Chlorine
Dioxide
Toxicology
Disciplinary
Chapter
Case
4023
Timothy
McMahon,
Ph.
D.
Office
of
Pesticide
Programs
Antimicrobials
Division
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
April
5,
2006
Page
2
of
32
1.0
HAZARD
CHARACTERIZATION
Chlorine
dioxide
(
ClO2;
CASRN
10049­
04­
4)
is
a
yellow
to
reddish­
yellow
gas
at
room
temperature
that
is
stable
in
the
dark
but
is
unstable
in
light.
It
is
a
strong
oxidizing
agent
that
under
oxidant
demand
conditions
is
readily
reduced
to
chlorite
(
ClO2­;
CASRN
7758­
19­
2),
another
strong
oxidizing
agent,
and
to
a
lesser
extent,
chlorate.
These
substances
are
water
soluble.
Therefore,
what
exists
in
water
or
the
stomach
is
a
mixture
of
these
chemical
species
(
i.
e.,
chlorine
dioxide,
chlorite,
and
chlorate)
and
possibly
their
reaction
products
with
the
gastrointestinal
contents.
As
a
result,
chlorine
dioxide
and
chlorite
are
characterized
together
in
this
report
because
studies
conducted
with
chlorite
are
relevant
to
characterizing
the
toxicity
of
chlorine
dioxide.

Chlorine
dioxide
is
used
as
an
alternative
to
chlorine
for
disinfection
of
municipal
drinking
water.
It
is
also
registered
for
use
on
a
variety
of
sites,
including
swimming
pool
water
systems,
fruits
and
vegetables,
wood
protection,
household
uses,
and
metalworking
cutting
fluids.
The
Antimicrobials
Division
has
previously
supported
a
Section
18
use
of
chlorine
dioxide
on
stored
potatoes
for
control
of
late
blight
and
silver
scurf.
However,
a
formal
risk
assessment
is
necessary
to
support
renewal
of
the
Section
18
as
well
as
existing
and
potential
new
use
patterns.
The
ADTC
evaluated
the
existing
database
and
selected
toxicity
endpoints
for
dietary
and
non­
dietary
exposures
to
chlorine
dioxide.
For
this
evaluation,
one
human
study
is
included,
the
dermal
sensitization
study.

Other
uses
of
chlorine
dioxide
include
bleaching
textiles
and
wood
pulp
for
paper
manufacturing,
antimicrobial
applications,
and
reducing
loads
of
adsorbable
organic
halogenated
compounds
in
industrial
effluents.
Chlorite
is
also
used
for
etching
printed
circuit
boards.

The
acute
toxicity
of
chlorine
dioxide
(
79%
ai.)
is
moderate
by
the
oral
route
(
LD50
=
292
mg/
kg
[
males];
340
mg/
kg
[
females];
Toxicity
Category
II).
The
acute
toxicity
of
chlorine
dioxide
using
sodium
chlorite
as
the
test
material
(
80%
ai.)
is
considered
minimal
by
the
dermal
route
(
LD50
>
2000
mg/
kg;
Toxicity
Category
III).
By
the
inhalation
route
using
sodium
chlorite
as
the
test
material
(
80.6%),
chlorine
dioxide
was
moderately
toxic
(
LC50
=
0.29
mg/
L).
For
primary
eye
irritation,
chlorine
dioxide
(
2%
a.
i.)
was
a
mild
irritant
(
Toxicity
Category
III),
but
the
technical
test
material
was
not
used.
For
primary
dermal
irritation,
sodium
chlorite
(
80%
a.
i.)
was
a
primary
irritant
(
Toxicity
Category
II).
For
dermal
sensitization,
there
are
no
acceptable
animal
studies
for
chlorine
dioxide
or
sodium
chlorite.

The
subchronic
toxicity
database
is
considered
adequate
for
characterizing
the
subchronic
oral
and
inhalation
toxicity
of
chlorine
dioxide/
chlorite.
Daniel
et
al.
(
1990)
exposed
groups
of
10
male
and
10
female
Sprague­
Dawley
rats
to
chlorine
dioxide
in
drinking
water
for
90
days
at
concentrations
of
0,
25,
50,
100,
or
200
mg/
L
(
0,
2,
4,
6,
or
12
mg/
kg­
day
chlorine
dioxide
for
males
and
0,
2,
5,
8,
or
15
mg/
kg­
day
chlorine
dioxide
for
females).
The
LOAEL
for
this
study
is
25
mg/
L
(
2
mg/
kg­
day)
based
on
a
significant
increase
in
incidence
of
nasal
lesions.
In
a
study
by
Harrington,
et
al.
(
1995a),
Crl:
CD
(
SD)
BR
rats
(
15/
sex/
group)
were
administered
doses
of
0,
10,
25,
or
80
mg/
kg­
day
sodium
chlorite
(
equivalent
to
0,
7.4,
19,
or
60
mg
chlorite/
kg­
day,
respectively)
via
gavage
for
13
weeks.
The
NOAEL
for
this
study
is
7.4
mg/
kg­
day,
and
the
Page
3
of
32
LOAEL
is
19
mg/
kg­
day,
based
on
stomach
lesions
and
increases
in
spleen
and
adrenal
weights.
Dalhamn
(
1957)
and
Paulet
and
Desbrousses
(
1970,
1972,
and
1974)
are
co­
critical
inhalation
toxicity
studies
included
in
the
subchronic
toxicity
database
for
chlorine
dioxide/
chlorite.
A
NOAEL
of
0.1
ppm
(~
0.28
mg/
m3)
was
selected
from
Dalhamn
(
1957)
and
a
LOAEL
of
1.0
ppm
(~
2.8
mg/
m3)
was
selected
from
Paulet
and
Desbrousses
(
1970,
1972,
and
1974),
based
on
respiratory
distress
and
decreased
body
weights
observed
in
exposed
animals.

One
developmental
toxicity
study
conducted
using
rats
(
Orme
et
al.,
1985)
is
included
in
the
developmental
toxicity
database
for
chlorine
dioxide
and
chlorite.
In
Orme
et
al.
(
1985),
a
NOAEL
of
20
mg/
L
(
3
mg/
kg/
day)
was
established
based
on
neurodevelopment
effects
in
the
offspring
of
rats
exposed
to
chlorine
dioxide
in
drinking
water.

A
two­
generational
reproductive
toxicity
study
(
CMA,
1996)
was
conducted
with
sufficient
numbers
of
animals
of
both
sexes
and
examined
numerous
endpoints.
The
study
is
acceptable
and
consistent
with
EPA
testing
guidelines
that
were
in
effect
at
the
time
of
the
study.
The
NOAEL
for
this
study
is
35
ppm
(
2.9
mg/
kg­
day
chlorite)
and
the
LOAEL
is
70
ppm
(
5.9
mg/
kg­
day
chlorite)
based
on
lowered
auditory
startle
amplitude
and
altered
liver
weights
in
two
generations.

Chlorine
dioxide
has
not
been
formally
assessed
for
carcinogenic
potential.
The
following
studies
do
not
definitively
characterize
the
carcinogenicity
of
chlorine
dioxide,
and
additional
studies
may
be
required.

One
subchronic
study
(
Daniel
et
al.,
1990)
examined
the
effects
of
administration
of
chlorine
dioxide
to
groups
of
male
and
female
Sprague­
Dawley
rats
(
10/
sex/
dose)
at
dose
levels
of
0,
25,
50,
100,
or
200
mg/
L
for
90
days
in
drinking
water.
A
significant
increase
in
the
incidence
of
nasal
lesions
(
goblet
cell
hyperplasia
and
inflammation
of
nasal
turbinates)
was
found
at
all
dose
levels
tested.
The
significance
of
these
findings
is
uncertain
as
they
have
not
been
observed
in
other
long­
term
studies
of
chlorine
dioxide.

