Interregional
Research
Project
Number
4
(
IR­
4)

4E6834
EPA
has
received
a
pesticide
petition
(
PP
#
4E6834)
from
IR­
4,
681
US
Highway
#
1
South,
North
Brunswick,
NJ
08902
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act,
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
180.598
by
establishing
a
tolerance
for
residues
of
novaluron
(
1­[
3­
chloro­
4­(
1,1,2­
trifluoro­
2­
trifluoromethoxyethoxy)
phenyl]­
3­[
2,6­
difluorobenzoyl]
urea)
in
or
on
Brassica
vegetables,
head
and
stem
(
Subgroup
5A)
at
0.5
ppm.
Makhteshim­
Agan
of
North
America,
Inc.,
551
Fifth
Avenue,
Suite
1100,
New
York,
NY
10176
is
the
manufacturer
and
basic
registrant
of
novaluron.
Makhteshim­
Agan
of
North
America
Inc,
prepared
and
summarized
the
following
information
in
support
of
the
pesticide
petition
for
novaluron.
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
qualitative
nature
of
the
residue
of
novaluron
in
plants
is
adequately
understood
based
on
acceptable
apple,
cabbage,
cotton,
and
potato
metabolism
studies.
These
plant
metabolism
studies
have
demonstrated
that
novaluron
does
not
metabolize
and
is
nonsystemic
(
does
not
translocate
within
the
plant).
The
results
observed
in
the
plant
and
livestock
metabolism
studies
show
similar
metabolic
pathways.
The
residue
of
concern,
which
should
be
regulated,
is
the
parent
compound,
novaluron,
only.

2.
Analytical
Method
An
adequate
analytical
method,
gas
chromatography/
electron
capture
detector
(
GC/
ECD),
is
available
for
enforcing
tolerances
of
novaluron
residues
in
or
on
head
and
stem
Brassica
vegetables,
as
recently
published
in
the
Federal
Register
of
June
2,
2004
(
69
FR
31013;
FRL­
7359­
2).
The
limit
of
quantitation
(
LOQ
=
0.05
ppm)
was
taken
as
the
lowest
level
validated
by
this
method.

3.
Magnitude
of
Residues
A
series
of
field
residue
trials,
six
each
in
the
representative
crops,
cabbage
and
broccoli,
were
conducted
covering
the
major
growing
areas
in
the
United
States.
Novaluron
was
applied
three
times,
following
a
5
to
8
day
spray
interval,
using
an
application
rate
of
0.05
lb
active
ingredient
per
acre
with
the
last
application
7
days
before
harvest.
In
addition,
residue
decline
studies
in
cabbage
and
broccoli
were
performed
with
sampling
dates
of
0,
3,
10,
and
14
days
after
the
last
application.
The
majority
of
the
analyzed
broccoli
samples
had
residues
in
the
range
of
0.06
to
0.38
ppm.
The
highest
average
field
residue
found
was
0.48
ppm,
measured
on
cabbage,
which
included
the
wrapper
leaves.
All
the
cabbage
samples
without
the
wrapper
leaves,
showed
no
detectable
residues,
except
one
sample
at
0.08
ppm.
Makhteshim­
Agan
of
North
America
Inc,
concludes
that
the
generated
data
set
is
in
full
support
of
the
proposed
tolerance
of
0.5
ppm.

B.
Toxicological
Profile
1.
Acute
Toxicity
In
an
acute
oral
toxicity
study
in
rats,
novaluron
had
an
LD50
>
5,000
mg/
kg.
A
dermal
toxicity
study
in
rats
resulted
in
an
LD50
greater
than
2,000
mg/
kg.
The
LC50
for
acute
inhalation
in
rats
was
greater
than
5.15
mg/
l.
In
rabbits,
novaluron
is
not
a
skin
irritant,
but
it
is
a
mild
eye
irritant.
Novaluron
is
not
a
sensitizer
in
guinea
pigs.

