EPA
Registration
Division
contact:
Sidney
Jackson,
(
703)
305­
7610
Interregional
Research
Project
#
4
(
IR­
4)

PP#
3E6755,
5E6969,
5E6970
EPA
has
received
pesticide
petitions
(
PP#
5E6755,
5E6969,
and
5E6970)
from
Interregional
Research
Project
#
4
(
IR­
4),
681
U.
S.
Highway
#
1
South,
North
Brunswick,
NJ
08902­
3390,
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180.588
by
establishing
tolerances
for
residues
of
[
quinoxyfen
(
5,7­
dichloro­
4­(
4­
fluorophenoxy)
quinoline
in
or
on
the
raw
agricultural
commodities
lettuce
(
head
and
leaf)
at
17
parts
per
million
(
ppm)
(
PP#
5E6970);
melon
subgroup
9A
at
0.1
ppm
(
PP#
5E6969);
peppers
(
bell
and
non­
bell)
at
1.0
ppm
(
PP#
3E6755);
eggplant
at
1.0
ppm
(
PP#
3E6755)
and
strawberry
at
0.8
ppm
(
PP#
5E6970).
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
The
metabolism
of
quinoxyfen
has
been
studied
in
a
variety
of
crops
under
both
outdoor
(
wheat,
tomatoes
and
sugar
beets)
and
glasshouse
(
grapes
and
cucumbers)
conditions.
The
nature
of
residues
(
NOR)
is
adequately
understood
for
the
purposes
of
these
tolerances.
Based
on
the
findings
from
these
studies,
quinoxyfen
is
the
primary
residue
in
all
crops
and
therefore,
the
only
residue
of
concern.
Metabolites
were
present
at
low
levels
(<
10%
of
total
radioactive
residue).
A
confined
rotational
crop
study
was
conducted
with
quinoxyfen
which
confirmed
minimal
carryover
of
residues
(>
0.003
:
g/
g)
to
succeeding
crops.]

2.
Analytical
method.
A
practical
analytical
method
is
available
to
monitor
and
enforce
the
tolerances
of
quinoxyfen
residues
in
crops.
The
analytical
method
uses
capillary
gas
chromatography
and
mass
selective
detection
(
GC­
MSD)
with
limits
of
quantitation
(
LOQ)
of
approximately
0.01
ppm.
An
independent
laboratory
has
validated
the
method.]

3.
Magnitude
of
residues.
The
residue
data
in
support
of
the
proposed
tolerances
was
generated
from
the
magnitude
of
residue
studies
on
lettuce
(
head
and
leaf),
melon,
peppers
(
bell
and
non­
bell)/
eggplant
and
strawberry.

i.
Lettuce.
Magnitude
of
residue
studies
were
conducted
on
head
lettuce
at
8
sites
and
leaf
lettuce
at
8
sites.
Each
treated
plot
received
4­
5
foliar
applications
at
6­
8
day
intervals
at
a
rate
of
about
0.13
lb
ai/
A
per
application
with
a
total
rate
of
0.52
to
0.65
lb
ai/
A
for
the
season.
Residues
of
quinoxyfen
in
lettuce
collected
one
day
after
the
last
application
were0.22
to
14
ppm.
The
proposed
tolerance
for
quinoxyfen
in
or
on
lettuce
(
head
and
leaf)
is
17
ppm
and
is
adequate
to
cover
the
highest
expected
field
residues
from
the
labeled
use
of
quinoxyfen
in
lettuce.
2
ii.
Melon.
Sub­
group
9A,
melons.
A
magnitude
of
residue
study
was
conducted
on
cantaloupes
at
11
sites.
Each
treated
plot
received
4
foliar
applications
at
6­
12
day
intervals
at
a
rates
ranging
from
0.124
to
0.151
lb
ai/
A
per
application.
The
total
rate
range
was
0.52­
0.65
lb
ai/
A
for
the
season.
Cantaloupes
were
harvested
2­
4
days
after
the
last
application.
Residues
of
quinoxyfen
ranged
from
0.22
ppm
to
14
ppm.
The
proposed
tolerance
for
quinoxyfen
in
or
on
subgroup
9A,
melons
is
0.1
ppm.
This
tolerance
is
adequate
to
cover
the
highest
expected
field
residues
from
the
labeled
use
of
quinoxyfen
in
melons,
subgroup
9A.

