1
of
39
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
Date:
January
18,
2006
Subject:
Human
Health
Risk
Assessment
for
Sulfuryl
Fluoride
and
Fluoride
Anion
Addressing
the
Section
3
Registration
of
Sulfuryl
Fluoride
as
a
Fumigant
for
Foods
and
Food
Processing
Facilities.
PP#
3F6573.

DP
Number:
312659
Class:
Fumigant
PC
Code:
078003
40
CFR
180:
575
(
sulfuryl
fluoride)
145
(
fluorine
compounds)

From:
Michael
Doherty,
Chemist
Registration
Action
Branch
2
Health
Effects
Division
(
7509C)

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

To:
Dan
Kenny/
Meredith
Laws
Insecticide/
Rodenticide
Branch
Registration
Division
(
7505C)

Note:
This
risk
assessment
post­
dates
the
Federal
Register
notice
establishing
tolerances
for
residues
of
sulfuryl
fluoride
and
fluoride
resulting
from
fumigation
of
some
foods
and
of
food
processing
facilities
[
Federal
Register
­
July
15,
2005
(
Volume
70,
Number
135)].
During
the
internal
peer­
review
process
in
OPP,
errors
were
noted
in
the
residue
files
used
to
estimate
dietary
exposure
and
it
was
found
that
there
were
discrepancies
between
the
assumptions
made
in
the
risk
assessment
and
the
uses
that
were
being
allowed
on
the
product
label.
Those
errors
and
discrepancies
have
been
resolved.
While
the
dietary
and
aggregate
exposure
and
risk
estimates
presented
in
this
document
are
slightly
greater
than
those
presented
in
the
Federal
Register
notice,
HED's
conclusions
and
regulatory
recommendations
remain
unchanged.
HED
is
still
recommending
for
a
conditional
registration
of
sulfuryl
fluoride
for
the
sought
after
uses
and
the
establishment
of
permanent
tolerances
for
residues
of
sulfuryl
fluoride
and
fluoride
anion.
2
of
39
Table
of
Contents
1.0
EXECUTIVE
SUMMARY...................................................................................................
3
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
......................................
5
3.0
HAZARD
CHARACTERIZATION......................................................................................
6
3.1
Sulfuryl
Fluoride..............................................................................................................
6
3.1.1
Hazard
Profile.........................................................................................................
6
3.1.2
FQPA
Considerations
...........................................................................................
12
3.1.3
Dose­
Response
Assessment
..................................................................................
13
3.1.4
Endocrine
Disruption............................................................................................
17
3.2
Fluoride
Anion...............................................................................................................
17
3.2.1
Hazard
Profile.......................................................................................................
18
3.2.2
FQPA
Considerations
...........................................................................................
19
3.2.3
Dose­
Response
Assessment
..................................................................................
19
3.2.4
Endocrine
Disruption............................................................................................
19
4.0
EXPOSURE
ASSESSMENT..............................................................................................
20
4.1
Summary
of
Proposed
Uses
...........................................................................................
20
4.2
Dietary
Exposure/
Risk
Pathway.....................................................................................
20
4.2.1
Residue
Profile......................................................................................................
21
4.2.1.1
Sulfuryl
Fluoride
and
Fluoride
Residues
from
the
use
of
Sulfuryl
Fluoride
...
21
4.2.1.5
Other
Sources
of
Fluoride
...........................................................................
23
4.2.2
Acute
Dietary
.......................................................................................................
23
4.2.3
Chronic
Dietary
....................................................................................................
23
4.2.4
Cancer
Dietary......................................................................................................
25
4.3
Water
Exposure/
Risk
Pathway.......................................................................................
25
4.4
Residential
Exposure/
Risk
Pathway
...............................................................................
26
4.4.1
Other
....................................................................................................................
26
5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION....................
27
6.0
CUMULATIVE
RISK
........................................................................................................
28
7.0
OCCUPATIONAL
EXPOSURE.........................................................................................
29
8.0
DATA
NEEDS
AND
LABEL
REQUIREMENTS
..............................................................
30
9.0
REFERENCES
...................................................................................................................
33
APPENDIX
I
­
Risk
Estimates
for
Development
of
Skeletal
Fluorosis
Based
on
Institute
of
Medicine
Toxicological
Findings..........................................................................................
35
APPENDIX
II
­
Risk
Estimates
for
Development
of
Dental
Fluorosis........................................
36
3
of
39
1.0
EXECUTIVE
SUMMARY
Dow
AgroSciences
has
petitioned
the
Agency
to
register
sulfuryl
fluoride
for
the
control
of
numerous
pests
in
foods
and
food
processing
facilities.
In
conjunction
with
that
petition,
Dow
AgroSciences
has
requested
the
establishment
of
permanent
tolerances
for
residues
of
sulfuryl
fluoride
and
of
fluoride
anion
on
a
suite
of
commodities
related
to
the
proposed
use.
Sulfuryl
fluoride
is
a
potential
methyl
bromide
replacement
for
these
uses.
Under
the
proposed
use,
foods
and
food
processing
facilities
will
be
fumigated
with
sulfuryl
fluoride
formulated
as
the
99%
a.
i.
ProFume.
Fumigation
may
be
carried
out
at
ambient
pressures
or,
where
practical,
under
vacuum
conditions.
Dow
AgroSciences
has
developed
software
to
tailor
the
application
rate
based
on
pressure,
volume
of
the
structure/
chamber
being
fumigated,
and
pest
species.
Maximum
fumigation
rates
are
1500
oz@
hrs/
1000
ft3
(
1500
mg@
hrs/
L)
at
ambient
pressure
and
200
mg@
hrs/
L
under
vacuum
conditions.

This
assessment
also
addresses
a
revised
use
pattern
for
the
previously
registered
use
of
sulfuryl
fluoride
in
cereal
grain
milling
facilities.
The
directions
for
that
use
have
been
revised
to
eliminate
the
required
blending
of
fumigated
flour
with
untreated
flour.

HED
has
reviewed
the
toxicology
and
residue
chemistry
data
submitted
to
support
the
petition
and
has
examined
the
potential
for
exposures
via
dietary
(
food
and
drinking
water),
nondietary
oral,
inhalation,
and
dermal
routes.
Residues
of
concern
for
sulfuryl
fluoride
are
sulfuryl
fluoride,
per
se,
and
fluoride
anion
(
also
referred
to
as
Afluoride@
in
this
document).
This
assessment
addresses
the
human
health
risks
associated
with
sulfuryl
fluoride
and
fluoride
anion.
Due
to
the
different
toxicological
effects
elicited
by
these
two
chemicals,
their
risks
have
been
assessed
separately.
This
risk
assessment
builds
on
the
previous
human
health
risk
assessment
issued
by
HED
(
M.
Doherty,
D309013,
10/
12/
04).
Much
of
the
detail
regarding
exposure
estimates
to
fluoride
from
water,
background
residues
in
food,
toothpaste,
inhalation,
and
use
of
cryolite
(
which
also
results
in
fluoride
residues
in
food)
can
be
found
in
that
document.

Sulfuryl
Fluoride.
Based
on
the
submitted
toxicology
data,
taken
in
conjunction
with
the
proposed
uses,
and
the
physical­
chemical
properties
of
sulfuryl
fluoride,
HED
has
determined
that
acute,
short­
term,
and
intermediate­
term
assessments
are
not
appropriate
for
addressing
risks
to
persons
who
are
not
working
directly
with
sulfuryl
fluoride.
Chronic
exposure
to
sulfuryl
fluoride
may
occur
through
dietary
exposure.
Because
of
its
chemical
properties,
sulfuryl
fluoride
is
extremely
unlikely
to
occur
in
water;
therefore,
chronic
dietary
exposure
would
occur
only
through
residues
in/
on
food.
In
conducting
the
chronic
dietary
assessment,
HED
has
assumed
average
residue
levels
based
on
residue
trials
conducted
at
the
maximum
fumigation
rate
and
has
incorporated
estimates
of
the
percent
of
commodities
treated.
Additionally,
we
assumed
that
commodities
might
be
serially
fumigated,
first
as
part
of
a
post­
harvest
and/
or
grain
mill
fumigation
and
then
again
due
to
food
processing
facility
fumigation.
The
actual
probability
of
this
occurring
is
likely
to
be
very
small;
therefore,
this
assumption
results
in
an
overestimate
of
exposure.
Even
with
this
assumption,
the
estimated
dietary
exposures
for
the
general
U.
S.
population
and
all
population
subgroups,
including
those
of
infants
and
children,
are
less
than
or
equal
to
8%
of
the
chronic
PAD.
Generally,
HED
is
concerned
about
estimated
risk
levels
when
they
exceed
100%
of
the
PAD;
therefore,
these
risk
estimates
are
well
below
HED=
s
level
of
concern.
As
noted
above,
chronic
dietary
(
food
only)
exposure
is
the
only
relevant
exposure
4
of
39
pathway
for
inclusion
in
aggregate
risk
estimates.
Aggregate
risk
estimates
from
exposure
to
sulfuryl
fluoride,
therefore,
are
below
HED=
s
level
of
concern
for
all
population
subgroups.

HED
has
also
evaluated
the
potential
risks
to
workers
conducting
fumigations
with
sulfuryl
fluoride
and
to
personnel
engaged
in
post­
fumigation
activities.
The
most
current
proposed
label
and
use
booklet
mandates
that
all
workers
must
wear
approved
self­
contained
breathing
apparatus
if
they
will
be
in
an
area
where
the
concentration
of
sulfuryl
fluoride
exceeds
1
ppm
or
is
unknown.
Workers
not
wearing
proper
respiratory
protection
may
enter
a
fumigated
area
only
after
the
concentration
of
sulfuryl
fluoride
has
been
shown
to
be
below
1
ppm.
Based
on
information
available
to
HED,
short­
term,
intermediate­
term
and
chronic
exposure
to
sulfuryl
fluoride
may
occur
for
professionals
working
with
sulfuryl
fluoride
or
sulfuryl
fluoride
fumigated
commodities.
HED
has
estimated
exposures
and
risks
for
fumigators
and
tent
workers
based
on
sulfuryl
fluoride
data
depicting
exposure
to
workers
following
structural
fumigation
with
Vikane.
The
Vikane
data
were
collected
based
on
a
5­
ppm
reentry
concentration.
ProFume
has
a
1­
ppm
reentry
concentration.
Therefore,
the
exposure
estimates
from
Vikane
were
reduced
by
5­
fold.
Occupational
MOEs
for
ProFume
range
from
300
to
2100.
Since
levels
of
concern
are
100
for
short­
and
intermediate­
term
exposures,
and
300
for
long­
term
exposures,
the
risk
estimates
represented
by
the
occupational
MOEs
are
below
HEDs
level
of
concern.

Fluoride
Anion.
In
assessing
the
risks
associated
with
exposure
to
fluoride,
HED
has
relied
on
the
toxicological
assessment
completed
by
the
Agency=
s
Office
of
Water.
That
assessment
identified
crippling
skeletal
fluorosis
as
the
endpoint
of
regulatory
concern
and
determined
that
a
value
of
8
mg/
day
is
protective
against
skeletal
fluorosis
without
being
so
low
as
to
negate
the
beneficial,
cavity­
fighting
effects
of
fluoride
exposure.
The
Office
of
Water
has
acknowledged
that
dental
fluorosis
may
occur
at
exposures
of
less
than
8
mg/
day.
At
this
time,
based
on
the
information
available
to
the
Agency,
EPA
is
not
concluding
that
mild
to
moderate
dental
fluorosis
associated
with
fluoride
exposure
is
an
adverse
health
effect
under
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA).
The
current
arguments
that
dental
fluorosis
is
more
than
a
cosmetic
effect
are
not
sufficiently
persuasive
to
warrant
regulation
as
an
adverse
health
effect
under
the
FFDCA.
Accordingly,
consistent
with
the
action
taken
by
the
Office
of
Water
under
the
Safe
Drinking
Water
Act,
40
FR
47142
(
November
14,
1985)
(
WH­
FRL­
2913­
8(
b)),
the
Agency
believes
that
the
appropriate
endpoint
for
regulation
under
the
FFDCA
is
skeletal
fluorosis.
While
the
tolerance
safety
determination
under
the
FFDCA
is
a
health
based
standard,
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
requires
the
balancing
of
all
costs,
taking
into
account
the
economic,
social,
and
environmental
effects,
as
well
as
health­
based
risks,
against
the
benefits
associated
with
the
pesticide
use.
Therefore,
the
Agency
has
considered
dental
fluorosis
in
determining
whether
sulfuryl
fluoride
meets
the
requisite
standard
under
FIFRA
(
see
Appendix
II).

OPP
notes
that
a
more
recent
assessment
of
fluoride
by
the
National
Academy
of
Sciences=
Institute
of
Medicine
(
IOM)
identified
a
skeletal
fluorosis
NOAEL
at
10
mg/
day1.
Their
assessment
of
the
data
concluded
that
no
safety
or
uncertainty
factors
were
needed.
The
IOM
1
Dietary
reference
intakes
for
calcium,
phosphorus,
magnesium,
vitamin
D
and
fluoride.
Report
of
the
Standing
Committee
on
the
Scientific
Evaluation
of
Dietary
Reference
Intakes.
Washington,
DC:
National
Academy
Press,
1997.
5
of
39
also
notes
that
high
exposures
for
long
durations
(
on
the
order
of
10
years)
are
required
to
develop
skeletal
fluorosis
and
that
such
a
condition
is
not
expected
to
occur
in
children
under
the
age
of
8.
Although
the
values
of
8
mg/
day
and
10
mg/
day
are
equally
appropriate
for
use
in
a
human
health
risk
assessment,
OPP
has
used
the
8­
mg/
day
value
in
order
to
be
slightly
more
conservative
in
assessing
risk.
For
fluoride
risk
assessments
addressed
in
this
document,
the
8
mg/
day
value
has
been
used
in
a
manner
analogous
to
a
reference
dose
(
RfD)
and
for
ease
of
communication
will
be
referred
to
as
such.

This
assessment
includes
quantitative
estimates
of
dietary
exposure
from
background
levels
of
fluoride
in
food,
fluoride
in
water,
and
fluoride
from
the
pesticidal
food
uses
of
cryolite
and
sulfuryl
fluoride,
non­
dietary
exposure
from
the
use
of
fluoridated
toothpaste,
and
non­
dietary
exposure
from
fluoride
residues
in
air.
For
each
of
these
pathways
of
exposure,
residue
estimates
are
conservative
to
moderately
conservative
in
nature.
For
foods,
we
have
assumed
that
all
commodities
are
serially
fumigated
(
as
described
above
for
sulfuryl
fluoride),
with
cryolite
included
as
a
potential
addition
source
of
elevated
fluoride
residues.
Other
potential
sources
of
fluoride
exposure
have
not
been
included
in
this
assessment
in
a
quantitative
manner,
primarily
due
to
lack
of
demographic
and/
or
exposure
information.
Non­
quantified
pathways
of
exposure
are
not
expected
to
significantly
increase
exposure
estimates
for
the
various
population
subgroups
at
large.

Risk
estimates
for
individual
fluoride
exposure
pathways
are
below
100%
of
the
RfD
for
the
general
U.
S.
population
and
all
population
subgroups,
including
those
of
infants
and
children.
When
all
quantified
dietary
and
non­
dietary
exposure
pathways
are
combined,
risk
estimates
range
from
17
to
43%
of
the
RfD.
These
aggregate
risk
estimates
are
below
HED=
s
level
of
concern
for
all
population
subgroups.

HED
notes
that
this
assessment
is
predicated
upon
the
removal
of
dried
eggs
from
the
list
of
"
Commodities
That
Can
Be
Fumigated"
on
the
ProFume
Label.
Dow
AgroSciences
recently
submitted
a
proposed
label
with
that
deletion.

Deficiencies
in
the
sulfuryl
fluoride
data
are
noted
in
Section
8
and
HED=
s
recommended
tolerance
levels
are
summarized
in
Table
8.1.
HED=
s
recommendations
involving
the
method
for
fluoride
may
impact
tolerance
levels.
Because
of
this,
we
are
recommending
that
the
registration,
if
granted,
be
conditional
upon
receipt
and
evaluation
of
the
data
outlined
in
Section
8.
Furthermore,
HED
notes
that
the
Office
of
Water,
via
the
National
Academy
of
Sciences,
is
reevaluating
the
available
information
regarding
fluoride
and
recommends
that
OPP
reexamine
this
risk
assessment
once
the
Office
of
Water
has
completed
its
review.