2.
Genotoxicity
The
mutagenic
potential
of
Novaluron
was
investigated
in
several
in
vivo
and
in
vitro
studies.
Results
in
two
Ames
assays,
an
in
vivo
mouse
micronucleus
assay,
an
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assay,
an
in
vitro
cell
mutation
assay,
and
an
in
vitro
human
lymphocyte
clastogenicity
test
were
negative.
Novaluron
is
therefore
considered
to
have
no
potential
to
induce
mutagenicity.

3.
Reproductive
and
Developmental
Toxicity
i.
A
two
generation
rat
reproduction
study
was
conducted
with
dose
levels
of
1,000,
4,000,
and
12,000
ppm
(
74.2,
297.5,
894.9
mg/
kg/
day,
and
84,
336.7,
1,009.8
mg/
kg/
day
for
males
and
females,
respectively).
Maternal
and
offspring
toxicity
was
evidenced
by
increased
absolute
and
relative
spleen
weights,
whereas
reproductive
toxicity
was
observed
only
in
males
at
297.5
mg/
kg/
day
(
LOAEL)
based
on
decreased
epididymal
sperm
counts
and
increased
age
at
preputial
separation
in
the
F1
generation.
The
no
observed
adverse
effect
level
(
NOAEL)
in
males
was
1,000
ppm
(
74.2
mg/
kg/
day)
and
in
females
it
was
$
12,000
ppm
(
1,009.8
mg/
kg/
day).

ii.
Teratology
studies
were
conducted
in
the
rat
and
rabbit.
No
treatment­
related
mortalities
were
observed
in
either
study.
No
effect
on
survival,
development
or
growth
of
fetuses
was
noted
in
either
species
in
either
study.
No
maternal
or
developmental
toxicity
was
observed
up
to
and
including
the
limit
dose
of
1,000
mg/
kg/
day
(
NOAEL).
These
two
studies
demonstrate
that
novaluron
was
not
teratogenic
in
either
rats
or
rabbits.

4.
Subchronic
Toxicity
Rats,
mice
and
dogs
all
show
the
same
toxicologic
response.
Generally,
novaluron
induces
small
increases
in
methemoglobin;
red
cells
are
sequestered;
and,
compensatory
hematopoiesis
occurs.
The
severity
of
these
changes
is
well
within
the
physiological
capacity
of
the
animals
and
is
judged
not
adverse.

Rats
treated
topically
with
novaluron
in
a
28­
day
study
at
0,
75,
400
and
1,000
mg/
kg/
day
did
not
show
signs
of
systemic
toxicity.
Small
treatment­
related
increases
in
methemoglobin
were
seen
in
both
sexes
at
1,000
mg/
kg/
day
and
in
females
at
400
mg/
kg/
day.
The
highest
methemoglobin
value
seen
in
females
was
1.28%
compared
with
0.86%
in
controls.
Organ
weights,
macroscopic
and
microscopic
examination
of
organs
and
tissues
did
not
reveal
any
treatment­
related
changes.

Two
13­
week
rat
studies
were
conducted.
In
one
study,
doses
were
administered
at
50,
100,
200,
400
ppm
(
3.52,
6.93,
13.83,
27.77
mg/
kg/
day
and
4.38,
8.64,
17.54
and
34.39
mg/
kg/
day
for
males
and
females,
respectively).
The
LOAELs
from
the
combined
results
were
27.77
mg/
kg/
day
in
males
based
on
increased
occurrence
of
extramedullary
hematopoiesis
and
hemosiderosis
in
spleen;
and
8.64
mg/
kg/
day
in
females
based
on
reduction
in
hemoglobin,
hematocrit
and
RBC
count;
increased
occurrence
of
extramedullary
hematopoiesis
and
hemosiderosis
in
spleen
and
liver.
The
NOAEL
was
determined
to
be
4.38
mg/
kg/
day.

