Section
H
FQPA
Supplemental
Information
for
the
Tolerance
Petition
A.
Executive
Summary
Bayer
CropScience
is
proposing
to
amend
40CFR
180.472
by
requesting
tolerances
be
established
for
oats
and
rye.

Analysis
of
imidacloprid
and
metabolites
is
by
conversion
to
6­
chloronicotinic
acid
(
6­
CAN)
and
derivitization
before
injection
onto
a
gas
chromatograph
equipped
with
mass
selective
detection.
The
limit
of
quantitation
is
0.05
ppm.
Aggregate
exposure
comes
from
seed
treatment,
in­
furrow,
and
foliar
uses
as
veterinary
uses.

B.
Background
Information
and
Profile
Bayer
CropScience
is
proposing
to
amend
40CFR
180.472
by
establishing
tolerances
for
residues
of
imidacloprid
(
1­[(
6­
chloro­
3­
pyridinyl)
methyl]­
N­
nitro­
2­
imidazolidinimine)
and
its
metabolites
containing
the
6­
chloropyridinyl
moiety,
all
expressed
as
1­[(
6­
chloro­
3­
pyridinyl)
methyl]­
N­
nitro­
2­
imidazolidinimine
in
or
on
the
raw
agricultural
commodities:

Oats,
grain
0.5ppm
Oats,
forage
2.0ppm
Oats,
hay
6.0ppm
Oats,
straw
3.0ppm
Rye,
grain
0.5ppm
Rye,
forage
2.0ppm
Rye,
hay
6.0ppm
Rye,
straw
3.0ppm
The
nature
of
the
metabolic
pathway
in
plants
is
adequately
understood.
The
analytical
method
for
determining
residues
is
the
conversion
to
6­
CAN
and
derivitization
before
injection
onto
a
gas
chromatograph
equipped
with
mass
selective
detection.
The
limit
of
quantitation
is
0.05
ppm.
Imidacloprid
is
an
excellent
insecticide
for
providing
early
season
protection
of
seedlings
against
injury
by
aphids
and
wireworm.

The
Agency
requested
this
tolerance
submission
to
add
oats
and
rye
to
the
imidaclorid
seed
treatment
labels
as
an
alternative
to
other
insecticides.
The
tolerances
are
based
on
existing
tolerances
for
wheat
and
barley.

C.
Toxicological
Profile
1.
Acute
toxicity.
The
acute
oral
LD50
values
for
imidacloprid
technical
ranged
from
424
milligrams/
kilograms
(
mg/
kg)
in
the
male
rat
and
<
450
mg/
kg
in
the
female
rat.
The
acute
dermal
LD50
was
<
5,000
mg/
kg
in
the
rat.
The
4­
hour
rat
inhalation
LC50
was
<
5.33
mg/
L.
Imidacloprid
was
not
irritating
to
rabbit
skin
or
eyes.
Imidacloprid
did
not
cause
skin
sensitization
in
guinea
pigs.
In
an
acute
neurotoxicity
study
the
lowest
observed
adverse
effect
level
(
LOAEL)
=
42
mg/
kg
body
weight
day
(
bwt/
day).
2.
Genotoxicity.
Mutagenicity
studies
have
demonstrated
that
imidacloprid
is
non­
mutagenic
both
in
vivo
and
in
vitro.
3.
Reproductive
and
developmental
toxicity.
In
a
developmental
toxicity
study
with
Sprague­
Dawley
rats,
groups
of
pregnant
animals
(
25/
group)
received
oral
administration
of
imidacloprid
(
94.2%)
at
0,
10,
30,
or
100
mg/
kg
bwt/
day
during
gestation
days
6
through
16.
Maternal
toxicity
was
manifested
as
decreased
body
weight
gain
at
all
dose
levels
and
reduced
food
consumption
a
t
100
milligrams/
kilograms
of
body
weight/
day
(
mg/
kg
bwt/
day).
No
treatment­
related
effects
were
seen
in
any
of
the
reproductive
parameters
(
i.
e.,
Cesarean
section
evaluation).
At
100
mg/
kg
bwt/
day,
developmental
toxicity
manifested
as
wavy
ribs
(
fetus
 
