
low
acute
toxicity.
In
subchronic
and
chronic
studies
in
animals,
it
was
shown
to
affect
2
major
target
organs:
the
liver
and
the
hematopoietic
system.
None
of
the
observed
effects
in
the
toxicological
studies
on
HOE
107892
are
of
major
toxicological
significance.
They
are
all
mild.
The
most
significant
effects
appear
to
be
decreased
mean
body
weight
and
mean
body
weight
gain,
increased
mean
spleen
weights
and
an
increase
in
the
severity
(
but
not
in
the
incidence)
of
splenic
extramedullary
hematopoiesis
in
rats
in
a
2­
generation
reproduction
study.
Minimal
intrahepatic
cholestasis
in
the
liver
was
observed
in
dogs,
accompanied
by
increases
in
liver
weights
and
alkaline
phosphatase.
Hepatocellular
hypertrophy
and
increases
in
liver
weights
were
observed
in
other
studies
and
are
usually
considered
to
be
related
to
induction
of
drug
metabolizing
enzymes.
There
is
no
evidence
of
carcinogenicity
in
either
rats
or
mice
and
no
evidence
of
a
mutagenic,
clastogenic
or
genotoxic
response.
There
does
not
appear
to
be
any
increased
susceptibility
in
rats
or
rabbits
to
in
utero
and/
or
postnatal
Page
4
of
26
exposure
to
HOE
107892.
Developmental
effects
were
only
observed
at
levels
which
were
parentally
toxic.
In
addition,
there
is
no
evidence
of
neurotoxicity
in
any
of
the
available
studies.
Finally,
HOE
107892
does
not
appear
to
be
an
endocrine
disrupter.

FQPA
Decision
The
HED
FQPA
Safety
Factor
Committee
(
SFC)
met
on
December
7,
1998
to
evaluate
the
hazard
and
exposure
data
for
HOE
107892
and
recommended
that
the
FQPA
Safety
Factor
(
as
required
by
the
Food
Quality
Protection
Act
of
August
3,
1996)
be
removed
because
there
is
no
indication
of
increased
susceptibility
to
infants
and
children,
dietary
exposure
estimates
are
likely
to
result
in
an
overestimate
of
the
actual
exposure,
estimates
for
ground
and
surface
source
drinking
water
exposure
are
upper­
bound
concentrations
and
there
are
currently
no
registered
residential
uses
and
thus,
this
type
of
exposure
to
infants
and
children
is
not
expected.

Dose
Response
Assessment
The
HIARC
selected
a
chronic
RfD
of
0.57
mg/
kg/
day
(
NOAEL
=
57.3;
Uncertainty
Factor
=
100)
for
use
in
assessing
chronic
dietary
risk.
This
RfD
is
based
on
the
2­
generation
reproduction
study
in
the
rat,
in
which
decreases
in
mean
body
weight
and
body
weight
gain,
increases
in
mean
spleen
weight
and
increases
in
the
severity
of
splenic
extramedullary
hematopoiesis
were
observed.

Acute
dietary
and
short­,
intermediate­
and
long­
term
dermal
and
inhalation
toxicological
endpoints
were
not
selected
because
no
appropriate
endpoint
could
be
identified
in
the
available
studies,
including
the
developmental
studies
in
rats
and
rabbits;
a
28
day
dermal
study
in
rats
(
21
exposure
periods
over
29
days)
showed
no
dermal
or
systemic
toxicity
at
dose
levels
up
to
1000
mg/
kg/
day;
HOE
107892
has
low
acute
inhalation
toxicity
and/
or
because
the
use
pattern
indicates
that
there
is
minimal
concern
for
either
long­
term
dermal
exposure
or
any
significant
inhalation
exposure.
Therefore,
no
risk
assessments
were
conducted
for
these
exposure
scenarios.

As
stated
previously,
on
10/
13/
98,
HOE
107892
was
classified
by
the
HIARC
as
"
not
likely
to
be
a
human
carcinogen".
This
was
based
on
weight
of
the
evidence
from
negative
rat
and
mouse
carcinogenicity
studies
as
well
as
negative
mutagenicity
studies.
In
light
of
the
negative
mouse
and
mutagenicity
studies,
although
the
dose
levels
in
the
rat
study
are
not
adequate,
the
Committee
determined
that
a
new
rat
study
would
not
provide
any
additional
information
on
the
effects
of
concern
for
this
particular
use.

Exposure
Scenarios
and
Risk
Conclusions
Residential
Exposure
Estimates
Page
5
of
26
HOE
107892
currently
has
no
registered
or
proposed
residential
uses.
Therefore,
a
residential
exposure
assessment
is
not
required
at
this
time.

Dietary
Exposure
Estimates
On
2/
8/
00,
the
HED's
Metabolism
Assessment
Review
Committee
(
MARC)
determined
that
the
regulable
residues
in
animal
commodities
should
be
the
parent
compound
and
the
three
2,4­
dichlorophenyl­
pyrazoline
containing
metabolites
HOE
113225,
HOE
109453,
and
HOE
094270
(
Memo
of
Y.
Donovan,
3/
27/
00,
D263039).

Based
on
data
from
a
barley
metabolism
study,
the
MARC
has
recommended
that
regulation
of
HOE
on
plants
be
based
on
the
parent
compound
and
the
three
metabolites
(
HOE
113225,
HOE
109453,
and
HOE
094270)
which
are
also
detected
by
the
proposed
polar
extraction
GC/
MS
method
(
7/
16/
96
memo
of
D.
Davis).
The
above
metabolites
are
formed
by
hydrolysis
of
one
or
both
ethyl
ester
groups
followed
by
decarboxylation
in
the
case
of
HOE
094270.

A
GC/
MSD
method
for
the
enforcement
of
tolerances
for
barley
and
wheat
commodities
has
been
forwarded
to
the
Agency
analytical
lab
for
petition
method
validation.
The
Agency
analytical
lab
concluded
that
this
method
is
suitable
for
food
tolerance
enforcement
of
HOE107892
and
the
three
metabolites
HOE
094270,
HOE
113225
and/
or
HOE
109453
in/
on
plants.

An
adequate
enforcement
method
capable
of
determining
residues
in/
on
animal
commodities
is
required
since
the
Agency
is
recommending
tolerances
be
established
on
meat
byproducts
(
liver
and
kidney).
The
petitioner
has
proposed
a
study
protocol
for
development
of
an
animal
method.
RAB2
concluded
that
this
requirement
can
be
made
a
condition
of
registration.

HOE­
107892
chronic
dietary
exposure
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
1.3),
which
incorporates
consumption
data
from
USDA's
Continuing
Survey
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
96,
98
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
"
as
consumed"
(
e.
g.,
apple
pie)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
exposure
assessment,
but
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

The
analysis
assumed
tolerance­
level
residues
and
100%
crop
treated
for
all
proposed
uses
(
i.
e.,
a
Tier
1
analysis).
Estimated
exposures
are
less
than
1%
of
the
chronic
Population
Adjusted
Dose
(
cPAD)
for
the
general
U.
S.
population
and
all
population
subgroups,
including
those
of
infants
and
children.
The
proposed
use
of
HOE­
107892
on
barley
and
wheat
is
expected
to
result
in
dietary
(
food
only)
risks
that
are
less
than
the
Agency's
level
of
concern
for
the
general
U.
S.
population
and
all
population
subgroups,
including
those
of
infants
and
children.

Drinking
Water
Exposure
Estimates
Page
6
of
26
EFED
provided
the
environmental
fate
analysis
and
the
results
of
maximum
estimated
environmental
concentrations
(
EECs)
of
HOE
107892
in
surface
and
ground
water
for
chronic
exposure.
For
surface
water,
the
FIRST
(
Tier
1)
index
reservoir
simulation
model
for
a
single
application
of
HOE­
107892
at
an
exaggerated
rate
of
0.090
kg/
ha
(
0.080
lb/
acre)
results
in
the
peak
and
chronic
concentrations
of
combined
parent
and
metabolites
of
5
ppb
and
3
ppb,
respectively.
The
groundwater
result
from
SCI­
GROW2
is
approximately
4
µ
g/
L
(
ppb).

Aggregate
Risk
Assessment
Conclusions:

Acute
Aggregate
Risk
(
Food
+
Water)

Not
required
since
no
endpoint
was
selected.

Chronic
Aggregate
Risk
(
Food
+
Water
+
Residential)

Chronic
aggregate
risk
includes
exposures
from
food,
water,
and
residential
uses.
Using
the
most
conservative
Tier
I
analysis,
it
is
estimated
that
the
chronic
exposures
to
HOE
107892
from
food
for
the
general
US
population
and
all
population
subgroups
will
utilize
<
1%
of
the
cPAD.
EFED's
EEC
of
HOE
107892
in
surface
and
ground
water
for
chronic
exposure
is
very
small
compared
to
the
DWLOC,
which
ranged
from
5700
to
20000
ppb.
Currently
there
are
no
registered
or
proposed
residential
uses
that
could
result
in
residential
exposures.
Therefore,
HED
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
adults,
infants
and
children
from
chronic
aggregate
exposure
to
HOE
107892
residues.