A
13­
week
mouse
study
was
conducted
with
dose
levels
of
30,
100,
1,000,
10,000
ppm
(
4.2,
12.8,
135.9,
1,391.9
and
4.7,
15.2,
135.6,
1,493.1
mg/
kg/
day,
for
males
and
females,
respectively).
The
NOAEL
was
determined
to
be
100
ppm
(
12.8
and
15.2
mg/
kg/
day,
male
and
females,
respectively).
The
LOAEL
was
1,000
ppm
(
135.9
and
135.6
mg/
kg/
day,
males
and
females,
respectively)
based
on
increased
body
weight
gain,
low
erythrocyte
counts,
and
secondary
splenic
changes.
There
were
no
clinical
treatment­
related
signs
noted.

Two
13­
week
dog
studies
were
conducted.
One
study
resulted
in
an
NOAEL
of
100
mg/
kg/
day
and
a
LOAEL
of
300
mg/
kg/
day
based
on
low
erythrocyte
counts
and
secondary
splenic
and
liver
changes.
No
clinical
treatment­
related
signs
were
noted.
Another
study,
was
conducted
using
only
one
dose
level
of
10
mg/
kg/
day.
There
were
no
clinical
or
histopathological
treatment­
related
signs
and
the
NOEL
was
determined
to
be
10
mg/
kg/
day.

5.
Chronic
Toxicity
i.
Chronic
toxicity
and
oncogenicity
was
evaluated
in
the
rat,
mouse
and
dog.
The
rat
chronic
toxicity
and
oncogenicity
was
conducted
with
dose
levels
of
25,
700,
20,000
ppm
(
1.1,
30.6,
884.2
and
1.4,
39.5,
1,113.5
mg/
kg/
day
for
males
and
females,
respectively).
The
LOAEL
in
male
and
female
rats
was
30.6
and
39.5
mg/
kg/
day,
respectively,
based
on
evidence
of
erythrocyte
damage
and
turnover
resulting
in
a
regenerative
anemia
in
both
sexes.
The
corresponding
NOAEL
was
25
ppm
(
1.1
and
1.4
mg/
kg/
day
for
male
and
female
rats,
respectively).
There
was
no
evidence
of
carcinogenicity
in
this
study.
A
mouse
chronic
toxicity
study
was
conducted
with
dose
levels
of
30,
450,
7,000
ppm
(
3.6,
53.4,
800.0
and
4.3,
63.3,
913.4
mg/
kg/
day
for
males
and
females,
respectively).
The
LOAEL
in
male
and
female
mice
was
53.4
and
63.3
mg/
kg/
day,
respectively,
based
on
erythrocyte
turnover
due
to
hemoglobin
oxidation
and
resulting
in
a
compensated
anemia.
The
corresponding
NOAEL
was
30
ppm
(
3.6
and
4.3
mg/
kg/
day
for
male
and
female
mice,
respectively).
There
was
also
no
evidence
of
carcinogenicity
in
this
study.
Chronic
toxicity
was
investigated
in
dogs
using
dose
levels
of
10,
100,
1,000
mg/
kg/
day.
The
NOAEL
of
100
mg/
kg/
day
was
based
on
methemoglobin.

ii.
The
chronic
reference
dose
(
cRfD)
of
0.011
mg/
kg/
day
has
been
established
on
the
basis
of
the
chronic
carcinogenicity
study
in
rats.
An
uncertainty
factor
(
UF)
of
100
was
applied
to
the
NOAEL
of
1.1
mg/
kg/
day
for
male
rats
deriving
to
the
cRfD.

iii.
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July
1999),
novaluron
is
classified
as
Anot
likely
to
be
carcinogenic
to
humans@
due
to
results
of
oncogenicity
studies
that
show
no
evidence
of
carcinogenicity
in
rats
and
mice.

6.
Animal
Metabolism
Metabolism
studies
in
rats
and
goats
were
conducted
with
the
parent
material
labeled
in
both
the
difluorophenyl
and
chlorophenyl
moieties.
Rats
absorb
little
novaluron
when
it
is
administered
orally.
More
than
90%
of
the
dietary
administered
[
chlorophenyl
14C(
U)]
novaluron
is
recovered
in
the
feces.
When
the
diflurophenyl
ring
of
the
molecule
is
labeled,
the
recovered
14C
activity
in
the
feces
is
lower
but
still
above
75%.
The
difference
is
thought
to
reflect
intestinal
metabolism
by
microbial
flora
and
the
higher
absorption
of
the
diflurophenyl
metabolites.