The
potential
for
chlorine
dioxide
to
induce
proliferative
epidermal
hyperplasia
was
examined
by
Robinson
et
al.
(
1986).
Groups
of
five
dorsally
shaved
female
SENCAR
mice
were
placed
in
chambers
filled
with
0,
1,
10,
100,
300,
or
1,000
ppm
liquid
chlorine
dioxide.
The
animals
were
exposed
10
minutes/
day
for
4
days.
A
significant
increase
in
interfollicular
epidermal
thickness
was
observed
in
the
1,000
ppm
group,
but
not
at
the
lower
concentrations.
Increases
in
total
cell
numbers
and
basal
cell
numbers
in
skin
sections
were
observed
in
both
the
300
and
1,000
ppm
groups.
In
a
follow­
up
study,
groups
of
40
mice
were
immersed
in
0
or
1,000
ppm
chlorine
dioxide
for
10
minutes;
animals
(
5/
group)
were
killed
1,
2,
3,
4,
5,
8,
10,
or
12
days
postexposure
A
significant
increase
in
interfollicular
epidermis
thickness
was
observed
at
all
time
periods,
with
the
highest
values
at
10
and
12
days
post­
exposure.
The
authors
concluded
that
even
short­
term
dermal
exposure
to
high
concentrations
of
chlorine
dioxide
is
capable
of
inducing
hyperplastic
responses
in
the
mouse
skin.

In
a
carcinogenicity
study
by
Kurokawa
et
al.
(
1984),
chlorite
did
not
show
increases
in
tumor
incidences
in
rats
and
mice;
this
study
is
considered
inadequate
for
assessing
human
carcinogenicity
because
the
exposure
was
for
less
than
a
lifetime,
a
high
incidence
of
Sendai
virus
Page
4
of
32
was
found
in
the
rats,
and
mortality
was
high
in
the
mouse
control
group
because
of
excessive
fighting.

Data
on
the
mutagenicity
of
chlorine
dioxide
exist
in
the
open
scientific
literature
as
well
as
within
the
Agency's
database
of
submitted
studies.
In
Miller
et
al.
(
1986)
negative
effects
were
reported
in
Salmonella
strains
TA98
and
TA100
from
a
400­
fold
drinking
water
concentrate
of
chlorine
dioxide,
whereas
a
4000­
fold
concentrate
was
mutagenic
to
strain
TA98
only
in
the
absence
of
metabolic
activation.
In
Accession
No.
265867,
chlorine
dioxide
was
positive
for
forward
mutations
under
non­
activated
conditions
(
dose­
related
from
3.2­
24.3
µ
g/
ml)
and
activated
conditions
(
48.3
µ
g/
mL)
in
L5178Y/
TK
cells,
positive
for
structural
chromosome
aberrations
under
non­
activated
and
activated
conditions
(
10,
15,
and
50
µ
g/
ml),
and
negative
for
increased
transformed
foci
up
to
cytotoxic
levels.
In
vivo
micronucleus
and
bone
marrow
chromosomal
aberration
assays
in
Swiss
CD­
1
mice
administered
0.1 
0.4
mg
chlorine
dioxide
via
gavage
for
5
consecutive
days
were
negative,
as
was
a
sperm­
head
abnormality
assay
in
B6C3F1
mice
administered
0.1 
0.4
mg
via
gavage
for
5
consecutive
days
(
0,
3.2,
8,
and
16
mg/
kg­
day)
(
Meier
et
al.,
1985).

Neurotoxicity
of
chlorine
dioxide
has
been
observed.
In
the
two­
generation
reproduction
toxicity
study
(
CMA
1996),
significant
changes
were
observed
in
maximum
response
in
startle
amplitude
and
absolute
brain
weight
in
F1
rat
pups
at
a
dose
of
3
mg/
kg/
day.
In
the
Orme
et
al.
(
1985)
developmental
toxicity
study,
neurobehavioral
deficits
in
offspring
were
observed
also
at
a
dose
of
14
mg/
kg/
day
administered
to
maternal
rats.

Information
regarding
the
pharmacokinetics
of
chlorine
dioxide
and
chlorite
is
predominantly
derived
from
oral
studies
in
laboratory
animals.
Chlorite
(
ClO2­)
does
not
persist
in
the
atmosphere
either
in
ionic
form
or
as
chlorite
salt.
The
rapid
appearance
of
36Cl
in
plasma
following
oral
administration
of
chlorine
dioxide
(
36ClO2)
or
chlorite
(
36ClO2­)
has
been
shown
in
laboratory
animals
(
Abdel­
Rahman
et
al.,
1984).
In
rats,
absorbed
36Cl
(
from
36ClO2
or
36ClO2
sources)
is
slowly
cleared
from
the
blood
and
is
widely
distributed
throughout
the
body
(
Abdel­
Rahman
et
al.,
1984).
Chlorine
dioxide
rapidly
dissociates,
predominantly
into
chlorite
(
which
itself
is
highly
reactive)
and
chloride
ion
(
Cl­),
ultimately
the
major
metabolite
of
both
chlorine
dioxide
and
chlorite
in
biological
systems
(
Abdel­
Rahman
et
al.,
1984).
Urine
is
the
primary
route
of
elimination,
predominantly
in
the
form
of
chloride
ion
(
Abdel­
Rahman
et
al.,
1984).
Additional
pharmacokinetic
studies
of
chlorine
dioxide
and
chlorite
should
be
designed
to
examine
mechanisms
of
absorption
and
metabolic
changes
that
might
account
for
observed
neurodevelopment
effects.

2.0
TOXICOLOGY
DATA
REQUIREMENTS
With
the
exception
of
the
acute
toxicity
studies
and
the
reproductive
toxicity
study
(
CMA,
1996),
the
Antimicrobials
Division
has
relied
upon
available
published
scientific
data
to
characterize
the
hazard
of
chlorine
dioxide,
as
the
data
are
from
peer­
reviewed
journals
and
also
are
consistent
with
regard
to
the
type
of
toxicity
and
effect
levels
observed.
These
same
data
are
also
found
in
the
recently
published
Toxicological
review
for
chlorine
dioxide
and
chlorite
in
the
EPA's
IRIS
database
(
USEPA,
2002)
and
in
the
Agency
for
Toxic
Substances
and
Disease
Registry's
Page
5
of
32
Toxicological
Profile
for
chlorine
dioxide
(
ATSDR,
2004).
The
Agency
considers
these
hazard
data
adequate
to
support
reregistration
eligibility
of
chlorine
dioxide
unless
otherwise
noted.

3.0
DATA
GAPS
For
chlorine
dioxide/
chlorite,
carcinogenicity
data
are
lacking
.
As
noted
in
the
recent
IRIS
toxicological
review,
no
studies
have
examined
the
carcinogenic
potential
of
chlorine
dioxide.
Based
on
the
registered
uses
of
chlorine
dioxide
in
swimming
pool
water
systems
and
as
a
metalworking
fluid,
additional
data
addressing
the
carcinogenic
potential
of
chlorine
dioxide
are
required.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
database
for
Acute
Toxicity:
The
acute
toxicity
of
chlorine
dioxide
(
79%
ai.)
is
considered
severe
by
the
oral
route
(
LD50
=
292
mg/
kg
[
males];
340
mg/
kg
[
females];
Toxicity
Category
II).
The
acute
toxicity
of
sodium
chloride
(
80%
ai.)
is
considered
moderate
by
the
dermal
route
(
LD50
>
2000
mg/
kg;
Toxicity
Category
III).
For
primary
eye
irritation,
chlorine
dioxide
(
2%
a.
i.)
was
a
mild
irritant
(
Toxicity
Category
III).
For
primary
dermal
irritation,
sodium
chloride
(
80%
a.
i.)
was
a
primary
irritant
(
Toxicity
Category
II).
For
dermal
sensitization,
there
are
no
acceptable
animal
studies
for
chlorine
dioxide
or
sodium
chlorite.
The
acute
toxicity
data
for
chlorine
dioxide
and
sodium
chlorite
are
summarized
below
in
Table
1.

