Document ID: EPA-HQ-OPP-2003-0217-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-06-04T04:00Z

Overview
of
Imazalil
Risk
Assessment
Introduction
This
document
summarizes
EPA's
occupational
and
ecological
risk
findings
for
the
pesticide
imazalil,
as
presented
fully
in
the
documents,
"
Imazalil:
HED
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
(
RED)
Document,"
dated
February
7,
2002,
and
"
Environmental
Risk
Assessment
for
the
Reregistration
of
Imazalil,"
dated
September
22,
1999.
EPA's
dietary
risk
assessment
and
tolerance
reassessment
for
Imazalil
can
be
found
in
the
Tolerance
Reassessment
Decision
document
(
TRED)
issued
for
Imazalil
on
July
12,
2002.
The
purpose
of
this
overview
is
to
help
the
reader
understand
the
conclusions
reached
in
the
risk
assessments
by
identifying
the
key
features
and
findings
of
the
assessments.
This
overview
was
developed
in
response
to
general
comments
from
the
public
which
indicated
that
EPA's
risk
assessments
were
difficult
to
understand,
that
they
were
too
lengthy,
and
that
it
was
not
easy
to
compare
the
assessments
for
different
chemicals
due
to
the
use
of
different
formats.

The
imazalil
risk
assessments
and
additional
supporting
documents
are
posted
on
EPA's
Internet
website
(
http://
www.
epa.
gov/
pesticides/
imazalil.
htm)
and
are
available
in
the
Pesticide
Docket
for
public
viewing.
Meetings
with
stakeholders
(
i.
e.,
growers,
extension
officials,
commodity
group
representatives,
worker
and
environmental
advocates,
and
other
government
officials)
will
be
held
to
discuss
the
risk
assessments,
the
identified
risk
and
solicit
input
on
risk
mitigation
strategies,
if
needed.
This
feedback
will
be
used
to
complete
the
Reregistration
Eligibility
Decision
(
RED)
document,
which
will
include
the
resulting
risk
management
decisions.
The
Agency
plans
to
conduct
a
close­
out
conference
call
with
interested
stakeholders
to
describe
the
regulatory
decisions
presented
in
the
RED.

The
Agency
is
in
the
process
of
developing
criteria
for
characterizing
and
testing
endocrine
disrupting
chemicals
and
plans
to
implement
an
Endocrine
Disruptor
Screening
Program.
Imazalil
will
be
reevaluated
at
that
time
and
additional
testing
may
be
required.
2
Use
Profile
°
Fungicide
(
systemic):
Registered
for
post­
harvest
treatment
of
citrus
fruits,
for
seed
treatment
of
barley
and
wheat
prior
to
planting,
and
as
a
disinfectant
in
chicken
hatcheries.
There
is
also
an
import
tolerance
for
bananas.

°
Formulations:
Formulated
as
impregnated
material
(
14.9%
active
ingredient(
ai)),
liquid
(
up
to
31%
ai),
emulsifiable
concentrate
(
up
to
68.25%
ai),
and
flowable
concentrate
(
10%
ai).

°
Methods
of
Application:
Applied
by
seed
treatment
methods,
drenches,
smoke
generators,
fruit
waxing
equipment,
and
hand
held
equipment.

°
Use
Rates:
For
treating
citrus,
the
maximum
rate
by
wax
treatment
is
2,000
ppm
(
1.665
lb
ai/
100
gal).
The
seed
treatment
maximum
application
rate
is
0.01008
lb
ai/
100
lb
of
seed
(
slurry­
type
seed
treatment).
In
egg
handling
facilities
(
hatchery
and
equipment),
the
maximum
rates
are
0.00032
lb
ai/
1,000
ft3
for
spray
and
0.022
lb
ai/
1,000
ft3
for
smoke
generator.