The
parent
molecule
as
well
as
its
degradates
are
absorbed
from
the
gastrointestinal
tract.
All
parent
material
is
metabolized
either
upon
initial
entry
into
the
systemic
circulation
or,
if
sequestered
to
the
fat,
upon
its
depuration
back
to
the
systemic
circulation.
There
is
no
intact
novaluron
found
in
the
urine.
Novaluron=
s
high
octanolwater
partition
coefficient
is
responsible
for
its
preferential
movement
to
fat.
The
halflife
in
fat
calculated
from
the
rat
metabolism
study
is
approximately
55
hours.

Two
groups
of
metabolites
are
formed
after
oral
administration
of
novaluron.
One
group
is
typified
by
the
aniline
metabolite
3­
chloro­
4­(
1,1,2­
trifluoro­
2­
trifluoromethoxyethoxy)
aniline,
referred
to
as
3­
TFA.
The
other
group
of
metabolites
is
typified
by
2,6­
difluorobenzoic
acid
is
from
the
diflurophenyl
moiety
of
the
molecule.
Nearly
all
the
metabolites
are
formed
at
a
level
of
1%
or
less
of
the
applied
dose.
They
are
rapidly
excreted.

The
metabolism
in
goats
mimics
that
seen
in
rats.

7.
Metabolite
Toxicology
Makhteshim­
Agan
of
North
America
Inc.,
has
determined
that
there
are
no
metabolites
of
toxicological
concern
and
therefore,
no
metabolites
need
to
be
included
in
the
tolerance
expression
and
require
regulation.
For
drinking
water
assessment
the
soil
degradates,
chlorophenyl
urea
and
chloroaniline
will
be
included
besides
the
parent,
novaluron.

8.
Endocrine
Disruption
No
special
studies
investigating
potential
estrogenic
or
other
endocrine
effects
of
novaluron
have
been
conducted.
However,
inspection
of
in­
life
data
from
toxicology
studies
does
not
indicate
that
novaluron
is
an
endocrine
disruptor.
Specifically,
endocrine
organ
weights
(
e.
g.,
thyroid,
testes,
ovaries,
pituitary
from
the
twogeneration
study)
were
not
adversely
affected
by
novaluron.
Milestones
of
sexual
development
were
not
affected
by
novaluron;
and,
reproduction
was
not
adversely
affected.
Based
on
these
observations,
there
is
no
evidence
to
suggest
that
novaluron
has
an
adverse
effect
on
the
endocrine
system.

C.
Aggregate
Exposure
Dietary
Exposure.
Current
tolerances
for
residues
of
novaluron
have
been
established
in
or
on
fruit,
pome
fruit
(
Group
11),
apple
wet
pomace;
cotton,
undelinted
seed;
cotton,
gin
byproducts;
vegetables,
tuberous
and
corm
(
Subgroup
1C),
ruminant
commodities
and
milk
(
40CFR
180.598),
as
recently
published
in
the
Federal
Register
of
June
2,
2004
(
69
FR
31013;
FRL­
7359­
2).
In
addition
to
the
existing
tolerances,
this
Notice
of
Filing
includes
exposure
assessments
for
potential
residues
of
novaluron
in
or
on
Brassica
vegetables,
head
and
stem.

