(
September
15,
2004)
1
RISK
SCREEN
ON
THE
USE
OF
SUBSTITUTES
FOR
OZONE­
DEPLETING
SUBSTANCES
Proposed
Substitute:
IoGas
 
Sterilants
1,
3,
and
6
End
Use:
Sterilization
This
risk
screen
does
not
contain
Clean
Air
Act
(
CAA)
Confidential
Business
Information
(
CBI)
and,
therefore,
may
be
disclosed
to
the
public.

1.
INTRODUCTION
Stratospheric
ozone­
depleting
substances
(
ODS)
are
being
phased
out
of
production
in
response
to
a
series
of
diplomatic
and
legislative
efforts
that
have
taken
place
over
the
past
decade,
including
the
Montreal
Protocol
and
the
Clean
Air
Act
Amendments
of
1990
(
CAA).
The
U.
S.
Environmental
Protection
Agency
(
EPA),
as
authorized
by
Section
612
of
the
CAA,
has
developed
a
program
to
evaluate
the
human
health
and
environmental
risks
posed
by
alternatives
to
ODS.
The
main
purpose
of
EPA's
program,
called
the
Significant
New
Alternatives
Policy
(
SNAP)
Program,
is
to
identify
acceptable
and
unacceptable
substitutes
for
ODS
in
specific
end
uses.

EPA's
decision
on
the
acceptability
of
a
substitute
is
based
largely
on
the
findings
of
a
screening
assessment
of
potential
human
health
and
environmental
risks
posed
by
the
substitute
in
specific
applications.
EPA
has
already
screened
a
large
number
of
substitutes
in
many
end
uses
within
all
of
the
major
ODS­
using
sectors,
including
refrigeration
and
air
conditioning;
solvent
cleaning;
foam­
blowing;
aerosols;
fire
extinguishing;
adhesives,
coatings,
and
inks;
and
sterilization.
The
results
of
these
risk
screens
are
presented
in
a
series
of
background
documents
that
are
available
in
this
docket.

The
purpose
of
this
report
is
to
supplement
EPA's
background
document
(
EPA,
1994)
on
the
sterilant
application
of
IoGas
 
blends,
which
are
used
as
substitutes
for
blends
of
ethylene
oxide
(
EtO)
and
CFC­
12,
HCFC­
22
or
HCFC­
124.
IoGas
 
is
a
blend
of
EtO,
carbon
dioxide,
and
trifluoroiodomethane.
EtO
has
been
shown
to
exhibit
toxicity
upon
inhalation
and
has
been
examined
at
length
in
the
Background
Document.
The
reader
is
referred
to
this
reference
for
a
detailed
discussion
of
the
methodologies
used
to
conduct
this
risk
screen.
In
addition,
EPA's
SNAP
Program
has
previously
found
pure
EtO
to
be
an
acceptable
substitute
for
the
use
of
EtO
and
CFC­
12
blends
in
sterilization
processes.
Because
EtO
has
previously
been
approved
as
a
substitute
under
the
SNAP
program,
the
toxicity
of
this
ODS
substitute
will
not
be
discussed
in
detail
in
this
document.

Occupational
exposure
and
general
population
analyses
were
performed
to
ensure
that
use
of
the
IoGas
 
in
the
applications
listed
above
did
not
pose
unacceptable
risk
to
workers
or
the
general
public.
Consumer
exposure
modeling
was
not
performed
because
no
consumer
applications
are
proposed
for
the
blend.
(
September
15,
2004)
2
Section
2
of
this
report
summarizes
the
results
of
the
risk
screen
for
the
proposed
substitute
blends
listed
in
Tables
1
­
3.
The
remainder
of
the
report
is
organized
similarly
to
the
Background
Document:
Section
3
presents
the
toxicity
values
used
for
the
risk
screen,
Section
4
presents
the
results
of
the
atmospheric
assessment,
Sections
5,
6,
and
7
discuss
occupational,
general
population,
and
consumer
exposures,
respectively
and
Section
8
discusses
potential
increases
in
atmospheric
releases
of
volatile
organic
compounds
(
VOCs).