Short­
and
Intermediate­
Term
Aggregate
risk
(
Residential
+
Chronic
Food
+
Chronic
Water)

There
are
no
registered
residential
uses
of
HOE
107892.
Therefore,
a
short­
and
intermediateterm
aggregate
risk
assessment
for
HOE
107892
is
not
required.

Cancer
HOE
107892
has
been
classified
by
HED
HIARC
as
a
"
not
likely
human
carcinogen."
A
cancer
risk
assessment
is
not
required.

Occupational
Exposure
Workers
may
be
exposed
to
HOE
107892
during
mixing,
loading,
application
and
postapplication
activities.
Based
on
the
proposed
application
rates
and
use
scenarios,
short­
and
intermediateterm
exposures
may
occur.
Chronic
exposure
(
6
or
more
months
of
continuous
exposure)
is
not
expected.
Since
the
HIARC
did
not
select
dermal
or
inhalation
toxicological
endpoints,
neither
dermal
nor
inhalation
risk
assessments
were
performed.

The
acute
toxicity
effects
for
HOE
107892
are
all
in
categories
III
and
IV
and
therefore
only
require
a
12­
hour
REI.

Recommendations:
Page
7
of
26
Cl
N
N
Cl
COOCH
2
CH
3
C
H
3
COOCH
2
CH
3
HED
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
the
U.
S.
Population
including
infants
and
children
from
chronic
aggregate
exposure
to
HOE
107892
residues.
HED
recommends
that
permanent
tolerances
be
established
for
residues
of
HOE
107892
and
its
2,4­
dichlorophenyl­
pyrazoline
containing
metabolites
in/
on
the
following
commodities:

Barley,
grain
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.05
ppm
Barley,
hay
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.2
ppm
Barley,
straw
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.5
ppm
Wheat,
grain
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.05
ppm
Wheat,
forage
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.2
ppm
Wheat,
hay
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.2
ppm
Wheat,
straw
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
0.5ppm
Meat
byproducts
(
of
cattle,
goats,
hogs,
horses
and
sheep).
.
.
.
.
.
.
.
.
.
.
.
.
.
0.1ppm
Residue
Chemistry
deficiencies

Multiresidue
method
testing
for
parent
and
metabolites;

Animal
analytical
method
(
condition
of
registration);

A
revised
Section
F
to
change
the
proposed
tolerances
to
match
the
above
recommended
tolerances.

Agency
memoranda
supporting
this
risk
assessment
include
the
following:

1.
HIARC
report
on
HOE
107892
(
11/
24/
98);
2.
FQPA
report
on
HOE
107892
(
12/
17/
98);
3.
HED
Residue
Chemistry
memo
of
11/
22/
02,
Y.
Donovan,
D238730
;
4
HED
DEEM
memo
of
11/
22/
02,
Y.
Donovan,
D286489;
5.
EFED
memos
of
03/
18/
97,
Alex
Clem,
D226076,
and
11/
26/
01,
Alex
Clem,
D262735;
6.
HED
ORE
memo
of
04/
12/
00,
M.
Collantes,
D263518.

2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
The
chemical
structure
of
HOE
107892
is
as
follows:

HOE
107892
Page
8
of
26
Product
chemistry
for
HOE
107892
has
been
previously
reviewed
by
HED
(
memo
of
6/
24/
99,
J.
Stokes,
D231514,
PP#
6E4722).
Some
of
the
physical
properties
of
HOE
107892
are
summarized
below:

Color:
white
to
light
beige
Physical
State:
normally
solid,
but
can
also
occur
as
a
supercooled
molten
mass
Odor:
weak,
non­
characteristic
odor
M.
P.:
43
0
to
47
0C
(
109
­
116
F)
Density:
1.31
g/
cm3
at
20
0C
Vapor
pressure:
N/
A
pH:
Neat
Water
insolubility/
non­
dispersibility
prevented
measurement
of
pH
Octanol/
Water
Partition
Coefficient:
log
P
=
3.83
Solubility:
20
mg/
L,
pH
6.2
(
distilled
water,
20
0C)
17
mg/
L,
pH
0.9
(
sulfuric
acid,
pH
1,
20
0C)
organic
solvents:
n­
hexane,
35
g/
L
acetone,
>
500
g/
L
Hydrolysis:
in
Citrate:
>
365
days,
in
Borate/
KCl:
0.35
days.
Half­
life:
17
days(
photolysis)
3
days
(
aerobic
soil
metabolism)

3.0
HAZARD
CHARACTERIZATION
(
Attachment
1,
HIARC
report
on11/
24/
98)

3.1
Hazard
Profile
Table
1.
Acute
Toxicity
of
HOE
107892
Technical.

Guideline
Number
Study
Type
MRID
#(
S).
Results
Toxicity
Category
81­
1
Acute
Oral
43972211
Oral
LD50:
Males
>
5,000
mg/
kg
Females
>
5,000
mg/
kg
IV
81­
2
Acute
Dermal
43972213
Dermal
LD50:
M
>
4,000
mg/
kg
F
>
4,000
mg/
kg
III
81­
3
Acute
Inhalation
43972214
Inhalation
LC50:
Males:
>
1.32
mg/
L
Females
>
1.32
mg/
L
III
81­
4
Primary
Eye
Irritation
43972215
Slight
ocular
irritant.
PIS:
12.8.
III
81­
5
Primary
Dermal
Irritation
43972216
PII:
0.17.
Not
a
dermal
irritant.
IV
81­
6
Dermal
Sensitization
43972217,
44280001
A
slight
dermal
sensitizer.
N/
A
Page
9
of
26
Table
2.
Toxicity
Profile
of
HOE
107892
Technical.

Study
Type
MRID
No.
Results
28­
Day
Dermal
Toxicity­
Rat
44089201
NOAEL
=
1000
mg/
kg/
day
(
HDT);
LOAEL
not
determined.
No
effects
were
observed
in
the
study.

Subchronic­
Feeding­
Mouse
43972218
NOAEL
89.3/
105.4
mg/
kg/
day
(
M/
F)
LOAEL=
449.0/
523.5
mg/
kg/
day
(
M/
F;
decreased
body
and
kidney
weight,
increased
liver
weight
and
hepatocyte
hypertrophy
in
males;
decreased
bilirubin
and
increased
lactic
acid
dehydrogenase
values
in
females)

Subchronic­
Feeding­
Rat
43972219
NOAEL
=
206.7/
223.0
(
M/
F)
mg/
kg/
day
LOAEL
=
660.6/
708.9
(
M/
F)
mg/
kg/
day
(
decreased
body
weight
gains;
decreased
erythrocyte
counts,
hemoglobin
and
hematocrit
values;
and
increased
reticulocyte
counts
and
mean
corpuscular
volume).

Subchronic­
Feeding­
Dog
43972220
NOAEL
=
80.5/
81.2
mg/
kg/
day
(
M/
F)
LOAEL
=
341.0/
336.1
mg/
kg/
day
(
M/
F;
increased
absolute
and
relative
liver
weights
and
alkaline
phosphatase
activities
in
both
sexes;
focal
liver
lesions
in
females;
slight
anemia
in
both
sexes;
decrease
in
mean
body
weight
and
body
weight
gain
in
females
and
decreased
food
consumption
in
both
sexes).

Chronic­
Feeding­
Dog
44316402
NOAEL
=
51.4/
57.6
mg/
kg/
day
(
M/
F)
LOAEL=
260.2/
282.2
mg/
kg/
day
(
M/
F;
high
ALP
levels
and
increased
absolute
and
relative
liver
weights
in
both
sexes
and
grade
1
(
minimal)
intrahepatic
cholestasis
in
the
liver:
2/
sex).

Chronic
toxicity/
Carcinogenicit
y­
Rat
43972222
43972223
NOAEL=
48.5/
60.0
mg/
kg/
day
(
M/
F)
LOAEL=
251.6/
318.0
mg/
kg/
day
(
M/
F:
significant
increases
in
reticulocyte
counts).

Carcinogenicity­
Mouse
43972224
43972225
NOAEL
(
males)
=
350.8
mg/
kg/
day
NOAEL
(
females)
=
463.4
mg/
kg/
day
LOAEL
(
males
&
females)
=
Not
determined,
however
study
considered
adequate
for
carcinogenicity
based
on
results
of
subchronic
study.