Table
1.
Acute
Toxicity
Profile
for
Chlorine
Dioxide/
Sodium
chlorite
Guideline
Number
Study
Typea
/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
oral
(
79%
chlorine
dioxide)
43558601
LD50
=
292
mg/
kg
(
males)
LD50
=
340
mg/
kg
(
females)
II
870.1200
(
§
81­
2)
Acute
dermal
(
80%
sodium
chlorite)
40168704
LD50
>
2000
mg/
kg
III
870.1300
(
§
81­
3)
Acute
inhalation
(
80.6%
sodium
chlorite)
42484101
LC50
=
0.29
mg/
L
II
870.2400
(
§
81­
4)
Primary
eye
irritation
(
2%
chlorine
dioxide)
43441903
Mild
irritant
III
870.2500
(
§
81­
5)
Primary
dermal
irritation
(
80%
sodium
chlorite)
40168704
Primary
irritant
II
870.2600
(
§
81­
6)
Dermal
sensitization
No
acceptable
sensitization
study
available.

a
The
available
acute
studies
are
all
graded
as
acceptable.
An
acceptable
dermal
sensitization
study
is
not
available
in
Page
6
of
32
the
database.

4.2
Subchronic
Toxicity
Adequacy
of
database
for
Subchronic
Toxicity:
The
subchronic
toxicity
database
includes
oral
toxicity
studies
conducted
by
Daniel
et
al.
(
1990)
and
Harrington
et
al.
(
1995a)
as
well
as
inhalation
toxicity
studies
conducted
by
Dalhamn
(
1957)
and
Paulet
and
Desbrousses
(
1970,
9172,
and
1974).
These
data
are
considered
adequate
for
characterizing
the
subchronic
toxicity
of
chlorine
dioxide/
chlorite.

870.3100
Subchronic
(
Oral)
Toxicity
­
Chlorine
dioxide
 
Rat
Daniel
et
al.
(
1990)
exposed
groups
Sprague­
Dawley
rats
(
10/
sex/
dose)
to
chlorine
dioxide
in
drinking
water
for
90
days
at
concentrations
of
0,
25,
50,
100,
or
200
mg/
L
(
equivalent
to
0,
2,
4,
6,
or
12
mg/
kg­
day
chlorine
dioxide
for
males
and
0,
2,
5,
8,
or
15
mg/
kg­
day
chlorine
dioxide
for
females,
respectively).
No
exposure­
related
deaths
were
reported.
Exposure
to
200
mg/
L
resulted
in
significant
reductions
in
terminal
body
weights
and
body
weight
gain
(
26% 
29%
lower
than
controls).
Significant
reductions
in
water
consumption
were
observed
in
the
males
exposed
to
 
50
mg/
L
and
in
females
exposed
to
 
25
mg/
L;
decreases
in
food
consumption
were
also
observed
in
the
200
mg/
L
males.
Absolute
liver
weights
were
decreased
in
males
at
 
50
mg/
L,
and
absolute
spleen
weights
were
decreased
in
females
at
 
25
mg/
L.
No
consistent
alterations
in
hematology
were
observed.
Serum
lactate
dehydrogenase
and
aspartate
aminotransferase
levels
were
decreased
and
serum
creatinine
levels
were
increased
in
the
males
exposed
to
100
or
200
mg/
L;
no
other
alterations
in
serum
chemistry
parameters
were
consistently
found.
A
significant
increase
in
incidence
of
nasal
lesions
(
goblet
cell
hyperplasia
and
inflammation
of
nasal
turbinates)
was
found
in
males
exposed
to
 
25
mg/
L
and
in
females
at
 
100
mg/
L.
The
study
authors
postulated
that
these
lesions
were
likely
caused
by
inhalation
of
chlorine
dioxide
vapors
at
the
drinking
water
sipper
tube
or
from
off­
gassing
of
the
vapors
after
drinking
rather
than
ingestion
of
the
drinking
water.
Thus,
25
mg/
L
(
2
mg/
kg­
day)
can
be
described
as
a
lowest­
observed­
adverseeffect
level
(
LOAEL),
but
the
toxicological
significance
of
the
nasal
lesions
is
not
known.
Respiratory
tract
pathologies
have
not
been
reported
in
other
oral
studies
and
the
effect
may
possibly
be
an
artifact
of
treatment.

870.3100
Subchronic
(
Oral)
Toxicity
­
Sodium
chlorite
 
Rat
In
a
14­
day
range­
finding
study
(
Harrington,
et
al.,
1995),
rats
were
administered
gavage
doses
of
sodium
chlorite
in
the
range
of
25
to
200
mg/
kg/
day
(
equivalent
to
18.6
to
149.2
mg
chlorite/
kg/
day).
One
exposure­
related
death
was
observed
in
each
sex
in
the
200
mg/
kg/
day
group
on
treatment
days
2
and
3.
No
treatment­
related
deaths
occurred
in
the
groups
receiving
chlorite
doses
 
56
mg/
kg/
day.

In
the
main
study
performed
by
Harrington
et
al.
(
1995a)
Crl:
CD
(
SD)
BR
rats
(
15/
sex/
group)
were
administered
doses
of
0,
10,
25,
or
80
mg/
kg­
day
sodium
chlorite
(
equivalent
to
0,
7.4,
19,
or
60
mg
chlorite/
kg­
day,
respectively)
via
gavage
for
13
weeks.
In
the
60
mg/
kg­
day
group,
four
animals
died
during
treatment
and
both
sexes
exhibited
salivation,
significantly
decreased
Page
7
of
32
erythrocyte
counts,
and
decreased
total
serum
protein
levels.
The
males
receiving
60
mg/
kg­
day
exhibited
significantly
decreased
hematocrit
and
hemoglobin
levels
and
increased
methemoglobin
and
neutrophil
levels,
whereas
in
the
females,
methemoglobin
levels
were
significantly
decreased.
Possible
reasons
for
the
decrease
in
methemoglobin
in
females,
which
is
unexpected
considering
the
known
oxidative
effects
of
sodium
chlorite,
were
not
discussed
by
the
study
authors.
The
following
observations
were
also
noted
in
the
60
mg/
kg­
day
group:
morphological
changes
in
erythrocytes
in
some
animals
of
both
sexes,
significant
increases
in
relative
adrenal
and
spleen
weights
in
the
males,
increases
in
absolute
and
relative
spleen
and
adrenal
weight
in
females,
and
increases
in
relative
liver
and
kidney
weights
in
the
females.
Body
weight
and
food
consumption
were
not
affected
by
treatment.
Histopathologic
alterations
in
the
60
mg/
kg­
day
group
included
squamous
epithelial
hyperplasia,
hyperkeratosis,
ulceration,
chronic
inflammation,
and
edema
in
the
stomachs
of
seven
males
and
eight
females.
At
19
mg/
kg­
day,
the
following
alterations
were
reported:
occasional
salivation
in
two
males,
hematologic
alterations
in
males
(
increased
methemoglobin
levels
and
neutrophil
count,
decreased
lymphocyte
count),
increases
in
absolute
and
relative
spleen
and
adrenal
weights
in
females,
and
histologic
alterations
in
the
stomach
of
two
males,
similar
to
those
seen
in
the
high­
dose
group.
The
increase
in
absolute
spleen
weight
was
attributed
to
morphological
alterations
in
erythrocytes,
but
no
explanation
was
provided
for
alterations
in
absolute
adrenal
weight.
The
NOAEL
in
this
study
is
determined
to
be
7.4
mg/
kgday
and
the
LOAEL
is
19
mg/
kg­
day
for
stomach
lesions
and
increases
in
spleen
and
adrenal
weights
in
rats
subchronically
treated
with
sodium
chlorite.