2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
Sulfuryl
fluoride
(
SO2F2)
is
a
fumigant
that
is
being
proposed
as
a
methyl
bromide
replacement
for
the
control
of
pests
in
food
processing
facilities.
Sulfuryl
fluoride
is
a
gas
at
standard
temperature
and
pressure.
It
has
a
melting
point
of
­
136
°
C,
a
boiling
point
of
­
55
°
C,
and
a
vapor
pressure
of
11552
mm
Hg
(
Torr)
at
20
°
C.
Sulfuryl
fluoride
rapidly
breaks
down
to
form
sulfate
and
fluoride
anion.
As
ProFume7
and
Vikane7,
sulfuryl
fluoride
constitutes
99%
of
the
product
and
there
are
no
known
impurities
of
toxicological
concern.
6
of
39
Fluorine
has
an
atomic
mass
of
18.99,
is
extremely
electronegative
and
reactive,
and
occurs
as
the
diatomic
F2
in
its
elemental
form.
Due
to
its
high
reactivity,
fluorine
does
not
typically
exist
outside
of
the
laboratory.
In
the
environment,
fluorine
readily
reacts
with
all
other
elements
except
nitrogen,
oxygen,
and
the
lighter
noble
gases
to
form
various
fluoride
complexes.
It
is
these
fluoride
complexes
that
govern
the
behavior
and
bioavailability
of
fluoride.
Due
to
fluorine=
s
ability
to
readily
react
with
other
elements
and
molecules,
fluoride
has
the
potential
to
occur
in
food,
water,
and
air,
and
exposure
to
humans
may
occur
through
any
of
these
media.

3.0
HAZARD
CHARACTERIZATION
3.1
Sulfuryl
Fluoride
3.1.1
Hazard
Profile
Table
3.1.1.
Acute
Toxicity
of
Technical
Grade
Sulfuryl
Fluoride
(
99.8%
active
ingredient)

Guideline
No.
Study
Type
MRID
Results
Tox
Category
870.11
Acute
Oral
Rats
43314
M:
LD50
=
100
mg/
kg
F:
LD50
=
100
mg/
kg
II*

870.12
Acute
Dermal
­­­­­
Study
Waived
*
IV**

870.13
Acute
Inhalation
Mice
(
4
hour
exposure)
41769101
M:
LC50
=
660
ppm
(
2.56
mg/
L)
F:
LC50
=
642
ppm
(
2.49
mg/
L)
I*

870.13
Acute
Inhalation
Rats
(
1
hour
exposure)
238663
LC50
=
4512
ppm
(
17.5
mg/
L)
I*

870.24
Primary
Eye
Irritation
­­­­­
Study
Waived
*
I**

870.25
Primary
Skin
Irritation
­­­­­
Study
Waived
*
IV**

870.26
Dermal
Sensitization
­­­­­
Study
Waived
*
Non­
Sensitizer
**

­­­­­­­­
Dermal
Vapor
Rats
(
4
hour
dermal
exposure)
41712001
No
adverse
effects
at
9600
ppm
(
40.3
mg/
L)
N/
A
*
Memorandum
by
M.
Lewis
(
SRRD)
to
V.
Dutch
(
SRRD),
11/
17/
99,
HED
Doc.
No.
078003.
**
Assumed
Toxicity
Category.
See
memorandum
by
M.
Lewis
(
above).
N/
A
Not
applicable
Table
3.1.2.
Toxicity
Profile
of
Technical
Grade
Sulfuryl
Fluoride
(
99.8%
active
ingredient)

Guideline
No.
Study
Type
Results
­­­­­­­­
2­
Week
inhalation
toxicity,
rats
NOAEL:
83/
89
mg/
kg/
day
(
M/
F)
LOAEL:
249/
267
mg/
kg/
day
(
M/
F):
M&
F
=
slightly
increased
kidney
weights,
minimal
histopathology
in
kidney.
7
of
39
Table
3.1.2.
Toxicity
Profile
of
Technical
Grade
Sulfuryl
Fluoride
(
99.8%
active
ingredient)

Guideline
No.
Study
Type
Results
(
inhalation
study)
0,
100,
300,
600
ppm
(
0/
0,
83/
89,
249/
267,
498/
534
mg/
kg/
day)
(
M/
F)
At
498/
534
mg/
kg/
day
(
M/
F):
M&
F
=
high
mortality,
decreased
body
weights,
severe
histopathology
in
kidney,
gross
and
histopathology
in
many
tissues/
organs
(
secondary
to
kidney
effects);
severe
inflammation
of
respiratory
tissues
in
1
survivor.
No
treatment­
related
neurotoxicity.
­­­­­­­­

(
inhalation
study)
2­
Week
inhalation
toxicity,
dogs
0,
30,
100,
300
ppm
(
0/
0,
7.9/
8.0,
26/
27,
79/
80
mg/
kg/
day)
(
M/
F)
NOAEL:
26/
27
mg/
kg/
day
(
M/
F)
LOAEL:
79/
80
mg/
kg/
day
(
M/
F):
M&
F
=
intermittent
tremors
and
tetany
during
exposures,
minimal
inflammatory
changes
in
upper
respiratory
tract,
decreased
body
weight
(
F
only).
Note
B
increased
serum
fluoride
at
>
26/
27
mg/
kg/
day.

­­­­­­­­

(
inhalation
study)
2­
Week
inhalation
toxicity,
rabbits
0,
100,
300,
600
ppm
(
0/
0,
30/
30,
90/
90,
180/
180
mg/
kg/
day)
(
M/
F)
NOAEL:
30/
30
mg/
kg/
day
(
M/
F)
LOAEL:
90/
90
mg/
kg/
day
(
M/
F):
M&
F
=
malacia
(
necrosis)
in
cerebrum,
vacuolation
of
cerebrum,
moderate
inflammation
of
respiratory
tissues.
At
180/
180
mg/
kg/
day
(
M/
F):
M&
F
=
convulsions,
hyperactivity,
malacia
(
necrosis)
in
cerebrum,
vacuolation
of
cerebrum,
moderate
inflammation
of
respiratory
tissues.

(
870.3100)

(
inhalation
study)
90­
Day
inhalation
toxicity,
rats
0,
30,
100,
300
ppm
(
0/
0,
24/
25,
80/
83,
240/
250
mg/
kg/
day)
(
M/
F)
NOAEL:
24/
25
mg/
kg/
day
(
M/
F)
LOAEL:
80/
83
mg/
kg/
day
(
M/
F):
M&
F
=
dental
fluorosis.
At
240/
250
mg/
kg/
day
(
M/
F):
M&
F
=
vacuolation
of
caudate­
putamen
nucleus
and
white
fiber
tracts
of
the
internal
capsule
of
the
brain,
decreased
body
weight,
inflammation
of
nasal
passages,
alveolar
histiocytosis;
slight
hyperplasia
of
renal
collecting
ducts
(
F
only).

(
870.3100)

(
inhalation
study)
90­
Day
inhalation
toxicity,
mice
0,
10,
30,
100
ppm
(
0/
0,
12.5/
12.1,
38/
36,
125/
121
mg/
kg/
day)
(
M/
F)
NOAEL:
38/
36
mg/
kg/
day
(
M/
F)
LOAEL:
125/
121
mg/
kg/
day
(
M/
F):
M&
F
=
microscopic
lesions
in
caudate­
putamen
nucleus
and
external
capsule,
decreased
body
weight,
decreased
body
weight
gain,
follicular
cell
hypertrophy
in
thyroid.
Note
B
increased
serum
fluoride
at
>
38/
36
mg/
kg/
day.

(
870.3150)

(
inhalation
study)
90­
Day
inhalation
toxicity,
dogs
0,
30,
100,
200
ppm
(
0/
0,
7.5/
7.6,
25/
26,
50/
51
mg/
kg/
day)
(
M/
F)
NOAEL:
25/
26
mg/
kg/
day
(
M/
F)
LOAEL:
50/
51
mg/
kg/
day
(
M/
F):
M&
F
=
slight
histopathology
of
the
caudate
nucleus
of
the
basal
ganglia,
decreased
bodyweight,
decreased
body
weight
gain,
transient
neurological
signs
(
lateral
recumbancy,
tremors,
incoordination,
salivation,
tetany,
inactivity)
starting
at
day
19
in
1
M.

(
870.3150)

(
inhalation
study)
90­
Day
inhalation
toxicity,
rabbits
0,
30,
100,
600/
300*
ppm
(
0/
0,
8.6/
8.5,
29/
28,
86/
85
mg/
kg/
day)
(
M/
F)

*
600
ppm
reduced
to
300
ppm
after
9
exposures
due
to
convulsions
and
hind
leg
paralysis
.
NOAEL:
8.6/
8.5
mg/
kg/
day
(
M/
F)
LOAEL:
29/
28
mg/
kg/
day
(
M/
F):
M&
F
=
decreased
body
weight,
decreased
liver
weight,
dental
fluorosis,
vaculoation
of
white
matter
of
the
brain
(
F
only).
At
86/
85
mg/
kg/
day
(
M/
F):
M&
F
=
malacia
(
necrosis)
and
vacuolation
of
putamen,
globus
pallidus
and
internal
&
external
capsules
in
brain,
decreased
body
weight
gain,
alveolar
histiocytosis,
histopathology
in
nasal
epithelium.
Note
B
increased
serum
fluoride
at
all
dose
levels
(>
8.6/
8.5
mg/
kg/
day).
8
of
39
Table
3.1.2.
Toxicity
Profile
of
Technical
Grade
Sulfuryl
Fluoride
(
99.8%
active
ingredient)

Guideline
No.
Study
Type
Results
(
870.3700)

(
inhalation
study)
Developmental
toxicity
inhalation
study,
rats
0,
25,
75,
225
ppm
(
0,
27,
81,
243
mg/
kg/
day)(
F)
Maternal
NOAEL:
243
mg/
kg/
day
(
F):
highest
dose
tested.
Maternal
LOAEL:
>
243
mg/
kg/
day
(
F).
Note­
significant
maternal
toxicity
observed
in
range­
finding
study
at
300
ppm.
Developmental
NOAEL:
243
mg/
kg/
day
(
F):
highest
dose
tested.
Developmental
LOAEL:
>
243
mg/
kg/
day
(
F)
(
870.3700)

(
inhalation
study)
Developmental
toxicity
inhalation
study
,
rabbits
0,
25,
75,
225
ppm
(
0,
9.5,
29,
86
mg/
kg/
day)(
F)
Maternal
NOAEL:
29
mg/
kg/
day
(
F)
Maternal
LOAEL:
86
mg/
kg/
day
(
F):
F
=
decreased
body
weight
and
decreased
body
weight
gain
during
treatment.
Note­
significant
maternal
toxicity
observed
in
range­
finding
study
at
300
ppm.
Developmental
NOAEL:
29
mg/
kg/
day
(
F)
Developmental
LOAEL:
86
mg/
kg/
day
(
F):
F
=
decreased
fetal
body
weight,
decreased
crown­
rump
length,
possibly
increased
fetal
liver
pathology
(
pale
liver).
(
870.3800)

(
inhalation
study)
2­
Generation
reproduction
inhalation
study,
rats
0,
5,
20,
150
ppm
(
0/
0,
3.6/
3.6,
14/
14,
108/
108
mg/
kg/
day
)
(
M/
F)
Parental
NOAEL:
3.6/
3.6
mg/
kg/
day
(
M/
F)
Parental
LOAEL:
14/
14
mg/
kg/
day
(
M/
F):
M&
F
=
pale
foci
in
lungs,
increased
alveolar
macrophages
in
lungs.
At
108/
108
mg/
kg/
day
(
M/
F):
M&
F
=
vacuolation
of
caudate
putamen
tracts
in
brain,
decreased
body
weight,
histopathology
in
lungs,
dental
fluorosis.
Offspring
NOAEL:
14/
14
mg/
kg/
day
(
M/
F)
Offspring
LOAEL:
108/
108
(
M/
F):
Decreased
pup
weights
in
F1
and
F2
generations
(
probably
secondary
to
maternal
body
weight
loss).
870.41
Chronic
toxicity,
rats
See
(
870.4300)
(
870.4100)

(
inhalation
study)
1­
Year
chronic
inhalation
toxicity,
dogs
0,
20,
80,
200
ppm
(
0/
0,
5.0/
5.1,
20/
20,
50/
51
mg/
kg/
day)
(
M/
F)
NOAEL:
5.0/
5.1
mg/
kg/
day
(
M/
F)
LOAEL:
20/
20
mg/
kg/
day
(
M/
F):
M&
F
=
decreased
body
weight
gain,
increased
alveolar
macrophages
in
lungs,
dental
fluorosis.
At
50/
51
mg/
kg/
day
(
M/
F):
M&
F
=
increased
mortality,
malacia
(
necrosis)
in
caudate
nucleus
of
brain,
follicular
cell
hypertrophy
in
thyroid,
histopathology
in
lung.
870.42
Carcinogenicity,
rats
See
(
870.4300)
(
870.4200)

(
inhalation
study)
18­
Month
carcinogenicity
inhalation
study,
mice
0,
5,
20,
80
ppm
(
0/
0,
5.3/
6.3,
25/
25,
101/
101
mg/
kg/
day)
(
M/
F)
NOAEL:
25/
25
mg/
kg/
day
(
M/
F)
LOAEL:
101/
101
mg/
kg/
day
(
M/
F):
M&
F
=
cerebral
vacuolation
in
brain,
decreased
body
weight
gain;
follicular
cell
hypertrophy
in
thyroid
(
M
only);
increased
mortality
(
F
only),
heart
thrombus
(
F
only),
lung
congestion
(
F
only).

Negative
for
carcinogenicity
in
M
and
F.

(
870.4300)

(
inhalation
study)
2­
Year
combined
chronic
toxicity/
carcinogenicity
inhalation
study,
rats
0,
5,
20,
80
ppm
(
0/
0,
3.5/
3.9,
14/
16,
56/
62
mg/
kg/
day)
(
M/
F)
NOAEL
(
M):
3.5
mg/
kg/
day
LOAEL
(
M):
14
mg/
kg/
day:
M
=
dental
fluorosis.
At
56
mg/
kg/
day
(
M):
M
=
effects
similar
to
those
in
F
at
62
mg/
kg/
day.
NOAEL
(
F):
16
mg/
kg/
day
LOAEL
(
F):
62
mg/
kg/
day:
F
=
greatly
increased
mortality
(
due
mostly
to
severe
kidney
toxicity
which
led
to
kidney
failure);
histopathology
in
brain
(
vacuolation
in
cerebrum
and
thalamus/
hypothalamus),
adrenal
cortex,
eyes,
liver,
nasal
tissue,
and
respiratory
tract;
dental
fluorosis.

Negative
for
carcinogenicity
in
M
and
F.
9
of
39
Table
3.1.2.
Toxicity
Profile
of
Technical
Grade
Sulfuryl
Fluoride
(
99.8%
active
ingredient)

Guideline
No.
Study
Type
Results
870.5100
Mutagenicity
­
Reverse
gene
mutation
(
S.
typhimurium)
Negative
without
and
with
S­
9
activation.

870.5395
Mutagenicity
­
in
vivo
micronucleus
assay,
mice
(
bone
marrow
cells)
Negative.

870.5500
Mutagenicity
­
unscheduled
DNA
synthesis
(
primary
rat
hepatocytes)
Negative.

(
870.6200)

(
inhalation
study)
Acute
inhalation
neurotoxicity
study,
rats
(
special
design)

0,
100,
300
ppm
(
0,
118,
354
mg/
kg/
day)
(
F
only)
Systemic
NOAEL:
354
mg/
kg/
day
(
F):
highest
dose
tested.
Systemic
LOAEL:
>
354
mg/
kg/
day
(
F).
Neurotoxic
NOAEL:
354
mg/
kg/
day
(
F):
highest
dose
tested.
Neurotoxic
LOAEL:
>
354
mg/
kg/
day
(
F).
Note­
study
included
electrophysiological
parameters,
but
no
microscopic
pathology.

(
870.6200)

(
inhalation
study)
90­
Day
inhalation
neurotoxicity
study,
rats
(
special
design)

0,
30,
100,
300
ppm
(
0/
0,
24/
25,
80/
83,
240/
250
mg/
kg/
day)
(
M/
F)
Systemic
NOAEL:
24/
25
mg/
kg/
day
(
M/
F)
Systemic
LOAEL:
80/
83
mg/
kg/
day
(
M/
F):
M&
F
=
pale
foci
in
pleura
and
macrophages
in
lungs,
dental
fluorosis
At
240/
250
mg/
kg/
day
(
M/
F):
M&
F
=
decreased
body
weight,
excessive
salivation,
poor
grooming.
Neurotoxic
NOAEL:
24/
25
mg/
kg/
day
(
M/
F)
Neurotoxic
LOAEL:
80/
83
mg/
kg/
day
(
M/
F):
M&
F
=
disturbances
in
electrophysiologic
parameters
(
slowing
of
VER
and
SER
waveforms
in
F
and
ABR
waveforms
in
M).
At
240/
250
mg/
kg/
day
(
M/
F):
M&
F
=
slowing
of
all
waveforms
except
CNAP,
vacuolation
of
white
matter
in
caudate
putamen
in
cerebrum.