Table
1.
Proposed
Substitute
Blend
1
Sterilant
Blend
(
Trade
Name)
Constituents
Percent
Composition
by
Weight
Percent
Composition
by
Volume
CAS
Number
Ethylene
oxide
(
EtO)
75­
21­
8
Carbon
Dioxide
(
CO2)
124­
38­
9
IoGas
 
Trifluoroiodomethane
(
CF3I)
2314­
97­
8
Table
2.
Proposed
Substitute
Blend
3
Sterilant
Blend
(
Trade
Name)
Constituents
Percent
Composition
by
Weight
Percent
Composition
by
Volume
Ethylene
oxide
(
EtO)

Carbon
Dioxide
(
CO2)
IoGas
 
Trifluoroiodomethane
(
CF3I)
(
September
15,
2004)
3
Table
3.
Proposed
Substitute
Blend
6
Sterilant
Blend
(
Trade
Name)
Constituents
Percent
Composition
by
Weight
Percent
Composition
by
Volume
Ethylene
oxide
(
EtO)

Carbon
Dioxide
(
CO2)
IoGas
 
Trifluoroiodomethane
(
CF3I)

2.
SUMMARY
OF
RESULTS
IoGas
 
is
recommended
for
SNAP
approval
for
all
the
proposed
end
uses.
EPA's
risk
screen
indicates
that
the
use
of
the
proposed
substitute
and
its
constituents
will
be
less
harmful
to
the
atmosphere
than
the
continued
use
of
CFC­
12.
Additionally,
general
population
exposure
to
the
substitute
is
expected
to
be
below
levels
of
concern
for
noncancer
risks.
EPA
believes
that
by
following
existing
regulations
and
installing
the
proper
control
systems,
use
or
manufacture
of
IoGas
 
is
not
likely
to
pose
a
significant
risk
to
consumers,
workers,
or
the
general
public.

3.
TOXICITY
REFERENCE
VALUES
FOR
SUBSTITUTES
To
assess
potential
health
risks
from
exposure
to
this
substitute
for
ODS
in
the
sterilant
sector;
EPA
identified
the
relevant
toxicity
threshold
values,
including
available
published
occupational
exposure
limits.
For
the
occupational
exposure
analysis
provided
in
this
risk
screen,
potential
risks
from
chronic
worker
exposure
were
evaluated
by
comparing
exposure
concentrations
to
published
values
(
i.
e.,
OSHA
PELs)
or
to
ones
derived
by
EPA,
namely
acceptable
exposure
limits
(
AELs)
for
purposes
of
evaluating
exposure
concerns.
Potential
risks
from
short­
term
occupational
exposures
were
also
evaluated
through
comparison
with
published
values
(
i.
e.,
OSHA
STELs)
or
to
ones
derived
by
EPA,
namely
emergency
guidance
levels
(
EGLs).
Table
4
presents
the
toxicity
reference
values
used
in
the
analysis.
(
September
15,
2004)
4
TABLE
4.
Toxicity
Reference
Values
for
Substitutes
Chemical
Acceptable
Exposure
Level
(
AEL)
ppm
Short­
term
Exposure
Limits
(
STEL)
ppm
EtO
1a,
b
5b
CO2
5,000a
30,000e
CF3I
150d
2,000c
a
Value
presented
above
is
the
OSHA
PEL.
b
OSHA
EtO
standard,
29
CFR
1910.1045.
c
EGL
based
on
2,000
ppm
NOAEL
for
cardiotoxicity.
d
See
Attachment
1.
ICF
1998.
"
Recommendation
for
an
Acceptable
Exposure
Limit
for
CF3I."
e
ACGIH,
2002
STEL.

4.
ATMOSPHERIC
MODELING
This
section
presents
EPA's
assessment
for
the
potential
impact
of
each
substitute
on
ozone
depletion
and
global
warming.
The
atmospheric
lifetime
(
ALT)
of
ethylene
oxide
is
short,
on
the
order
of
50
to
200
days
based
on
rapid
destruction
by
radicals
present
in
the
lower
atmosphere.
For
each
blend,
the
combined
ODP
is
less
than
0.001
and
the
100­
year
GWP,
relative
to
CO2,
is
less
than
1.
Table
5
presents
the
ODP,
GWP
and
ALT
for
each
proposed
substitute
blend
and
its
components.

Table
5.
ODP,
GWP,
and
ALT
for
Proposed
Sterilization
Substitutes
Substitute
ODP
100­
Year
GWP
(
relative
to
CO2)
ALT
(
years)

EtO
0
<
1
0.3
CO2
0
1
100a
CF3I
<
0.0025
<
1
0.007
IoGas
 
Blend
1
<
0.001
<
1
NA
IoGas
 
Blend
3
<
0.001
<
1
NA
IoGas
 
Blend
6
<
0.001
<
1
NA
a
One­
hundred
years
represents
CO2'
s
first
atmospheric
lifetime,
which
is
defined
as
the
time
it
takes
for
a
compound
to
be
reduced
to
1/
e
or
36.8%
of
its
original
concentration.
Most
gases
only
have
one
atmospheric
lifetime
because
they
follow
pure
exponential
decay.
However,
for
CO2,
as
time
increases,
the
amount
of
time
it
takes
to
reduce
CO2
to
36.8%
of
its
concentration
increases.
Therefore,
CO2'
s
second
atmospheric
lifetime
is
several
hundreds
of
years.
NA
 