870.3465
Subchronic
(
Inhalation)
Toxicity
­
Chlorine
dioxide
 
Rat
Dalhamn
(
1957)
reported
the
results
of
several
inhalation
studies
in
laboratory
animals.
In
one
study,
a
single
2­
hour
inhalation
exposure
of
four
rats
to
a
chlorine
dioxide
concentration
of
260
ppm
(
728
mg/
m3)
resulted
in
pulmonary
edema
and
nasal
bleeding.
In
another
study,
rats
were
subject
to
3­
minute
exposures
to
decreasing
concentrations
of
airborne
chlorine
dioxide
from
3,400
to
800
ppm
(
from
9,520
to
2,240
mg/
m3)
once
a
week
for
3
consecutive
weeks.
Respiratory
distress
was
reported
in
three
rats
subjected
and
bronchopneumonia
was
observed
in
two
of
these
rats.
In
a
third
rat
study,
repeated
exposure
to
approximately
10
ppm
(
28
mg/
m3)
of
chlorine
dioxide
(
4
hours/
day
for
9
days
in
a
13­
day
period)
resulted
in
rhinorrhea,
altered
respiration,
and
respiratory
infection.
No
indications
of
adverse
effects
were
seen
in
rats
exposed
to
approximately
0.1
ppm
(
0.28
mg/
m3)
of
chlorine
dioxide
5
hours
/
day
for
10
weeks.

870.3465
Subchronic
(
Inhalation)
Toxicity
­
Chlorine
dioxide
 
Rat
Paulet
and
Desbrousses
(
1970,
1972,
and
1974)
conducted
a
series
of
studies
in
which
laboratory
animals
were
exposed
to
atmospheres
of
chlorine
dioxide.
Nasal
discharge
and
localized
bronchopneumonia
(
with
desquamation
of
alveolar
epithelium)
were
noted
in
rats
exposed
to
an
airborne
concentration
of
10
ppm
(
28
mg/
m3),
2
hours/
day
for
30
days.
Another
group
of
rats
exposed
to
a
concentration
of
5
ppm
(
14
mg/
m3)
exhibited
similar,
but
less
severe,
respiratory
tract
effects.
Bronchial
inflammation
and
alveolar
congestion
and
hemorrhage
were
observed
in
Page
8
of
32
rats
exposed
to
2.5
ppm
(
7
mg/
m3),
7
hours/
day
for
30
days.
Alveolar
congestion
and
hemorrhage
were
also
seen
in
rabbits
following
inhalation
exposure
to
2.5
ppm
(
7
mg/
m3),
4
hours/
day
for
45
days.
In
a
group
of
rats
and
rabbits
sacrificed
15
days
after
exposure
termination,
recovery
from
the
pulmonary
lesions
was
apparent
(
Paulet
and
Desbrousses
1970).
Vascular
congestion
and
peribronchiolar
edema
were
noted
in
the
lungs
of
rats
exposed
to
a
concentration
of
1
ppm
(
2.8
mg/
m3),
5
hours/
day,
and
5
days/
week
for
2
months
(
Paulet
and
Desbrousses
1972).
A
LOAEL
of
1
ppm
for
respiratory
effects
was
identified
in
this
study.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
Two
developmental
toxicity
drinking
water
studies
are
included
in
the
toxicity
database
for
chlorine
dioxide/
sodium
chlorite.
In
one,
chlorine
dioxide
was
administered
to
(
Orme
et
al.,
1985)
while
in
the
other
study,
rabbits
were
administered
sodium
chlorite.
The
studies
are
acceptable
and
consistent
with
EPA
testing
guidelines.

870.3700
Prenatal
Developmental
Toxicity
(
Oral)
Study
 
Rat
In
a
study
conducted
by
Orme
et
al.
(
1985)
designed
to
assess
toxicity
of
chlorine
dioxide,
female
Sprague­
Dawley
rats
(
13­
16/
dose)
were
administered
drinking
water
containing
0,
2,
20,
or
100
mg/
L
(
0,
1,
3,
and
14
mg/
kg/
day
estimated
doses)
chlorine
dioxide
from
2
weeks
prior
to
mating
until
day
21
post­
partum,
and
the
effects
on
brain
development
in
pups
examined.
There
were
no
significant
effects
of
chlorine
dioxide
on
body
weight
of
dams
or
pups
at
any
dose
level
tested.
Depression
of
serum
thyroxin
(
T4)
and
increased
serum
triiodothyronine
(
T3)
were
observed
in
pups
at
weaning
at
the
100
mg/
L
(
14
mg/
kg/
day)
dose
level.
Neurobehavioral
exploratory
and
locomotor
activities
were
decreased
in
pups
at
the
14
mg/
kg/
day
dose
(
p
=
0.08).
These
effects
were
not
observed
in
pups
at
the
20
mg/
L
dose
level
(
3
mg/
kg).
Pups
administered
chlorine
dioxide
by
gavage
at
14
mg/
kg/
day
on
post­
natal
days
5­
20
showed
a
larger
depression
of
serum
T4
levels
and
greater
delays
in
development
of
exploratory
and
locomotor
behavior
activity.
There
were
no
apparent
effects
in
maternal
animals
up
to
the
14
mg/
kg/
day
dose
level.
The
developmental
toxicity
NOAEL
of
3
mg/
kg/
day
was
selected
based
on
depression
of
serum
T4
levels
in
pups
from
dosed
maternal
rats
and
delays
in
development
of
locomotor
and
exploratory
behavior
activity.