iii.
Peppers
(
bell
and
non_
bell)/
eggplant.
A
magnitude
of
residue
study
was
conducted
on
bell
and
non­
bell
peppers
at
11
sites.
Each
treated
plot
received
4
foliar
applications
at
6­
8
day
intervals
at
a
rate
of
approximately
0.13
lb
ai/
A
for
a
total
seasonal
use
rate
of
0.52
lb
ai/
A.
Peppers
were
harvested
at
2­
5
days
following
the
final
application.
Residues
of
quinoxyfen
in
bell
and
non­
bell
peppers
ranged
from
0.0090
to
0.6549
ppm.
The
proposed
tolerance
for
quinoxyfen
in
or
on
peppers
(
bell
and
non­
bell)
and
eggplant
is
1.0
ppm
and
is
adequate
to
cover
the
highest
expected
field
residues
from
the
labeled
use
of
quinoxyfen.

iv.
Strawberry.
Magnitude
of
residue
studies
were
conducted
on
strawberries
at
8
sites.
Each
treated
plot
received
4_
5
foliar
applications
at
6­
8
day
intervals
at
a
rate
of
about
0.13
lb
ai/
A
per
application
with
a
total
rate
of
0.52
lb
ai/
A
for
the
season.
Residues
of
quinoxyfen
in
strawberries
collected
one
day
after
the
last
application
were
0.32
to
0.58
ppm.
The
proposed
tolerance
for
quinoxyfen
in
or
on
strawberries
is
0.8
ppm
and
is
adequate
to
cover
the
highest
expected
field
residues
from
the
labeled
use
of
quinoxyfen
in
strawberries.

B.
Toxicological
Profile
1.
Acute
toxicity.
Quinoxyfen
(
technical)
has
low
acute
toxicity.
The
acute
oral
LD50
in
rats
was
>
5000
mg/
kg
whereas
the
dermal
LD50
in
rabbits
was
>
2000
mg/
kg.
The
acute
inhalation
LC50
in
rats
was
greater
than
the
highest
attainable
aerosol
concentration
(
3.38
mg/
L).
Quinoxyfen
produced
no
dermal
irritation
and
only
mild
eye
irritation
in
rabbits.
A
guinea
pig
dermal
sensitization
study
conducted
by
the
modified
Buehler
method
found
no
sensitization,
whereas
a
study
conducted
by
the
Magnusson
and
Kligman
maximization
test
showed
a
positive
sensitization
reaction.
Formulations
of
quinoxyfen
are
water
based
suspension
concentrates
that
have
similar
low
acute
toxicity.
These
suspension
concentrates
are
classified
as
non_
sensitizer,
based
on
the
results
from
testing
in
guinea
pigs.

2.
Genotoxicty.
Quinoxyfen
was
negative
for
genotoxicity
when
tested
in
in
vitro
and
in
vivo
systems.

3.
Reproductive
and
developmental
toxicity.
Quinoxyfen
did
not
have
any
effect
on
reproductive
parameters
at
dose
levels
that
induced
treatment_
related
effects
in
parental
rats.
Transient
decreases
in
pup
body
weights
were
seen
prior
to
weaning,
but
dietary
concentrations
were
targeted
for
adults
and
consumption
of
treated
diets
by
the
pups
resulted
in
dose
levels
to
3
the
pups
approximately
3_
fold
higher
than
in
adults.
Post_
weaning
weights
were
comparable
to
controls.
A
teratogenic
potential
for
quinoxyfen
was
not
demonstrated
in
either
rats
or
rabbits
at
dose
levels
that
induced
maternal
toxicity.

4.
Subchronic
toxicity.
Quinoxyfen
caused
increased
liver
weights
and
microscopic
hepatocellular
hypertrophy
when
given
at
sufficiently
high
dose
levels
in
rats
and
mice
for13
weeks;
no
effects
were
observed
in
the
subchronic
dog
study
at
the
highest
dose
tested.
Very
high
dietary
levels
were
associated
with
slight
hepatocellular
necrosis.
Similar
increases
in
liver
weights
were
seen
in
chronic
studies.
In
addition,
increased
kidney
weights,
and
an
increase
in
the
incidence
of
chronic
progressive
glomerulonephropathy,
were
seen
after
24
months
in
female
rats
given
high
dose
levels
of
quinoxyfen.