Note­
study
included
electrophysiological
parameters.
(
870.6200)

(
inhalation
study)
1­
Year
inhalation
neurotoxicity
study,
rats
(
special
design)

0,
5,
20,
80
ppm
(
0/
0,
3.5/
3.9,
14/
16,
56/
62
mg/
kg/
day)
(
M/
F)
Systemic
NOAEL:
3.5/
3.9
mg/
kg/
day
(
M/
F)
Systemic
LOAEL:
14/
16
mg/
kg/
day
(
M/
F):
M&
F
=
dental
fluorosis.
At
56/
62
mg/
kg/
day
(
M/
F):
M&
F
=
increased
kidney
and
liver
weights,
progressive
kidney
disease,
histopathology
in
lung.
Neurotoxic
NOAEL:
56/
62
mg/
kg/
day
(
M/
F):
highest
dose
tested.
Neurotoxic
LOAEL:
>
56/>
62
mg/
kg/
day
(
M/
F).

Note­
study
did
not
include
electrophysiological
parameters.
870.6300
Developmental
neurotoxicity,
rats
No
study
available.
Required
to
be
performed
and
submitted
by
HIARC
(
April
11,
2001
and
October
21,
2003).
That
requirement
has
subsequently
been
waived
(
2004,
see
attachment)
870.7485
Metabolism
and
pharmacokinetics,
rats
No
study
available.
Study
waived
in
Reregistration
Eligibility
Document
(
RED)
published
by
EPA
in
1993.
870.7600
Dermal
Penetration,
rats
No
study
available.
Not
required.

Technical
grade
sulfuryl
fluoride
(
99.8%
active
ingredient)
is
marketed
as
a
liquefied
gas
in
pressurized
steel
cylinders.
The
acute
oral
LD50
of
sulfuryl
fluoride
has
been
estimated
to
be
approximately
100
mg/
kg
in
rats
(
Toxicity
Category
II).
The
acute
inhalation
LC50
in
mice
(
4
hour
exposure)
is
660
ppm
(
2.56
mg/
L)
in
males
and
642
ppm
(
2.49
mg/
L)
in
females.
The
acute
10
of
39
inhalation
LC50
in
rats
(
1
hour
exposure)
is
4512
ppm
(
17.5
mg/
L).
Based
on
the
use
pattern
for
sulfuryl
fluoride
and
several
reported
incidences
of
human
poisonings
in
the
general
toxicological
literature,
the
Agency
has
classified
sulfuryl
fluoride
as
Toxicity
Category
I
for
acute
inhalation
toxicity.
When
released
from
pressurized
steel
cylinders,
sulfuryl
fluoride
causes
freezing
of
skin
and
eye
tissues
on
contact.
Therefore,
no
dermal
studies
or
eye
irritation
studies
have
been
required
to
be
submitted.
The
acute
dermal
toxicity
study
(
assumed
Toxicity
Category
of
IV),
the
primary
skin
irritation
study
(
assumed
Toxicity
Category
of
IV),
the
primary
eye
irritation
study
(
assumed
Toxicity
Category
of
I),
and
the
dermal
sensitization
study
(
assumed
to
be
a
nonsensitizer
have
been
waived.
In
a
non­
guideline
study
in
which
rats
were
dermally
exposed
(
with
no
inhalation
exposure)
to
vapors
of
sulfuryl
fluoride
gas
at
an
exposure
concentration
of
9600
ppm
(
40.3
mg/
L)
for
4
hours,
no
treatment­
related
adverse
effects
were
observed.

In
2­
week
inhalation
studies
in
rats,
dogs
and
rabbits,
different
target
organs
were
affected.
In
rats,
the
primary
target
organ
was
the
kidney,
in
which
severe
histopathological
lesions
were
observed.
These
lesions
included
papillary
necrosis,
hyperplasia
of
the
epithelial
cells
of
the
papillae,
and
degeneration/
regeneration
of
collecting
tubules
and
proximal
tubules.
In
dogs,
the
primary
target
organ
was
the
upper
respiratory
tract,
in
which
minimal
inflammation
was
observed.
Intermittent
tremors
and
tetany
were
also
noted
in
dogs.
In
rabbits,
the
primary
target
organ
was
the
brain,
in
which
malacia
(
necrosis)
and
vacuolation
were
observed
in
the
cerebrum.
Inflammation
of
the
upper
respiratory
tract
was
also
noted
in
rabbits.

In
subchronic
(
90­
day)
inhalation
studies
in
rats,
mice,
dogs
and
rabbits,
the
brain
was
the
major
target
organ.
Malacia
and/
or
vacuolation
were
observed
in
the
white
matter
of
the
brain
in
all
four
species.
The
portions
of
the
brain
most
often
affected
were
the
caudate­
putamen
nucleus
in
the
basal
ganglia,
the
white
fiber
tracts
in
the
internal
and
external
capsules,
and
the
globus
pallidus
of
the
cerebrum.
In
dogs
and
rabbits,
clinical
signs
of
neurotoxicity
(
including
tremors,
tetany,
incoordination,
convulsions
and/
or
hind
limb
paralysis)
were
also
observed.
Inflammation
of
the
nasal
passages
and
histiocytosis
of
the
lungs
were
observed
in
rats
and
rabbits,
but
not
in
dogs,
in
which
species
inflammation
of
the
upper
respiratory
tract
was
more
prominent
in
the
2­
week
study.
In
rats,
kidney
damage
was
also
observed.
In
mice,
follicular
cell
hypertrophy
was
noted
in
the
thyroid
gland.
Decreased
body
weights
and
body
weight
gains
were
also
observed
in
rats,
dogs
and
mice.

In
chronic
(
1­
2
year)
inhalation
studies
in
rats,
dogs
and
mice,
target
organs
were
the
same
as
in
the
90­
day
studies.
In
rats,
severe
kidney
damage
caused
renal
failure
and
mortality
in
many
animals.
Additional
gross
and
histopathological
lesions
in
numerous
organs
and
tissues
were
considered
to
be
secondary
to
the
primary
effect
on
the
kidneys.
Other
treatment­
related
effects
in
rats
included
effects
in
the
brain
(
vacuolation
of
the
cerebrum
and
thalamus/
hypothalamus)
and
respiratory
tract
(
reactive
hyperplasia
and
inflammation
of
the
respiratory
epithelium
of
the
nasal
turbinates,
lung
congestion,
aggregates
of
alveolar
macrophages).
In
dogs
and
mice,
increased
mortality,
malacia
and/
or
vacuolation
in
the
white
matter
in
the
brain,
histopathology
in
the
lungs,
and
follicular
cell
hypertrophy
in
the
thyroid
gland
were
observed.
Decreased
body
weights
and
body
weight
gains
were
also
noted
in
all
three
species.
No
evidence
of
carcinogenicity
was
observed
in
either
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats
or
in
the
18­
month
carcinogenicity
study
in
mice.
11
of
39
In
many
subchronic
and
chronic
inhalation
studies
in
rats,
dogs,
and
rabbits,
dental
fluorosis
was
the
most
sensitive
effect
observed
in
the
study.
In
two
90­
day
studies
in
mice
and
rabbits,
in
which
serum
fluoride
levels
were
determined,
an
increased
serum
level
of
fluoride
anions
was
observed
at
even
lower
dose
levels.
The
increased
serum
fluoride
levels
were
due
to
the
conversion
of
sulfuryl
fluoride
to
fluoride
anions
in
the
body.

In
specially
designed
acute
and
subchronic
inhalation
neurotoxicity
studies
in
rats,
several
electrophysiological
parameters
(
electroencephalograms,
EEGs)
were
recorded
in
addition
to
observations
for
clinical
signs
of
neurotoxicity,
functional
observational
battery
(
FOB)
and
motor
activity
testing,
and/
or
neurohistopathologic
examination.
Following
two
exposures
on
consecutive
days
for
6
hours/
day
at
300
ppm
of
sulfuryl
fluoride
(
354
mg/
kg/
day),
no
treatmentrelated
neurotoxic
effects
were
noted.
In
a
90­
day
study,
changes
in
some
EEG
patterns
were
observed
at
100
ppm
(
80
mg/
kg/
day)
and
in
several
additional
patterns
at
300
ppm
(
240
mg/
kg/
day).
Vacuolation
of
the
white
matter
in
the
cerebrum
was
also
observed
at
300
ppm
in
this
study.
In
a
specially
designed
1­
year
chronic
inhalation
neurotoxicity
study
in
rats,
no
treatment­
related
neurotoxic
effects
were
observed
at
80
ppm
(
56
mg/
kg/
day).
EEGs
were
not
recorded
in
this
study.

In
a
developmental
toxicity
inhalation
study
in
rats,
no
developmental
toxicity
was
observed
in
the
pups.
Although
no
maternal
toxicity
was
observed
in
this
study
at
the
highest
dose
tested
(
225
ppm),
significant
maternal
toxicity
(
decreased
body
weight,
body
weight
gain
and
food
consumption;
increased
water
consumption
and
kidney
weights;
and
gross
pathological
changes
in
the
kidneys
and
liver)
was
observed
in
a
previously
conducted
range­
finding
study
at
a
slightly
higher
dose
level
(
300
ppm).
In
a
developmental
toxicity
inhalation
study
in
rabbits,
decreased
fetal
body
weights
were
observed
in
the
pups.
At
the
same
dose
level,
decreased
body
weight
and
body
weight
gain
were
observed
in
the
dams.
In
a
2­
generation
reproduction
inhalation
study
in
rats,
vacuolation
of
the
white
matter
in
the
brain,
pathology
in
the
lungs
(
pale,
gray
foci;
increased
alveolar
macrophages)
and
decreased
body
weights
were
observed
in
the
parental
animals.
Decreased
pup
body
weights
in
the
F1
and
F2
generations
were
observed
in
the
offspring.
No
effects
on
reproductive
parameters
were
noted
in
this
study.
No
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
fetuses
or
pups
was
observed
in
the
developmental
toxicity
or
reproduction
studies
on
sulfuryl
fluoride.

A
battery
of
mutagenicity
studies
was
negative
for
genotoxic
potential.
The
studies
included
a
reverse
gene
mutation
assay
in
Salmonella
typhimurium,
an
unscheduled
DNA
synthesis
assay
in
primary
rat
hepatocytes,
and
a
micronucleus
assay
in
mouse
bone
marrow
cells.

In
carcinogenicity
studies
in
male
and
female
rats
and
in
male
and
female
mice,
sulfuryl
fluoride
did
not
demonstrate
evidence
of
carcinogenic
potential.
Sulfuryl
fluoride
is
classified
as
A
not
likely
to
be
carcinogenic
to
humans@
according
to
the
July
2,
1999
EPA
Draft
Proposed
Guidelines
for
Carcinogen
Risk
Assessment.

Poisonings
and
fatalities
have
been
reported
in
humans
following
inhalation
exposure
to
sulfuryl
fluoride.
The
severity
of
these
effects
has
depended
on
the
concentration
of
sulfuryl
fluoride
and
the
duration
of
exposure.
Short­
term
inhalation
exposure
to
high
concentrations
has
caused
respiratory
irritation,
pulmonary
edema,
nausea,
abdominal
pain,
central
nervous
system
12
of
39
depression,
and
numbness
in
the
extremities2.
In
addition,
there
have
been
two
reports
of
deaths
of
persons
entering
houses
treated
with
sulfuryl
fluoride.
One
person
entered
the
house
illegally
and
was
found
dead
the
next
morning.
A
second
person
died
of
cardiac
arrest
after
sleeping
in
a
house
overnight
following
fumigation.
A
plasma
fluoride
level
of
0.5
mg/
L
(
10
times
normal)
was
found
in
this
person
following
exposure3.
These
acute
poisonings
in
humans,
however,
occurred
only
after
label
directions
were
grossly
violated
and
persons
were
subsequently
exposed
to
extremely
high
concentrations
of
sulfuryl
fluoride.
Prolonged
chronic
inhalation
exposures
to
concentrations
of
sulfuryl
fluoride
gas
significantly
above
the
threshold
limit
value
(
TLV)
of
5
ppm
have
caused
fluorosis
in
humans
because
sulfuryl
fluoride
is
converted
to
fluoride
anion
in
the
body.
Fluorosis
results
from
the
binding
of
fluoride
anion
to
teeth
(
causing
mottling
of
the
teeth)
and
to
bone.

3.1.2
FQPA
Considerations
On
October
21,
2003,
the
HED
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
met
to
re­
evaluate
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
sulfuryl
fluoride,
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996,
according
to
the
2002
OPP
10X
Guidance
Document.
This
re­
evaluation
was
conducted
to
update
the
decision
which
was
reached
on
April
11,
2001
using
previous
OPP
policy.

Based
on
the
available
evidence,
HIARC
reiterated
its
earlier
recommendation
that
an
inhalation
developmental
neurotoxicity
(
DNT)
study
in
rats
(
Guideline
No.
870.6300)
be
required
in
order
to
more
clearly
and
fully
characterize
the
potential
for
neurotoxic
effects
in
young
animals.

HIARC
determined
that
a
10X
database
uncertainty
factor
(
UFDB)
is
needed
to
account
for
the
lack
of
the
DNT
study
since
the
available
data
provide
no
basis
to
support
reduction
or
removal
of
the
default
10X
factor.
The
following
points
were
considered
in
this
determination:

$
The
current
regulatory
dose
for
chronic
dietary
risk
assessment
is
the
NOAEL
of
8.5
mg/
kg/
day
(
30
ppm;
0.13
mg/
L)
selected
from
a
90­
day
inhalation
toxicity
study
in
rabbits.
This
dose
is
also
used
for
intermediate­
and
long­
term
inhalation
exposure
risk
assessments.
The
current
dose
for
the
short­
term
inhalation
exposure
risk
assessment
is
the
NOAEL
of
30
mg/
kg/
day
(
100
ppm;
0.42
mg/
L)
from
a
2­
week
inhalation
toxicity
study
in
rabbits.

$
After
considering
the
dose
levels
used
in
the
neurotoxicity
studies
and
in
the
2­
generation
reproduction
study,
it
is
assumed
that
the
DNT
study
with
sulfuryl
fluoride
will
be
conducted
at
dose
levels
similar
to
those
used
in
the
2­
generation
reproduction
study
(
0,

2U.
S.
EPA,
Structural
fumigation
using
sulfuryl
fluoride:
DowElanco=
s
Vikane
TM
Gas
Fumigant,
Methyl
bromide
alternative
case
study,
Part
of
EPA
430­
R­
021,
10
Case
studies,
volume
2,
December
1996,
p.
3.
Available
at
http://
www.
epa.
gov/
spdpublc/
mbr/
sulfury2.
html.

3U.
S.
EPA,
Reregistration
Eligibility
Decision
(
RED);
Sulfuryl
fluoride,
1993,
p.
9.
13
of
39
5,
20,
150
ppm;
0,
0.02,
0.08,
0.6
mg/
L).
It
is
considered
possible
that
the
results
of
the
DNT
study
could
impact
the
endpoint
selection
for
risk
assessments
because
the
lowest
dose
that
may
be
tested
in
the
DNT
(
5
ppm
or
0.02
mg/
L),
based
on
the
HIARC=
s
dose
analysis,
could
become
an
effect
level
which
would
necessitate
an
additional
factor
resulting
in
doses
which
would
then
be
lower
than
the
current
doses
used
for
chronic
dietary
(
8.5
mg/
kg/
day),
intermediate
and
long­
term
inhalation
(
30
ppm
or
0.13
mg/
L)
and
short
term
inhalation
(
100
ppm
or
0.42
mg/
L)
risk
assessments.
Given
these
circumstances,
the
HIARC
does
not
have
sufficient
reliable
data
justifying
selection
of
an
additional
safety
factor
for
the
protection
of
infants
and
children
lower
than
the
default
value
of
10X.
Therefore,
a
UFDB
of
10X
will
be
applied
to
repeated
dose
exposure
scenarios
(
i.
e.
chronic
RfD,
and
residential
short,
intermediate
and
long
term
inhalation)
to
account
for
the
lack
of
the
DNT
study
with
sulfuryl
fluoride.

The
HIARC
determined
that
there
is
no
need
for
a
special
FQPA
safety
factor
(
i.
e.,
1X)
since
there
are
no
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
based
on
the
following:

$
In
the
developmental
toxicity
study
in
rats,
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
sulfuryl
fluoride
was
observed.

$
In
the
developmental
toxicity
study
in
rabbits,
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
fetuses
to
in
utero
exposure
to
sulfuryl
fluoride
was
observed.

$
In
the
2­
generation
reproduction
toxicity
study
in
rats,
neither
quantitative
nor
qualitative
evidence
of
increased
susceptibility
of
fetuses
to
sulfuryl
fluoride
was
observed.

In
April
2004,
the
Health
Effects
Division
evaluated
rational
submitted
by
the
registrant
requesting
a
waiver
of
the
DNT
study.
HED
granted
the
waiver
request
(
Attachment
1)
because,
given
the
relatively
minimal
exposure
to
sulfuryl
fluoride
relative
to
the
identified
endpoints,
any
lowering
of
the
regulatory
endpoints
due
to
DNT
study
results
would
be
unlikely
to
affect
the
safety
determination.
However,
because
there
remains
uncertainty
with
regard
to
the
regulatory
endpoints
for
sulfuryl
fluoride
in
the
absence
of
a
DNT,
EPA
has
retained
the
FQPA
10X
factor
in
assessing
the
risk
posed
by
sulfuryl
fluoride.