870.3700
Prenatal
Developmental
Toxicity
(
Oral)
Study
 
Rabbit
In
a
developmental
drinking
water
study
(
MRID
41715701),
time­
mated
female
New
Zealand
White
rabbits
(
16­
17/
dose)
were
administered
sodium
chlorite
(
purity
80.58%)
from
gestation
days
7
through
19
at
0,
200,
600,
or
1200
ppm
(
calculated
intake
0,
12.2­
13.8,
30.1­
38.3,
or
32.0­
60.1
mg/
kg/
day).
Mean
intake
of
the
test
compound
via
the
drinking
water
was
consistent
throughout
the
dosing
period
only
at
the
lowest
level,
but
was
suppressed
in
a
dose­
related
fashion
at
the
highest
levels,
especially
over
the
first
few
days
of
dosing.
These
variations
in
Page
9
of
32
compound
intake
were
considered
to
reflect
problems
in
palatability
of
the
preparations
at
high
concentrations.
There
was
no
compound­
related
mortality,
but
two
doses
had
to
be
sacrificed
in
extremis
for
other
(
incidental)
reasons.
The
sole
treatment­
related
clinical
effect
was
a
doserelated
increase
in
incidence
of
does
with
reduced
fecal
output
during
the
dosing
period,
days
7
to
19,
which
was
considered
consistent
with
decreased
food
consumption.
At
necropsy,
there
were
no
abnormalities
considered
treatment­
related
in
survivors.
Among
gross
findings
in
scheduled
sacrifices
were:
pitted
kidneys
in
two
mid­
dose
and
one
high­
dose
animal;
alopecia
in
two
lowdose
three
mid­
dose,
and
two
high­
dose
does;
and
thoracic
fluid
in
one
low­
dose
animal.
No
significant
differences
from
control
were
observed
in
pregnancy
rate,
mean
gavid
uterine
weight,
or
reproductive
indices.
Mean
fetal
weights
were
comparable
in
all
groups.
External,
visceral,
and
skeletal
examinations
of
all
live
fetuses
revealed
no
major
abnormalities
which
could
be
considered
related
to
sodium
chlorite
treatment.
An
increased
incidence
of
minor
skeletal
variants
was
observed
among
600
and
1200
ppm
fetuses,
which
was
considered
generally
related
to
retardation
and/
or
delayed
ossification,
rather
than
structural
abnormalities.
No
evidence
of
embryolethality,
fetotoxicity,
or
teratogenicity
was
found.
There
was
a
slight
effect
on
embryonic
growth
of
mid­
and
high­
dose
levels,
but
no
clear
dose­
response
was
evident.
The
maternal
toxicity
NOAEL
of
200
ppm
(
12­
14
mg/
kg/
day)
and
LOAEL
of
600
ppm
(
36­
42
ppm)
were
selected
based
on
decreases
in
feces,
food
consumption,
and
water
intake.
The
developmental
toxicity
NOAEL
of
200
ppm
(
12­
14
mg/
kg/
day)
and
LOAEL
of
600
ppm
(
36­
42
mg/
kg/
day)
were
selected
based
on
decreased
fetal
weight
and
skeletal
retardation.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive:
A
two­
generation
reproduction
toxicity
study
was
conducted
by
the
Chlorine
Dioxide
Panel
of
the
Chemical
Manufacturers
Association
(
now
called
the
American
Chemistry
Council)
in
1996
and
reviewed
by
the
Agency's
Office
of
Water.
The
CMA
(
1996)
study
was
conducted
with
sufficient
numbers
of
animals
of
both
sexes
and
examined
numerous
endpoints.
The
study
is
acceptable
and
consistent
with
EPA
testing
guidelines
that
were
in
effect
at
the
time
of
the
study.

870.3800
Reproduction
and
Fertility
Effects
 
Rat
The
Chemical
Manufacturers
Association
(
CMA)
conducted
a
two­
generation
study
to
examine
reproductive,
developmental
neurotoxicity,
and
hematologic
endpoints
in
rats
exposed
to
sodium
chlorite
(
CMA,
1996).
Thirty
male
and
30
female
Sprague­
Dawley
rats
of
the
OFA(
SD)
IOPSCaw
strain
(
F0)
generation
received
drinking
water
containing
35,
70,
or
300
ppm
sodium
chlorite
for
10
weeks
and
were
then
paired
(
1M:
1F)
for
mating.
A
similar
group
received
purified
water
and
served
as
controls.
Males
were
exposed
throughout
mating
and
then
were
sacrificed.
Exposure
for
the
females
continued
through
mating,
pregnancy,
and
lactation
until
necropsy
following
weaning
of
their
litters.
Sodium
chlorite
concentrations
were
adjusted
downward
during
lactation
to
offset
increases
in
the
volume
of
water
consumed
so
that
a
constant
intake
(
mg/
kg­
day)
could
be
maintained.
Twenty­
five
males
and
females
from
each
of
the
first
25
litters
to
be
weaned
in
a
treatment
group
were
chosen
to
produce
the
F1
generation.
The
F1
pups
were
continued
on
the
same
treatment
regimen
as
their
parents.
At
approximately
14
weeks
of
age,
they
were
mated
to
produce
the
F2a
generation.
Because
of
a
reduced
number
of
litters
in
the
70
Page
10
of
32
ppm
F1­
F2a
generation,
the
F1
animals
were
re­
mated
following
weaning
of
the
F2a
to
produce
the
F2b
generation.
Pregnant
F1
females
were
allowed
to
litter
and
rear
the
F2a
and
F2b
generations
until
weaning
at
postnatal
day
21.
Doses
for
the
F0
animals
were
0,
3,
5.6,
and
20
and
0,
3.8,
7.5,
and
28.6
mg/
kg­
day
chlorite
for
males
and
females,
respectively.
For
the
F1
animals,
doses
were
0,
2.9,
5.9,
and
22.7
mg/
kg­
day
chlorite
for
the
males
and
0,
3.8,
7.9,
and
28.6
mg/
kg­
day
chlorite
for
the
females.
Body
weight,
food
and
water
consumption,
estrus
cycle
in
the
F0
and
F1
rats,
and
hematology
and
T3
and
T4
levels
in
the
F1
rats
(
blood
samples
collected
from
1
male
and
1
female
from
the
first
20
F1
litters
at
age
25
days
and
another
group
at
13
weeks),
gestation
duration,
litter
size,
pup
sex,
pup
body
weight,
pup
developmental
landmarks,
number
alive/
dead
pups
in
the
F1
and
F2
generations,
total
caudal
sperm
number
and
percent
motile,
morphology
by
computer­
assisted
sperm
motility
analysis
in
the
F0
and
F1
rats,
and
organ
weight
and
histopathology
examination
of
the
brain,
pituitary
gland,
liver,
adrenal
gland,
spleen,
thymus,
kidneys,
and
reproductive
organs
of
all
F0
and
F1
controls
and
high­
dose
animals
were
measured.
An
additional
group
of
F1
pups
was
chosen
for
neurohistopathology
on
postnatal
day
11
(
examination
of
the
brain
and
spinal
cord)
or
postnatal
day
60
(
sensory
ganglia,
dorsal
and
ventral
nerve
roots,
and
several
peripheral
nerves
and
muscles).
Another
group
of
F1
rats
was
examined
for
neurotoxicological
endpoints
(
motor
activity
in
a
­
Figure
8"
Activity
System
and
neuropathology
on
postnatal
day
60,
auditory
startle
in
the
SR­
Screening
System,
learning
and
memory
retention
in
a
water
E­
maze).
A
functional
observational
battery
(
FOB)
was
also
conducted
on
the
pups
undergoing
auditory
and
learning
assessments.
This
group
was
composed
of
2
males
and
2
females
from
20
litters,
and
exposure
was
discontinued
after
weaning.
Reevaluation
of
the
auditory
startle
response
was
conducted
in
20
males
and
20
females
in
the
F2a
and
F2b
generations.

There
were
reductions
in
water
consumption,
food
consumption,
and
body
weight
gain
in
both
sexes
in
all
generations
at
various
times
throughout
the
experiment
(
e.
g.,
during
pre­
mating,
pregnancy,
gestation,
post­
weaning),
primarily
in
the
70
and
300
ppm
groups.
The
authors
attributed
these
reductions
to
lack
of
palatability
of
the
drinking
water
solution,
but
did
not
show
data
to
support
this
contention.
Significant
alterations
related
to
treatment
at
300
ppm
include
reduced
absolute
and
relative
liver
weight
in
F0
females
and
F1
males
and
females,
reduced
pup
survival,
and
reduced
body
weight
at
birth
and
throughout
lactation
in
F1
and
F2
rats,
lower
thymus
and
spleen
weight
in
both
generations,
lowered
incidence
of
pups
exhibiting
normal
righting
reflex
and
with
eyes
open
on
postnatal
day
15,
alteration
in
clinical
condition
in
F2
animals
chosen
for
neurotoxicity,
decrease
in
absolute
brain
weight
for
F1
males
and
F2
females,
delay
in
sexual
development
in
males
(
preputial
separation)
and
females
(
vaginal
opening)
in
F1
and
F2
rats,
and
lower
red
blood
cell
parameters
in
F1
rats.
The
reported
alterations
in
pup
sexual
maturation
measures
might
be
due
to
reduced
pup
body
weight,
but
a
definitive
conclusion
cannot
be
drawn.
In
the
70
ppm
groups,
reduced
absolute
and
relative
liver
weight
in
F0
females
and
F1
males
was
observed.
A
significant
decrease
in
maximum
response
to
an
auditory
startle
stimulus
was
noted
in
the
70
and
300
ppm
groups
on
postnatal
day
24,
but
not
on
postnatal
day
60.
Analysis
of
the
21E­
maze
data
by
EPA
personnel
indicated
possible
alterations
in
learning
behavior
in
the
70
ppm
group,
but
the
differences
from
the
conclusions
of
the
report
could
not
be
resolved.