°
Annual
Poundage:
Estimates
for
total
annual
domestic
use
averages
approximately
6000
pounds
of
active
ingredient.
Crops
with
the
highest
percent
crop
treated
are
grapefruit
22%,
tangerines
26%,
lemons
no
storage
22%,
pre­
storage
24%,
and
post
storage
3%,
and
limes
50%.
In
terms
of
pounds
applied,
oranges,
grapefruit,
and
lemons
account
for
the
greatest
agricultural
use.

°
Registrants:
Jansen
Pharmaceutica
(
basic
producer)
and
Makhteshim­
Agan
of
North
America.

Human
Health
Risk
Assessment
This
section
addresses
occupational
risk
issues
only.
Please
see
the
July
12,
2002
TRED
to
see
the
specifics
of
the
Agency's
tolerance
reassessment
decision
for
acute
and
chronic
dietary,
and
drinking
water
risk.
Since
the
July
12,
2002,
TRED,
the
registrant
conducted
a
study
and
submitted
new
data
to
address
whether
a
linear
low
dose
(
Q*)
model
or
a
threshold
cancer
model
should
be
used
to
characterize
the
cancer
risk
for
imazalil.
The
Agency
reviewed
the
study
and
concluded
the
Q*
model
was
most
appropriate.
The
registrant
indicated
they
will
provide
additional
analysis
and
data
on
this
issue
during
the
Phase
5
comment
period.
There
is
the
possibility
that
this
additional
data
may
result
in
a
determination
that
a
threshold
cancer
model
is
more
appropriate.
The
Agency
will
consider
their
comments
and
adjust
the
cancer
model
if
appropriate.
3
°
Imazalil
is
classified
as
"
Likely
to
be
carcinogenic
in
humans,"
according
to
EPA's
July
1999
Draft
Guidelines
for
Carcinogenic
Assessment.
Carcinogenicity
studies
in
rodents
indicate
imazalil
is
carcinogenic
to
male
Swiss
albino
mice
and
Wistar
rats,
based
on
a
significant
increase
in
liver
adenomas
and
combined
adenomas/
carcinomas.
In
rats,
there
was
also
an
increased
incidence
of
combined
thyroid
follicular
cell
adenomas/
carcinomas.

$
Based
on
current
science
policy
and
absent
information
supporting
a
mode
of
action
in
test
animals,
EPA
quantified
the
human
cancer
risk
by
a
linear
low­
dose
(
Q
1
*)
extrapolation.
The
most
potent
unit
risk,
Q
1
*(
mg/
kg/
day)­
1
for
imazalil
based
on
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates
is
6.1
x
10­
2
(
mg/
kg/
day)­
1
in
human
equivalents.

°
Imazalil
is
a
Toxicity
Category
I
for
primary
eye
irritation,
Toxicity
Category
II
for
oral,
Toxicity
Category
III
for
dermal,
and
Toxicity
Category
IV
for
inhalation.

°
The
primary
target
organ
for
imazalil
toxicity
in
animals
is
the
liver.

Occupational
Risk
(
For
a
complete
discussion,
see
section
4.4
of
the
Human
Health
Risk
Assessment)

Workers
can
be
exposed
to
a
pesticide
while
mixing
and
loading,
or
applying
a
pesticide,
and
entering
a
treated
site.
For
non­
cancer
risks,
handlers
and
worker
risks
are
measured
by
a
Margin
of
Exposure
(
MOE)
which
determine
how
close
the
occupational
exposure
comes
to
a
No
Observed
Adverse
Effect
Level
(
NOAEL)
from
animal
studies.
For
imazalil,
MOEs
greater
than
100
do
not
exceed
the
Agency's
level
of
concern.
The
target
for
cancer
risks
is
1
x
10­
6,
however,
the
Agency
is
concerned
with
risks
above
1
x
10­
4.
For
risks
between
1
x
10­
6
and
1
x
10­
4,
the
Agency
will
pursue
risk
mitigation
where
feasible.
For
workers
entering
a
treated
site,
entry
restrictions
are
calculated
to
determine
the
minimum
length
of
time
required
before
workers
or
others
are
allowed
to
re­
enter.

