HED
DOC.
NO.
012598
23­
APR­
1998
MEMORANDUM
SUBJECT:
IMIDACLOPRID
­
Report
of
the
FQPA
Safety
Factor
Committee.

FROM:
Brenda
Tarplee,
Executive
Secretary
FQPA
Safety
Factor
Committee
Health
Effects
Division
(
7509C)
and
Jess
Rowland,
Executive
Secretary
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

THROUGH:
Ed
Zager,
Chairman
FQPA
Safety
Factor
Committee
Health
Effects
Division
(
7509C)

TO:
Rick
Loranger,
Branch
Senior
Scientist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

PC
Code:
129099
The
Health
Effects
Division
(
HED)
FQPA
Safety
Factor
Committee
met
on
April
13,
1998
to
evaluate
the
hazard
and
exposure
data
for
Imidacloprid
and
recommend
application
of
the
FQPA
Safety
Factor
(
as
required
by
FQPA),
to
ensure
the
protection
of
infants
and
children
from
exposure
to
this
chemical.
The
Committee
recommended
that
the
10x
Safety
Factor
for
enhanced
sensitivity
to
infants
and
children
(
as
required
by
FQPA)
should
be
reduced
to
3x.
2
I.
HAZARD
ASSESSMENT
1.
Determination
of
Susceptibility
The
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
determined
that
the
available
studies
demonstrated
no
indication
of
increased
sensitivity
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
Imidacloprid.
In
the
prenatal
developmental
toxicity
studies
in
rats
and
rabbits
and
in
the
two­
generation
reproduction
study
in
rats,
developmental
toxicity
to
the
offspring
occurred
at
equivalent
or
higher
doses
than
maternal
toxicity
(
Memorandum:
J.
Rowland
to
D.
Davis,
dated
September
22,
1997).

2.
Adequacy
of
Toxicity
Database
There
are
no
data
gaps
for
the
assessment
of
the
effects
of
Imidacloprid
following
in
utero
and/
or
postnatal
exposure.
However,
the
HIARC
determined
that
a
postnatal
developmental
neurotoxicity
study
in
rats
is
required
for
Imidacloprid
based
on
the
following
weight­
of­
the­
evidence
considerations:


Imidacloprid
is
a
neurotoxic
chemical.
Evidence
of
functional
neurotoxicity
was
seen
in
the
acute
neurotoxicity
study
where
a
single
oral
dose
caused
a
dose­
related
decreased
motor
activity
in
all
dosed
females,
including
a
25%
decrease
at
the
lowest
dose
tested
(
42
mg/
kg/
day).


Imidacloprid
is
a
nicotine
analog
and
is
expected
to
act
as
a
nicotinic
agonist.
A
review
of
the
literature
suggests
that
nicotine
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
exposed
in
utero.


With
this
class
of
chemical,
there
is
no
readily
available
biomarker
(
e.
g.,
Cholinesterase
inhibition)
for
assessment
of
subtle
neurotoxic
effects.


In
the
1993
2­
year
chronic
study
in
rats,
significant
alterations
to
brain
weight
were
noted
in
males
and
females
at
900
ppm
(
51.3
and
73
mg/
kg/
day
in
males
and
females).
3
II.
EXPOSURE
ASSESSMENT
1.
Dietary
Exposure
Considerations
Imidacloprid
is
a
systemic
insecticide.
Its
primary
use
is
on
various
vegetable
crops,
cereal
grains,
and
pome
fruits.
Established
plant
and
animal
commodity
tolerances
(
40
CFR
180.472)
range
from
0.05
­
15
ppm.
Per
40
CFR
180.472,
the
regulated
residue
in
plant
and
animal
commodities
consists
of
the
combined
residues
of
parent
Imidacloprid
and
its
metabolites
containing
the
6­
chloropyridinyl
moiety,
all
expressed
as
parent
Imidacloprid.
Meat,
milk,
poultry,
and
egg
tolerances
are
established.

Imidacloprid
and
its
residues
are
systemic.
Residues
will
translocate
throughout
the
plant,
regardless
of
the
method
of
application:
seed,
soil,
or
foliar.
Use
is
via
seed
treatment,
banded
soil
application,
and/
or
foliar
spray.
Use
rates
via
soil
application
range
from
0.2­
0.4
lb
ai/
A/
application,
depending
on
the
crop;
and
via
foliar
sprays
range
from
0.05­
0.25
lb
ai/
A/
application,
depending
on
the
crop
and/
or
pest
to
be
controlled.
Regardless
of
formulation
or
type
of
application,
no
more
than
a
TOTAL
of
0.5
lb
ai/
A/
year
may
be
used
(
from
any
combination
of
seed
+
soil
+
foliar
treatments).

The
HED
DRES
system
was
used
to
assess
the
chronic
and
acute
risk
from
dietary
exposure
to
Imidacloprid
in
food.
The
chronic
dietary
risk
assessment
is
partially
refined
to
reflect
a
slightly
less
exaggerated
level
of
exposure
by
using
tolerance
values
for
all
crops
and
the
available
percent
crop
treated
(%
CT)
information.
The
acute
dietary
risk
assessment
was
not
refined,
it
included
the
very
conservative
assumption
that
all
commodities
will
contain
residues
of
Imidacloprid
at
the
level
of
the
tolerance.
This
results
in
an
overestimate
of
acute
dietary
exposure.