The
NOAEL
for
this
study
is
35
ppm
(
2.9
mg/
kg­
day
chlorite)
and
the
LOAEL
is
70
ppm
(
5.9
Page
11
of
32
mg/
kg­
day
chlorite)
based
on
lowered
auditory
startle
amplitude
and
altered
liver
weights
in
two
generations.

4.5
Chronic
Toxicity
Adequacy
of
database
for
Chronic
Toxicity:
One
chronic
toxicity
study,
Haag
(
1949)
is
included
in
the
toxicity
database
for
chlorine
dioxide.
The
study
was
limited
because
an
insufficient
number
of
animals
were
tested
per
group,
pathology
was
conducted
on
a
small
number
of
animals,
and
it
did
not
provide
adequate
evaluations
of
more
sensitive
parameters,
which
would
have
been
more
useful
in
the
overall
assessment
of
chronic
toxicity.

870.4100
Chronic
Toxicity
(
Oral)
 
Rat
In
a
chronic
study
by
Haag
(
1949),
groups
of
rats
(
7/
sex/
group)
were
exposed
to
0,
1,
2,
4,
8,
100,
or
1,000
mg/
L
chlorite
in
the
drinking
water
(
0,
0.09,
0.18,
0.35,
0.7,
9.3,
or
81
mg/
kg­
day)
for
2
years.
Animals
exposed
to
chlorite
concentrations
of
100
or
1,000
mg/
L
exhibited
treatment­
related
renal
pathology,
characterized
by
distention
of
the
glomerular
capsule
and
appearance
of
a
pale
pinkish
staining
material
in
the
renal
tubules.
These
effects
were
also
observed
in
a
group
of
animals
administered
sodium
chloride
at
a
concentration
equimolar
to
1,000
mg
sodium
chlorite/
L.
The
study
author
concluded
that
the
renal
pathology
was
a
nonspecific
salt
effect,
but
this
observation
does
not
alter
the
observation
that
concentrations
of
100
mg/
L
or
higher
led
to
adverse
effects.
Based
on
renal
effects,
this
study
identifies
a
NOAEL
of
8
mg/
L
(
0.7
mg/
kg­
day)
and
a
LOAEL
of
100
mg/
L
(
9.3
mg/
kg­
day).

4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
Robinson
et
al.
(
1986)
assessed
the
potential
for
chlorine
dioxide
to
induce
proliferative
epidermal
hyperplasia,
but
these
data
are
considered
inadequate
for
characterizing
the
carcinogenicity
of
chlorine
dioxide/
chlorite.
A
dermal
carcinogenicity
study
(
Kurokawa
et
al.,
1984),
conducted
to
assess
the
ability
of
chlorite
to
act
as
a
complete
carcinogen,
was
considered
inadequate
because
the
exposure
was
for
less
than
a
lifetime,
a
high
incidence
of
Sendai
virus
was
found
in
the
rats,
and
mortality
was
high
in
the
mouse
control
group
because
of
excessive
fighting.
These
data
are
considered
inadequate
to
assess
the
carcinogenicity
of
chlorine
dioxide
/
chlorite
in
humans
and
additional
studies
may
be
required.

870.4200
Carcinogenicity
(
Dermal)
 
Mouse
The
potential
for
chlorine
dioxide
to
induce
proliferative
epidermal
hyperplasia
was
examined
by
Robinson
et
al.
(
1986).
Groups
of
five
dorsally
shaved
female
SENCAR
mice
were
placed
in
chambers
filled
with
0,
1,
10,
100,
300,
or
1,000
ppm
liquid
chlorine
dioxide.
The
animals
were
exposed
10
minutes/
day
for
4
days.
A
significant
increase
in
interfollicular
epidermal
thickness
was
observed
in
the
1,000
ppm
group,
but
not
at
the
lower
concentrations.
Increases
in
total
cell
numbers
and
basal
cell
numbers
in
skin
sections
were
observed
in
both
the
300
and
1,000
ppm
groups.
Page
12
of
32
In
a
follow­
up
study,
groups
of
40
mice
were
immersed
in
0
or
1,000
ppm
chlorine
dioxide
for
10
minutes;
animals
(
5/
group)
were
killed
1,
2,
3,
4,
5,
8,
10,
or
12
days
post­
exposure.
A
significant
increase
in
interfollicular
epidermis
thickness
was
observed
at
all
time
periods,
with
the
highest
values
at
10
and
12
days
post­
exposure.
The
authors
concluded
that
even
short­
term
dermal
exposure
to
high
concentrations
of
chlorine
dioxide
is
capable
of
inducing
hyperplastic
responses
in
the
mouse
skin.

870.4200
Carcinogenicity
 
Rat
and
Mouse
Kurokawa
et
al.
(
1984)
conducted
a
dermal
carcinogenicity
study
to
assess
the
ability
of
chlorite
to
act
as
a
complete
carcinogen.
Groups
of
20
female
SENCAR
mice
were
exposed
twice
weekly
for
51
weeks
to
20
mg/
mL
sodium
chlorite
in
acetone.
The
solution
(
0.2
mL;
100
mg/
kg
sodium
chlorite
per
application)
was
applied
to
the
shaved
backs
of
the
mice.
The
sodium
chlorite
exposure
did
not
result
in
increased
tumor
incidence.

To
test
the
ability
of
chlorite
to
act
as
a
tumor
promoter,
a
single
initiating
dose
of
20

mol
of
dimethylbenzanthracene
(
DMBA)
was
applied
to
the
skin
of
20
SENCAR
mice.
The
DMBA
application
was
followed
by
a
51­
week
exposure
to
sodium
chlorite
(
as
described
for
the
complete
carcinogen
study).
Tumor
incidence
was
6/
20
(
30%)
compared
with
0/
20
in
mice
that
received
DMBA
followed
by
acetone
treatments
for
51
weeks.
Squamous
cell
carcinomas
were
observed
in
5/
20
animals
in
the
chlorite
group.
However,
the
results
were
not
statistically
significant.

4.7
Mutagenicity
Data
on
the
mutagenicity
of
chlorine
dioxide
exist
in
the
open
scientific
literature
as
well
as
within
the
Agency's
database
of
submitted
studies.
The
following
studies
have
been
reviewed
by
the
Agency
and
are
considered
acceptable:

1)
Miller
et
al.
(
1986)
reported
negative
effects
in
Salmonella
strains
TA98
and
TA100
from
a
400­
fold
drinking
water
concentrate
of
chlorine
dioxide
and
positive
effects
in
a
4000­
fold
concentrate
to
strain
TA98
only
in
the
absence
of
metabolic
activation.

2)
In
L5178Y/
TK
cells,
chlorine
dioxide
was
positive
for
forward
mutations
under
nonactivated
conditions
(
dose­
related
from
3.2­
24.3
µ
g/
ml)
and
activation
conditions
(
48.3
µ
g/
mL)
[
Accession
no.
265867].

3)
Chlorine
dioxide
was
positive
for
structural
chromosome
aberrations
under
nonactivated
and
activated
conditions
(
10,
15,
and
50
µ
g/
ml)
[
Accession
no.
265867].