Developmental
Toxicity­
Rat
43972221
Maternal
NOAEL
<
1000
mg/
kg/
day
(
only
dose
tested)
Maternal
LOAEL
=
1000
mg/
kg/
day
(
decreases
in
body
weight
gain
and
food
efficiency
during
the
first
week
of
treatment
and
on
increases
in
absolute
and
relative
spleen
weights).
Developmental
NOAEL
=
1000
mg/
kg/
day
Developmental
LOAEL
=
Not
achieved
Postnatal
Developmental
Toxicity­
Rat
44654201
Maternal
NOAEL
<
1000
mg/
kg/
day
(
only
dose
tested)
Maternal
LOAEL
=
1000
mg/
kg/
day
(
decreases
in
body
weight
gain
and
food
efficiency
during
the
first
week
of
treatment).
Developmental
NOAEL
<
1000
mg/
kg/
day
Developmental
LOAEL
=
1000
mg/
kg/
day
(
marginal
decreases
in
fetal
body
weight
and
body
weight
gain
during
lactation).
Study
Type
MRID
No.
Results
Page
10
of
26
Developmental
Toxicity­
Rabbit
44089202
Maternal
NOAEL
=
100
mg/
kg/
day
Maternal
LOAEL
=
250
mg/
kg/
day
(
higher
rate
of
abortions
and
marginal
decreases
in
body­
weight
gain,
food
efficiency
index
and
food
consumption).
Developmental
NOAEL
=
100
mg/
kg/
day
Developmental
LOAEL
=
250
mg/
kg/
day
(
higher
rate
of
abortions).

Reproductive
Toxicity
44661601
Parental­
Offspring/
Systemic
NOAEL
=
57.3
mg/
kg/
day
for
males;
76.0
mg/
kg/
day
for
females.
Parental­
Offspring/
Systemic
LOAEL
=
306.0
mg/
kg/
day
for
males;
392.0
mg/
kg/
day
for
females
(
decreased
mean
body
weight
and
mean
body
weight
gain
in
parents
and
offspring
and
an
increase
in
mean
spleen
weight
and
an
increase
in
the
severity
(
but
not
in
the
incidence)
of
splenic
extramedullary
hematopoiesis
in
females).
Reproductive
NOAEL
=
306.0
mg/
kg/
day
(
males),
392.0
mg/
kg/
day
(
females):
HDT
Reproductive
LOAEL
=
Not
determined
Gene
Mutation
­
Salmonella
&
E.
Coli
43972226
Non­
mutagenic
(
±
)
activation.

Gene
Mutation
­
HGPRT
with
V79
cells
43972230
Non­
mutagenic
(
±
)
activation.

Micronucleus
Assay
43972228
No
clastogenic
response
at
any
dose
or
sacrifice
time.

DNA
Repair
Assay
43972229
No
clear
evidence
of
genotoxicity.
However,
study
not
acceptable.

Chinese
Hamster
Lung
Fibroblast
Assay
43972227
No
clastogenic
response
(
±
)
activation.
Study
Type
MRID
No.
Results
Page
11
of
26
Metabolism­
Rat
44654204
44654203
44661602­
3
Single
dose
of
1
or
100
mg/
kg
bw:
urinary
excretion
­
76­
88%
of
administered
radioactivity
with
59­
72%
excreted
within
first
24
hours.
Fecal
excretion
ranged
from
13­
32%.
83­
91%
of
administered
dose
excreted
(
urine
and
feces)
by
24
hours
and
91
to
>
99%
excreted
by
48
hours.
At
least
68­
88%
of
administered
dose
absorbed.
Recovery
in
tissues/
animal:
0.24%
of
administered
radioactivity
(
range:
0.07
­
0.51%).
General
order
of
concentration
plasma
>
whole
blood
>
lungs
>
subcutaneous
fat
>
heart
>
kidneys>
retroperitoneal
fat
>
liver>
gonads
>
pancreas
>
skeletal
muscle.
No
volatile
radioactivity
detected
0­
24
hours
after
dosing.
Between
100­
106%
of
administered
radioactivity
recovered.

Single
dose
of
1
or
100
mg/
kg
bw:
Radioactivity
rapidly
excreted:
total
of
78­
92%
excreted
by
48
hours.
Renal
excretion
predominant
route
of
elimination
(
65­
72%
by
48
hours),
indicating
that
at
least
65­
72%
of
the
administered
dose
was
absorbed.
None
of
test
material
found
in
its
original
form
in
urine.
Three
metabolites
identified
in
urine:
Hoe
109453
(
63­
62%
and
42­
48%),
Hoe
113225
(
0.2­
2%
and
14­
28%),
and
Hoe
094270
(
2­
3%
and
2%)
each
for
males
and
females,
respectively.
13­
26%
of
the
radioactivity
was
recovered
in
the
feces
by
48
hours.
In
addition
to
the
three
metabolites
identified
in
urine,
the
parent
was
also
present
in
the
feces:
Hoe
107892
(
8%
and
1­
3%),
Hoe
109453
(
2­
8%
and
4­
7%),
Hoe
113225
(
5­
6%
and
1­
3%),
and
Hoe
094270
(
0.30­
0.50
and
0.53­
1.16%)
each
for
males
and
females,
respectively.
Proposed
metabolic
steps:
consecutive
hydrolysis
(
saponification)
of
the
two
carboxylic
acid
ester
groups
and
a
decarboxylation
of
one
of
the
carboxylic
groups,
resulting
in
an
aromatization
of
the
pyrazoline
ring
(
Hoe
107892

Hoe
113225

Hoe
109453

Hoe
094270).
Enterohepatic
circulation
is
unlikely
to
play
a
major
role.
In
males,
there
appears
to
be
either
lower
intestinal
absorption
or
a
higher
biliary
excretion
of
Hoe
107892
compared
to
females.

General
Toxicity
Profile
HOE
107892
has
low
acute
toxicity.
It
is
classified
in
Toxicity
Categories
III
or
IV
in
the
acute
oral,
dermal,
inhalation
and
irritation
studies.
It
is
a
slight
dermal
sensitizer.

The
database
on
HOE
107892
indicates
that
there
appears
to
be
2
major
target
organs:
the
liver
and
the
hematopoietic
system.
Both
the
liver
and
hematological
effects
are
observed
in
NMRI
mice
(
both
sexes),
Wistar
rats
(
both
sexes),
and
Beagle
dogs
(
both
sexes).
There
does
not
appear
to
be
sex
sensitivity.
There
appears
to
be
a
dose­
response
relationship
between
the
doses
tested
and
the
effects
observed;
however,
in
the
case
of
the
effects
on
the
hematopoietic
system,
often
the
effects
are
very
mild
and
are
only
observed
at
the
highest
dose
level
tested.

Liver
Page
12
of
26
Following
administration
of
the
test
chemical,
increases
in
liver
weight
and
hepatocellular
hypertrophy
were
observed
in
short­,
intermediate­
and
long­
term
studies
in
mice;
effects
were
observed
at
lower
dose
levels
in
the
longer­
term
studies.
In
dogs,
increases
in
liver
weights
and
alkaline
phosphatase
levels
were
observed
in
short­,
intermediate­
and
long­
term
studies.
Liver
pathology
(
focal
lesion:
hemorrhage,
necrosis
and
inflammation)
appeared
by
13
weeks
at
336
mg/
kg/
day
(
a
4­
week
study
at
a
similar
dose
level
showed
no
microscopic
effects).
After
1
year
exposure,
increased
liver
weights,
intrahepatic
cholestasis
and
high
alkaline
phosphatase
levels
were
observed
at
a
dose
level
in
the
same
range
(
282
mg/
kg/
day).
In
general,
longer
exposure
periods
did
not
produce
liver
effects
at
lower
dose
levels;
however,
intrahepatic
cholestasis
is
likely
to
be
a
more
serious
effect
than
the
focal
lesion
observed
in
the
13­
week
study
and
the
former
was
observed
in
2
male
and
2
female
dogs,
whereas
the
latter
was
only
observed
in
1
female.
In
rats,
one
special
4­
week
study
showed
that
HOE
107892
induces
hepatic
drug
metabolizing
enzymes.
Induction
of
hepatic
drug
metabolizing
enzymes
are
not
considered
to
be
adverse,
i.
e.
they
are
considered
to
be
biologically
but
not
toxicologically
significant.