3.1.3
Dose­
Response
Assessment
The
endpoint
selection
and
rationale
are
provided,
below
and
in
Table
3.1.3,
for
the
various
exposure
route
and
duration
combinations.

Acute
Reference
Dose
(
RfD):
None.
No
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
on
sulfuryl
fluoride
that
would
be
appropriate
for
an
acute
risk
assessment
and
would
be
applicable
to
females
(
13­
50
years
old)
or
to
the
general
population
(
including
infants
and
children).

Chronic
Reference
Dose
(
RfD):
0.003
mg/
kg/
day
from
the
90­
Day
subchronic
inhalation
toxicity
study
in
rabbits.
In
that
study,
the
LOAEL
is
28
mg/
kg/
day
based
on
vacuolation
of
14
of
39
white
matter
in
the
brain
of
females,
and
decreased
body
weights,
decreased
liver
weights
and
dental
fluorosis
in
males
and
females.
The
NOAEL
is
8.5
mg/
kg/
day.
The
Uncertainty
Factor
associated
with
the
chronic
RfD
is
3000
and
is
based
on
10X
for
intraspecies
variation,
10X
for
interspecies
extrapolation,
3X
Uncertainty
Factor
for
using
a
subchronic
(
90­
day)
study
for
chronic
risk
assessment
(
UFS),
and
10X
Database
Uncertainty
Factor
(
UFDB)
for
lack
of
a
DNT
study.
We
note
that
a
chronic
dog
study
with
an
NOAEL
of
5
mg/
kg/
day
is
available.
In
that
study,
the
noted
effects
at
the
LOAEL
of
20
mg/
kg/
day
were
decreased
body
weight
gain,
increased
alveolar
macrophages,
and
dental
fluorosis.
This
study
was
not
selected
as
the
basis
for
the
RfD
because
the
effects
from
the
rabbit
study
are
considered
to
be
more
severe.
Had
this
dog
study
been
used,
the
resulting
RfD
(
0.005
mg/
kg/
day)
would
have
been
nearly
identical
to
that
derived
from
the
90­
day
rabbit
study.
A
chronic
rat
study
with
an
NOAEL
of
3.5
mg/
kg/
day
is
also
available.
In
that
study,
the
effect
at
the
LOAEL
of
14
mg/
kg/
day
was
dental
fluorosis.
The
effects
in
the
rabbit
study
are
considered
to
be
more
severe
than
those
in
the
rat
study.
If
this
rat
study
had
been
selected,
the
resulting
RfD
(
0.0035
mg/
kg/
day)
also
would
have
been
nearly
identical
to
that
derived
from
the
90­
day
rabbit
study.
The
selected
chronic
RfD
for
sulfuryl
fluoride
is
considered
to
be
protective
of
all
effects,
including
dental
fluorosis.

For
sulfuryl
fluoride,
the
endpoint
from
an
inhalation
toxicity
study
was
used
to
calculate
the
chronic
RfD
which
is
to
be
used
to
perform
risk
assessments
for
oral
exposures.
HIARC
believes
this
is
a
very
conservative
methodology
which
is
supported
by
the
following
considerations:

$
A
higher
and
more
persistent
level
of
parent
test
material
in
the
body
may
occur
following
inhalation
exposure
as
compared
to
an
oral
exposure
because
the
parent
test
material
is
immediately
distributed
throughout
the
circulatory
system
following
inhalation,
rather
than
first
being
directly
shunted
to
the
liver
(
where
most
metabolism
occurs)
as
in
the
case
of
oral
exposure.

$
In
addition,
for
sulfuryl
fluoride,
the
NOAEL
on
which
the
chronic
RfD
was
calculated
is
from
a
study
in
rabbits
(
which
is
the
most
sensitive
species
for
neurotoxic
effects)
and
the
LOAEL
in
this
study
was
close
to
a
threshold
effect
level
(
the
effect
was
observed
in
only
one
female
rabbit).

The
LOAEL
of
100
ppm
(
equivalent
to
28
mg/
kg/
day)
in
the
90­
day
rabbit
study,
which
was
used
to
calculate
the
chronic
RfD,
was
considered
to
be
close
to
a
threshold
effect
level
because
only
one
female
rabbit
at
this
concentration
had
vacuolation
of
the
white
matter
in
the
brain.
The
HIARC
considered
applying
an
additional
uncertainty
factor
to
the
NOAEL
in
this
study
due
to
the
severity
of
the
effect
at
the
LOAEL,
but
concluded
that
application
of
an
additional
uncertainty
factor
would
not
be
necessary
since
the
LOAEL
was
an
approximate
threshold
effect
level.

For
the
purpose
of
determining
a
chronic
oral
RfD,
the
HIARC
believes
that
an
endpoint
based
on
a
well­
defined
morphological/
pathological
effect,
such
as
the
neurological
effect
observed
in
the
90­
day
rabbit
study,
is
preferable
to
one
based
on
a
more
equivocal
and/
or
dubious
effect
such
as
dental
fluorosis
(
mottling
of
teeth).
The
HIARC
also
believes
that
it
is
not
appropriate
to
utilize
an
effect
on
the
respiratory
system
in
an
inhalation
study
as
the
basis
for
15
of
39
calculating
an
oral
RfD.
Therefore,
the
NOAEL
of
5
ppm
(
equivalent
to
3.5
mg/
kg/
day)
for
male
rats
in
the
combined
2­
year
chronic/
carcinogenicity
inhalation
study
in
rats
(
MRID
43354902)
was
not
used
to
calculate
the
chronic
RfD
because
the
effect
observed
at
the
LOAEL
of
20
ppm
(
equivalent
to
14
mg/
kg/
day)
was
dental
fluorosis.
Also,
the
parental
NOAEL
of
5
ppm
(
equivalent
to
3.6
mg/
kg/
day)
in
the
2­
generation
reproduction
inhalation
study
in
rats
(
MRID
42179801)
was
not
used
because
the
effect
observed
at
the
parental
LOAEL
of
20
ppm
(
equivalent
to
14
mg/
kg/
day)
was
pathological
changes
in
the
lungs.
In
addition,
the
NOAEL
of
20
ppm
(
equivalent
to
5.0
mg/
kg/
day)
in
the
1­
year
chronic
inhalation
toxicity
study
in
dogs
(
MRID
43354901)
was
not
used
because
the
effect
observed
at
the
LOAEL
of
80
ppm
(
equivalent
to
20
mg/
kg/
day)
was
decreased
body
weight
gain,
dental
fluorosis,
and
histopathological
changes
in
the
lungs.

Incidental
Oral
Exposure
(
All
Durations):
None.
Sulfuryl
fluoride
is
a
gas
at
ordinary
temperatures
and
pressures
and
because
of
its
use
pattern
as
a
fumigant
in
enclosed
structures
and
spaces
only,
it
is
not
anticipated
that
toxicologically
significant
residues
of
sulfuryl
fluoride
or
its
degradates
will
remain
in/
on
the
contents
of
residential
or
other
structures
after
the
aeration
period
is
completed.
Consequently,
there
is
no
potential
for
incidental
ingestion
by
toddlers.
Therefore,
HIARC
did
not
select
endpoints
for
this
exposure
scenario.

Dermal
Exposure
(
All
Durations):
None.
No
hazard
was
identified
and
quantification
of
risk
is
not
necessary.

Inhalation
­
Short­
term
(
1­
30
days):
NOAEL
=
30
mg/
kg/
day
(
100
ppm;
0.42
mg/
L)
from
the
2­
week
inhalation
toxicity
study
in
rabbits.
The
NOAEL
is
based
on
malacia
(
necrosis)
in
the
cerebrum
in
1
male
and
1
female,
vacuolation
in
the
cerebrum
in
all
male
and
females,
and
moderate
inflammation
of
nasal
tissues
in
most
animals
and
acute
inflammation
of
the
trachea
in
some
animals
at
the
LOAEL
of
90
mg/
kg/
day
(
300
ppm;
1.25
mg/
L).
The
results
of
this
study
provide
the
best
information
available
pertaining
to
assessment
of
the
potential
short­
term
(
1
­
30
days)
risk
via
inhalation
exposure.

The
HIARC
determined
there
is
no
need
to
quantify
the
inhalation
risk
resulting
from
a
single
residential
or
occupational
inhalation
exposure
to
sulfuryl
fluoride.
No
treatment­
related
neurotoxic
or
other
effects
were
observed
in
a
specially
designed
acute
neurotoxicity
inhalation
study
(
MRID
42772001)
in
which
rats
were
exposed
on
two
consecutive
days
for
6
hours/
day
to
concentrations
up
to
300
ppm
of
sulfuryl
fluoride
(
equivalent
to
1.25
mg/
L).
Further,
no
appropriate
endpoints
resulting
from
a
single
inhalation
exposure
were
identified
in
any
of
the
available
toxicity
studies
on
sulfuryl
fluoride.
Therefore,
no
hazard
attributable
to
a
single
inhalation
exposure
was
identified
and
quantification
of
risk
for
single
inhalation
exposures
was
determined
to
be
unnecessary.
The
HIARC
noted
that
poisonings
and
fatalities
have
been
reported
in
humans
following
inhalation
exposure
to
sulfuryl
fluoride.
The
severity
of
these
effects
has
depended
on
the
concentration
of
sulfuryl
fluoride
and
the
duration
of
exposure.
Short­
term
inhalation
exposure
to
high
concentrations
has
caused
respiratory
irritation,
pulmonary
edema,
nausea,
abdominal
pain,
central
nervous
system
depression,
and
numbness
in
the
extremities4.
In
addition,
there
have
been
two
reports
of
deaths
of
persons
entering
houses
4U.
S.
EPA,
Structural
fumigation
using
sulfuryl
fluoride:
DowElanco=
s
Vikane
TM
Gas
16
of
39
treated
with
sulfuryl
fluoride
(
see
end
of
section
3.1.1).
As
previously
stated,
these
acute
poisonings
in
humans,
however,
occurred
only
after
label
directions
were
grossly
violated
and
persons
were
subsequently
exposed
to
extremely
high
concentrations
of
sulfuryl
fluoride.

Inhalation
­
Intermediate­
term
(
1­
6
months):
NOAEL
=
8.5
mg/
kg/
day
(
30
ppm;
0.13
mg/
L)
from
the
90­
day
subchronic
inhalation
toxicity
study
in
rabbits.
The
NOAEL
is
based
on
vacuolation
of
white
matter
in
the
brain
of
females
at
the
LOAEL
of
28
mg/
kg/
day
(
100
ppm;
0.42
mg/
L).
The
route
and
dosing
regimen
of
this
study
is
appropriate
for
the
route
and
duration
of
exposure
of
concern.

Inhalation
­
Long­
term
(
several
months
to
lifetime):
NOAEL
=
8.5
mg/
kg/
day
(
30
ppm;
0.13
mg/
L)
from
the
90­
day
subchronic
inhalation
toxicity
study
in
rabbits.
The
NOAEL
is
based
on
vacuolation
of
white
matter
in
the
brain
of
females
at
the
LOAEL
of
28
mg/
kg/
day
(
100
ppm;
0.42
mg/
L).
This
is
the
same
study
used
to
establish
the
chronic
RfD.

Table
3.1.3.
Summary
of
Dose
and
Endpoint
Selection
for
use
in
Human
Health
Risk
Assessments
for
Sulfuryl
Fluoride.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
None
UF
=
N/
A
Not
applicable
No
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
on
sulfuryl
fluoride.

Chronic
Dietary
(
All
populations)
NOAEL=
8.5
mg/
kg/
day
UF
=
3000
Chronic
RfD
=
0.003
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.003
mg/
kg/
day
90­
Day
Inhalation
­
Rabbit
LOAEL
=
28
mg/
kg/
day
based
on
vacuolation
of
white
matter
in
the
brain
of
females.

Incidental
Oral
(
All
durations)
None
Not
applicable
Due
to
sulfuryl
fluoride
being
a
gas
and
pattern
of
use,
no
significant
incidental
oral
exposure
is
anticipated.

Dermal
(
All
durations)
None
Not
applicable
Due
to
sulfuryl
fluoride
being
a
gas
and
pattern
of
use,
no
significant
dermal
exposure
is
anticipated.
No
hazard
identified,
therefore,
no
quantification
is
required.

Short­
Term
Inhalation
(
1
to
30
days)
Inhalation
study
NOAEL=
30
mg/
kg/
day
(
100
ppm;
0.42
mg/
L)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
2­
Week
Inhalation
­
Rabbit
LOAEL
=
90
mg/
kg/
day
(
300
ppm;
1.25
mg/
L)
based
on
malacia
(
necrosis)
and
vacuolation
in
brain,
inflammation
of
nasal
tissues
and
trachea.

Intermediate­
Term
Inhalation
(
1
to
6
Inhalation
study
NOAEL
=
8.5
Residential
LOC
for
90­
Day
Inhalation
­
Rabbit
LOAEL
=
28
mg/
kg/
day
(
100
ppm;
0.42
Fumigant,
Methyl
bromide
alternative
case
study,
Part
of
EPA
430­
R­
021,
10
Case
studies,
volume
2,
December
1996,
p.
3.
Available
at
http://
www.
epa.
gov/
spdpublc/
mbr/
sulfury2.
html.
17
of
39
Table
3.1.3.
Summary
of
Dose
and
Endpoint
Selection
for
use
in
Human
Health
Risk
Assessments
for
Sulfuryl
Fluoride.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
months)
mg/
kg/
day
(
30
ppm;
0.13
mg/
L)
MOE
=
1000
Occupational
LOC
for
MOE
=
100
mg/
L)
based
on
vacuolation
of
white
matter
in
the
brain
of
females.

Long­
Term
Inhalation
(>
6
months)
Inhalation
study
NOAEL
=
8.5
mg/
kg/
day
(
30
ppm;
0.13
mg/
L)
Residential
LOC
for
MOE
=
3000
Occupational
LOC
for
MOE
=
300
90­
Day
Inhalation
­
Rabbit
LOAEL
=
28
mg/
kg/
day
(
100
ppm;
0.42
mg/
L)
based
on
vacuolation
of
white
matter
in
the
brain
of
females.

Cancer
(
oral,
dermal,
inhalation)
Classified
as
A
Not
likely
to
be
carcinogenic
to
humans
@

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
3.1.4
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
Amay
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate.@
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC=
s
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).
In
the
available
toxicity
studies
on
sulfuryl
fluoride,
there
was
no
toxicologically
significant
evidence
of
endocrine
disruptor
effects.
Follicular
cell
hypertrophy
in
the
thyroid
of
mice
in
the
90­
day
toxicity
study
and
in
the
18­
month
carcinogenicity
study,
and
in
the
thyroid
of
dogs
in
the
1­
year
chronic
toxicity
study
was
observed.
At
the
same
dose
levels
at
which
these
effects
were
observed,
however,
considerably
more
serious
effects
(
microscopic
lesions
in
the
brain
in
mice
and
dogs
and
increased
mortality
in
dogs)
were
also
observed.
Consequently,
there
is
only
minimal
concern
for
potential
endocrine
disruptor
effects
at
these
dose
levels
in
these
species.
When
additional
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency=
s
EDSP
have
been
developed,
sulfuryl
fluoride
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

3.2
Fluoride
Anion
18
of
39
3.2.1
Hazard
Profile
A
very
large
body
of
information
regarding
the
toxicology
of
fluoride
is
available
in
the
open
literature.
A
complete
review
or
re­
presentation
of
that
information
is
beyond
the
scope
of
this
assessment.
For
a
comprehensive
review
of
the
toxicology
of
fluoride,
the
reader
is
referred
to
publications
by
the
World
Health
Organization
(
2002),
the
Department
of
Health
and
Human
Services
(
2001),
the
National
Research
Council
(
1993),
the
Medical
Research
Council
(
2002),
and
NHS
CRD
(
2000).
In
conducting
the
assessment
for
fluoride,
HED
has
used
the
toxicological
assessment
conducted
by
the
Agency=
s
Office
of
Water.
The
regulatory
findings
in
that
assessment
[
FR
51
(
63)]
are
based
on
a
LOAEL
of
20
mg/
day
and
a
safety
factor
of
2.5,
giving
a
maximum
allowable
intake
of
8
mg/
day.
The
use
of
a
safety
factor
of
2.5
ensures
public
health
criteria
while
still
allowing
sufficient
concentration
of
fluoride
in
water
to
realize
its
beneficial
effects
in
protecting
against
dental
caries.
The
typical
100X
factor
used
by
HED
to
account
for
inter­
and
intra­
species
variability
have
been
removed
due
to
the
large
amounts
of
human
epidemiological
data
surrounding
fluoride
and
skeletal
fluorosis.
In
a
more
recent
review
of
the
data,
the
National
Academy
of
Sciences=
Institute
of
Medicine
(
IOM)
identified
a
skeletal
fluorosis
NOAEL
at
10
mg/
day5.
Their
assessment
of
the
data
concludes
that
no
safety
or
uncertainty
factors
are
needed.
The
IOM
also
notes
that
high
exposures
for
long
durations
(
on
the
order
of
10
years)
are
required
to
develop
skeletal
fluorosis
and
that
such
a
condition
is
not
expected
to
occur
in
children
under
the
age
of
8.
The
findings
of
the
IOM
are
nearly
identical
with
respect
to
upper
limits
of
exposure
as
those
of
the
Office
of
Water.
Although
the
values
of
8
mg/
day
and
10
mg/
day
are
essentially
equivalent,
OPP
has
used
the
8­
mg/
day
value
in
order
to
be
slightly
more
conservative
in
assessing
risk.
For
fluoride
risk
assessments
addressed
in
this
document,
the
8
mg/
day
value
has
been
used
in
a
manner
analogous
to
a
reference
dose
(
RfD)
and
is
referred
to
as
such
for
ease
of
communication.
We
note
that
the
previous
human
health
risk
assessment
for
sulfuryl
fluoride
(
M.
Doherty,
10/
12/
2004,
D309013)
expressed
toxicology
and
exposure
in
terms
of
mg/
kg/
day
in
order
to
match
the
units
used
by
the
dietary
exposure
model.
In
this
assessment,
those
values
are
being
expressed
in
mg/
day
to
better
harmonize
with
the
more
typical
units
found
in
the
open
literature
describing
fluoride
exposures.
In
both
cases,
the
values
listed
are
derived
from
the
same
toxicological
data
and
conclusions.