7/
149
in
treated
vs.
2/
158
in
controls
and
litters,
4/
25
vs.
1/
25).
For
maternal
toxicity,
the
LOAEL
was
10
mg/
kg
bwt/
day
lowest
dose
tested
(
LDT)
based
on
decreased
body
weight
gain;
a
NOAEL
was
not
established.
For
developmental
toxicity,
the
NOAEL
was
30
mg/
kg
bwt/
day
and
the
LOAEL
was
100
mg/
kg
bwt/
day
based
on
increased
wavy
ribs
master
record
identification
(
MRID
No.
42256338).
In
a
developmental
toxicity
study
with
Chinchilla
rabbits,
groups
of
16
pregnant
does
were
given
oral
doses
of
imidacloprid
(
94.2%)
at
0,
8,
24,
or
72
mg/
kg
bwt/
day
during
gestation
days
6
through
18.
For
maternal
toxicity,
the
NOAEL
was
24
mg/
kg
bwt/
day
and
the
LOAEL
was
72
mg/
kg
bwt/
day
based
on
mortality,
decreased
body
weight
gain,
increased
resorptions,
and
increased
abortions.
For
developmental
toxicity,
the
NOAEL
was
24
mg/
kg
bwt/
day
and
the
LOAEL
was
2
mg/
kg
bwt/
day
based
on
decreased
fetal
body
weight,
increased
resorptions,
and
increased
skeletal
abnormalities
(
MRID
No.
42256339).
In
a
2­
generation
reproductive
toxicity
study,
imidacloprid
(
95.3%)
was
administered
to
Wistar/
Han
rats
at
dietary
levels
of
0,
100,
250,
or
700
ppm
(
0,
7.3,
18.3,
or
52.0
mg/
kg
bwt/
day
for
males
and
0,
8.0,
20.5,
or
57.4
mg/
kg
bwt/
day
for
females)
(
MRID
No.
42256340,
Doc.
No.
010537).
For
parental/
systemic/
reproductive
toxicity,
the
NOAEL
was
250
ppm
(
18.3
mg/
kg
bwt/
day)
and
the
LOAEL
was
750
ppm
(
52
mg/
kg
bwt/
day),
based
on
decreases
in
body
weight
in
both
sexes
in
both
generations.
Based
on
these
factors,
EPA
recommended
that
the
Data
Evaluation
Record
should
be
revised
to
indicate
the
parental/
systemic/
reproductive
NOAEL
and
LOAEL
to
be
250
and
700
ppm,
respectively,
based
upon
the
body
weight
decrements
observed
in
both
sexes
in
both
generations.
4.
Subchronic
toxicity.
In
a
dermal
toxicity
study,
groups
of
five
male
and
five
female
New
Zealand
white
rabbits
received
repeated
dermal
applications
of
imidacloprid
(
95%)
at
1,000
mg/
kg
bwt/
day
(
LD),
6
hours/
day,
5
days/
week
for
3
weeks.
No
dermal
or
systemic
toxicity
was
seen.
For
systemic
and
dermal
toxicity,
the
NOAEL
was
<
1,000
mg/
kg
bwt/
day,
a
LOAEL
was
not
established
(
MRID
No.
42256329).
In
an
oral
toxicity
study,
groups
of
Fischer
344
rats
(
12/
sex/
dose)
were
fed
diets
containing
imidacloprid
(
98.8%)
at
8,
150,
1,000,
or
3,000
ppm
(
0,
9.3,
63.3,
or
196
mg/
kg
bwt/
day
in
males
and
0,
10.5,
69.3,
or
213
mg/
kg
bwt/
day
in
females,
respectively)
for
90
days.
No
treatment­
related
effects
were
seen
at
150
ppm.
Treatment­
related
effects
included
decreases
in
body
weight
gain
during
the
first
4
weeks
of
the
study
at
1,000
ppm
(
22%
in
males
and
18%
in
females)
and
3,000
ppm
(
50%
in
males
and
25%
in
females)
with
an
associated
decrease
in
forelimb
grip
strength
especially
in
males.
The
NOAEL
was
150
ppm
(
9.3
and
10.5
mg/
kg
bwt/
day
in
males
and
females,
respectively)
and
the
LOAEL
was
1,000
ppm
(
63.3
and
69.3
mg/
kg
bwt/
day
in
males
and
females,
respectively)
(
MRID
No.
43286401).
In
a
rat
inhalation
study
(
28­
day
study
in
which
rats
were