Hematopoietic
System
The
effects
on
the
hematopoietic
system
are
very
mild
(
in
some
cases
they
are
not
even
considered
to
be
adverse
effects);
however,
they
indicate
that
the
chemical
is
causing
hemolysis
of
the
red
blood
cells.
As
a
result,
cells
are
being
produced
in
the
bone
marrow
so
fast
that
they
are
immature
and
low
in
hemoglobin.
This
is
indicated
by
decreases
in
erythrocytes,
hemoglobin
and
hematocrit
levels,
decreased
mean
corpuscular
hemoglobin
concentration,
increases
in
reticulocyte
and
mean
corpuscular
volume,
enlarged
spleens,
more
severe
hematopoiesis
and
hemosiderin
deposits.
The
hematological
effects
are
observed
after
short
and
intermediate
exposure
in
mice,
intermediate
exposure
in
dogs
and
after
short­,
intermediate
and
long­
term
exposure
in
rats.
Although
the
effects
on
the
hematopoietic
system
are
similar
in
both
the
short­
and
longer­
term
studies,
they
do
not
necessarily
occur
at
lower
doses
in
the
longer
term
studies.
For
example,
the
effects
are
not
observed
in
the
1­
year
dog
study
(
highest
dose
tested:
282
mg/
kg/
day);
whereas,
they
are
observed
at
336
mg/
kg/
day
in
the
13­
week
dog
study.

Carcinogenic
Effects:

In
accordance
with
the
EPA
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
April
10,
1996),
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC,
10/
13/
98)
classified
HOE
107892
as
a
"
not
likely
to
be
a
human
carcinogen".
This
classification
is
based
on
the
lack
of
evidence
of
carcinogenicity
in
male
and
female
mice
as
well
as
in
male
and
female
rats.
In
addition,
none
of
the
mutagenicity
studies
tested
positively.
Although
the
dose
levels
in
the
rat
study
were
not
adequate,
the
Committee
determined
that
a
new
rat
study
would
not
provide
any
additional
information
on
the
effects
of
concern
for
this
particular
use.
Therefore,
a
new
rat
carcinogenicity
study
will
not
be
requested
unless
new
uses
result
in
significantly
higher
residues
in
human
foods
and/
or
there
is
significantly
higher
occupational
(
or
future
residential)
exposure
due
to
changes
in
parameters
such
as
the
method
of
application.

Developmental/
Reproductive
Effects:
Page
13
of
26
Two
developmental
rat
studies
were
conducted,
one
using
the
standard
guideline
and
the
other
allowing
the
dams
to
give
birth
and
following
the
pups
until
weaning.
In
the
prenatal
developmental
toxicity
study
in
rats,
no
evidence
of
developmental
toxicity
was
seen,
even
in
the
presence
of
maternal
toxicity.
In
the
developmental
toxicity
study
in
rabbits,
developmental
toxicity
was
seen
in
the
presence
of
maternal
toxicity.
A
higher
rate
of
abortions
occurred
at
the
highest
dose
level
tested
(
250
mg/
kg/
day).
An
examination
of
the
individual
litter
data
provided
no
evidence
as
to
whether
or
not
the
higher
rate
was
due
to
maternal
toxicity
or
developmental
toxicity.
Therefore,
both
the
maternal
and
developmental
NOAELs
and
LOAELs
were
based
on
this
effect.
In
the
two­
generation
reproduction
study
and
in
the
postnatal
developmental
toxicity
study
in
rats,
effects
in
the
offspring
were
observed
only
at
or
above
treatment
levels
which
caused
parental
toxicity.
Developmental
effects
in
these
two
studies
consisted
of
decreases
in
body
weight
and
body
weight
gain
of
the
pups
in
the
presence
of
either
decreased
body
weight
and
body
weight
gain
or
hematopoietic
effects
in
the
parents.

Mutagenic
Effects:

HOE
107892
was
tested
in
gene
mutation
assays
in
Salmonella
typhimurium,
E.
coli
and
Chinese
hamster
lung
fibroblasts
V79
cells,
in
in
vitro
and
in
vivo
cytogenetics
assay
(
Chinese
hamster
lung
fibroblasts
and
mouse
micronucleus)
and
in
an
unscheduled
DNA
synthesis
assay
in
human
A
549
cells.
There
was
no
evidence
of
a
mutagenic,
clastogenic
or
genotoxic
response
under
the
conditions
of
the
assays,
either
with
or
without
metabolite
activation.
In
the
unscheduled
DNA
synthesis
assay,
a
cytotoxic
and/
or
insoluble
level
was
not
evaluated
in
the
S9­
activated
phase
of
the
study
and
overall
assay
sensitivity
was
compromised
because
of
the
high
levels
of
radioactive
label
(
indicating
that
replicative
DNA
synthesis
was
not
successfully
blocked)
in
all
experimental
groups.
Therefore,
this
particular
study
was
classified
as
Unacceptable
and
does
not
satisfy
the
guideline
requirement
for
a
UDS
assay
(
§
84­
2).

Neurotoxic
Effects:

No
neurotoxicity
studies
are
available.
There
is
no
evidence
of
neurotoxicity
in
any
of
the
available
studies.

Metabolites:

The
HED
Metabolism
Committee
met
on
6/
20/
96
and
on
02/
08/
00
and
determined
that
the
residues
of
concern
for
HOE
107892
are
the
parent
compound
and
free
metabolites,
HOE
113225,
HOE
109453
and
HOE
094270.
No
additional
potential
HOE
107892
degradates
of
significant
toxicological
concern
were
either
identified
or
expected
which
should
be
included
in
the
tolerance
expression
or
risk
assessment.

Endocrine
Disruption:

There
is
no
evidence
of
endocrine
disruption
with
HOE
107892.

Toxicological
Significance
of
Effects:
Page
14
of
26
None
of
the
observed
effects
in
the
toxicological
studies
on
HOE
107892
are
of
major
toxicological
significance.
They
are
all
mild.
Of
the
observed
effects
previously
discussed,
the
HIARC
believed
that
the
endpoints
from
the
2­
generation
reproduction
study
(
decreased
mean
body
weight
and
mean
body
weight
gain
in
parents
and
offspring,
increased
mean
spleen
weights
and
an
increase
in
the
severity
(
but
not
in
the
incidence)
of
splenic
extramedullary
hematopoiesis)
were
considered
to
be
the
most
significant.
The
observed
intrahepatic
cholestasis
in
the
liver
in
the
chronic
dog
study
was
minimal,
although
it
was
seen
in
4/
12
dogs.
In
that
study,
it
was
considered
to
be
a
toxicological
effect
(
although
minor)
along
with
the
increases
in
liver
weights
and
alkaline
phosphatase.
Hepatocellular
hypertrophy
and
increases
in
liver
weights
are
often
related
to
induction
of
drug
metabolizing
enzymes
(
actually
measured
in
the
rat)
and
are
not
considered
to
be
significant
toxicological
effects,
except
in
the
case
of
the
chronic
dog
study
due
to
the
presence
of
other
microscopic
effects
in
the
liver.

3.2
FQPA
Considerations
(
Attachment
2,
FQPA
report
on
12/
17/
98)

Rationale
and
Findings
Regarding
Recommendation
on
Special
FQPA
Safety
Factor
Although
no
neurotoxicity
studies
are
available,
there
is
no
evidence
of
neurotoxicity
in
any
of
the
subchronic,
developmental,
reproductive
or
chronic
toxicity
studies.
The
postnatal
developmental
toxicity
study
provided
no
evidence
of
developmental
neurotoxicity
with
any
of
the
parameters
examined
(
sex,
external
abnormalities,
viability,
general
behavior,
times
of
pinna
separation,
coat
growth
start,
incisor
eruption
and
eyelid
opening,
hearing,
vision,
righting
reflex,
trainability,
memory
and
retrainability).

The
data
provided
no
indication
of
increased
susceptibility
in
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
HOE
107892
and
there
are
no
exposure
or
toxicity
data
gaps
that
are
critical
to
the
assessment
of
potential
hazard
to
infants
and
children.

The
FQPA
Committee
recommended
that
the
FQPA
safety
factor
be
removed
because:
1)
the
toxicology
data
base
is
complete;
2)
there
is
no
indication
of
increased
susceptibility
of
rats
or
rabbit
fetuses
to
in
utero
and/
or
postnatal
exposure
in
the
developmental
and
reproductive
toxicity
studies;
3)
a
developmental
neurotoxicity
study
is
not
required;
4)
dietary
(
food)
exposure
estimates
are
expected
to
be
unrefined
(
assuming
tolerance
level
residues
and
100%
CT)
and
will
likely
result
in
an
overestimate
of
the
actual
dietary
exposure;
5)
EFED
models
are
used
for
ground
and
surface
source
drinking
water
exposure
assessments
resulting
in
estimates
that
are
upper­
bound
concentrations;
and
6)
there
are
currently
no
registered
residential
uses
of
HOE
107892,
therefore,
this
type
of
exposure
to
infants
and
children
is
not
expected.

Application
of
the
FQPA
Safety
Factors
(
Population
Subgroups
/
Risk
Assessment
Scenarios)
This
recommendation
is
applicable
to
all
population
subgroups
for
all
exposure
routes
and
durations.