2.
Drinking
Water
Exposure
Considerations
EFED
reports
that
the
surface
and
groundwater
drinking
water
assessments
were
not
complete
for
Imidacloprid
at
the
time
of
this
meeting.
No
ground
or
surface
water
monitoring
data
are
available
for
Imidacloprid.
Therefore,
for
surface
water,
PRZM3.1/
EXAMS
modeling
will
be
conducted
to
estimate
representative
concentrations.

3.
Residential
Exposure
Considerations
Imidacloprid
is
registered
for
home
lawn
and
garden
use
and
for
"
localized"
pet
treatments
products
are
applied
either
to
back
of
the
neck
or
onto
the
back
of
the
animals).
Chemical
specific
or
site
specific
data
were
not
provided
to
assess
exposure
associated
with
these
uses,
therefore,
the
DRAFT
Standard
Operating
Procedures
(
SOPs)
for
Residential
Exposure
Assessments
were
utilized.
The
DRAFT
SOPs
normally
rely
on
one
or
more
upper­
percentile
assumptions
and
are
intended
to
represent
Tier
1
assessments.
4
Since
the
Draft
SOPs
do
not
specifically
address
"
localized"
per
applications,
a
modified
approach
was
developed
to
assess
post
application
hand­
to­
mouth
ingestion
exposure
for
toddlers.
The
following
assumptions
were
made:
1)
1%
of
the
application
rate
is
available
on
the
pets
as
dislodgeable
residue
on
the
day
of
application.
(
SOP
uses
10%
for
pet
dips
and
1%
for
flea
collars);
2)
there
is
a
one­
to­
one
relationship
between
the
dislodgeable
residue
on
the
surface
of
the
pet
and
on
the
surface
area
of
the
skin
after
contact;
3)
postapplication
activities
are
assessed
on
the
day
of
application
since
toddlers
could
handle/
touch
pets
immediately
after
application;
and
4)
toddlers
(
age
3
years)
are
used
to
represent
the
1
to
6
year
old
age
group
and
weigh
15
kg.

PHED
Version
1.1
is
also
used
for
residential
turf
handler
(
mixer/
loader/
applicator)
scenarios.
The
PHED
scenarios
reflect
the
actual
use
patterns
and
the
data
ranges
from
low
to
medium
level
quality.
Mixer/
loader/
applicators
are
assumed
to
be
wearing
short
pants,
short
sleeves,
and
no
gloves.

III.
RISK
CHARACTERIZATION
1.
Determination
of
the
Factor
The
Committee
recommended
that
the
10x
factor
for
enhanced
sensitivity
to
infants
and
children
(
as
required
by
FQPA)
should
be
reduced
to
3x.

2.
Rationale
for
Selection
of
the
FQPA
Factor
Although
the
available
studies
demonstrated
no
indication
of
increased
sensitivity
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
exposure
to
Imidacloprid,
the
Committee
determined
that
the
10x
Safety
Factor
should
be
reduced
to
3x
based
on
the
following
weight­
of­
the­
evidence
considerations:

(
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
causes
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
rats
in
the
2­
year
carcinogenicity
study.

(
iii)
There
is
concern
for
accidental
oral
exposure
(
hand­
to­
mouth)
for
infants
and
children
from
the
use
pattern
(
pet
and
outdoor
residential).
5
3.
Identification
of
Population
Subgroup
The
Committee
determined
that
the
FQPA
Safety
Factor
(
3x)
is
applicable
for
the
following
subpopulations:

Acute
Dietary:
General
populations
which
include
Infants
and
Children
because:
1)
There
is
concern
for
structure
activity
relationship
since
Imidacloprid,
a
chloronicotinyl
compound,
is
an
analog
to
nicotine
and
studies
in
the
published
literature
suggests
that
nicotine,
when
administered
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
that
are
exposed
in
utero;
2)
There
is
evidence
that
Imidacloprid
administration
causes
neurotoxicity
following
a
single
oral
exposure
and
was
selected
as
the
endpoint
for
this
risk
assessment;
and
3)
There
is
concern
for
accidental
oral
exposure
(
hand­
to­
mouth)
for
infants
and
children
from
the
use
pattern
(
pet
and
outdoor
residential).

Chronic
Dietary:
General
populations
which
include
Infants
and
Children
because:
1)
There
is
concern
for
structure
activity
relationship
since
Imidacloprid,
a
chloronicotinyl
compound,
is
an
analog
to
nicotine
and
studies
in
the
published
literature
suggests
that
nicotine,
when
administered
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
that
are
exposed
in
utero;
2)
There
is
evidence
that
Imidacloprid
administration
causes
neurotoxicity
following
repeated
exposure
characterized
as
alterations
in
brain
weight;
3)
The
endpoint
used
for
this
risk
assessment
is
thyroid
lesions;
and
4)
There
is
concern
for
accidental
oral
exposure
(
hand­
to­
mouth)
for
infants
and
children
from
the
use
pattern
(
pet
and
outdoor
residential).

Residential:
General
populations
which
include
Infants
and
Children
because
1)
There
is
concern
for
structure
activity
relationship
since
Imidacloprid,
a
chloronicotinyl
compound,
is
an
analog
to
nicotine
and
studies
in
the
published
literature
suggests
that
nicotine,
when
administered
causes
developmental
toxicity,
including
functional
deficits,
in
animals
and/
or
humans
that
are
exposed
in
utero;
2)
There
is
evidence
that
Imidacloprid
administration
causes
neurotoxicity
following
a
single
oral
dose
in
the
acute
study
and
alterations
in
brain
weight
in
rats
in
the
2­
year
carcinogenicity
study;
3)
the
pet
and
outdoor
residential
uses
of
Imidacloprid
are
a
potential
source
of
exposure
to
infants
and
children.