In
the
case
of
imazalil,
dermal
and
inhalation
risks
are
assessed
separately
since
the
toxicological
endpoints
for
these
exposures
are
not
the
same
and
Agency
policy
is
to
not
aggregate
the
risks
(
inhalation
plus
dermal)
if
the
toxicological
effects
are
not
similar.
Exposures
to
imazalil
are
expected
to
be
short­,
intermediate­
and
long­
term
by
dermal
and/
or
inhalation
routes
of
exposure.
Life­
time
cancer
risk
is
also
calculated
for
the
various
scenarios.

$
For
the
short­
term
dermal
toxicity
endpoint,
the
NOAEL
of
160
mg/
kg/
day
is
based
on
skin
effects
and
swollen
livers
from
a
21­
day
dermal
study
in
the
rabbit.
The
LOAEL
is
250
mg/
kg/
day.

°
For
estimating
intermediate­
and
long­
term
dermal
risks,
EPA
used
oral
animal
studies
in
the
absence
of
appropriate
dermal
toxicity
studies.
The
dermal
absorption
factor
is
40%,
based
upon
the
maximum
blood
concentration
observed
in
a
rat
dermal
absorptions
study.
This
factor
was
used
for
converting
dermal
exposures
to
equivalent
oral
doses.
(
A
4
comparison
of
oral
and
dermal
toxicity
studies
suggests
that
the
actual
dermal
absorption
rate
for
imazalil
may
be
lower;
the
apparent
rate
may
be
as
low
as
4%
in
the
rabbit.
Thus,
the
dermal
absorption
factor
may
over
predict
the
amount
of
imazalil
available
to
elicit
a
toxic
response,
making
both
the
intermediate­
and
long­
term
dermal
risks
assessments
conservative.)

°
For
the
intermediate­
term
dermal
toxicity
endpoint,
the
NOAEL
of
16
mg/
kg/
day
is
based
on
severe
liver
effects
at
the
oral
LOAEL
of
32
mg/
kg/
day
from
a
90­
day
feeding
study
in
the
rat.

°
For
the
long
term
dermal
toxicity
endpoint,
a
NOAEL
of
2.5
mg/
kg/
day
is
based
on
systemic
toxicity,
decreased
body
weight
gain,
increased
liver
weight
and
increased
alkaline
phosphates
at
the
oral
LOAEL
of
20
mg/
kg/
day
from
the
one
year
feeding
study
in
the
dog.

°
For
estimating
short­,
intermediate­
and
long­
term
inhalation
risks,
EPA
used
oral
animal
studies
in
the
absence
of
appropriate
inhalation
toxicity
studies.
EPA
assumes
100%
of
the
inhaled
imazalil
dose
is
absorbed
by
the
body.

°
For
the
short­
term
inhalation
toxicity
endpoint,
a
NOAEL
of
5
mg/
kg/
day
is
based
on
an
increased
incidence
of
reabsorption
and
decreased
number
of
fetuses
from
a
developmental
toxicity
study
in
rabbits
where
the
LOAEL
is
10
mg/
kg/
day.

°
For
the
intermediate­
term
and
long­
term
inhalation
toxicity
endpoints,
a
NOAEL
of
2.5
mg/
kg/
day
is
based
on
the
above
one
year
feeding
study
in
the
dog.

°
As
described
above,
based
on
current
science
policy
and
absent
information
supporting
a
mode
of
action
in
test
animals,
EPA
quantified
the
human
cancer
risk
by
a
linear
low­
dose
(
Q
1
*)
extrapolation.
The
most
potent
unit
risk,
Q
1
*(
mg/
kg/
day)­
1
for
imazalil
based
on
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates,
is
6.1
x
10­
2
(
mg/
kg/
day)­
1
in
human
equivalents.