3.3
Dose
Response
Assessment
Discussion
of
Toxicological
Database
for
Risk
Assessment
Purposes:
Page
15
of
26
The
toxicology
database
for
HOE
107892
is
complete
for
the
purpose
of
this
risk
assessment
and
it
defines
the
toxicity
of
the
chemical
to
a
certain
extent.
In
some
cases
the
test
chemical
was
not
tested
at
sufficiently
high
dose
levels
for
an
adequate
study.
However,
based
on
the
overall
data,
it
is
unlikely
that
repeating
any
studies
with
higher
dose
levels
would
significantly
change
the
target
organs
or
the
effects
observed.
Most
likely,
the
effects
already
noted
would
be
more
severe.
There
is
a
fairly
high
degree
of
confidence
in
the
scientific
quality
of
the
toxicology
database.
There
are
no
problems
with
the
reproduction
study,
the
study
on
which
the
chronic
dietary
endpoint
is
based.
There
are
no
other
studies
upon
which
toxicological
endpoints
are
based.

With
the
exception
of
the
chronic
feeding/
carcinogenicity
study
in
the
rat
and
the
unscheduled
DNA
synthesis
study,
all
of
the
studies
are
considered
to
be
acceptable
guideline
studies
(
the
rabbit
developmental
toxicity
study
is
only
marginally
acceptable
because
only
8
litters
were
ultimately
available
for
examination
in
the
high
dose
group).
Although
the
dose
levels
in
the
chronic
feeding/
carcinogenicity
study
in
the
rat
are
not
adequate
for
a
negative
carcinogenicity
study,
the
HIARC
Committee
determined
that
a
new
rat
study
would
not
provide
any
additional
information
on
the
effects
of
concern
for
this
particular
use.
The
main
target
organs
for
this
chemical
have
been
adequately
defined
by
other
studies
in
the
rat
and
in
other
species.
Therefore,
a
new
study
will
not
be
requested
unless
new
uses
result
in
significantly
higher
residues
in
human
foods
and/
or
there
is
significantly
higher
occupational
(
or
future
residential)
exposure
due
to
changes
in
parameters
such
as
the
method
of
application.
The
unscheduled
DNA
synthesis
study
is
also
classified
as
unacceptable;
however,
there
are
sufficient
acceptable
mutagenicity
studies
available
to
satisfy
the
testing
requirements
for
mutagenicity.

In
the
developmental
rat
studies,
although
a
maternal
NOAEL
cannot
be
defined,
the
observed
effects
are
not
of
sufficient
severity
to
rate
the
study
unacceptable
(
decreases
in
body
weight
gain
and
food
consumption
in
the
first
week
only
at
the
limit
dose,
1000
mg/
kg/
day).
Also,
in
the
standard
rat
developmental
study,
no
developmental
toxicity
is
observed
at
the
limit
dose.
Therefore,
sensitivity
to
infants
and
children
as
defined
by
FQPA
can
be
addressed.
In
the
postnatal
developmental
toxicity
study,
marginal
decreases
in
fetal
body
weight
and
body
weight
gain
during
lactation
are
observed
at
1000
mg/
kg/
day.
Since
this
effect
is
only
marginal
and
since
the
maternal
effects
are
similar
and
are
also
marginal,
sensitivity
to
infants
and
children
can
still
be
addressed,
particularly
because
some
parameters
for
postnatal
behavioral/
developmental
effects
were
examined
in
this
study
(
sex,
external
abnormalities,
viability,
general
behavior,
times
of
pinna
separation,
coat
growth
start,
incisor
eruption
and
eyelid
opening,
hearing,
vision,
righting
reflex,
trainability,
memory
and
retrainability).

Only
one
endpoint
was
selected
for
risk
assessment
­
the
chronic
dietary
endpoint.
The
adverse
effects
associated
with
this
endpoint
are
decreases
in
mean
body
weight
and
body
weight
gain,
increases
in
mean
spleen
weight
and
an
increase
in
the
severity
(
but
not
the
incidence)
of
splenic
extramedullary
hematopoiesis.
This
endpoint
is
considered
to
be
conservative
because
the
level
of
concern
is
not
high
for
these
effects.
The
hematological
effects
observed
in
the
selected
study
are
very
mild
and
consist
of
only
an
increase
in
severity,
not
incidence.
The
decreases
in
body
weight
and
body
weight
gain
are
borderline
toxicologically
significant.
Decreases
in
mean
body
weight
and
body
weight
gain
are
indicators
of
the
overall
well
being
of
the
animal.
If
the
decreases
are
significant,
usually
other
effects
are
observed
as
well.
In
this
Page
16
of
26
case,
the
decreases
in
body
weight
gain
are
observed
predominantly
in
parental
males
from
the
reproduction
study.
Body
weights
were
generally
8­
11%
lower
than
controls
and
body
weight
gains
were
generally
12­
13%
lower
than
controls.
These
decreases
are
not
huge
and
are
only
slight
in
females.

For
the
chronic
dietary
endpoint,
the
chronic
dog
study,
the
chronic
rat
study
and
the
rat
reproduction
study
have
the
most
sensitive
endpoints.
The
chronic
rat
study
has
a
slightly
lower
endpoint;
however,
the
NOAEL
is
based
on
increases
in
reticulocyte
counts
with
no
supporting
histopathology
or
statistically
significant
changes
in
other
hematological
effects.
The
chronic
dog
study
also
has
a
slightly
lower
endpoint;
however,
the
NOAEL
is
based
on
minimal
intrahepatic
cholestasis
in
the
liver
and
increased
alkaline
phosphatase
values
and
liver
weights.
The
HIARC
decided
that
the
endpoints
from
the
2­
generation
reproduction
study
(
decreased
mean
body
weight
and
mean
body
weight
gain
in
parents
and
offspring,
increased
mean
spleen
weights
and
an
increase
in
the
severity
(
but
not
in
the
incidence)
of
splenic
extramedullary
hematopoiesis)
were
considered
to
be
the
most
significant
and
thus
appropriate
for
risk
assessment.

An
acute
dietary
endpoint
was
not
selected
because
no
appropriate
endpoint
could
be
identified
in
any
of
the
oral
toxicity
studies
including
the
developmental
studies
in
rats
and
rabbits.

Endpoints
for
dermal
risk
assessment
were
not
selected
because
a
28
day
dermal
study
in
rats
showed
no
dermal
or
systemic
toxicity
at
dose
levels
up
to
1000
mg/
kg/
day.
In
addition,
no
developmental
effects
were
observed
in
the
developmental
rat
study
at
1000
mg/
kg/
day,
the
limit
dose.

No
endpoints
for
inhalation
risk
assessment
were
selected
because
HOE
107892
has
low
acute
inhalation
toxicity
(
Category
III)
and
because
the
use
pattern
(
1
application/
growing
season
with
either
aerial
application
or
spray
boom
equipment
that
is
as
low
to
the
ground
as
possible)
indicates
that
there
is
minimal
concern
for
potential
inhalation
exposure.

The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

Table
3.
Summary
of
Toxicological
Endpoints
for
Use
in
Human
Risk
Assessment
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
No
appropriate
endpoint
for
risk
assessment
was
identified
in
oral
toxicity
studies
including
the
developmental
studies
in
rats
and
rabbits.

Chronic
Dietary
NOAEL
=
57.3
Decrease
in
mean
body
weight
and
body
weight
gain
in
parents
and
offspring
and
an
increase
in
mean
spleen
weight
and
in
severity
of
splenic
extramedullary
hematopoiesis
in
females.
2­
generation
reproduction
study
Table
3.
Summary
of
Toxicological
Endpoints
for
Use
in
Human
Risk
Assessment
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Page
17
of
26
UF
=
100
Chronic
RfD
=
0.57
mg/
kgday
Chronic
PADa
=
0.57
mg/
kg/
day
Short­
Term
(
Dermal)
No
dermal
or
systemic
toxicity
observed
in
28­
day
dermal
study
up
to
1000
mg/
kg/
day
and
no
developmental
effects
observed
in
developmental
rat
study
at
1000
mg/
kg/
day.
Therefore,
no
endpoint
was
identified
for
risk
assessment.

Intermediate­
Term
(
Dermal)
See
short­
term
dermal.

Long­
Term
(
Dermal)
Based
on
the
current
use
pattern
(
i.
e.
1
application/
season),
long­
term
exposure
via
dermal
route
is
not
expected.
Therefore,
an
endpoint
was
not
identified.

Inhalation
(
Any
Time
Period)
Based
on
the
low
acute
toxicity
(
Category
III)
and
the
use
pattern
(
1
application/
growing
season
with
either
aerial
application
or
spray
boom
equipment
that
is
as
low
to
the
ground
as
possible),
there
is
minimal
concern
for
potential
inhalation
exposure.
Therefore,
no
endpoint
was
identified.