The
Agency
is
aware
of
concern
regarding
dental
fluorosis.
The
National
Academy
of
Sciences
has
stated
that
"...
dental
fluorosis
is
accepted
as
a
purely
cosmetic
defect
with
no
general
health
ramifications.
However,
the
most
severe
forms
of
dental
fluorosis
might
be
more
than
a
cosmetic
defect
if
enough
fluorotic
enamel
is
fractured
and
lost
to
cause
pain,
adversely
affect
food
choices,
compromise
chewing
efficiency
and
require
complex
dental
treatment."
(
NRC,
1993).
The
Office
of
Water
has
established
a
secondary
maximum
contaminant
level
(
SMCL)
for
fluoride
at
2.0
ppm
to
be
protective
against
objectionable
dental
fluorosis.
The
SMCL
is
a
nonenforceable
level
established
to
be
protective
against
the
cosmetic
and
aesthetic
effects
of
a
contaminant.
Appendix
II
of
this
risk
assessment
addresses
dental
fluorosis.

5
Dietary
reference
intakes
for
calcium,
phosphorus,
magnesium,
vitamin
D
and
fluoride.
Report
of
the
Standing
Committee
on
the
Scientific
Evaluation
of
Dietary
Reference
Intakes.
Washington,
DC:
National
Academy
Press,
1997.
19
of
39
3.2.2
FQPA
Considerations
HED
has
not
applied
an
additional
FQPA
safety
factor
to
the
fluoride
assessment.
Skeletal
fluorosis
is
an
effect
that
requires
chronic
(
10+
years)
high
exposures
in
order
to
be
manifested.
As
such,
infants
and
children
will
not
exhibit
this
effect
and
an
additional
factor
to
account
for
potential
enhanced
sensitivity
is
not
necessary.

3.2.3
Dose­
Response
Assessment
Toxicological
Dose
for
Use
in
Acute
Risk
Assessments:
None.
HED
has
not
identified
any
toxicological
endpoint
attributable
to
a
single
exposure
of
fluoride
that
would
be
applicable
to
females
(
13­
50
years
old)
or
to
the
general
population
(
including
infants
and
children).
The
Agency
is
aware
of
cases
of
acute
toxicity
following
exposure
to
extremely
high
concentrations
of
fluoride
in
drinking
water.
These
incidents
appear
to
be
due
to
malfunctioning
fluoridation
equipment
and
fall
far
outside
the
realm
of
expected
exposures.
As
such,
HED
has
not
tried
to
assess
acute
toxicity
for
fluoride.

Toxicological
Dose
for
Use
in
Non­
Acute
Risk
Assessments:
For
all
short­
term,
intermediate­
term,
and
chronic
assessments,
HED
has
used
the
8­
mg/
day
value
derived
by
the
Office
of
Water
in
a
manner
analogous
to
a
chronic
PAD.

Carcinogenicity:
In
its
assessment
of
the
health
effects
of
fluoride,
the
National
Research
Council
came
to
the
following
conclusion:

The
subcommittee
concludes
that
the
available
laboratory
data
are
insufficient
to
demonstrate
a
carcinogenic
effect
of
fluoride
in
animals.
The
subcommittee
also
concludes
that
the
weight
of
the
evidence
from
more
than
50
epidemiological
studies
does
not
support
the
hypothesis
of
an
association
between
fluoride
exposure
and
increased
cancer
risk
in
humans.
National
Research
Council,
1993.

The
Agency
for
Toxic
Substances
and
Disease
Registry
(
ATSDR,
2001)
and
the
World
Health
Organization
(
2002)
have
come
to
similar
conclusions.
Based
on
the
findings
of
those
bodies,
HED
believes
that
a
cancer
risk
assessment
for
fluoride
is
not
appropriate.

3.2.4
Endocrine
Disruption
As
noted
in
Section
3.1.4,
HED
is
required
to
consider
potential
endocrine
effects
when
conducting
its
risk
assessments.
The
Agency
is
aware
of
potential
endocrine
effects
of
fluoride
being
noted
in
the
open
literature.
From
a
preliminary
review
of
this
literature
(
Baetcke,
et
al.,
2003),
there
does
not
appear
to
be
a
sufficient
scientific
foundation
to
permit
confident
conclusions
regarding
the
ability
of
fluoride
to
produce
endocrine
effects.
Thus,
the
available
body
of
literature
does
not
provide
a
compelling
basis
to
depart
from
OPP=
s
use
of
the
current
Agency
MCL
in
pesticide
risk
assessments
at
this
time.
This
conclusion
is
supported
by
the
recent
York
Review
(
2000)
and
the
conclusions
of
the
Medical
Research
Council
(
2002).
The
National
Academy
of
Sciences
is
currently
in
the
process
of
reviewing
the
toxicological
data
for
fluoride.
When
their
review
is
available,
EPA
will
reexamine
this
conclusion.
20
of
39
4.0
EXPOSURE
ASSESSMENT
4.1
Summary
of
Proposed
Uses
Sulfuryl
fluoride
is
being
proposed
as
a
methyl
bromide
replacement
to
control
pests
in
food
processing
facilities.
Sulfuryl
fluoride
is
a
fumigant
and,
in
the
form
of
ProFume
J
,
is
formulated
as
99+%
active
ingredient.
The
fumigation
rate
for
sulfuryl
fluoride
is
the
product
of
the
fumigant
concentration
and
exposure
time.
The
maximum
target
rate
is
1500
mgAhr/
L
for
normal
atmospheric
fumigations
and
200
mgAhr/
L
for
vacuum
fumigations.
Double
fumigations
are
recommended
for
insect
infestations
where
eggs
may
be
present,
with
the
second
fumigation
timed
to
control
newly
hatched,
immature
stages.
The
proposed
label
specifies
that
all
food
commodities
be
aerated
for
a
minimum
of
24
hours
prior
to
the
foods
entering
commerce.

Sulfuryl
fluoride
is
a
highly
volatile
compound
with
a
boiling
point
of
­
55
°
C
and
a
vapor
pressure
of
11552
Torr
(
20
°
C).
At
20
°
C,
sulfuryl
fluoride
has
a
vapor
density
of
4.3
g/
L
(
heavier
than
air)
and
is
both
colorless
and
odorless.
The
log
KOW
is
estimated
to
be
0.41.
Sulfuryl
fluoride
has
a
very
low
solubility
in
water
(
0.075
g/
100
g).
Solubilities
in
other
solvents
are
0.78
g/
100
g
in
Wesson
oil,
1.74
g/
100
g
in
acetone,
and
2.12
g/
100
g
in
chloroform.

Table
4.1.1.
Summary
of
Directions
for
the
Use
of
Sulfuryl
Fluoride
from
the
Proposed
Label.

Applic.
Timing,
Type,
and
Equip.
Formulation
[
EPA
Reg.
No.]
Max.
per
Applic.
Rate
(
mgAhr/
L)
Max.
No.
Applic.
per
Batch
Max.
Cumulative
Applic.
Rate
(
mgAhr/
L)
Aeration
(
hours)
Use
Directions
and
Limitations
Fumigation
of
foods
and
sealed
food
processing
facilities
ProFume
[
62719­
XXX]
1500
(
ambient
pressure)

200
(
vacuum
fumigation)
2
1500
(
ambient
pressure)

200
(
vacuum
fumigation)
24
Food
commodities
must
be
aerated
for
24
hours
prior
to
entering
commerce.

Provided
the
proposed
label
is
amended
to
remove
dried
eggs
as
a
targeted
commodity
for
food
fumigations
and
to
prohibit
targeted
fumigation
of
edible
oils,
the
label
has
sufficient
information
to
allow
the
Agency
to
evaluate
the
residue
trials
in
light
of
the
proposed
use
patterns.
Dow
AgroSciences
has
submitted
a
draft
label
in
which
dried
egg
has
been
deleted
as
a
targeted
commodity
for
food
fumigations.

Fluoride,
as
a
chemical
species,
does
not
have
a
set
of
registered
pesticidal
uses.
Pesticide
chemicals
that
are
known
to
increase
fluoride
residues
in
foods
above
background
levels
are
cryolite
and
sulfuryl
fluoride.
This
assessment
addresses
those
pesticidal
sources
of
fluoride
as
well
as
other,
non­
pesticidal
sources.

4.2
Dietary
Exposure/
Risk
Pathway
21
of
39
The
residue
chemistry
databases
for
both
sulfuryl
fluoride
and
fluoride
anion
are
considered
marginally
adequate
to
set
tolerances
based
on
the
proposed
use
pattern.
As
a
condition
of
registration,
HED
is
recommending
that
further
residue
data
are
collected
to
ensure
that
the
tolerances
being
recommended
by
HED
are
appropriate.
Residue
chemistry
data
needs,
including
label
modifications,
are
listed
in
Section
8.
Provided
the
label
changes
are
made,
HED
is
recommending
a
conditional
registration
with
the
sulfuryl
fluoride
and
fluoride
anion
tolerances
summarized
in
Table
8.1.
Details
regarding
the
dietary
analyses
and
residue
profiles
used
in
this
assessment
are
provided
below.

4.2.1
Residue
Profile
4.2.1.1
Sulfuryl
Fluoride
and
Fluoride
Residues
from
the
use
of
Sulfuryl
Fluoride
(
M.
Doherty,
DP
Number
317730,
7/
13/
05
and
M.
Doherty,
DP
Number
317731,
1/
18/
06)

Tolerances
are
currently
established
for
sulfuryl
fluoride
(
40
CFR
180.575)
and
for
residues
of
inorganic
fluoride
resulting
from
the
use
of
either
sulfuryl
fluoride
or
cryolite
(
40
CFR
180.145).
Sulfuryl
fluoride
is
highly
reactive
and
breaks
down
to
form
sulfate
and
fluoride
anion.
Parent
sulfuryl
fluoride
and
the
fluoride
anion
are
the
residues
of
concern
for
both
tolerance
expression
and
risk
assessment
purposes.

To
support
the
requested
uses,
Dow
AgroSciences
has
submitted
residue
data
for
sulfuryl
fluoride
and
fluoride
anion
from
a
number
of
finished
food
products
(
chips,
cookies,
etc.)
as
well
as
foods
considered
to
be
Akey@
ingredients
(
salt,
sugar,
powdered
milk,
etc.).
Foods
were
fumigated
at
approximately
the
maximum
label
rate
(
1500
mgAhr/
L)
and
allowed
to
aerate
for
24
hours
prior
to
residue
analysis.
Fumigation,
aeration,
and
storage
were
all
done
at
30
°
C
in
order
to
maximize
the
potential
conversion
of
sulfuryl
fluoride
to
fluoride
anion.
For
finished
foods,
items
were
fumigated
in
an
open
configuration
(
i.
e.,
a
box
or
other
open
container)
as
well
as
in
their
original
packaging.
Key
ingredients
were
fumigated
only
in
the
open
configuration.
HED
has
matched
the
available
data
to
the
various
food
types
in
the
dietary
exposure
model
to
obtain
dietary
exposure
estimates.

Separate
analytical
methods
for
each
residue
of
concern
are
available
for
most
commodities;
however,
the
data
submitted
to
support
this
petition
shows
that
the
methods
are
not
suitable
for
all
commodities
that
may
be
treated.
Furthermore,
storage
stability
data
for
fluoride
were
not
submitted
and
there
is
concern
that
fluoride
may
have
reacted
with
food
components
during
storage
and
become
Abound.@
There
is
evidence
from
previous
storage
stability
studies
with
fluoride
(
MRID
45510302)
that
this
may
occur.

Residues
of
sulfuryl
fluoride
were
highly
dependent
on
the
nature
of
the
fumigated
material
and
ranged
from
<
0.004
ppm
to
approximately
2
ppm.
Similarly,
fluoride
residues
were
dependent
on
the
commodity
and
ranged
from
<
1
to
approximately
820
ppm.
Generally,
commodities
with
higher
protein
and/
or
fat
content
have
higher
residues
of
sulfuryl
fluoride
or
fluoride
(
an
extreme
case
being
powdered
eggs).
For
a
number
of
finished
products,
the
residues
of
sulfuryl
fluoride
in
the
packaged
configuration
were
greater
than
in
the
open
configuration.
In
all
such
cases,
the
packaging
contained
a
polymer
film,
either
as
a
bag
liner
or
as
lined
paper.
The
22
of
39
phenomena
were
not
mirrored
in
the
fluoride
residue
levels.
HED
does
not
have
a
satisfactory
theory
to
explain
these
observations
at
this
time.
Method
performance
leaves
a
high
degree
of
uncertainty
surrounding
residues
of
sulfuryl
fluoride
in
Oreo
7
cookies,
powdered
eggs,
and
baking
soda;
and
for
residues
of
fluoride
in
white
cake
mix,
pet
foods,
parsley,
and
baking
powder.
Given
the
transient
nature
of
sulfuryl
fluoride
residues
and
the
potential
for
fluoride
to
serve
as
a
marker
compound,
HED
does
not
believe
that
the
lack
of
a
universal
method
for
sulfuryl
fluoride
warrants
development
of
a
new
sulfuryl
fluoride
method.
HED
is,
however,
concerned
about
the
lack
of
performance
of
the
fluoride
method
for
some
commodities
and
the
fluoride
storage
stability
issue
noted
above.
The
use
of
a
total
fluoride
analysis
method
would
resolve
both
the
method
and
the
storage
stability
issues
and
recommends
that
the
petitioner
investigate
and,
if
necessary,
validate
a
total
fluoride
method
using
representative
commodities
from
all
crop
groups
and
animal
commodities
(
meat,
fat,
milk,
eggs).
Further,
HED
recommends
that
the
petitioner
consult
with
the
HED
prior
to
the
onset
of
any
such
investigation.
HED
is
recommending
that
the
registration,
if
granted,
be
made
conditional
on
the
proposal
of
a
more
universal
fluoride
method,
acceptance
of
that
method
by
the
Agency,
and
submission
of
residue
data
collected
from
control
and
fumigated
representative
commodities.
As
of
1/
13/
06,
the
Analytical
Chemistry
Laboratory
had
not
received
reference
standards
of
either
sulfuryl
fluoride
or
a
suitable
fluoride
salt.
Due
to
the
nature
of
sulfuryl
fluoride,
the
laboratory
is
not
requesting
that
a
standard
be
submitted
at
this
time;
however,
a
reference
standard
for
fluoride
should
be
provided.

Based
on
the
data
available
at
this
time,
HED
is
recommending
that
the
following
tolerances
be
established:

Tolerance,
ppm
Commodity
Sulfuryl
Fluoride
Fluoride
Ion
All
processed
food
commodities
not
otherwise
listed
2.0
70
Cattle,
meat,
dried
0.01
40
Cheese
2.0
5.0
Cocoa
bean,
postharvest
0.2
20
Coconut,
postharvest
1.0
40
Coffee,
postharvest
1.0
15
Cottonseed,
postharvest
0.5
70
Eggs,
dried
1.0
900
Ginger,
postharvest
0.5
70
Ham
0.02
20
Herbs
and
Spices,
Group
19,
postharvest
0.5
70
Milk,
powdered
2.0
5.0
Nut,
pine,
postharvest
0.2
20
Peanut,
postharvest
0.5
15
Rice,
flour,
postharvest
0.05
45
Vegetables,
Legume,
Group
6,
postharvest
0.5
70
23
of
39
4.2.1.5
Other
Sources
of
Fluoride
(
M.
Doherty,
DP
Number
309013)

This
risk
assessment
includes
quantitative
estimates
of
fluoride
exposure
from
residues
in
foods
from
the
use
of
sulfuryl
fluoride
and/
or
cryolite,
background
levels
in
foods,
and
consumption
of
fluoride­
containing
water.
Also
addressed
quantitatively
are
exposure
from
the
use
of
fluoridated
toothpaste
and
inhalation
of
fluoride
from
the
atmosphere.
These
sources
are
addressed
in
Section
4.4
of
the
previous
risk
assessment.
The
exposure
estimates
are
summarized
in
Table
4.2.3.2,
below.
Other
known
potential
sources
of
fluoride
exposure
were
not
addressed
quantitatively
either
due
to
lack
of
data
regarding
residues
and/
or
data
regarding
the
demographics
of
exposure.
Sections
4.4
and
5
provide
more
information.