exposed
6
hours/
day,
5
days/
week
for
4
weeks),
the
NOAEL
for
imidacloprid
was
5.5
mg/
m3
(
MRID
No.
422730­
01).
5.
Chronic
toxicity.
In
a
chronic
toxicity
study,
groups
of
beagle
dogs
(
4/
sex/
dose)
were
fed
diets
containing
imidacloprid
(
94.9%)
at
0,
200
or
1,250/
2,500
ppm
(
0,
6.1,
15
or
41/
72
mg/
kg
bwt/
day,
respectively)
for
52
weeks.
The
1,250
ppm
dose
was
increased
to
2,500
ppm
from
week
17
onwards.
The
threshold
NOAEL
was
1,250
ppm
(
41
mg/
kg
bwt/
day).
The
LOAEL
was
2,500
ppm
(
72
mg/
kg
bwt/
day)
based
on
increased
cytochrome­
P­
450
levels
in
both
sexes
and
was
considered
to
be
a
threshold
dose.
Due
to
the
lack
of
toxicity
at
1,250
ppm,
a
LOAEL
was
not
established
in
this
study
following
the
dose
increase
to
the
2,500
ppm
level,
toxicity
was
observed,
thus
making
1,250
ppm
the
threshold
NOAEL
and
2,500
ppm
the
threshold
LOAEL
(
MRID
No.
42273002).
6.
Animal
metabolism.
The
metabolism
imidacloprid
in
rats
was
reported
in
seven
studies.
These
data
show
that
imidacloprid
was
rapidly
absorbed
and
eliminated
in
the
excreta
(
90%
of
the
dose
within
24
hours),
demonstrating
no
biologically
significant
differences
between
sexes,
dose
levels,
or
route
of
administration.
Elimination
was
mainly
renal
(
70­
80%
of
the
dose)
and
fecal
(
17­
25%).
The
major
part
of
the
fecal
activity
originated
in
the
bile.
Total
Body
accumulation
after
48
hours
consisted
of
0.5%
of
the
radio
activity
with
the
liver,
kidney,
lung,
skin
and
plasma
being
the
major
sites
of
accumulation.
Therefore,
bioaccumulation
of
imidacloprid
is
low
in
rats.
Maximum
plasma
concentration
was
reached
between
1.1
and
2.5
hours.
Two
major
routs
of
biotransformation
were
proposed
for
imidacloprid.
The
first
route
included
an
oxidative
cleavage
of
the
parent
compound
rendering
6­
chloronicotinic
acid
and
its
glycine
conjugate.
Dechlorination
of
this
metabolite
formed
the
6­
hydroxynicotinic
acid
and
its
mercapturic
acid
derivative.
The
second
route
included
the
hydroxylation
followed
by
elimination
of
water
of
the
parent
compound
rendering
imidacloprid.
A
comparison
between
[
methylene­
14C]­
imidacloprid
and
[
imidazolidine­
4,5­
14C]­
imidacloprid
showed
that
while
the
rate
of
excretion
was
similar,
the
renal
portion
was
higher
with
the
imidazolidine­
labeled
compound.
In
addition,
accumulation
in
tissues
was
generally
higher
with
the
imidazolidine­
labeled
compound.
A
comparison
between
imidacloprid
and
one
of
its
metabolites.
WAK
3839
showed
that
the
total
elimination
was
the
same
for
both
compounds.
The
proposed
metabolic
pathways
for
these
two
compounds
were
different.
WAK
3839
was
formed
following
pretreatment
(
repeated
dosing)
of
imidacloprid.
7.
Endocrine
disruption.
The
toxicology
data
base
for
imidacloprid
is
current
and
complete.
Studies
in
this
data
base
include
evaluation
of
the
potential
effects
on
reproduction
and
development
effects
on
reproduction
and
development,
and
an
evaluation
of
the
pathology
of
the
endocrine
organs
following
short­
term
or
long­
term
exposure.
These
studies
revealed
no
primary
endocrine
effects
due
to
imidacloprid.