1.
Food
i.
Acute
Dietary
Exposure.
No
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies,
including
the
rat
and
rabbit
developmental
studies.
Therefore,
the
acute
aggregate
risk
is
negligible.

ii.
Chronic
Dietary
Exposure.
A
chronic
dietary
risk
assessment
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM)
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCIDJ),
which
incorporates
consumption
data
derived
from
the
1994
­
1996
and
1998
USDA
Continuing
Surveys
of
Food
Intake
by
Individuals
(
CSFII).
The
assessment
included
all
uses
(
existing
and
proposed),
assuming
100%
crop
treated
values
for
all
commodities,
average
field
residues,
empirical
processing
factors
for
apple
juice
(
translated
to
pear
juice),
and
DEEM
default
processing
factors
for
the
remaining
commodities.
Anticipated
residues
were
calculated
for
meat
and
milk;
recommended
tolerances
were
used
for
poultry
commodities.
The
appropriate
RfD
value
for
novaluron
is
0.011
mg/
kg/
day,
based
upon
the
NOAEL
of
1.1
mg/
kg/
day
from
the
chronic
carcinogenicity
study
in
rats,
and
an
UF
of
100.
Based
on
these
assumptions
the
chronic
dietary
exposure
estimate
for
the
overall
U.
S.
population
is
18%
of
the
cRfD.
Children
1
to
2
years
old,
the
most
exposed
population
subgroup,
utilize
68%
of
the
cRfD.
Therefore,
Makhteshim­
Agan
of
North
America
Inc.,
concludes
that
there
is
reasonable
certainty
of
no
harm
for
the
additional,
new
use
of
novaluron
on
Brassica
vegetables
(
head
and
stem).

III.
Cancer.
Novaluron
is
not
likely
to
be
carcinogenic
to
humans.
Therefore,
a
quantitative
cancer
risk
assessment
was
not
conducted.

2.
Drinking
Water
I.
Acute
Exposure.
Since
no
acute
dietary
endpoint
was
determined,
Makhteshim­
Agan
of
North
America,
Inc.,
concludes
there
is
reasonable
certainty
of
no
harm
from
acute
drinking
water
exposure.

II.
Chronic
Exposure.
There
are
no
monitoring
data
for
novaluron
to
complete
a
comprehensive
risk
assessment
for
novaluron
in
drinking
water.
Therefore,
the
Pesticide
Root
Zone
Model/
Exposure
Analysis
Modeling
System
(
PRZM/
EXAMS,
Tier
2
model)
was
used
for
the
concentration
of
novaluron
(
parent)
in
surface
water,
the
Food
Quality
Protection
Act
(
FQPA)
Index
Reservoir
Screening
Tool
(
FIRST,
Tier
I
model)
was
used
to
estimate
surface
water
concentrations
of
the
chlorophenyl
urea
and
chloroaniline
degradates.
For
Screening
Concentrations
In
Ground
Water
the
SCIGROW
model
was
used,
assuming
that
novaluron
may
reach
the
surface
or
the
ground
water
via
the
parent
compound
or
via
the
its
degradates.
The
modeling
represents
upper­
bound
estimates
based
on
the
environmental
characteristics,
the
current
and
proposed
use
rates
for
novaluron.
Chronic
estimates
for
the
terminal
degradate,
chloroaniline,
represent
the
worst
case,
assuming
100%
conversion
of
the
parent
compound.
The
calculated
EECs
of
novaluron
derived
from
these
models
are
2.61
parts
per
billion
(
ppb)
for
surface
water
and
0.009
ppb
for
ground
water.

Non­
Dietary
Exposure.
Presently
and
in
the
future,
novaluron
is
not
considered
for
residential
uses.
Thus,
potential
sources
of
non­
occupational
exposure
to
novaluron
would
consist
only
of
any
potential
residues
in
food
and
drinking
water.
Therefore,
there
is
no
non­
dietary
exposure
(
acute,
short­
term,
intermediate­
term
or
chronic).

D.
Cumulative
Effects
To
Makhteshim­
Agan
of
North
America=
s
Inc.,
knowledge,
there
are
currently
no
available
data
or
other
reliable
information
indicating
that
any
toxic
effects
produced
by
novaluron
would
be
cumulative
with
those
of
other
chemical
compounds;
thus
only
the
potential
risks
of
novaluron
have
been
considered
in
this
assessment
of
its
aggregate
exposure.