5.
Chronic
toxicity.
i.
Dog.
Chronic
toxicity
seen
in
dogs
included
liver
effects
as
noted
above,
along
with
regenerative
anemia
at
high
dose
levels.

ii.
Mouse.
Very
high
dietary
levels
were
associated
with
slight
hepatocellular
necrosis.
Similar
increases
in
liver
weights
were
seen
in
chronic
studies.

iii.
Rat.
In
addition,
increased
kidney
weights,
and
an
increase
in
the
incidence
of
chronic
progressive
glomerulonephropathy,
were
seen
after
24
months
in
female
rats
given
high
dose
levels
of
quinoxyfen.

iv.
Carcinogenicity.
Using
the
Guidelines
for
Carcinogen
Risk
Assessment
Using
the
Guidelines
for
Carcinogen
Risk
Assessment
published
September
24,
1986
(
51
FR
33992),
it
is
proposed
that
quinoxyfen
be
classified
as
Group
E
for
carcinogenicity
(
no
evidence
of
carcinogenicity)
based
on
the
results
of
studies
in
two
species.
Dow
AgroSciences
believes
there
was
no
evidence
of
carcinogenicity
in
an
18­
month
mouse
feeding
study
and
a
24­
month
rat
feeding
study
at
any
dosage
tested.]

6.
Animal
metabolism.
Quinoxyfen
is
rapidly
absorbed,
extensively
metabolized
and
rapidly
eliminated
in
the
urine
and
feces.
Studies
conducted
with
14C_
quinoxyfen,
labeled
in
either
the
phenyl
ring
or
the
quinoline
ring,
indicated
extensive
cleavage
of
the
diaryl
ether
linkage.
There
were
no
substantive
differences
in
the
metabolism
and
disposition
of
quinoxyfen
between
males
and
females,
or
between
single
or
repeated
exposure.
Parent
quinoxyfen
was
not
found
in
the
urine,
though
it
was
identified
in
the
feces.
The
major
metabolites
found
in
urine
and/
or
feces
included
(
1)
acid_
labile
conjugates
of
the
phenyl
ring
moiety
(
4­
FP)
and
quinoline
ring
moiety
(
DCHQ);
(
2)
lesser
quantities
of
free
4­
FP
and
DCHQ;
and,
(
3)
isomers
of
fluorophenyl_
ring
hydroxy_
quinoxyfen,
both
free
and
glucuronide
and/
or
sulfate
conjugates.
Trace
quantity
of
the
3­
OH
metabolite
was
also
identified
in
the
urine
and
feces
of
rats.

7.
Metabolite
toxicology.
The
nature
of
residue
studies
(
NOR)
of
quinoxyfen
in
plants
indicated
that
the
majority
of
applied
radiolabeled
material
remained
as
the
parent
compound.
Analyses
from
NOR
studies
in
a
number
of
crops
revealed
low
residues
of
metabolites
(<
10%
TRR)
identified
as
(
1)
a
quinoline_
ring
hydroxylated
metabolite,
most
likely
3­
OH;
(
2)
a
4
cyclized
deschloro
photoproduct
(
CFBPQ);
(
3)
4­
FP;
and,
(
4)
a
metabolite
in
which
the
fluorine
was
replaced
by
a
hydroxyl
group.

Of
these
metabolites,
4­
FP
(
formed
by
ether
bridge
cleavage),
and
DCHQ
(
corresponding
to
the
other
half
of
the
molecule),
as
well
as
trace
quantities
of
3­
OH,
have
been
identified
in
rat
urine
and/
or
feces.
These
data
suggest
that
most
metabolites
formed
in
plants
are
similarly
formed
in
mammals
and
are
of
little
toxicologic
concern,
based
on
the
existing
data
for
quinoxyfen.

8.
Endocrine
disruption.
There
is
no
evidence
from
any
studies
to
suggest
that
quinoxyfen
has
an
effect
on
any
endocrine
system.