A.
Aggregate
Exposure
Dietary
Exposure.
Dietary
exposure
for
oats
and
rye
has
been
previously
accounted
for
in
rotational
crop
inadvertent
tolerances
for
imidacloprid
on
cereal
grain,
group
15
and
forage,
hay,
and
straw.
So
no
additional
dietary
burden
is
expected.

i.
Food.
Acute
and
chronic
risk
assessments
will
not
be
different
from
the
current
risk
assessments
since
there
is
no
increase
in
exposure
for
earlier
assessments
containing
the
rotational
crop
inadvertent
tolerances
for
cereal
grains.

ii.
Drinking
water.
EPA,
as
published
in
the
Federal
Register
of
April
10,
2001
(
66
FR
18554)
(
FRL­
6777­
6),
calculated
acute
and
chronic
DWLOCs
and
compared
them
with
the
EECs
for
surface
and
ground
water.
Based
on
this
comparison,
they
determined
that
acute
exposure
and
chronic
exposure
would
not
be
expected
to
exceed
the
aPAD
and
cPAD,
respectively.

1.
Non­
dietary
exposure 
i.
Residential
turf.
Bayer
CropScience
has
conducted
an
exposure
study
to
address
the
potential
exposures
of
adults
and
children
from
contact
with
imidacloprid
treated
turf.
The
population
considered
to
have
the
greatest
potential
exposure
from
contact
with
pesticide
treated
turf
soon
after
pesticides
are
applied
are
young
children.
Margins
of
safety
(
MOS)
of
7,587
 
41,546
for
10­
year
old
children
and
6,859
 
45,249
for
5­
year
old
children
were
estimated
by
comparing
dermal
exposure
doses
to
the
imidacloprid
NOAEL
of
1,000
mg/
kg/
day
established
in
a
15­
day
dermal
toxicity
study
in
rabbits.
The
estimated
safe
residue
levels
of
imidacloprid
on
treated
turf
for
10­
year
old
children
ranged
from
5.6
 
38.2
µ
g/
cm2
and
for
5­
year
old
children
from
5.1
 
33.5
µ
g/
cm2.
This
compares
with
the
average
imidacloprid
transferable
residue
level
of
0.080
µ
g/
cm2
present
immediately
after
the
sprays
have
dried.
These
data
indicate
that
children
can
safely
contact
imidaclopridtreated
turn
as
soon
after
application
as
the
spray
has
dried.
ii.
Termiticide.
Imidacloprid
is
registered
as
a
termiticide.
Due
to
the
nature
of
the
treatment
for
termites,
exposure
would
be
limited
to
that
from
inhalation
and
was
evaluated
by
EPA
and
Bayer
CropScience.
Data
indicate
that
the
MOS
for
the
worst
case
exposures
for
adults
and
infants
occupying
a
treated
building
who
are
exposed
continuously
(
24
hours/
day)
are
8.0
x
10­
7
and
2.4
x
10­
8,
respectively
 
and
exposure
can
thus
be
considered
negligible.
iii.
Tobacco.
Smoke
Studies
have
been
conducted
to
determine
residues
in
tobacco
and
the
resulting
smoke
following
treatment.
Residues
of
imidacloprid
in
cured
tobacco
following
treatment
were
a
maximum
of
31
ppm
(
7
ppm
in
fresh
leaves).
When
this
tobacco
was
turned
in
a
pyrolysis
study
only
2%
of
the
initial
residue
was
recovered
in
the
resulting
smoke
(
main
stream
plus
side
stream).
This
would
result
in
an
inhalation
exposure
to
imidacloprid
from
smoking
of
approximately
0.005
mg
per
cigarette.
Using
the
measured
subacute
rat
inhalation
NOAEL
of
5.5
mg/
m3,
it
is
apparent
that
exposure
to
imidacloprid
from
smoking
(
direct
and/
or
indirect
exposure)
would
not
be
significant.
iv.
Pet
treatment.
Human
exposure
from
the
use
of
imidacloprid
to
treat
dogs
and
cats
for
fleas
has
been
addressed
by
EPA
with
the
conclusion
that
due
to
the
fact
that
imidacloprid
is
not
an
inhalation
or
dermal
toxicant
and
that
while
dermal
absorption
data
are
not
available,
imidacloprid
is
not
considered
to
present
a
hazard
via
the
dermal
route.

A.
Cumulative
Effects
Imidacloprid
is
a
chloronicotinyl
insecticide.
At
this
time,
EPA
has
not
made
a
determination
that
imidacloprid
and
other
substances
that
may
have
a
common
mechanism
of
toxicity
would
have
cumulative
effects.
Therefore,
for
these
tolerance
petitions,
it
is
assumed
that
imidacloprid
does
not
have
a
common
mechanism
of
toxicity
with
other
substances
and
only
the
potential
risks
of
imidacloprid
in
its
aggregate
exposure
are
considered.

B.
Safety
Determination
1.
U.
S.
population.
EPA
has
considered
data
from
developmental
toxicity
studies
in
the
rat
and
rabbit
and
a
2­
generation
reproduction
study
in
the
rat.
These
studies
are
discussed
under
section
A
(
Toxicology
Profile)
above.
The
developmental
toxicity
data
demonstrated
no
increased
sensitivity
of
rats
or
rabbits
to
in
utero
exposure
to
imidacloprid.
In
addition,
the
multigeneration
reproductive
toxicity
study
did
not
identify
any
increased
sensitivity
of
rats
to
in
utero
or
post­
natal
exposure.
Parental
NOAELs
were
lower
or
equivalent
to
developmental
or
offspring
NOAELs.
The
developmental
toxicity
studies
are
designed
to
evaluate
adverse
effects
on
the
developing
organism
resulting
from
maternal
pesticide
exposure
during
gestation.
Reproduction
studies
provide
information
relating
to
effects
from
exposure
to
the
pesticide
on
the
reproductive
capability
of
mating
animals
and
data
on
systemic
toxicity.