E.
Safety
Determination
1.
U.
S.
Population
No
acute
aggregate
risk
assessment
was
conducted
because
there
is
no
toxicological
endpoint
attributable
to
a
single
exposure.
Short­
and
intermediate­
term
aggregate
risk
assessments
were
not
performed
because
of
no
current
or
future
residential
uses.
No
cancer
aggregate
risk
assessment
was
conducted
because
novaluron
has
not
been
shown
to
be
carcinogenic.
Therefore,
only
a
chronic
aggregate
risk
assessment
was
performed
based
on
potential
exposure
from
food
and
drinking
water,
considering
all
existing
and
proposed
uses.
The
chronic
exposure
of
the
U.
S.
population
utilizes
18%
of
the
cRfD,
and
the
most
sensitive
population
subgroup
(
children
1
to
2
years
old)
utilizes
68%
of
the
cRfD.
In
view
of
these
assessments,
Makhteshim­
Agan
of
North
America
Inc.,
concludes
that
there
is
reasonable
certainty
that
no
harm
will
result
from
the
proposed
uses
of
novaluron.

2.
Infants
and
Children
Section
408
of
FFDCA
provides
that
EPA
may
apply
an
additional
safety
factor
for
infants
and
children
to
account
for
prenatal
and
postnatal
toxicity
and
the
completeness
of
the
database.
The
toxicology
database
for
novaluron
is
complete
including
acceptable
data
from
rat
and
rabbit
developmental
toxicity
studies
and
a
two
generation
rat
reproduction
study
that
have
been
used
to
assess
the
potential
for
increased
sensitivity
of
infants
and
children.
The
data
provided
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
novaluron.
In
addition
there
is
no
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
novaluron,
and
a
developmental
neurotoxicity
study
is
not
required.
Therefore,
the
Agency
determined
in
its
recent
review
to
reduce
the
FQPA
Safety
Factor
to
1X
(
Federal
Register
of
June
2,
2004;
69
FR
31013;
FRL­
7359­
2).
Thus,
the
chronic
population
adjusted
dose
(
cPAD)
is
considered
0.011
mg/
kg/
day.
The
DEEM
analysis
regarding
the
aggregate
chronic
exposure
calculations
utilizes
less
than
68%
of
the
cPAD
for
the
most
sensitive
subgroup,
children
1
to
2
years
old.
Therefore,
Makhteshim­
Agan
of
North
America
Inc.,
concludes
that
there
is
reasonable
certainty
that
no
harm
will
result
to
infants
and
children
from
aggregate
exposure
to
novaluron
residues.

3.
Drinking
Water
For
assessing
chronic
aggregate
dietary
risk,
EPA
calculates
Drinking
Water
Levels
Of
Concern
(
DWLOC),
which
are
used
as
a
point
of
comparison
against
the
Estimated
Environmental
Concentrations
(
EECs).
If
the
DWLOCs
exceed
the
EEC
values
then
there
is
reasonable
certainty
that
no
harm
will
result
from
the
aggregate
exposure
to
novaluron
residues.
Estimated
chronic
DWLOC
values
for
novaluron
range
from
35
ppb
for
children
(
1
to
2
years
old)
to
320
ppb
for
the
U.
S.
population.
The
calculated
DWLOC
values
for
the
U.
S.
population
and
all
its
subgroups
considerably
exceed
the
EECs
of
2.61
ppb
in
surface
water,
and
0.009
ppb
in
groundwater.
Makhteshim­
Agan
of
North
America
Inc.,
concludes
that
there
is
reasonable
certainty
that
residues
of
novaluron
in
drinking
water
will
not
contribute
significantly
to
the
aggregate
chronic
human
health
risk
and
that
the
chronic
aggregate
exposure
from
novaluron
residues
in
food
and
drinking
water
will
not
exceed
EPA=
s
level
of
concern
(
less
than
100%
of
cPAD).
F.
International
Residue
Limits
There
are
no
Canadian,
Mexican,
or
Codex
maximum
residue
limits
(
MRLs)
established
for
novaluron.
Therefore,
international
harmonization
is
not
an
issue
at
this
time.