Not
applicable.
(
September
15,
2004)
5
5.
OCCUPATIONAL
EXPOSURE
AND
RISK
SCREENING
ANALYSIS
Sterilization
workers
may
be
exposed
to
trace
amounts
of
IoGas
 
during
manufacture,
when
filling
containers,
transporting
containers,
and
charging
sterilization
equipment.
In
general,
exposures
are
expected
to
occur
only
in
cases
of
accidental
leakages,
discharges,
or
equipment
rupture.
Because
the
sterilant
gases
are
normally
handled
only
in
gas­
tight
systems
at
all
times,
no
significant
exposure
is
anticipated
for
any
handling
activities
at
the
filling
stage.

The
estimated
maximum
duration
of
activity
for
workers
handling
the
IoGas
 
sterilant
under
initial
production
capacity
is
8
hours/
day,
150
days/
year.
When
IoGas
 
production
is
well­
established,
then
the
estimated
maximum
duration
of
activity
for
workers
is
8
hours/
day,
200
days/
year.
According
to
the
submission,
average
exposures
can
be
kept
below
0.1
ppm
using
local
exhaust
systems.
It
is
estimated
that
in
the
case
of
a
leak,
exposure
to
IoGas
 
can
be
kept
below
5
ppm
by
use
of
detectors,
evacuation
of
personnel,
and
the
use
of
self­
contained
breathing
apparatuses
(
SCBA)
(
IoGas
 
Submission
2003).

Using
the
estimated
IoGas
 
exposure
values
presented
in
the
submission
(
average
exposure
of
less
than
0.1
ppm
and
high­
end
exposure
of
5
ppm),
the
average
worker
exposure
to
each
constituent
within
a
blend
was
estimated;
these
values
are
presented
in
Table
6
and
7.
For
EtO
(
the
most
toxic
constituent
of
the
blend)
the
exposure
estimates
are
less
than
the
OSHA
PEL
of
1
ppm
and
the
OSHA
STEL
of
5
ppm
for
the
compound,
with
the
exception
of
Blend
6
during
high­
end
exposure.
Both
the
National
Institute
for
Occupational
Safety
and
Health
(
NIOSH)
and
the
AIHA
Exposure
Assessment
Strategies
Committee
(
EASC)
stipulate
that
95%
of
exposures
should
be
kept
below
the
PEL
(
AIHA
2002).
Since
sterilants
have
been
shown
to
have
average
exposures
below
0.1
ppm,
the
5ppm
high­
end
exposure
is
expected
to
be
a
rare
occurrence
and
within
these
PEL
guidelines.
Furthermore,
manufacturers
should
be
knowledgeable
of
how
to
minimize
the
risks
associated
with
the
use
of
EtO
because
EtO
is
so
commonly
used.
Therefore,
to
ensure
compliance
with
this
OSHA
PEL,
and
consequently
guarantee
worker
safety,
sterilization
facilities
should
post
signs
that
outline
hygiene
and
handling
procedures
and
train
their
employees
on
the
proper
handling
of
IoGas
 
.
To
ensure
worker
safety
in
the
event
of
an
accidental
release
or
spill,
workers
must
wear
butyl
rubber
gloves
and
safety
goggles.
It
is
also
recommended
that
workers
wear
butyl
rubber
aprons
and
shoes
and
that
SCBA
gear
be
made
available
to
workers
in
the
event
of
a
release
of
IoGas
 
.

Average
and
high
exposures
to
CO2
and
CF3I
are
not
expected
to
exceed
toxicity
threshold
values.
The
average
worker
exposures
to
the
constituents
of
IoGas
 
in
a
conventional
8­
hour
workday
(
based
on
daily
average
exposure
to
0.1
ppm
of
IoGas
 
)
are
presented
in
Table
6.
The
exposure
values
are
significantly
less
than
the
established
AEL
and
PEL
values
for
the
compounds.
Similarly,
in
the
event
of
a
leak
(
high­
end
exposure
to
5
ppm
of
IoGas
 
)
a
worker
would
be
exposed
to
levels
of
CO2
and
CF3I
which
are
less
than
the
established
STEL
values
for
the
compounds
(
Table
7).