C.
Aggregate
Exposure
1.
Dietary
exposure.
i.
Food.
Potential
dietary
exposure
and
risk
assessment
was
estimated
using
DEEM
(
Dietary
Exposure
Evaluation
Model,
Version
7.76)
with
USDA
food
consumption
data
CSFII
Survey
1994­
1998.
The
dietary
exposure
assessment
was
performed
using
a
conservative
approach
(
Tier
I)
and
the
estimated
theoretical
maximum
residue
contribution
(
TMRC)
was
based
on
the
existing
uses
on
cherry,
hops
and
grapes
as
well
as
the
proposed
tolerances
for
quinoxyfen
on
or
in
peppers,
eggplant,
subgroup
9A,
melons,
lettuce
and
strawberries
with
the
assumption
that
100%
of
these
crops
were
treated
with
quinoxyfen.

The
chronic
dietary
exposure
was
evaluated
using
a
chronic
reference
dose
(
RfD)
of
0.2
mg/
kg/
day
based
on
NOEL
of
20
mg/
kg/
day
from
chronic
rat,
chronic
dog,
and
rat
reproduction
studies
and
uncertainty
factor
of
100.
No
additional
FQPA
uncertainty
factor
is
needed.
For
the
U.
S.
general
population,
the
exposure
was
estimated
to
be
0.004650
mg/
kg/
day
which
utilizes
only
2.3%
of
the
RfD.
The
population
sub­
group
with
the
highest
potential
exposure
are
females
13+
(
nursing)
with
an
exposure
of
0.005595
mg/
kg/
day
that
represents
2.8%
of
the
RfD.
The
%
of
the
RfD
is
significantly
below
the
acceptable
100%;
therefore,
it
demonstrates
no
chronic
dietary
concern.

a.
Acute
dietary
exposure.
No
acute
dietary
risk
for
quinoxyfen
was
evaluated
since
no
appropriate
toxicity
endpoint
attributable
to
a
single
dose
could
be
identified.
Therefore,
an
acute
reference
dose
was
not
established.

b.
Chronic
dietary
exposure.
The
chronic
dietary
exposure
was
evaluated
using
a
chronic
reference
dose
(
RfD)
of
0.2
mg/
kg/
day
based
on
NOEL
of
20
mg/
kg/
day
from
chronic
rat,
chronic
dog,
and
rat
reproduction
studies
and
uncertainty
factor
of
100.
No
additional
FQPA
uncertainty
factor
is
needed.
For
the
U.
S.
general
population,
the
exposure
was
estimated
to
be
0.004650
mg/
kg/
day
which
utilizes
only
2.3%
of
the
RfD.
The
population
sub­
group
with
the
highest
potential
exposure
are
females
13+
(
nursing)
with
an
exposure
of
0.005595
mg/
kg/
day
that
represents
2.8%
of
the
RfD.
The
%
of
the
RfD
is
significantly
below
the
acceptable
100%;
therefore,
it
demonstrates
no
chronic
dietary
concern.
5
c.
Cancer
dietary
exposure.
Using
the
Guidelines
for
Carcinogen
Risk
Assessment
published
September
24,
1986
(
51
FR
33992),
it
is
proposed
that
quinoxyfen
be
classified
as
Group
E
for
carcinogenicity
(
no
evidence
of
carcinogenicity)
based
on
the
results
of
studies
in
two
species.
Dow
AgroSciences
believes
there
was
no
evidence
of
carcinogenicity
in
an
18_
month
mouse
feeding
study
and
a
24­
month
rat
feeding
study
at
any
dosage
tested.

ii.
Drinking
water.
Based
on
the
rapid
degradation
of
quinoxyfen
in
water
and
its
high
tendency
to
sorb
to
soils,
no
surface
water
or
groundwater
contamination
is
expected.
In
a
recent
assessment,
the
Agency
used
FIRST
and
SCI­
GROW
models
to
estimate
the
environmental
concentration
(
EEC)
for
surface
water
and
ground
water
respectively.
The
EECs
of
quinoxyfen
for
chronic
exposure
were
estimated
to
be
0.8
ppb
for
surface
water
and
0.006
ppb
for
ground
water.