4.2.2
Acute
Dietary
No
toxicological
endpoint
attributable
to
a
single
exposure
was
identified
in
the
available
toxicology
studies
on
sulfuryl
fluoride
or
fluoride
anion.
Therefore,
acute
dietary
assessments
were
not
conducted.

4.2.3
Chronic
Dietary
The
Health
Effects
Division
has
conducted
two
dietary
assessments
to
evaluate
the
potential
dietary
exposures
to
sulfuryl
fluoride
and
fluoride
anion
associated
with
the
requested
uses.
The
first
assessment
addresses
food
fumigations
and
includes
use
on
dried
fruits,
stored
cereal
grains,
herbs
and
spices,
dried
peas
and
beans,
tree
nuts,
cocoa
beans,
coconut,
coffee
beans,
cottonseed,
ginger,
powdered
milk,
cheese,
peanut,
pine
nut,
and
ham.
The
second
analysis
addresses
inadvertent
residues
that
may
occur
during
space
fumigations
of
grain
milling
facilities
and
food
processing
facilities.
Both
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.
There
is
the
potential
for
a
given
commodity
to
receive
post­
harvest
treatment
with
sulfuryl
fluoride
and
to
then
be
exposed
to
the
fumigant
again
as
part
of
a
space
fumigation.
Therefore,
the
dietary
exposure
estimates
from
the
food
fumigation
and
space
fumigation
analyses
have
been
combined
to
give
total
dietary
exposure
estimates.
Since
the
likelihood
of
this
serial
treatment
is
highly
unlikely,
adding
the
exposure
estimates
is
considered
to
be
a
highly
healthprotective
assumption.

The
Biological
and
Economic
Analysis
Division
has
supplied
HED
with
information
regarding
the
amount
of
commodities
that
may
be
treated
per
year.
For
food
fumigations,
estimates
are
2%
for
stored
cereal
grains,
20%
for
tree
nuts,
and
40%
for
dried
fruits.
All
other
commodities
in
the
food
fumigation
assessments
were
assigned
a
percent
crop
treated
value
of
100%.
The
space
fumigation
assessments
include
estimates
of
the
fraction
of
commodities
treated.
The
estimates
include
the
percentage
of
facilities
that
may
be
fumigated
per
year
as
well
as
the
amount
of
the
various
commodities
that
may
be
exposed
to
sulfuryl
fluoride
during
fumigation.
It
is
estimated
that
approximately
40%
of
the
processing
facilities
would
receive
sulfuryl
fluoride
fumigation
with,
on
average,
2.5
fumigations
per
year.
Approximately
one
day's
worth
of
production
could
24
of
39
be
stored
on­
site
and
the
facilities
typically
operate
over
300
days
per
year.
Combining
these
estimates
gives
a
fraction
of
commodity
treated
estimate
of
0.4
×
2.5
×
1
÷
300
=
0.003.
This
estimate
was
rounded
up
to
0.004
for
the
space
fumigation
analyses.
For
grain
mills,
HED
assumed
that
40%
of
the
facilities
would
be
treated,
that
there
could
be
3
fumigations
per
year,
and
2
days
worth
of
production
exposed,
giving
an
estimate
of
0.4
×
3
×
2
÷
300
=
0.008.
Since
cereal
grain
commodities
could
be
exposed
to
sulfuryl
fluoride
at
the
mill
and
at
the
food
processing
facility,
these
two
percent­
commodity­
treated
estimates
were
added
together
for
an
overall
inadvertent
cereal
grain
commodity
treated
estimate
of
1.1%.

The
previous
human
health
risk
assessment
included
a
0.1X
processing
factor
for
flour
commodities
to
account
for
the
practice
of
drawing
down
grain
in
the
mills
prior
to
fumigation
and
then
flushing
any
residual
grain/
flour
out
of
the
mill
with
fresh
material
during
startup
and
mill
equilibration.
The
present
assessment
has
removed
that
0.1X
factor
to
account
for
the
ProFume
label
having
been
revised
in
2005
to
eliminate
blending
of
fumigated
flour
with
untreated
flour.

Sulfuryl
Fluoride.
The
chronic
analysis
for
sulfuryl
fluoride
used
average
residue
values
from
residue
trials
reflecting
the
maximum
proposed
use.
The
refined
chronic
dietary
risk
estimates
for
all
population
subgroups
are
less
than
or
equal
to
8%
of
the
chronic
population­
adjusted
dose
(
cPAD)
of
0.003
mg/
kg/
day
when
combined
for
the
food
fumigation
and
space
fumigation
uses.

Table
4.2.3.1.
Sulfuryl
Fluoride
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Fumigation
of
Food
and
Food
Processing
Facilities
with
Sulfuryl
Fluoride.
The
cPAD
for
sulfuryl
fluoride
is
0.003
mg/
kg/
day
for
all
population
subgroups.

Food
Fumigations
Space
Fumigations
Food
+
Space
Population
Subgroup
Exposure
Estimate,
mg/
kg/
day
%
cPAD
Exposure
Estimate,
mg/
kg/
day
%
cPAD
Exposure
Estimate,
mg/
kg/
day
%
cPAD
U.
S.
Pop.
(
total)
0.000064
2
0.000017
1
0.000082
3
All
infants
(<
1
year)
0.000041
1
0.000097
3
0.000138
5
Children
1­
2
yrs
0.000189
6
0.000036
1
0.000225
8
Children
3­
5
yrs
0.000177
6
0.000036
1
0.000213
7
Children
6­
12
yrs
0.000100
3
0.000026
1
0.000126
4
Youth
13­
19
yrs
0.000058
2
0.000017
1
0.000075
3
Adults
20­
49
yrs
0.000047
2
0.000014
<
1
0.000061
2
Adults
50+
yrs
0.000045
2
0.000011
<
1
0.000056
2
Females
13­
49
yrs
0.000046
2
0.000013
<
1
0.000059
2
Fluoride.
The
chronic
analyses
for
fluoride
are
presented
in
Table
4.2.3.2.
The
separate
food­
fumigation
and
space­
fumigation
risk
estimates
are
below
HED=
s
level
of
concern
for
all
population
subgroups.
It
should
be
noted
that
crippling
skeletal
fluorosis
requires
high
exposure
for
extended
time
(
on
the
order
of
decades);
therefore,
it
is
not
really
appropriate
to
include
children
in
an
assessment
for
this
condition.
Children
are
included
in
Table
4.2.3.2,
and
subsequent
tables,
for
completeness.

Table
4.2.3.3
combines
dietary
exposure
estimates
from
sulfuryl
fluoride,
cryolite,
background
levels
in
food,
and
drinking
water
to
give
an
overall
dietary
exposure
estimate.
Note
that
exposure
estimates
in
Tables
4.2.3.2
and
4.2.3.3
are
expressed
in
mg/
day.
Total
dietary
risk
25
of
39
estimates
range
from
13
to
38%
of
the
RfD
and
are
below
HED's
level
of
concern
for
all
population
subgroups.

Table
4.2.3.2.
Fluoride
Chronic
Dietary
Exposure
and
Risk
Estimates
for
Fumigation
of
Food
and
Food
Processing
Facilities
with
Sulfuryl
Fluoride.
The
RfD
for
fluoride
is
8
mg/
day
for
all
population
subgroups.

Food
Fumigations
Space
Fumigations
Food
+
Space
Exposure
Estimate,
Exposure
Estimate,
Population
Subgroup
NHANES
Estimated
Body
Weight,
kg*
mg/
kg/
day
mg/
day
%
RfD
mg/
kg/
day
mg/
day
%
RfD
Exposure
Estimate,
mg/
day
%
RfD
U.
S.
Pop.
(
total)
70
0.008701
0.6091
8
0.000820
0.0574
1
0.6665
8
All
infants
(<
1
year)
7
0.010972
0.0768
1
0.000876
0.0061
<
1
0.0829
1
Children
1­
2
yrs
13
0.017980
0.2337
3
0.002052
0.0267
<
1
0.2604
3
Children
3­
5
yrs
22
0.019274
0.4240
5
0.002009
0.0442
1
0.4682
6
Children
6­
12
yrs
40
0.012879
0.5152
6
0.001361
0.0544
1
0.5696
7
Youth
13­
19
yrs
60
0.008014
0.4808
6
0.000795
0.0477
1
0.5285
7
Adults
20­
49
yrs
70
0.007212
0.5048
6
0.000660
0.0462
1
0.5510
7
Adults
50+
yrs
70
0.006670
0.4669
6
0.000516
0.0361
<
1
0.5030
6
Females
13­
49
yrs
61
0.006398
0.3903
5
0.000603
0.0368
<
1
0.4271
5
*
National
Health
and
Nutrition
Examination
Survey.
U.
S.
EPA.
2000.
Methodology
for
Deriving
Ambient
Water
Quality
Criteria
for
the
Protection
of
Human
Health.
Office
of
Science
and
Technology,
Office
of
Water
EPA­
822­
B­
00­
004.
Washington,
DC.

Table
4.2.3.3.
Total
Chronic
Exposure
and
Risk
Estimates
for
Fluoride
from
Dietary
Sources.
Dietary
Fluoride
Anion
Exposure
Estimates,
mg/
day
Population
Subgroup
RfD,
mg/
day
Sulfuryl
Fluoride
Cryolite
Food
Water
Total
Dietary
Risk,
%
RfD
U.
S.
Population
(
total)
8
0.667
0.049
0.476
1.883
3.075
38
All
infants
(<
1
year)
8
0.083
0.007
0.065
0.997
1.152
14
Children
1­
2
yrs
8
0.260
0.043
0.228
0.529
1.060
13
Children
3­
5
yrs
8
0.468
0.046
0.328
0.744
1.586
20
Children
6­
12
yrs
8
0.570
0.036
0.376
0.908
1.890
24
Youth
13­
19
yrs
8
0.529
0.018
0.372
1.056
1.975
25
Adults
20­
49
yrs
8
0.551
0.028
0.399
1.764
2.742
34
Adults
50+
yrs
8
0.503
0.035
0.35
1.792
2.680
34
Females
13­
49
yrs
8
0.427
0.031
0.329
1.452
2.239
28
4.2.4
Cancer
Dietary
As
noted
in
Section
3,
sulfuryl
fluoride
has
been
classified
as
Anot
likely
to
be
carcinogenic
to
humans@
and
there
is
no
evidence
showing
an
increased
risk
of
cancer
following
exposure
to
fluoride.
HED
has
not
conducted
an
assessment
of
cancer
risk
from
dietary
exposures
for
either
sulfuryl
fluoride
or
fluoride
anion.

4.3
Water
Exposure/
Risk
Pathway
Please
see
the
previous
human
health
risk
assessment
for
sulfuryl
fluoride/
fluoride
for
a
discussion
of
water
exposures
and
risks
(
M.
Doherty,
D309013,
10/
12/
04).
This
risk
assessment
assumed
an
average
2
ppm
level
of
fluoride
in
drinking
water
(
see
M.
Doherty
10/
12/
04
memo,
26
of
39
D309014).
This
level
represents
the
99th
percentile
of
exposure
for
the
US
population
as
presented
in
a
2003
Office
of
Water
publication
("
Occurrence
Estimation
Methodology
and
Occurrence
Findings
Report
for
the
Six­
Year
Review
of
Existing
National
Primary
Drinking
Water
Regulations").
The
latter
also
concluded
that
a
subpopulation
of
about
191,000
is
served
by
drinking
water
sources
containing
average
fluoride
residues
greater
than
the
MCL
of
4
ppm.
An
additional
535,900
and
1.98
million
individuals
are
estimated
to
be
served
by
sources
containing
more
than
3
ppm
and
2
ppm
average
fluoride,
respectively.
Public
notice
regulations
have
been
established
by
EPA
under
Chapter
40,
Part
141,
Subpart
Q
of
the
Code
of
Federal
Regulations
to
address
situations
wherein
fluoride
levels
exceed
2
ppm6.
These
regulations
require
operators
of
public
water
systems
to
inform
consumers
when
fluoride
levels
exceed
the
secondary
MCL
(
SMCL)
of
2
ppm
or
the
MCL
of
4
ppm.
Exceedances
of
the
SMCL
must
be
reported
as
soon
as
practical
but
within
12
months,
while
levels
higher
than
the
4
ppm
MCL
must
be
reported
within
30
days.
In
both
cases
the
public
notices
state
that
children
under
the
age
of
nine
should
be
provided
with
an
alternative
source
of
drinking
water
low
in
fluoride.
The
SMCL
exceedance
notice
states
that
older
children
and
adults
may
safely
drink
the
water,
but
the
notice
for
levels
greater
than
the
MCL
advises
adults
and
older
children
to
consult
their
dentist
or
doctor
to
determine
if
an
alternate
source
of
water
low
in
fluoride
should
be
used.
Based
on
the
existence
of
this
public
notice
system
for
consumers
in
areas
with
higher
fluoride
levels,
HED
considers
the
use
of
2
ppm
fluoride
in
drinking
water
as
a
reasonable
upper
limit
for
the
purposes
of
chronic
risk
assessment.

4.4
Residential
Exposure/
Risk
Pathway
Please
see
the
previous
human
health
risk
assessment
for
sulfuryl
fluoride/
fluoride
for
a
discussion
of
non­
dietary
exposures
and
risks
(
M.
Doherty,
D309013,
10/
12/
04).
Exposure
estimates
for
these
pathways
are
summarized
in
Table
4.4.1,
below.

Table
4.4.1.
Estimated
Fluoride
Exposure
from
Non­
Dietary
Sources.

Estimated
Exposure,
mg/
day
Population
Subgroup
Standard
Respiration,
m3/
day
Toothpaste
Air
U.
S.
Population
(
total)
13.3
0.30
0.0420
All
infants
(<
1
year)
4.5
0.30
0.0133
Children
1­
2
yrs
8.7
0.30
0.0260
Children
3­
5
yrs
8.7
0.30
0.0264
Children
6­
12
yrs
8.7
0.30
0.0280
Youth
13­
19
yrs
13.3
0.30
0.0420
Adults
20­
49
yrs
13.3
0.30
0.0420
Adults
50+
yrs
13.3
0.30
0.0420
Females
13­
49
yrs
11.3
0.30
0.0366
4.4.1
Other
6
For
guidance
on
the
public
notice
regulations,
the
reader
is
referred
to
the
"
Public
Notification
Handbook"
at
www.
epa.
gov/
safewater/
pws/
pn/
handbook.
pdf.
27
of
39
HED
has
not
conducted
a
quantitative
assessment
for
persons
living
near
fumigation
activities
(
i.
e.,
bystanders).
Due
to
the
rapid
dissipation
of
sulfuryl
fluoride
and
the
infrequency
of
fumigations
of
food
processing
facilities,
HED
is
not
concerned
with
potential
bystander
exposures
associated
with
fumigation
of
those
facilities.
As
noted
in
the
previous
assessment,
for
tree
nut
and
dried
fruit
fumigations,
there
is
more
of
a
potential
for
more
regular
bystander
exposure
to
sulfuryl
fluoride.
Based
on
the
properties
of
sulfuryl
fluoride
and
the
practices
associated
with
fumigation
facilities,
HED
does
not
believe
that
there
will
be
significant
exposure
to
bystanders;
however,
as
a
condition
of
registration
and
in
conjunction
with
the
monitoring
of
fumigation
workers
(
see
Section
7),
HED
has
requested
air
monitoring
data
from
areas
surrounding
fumigation
sites.

5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
Sulfuryl
Fluoride.
In
estimating
aggregate
risks
from
exposure
to
sulfuryl
fluoride,
HED
has
examined
potential
dietary
and
non­
dietary
exposure
pathways.
Due
to
the
use
pattern
of
sulfuryl
fluoride
and
associated
label
restrictions,
the
potential
non­
dietary
exposure
pathways
are
believed
to
result
in
negligible
exposures.
Therefore,
HED
has
not
included
non­
dietary
exposure
in
a
quantitative
aggregate
exposure
assessment.
Due
to
the
use
pattern
and
toxicology
of
sulfuryl
fluoride,
HED
has
determined
that
a
chronic
aggregate
assessment
is
appropriate
and
has
not
calculated
acute,
short­
term,
or
intermediate­
term
aggregate
risks.
As
discussed
in
Section
4.3,
residues
of
sulfuryl
fluoride
will
not
occur
in
drinking
water.
Therefore,
drinking
water
does
not
contribute
to
aggregate
exposure,
leaving
residues
in
or
on
food
as
the
only
quantifiable
exposure
pathway
for
estimating
aggregate
risks.
Estimated
chronic
dietary
risks,
and
therefore
chronic
aggregate
risks,
are
less
than
or
equal
to
8%
of
the
cPAD
for
the
U.
S.
population
and
all
population
subgroups
(
Table
4.2.3.1).
These
risk
estimates
are
well
below
HED=
s
level
of
concern.