The
installation
of
an
EtO
detection
system
guarantees
worker
safety
in
the
event
of
a
leak
in
an
occupational
setting.
Assuming
protective
actions
are
taken
(
e.
g.,
worker
evacuation
(
September
15,
2004)
6
or
use
of
protective
equipment)
when
concentrations
of
EtO
reach
the
OSHA
STEL
of
5
ppm,
exposures
to
CO2
and
CF3I
would
accordingly
remain
below
levels
of
concern.

Exposures
at
the
end­
use,
such
as
those
which
occur
when
a
sterilization
chamber
door
is
opened
in
a
health
care
facility,
are
expected
to
be
minimal.
At
the
end
of
a
sterilization
cycle,
the
chamber
being
sterilized
will
be
flushed
with
air
before
being
opened,
and
in
many
facilities,
a
fume
hood
will
exhaust
air
from
around
the
sterilization
chamber
to
the
outside.
As
a
further
precaution,
ethylene
oxide
sensors
are
used
to
detect
leaks
and
warn
occupants
to
evacuate
the
area.
Finally,
chambers
are
pressure
tested
periodically
and
seals
are
replaced
to
prevent
leaks
as
necessary.

Table
6:
Average
Exposure
to
IoGas
 
Blends
1,
3,
and
6.
Average
Exposure
of
0.1
ppm
Blend
1
Blend
3
Blend
6
Long­
term
Exposure
Limits
Short­
Term
Exposure
Limits
EtO
1
5
CO2
5,000
30,000
CF3I
150
2,000
Table
7:
High­
End
Exposure
to
IoGas
 
Blends
1,
3,
and
6.
High­
End
Exposure
of
5
ppm
Blend
1
Blend
3
Blend
6
Long­
term
Exposure
Limits
Short­
Term
Exposure
Limits
EtO
1
5
CO2
5,000
30,000
CF3I
150
2,000
Table
8:
Exposure
to
Constituents
of
IoGas
 
Blends
1,
3,
and
6
when
Levels
of
EtO
Reach
the
STEL
At
Concentrations
of
5
ppm
EtO
Blend
1
Blend
3
Blend
6
Long­
term
Exposure
Limits
Short­
Term
Exposure
Limits
CO2
5,000
30,000
CF3I
150
2,000
(
September
15,
2004)
7
6.
GENERAL
POPULATION
EXPOSURE
This
section
screens
potential
risks
to
the
general
population
from
exposure
to
releases
of
the
three
components
of
the
substitute
blend
examined
in
this
report.
Factory
releases
(
occurring
during
manufacture)
and
on­
site
use
of
IoGas
 
for
sterilization
of
equipment
are
examined
in
this
section.
Release
of
IoGas
 
is
not
expected
during
manufacturing,
which
consists
of
blending
the
components
in
the
correct
proportions,
because
the
process
is
performed
in
gas­
tight
systems.

When
IoGas
 
is
used
in
large
contract
sterilization
chambers,
the
general
population
exposure
may
be
limited
either
through
the
use
of
a
catalytic
oxidation
system,
which
converts
waste
EtO
into
CO2
and
water,
or
through
the
use
of
acid
water
scrubbers,
which
convert
waste
EtO
into
ethylene
glycol.
When
acid
water
scrubbers
are
used,
the
remaining
CO2
and
CF3I
are
available
for
recovery
and
re­
use.
When
a
catalytic
oxidation
system
is
employed,
CF3I
is
converted
to
the
acidic
gases
HF
and
HI.
These
acidic
gases
then
are
scrubbed
out
and
neutralized
with
a
base
such
as
Ca(
OH)
2,
or
an
aqueous
solution
such
as
NaOH
or
KOH.
One
of
the
acidic
products,
HF,
is
classified
as
both
a
Hazardous
Air
Pollutant
(
HAP)
and
as
a
substance
regulated
by
OSHA
and
the
Clean
Water
Act
(
CWA).
Air
emissions,
wastewater
discharges,
and
occupational
exposures
of
HF
must
all
be
controlled.

To
prevent
general
population
exposure,
rooms
or
buildings
being
sterilized
by
IoGas
 
would
first
be
prepared
by
sealing
all
doors,
windows,
and
vents,
while
providing
inlet
and
outlet
ports
for
the
gas.
Depending
on
state
regulations,
gases
released
during
the
sterilization
process
may
be
diluted
with
air
or
passed
through
a
scrubber,
with
or
without
a
thermal
oxidizer,
to
lower
the
concentration
of
ethylene
oxide
before
being
vented
to
the
atmosphere.