Carcinogenicity
(
Any
route
of
exposure)
HOE
107892
is
classified
as
not
likely
to
be
a
human
carcinogen.

a
Chronic
PAD
=
Chronic
Population
Adjusted
Dose
=
Chronic
RfD
÷
FQPA
Factor
(
1
in
this
case)

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

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
HOE
107892
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

4.0
EXPOSURE
ASSESSMENT
Page
18
of
26
4.1
Summary
of
Registered
Uses
HOE
107892
is
a
member
of
a
new
chemical
class.
Section
18
Emergency
Exemptions
were
approved
for
uses
on
durum
wheat
and
barley
in
1996
and
1998,
respectively,
and
as
a
result,
HOE
107892
has
temporary
tolerances
for
wheat
and
barley
raw
agricultural
commodities
(
40
CFR
180.509,
due
to
expire
12/
31/
03).
For
the
purposes
of
those
Section
18s
only,
it
was
assumed
that
there
would
be
no
quantifiable
residues
of
HOE­
107892
in
wheat
grain
or
straw
and
that
there
would
be
no
quantifiable
residues
in
meat,
milk,
poultry,
or
eggs
resulting
from
the
use.
HOE
107892
has
no
other
registered
uses;
PP#
7F04850
will
be
the
first
permanent
food
use.

4.2
Dietary
Exposure/
Risk
Pathway
Residue
chemistry
data
for
the
proposed
use
of
HOE
107892
on
wheat
and
barley
have
been
reviewed
by
HED.
Below
are
summaries
from
that
review
(
Memo
of
11/
22/
02,
Y.
Donovan,
D238730).

4.2.1
Residue
Profile
(
Attachment
3,
HED
memo
of
11/
22/
02,
Y.
Donovan,
D238730).

Nature
of
the
Residue
Based
on
summary
data
from
the
barley
metabolism
study,
the
Metabolism
Assessment
Review
Committee
has
recommended
that
regulation
of
HOE
be
based
on
the
parent
compound
and
those
free
metabolites
(
HOE
113225,
HOE
109453,
and
HOE
094270)
which
are
also
detected
by
the
proposed
polar
extraction
GC/
MS
method.
The
Committee
did
not
at
that
time
identify
any
additional
potential
degradation
compounds
of
toxicological
significance
which
might
be
included
in
the
tolerance
expression
and/
or
risk
assessment
(
7/
16/
96
memo
of
D.
Davis).
The
above
metabolites
are
formed
by
hydrolysis
of
one
or
both
ethyl
ester
groups
followed
by
decarboxylation
in
the
case
of
HOE
094270.

Additional
data
from
a
wheat
metabolism
study
conducted
primarily
to
generate
weathered
material
for
radiovalidation
of
the
proposed
enforcement
method,
show
the
same
metabolic
pathways
as
that
of
the
barley
metabolism
study.
HOE
094270
was
the
major
metabolite
in
wheat
grain
and
straw,
accounting
for
19.67%
of
total
radioactive
residues
(
TRR;
0.0079
ppm)
in
grain
and
7.1­
9.2%
TRR
(
0.60­
0.75
ppm)
in
straw;
metabolites
HOE
113225
and
HOE
109453
were
also
detected
at
low
levels.
The
parent,
HOE
107892
was
detected
in
wheat
straw
only
at
1.1%
TRR.
In
wheat
straw,
23%
of
the
TRR
was
shown
to
be
composed
of
minor
unknown
components
(
each
<
3­
4%
TRR),
which
released
HOE
109453
and
HOE
094270
on
hydrolysis.

The
qualitative
nature
of
the
residue
in
animals
is
adequately
understood
based
on
acceptable
studies
conducted
on
goats
and
laying
hens.
The
metabolic
pathways
are
the
same
as
those
in
plants.
These
data
have
been
presented
to
HED's
Metabolism
Assessment
Review
Committee
(
MARC),
and
the
MARC
concluded
that
the
regulable
residues
in
animal
commodities
should
be
the
parent
compound
and
the
free
metabolites
HOE
113225,
HOE
109453,
and
HOE
094270.
The
Committee
also
concluded
that
the
parent
compound
and
three
metabolites
(
HOE
113225,
HOE
109453,
and
HOE
094270)
are
also
residues
of
concern
in
water
and
soil
(
Memo
of
Y.
Donovan,
3/
27/
00,
D263039).
Page
19
of
26
Based
on
the
poultry
metabolism
study,
RAB2
tentatively
concludes
that
there
is
no
reasonable
expectation
of
finite
residues
[
§
180.6(
a)(
3)]
in
eggs
and
poultry
tissues;
however,
should
the
dietary
burden
for
poultry
increase
due
to
the
addition
of
HOE
107892­
treated
poultry
feed
commodities
through
new
uses,
a
poultry
feeding
study
may
be
needed.

Residue
Analytical
Methods
The
petitioner
proposes
a
new
GC/
MSD
method
for
the
enforcement
of
tolerances
for
barley
and
wheat
commodities.
Radiovalidation
and
independent
method
validation
(
ILV)
data
have
been
submitted
for
this
method.
This
method
has
been
forwarded
to
the
Agency
analytical
lab
for
petition
method
validation,
and
the
Agency
analytical
lab
concluded
that
this
method
is
suitable
for
food
tolerance
enforcement
of
HOE107892
and
the
three
metabolites
HOE
094270,
HOE
113225
and/
or
HOE
109453.

The
abilities
of
the
plant
methods
to
extract
aged
residues
were
demonstrated
by
the
plant
metabolism
studies
wherein
50­
72%
of
the
total
radioactive
residues
were
extracted
by
acetonewater
mixtures
similar
to
those
used
in
these
methods.

An
adequate
enforcement
method
capable
of
determining
residues
in/
on
animal
commodities
is
required
since
the
Agency
is
recommending
tolerances
be
established
on
meat
byproducts
(
liver
and
kidney).
The
petitioner
has
proposed
a
study
protocol
for
development
of
an
animal
method.
RAB2
concluded
that
this
requirement
can
be
made
a
condition
of
registration.

Multiresidue
Method
(
MRM)
No
data
have
been
submitted
concerning
recovery
of
residues
of
HOE
107892
using
FDA
multiresidue
method
protocols
(
PAM
Vol.
I).
All
petitioners
are
expected
to
provide
recovery
data
for
parent
compounds
and
all
metabolites
of
concern
through
these
methods.
Because
tolerances
are
being
proposed
for
HOE
107892
and
metabolites,
this
requirement
applies
to
the
safener
and
its
metabolites
as
well.
The
petitioner
should
refer
to
the
directions
for
the
protocols
found
in
PAM
I,
Appendix
II
for
further
information.
RAB2
does
not
object
to
this
requirement
being
made
a
condition
of
registration.

Crop
Field
Trials
The
petitioner
has
provided
adequate
residue
data
reflecting
higher
than
maximum
proposed
use
pattern
for
HOE
107892
specified
for
barley
and
wheat.
Field
studies
on
wheat
and
barley
were
conducted
such
that
the
application
of
the
safener
was
at
100g/
ha,
which
equals
to
0.089
lb
safener/
A.
Following
a
single
broadcast
foliar
application
of
HOE
107892
at
100g/
ha
(
0.089
lb
safener/
A),
grain
and
straw
samples
were
collected
at
55­
days
PHI,
hay
and
forage
were
harvested
just
prior
to
jointing.
Maximum
residues
of
HOE
107892
and
its
metabolite
HOE
094270
on
barley
and
wheat
grain
were
less
than
0.05
ppm.
On
barley
and
wheat
hay
total
residues
of
HOE
107892
and
the
three
metabolites
were
less
than
0.5
ppm,
and
on
barley
and
wheat
straw
were
less
than
1.0
ppm.
Although
the
other
metabolites
were
not
measured
in
grain,
the
barley
metabolism
study
showed
HOE
094270
to
be
the
only
identified
residue
in
grain
(
61%
TRR).
Therefore,
the
proposed
tolerance
of
0.05
ppm
on
wheat
and
barley
grain
is
adequate.
Residue
decline
data
were
inconclusive
for
both
barley
and
wheat
commodities
because
of
the
low
Page
20
of
26
levels
of
residues
detected.
Taking
into
account
the
exaggerated
application
rate,
RAB2
recommends
that
the
wheat
and
barley
forage
and
hay
tolerances
be
decreased
to
0.2
ppm,
and
wheat
and
barley
straw
tolerances
be
decreased
to
0.5
ppm.
A
revised
Section
F
is
needed.