4)
Chlorine
dioxide
was
negative
for
increased
transformed
foci
up
to
cytotoxic
levels
[
Accession
no.
265867].

5)
In
vivo
micronucleus
and
bone
marrow
chromosomal
aberration
assays
in
Swiss
CD­
1
Page
13
of
32
mice
administered
0.1 
0.4
mg
chlorine
dioxide
via
gavage
for
5
consecutive
days
were
negative,
as
was
a
sperm­
head
abnormality
assay
in
B6C3F1
mice
administered
0.1 
0.4
mg
via
gavage
for
5
consecutive
days
(
0,
3.2,
8,
and
16
mg/
kg­
day)
(
Meier
et
al.,
1985).

4.8
Neurotoxicity
Adequacy
of
database
for
Neurotoxicity:
Neurotoxicity
of
chlorine
dioxide
has
been
observed.
In
the
two­
generation
reproduction
toxicity
study
(
CMA
1996),
significant
changes
were
observed
in
maximum
response
in
startle
amplitude
and
absolute
brain
weight
in
F1
rat
pups
at
a
dose
of
3
mg/
kg/
day.
In
the
Orme
et
al.
(
1985)
developmental
toxicity
study,
neurobehavioral
deficits
in
offspring
were
observed
also
at
a
dose
of
14
mg/
kg/
day
administered
to
maternal
rats.

4.9
Metabolism
and
Pharmacokinetics
Adequacy
of
database
for
Metabolism
and
Pharmacokinetics:
Information
regarding
the
pharmacokinetics
of
chlorine
dioxide
and
chlorite
is
predominantly
derived
from
oral
studies
in
laboratory
animals.
Chlorite
(
ClO2­)
does
not
persist
in
the
atmosphere
either
in
ionic
form
or
as
chlorite
salt.
The
rapid
appearance
of
36Cl
in
plasma
following
oral
administration
of
chlorine
dioxide
(
36ClO2)
or
chlorite
(
36ClO2­)
has
been
shown
in
laboratory
animals
(
Abdel­
Rahman
et
al.,
1984).
In
rats,
absorbed
36Cl
(
from
36ClO2
or
36ClO2
sources)
is
slowly
cleared
from
the
blood
and
is
widely
distributed
throughout
the
body
(
Abdel­
Rahman
et
al.,
1984).
Chlorine
dioxide
rapidly
dissociates,
predominantly
into
chlorite
(
which
itself
is
highly
reactive)
and
chloride
ion
(
Cl­),
ultimately
the
major
metabolite
of
both
chlorine
dioxide
and
chlorite
in
biological
systems
(
Abdel­
Rahman
et
al.,
1984).
Urine
is
the
primary
route
of
elimination,
predominantly
in
the
form
of
chloride
ion
(
Abdel­
Rahman
et
al.,
1984).
Additional
pharmacokinetic
studies
of
chlorine
dioxide
and
chlorite
should
be
designed
to
examine
mechanisms
of
absorption
and
metabolic
changes
that
might
account
for
observed
neurodevelopment
effects.

4.10
Inhalation
Exposure
An
inhalation
risk
assessment
is
required
for
chlorine
dioxide
for
three
scenarios
involving
antimicrobial
uses
of
chlorine
dioxide.
Occupational
exposures
to
chlorine
dioxide
gas
are
expected
to
cover
a
typical
work
day/
work
week
(
8
hours/
day,
5
days/
week)
over
several
years
of
exposure.
There
are
also
two
homeowner
exposure
scenarios
for
chlorine
dioxide.
One
scenario
involves
one­
time
exposures
through
use
of
chlorine
dioxide
in
homes
involving
the
cleaning
of
HVAC
systems,
floors,
carpets,
etc.,
and
is
considered
short­
term
exposure,
while
the
other
exposure
scenario
involves
a
long­
term
exposure
from
the
proposed
use
of
chlorine
dioxide
in
continuous
release
products.
There
is
no
exposure
scenario
considered
as
intermediate­
term
in
the
current
inhalation
assessment.

For
these
assessments,
the
following
inhalation
toxicity
data
on
chlorine
dioxide
is
cited:

Dalhamn,
T.
(
1957):
Chlorine
Dioxide:
Toxicity
in
Animal
Experiments
and
Industrial
Risks.
Arch.
Page
14
of
32
Ind.
Health
15:
101­
107.

Paulet
G,
Desbrousses
S.
1970.
On
the
action
of
ClO2
at
low
concentrations
on
laboratory
animals.
Arch
Mal
Prof
31:
97­
106.

Paulet
G,
Desbrousses
S.
1972.
On
the
toxicology
of
chlorine
dioxide.
Arch
Mal
Prof
33:
59­
61.

Paulet
G,
Desbrousses
S.
1974.
Action
of
a
discontinuous
exposure
to
chlorine
dioxide
(
ClO2)
on
the
rat.
Arch
Mal
Prof
35:
797­
804.

Dalhamn
(
1957)
reported
the
results
of
several
inhalation
studies
in
laboratory
animals.
In
one
study,
a
single
2­
hour
inhalation
exposure
of
four
rats
to
a
chlorine
dioxide
concentration
of
260
ppm
(
728
mg/
m3)
resulted
in
pulmonary
edema
and
nasal
bleeding.
In
a
second
study,
respiratory
distress
was
reported
in
three
other
rats
subjected
to
3
weekly
3­
minute
exposures
to
decreasing
concentrations
of
airborne
chlorine
dioxide
from
3,400
to
800
ppm
(
from
9,520
to
2,240
mg/
m3);
bronchopneumonia
was
observed
in
two
of
these
rats.
In
a
third
rat
study,
repeated
exposure
to
approximately
10
ppm
(
28
mg/
m3)
of
chlorine
dioxide
(
4
hours/
day
for
9
days
in
a
13­
day
period)
resulted
in
rhinorrhea,
altered
respiration,
and
respiratory
infection.
In
a
fourth
study,
no
indications
of
adverse
effects
were
seen
in
rats
exposed
to
the
NOAEL
of
approximately
0.1
ppm
(
0.28
mg/
m3)
of
chlorine
dioxide
5
hours
/
day
for
10
weeks.

Paulet
and
Desbrousses
(
1970,
1972,1974)
conducted
a
series
of
studies
in
which
laboratory
animals
were
exposed
to
atmospheres
of
chlorine
dioxide.
Nasal
discharge
and
localized
bronchopneumonia
(
with
desquamation
of
alveolar
epithelium)
were
noted
in
rats
exposed
to
an
airborne
concentration
of
10
ppm
(
28
mg/
m3),
2
hours/
day
for
30
days.
Another
group
of
rats
exposed
to
a
concentration
of
5
ppm
(
14
mg/
m3)
exhibited
similar,
but
less
severe,
respiratory
tract
effects.
Bronchial
inflammation
and
alveolar
congestion
and
hemorrhage
were
observed
in
rats
exposed
to
2.5
ppm
(
7
mg/
m3),
7
hours/
day
for
30
days.
Alveolar
congestion
and
hemorrhage
were
also
seen
in
rabbits
following
inhalation
exposure
to
2.5
ppm
(
7
mg/
m3),
4
hours/
day
for
45
days.
In
a
group
of
rats
and
rabbits
sacrificed
15
days
after
exposure
termination,
recovery
from
the
pulmonary
lesions
was
apparent
(
Paulet
and
Desbrousses
1970).
Vascular
congestion
and
peribronchiolar
edema
were
noted
in
the
lungs
of
rats
exposed
to
a
concentration
of
1
ppm
(
2.8
mg/
m3),
5
hours/
day,
5
days/
week
for
2
months
(
Paulet
and
Desbrousses
1972).
A
LOAEL
of
1
ppm
(
2.8
mg/
m3)
for
respiratory
effects
was
identified
in
this
study.