When
using
IoGas
 
as
a
sterilant,
the
blend
should
not
be
vented
untreated
to
the
outside
given
the
potential
carcinogenicity
of
EtO
(
Table
2).
Furthermore,
as
a
HAP,
use
of
EtO
should
comply
with
air
emissions
standards
established
under
the
CAAA
(
Ethylene
Oxide
Emissions
Standards
for
Sterilization
Facilities:
Subpart
O,
40
CFR
63.360).
By
following
existing
regulations
and
installing
the
proper
control
systems,
EPA
believes
that
factory
or
onsite
releases
are
not
likely
to
pose
a
significant
threat
to
ambient
air,
surface
water,
or
solid
waste.
Consequently,
use
of
IoGas
 
is
not
expected
to
pose
significant
risk
to
the
general
population.

7.
CONSUMER
EXPOSURE
Consumer
exposure
occurs
through
the
use
of
products
that
have
been
sterilized
with
the
compound.
Some
of
the
products
for
which
this
sterilant
can
be
used
are
medical
equipment
and
facilities,
spices,
and
cosmetics.
They
can
also
be
used
to
decontaminate
buildings
and
vehicles.
When
sterilized
equipment
and
products
are
properly
aerated
after
sterilization,
exposure
to
the
IoGas
 
blend
is
negligible
(
IoGas
 
SNAP
Submission
2003).
EPA
believes
that
the
existing
safeguards
are
sufficient
to
ensure
that
consumer
exposures
and
the
associated
risks
are
neglible.
(
September
15,
2004)
8
8.
VOLATILE
ORGANIC
COMPOUND
(
VOC)
ANALYSIS
CF3I
has
been
exempted
from
a
listing
as
a
VOC
under
CAA
regulations
(
40
CFR
51.00).
EtO
has
not
been
exempted
from
this
listing,
hence
emissions
should
be
controlled.

REFERENCES
AIHA
2002
(
updated).
AIHA's
White
Paper
on
Permissible
Exposure
Limits
(
PELs).
http://
www.
aiha.
org/
GovernmentAffairs­
PR/
html/
GAWPpermexpo.
htm.
Accessed
on
December
1,
2003.

IoGas
 
SNAP
Submission.
2003.
Significant
New
Alternatives
Policy
Program
Submission
to
the
United
States
Environmental
Protection
Agency.

EPA
1994.
Significant
New
Alternatives
Policy
Technical
Background
Document:
Risk
Screen
on
the
Use
of
Substitutes
for
Class
I
Ozone­
depleting
Substances:
Sterilization
and
Refrigeration
and
Air
Conditioning.
Stratospheric
Protection
Division.
March,
1994.

ICF.
1998.
"
Recommendation
for
an
Acceptable
Exposure
Limit
for
CF3I."
Prepared
by
H.
Clewell
and
G.
Lawrence
under
EPA
Contract
No.
68­
D5­
0147,
WA
2­
09,
Task
3
(
September
15,
2004)
9
ATTACHMENT
1
Recommendation
for
an
Acceptable
Exposure
Limit
for
CF3I
The
purpose
of
this
report
is
to
recommend
an
Acceptable
Exposure
Limit
(
AEL)
for
occupational
exposure
to
trifluoroiodomethane
(
CF3I).
The
limited
toxicity
studies
that
have
been
performed
on
CF3I
include
acute
and
subchronic
inhalation
exposures
of
rats,
a
reproductive
toxicity
screen
in
rats,
cardiac
sensitization
evaluation
in
the
dog,
and
tests
of
genotoxicity
(
Salmonella
typhimurium
reverse
mutation
assay,
mouse
lymphoma
forward
mutation
assay,
and
in
vivo
rat
and
mouse
micronucleus
assays).

Recommended
AEL:
150
ppm
(
8­
hr
Time
Weighted
Average)
with
a
Ceiling
of
2,000
ppm
Basis:
TWA:
Endpoint:
Thyroid
hormone
alterations
Study:
Reproductive
Toxicity
Screen
of
Trifluoroiodomethane
(
CF3I)
in
Sprague­
Dawley
Rats
(
Dodd
et
al.
1998)
Protocol:
whole
body
inhalation,
6
hrs/
day,
5
or
7
days/
wk,
16
animals/
sex/
dose
Concentrations:
0.2,
0.7
and
2
%
(
2,000,
7,000
and
20,000
ppm)

NOAEL:
not
identified
LOAEL:
0.2%
LOAEL
[
adj]:
2,000
ppm
x
6
hr
/
8
hr
=
1,500
ppm
LOAEL
[
HEC]:
1,500
ppm
Uncertainty/
Modifying
Factors:

3
­
use
of
LOAEL
1
­
animal
to
human
3
­
human
variability
Ceiling:

Endpoint:
Cardiac
sensitization
Study:
Cardiac
sensitization
in
dogs
(
Kenny
et
al.
1995)
Protocol:
standard
epinephrine
challenge,
9
animals
Concentrations:
0.1,
0.2,
0.4,
and
1.0%
(
1,000,
2,000,
4,000,
and
10,000
ppm)

NOAEL:
0.2%
LOAEL:
0.4%
(
September
15,
2004)
10
NOAEL
[
adj]:
2,000
ppm
NOAEL
[
HEC]:
2,000
ppm
Uncertainty/
Modifying
Factors:
None
Justification:

TWA:

In
a
reproductive
toxicity
screen,
Sprague­
Dawley
rats
were
exposed
via
whole
body
inhalation
to
CF3I
6
hrs/
day,
5
or
7
days/
wk
for
7
or
14
weeks
(
Dodd
et
al.
1998).
Thyroid
hormone
levels
and
micronucleus
frequency
were
also
evaluated
in
the
study
based
on
results
reported
in
a
previous
study
(
Kinkead
et
al.
1996).
Serum
concentrations
of
thyroid
hormones
were
consistently
altered
in
a
dose­
related
manner.
Significant
concentration­
related
increases
in
thyroxine
(
T4),
reverse
triiodothyronine
(
rT3),
and
thyroid
stimulating
hormone
(
TSH),
and
significant
decreases
in
T3
were
reported
in
males
and
females
at
all
exposure
levels,
when
compared
to
controls,
with
the
exception
of
TSH
in
the
mid­
concentration
female
rats
and
the
low­
and
mid­
concentration
male
rats
after
14
weeks
of
exposure.
Also,
a
statistically
significant
decrease
in
the
male/
female
sex
ratio
was
reported
in
the
offspring
of
the
high­
concentration
group.
Because
the
thyroid
hormone
alterations
were
observed
at
lower
exposure
concentration,
however,
they
were
considered
the
critical
effects.

A
brief
review
of
thyroid
hormone
regulation
is
useful
to
explain
the
observed
spectrum
of
effects.
Iodine
is
taken
up
by
the
thyroid,
combined
with
tyrosine
and
other
components
to
form
thyroglobulin
(
a
high
molecular
weight
glycoprotein),
and
a
series
of
biochemical
transformations
result
in
the
formation
of
the
thyroid
hormones
T3
and
T4
(
Capen
and
Martin
1989).
Release
of
these
hormones
is
controlled
by
a
neuroendocrine
feedback
loop,
involving
the
hypothalamus,
pituitary
gland,
and
the
thyroid
gland
(
McDonald
1980).
In
response
to
demand
for
thyroid
hormone,
the
hypothalamus
releases
thyroid
stimulating
hormone
releasing
factor,
which
in
turn
stimulates
the
pituitary
gland
to
release
TSH.
The
thyroid
hormones
T3
and
T4
exert
similar
effects
on
target
tissues,
but
T3
is
more
biologically
active
(
Capen
and
Martin
1989).
T4
secreted
into
the
circulation
is
converted
to
T3
by
the
enzyme
5'­
deiodinase.
Excess
T4
can
be
converted
to
an
inactive
form
of
T3,
reverse
T3
(
rT3),
by
another
enzyme,
5­
deiodinase.

The
study
authors
proposed
that
the
observed
changes
in
thyroid
hormone
regulation
were
likely
the
result
of
CF3I
interfering
with
5'­
deiodinase,
the
enzyme
responsible
for
the
conversion
of
T4
to
T3.
Such
a
mechanism
could
explain
the
changes
in
T4,
T3,
rT3,
and
TSH
levels
reported
following
exposure
to
CF3I.
The
resulting
decrease
in
T3
could
lead
to
a
loss
of
negative
inhibition
and
a
subsequent
increase
in
TSH
and
T4,
with
the
excess
T4
partially
converted
to
rT3.