Meat,
Milk,
Poultry,
Eggs
(
MMPE)
According
to
the
goat
metabolism
study
conducted
at
11.23
ppm
(

25x
and

20x
the
maximum
theoretical
dietary
burden
for
beef
and
dairy
cattle,
respectively),
the
TRR
were

0.001
ppm
in
milk,
0.061
ppm
in
liver,
0.170
ppm
in
kidney,
0.003­
0.004
ppm
in
muscle
(
hindquarter,
flank,
and
loin),
and
0.010­
0.016
ppm
in
fat
(
subcutaneous,
perirenal,
and
omental).
Residues
in
milk
plateaued
at
0.001
ppm
by
Day
3
of
dosing.
These
residues
(
especially
those
in
kidneys)
are
at
such
significant
levels
that,
normally
a
ruminant
feeding
study
would
be
required
to
determine
the
levels
at
which
tolerances
for
milk
and
ruminant
tissues.
However
in
this
case
where
the
chemical
poses
very
low
dietary
risk
(
HED
DEEM
memo
of
11/
22/
02,
Y.
Donovan,
D286489),
RAB
2
is
willing
to
waive
the
feeding
study
based
on
the
fact
that
the
petitioner
is
going
to
develop
an
animal
analytical
method
for
enforcement
purpose,
and
RAB2
will
recommend
a
conservative
tolerance
of
0.1
ppm
be
set
on
meat
byproduct
based
on
the
goat
metabolism
study.
For
risk
assessment,
RAB2
recommends
using
the
following
levels:
meat
at
0.002
ppm,
meat
byproduct
at
0.1
ppm,
fat
at
0.01
ppm,
and
milk
at
0.002
ppm.
The
tissue
residues
apply
to
cattle,
goats,
hogs,
horses
and
sheep.

Rotational
Crops
Rotational
crop
data
were
submitted
with
this
petition.
[
Phenyl­
14C]
HOE
107892
was
applied
to
soil
at
a
rate
significantly
higher
than
the
proposed
use
rate.
Spinach,
carrot,
and
wheat
were
planted
back
at
29
days
and
1
year.
Based
on
the
results
of
the
residue
uptakes,
RAB2
recommends
a
30­
day
plantback
for
leafy,
fruiting,
and
root
vegetables,
and
12­
month
plantback
for
all
other
crops
other
than
wheat
and
barley,
which
can
be
replanted
at
any
time.
If
the
petitioner
desires
to
have
30­
day
plantback
for
all
other
crops,
limited
field
trials
are
needed,
or
the
petitioner
can
choose
to
analyze
the
TRR
in
the
29­
day
wheat
grain
and
straw
samples
in
the
rotational
crop
studies
to
determine
if
there
are
any
residues
of
concern
in
the
rotational
crops.

International
Harmonization
of
Tolerances
No
Codex,
Canada,
or
Mexican
tolerances
are
established
for
residues
of
HOE
107892
and
metabolites.
Therefore,
international
harmonization
is
not
an
issue
for
this
petition.

4.2.2
Acute
And
Chronic
Dietary
(
Attachment
4
HED
memo
of
11/
22/
02,
Y.
Donovan,
D286489)

Acute
dietary
exposure
analysis
is
not
needed
because
no
endpoint
was
selected.

Chronic
Dietary
Exposure
and
Risk.
cPAD
=
chronic
RfD
=
0.57
mg/
kg
bwt/
day.

HOE­
107892
chronic
dietary
exposure
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
1.3),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intakes
by
Page
21
of
26
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
96,
98
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
"
as
consumed"
(
e.
g.,
apple
pie)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
Consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups
for
chronic
exposure
assessment,
but
are
retained
as
individual
consumption
events
for
acute
exposure
assessment.

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

The
analysis
assumed
tolerance­
level
residues
and
was
also
assumed
that
100%
of
the
crop
would
be
treated.
No
processing
studies
was
required
due
to
the
fact
that
field
trials
conducted
at
exaggerated
rate
(>
5X)
showed
no
detectable
residues
in
wheat
and
barley
grains,
and
therefore
no
tolerance
is
needed
for
processed
commodities.
A
default
processing
factor
of
1.92
was
used
for
dried
beef
in
this
dietary
exposure
analysis.
No
other
commodities
in
this
analysis
used
DEEM
default
processing
factors.

The
DEEM­
FCID
 
analyses
estimate
the
dietary
exposure
of
the
U.
S.
population
and
various
population
subgroups.
The
results
reported
in
Table
2
are
for
the
general
U.
S.
Population,
all
infants
(<
1
year
old),
children
1­
2,
children
3­
5,
children
6­
12,
youth
13­
19,
Adults
20­
49
years,
females
13­
49,
and
adults
50+
years.

Risk
estimates
for
dietary
(
food
only)
exposure
to
HOE­
107892
are
less
than
1%
of
the
cPAD
for
all
population
subgroups.
Exposure
estimates
for
the
major
population
subgroups
are
shown
in
Table
4.
The
complete
list
of
results
from
the
chronic
exposure
analysis
are
included
as
Attachment
2.

Table
4.
Results
of
the
Tier
1
chronic
dietary
(
food
only)
exposure
analysis
for
HOE­
107892
proposed
uses
on
barley
and
wheat.

Population
Subgroup
Estimated
Dietary
Exposure,
mg/
kg
bwt/
day
%
cPAD*

U.
S.
Population
0.000113
<
1%

All
Infants
(<
1
year)
0.000068
<
1%

Children,
1­
2
years
0.000295
<
1%

Children,
3­
5
years
0.000273
<
1%

Children,
6­
12
years
0.000186
<
1%

Youth
13­
19
years
0.000107
<
1%
Table
4.
Results
of
the
Tier
1
chronic
dietary
(
food
only)
exposure
analysis
for
HOE­
107892
proposed
uses
on
barley
and
wheat.

Page
22
of
26
Adults
20­
49
years
0.000091
<
1%

Females,
13­
49
years
0.000082
<
1%

Adults
50+
years
0.000074
<
1%

*
Actual
values
range
from
0.0
to
0.1%.

This
analysis
represents
a
conservative
estimate
of
dietary
(
food
only)
exposure
and
risk
from
the
proposed
use
of
HOE­
107892
on
barley
and
wheat.
Further
refinement,
through
the
use
of
anticipated
residues,
percent­
of­
crop
treated
estimates
and/
or
monitoring
data,
would
result
in
a
reduction
in
the
exposure
estimates
and
the
associated
risk.
In
this
analysis,
even
without
further
refinement,
the
risk
estimate
is
below
the
Agency's
level
of
concern
(
100%
of
the
PAD)
for
the
general
U.
S.
population
and
all
population
subgroups.

4.3
Water
Exposure/
Risk
Pathway
(
Attachment
5,
EFED
memos
of
03/
18/
97,
Alex
Clem,
D226076,
and
of
11/
26/
01,
Alex
Clem,
D262735)

Laboratory
studies
indicate
the
principal
mode
of
dissipation
of
HOE­
107892
to
be
aerobic
metabolism
in
soil
(
microbially
mediated
hydrolysis),
with
secondary
contribution
by
soil
sensitized
photolysis.
Concentrations
of
HOE­
107892
would
decrease
relatively
rapidly
in
soil
with
a
DT50
of
approximately
a
few
days
to
one
week.
However,
in
the
process,
by­
products
which
are
structurally
very
similar
to
parent
and
longer­
lived
are
formed
(
HOE­
094270,
HOE­
113225,
and
HOE­
109453).

Surface
Water:
Results
from
the
EFED
FIRST
(
Tier
1)
index
reservoir
simulation
model
for
a
single
application
of
HOE­
107892
at
an
exaggerated
rate
of
0.090
kg/
ha
(
0.080
lb/
acre)
are
calculated.
As
discussed
in
the
attached
1997
assessment,
the
tabulated
concentrations
are
the
summations
(
in
parent
equivalent
concentrations)
of
relatively
short­
lived
parent
and
several
longer­
lived
transformation
products
that
are
structurally
similar
to
parent.
Although
parent
has
soil
half­
lives
of
approximately
a
few
days
to
a
week,
the
similar
by­
products
are
much
longer
lived.
For
example,
the
metabolite
HOE­
094270
reached
a
maximum
concentration
that
was
equivalent
to
about
72%
of
parent
after
around
30­
60
days
of
aerobic
soil
incubation,
and
had
an
estimated
DT50
of
100­
200
days.
The
peak
and
chronic
concentrations
of
combined
parent
and
metabolites
computed
from
FIRST
in
parent
equivalents
are
about
5
ppb
and
3
ppb,
respectively
Groundwater
Results
from
SCI­
GROW2:
The
database
of
pesticide
chemicals
used
to
develop
and
update
the
SCI­
GROW2
regression
model
shows
that
the
highest
pesticide
concentration
measured
on
a
one
pound
per
acre
application
basis
for
a
certain
mobile
and
persistent
pesticide
of
similar
molecular
weight
is
roughly
55
µ
g/
L
(
ppb).
The
current
minimum
value
for
Koc
in
the
database
used
to
develop
SCI­
GROW2
is
11
mL/
g,
while
maximum
values
for
aerobic
soil
metabolism
half­
life
are
roughly
1000
days.
Since
HOE­
107892
has
Koc
and
aerobic
soil
metabolism
half­
lives
well
within
the
bounds
covered
by
the
model,
as
do
its
structurally
similar
transformation
products
(
from
collateral
laboratory
evidence
and
reasonable
Page
23
of
26
inference),
groundwater
concentrations
of
HOE­
107892
applied
at
exaggerated
rate
of
0.080
lb/
acre/
year
and
any
associated
transformation
products
(
in
equivalent
molar
concentrations)
are
not
likely
to
exceed
individually
or
in
combination
55
µ
g/
L/(
lb/
acre)
x
0.080
lb/
acre
or
approximately
4
µ
g/
L
(
ppb).