FFDCA
section
408
provides
that
EPA
shall
apply
an
additional
tenfold
margin
of
safety
for
infants
and
children
in
the
case
of
threshold
effects
to
account
for
prenatal
and
postnatal
toxicity
and
the
completeness
of
the
data
base
unless
EPA
determines
that
a
different
MOS
will
be
safe
for
infants
and
children.
MOS
are
incorporated
into
EPA
risk
assessments
either
directly
through
use
of
a
MOE
analysis
or
through
using
uncertainty
(
safety)
factors
(
UF)
in
calculating
a
dose
level
that
poses
no
appreciable
risk
to
humans.
EPA
believes
that
reliable
data
support
using
the
standard
UF
(
usually
100
for
combined
inter­
species
and
intra­
species
variability)
and
not
the
additional
tenfold
MOE/
UF
when
EPA
has
a
complete
data
base
under
existing
guidelines
and
when
the
severity
of
the
effect
in
infants
or
children
or
the
potency
or
unusual
toxic
properties
of
a
compound
do
not
raise
concerns
regarding
the
adequacy
of
the
standard
MOE/
UF.

Although
developmental
toxicity
studies
showed
no
increased
sensitivity
in
fetuses
as
compared
to
maternal
animals
following
in
utero
exposures
in
rates
and
rabbits,
no
increased
sensitivity
in
pups
as
compared
to
adults
was
seen
in
the
2­
generation
reproduction
toxicity
study
in
rats,
and
the
toxicology
data
base
is
complete
as
to
core
requirements,
EPA
has
determined
that
the
additional
safety
factor
for
the
protection
of
infants
and
children
will
be
retained
but
reduced
to
3x
based
on
the
following
weight­
of­
the­
evidence
considerations
relating
to
potential
sensitivity
and
completeness
of
the
data:

i.
There
is
concern
for
structure
activity
relationship.
Imidacloprid,
a
chloronicotinyl
compound,
is
an
analog
to
nicotine
and
studies
in
the
published
literature
suggests
that
nicotine,
when
administered
caused
developmental
toxicity,
including
functional
deficits,
in
animals
and
/
or
humans
that
are
exposed
in
utero.
ii.
There
is
evidence
that
imidacloprid
administration
causes
neurotoxicity
following
a
single
oral
dose
in
the
acute
study
and
alterations
in
brain
weight
in
rat
in
the
2­
year
carcinogenicity
study.
iii.
The
concern
for
structure
activity
relationship
along
with
the
evidence
of
neurotoxicity
dictates
the
need
of
a
developmental
neurotoxicity
study
for
assessment
of
potential
alterations
on
functional
development.
Because
a
developmental
neurotoxicity
study
potentially
relates
to
both
acute
and
chronic
effects
in
both
the
mother
and
fetus,
EPA
has
applied
the
additional
UF
for
FQPA
for
all
population
subgroups,
and
in
both
acute
and
chronic
risk
assessments.
Based
on
the
exposure
assessments
described
above
and
on
the
completeness
and
reliability
of
the
toxicity
data,
it
can
be
concluded
that
the
dietary
exposure
estimates
from
all
label
and
pending
uses
of
imidacloprid
are
9.4%
of
the
aPAD
at
the
99.9th
percentile
and
1.2%
of
the
cPAD
for
the
U.
S.
population.
Thus,
it
can
be
concluded
that
there
is
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
imidacloprid
residues.

1.
Infants
and
children.
Based
on
the
exposure
assessments
described
above
for
the
safety
determination
of
the
U.
S.
population
and
on
the
completeness
and
reliability
of
the
toxicity
data,
it
can
be
concluded
that
the
dietary
exposure
estimates
from
all
label
and
pending
uses
of
imidacloprid
are
27.1%
of
the
aPAD
at
the
99.9th
percentile
and
2.6%
of
the
cPAD
for
the
most
sensitive
population
subgroup,
children
1­
2
years.
Thus,
it
can
be
concluded
that
there
is
a
reasonable
certainty
that
no
harm
will
result
from
aggregate
exposure
to
imidacloprid
residues.

A.
International
Tolerances
No
CODEX
Maximum
Residue
Levels
have
been
established
for
residues
of
imidacloprid
on
oats
or
rye.