Dosimetric
adjustments:
The
human
equivalent
concentration
(
HEC)
was
calculated
using
the
rat
blood:
air
partition
coefficient
of
1.75
and
the
human
blood:
air
partition
coefficient
of
0.97
(
Williams
et
al.
1994,
Vinegar
and
Jepson
1996).
Because
the
human
partition
coefficient
is
smaller
than
the
animal
one,
the
default
value
of
1
was
used
instead.
The
exposure
(
September
15,
2004)
11
duration
of
6
hours/
day
was
adjusted
for
the
normal
8­
hour
occupational
exposure.
This
adjustment
is
important,
because
thyroid
toxicity
is
likely
related
to
the
total
amount
of
iodine
released
by
CF3I
metabolism
(
the
area
under
the
curve
of
the
metabolite's
time
course
of
elimination,
(
i.
e.,
metabolite
concentration
vs.
time).
No
adjustment
was
made
for
days/
week,
because
the
exposure
of
interest
(
occupational)
is
also
5
days/
week.
1
Uncertainty
factors:
The
rat
appears
to
be
a
highly
sensitive
species
for
chemicals
which
cause
disruption
of
thyroid
hormone
levels,
due
to
an
approximately
10­
fold
faster
clearance
(
i.
e.,
shorter
plasma
half­
life)
of
T3
and
T4
compared
to
the
human
(
Alison
et
al.
1994).
Levels
of
5'­
deiodinase
inhibition
that
cause
marked
effects
in
the
rat
may
not
cause
adverse
effects
in
the
human
because
the
slower
turnover
in
the
human
allows
for
a
physiological
"
buffer,"
making
it
easier
for
humans
to
maintain
normal
physiological
levels
of
T3.
Because
rats
are
much
more
sensitive
to
thyroid
hormone
disruptions,
the
indirect
mechanism
by
which
CF3I
acts
would
only
be
active
in
humans
following
exposure
to
concentrations
greater
than
those
to
which
the
rats
were
exposed.

The
RfC
dosimetry
guidelines
were
followed
for
obtaining
the
HEC
(
EPA
1994);
therefore,
the
default
animal­
to­
human
uncertainty
factor
of
3
for
differences
in
pharmacokinetics
was
not
applied.
Because
the
rat
is
more
sensitive
to
thyroid
effects
than
the
human,
as
discussed
above,
the
default
uncertainty
factor
of
3
for
pharmacodynamics
was
considered
unnecessary.
The
modifying
factor
for
use
of
a
LOAEL
was
decreased
to
3
(
the
default
is
10);
the
LOAEL
in
humans
for
thyroid
toxicity
is
expected
to
be
higher
than
that
observed
in
rats
due
to
the
greater
sensitivity
of
rats
to
these
effects.
An
additional
factor
of
3
was
applied
to
consider
sensitive
individuals,
such
as
workers
with
under­
or
over­
active
thyroids.
An
overall
uncertainty
factor
of
10
results.

Ceiling:

The
dog
epinephrine
challenge
results
(
Kenny
et
al.
1995)
indicate
that
CF3I
at
levels
above
0.2%
may
exacerbate
the
cardiac
effects
of
other
stressors.
However,
the
epinephrine
challenge
is
a
highly
sensitive
test
for
these
effects,
and
it
is
not
felt
that
any
uncertainty
factors
are
necessary
when
the
HEC
is
based
on
equal
exposure
concentration.

Other
comments:

Reproductive
effects:

Because
the
uncertainty
factors
used
in
deriving
an
AEL
based
on
thyroid
effects
were
reduced
from
the
default
values,
an
AEL
based
on
reproductive
effects
observed
in
rats
at
higher
concentrations
than
the
thyroid
effects
was
calculated
for
comparison.
A
NOAEL
for
the
reproductive
effects
reported
in
Dodd
et
al.
(
1998)
would
be
0.7%
(
7,000
ppm).
To
derive
an
1Although
the
exposure
period
in
the
Dodd
et
al.
(
1998)
study
varied
from
5­
7
days/
week
depending
on
the
period
of
gestation,
the
majority
of
exposure
occurred
on
a
5
day/
week
basis.
(
September
15,
2004)
12
Acceptable
Exposure
Level
(
AEL)
based
on
these
reproductive
effects,
the
NOAEL
would
be
adjusted
from
a
6
hour/
day
exposure
to
occupational
exposures
(
8
hours/
day)
resulting
in
a
LOAEL
[
HEC]
of
5,250
ppm
(
7,000
ppm
×
6
hours/
8
hours).
An
uncertainty
factor
of
3
would
be
applied
for
extrapolation
from
animals
to
humans
to
account
for
differences
in
pharmacokinetics.
An
additional
uncertainty
factor
of
10
would
be
applied
in
consideration
of
human
variability,
resulting
in
a
total
uncertainty
factor
of
30.
Note
that
the
uncertainty
factor
used
to
account
for
human
variability
for
reproductive
effects
is
higher
than
that
used
for
thyroid
effects
(
i.
e.,
3
for
thyroid
vs.
10
for
reproductive
effects).
In
contrast
to
thyroid
toxicity,
adverse
reproductive
effects
are
generally
considered
to
be
irreversible
and
"
silent."
Thyroid
toxicity
can
be
easily
diagnosed
in
the
early
stages
and
possibly
treated,
while
adverse
reproductive
effects
are
generally
not
diagnosed
until
much
later,
if
at
all.
Further,
although
the
reproductive
toxicity
screen
measured
many
endpoints
of
reproductive
success
(
e.
g.,
fecundity,
gestation
length,
pup
number,
pup
sex
ratio),
it
did
not
measure
any
histopathological
effects
on
the
males,
dams,
or
pups,
including
but
not
limited
to,
effects
on
the
thyroid
and
serum
levels
of
thyroid
hormones.
Thus,
the
reproductive
toxicity
screen
does
not
provide
a
comprehensive
analysis
of
potential
reproductive
and
developmental
effects
that
might
result
from
CF3I
exposure.
For
this
reason,
a
lower
uncertainty
factor
of
3
for
reproductive
effects
was
not
deemed
appropriate.
Application
of
the
total
uncertainty
factor
to
the
LOAEL
[
HEC]
(
5,250
ppm/
30)
results
in
a
recommended
AEL
of
175
ppm,
a
value
that
is
slightly
higher
than
the
AEL
of
150
ppm
based
on
the
thyroid
effects.
The
recommended
AEL
based
on
the
thyroid
effects
would
be
protective
of
both
the
thyroid
and
reproductive
effects.