Drinking
water
levels
of
comparison
(
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,
and
from
residential
uses.
DWLOC
is
not
a
regulatory
standard
for
drinking
water,
but
is
used
as
a
point
of
comparison
against
the
estimated
potential
concentrations
in
groundwater
or
surface
water.
It
is
calculated
by
subtracting
the
food
dietary
exposure
(
from
DEEM
analysis)
from
the
RfD
and
then
expressed
as
:
g/
L
using
default
body
weights
(
70
kg
for
adult
and
10
kg
for
infants)
and
drinking
water
consumption
(
2
L/
day
for
adults
and
1
L/
day
for
children).
The
DWLOC
for
the
general
U.
S.
population
and
1­
6
yrs
old
children
(
population
sub_
group
with
highest
potential
exposure)
was
calculated
to
be
6837
:
g/
L
and
1950
:
g/
L,
respectively.
The
DWLOCs
are
substantially
greater
than
the
estimated
residue
concentration
in
groundwater
or
surface
water,
therefore,
exposure
to
quinoxyfen
would
not
result
in
unacceptable
levels
of
aggregate
human
health
risk.

2.
Non­
dietary
exposure.
Quinoxyfen
is
not
currently
registered
for
use
on
any
sites
that
would
result
in
residential
exposure.
Thus,
the
risk
from
non_
dietary
exposure
would
be
considered
negligible.

D.
Cumulative
Effects
The
potential
for
cumulative
effects
of
quinoxyfen
and
other
substances
that
have
a
common
mechanism
of
toxicity
is
also
considered.
Quinoxyfen
is
a
member
of
the
quinoline
class
of
fungicides.
No
information
is
available
to
determine
whether
quinoxyfen
has
a
common
mechanism
of
toxicity
with
other
pesticides.
Therefore,
it
is
appropriate
to
consider
only
the
potential
risks
of
quinoxyfen
in
an
aggregate
exposure
assessment.

E.
Safety
Determination
1.
U.
S.
population.
Using
the
conservative
exposure
assumptions
described
above
and
based
on
the
completeness
and
reliability
of
the
toxicity
data,
the
aggregate
exposure
to
6
quinoxyfen
utilizes
2.3%
of
the
RfD
for
the
U.
S.
population.
EPA
generally
has
no
concern
for
exposures
below
100%
of
the
RfD
because
the
RfD
represents
the
level
at
or
below
which
daily
aggregate
dietary
exposure
over
a
lifetime
will
not
pose
appreciable
risks
to
human
health.
Thus,
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
quinoxyfen
residues
from
the
proposed
uses.

2.
Infants
and
children.
[
In
assessing
the
potential
for
additional
sensitivity
of
infants
and
children
to
residues
of
quinoxyfen,
data
from
developmental
toxicity
studies
in
rats
and
rabbits
and
a
2­
generation
reproduction
study
in
the
rat
are
considered.
The
developmental
toxicity
studies
are
designed
to
evaluate
adverse
effects
on
the
developing
organism
resulting
from
pesticide
exposure
during
prenatal
development.
Reproduction
studies
provide
information
relating
to
effects
from
exposure
to
the
pesticide
on
the
reproductive
capability
and
potential
systemic
toxicity
of
mating
animals
and
on
various
parameters
associated
with
the
well­
being
of
offspring.

FFDCA
Section
408
provides
that
EPA
may
apply
an
additional
safety
factor
for
infants
and
children
in
the
case
of
threshold
effects
to
account
for
pre­
and
post­
natal
toxicity
and
the
completeness
of
the
database.
Based
on
the
current
toxicological
data
requirements,
the
database
for
quinoxyfen
relative
to
pre­
and
post­
natal
effects
for
children
is
complete.
Quinoxyfen
had
no
effect
on
reproduction
or
embryo­
fetal
development
at
any
dosage
tested.
Therefore,
no
additional
FQPA
uncertainty
factor
is
needed.
The
NOEL
of
20
mg/
kg/
day
found
in
the
chronic
rat,
chronic
dog,
and
rat
reproduction
studies
was
used
to
calculate
the
RfD
of
0.2
mg/
kg/
day
and
is
appropriate
for
chronic
risk
assessment
to
infants
and
children.
Using
the
conservative
exposure
assumptions
previously
described,
the
percent
RfD
utilized
by
the
potential
aggregate
exposure
to
quinoxyfen
residues
is
about
2.5%
for
children
(
1­
6
yrs
old),
the
population
subgroup
with
highest
potential
exposure.
Therefore,
based
on
the
completeness
and
reliability
of
the
toxicity
data
and
the
conservative
exposure
assessment,
Dow
AgroSciences
concludes
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate
exposure
to
quinoxyfen
residues
from
proposed
uses.

F.
International
Tolerances
There
are
no
Codex
maximum
residue
levels
established
for
residues
of
quinoxyfen.