Occupational
Handler
Summary
EPA
identified
14
handler
exposure
scenarios
resulting
from
mixing/
loading
and
applying
(
liquid
and
dry)
imazalil
for
seed
treatment
(
on­
farm
and
commercial
seed­
treatment
equipment);
for
citrus,
mixing/
loading
and
applying
various
formulations
with
drenching,
waxing
and
foaming
equipment;
and
in
chicken
hatcheries,
mixing/
loading
and
applying
liquid
formulation
for
high
pressure
handwand
applications
and
applying/
lighting
smoke
canisters.

°
No
chemical­
specific
exposure
studies
are
available
for
the
occupational
assessment.
Surrogate
exposure
data
from
the
Pesticide
Handler
Exposure
Database
(
PHED)
and
other
available
data,
were
used
to
assess
potential
exposure
for
each
scenario.
5
°
The
following
assumptions
and
factors
were
used
for
completing
the
occupational
risk
assessment:

°
The
average
body
weight
of
70
kg
is
used,
representing
a
typical
adult.
°
Exposure
duration
is
assumed
to
be
35
years.
This
represents
a
typical
working
lifetime.
°
A
lifetime
is
assumed
to
be
70
years.
°
The
Q
1
*
used
in
the
cancer
assessment
was
6.11
x10­
2
(
mg/
kg/
day)­
1.
°
Exposure
frequencies
used
in
the
calculations
are:
250
days
for
chicken
hatcheries,
15
days
for
commercial
seed
treatment,
10
days
on
farm
seed
treatment,
and
100
days
for
commercial
citrus
applicator.

Handler
Risk
Scenarios
and
Results
The
Agency
evaluated
14
handler
exposure
scenarios,
resulting
from
application
of
imazalil
for
seed
treatment,
citrus,
and
chicken
hatcheries.
The
results
of
the
non­
cancer
short­,
intermediate­
and
long­
term
dermal
and
inhalation
risk
assessments
show
that
all
scenarios
provide
MOEs
greater
than
or
equal
to
100
at
baseline
attire
(
i.
e.,
long
pants,
long
sleeved
shirts,
no
gloves),
except
for
mixing/
loading
liquid
formulation
for
waxing
equipment.
With
the
addition
of
PPE,
the
MOE
for
this
scenario
is
also
much
greater
than
100.
In
this
case,
PPE
is
long
pants,
long
sleeved
shirts
and
chemical
resistant
gloves.

The
results
for
cancer
risk
show
that
of
the
14
scenarios
evaluated
with
PPE,
one
scenario
was
1.50
x
10­
4
(
mixing,
loading,
applying
for
on
farm
seed
treatment),
two
scenarios
were
in
the
10­
5
range
(
mixing,
loading,
applying
for
both
on
farm
and
commercial
seed
treatment),
and
the
remaining
scenarios
were
in
the
10­
6
to
10­
7
range.
Most
imazalil
labels
currently
prescribe
the
following
PPE
for
all
handlers:
long
sleeved
shirt
and
long
pants,
gloves,
shoes,
socks,
and
protective
eye­
wear.

There
was
insufficient
data
for
the
Agency
to
quantify
risks
for
the
following
5
scenarios.
°
Mix/
load
of
liquid
with
foaming
equipment
°
Application
of
liquid
with
drencher
°
Application
of
liquid
with
foaming
equipment
°
Application
of
liquid
with
waxing
equipment
°
Application
lighting
and
using
smoke
canister
for
chicken
hatchery
6
Although
the
risks
for
these
scenarios
have
not
been
quantified,
the
Agency
does
not
believe
there
are
risks
of
concern
associated
with
these
scenarios.
EPA
does
not
expect
the
risk
for
mixing
and
loading
liquid
for
foaming
equipment
to
be
substantially
different
from
mixing
and
loading
liquid
for
waxing,
which
has
acceptable
risks.
In
the
case
of
the
application
scenarios
for
the
drenching,
foaming
and
waxing,
occupational
exposure
is
unlikely
because
these
operations
are
mechanically
and
remotely
performed.
Finally,
the
Agency
did
a
very
conservative
risk
assessment
for
handler
risk
from
smoke
generators
containing
imazalil.
Even
with
these
very
conservative
assumptions,
the
risks
were
acceptable
with
the
use
of
an
organic
vapor
respirator.
EPA
does
not
expect
the
risks
to
applicators
lighting
and
using
smoke
canisters
to
be
very
different.
The
Agency
will
require
data
to
confirm
these
conclusions.