Fluoride.
In
estimating
aggregate
risks
for
skeletal
fluorosis,
HED
has
examined
potential
dietary
and
non­
dietary
exposure
pathways.
Based
on
the
toxicology
of
fluoride
and
the
behaviors
associated
with
fluoride
exposure
(
e.
g.,
brushing
teeth),
HED
has
examined
only
chronic
aggregate
exposure
scenarios.
As
discussed
in
Section
4.2.2.3,
moderately
conservative
estimates
of
dietary
exposure
were
quantified
based
on
fluoride
residues
coming
from
the
pesticidal
uses
of
sulfuryl
fluoride
and
cryolite,
from
background
residue
levels
in
food,
and
the
fluoride
content
of
drinking
water.
Non­
dietary
sources
for
which
sufficient
information
was
available
to
quantitate
exposure
were
toothpaste
and
air.
As
noted
in
Section
4.4,
the
exposure
estimates
from
these
sources
are
considered
to
be
conservative.
Aggregate
exposures
are
summarized
in
Table
5.1
for
the
representative
population
subgroups
addressed
in
the
chronic
exposure
module
of
the
DEEM­
FCID
software
(
the
general
U.
S.
population,
all
infants
(<
1
year
old),
children
1­
2,
children
3­
5,
children
6­
12,
youth
13­
19,
adults
20­
49,
females
13­
49,
and
adults
50+
years
old)
.
The
aggregate
risks
for
those
populations
are
also
presented
in
Table
5.1
as
a
percentage
of
the
RfD.
The
aggregate
risk
estimates
for
the
representative
subgroups
in
DEEM­
FCID
range
from
17%
(
children
1­
2
year
of
age)
to
43%
(
general
U.
S.
population)
of
the
RfD.
The
aggregate
risk
estimates
for
the
U.
S.
population
and
all
subgroups,
including
those
of
infants
and
children,
are
below
HED=
s
level
of
concern.
Risk
estimates
based
on
toxicological
findings
of
the
Institute
of
Medicine
(
1997)
are
presented
in
Appendix
I.
Risk
estimates
associated
with
dental
fluorosis
are
presented
in
Appendix
II.
28
of
39
Table
5.1.
Aggregate
Exposure
and
Risk
Estimates
for
Skeletal
Fluorosis.
Estimated
Fluoride
Exposure
by
Source,
mg/
day
Population
Subgroup
RfD,
mg/
day
Dietary
Toothpaste
Air
Total
Risk,
%
of
RfD
U.
S.
Population
(
total)
8
3.075
0.3
0.0420
3.417
43
All
infants
(<
1
year)
8
1.152
0.3
0.0133
1.465
18
Children
1­
2
yrs
8
1.060
0.3
0.0260
1.386
17
Children
3­
5
yrs
8
1.586
0.3
0.0264
1.912
24
Children
6­
12
yrs
8
1.890
0.3
0.0280
2.218
28
Youth
13­
19
yrs
8
1.975
0.3
0.0420
2.317
29
Adults
20­
49
yrs
8
2.742
0.3
0.0420
3.084
39
Adults
50+
yrs
8
2.680
0.3
0.0420
3.022
38
Females
13­
49
yrs
8
2.239
0.3
0.0366
2.576
32
In
developing
the
exposure
estimates
for
fluoride
from
water,
HED
has
used
the
national
median
fluoride
concentration
of
0.4
ppm
for
non­
tap
water
(
i.
e.,
food­
based
water,
commercially
processed
water,
and
bottled
water).
While
we
believe
that
the
median
value
is
a
reasonable
estimate
given
that
such
water,
as
a
whole,
will
come
from
various
sources,
we
acknowledge
that
certain
water
within
that
designation
may
come
from
a
fairly
localized
region
and
therefore
fluoride
levels
may
be
underestimated
by
use
of
a
national
median.
In
order
to
ascertain
the
impact
of
using
the
0.4­
ppm
value
on
the
aggregate
exposure
estimates,
HED
has
also
estimated
fluoride
exposure
from
water
using
the
2­
ppm
concentration
for
all
water
sources.
Using
the
2­
ppm
value
results
in
total
dietary
fluoride
exposure
estimates
that
range
from
20%
to
67%
of
the
RfD,
giving
a
maximum
aggregate
risk
estimate
of
approximately
71%
of
the
RfD
(
details
not
shown).
Although
HED
believes
that
this
risk
estimate
is
based
on
unreasonably
high
exposure
levels,
it
still
falls
below
our
level
of
concern.

Other
Sources
of
Fluoride
Exposure.
HED
is
aware
that
exposure
to
fluoride
may
come
from
sources
other
than
those
quantified
above.
Although
those
sources
have
not
been
incorporated
directly
in
the
aggregate
risk
assessment,
HED
believes
that
the
assessment
is
sufficiently
conservative
to
ensure
that
it
does
not
underestimate
actual
fluoride
exposures
experienced
by
members
of
the
U.
S.
population.

6.0
CUMULATIVE
RISK
The
Food
Quality
Protection
Act
(
1996)
stipulates
that
when
determining
the
safety
of
a
pesticide
chemical,
EPA
shall
base
its
assessment
of
the
risk
posed
by
the
chemical
on,
among
other
things,
available
information
concerning
the
cumulative
effects
to
human
health
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
other
substances
that
have
a
common
mechanism
of
toxicity.
The
reason
for
consideration
of
other
substances
is
due
to
the
possibility
that
low­
level
exposures
to
multiple
chemical
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
could
lead
to
the
same
adverse
health
effect
as
would
a
higher
level
of
exposure
to
any
of
the
other
substances
individually.
A
person
exposed
to
a
pesticide
at
a
level
that
is
considered
safe
may
in
fact
experience
harm
if
that
person
is
also
exposed
to
other
substances
that
cause
a
common
toxic
effect
by
a
mechanism
common
with
that
of
the
subject
pesticide,
even
if
the
individual
exposure
levels
to
the
other
substances
are
also
considered
safe.
29
of
39
HED
did
not
perform
a
cumulative
risk
assessment
as
part
of
this
risk
assessment
for
sulfuryl
fluoride
because
HED
has
not
yet
initiated
a
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
sulfuryl
fluoride.
For
purposes
of
this
petition,
EPA
has
assumed
that
sulfuryl
fluoride
does
not
have
a
common
mechanism
of
toxicity
with
other
substances.

On
this
basis,
the
petitioner
must
submit,
upon
EPA=
s
request
and
according
to
a
schedule
determined
by
the
Agency,
such
information
as
the
Agency
directs
to
be
submitted
in
order
to
evaluate
issues
related
to
whether
sulfuryl
fluoride
shares
a
common
mechanism
of
toxicity
with
any
other
substance
and,
if
so,
whether
any
tolerances
for
sulfuryl
fluoride
need
to
be
modified
or
revoked.
If
HED
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
sulfuryl
fluoride,
HED
will
perform
aggregate
exposure
assessments
on
each
chemical,
and
will
begin
to
conduct
a
cumulative
risk
assessment.

HED
has
recently
finalized
its
guidance
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
will
be
available
from
the
OPP
Website
(
http://
www.
epa.
gov/
pesticides).
In
the
guidance,
it
is
stated
that
a
cumulative
risk
assessment
of
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
will
not
be
conducted
until
an
aggregate
exposure
assessment
of
each
substance
has
been
completed.

Before
undertaking
a
cumulative
risk
assessment,
HED
will
follow
procedures
for
identifying
chemicals
that
have
a
common
mechanism
of
toxicity
as
set
forth
in
the
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity
(
64
FR
5795­
5796,
February
5,
1999).

7.0
OCCUPATIONAL
EXPOSURE
The
proposed
use
of
sulfuryl
fluoride
is
identical
with
respect
to
occupational
exposure
to
the
previously
assessed
uses.
Please
see
the
previous
human
health
risk
assessment
for
a
discussion
of
occupational
exposure
(
M.
Doherty,
D309013,
10/
12/
04).
For
convenience,
the
estimates
from
that
assessment
have
been
reproduced
in
Table
7.1,
below.
30
of
39
Table
7.1.
Occupational
Exposure
MOEs
for
ProFume.
MOEs
assume
one
fifth
the
geometric
mean
exposure
concentrations
of
0.08
ppm
(
fumigators)
and
0.17
ppm
(
tent
workers)
determined
from
structural
fumigation
studies
with
Vikane,
and
an
Activity
Factor
of
2.
The
5­
fold
reduction
factor
is
due
to
differences
in
reentry
concentrations
(
5
ppm
for
Vikane
vs.
1
ppm
for
ProFume).
MOEs
are
rounded
down
to
2
significant
figures.
Values
from
M.
Doherty,
D309013,
10/
12/
04.

Short­
Term
(
NOAEL
=
100
ppm)
Intermediate­
Term
(
NOAEL
=
30
ppm)
Long­
Term
(
NOAEL
=
30
ppm)
Work
Activity
Target
MOE
Estimated
MOE
Target
MOE
Estimated
MOE
Target
MOE
Estimated
MOE
Fumigator
100
2100
100
650
300
650
Tent
Worker
100
1000
100
300
300
300
MOE
=
[
NOAEL
H
Animal
Exposure
Duration
(
6
hrs/
day)
H
Animal
Activity
Factor
(
1)]
)
[
Human
Exposure
Concentration
H
Human
Exposure
Duration
(
8.6
hrs/
day)
H
Human
Activity
Factor
(
2)]

8.0
DATA
NEEDS
AND
LABEL
REQUIREMENTS
Toxicology
$
None
associated
with
this
petition.

Residue
Chemistry
Deficiencies
$
HED
believes
that
a
total
fluoride
analysis
method
would
resolve
the
method
performance
and
the
storage
stability
issues
that
came
to
light
as
a
result
of
this
and
the
previous
petition,
and
recommends
that
the
petitioner
investigate
and
validate
a
total
fluoride
method
using
control
and
fumigated
representative
commodities
from
all
crop
groups
and
animal
commodities
(
meat,
fat,
milk,
eggs).
HED
further
recommends
that
the
petitioner
consult
with
the
Agency
prior
to
initiating
any
such
validation.

$
HED
has
not
included
dried
eggs
in
dietary
exposure
and
risk
estimates
associated
with
food
fumigations,
and
is
recommending
that
food
fumigation
of
dried
eggs
be
removed
from
the
label
section
titled
"
Commodities
That
Can
Be
Fumigated."
Dow
AgroSciences
has
submitted
a
draft
label
making
that
change.
Incidental
treatment
of
dried
eggs
resulting
from
space
fumigations
may
be
permitted.

$
HED
has
not
included
edible
oils
in
dietary
exposure
and
risk
estimates
associated
with
food
fumigations,
and
is
recommending
that
the
label
be
modified
to
state
that
edible
oils
may
not
be
directly
fumigated.
Incidental
treatment
of
edible
oils
resulting
from
space
fumigations
may
be
permitted.

$
As
of
1/
13/
06,
the
Analytical
Chemistry
Laboratory
had
not
received
reference
standards
of
either
sulfuryl
fluoride
or
a
suitable
fluoride
salt.
Due
to
the
nature
of
sulfuryl
fluoride,
the
laboratory
is
not
requesting
that
a
standard
be
submitted
at
this
time;
however,
a
suitable
reference
standard
of
a
fluoride
salt
should
be
provided.
31
of
39
$
The
previous
risk
assessment
requested
information
regarding
the
transfer
of
fluoride
from
feedstuffs
into
livestock
commodities.
To
date,
HED
has
not
received
any
such
information.

$
The
previous
risk
assessment
also
requested
that
the
label
be
modified
to
specify
that
active
aeration
of
at
least
24
hours
at
not
less
than
1
chamber
volume/
min
shall
occur
for
all
commodities
prior
to
their
entering
commerce.

Occupational
and
Residential
Exposure
$
None
associated
with
this
petition.
Air
monitoring
data
around
fumigation
sites
have
been
received
by
the
Agency
but
have
not
yet
been
reviewed.

Table
8.1.
Tolerance
Summary
for
Sulfuryl
Fluoride
Commodity
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Flavorings,
leavening
agents
(
except
yeast),
dry
garlic,
dry
onion,
dry
pepper,
baking
powder,
baking
soda
0.05
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

Other
herbs,
spices,
chili
pepper
0.3
0.5
Herbs
and
spices,
group
19,
postharvest
Salt,
sugars,
high­
fructose
corn
syrup
0.02
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

Peanuts
0.2
0.5
Peanut,
postharvest
Coffee,
cocoa
beans
0.8
See
below
Separate
listings
should
be
made
for
Coffee,
postharvest
and
Cocoa
bean,
postharvest
Cocoa
beans,
postharvest
0.8
0.2
Coffee,
postharvest
0.8
1.0
Dried
legume
vegetables
(
beans,
peas,
soybean,
etc.)
0.02
0.5
Vegetables,
legume,
group
19,
postharvest
Powdered
milk,
powdered
cheese
1.5
See
below
Separate
listings
should
be
made
for
milk,
powdered
and
cheese
Cheese
1.5
2.0
Milk,
powdered
1.5
2.0
All
other
processed
foods
1.2
2.0
All
processed
food
commodities
not
otherwise
listed
Cattle,
meat,
dried
0.01
0.01
Coconut,
postharvest
1.0
1.0
Egg
0.7
1.0
Eggs,
dried
Ginger,
postharvest
0.2
0.5
32
of
39
Table
8.1.
Tolerance
Summary
for
Sulfuryl
Fluoride
Commodity
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Ham
0.01
0.02
Nut,
pine,
postharvest
3.0
0.2
Rice,
flour,
postharvest
0.08
0.05
Grain,
cereal
forage,
fodder,
and
straw,
group
16,
postharvest
2.0
None
No
data
to
support
tolerance
Grass,
forage,
fodder,
and
hay,
group
17,
postharvest
2.0
None
No
data
to
support
tolerance
Animal
Feed
2.0
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

Table
8.2.
Tolerance
Summary
for
Fluoride
Commodity
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Flavorings,
leavening
agents
(
except
yeast),
dry
garlic,
dry
onion,
dry
pepper,
baking
powder,
baking
soda
8
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

Other
herbs,
spices,
chili
pepper
70
70
Herbs
and
spices,
group
19,
postharvest
Salt,
sugars,
high­
fructose
corn
syrup
2
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

Peanuts
13
15
Peanut,
postharvest
Coffee,
cocoa
beans
12
See
below
Separate
listings
should
be
made
for
Coffee,
postharvest
and
Cocoa
bean,
postharvest
Cocoa
beans,
postharvest
12
20
Coffee,
postharvest
12
15
Dried
legume
vegetables
(
beans,
peas,
soybean,
etc.)
6
70
Vegetables,
legume,
group
19,
postharvest
Powdered
milk,
powdered
cheese
3
See
below
Separate
listings
should
be
made
for
milk,
powdered
and
cheese
Cheese
3
5.0
Milk,
powdered
3
5.0
All
other
processed
foods
70
70
All
processed
food
commodities
not
otherwise
listed
Cattle,
meat,
dried
40
40
33
of
39
Table
8.2.
Tolerance
Summary
for
Fluoride
Commodity
Proposed
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)

Coconut,
postharvest
40
40
Egg
850
900
Eggs,
dried
Ginger,
postharvest
13
70
Ham
20
20
Nut,
pine,
postharvest
10
20
Rice,
flour,
postharvest
98
45
Grain,
cereal
forage,
fodder,
and
straw,
group
16,
postharvest
130
None
No
data
to
support
tolerance
Grass,
forage,
fodder,
and
hay,
group
17,
postharvest
130
None
No
data
to
support
tolerance
Animal
Feed
130
None
Covered
under
AAll
processed
food
commodities
not
otherwise
listed.@

9.0
REFERENCES
OPP
Documents
Baetcke,
K.,
Blondell,
J.,
Burnam,
W.,
Dellarco,
V.
L.,
Donohue,
J.,
and
Hill,
R.
11/
18/
2003.
A
Preliminary
Evaluation
of
Articles
Related
to
Fluoride
Cited
by
the
Fluoride
Action
Network
(
FAN)
as
Objections
to
the
Sulfruryl
Fluoride
Pesticide
Tolerance
Rule.

Daiss,
B.
D274960.
5/
15/
01.
Residential
Risk
from
Dissipation
of
Sulfuryl
Fluoride
after
Structural
Fumigation
(
62719­
EUP­
45).

Doherty,
M.
D309013.
10/
12/
04.
Corrected
Human
Health
Risk
Assessment
for
Sulfuryl
Fluoride
and
Fluoride
Anion
Addressing
the
Section
3
Registration
of
Sulfuryl
Fluoride
Post­
Harvest
Fumigation
of
Stored
Cereal
Grains,
Dried
Fruits
and
Tree
Nuts
and
Pest
Control
in
Grain
Processing
Facilities.
PP#
1F6312.