4.4
Residential
Exposure/
Risk
Pathway
(
Attachment
6,
HED
memo
of
4/
12/
00,
M.
Collantes,
D263518)

At
present,
there
are
no
registered
or
proposed
residential
uses
of
HOE­
107892.
Therefore
a
residential
exposure
risk
assessment
is
not
required
at
this
time.

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

To
calculate
chronic
DWLOCs,
the
dietary
food
estimates
(
from
DEEM
 
)
were
subtracted
from
the
chronic
PAD
value
to
obtain
the
maximum
water
exposure
level.
DWLOCs
were
then
calculated
using
the
standard
body
weights
and
drinking
water
consumption
figures:
70kg/
2L
(
adult
male
and
US
Population),
60
kg/
2L
(
adult
female),
and
10kg/
1L
(
infant
&
children).

5.1
Acute
Risk
(
Food
+
Water)
Not
required.

5.2
Short­
and
Intermediate­
term
Risk
(
Food
+
Residential
+
Water)

Not
required.

5.3
Chronic
Risk
Assessment
(
Food
+
Residential
+
Water)

Table
5
summarizes
the
chronic
aggregate
exposure
to
HOE
107892
residues.
The
EECs
generated
by
EFED
are
less
than
HED's
DWLOCs.
There
are
no
residential
uses.
Thus,
chronic
aggregate
risk
estimates
are
below
HED's
level
of
concern.

Table
5.
Chronic
Aggregate
Exposures
to
HOE
107892
Residues.
Page
24
of
26
Scenario/
Population
Subgroup
cPAD,
(
mg/
kg/
day
)
Chronic
Food
Exposure,
(
mg/
kg/
day)
Maximum
Chronic
Water
Exposure1,
(
mg/
kg/
day)
Ground
Water
EEC2,
(
ppb)
Surface
Water
EEC2,
(
ppb)
Chronic
DWLOC
3,
(
ppb)

U.
S.
Population
0.57
0.000113
0.57
4
3
20000
All
infants
(<
1
year
old)
0.57
0.000068
0.57
4
3
5700
Children,
1­
2
years
0.57
0.000295
0.57
4
3
5700
Females
(
13­
49
years
old)
0.57
0.000082
0.57
4
3
17000
1
Maximum
chronic
water
exposure
(
mg/
kg/
day)
=
cPAD
(
mg/
kg/
day)
­
chronic
food
exposure
from
DEEM
(
mg/
kg/
day).
2
EECs
from
EFED
studies.
3
Chronic
DWLOCs
were
calculated
as
follows:

DWLOC
(
µ
g/
L)

maximum
water
exposure
(
mg/
kg/
day)
x
body
weight
(
kg)
consumption
(
L/
day)
x
0.001
mg/
µ
g
5.4
Cancer
Risk
HOE
107892
has
been
classified
by
HED
HIARC
as
a
"
not
likely
human
carcinogen."
A
cancer
risk
assessment
is
not
required.

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

HED
did
not
perform
a
cumulative
risk
assessment
as
part
of
this
tolerance
action
for
HOE
107892
because
HED
has
not
yet
initiated
a
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
HOE
107892.
For
purposes
of
this
tolerance
action,
EPA
has
assumed
that
HOE
107892
does
not
have
a
common
mechanism
of
toxicity
with
other
substances.

On
this
basis,
the
Registrant
must
submit,
upon
EPA's
request
and
according
to
a
schedule
determined
by
the
Agency,
such
information
as
the
Agency
directs
to
be
submitted
in
order
to
evaluate
issues
related
to
whether
HOE
107892
shares
a
common
mechanism
of
toxicity
with
any
Page
25
of
26
other
substance
and,
if
so,
whether
any
tolerances
for
HOE
107892.
need
to
be
modified
or
revoked.
If
HED
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
HOE
107892.
HED
will
perform
aggregate
exposure
assessments
on
each
chemical,
and
will
begin
to
conduct
a
cumulative
risk
assessment.

HED
has
recently
developed
a
framework
that
it
proposes
to
use
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
was
issued
for
public
comment
on
January
16,
2002
(
67
FR
2210­
2214)
and
is
available
from
the
OPP
Website
at:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cumulative_
guidance.
pdf.
In
the
guidance,
it
is
stated
that
a
cumulative
risk
assessment
of
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
will
not
be
conducted
until
an
aggregate
exposure
assessment
of
each
substance
has
been
completed.

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

7.0
Occupational
Exposure
(
HED
memo
of
04/
12/
00,
M.
Collantes,
D263518)

7.1
Occupational
Handler
HOE­
107892
(
mefenpyr­
diethyl)
is
a
safener
to
be
used
in
a
postemergent
herbicide.

Workers
may
be
exposed
to
HOE
107892
during
mixing,
loading,
application
and
postapplication
activities.
Based
on
the
proposed
application
rates
and
use
scenarios,
short­
and
intermediateterm
exposures
may
occur.
Chronic
exposure
(
6
or
more
months
of
continuous
exposure)
is
not
expected.

On
November
24,
1998,
the
HIARC
met
and
concluded
that
no
dermal
or
systemic
toxicity
was
observed
following
21
repeated
dermal
applications
of
HOE
107892
on
Wistar
rats
over
29
days.
Therefore,
the
potential
for
risk
from
dermal
exposure
is
negligible
and
no
short­
or
intermediateterm
dermal
endpoints
were
selected.
Furthermore,
HIARC
concluded
that
based
on
the
current
use
pattern
(
i.
e.,
1
application/
season),
long­
term
exposure
via
the
dermal
route
is
not
expected
and
no
endpoint
was
selected
for
long­
term
dermal
exposure.

HIARC
also
concluded
that
based
on
the
low
acute
inhalation
toxicity
(
Toxicity
Category
III)
and
the
use
pattern
(
1
application/
growing
season
with
either
aerial
application
or
spray
boom
equipment
that
is
as
low
to
the
ground
as
possible),
there
is
minimal
concern
for
potential
inhalation
exposure
and
risk.
Therefore,
the
Committee
did
not
select
an
inhalation
endpoint.
Since
the
HIARC
did
not
select
dermal
or
inhalation
toxicological
endpoints,
dermal
and
inhalation
risk
assessments
were
not
required.

7.2
Post­
Application
Page
26
of
26
In
accordance
with
the
Worker
Protection
Standards
(
WPS),
the
REI
is
based
on
the
acute
toxicity
of
the
"
technical
active
ingredient
material".

However,
the
acute
toxicity
effects
for
HOE
107892
are
all
in
categories
III
and
IV
and
therefore
would
require
a
12­
hour
REI
if
considered
as
an
active
ingredient.

8.0
DATA
NEEDS
There
are
no
data
gaps
pertaining
to
toxicity
studies.

RAB2
has
previously
concluded
that
data
gaps
pertaining
to
residue
chemistry
are
as
follow:

Multiresidue
method
testing
for
parent
and
metabolites

Animal
analytical
method
(
condition
of
registration)

A
revised
Section
F
to
change
the
proposed
tolerances
to
match
the
above
recommended
tolerances.

Attachments:
1.
HIARC
report
on
HOE
107892
(
11/
24/
98);
2.
FQPA
report
on
HOE
107892
(
12/
17/
98);
3.
HED
Residue
Chemistry
memo
of
11/
22/
02,
Y.
Donovan,
D238730
;
4
HED
DEEM
memo
of
11/
22/
02,
Y.
Donovan,
D286489;
5.
EFED
memos
03/
18/
97,
Alex
Clem,
D226076,
and
11/
26/
01,
Alex
Clem,
D262735;
6.
HED
ORE
memo
of
04/
12/
00,
M.
Collantes,
D263518.

cc
with
Attachments:
Y.
W.
Donovan.
cc
without
Attachments:
Pamela
Hurley,
Margarita
Collantes,
RAB2
reading
file,
PP#
7F04850.