Post­
Application
Occupational
Risk
EPA
has
determined
that
there
is
potential
exposure
to
workers
handling
citrus
fruits
after
waxing
or
foaming,
to
persons
working
in
egg
handling
facilities,
and
to
persons
handling
treated
seeds.

°
For
citrus,
the
main
activities
are
sorting/
culling
or
packing
of
products
following
wax
treatment.
The
Agency
has
no
data
specifically
addressing
the
exposure
from
those
activities.
Exposure
estimates
for
citrus
in
the
risk
assessment
were
derived
from
residue
chemistry
data,
surface
area
calculations,
and
a
reentry
study
for
citrus
found
in
the
scientific
literature.

$
For
non­
cancer
effects,
risk
from
handling
citrus
was
not
of
concern
for
intermediate
term
effects
at
baseline
protection
of
(
long
pants,
long
sleeved
shirt,
no
gloves).

$
For
cancer,
the
estimated
lifetime
cancer
risk
for
citrus
workers
exposed
to
imazalil
in
post
treatment
was
estimated
to
be
6.68
x
10­
4
under
the
baseline
exposure
scenario.
With
the
addition
of
protective
gloves,
risks
are
in
the
range
10­
5
to
10­
7.

$
Citrus
exposure
estimates
are
considered
very
conservative
because
(
1)
although
imazalil
is
usually
part
of
a
wax
matrix
which
substantially
impedes
transfer
to
the
skin,
it
was
assumed
that
all
of
the
imazalil
on
the
treated
surface
could
be
transferred
to
the
skin;
and
(
2)
the
transfer
coefficients
for
the
hands
were
obtained
from
a
field
study
in
which
contact
with
contaminated
foliage
was
highly
probable;
a
conveyor
belt
treatment
line
would
be
unlikely
to
have
such
a
high
degree
of
contact
(
exposure
would
likely
be
restricted
to
fingertips
only).

$
Given
the
nature
of
the
activities
at
egg
handling
facilities
as
described
in
February
7,
2002,
Human
Health
Risk
Assessment,
EPA
believes
that
there
is
minimal
risk
involved
in
dermal
or
inhalation
exposure
to
imazalil
in
chicken
hatcheries;
therefore
no
postapplication
inhalation
or
dermal
risk
assessment
was
performed
for
reentry
following
smoke
generator
or
spraying
applications
in
chicken
factories.

$
Post
application
exposure
to
imazalil
from
treated
seeds
following
soil
incorporation
is
7
considered
to
be
negligible
as
long
as
the
soil
is
not
directly
contacted.
Farmers
handling
treated
seed
which
has
been
stored
for
an
indefinite
time
before
use,
represented
a
minimal
exposure
hazard
to
the
handler
and
is
not
a
risk
of
concern.

Ecological
Risk
To
estimate
potential
ecological
risk,
EPA
integrates
the
results
of
exposure
and
ecotoxicity
studies
using
the
quotient
method.
Risk
quotients
(
RQs)
are
calculated
by
dividing
exposure
estimates
by
ecotoxicity
values,
both
acute
and
chronic,
for
various
wildlife
species.

RQs
are
then
compared
to
levels
of
concern
(
LOCs).
Generally,
the
higher
the
RQ,
the
greater
the
potential
risk.
Risk
characterization
provides
further
information
on
the
likelihood
of
adverse
effects
occurring
by
considering
the
fate
of
the
chemical
in
the
environment,
and
species
potentially
at
risk,
their
spatial
and
temporal
distributions
and
the
nature
of
the
effects
observed
in
studies.