Doherty,
M.
D309015.
10/
12/
04.
PP#
1F06312
B
Sulfuryl
Fluoride.
Section
3
Registration
for
the
Post­
harvest
Fumigation
of
Stored
Cereal
Grains,
Dried
Fruits,
and
Tree
Nuts,
and
Fumigation
of
Grain
Milling
Establishments.
Corrected
Summary
of
Analytical
Chemistry
and
Residue
Data.

Doherty,
M.
D309014.
10/
12/
04.
Corrected
Chronic
Dietary
Exposure
Assessments
for
Sulfuryl
Fluoride
and
Fluoride
Anion,
Addressing
the
Section
3
Registration
of
Sulfuryl
Fluoride
on
Stored
Cereal
Grains,
Grain
Processing
Facilities,
Dried
Fruits,
and
Tree
Nuts.
PP#
1F6312.
34
of
39
Doherty,
M.
D317730.
7/
13/
05.
Sulfuryl
Fluoride.
Evaluation
of
the
Proposed
Fumigation
of
Food
Processing
Establishments.
Summary
of
Analytical
Chemistry
and
Residue
Data.
Petition
Number
3F6573.

Doherty,
M.
D317731.
1/
18/
06.
Sulfuryl
Fluoride
and
Fluoride
Chronic
Dietary
Exposure
Assessments
for
the
Section
3
Registration
of
Sulfuryl
Fluoride
as
a
Fumigant
for
Food
Processing
Facilities.

Kidwell,
J.
TXR
No.
0052208.
10/
31/
03.
Sulfuryl
Fluoride
­
Second
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

Open
Literature
CDC.
2001.
Recommendations
for
Using
Fluoride
to
Prevent
and
Control
Dental
Caries
in
the
United
States.
Centers
for
Disease
Control
and
Prevention,
Recommendations
and
Reports.
August
17,
2001
/
50(
RR14);
1­
42.

Institute
of
Medicine.
1997.
Dietary
Reference
Intakes
for
Calcium,
Phosphorous,
Magnesium,
Vitamin
D,
and
Fluoride.
Institute
of
Medicine.
National
Academy
of
Sciences.
National
Academy
Press.
Washington,
DC.

IRIS
Database.
Fluorine
(
soluble
fluoride).
Entry
No.
0053.
Search
Date:
12/
9/
03
http://
www.
epa.
gov/
iris/
subst/
0053.
htm
Medical
Research
Council.
2002.
Water
fluoridation
and
health.
Medical
Research
Council,
London.

National
Research
Council.
1993.
Health
Effects
of
Ingested
Fluoride.
National
Academy
Press,
Washington
D.
C.

NHS
CRD.
2000.
A
Systematic
Review
of
Public
Water
Fluoridation
(
CRD
Report
No.
18).
NHS
Centre
for
Review
and
Dissemination,
University
of
York,
York,
UK.
Available
at
http://
www.
york.
ac.
uk/
inst/
crd/
fluorid.
htm
U.
S.
Dept.
of
Health
and
Human
Services,
Agency
for
Toxic
Substances
and
Disease
Registry.
2002.
Toxicological
Profile
for
Fluorides.
U.
S.
Government.
Printing
Office.

World
Health
Organization.
2002.
Fluorides.
Environmental
Health
Criteria
227.
World
Health
Organization,
Geneva.

cc:
M.
Doherty
(
RAB2)

Attachments:
Waiver
of
Rat
Developmental
Neurotoxicity
Study
with
Sulfuryl
Fluoride.
35
of
39
APPENDIX
I
­
Risk
Estimates
for
Development
of
Skeletal
Fluorosis
Based
on
Institute
of
Medicine
Toxicological
Findings
The
Institute
of
Medicine
of
the
National
Academies
(
IOM)
published,
in
1997,
dietary
reference
intakes
for
calcium,
phosphorus,
magnesium,
vitamin
D,
and
fluoride.
Their
examination
of
the
available
data
identified
a
NOAEL
of
10
mg/
day
as
relates
to
fluoride
intake
and
skeletal
fluorosis.
They
further
point
out
that
exposures
of
10
or
more
years
are
required
to
develop
this
condition
and
focus
their
attention
on
people
greater
than
8
years
of
age.
OPP
has
included
all
age
groups
in
its
assessment
for
the
sake
of
completeness.
The
IOM
analysis
results
in
a
tolerable
upper
intake
level
of
10
mg/
day
for
children
(>
8
years
old)
and
adults,
including
pregnant
or
lactating
females.
In
deriving
their
recommended
upper
limit
for
exposure,
the
Institute
used
an
uncertainty
factor
of
1,
noting
that
the
NOAEL
is
derived
from
human
studies
and
that
symptomatic
skeletal
fluorosis
is
not
observed
at
intakes
of
10
mg/
day.
As
noted
in
the
general
discussion
of
fluoride
toxicity,
the
FQPA
safety
factor
can
be
reduced
to
1X;
therefore,
the
cPAD
for
skeletal
fluorosis
based
on
the
IOM
analysis
is
10
mg/
day.
Due
to
the
constraints
of
the
chronic
dietary
exposure
model
output,
HED
has
included
children
aged
6­
12
in
this
assessment
even
though
such
a
group
includes
people
too
young
to
develop
skeletal
fluorosis.

When
the
dietary
and
non­
dietary
exposure
estimates
summarized
in
Section
5
are
compared
to
the
IOM­
based
toxicological
threshold,
the
risk
estimates
are
slightly
less
(
ranging
from
14
to
33%
cPAD;
Table
I­
2)
than
those
that
are
based
on
the
RfD
(
17
to
41%
RfD;
Table
5.1).

Table
I­
2.
Aggregate
Exposure
and
Risk
Estimates
for
Skeletal
Fluorosis
Based
on
Analysis
by
the
Institute
of
Medicine
of
the
National
Academies.
Estimated
Fluoride
Exposure
by
Source,
mg/
day
Population
Subgroup
RfD,
mg/
day
Dietary
Toothpaste
Air
Total
Risk,
%
of
RfD
U.
S.
Population
(
total)
10
3.075
0.3
0.0420
3.417
34
All
infants
(<
1
year)
10
1.152
0.3
0.0133
1.465
15
Children
1­
2
yrs
10
1.060
0.3
0.0260
1.386
14
Children
3­
5
yrs
10
1.586
0.3
0.0264
1.912
19
Children
6­
12
yrs
10
1.890
0.3
0.0280
2.218
22
Youth
13­
19
yrs
10
1.975
0.3
0.0420
2.317
23
Adults
20­
49
yrs
10
2.742
0.3
0.0420
3.084
31
Adults
50+
yrs
10
2.680
0.3
0.0420
3.022
30
Females
13­
49
yrs
10
2.239
0.3
0.0366
2.576
26
36
of
39
APPENDIX
II
­
Risk
Estimates
for
Development
of
Dental
Fluorosis
At
this
time,
based
on
the
information
available
to
the
Agency,
EPA
is
not
concluding
that
dental
fluorosis
associated
with
fluoride
exposure
is
an
adverse
health
effect
under
the
FFDCA.
The
current
arguments
that
dental
fluorosis
is
more
than
a
cosmetic
effect
are
not
sufficiently
persuasive
to
warrant
regulation
as
an
adverse
health
effect
under
the
FFDCA.
Accordingly,
consistent
with
the
action
taken
by
the
Office
of
Water
under
the
Safe
Drinking
Water
Act,
40
FR
47142
(
November
14,
1985)
(
WH­
FRL­
2913­
8(
b)),
the
Agency
believes
that
the
appropriate
endpoint
for
regulation
under
the
FFDCA
is
skeletal
fluorosis.

While
the
tolerance
safety
determination
under
the
FFDCA
is
a
health
based
standard,
FIFRA
requires
the
balancing
of
all
costs,
taking
into
account
the
economic,
social,
and
environmental
effects
as
well
as
health
based
risks,
against
the
benefits
associated
with
the
pesticide
use.
Therefore,
the
Agency
will
consider
dental
fluorosis
in
determining
whether
sulfuryl
fluoride
meets
the
requisite
standard
under
FIFRA.

The
Agency,
through
the
Office
of
Water,
has
set
a
Secondary
MCL
(
SMCL)
for
fluoride
at
2
ppm.
This
SMCL
is
set
to
be
protective
against
moderate
to
severe
dental
fluorosis.
Therefore,
at
exposures
from
2
ppm
fluoride
in
water,
and
assuming
a
source
contribution
of
100%
from
water,
dental
fluorosis
in
the
moderate­
to­
severe
category
is
not
expected
to
occur;
dental
fluorosis
in
the
mild­
to­
moderate
category
may
occur.
HED
notes
that
the
EPA=
s
Integrated
Risk
Information
System
(
IRIS)
lists
an
oral
RfD
of
1
ppm
fluoride
in
water
for
dental
fluorosis
(
IRIS
Database).
That
RfD
is
based
on
a
NOEL
of
1
ppm
with
an
LOEL
of
2
ppm
and
no
modifying
or
uncertainty
factors
since
the
effect
was
noted
in
a
sensitive
population
and
the
duration
of
exposure
was
appropriate
for
the
effect
and
the
population.
The
information
in
IRIS
supports
the
SMCL
of
2
ppm
given
that
mild
dental
fluorosis
is
a
cosmetic
effect.
In
addition
to
findings
by
the
Agency,
the
Institute
of
Medicine
of
the
National
Academies
(
IOM)
has
published
Tolerable
Upper
Intakes
for
fluoride
as
relates
to
dental
fluorosis.
The
Agency=
s
SMCL
and
the
IOM
values
are
presented
on
a
mg/
day
basis
in
Table
II­
1.

Table
II­
1.
Reference
Exposure
Levels
used
to
Estimate
Risk
of
Developing
Dental
Fluorosis.

Population
Subgroup
Water
Consumption,
L/
day
SMCL,
mg/
day*
Tolerable
Upper
Intake,
mg/
dayH
All
Infants
(<
1
year)
1
2
0.7
Children
1­
2
years
1
2
1.3
Children
3­
5
years
1
2
1.9
Children
6­
12
years
1
2
2.2
*
SMCL
(
mg/
day)
=
SMCL
(
mg/
L)
H
Water
Consumption
(
L/
day).

H
Tolerable
Upper
Intake
from
Institute
of
Medicine,
Food
and
Nutrition
Board.
Dietary
reference
intakes
for
calcium,
phosphorus,
magnesium,
vitamin
D
and
fluoride.
Report
of
the
Standing
Committee
on
the
Scientific
Evaluation
of
Dietary
Reference
Intakes.
Washington,
DC:
National
Academy
Press,
1997.
Values
have
been
matched
to
the
listed
age
groups
using
a
weighted
average.
37
of
39
HED
has
not
estimated
risks
for
dental
fluorosis
for
population
subgroups
greater
than
12
years
of
age.
Dental
fluorosis
is
an
effect
that
occurs
prior
to
eruption
of
the
teeth,
at
the
time
that
the
tooth
enamel
is
being
formed.
In
evaluating
dental
fluorosis,
the
National
Academy
of
Sciences
and
the
Office
of
Water
use
age
cutoffs
of
8
years
and
9
years,
respectively,
as
ages
above
which
it
is
not
appropriate
to
assess
this
effect.
In
this
assessment,
HED
has
used
a
maximum
age
of
12
years
due
to
the
population
grouping
of
the
exposure
modeling
software.

The
risk
estimates
for
dental
fluorosis
are
presented
in
Table
II­
2.
They
are
based
on
the
aggregate
exposure
assessment
discussed
in
Section
5
of
this
document.
The
use
of
both
the
SMCL
and
the
Tolerable
Upper
Intake
values
provides
a
range
of
risk
estimates
for
each
population
subgroup.
Both
estimates
should
be
considered
when
looking
at
the
potential
for
fluoride
exposures
to
result
in
dental
fluorosis.

Table
II­
2.
Aggregate
Exposure
and
Risk
Estimates
for
Dental
Fluorosis.

Population
Subgroup
Aggregate
Exposure,
mg/
day
(
without
toothpaste)
SMCL,
mg/
day
%
of
SMCL
(
without
toothpaste)
Tolerable
Upper
Intake,
mg/
day
%
of
Tolerable
Upper
Intake
(
without
toothpaste)

All
infants
(<
1
year)
1.465
(
1.165)
2
73
(
58)
0.70
209
(
166)
Children
1­
2
yrs
1.386
(
1.086)
2
69
(
54)
1.30
107
(
84)
Children
3­
5
yrs
1.912
2
96
1.90
101
Children
6­
12
yrs
2.218
2
111
2.20
101
Based
on
the
SMCL
values,
risks
slightly
exceed
HED=
s
level
of
concern
for
children
aged
6
to
12
years
old.
When
risk
estimates
are
based
on
the
Institute
of
Medicine=
s
Tolerable
Upper
Intake
values,
those
estimates
indicate
that
there
may
be
concern
for
infants.
The
exposure
estimates
for
the
Aall
infants@
group
includes
exposure
from
fluoridated
toothpaste.
Provided
parents
follow
the
recommendations
of
the
American
Academy
of
Pediatric
Dentistry
that
fluoridated
toothpaste
not
be
introduced
into
oral
hygiene
until
children
are
at
a
minimum
of
2
years
old,
the
aggregate
exposure
estimates
presented
in
Table
II­
2
represent
an
overestimate
of
exposure.
Exposure
and
risk
estimates
without
toothpaste
are
included
parenthetically
in
the
table
for
populations
less
than
2
years
old.
We
note
that
dental
fluorosis
which
occurs
in
the
infant
population
subgroup
will
be
to
their
deciduous
teeth7.
Therefore,
the
risk
estimate
of
209%
(
166%
without
toothpaste)
of
the
Tolerable
Upper
Intake
does
not
pertain
to
fluorosis
of
the
permanent
teeth.
Given
the
assumptions
in
the
exposure
assessments
and
the
range
of
numbers
presented
in
Table
II­
2,
HED
does
not
believe
that
these
risk
estimates
warrant
critical
concern
regarding
development
of
objectionable
dental
fluorosis.

7
Centers
for
Disease
Control.
"
Recommendations
for
Using
Fluoride
to
Prevent
and
Control
Dental
Caries
in
the
United
States".
http://
www.
cdc.
gov/
mmwr/
preview/
mmwrhtml/
rr5014a1.
htm.
38
of
39
Attachment
1.
Waiver
of
Rat
Developmental
Neurotoxicity
Study
with
Sulfuryl
Fluoride.

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
April
22,
2004
MEMORANDUM
SUBJECT:
Waiver
Justification
of
Inhalation
Rat
Developmental
Neurotoxicity
Study
With
Sulfuryl
Fluoride
FROM:
Vicki
L.
Dellarco,
Ph.
D.,
Senior
Science
Advisor
Karl
Baetcke,
Ph.
D.,
Senior
Scientist
Health
Effects
Division
Office
of
Pesticide
Programs
THRU:
Margaret
Stasikowski,
Director
Health
Effects
Division
Office
of
Pesticide
Programs
TO:
Lois
Rossi,
Director
Registration
Division
Office
of
Pesticide
Programs
We
have
conducted
a
review
of
the
waiver
justification
submitted
by
Dow
AgroSciences
for
the
sulfuryl
fluoride
inhalation
rat
developmental
neurotoxicity
study
(
DNT).
DOW
requested
this
waiver
on
the
basis
of:
 
Essentially
no
chronic
dietary
exposure
 
Minimal
potential
inhalation
exposures
or
short
duration
(
1­
2
days)
 
Animal
welfare
concerns
(
1500
to
4000
animals)
 
Potentially
confounded
scientific
and
technical
aspects
of
conducting
an
inhalation
DNT
Also,
Dow
indicated
in
their
waiver
justification
that
they
recently
conducted
a
rat
metabolism
study
that
showed
sulfuryl
fluoride
is
rapidly
release
to
fluoride.
Thus,
given
the
known
toxicology
of
fluoride
coupled
with
the
minimal
inhalation
exposure
to
humans,
neurotoxicity
to
the
adult
or
developmental
neurotoxicity
would
be
highly
unlikely.

It
is
important
to
evaluate
the
merit
of
this
rat
DNT
study
from
a
risk
perspective
that
considers
realistic
circumstances
of
human
exposure.
Therefore,
we
are
in
agreement
with
Dow's
scientific
arguments
concerning
the
minimal
potential
for
human
exposure
and
the
unlikelihood
that
neurotoxicity
or
developmental
neurotoxicity
would
occur
due
to
dietary
exposure
or
39
of
39
inhalation
exposure
to
sulfuryl
fluoride.
Furthermore,
a
composite
uncertainty
factor
(
UF)
of
1000
(
rather
than
the
standard
100X)
is
applied
and
will
be
retained
to
account
for
uncertainties
inherent
in
the
extrapolation
from
laboratory
animal
data
to
humans
(
10X),
variations
in
sensitivity
among
members
of
the
human
population
(
10X),
and
for
the
lack
of
a
DNT
(
10X)
in
the
sulfuryl
fluoride
risk
assessment.
Thus,
there
is
an
ample
level
of
protection
built
into
the
risk
assessment.

cc:
Michael
Doherty
Dennis
McNeilly
Jess
Rowland
Karen
Whitby