Evidence
of
carcinogenic
potential:

A
bone­
marrow
micronucleus
induction
assay
was
performed
as
part
of
a
90­
day
noseonly
inhalation
study
where
rats
were
exposed
to
0,
2,
4,
and
8%
(
0,
20,000,
40,000
and
80,000
ppm)
CF3I
for
2
hours/
day,
5
days/
week
for
30
or
90
days
(
Kinkead
et
al.
1996
).
After
30
days
of
exposure,
concentration­
related
increases
in
micronucleus
frequency
were
observed
in
the
mid­
and
high­
concentration
males
and
females,
with
statistically
significant
positive
trends
reported
for
each
sex.

Concentration­
related
decreases
in
polychromatic
erythrocyte/
normochromatic
erythrocyte
(
PCE/
NCE)
ratios,
an
indicator
of
bone
marrow
toxicity,
were
observed
in
all
treated
males
and
females
and
statistically
significant
trends
were
reported.
After
90
days
of
exposure,
concentration­
related
increases
in
micronucleus
frequency
and
decreases
in
PCE/
NCE
ratios
were
observed
in
all
treated
groups,
with
statistically
significant
trends
also
reported
for
each
endpoint.
Mitchell
(
1995a)
conducted
a
bone
marrow
micronucleus
assay,
where
male
and
female
mice
were
exposed
to
0,
2.5,
5
or
7.5%
CF3I
(
0,
25,000,
50,000
or
70,000
ppm)
via
noseonly
inhalation,
6
hours/
day
for
3
consecutive
days.
Statistically
significant
concentrationrelated
decreases
in
micronucleus
frequency
were
reported
in
the
low­
and
mid­
concentration
male
and
female
mice.

In
addition,
statistically
significant
concentration­
related
decreases
in
the
ratio
of
PCE/
1000
erythrocytes
were
reported
at
all
exposure
concentrations
in
female
mice.
However,
in
the
study
by
Dodd
et
al.
(
1998)
where
male
and
female
rats
were
exposed
to
0,
0.2,
0.7
or
(
September
15,
2004)
13
2.0%
CF3I
(
0,
2,000,
7,000
or
20,000
ppm)
via
whole­
body
inhalation
for
7
or
14
weeks,
there
were
no
statistically
significant
changes
in
micronuclei
frequency
or
in
PCE/
NCE
ratios.
An
Ames
assay
was
positive
(
Mitchell
1995b),
while
a
forward
mutation
assay
was
negative
(
Mitchell
1995c).
Although
CF3I
is
only
slowly
metabolized
(
Williams
et
al.
1994),
it
is
clear
that
it
has
the
potential
to
cause
genotoxic
effects.
However,
it
would
be
premature
to
base
a
quantitative
risk
assessment
on
these
data.
A
full
quantitative
assessment
for
potential
carcinogenicity
would
require
data
from
a
two
year
bioassay.

References
Alison
RH,
Capen
CC,
Prentice
DE.
1994.
Neoplastic
Lesions
of
Questionable
Significance
to
Humans.
Toxicol
Pathol
22:
179­
186.

Capen
CC
and
Martin
SL.
1989.
The
Effects
of
Xenobiotics
on
the
Structure
and
Function
of
Thyroid
Follicular
and
C­
Cells.
Toxicol
Pathol
17:
266­
293.

Dodd
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