Environmental
Fate
and
Transport
°
Imazalil
is
moderately
water
soluble,
very
stable
to
hydrolysis,
photodegrades
relatively
rapidly,
degrades
very
slowly
in
soil
under
aerobic
conditions,
is
immobile
in
soils,
is
not
expected
to
volatilize,
and
has
a
high
octanol
water
partition
coefficient.

°
Based
on
the
above
environmental
fate
properties,
and
with
consideration
of
the
product
formulations,
the
application
methods,
and
the
application
rates,
EPA
believes
that
the
immobile
and
relatively
persistent
parent
compound
is
not
likely
to
be
found
in
significant
concentrations
in
the
environment.

Terrestrial
Organism
Risk
°
Based
on
the
available
data,
imazalil
is
practically
nontoxic
to
slightly
toxic
to
birds,
and
moderately
toxic
to
rats
following
acute
exposure.
A
chronic
toxicity
study
with
mallard
ducks
indicated
effects
on
embryo
viability
and
hatchability,
while
body
weight
loss
was
observed
with
bobwhite
quails.
In
the
two
generation
rat
chronic
study,
effects
on
body
weight
and
litter
size
were
observed.

°
On
the
basis
of
risk
quotients,
imazalil
use
at
the
recommended
application
rates
will
not
result
in
an
acute
or
chronic
risk
to
either
avian
or
mammal
species.
No
LOCs
were
exceeded
due
to
the
low
application
rate
and
minimal
exposure.

Aquatic
Organism
Risk
8
°
Imazalil
is
moderately
toxic
to
both
freshwater
fish
and
invertebrates
in
terms
of
acute
toxicity.

°
On
the
basis
of
risk
quotients,
imazalil
did
not
exceed
any
of
the
Agency's
levels
of
concern
for
freshwater
organisms.
No
acute
levels
of
concern
for
freshwater
organisms
were
exceeded
due
to
the
extremely
low
exposure,
which
is
attributable
to
the
low
application
rate
(
0.01
lb
ai/
A)
and
the
seed
treatment
end­
use
(
only
1%
residue
left
on
soil
surface)

°
Because
of
the
extremely
low
exposure
to
freshwater
organisms,
acute
toxicity
testing
for
estuarine
aquatic
organisms
and
all
chronic
testing
have
been
waived.

Incident
Data
°
There
are
no
fish
or
wildlife
incident
reports
regarding
imazalil
in
EPA's
Ecological
Incident
Information
System.

Endangered
Species
°
None
of
imazalil
RQ
values
for
endangered
species
exceed
Levels
of
Concern
for
either
terrestrial
or
aquatic
non­
target
organisms.
The
risk
quotients
for
freshwater
fish
and
invertebrate
values
are
0.00005
and
0.00002,
respectively.
This
is
well
below
the
L0C
(
Level
of
Concern)
value
of
0.05.
The
RQ
values
for
avian
and
mammal
species
are
both
<
0.01
and
also
well
below
the
LOC
of
0.05.

Summary
of
Pending
Data
The
following
confirmatory
data
requirements
have
been
initially
identified
by
the
Agency:

Toxicology
Data
for
OPPTS
Guidelines:

°
870.6300
Developmental
Neurotoxicity
in
Rats
°
870.6200
Acute
Neurotoxicity
Study
in
Rats
°
870.6200
Subchronic
Neurotoxicity
Study
in
rats
Product
and
Residue
Chemistry
Data
for
OPPTS
Guidelines:

°
860.1340
Residue
analytical
Method
­
Animal
Commodities
°
860.1360
Multi
residue
Method
°
860.1480
Egg
and
poultry
fumigation
Study
Occupational
Exposure
Data
for
OPPTS
Guidelines
°
Exposure
study
of
citrus
treatment
applicators
(
wax,
foaming
and
drencher
applications).
9
°
Exposure
study
for
mixing/
loading
with
foaming
equipment.
°
Post
application
inhalation
and
dermal
exposure
following
smoke
generator
or
spraying
applications
in
chicken
hatcheries