LOAEL
and
NOAEL
values
were
not
always
available
from
the
above
studies
for
each
experimental
duration
studied.
Ideally,
each
inhalation
exposure
scenario
of
concern
(
i.
e.,
shortterm
intermediate­
term,
and
long­
term)
for
chlorine
dioxide
would
be
represented
in
the
database,
or,
a
single
value
of
sufficient
duration
would
cover
short­
term
and
longer­
term
inhalation
exposures.
However,
the
inhalation
data
for
chlorine
dioxide
does
not
contain
all
of
this
information.
Therefore,
the
HIARC
and
ADTC
selected
values
felt
to
best
represent
the
exposure
scenarios
of
interest.

The
scenarios
of
interest
include
occupational
exposure
(
typical
8
hour
workday
five
days
per
Page
15
of
32
week),
short­
term
homeowner
exposure
(
essentially
a
single
exposure
in
this
case),
and
long­
term
homeowner
exposure.
From
the
available
data,
a
LOAEL
value
of
10
ppm
(
28
mg/
m3)
was
chosen
from
the
Dalhamn
study
for
short­
term
homeowner
exposures;
for
occupational
exposures,
a
LOAEL
of
1.0
ppm
(
2.8
mg/
m3)
is
identified
from
the
Paulet
and
Desbrousses
study
and
a
NOAEL
of
0.1
ppm
(
0.28
mg/
m3)
is
identified
from
the
Dalhamn
study.
The
unit
conversion
for
chlorine
dioxide
is:
1
ppm
ClO2
x
67.46/
24.45
=
2.8
mg/
m3
As
shown
below
for
each
exposure
scenario
of
interest,
the
NOAEL
and
LOAEL
values
from
the
available
animal
data
are
used
to
derive
human
equivalent
concentrations
using
the
Agency's
RfC
guidance
(
USEPA,
1994:
Methods
for
Derivation
of
Inhalation
Reference
Concentrations
and
Application
of
Inhalation
Dosimetry.
Office
of
Research
and
Development,
publication
#
EPA/
600/
8­
90/
066F)
and
the
Agency's
updated
Toxicological
Profile
for
Chlorine
Dioxide
and
Chlorite
(
USEPA,
2000;
available
at
www.
epa.
gov/
iris/
toxreviews/
0496­
tr.
pdf
).
Derivation
of
human
equivalent
concentrations
reduces
the
magnitude
of
uncertainty
and
also
provides
a
more
direct
comparison
with
estimated
human
exposures
for
calculation
of
inhalation
risk.
The
steps
taken
in
this
process
are
detailed
within
the
report
of
the
HIARC
and
ADTC
committees,
dated
April
20,
2005.

5.0
Toxicity
Endpoint
Selection
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
2.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
100%

Based
on
the
lack
of
dermal
absorption
data,
a
default
value
of
100%
will
be
used
for
dermal
risk
assessments
for
those
applications
involving
use
of
aqueous
solution
of
chlorine
dioxide/
chlorite.

5.3
Classification
of
Carcinogenic
Potential
Chlorine
dioxide
has
not
been
formally
assessed
for
carcinogenic
potential.
One
subchronic
study
(
Daniel
et
al.,
1990)
examined
the
effects
of
administration
of
chlorine
dioxide
to
groups
of
male
and
female
Sprague­
Dawley
rats
(
10/
sex/
dose)
at
dose
levels
of
0,
25,
50,
100,
or
200
mg/
L
for
90
days
in
drinking
water.
A
significant
increase
in
the
incidence
of
nasal
lesions
(
goblet
cell
hyperplasia
and
inflammation
of
nasal
turbinates)
was
found
at
all
dose
levels
tested.
The
significance
of
these
findings
is
uncertain
as
they
have
not
been
observed
in
other
long­
term
studies
of
chlorine
dioxide.

The
potential
for
chlorine
dioxide
to
induce
proliferative
epidermal
hyperplasia
was
examined
by
Robinson
et
al.
(
1986).
Groups
of
five
dorsally
shaved
female
SENCAR
mice
were
placed
in
chambers
filled
with
0,
1,
10,
100,
300,
or
1,000
ppm
liquid
chlorine
dioxide;
the
chambers
were
designed
to
prevent
the
head
from
getting
wet
and
to
prevent
inhalation
of
vapors.
The
animals
were
exposed
10
minutes/
day
for
4
days.
A
significant
increase
in
interfollicular
epidermal
Page
16
of
32
thickness
was
observed
in
the
1,000
ppm
group,
but
not
at
the
lower
concentrations.
Increases
in
total
cell
numbers
and
basal
cell
numbers
in
skin
sections
were
observed
in
both
the
300
and
1,000
ppm
groups.
In
a
second
study,
dermal
immersion
of
40
dorsally
shaved
female
SENCAR
mice
in
an
aqueous
solution
of
chlorine
dioxide
at
a
concentration
of
1000
mg/
L
for
a
10­
minute
period,
with
subsequent
sacrifice
of
5
mice
per
day
on
days
1,
2,
3,
4,
5,
8,
10,
or
12
showed
an
increase
in
the
thickness
of
the
interfollicular
epidermis.
This
increase
was
apparent
within
24
hours
and
persisted
over
the
12­
day
period.
Highest
values
for
the
increase
in
skin
thickness
were
observed
on
days
10
and
12.
The
authors
concluded
that
even
short­
term
dermal
exposure
to
high
concentrations
of
chlorine
dioxide
is
capable
of
inducing
hyperplastic
responses
in
the
mouse
skin.

Miller
et
al.
(
1986)
tested
the
carcinogenic
potential
of
drinking
water
disinfected
with
chlorine
dioxide
using
three
short­
term
assays.
Following
disinfection
with
chlorine
dioxide,
the
water
samples
(
containing
0.5
mg/
L
chlorine
dioxide
residue)
were
concentrated
2,000H
or
4,000H
using
a
macroreticular
resin
process.
In
a
mouse
initiation­
promotion
assay,
groups
of
14 
34
SENCAR
mice
(
sex
not
specified)
were
orally
administered
0.5
mL
of
the
4000H
concentrate
in
2%
emulphor
3
times/
week
for
2
weeks
followed
by
topical
exposure
to
1.0
:
g
12­
tetradecanylphorbal­
13­
acetate
(
TPA)
in
acetone
applied
to
the
dorsal
skin
3
times/
week
for
20
weeks
and
then
sacrificed.
No
significant
increases,
compared
with
vehicle
controls,
in
the
number
of
skin
tumors
or
the
number
of
tumors
per
animal
were
observed.

In
a
lung
adenoma
assay
(
Miller
et
al.,
1986),
groups
of
20
male
and
20
female
Strain
A
mice
received
0.25
mL
gavage
doses
of
2000H
or
4000H
concentrates
in
2%
emulphor
3
times/
week
for
8
weeks
followed
by
a
16­
week
observation
period.
The
number
of
animals
with
lung
adenomas
and
the
number
of
adenomas
per
animal
were
not
significantly
altered
compared
with
vehicle
controls.

Miller
et
al.
(
1986)
also
examined
the
development
of
liver
foci
in
rats
in
a
short­
term
assay.
In
this
study,
groups
of
partially
hepatectomized
rats
received
a
single
dose
of
concentrated
water
(
chlorine
dioxide
concentration
not
reported)
in
2%
emulphor
followed
1
week
later
by
administration
of
500
ppm
sodium
phenobarbital
in
drinking
water
for
56
days;
animals
were
sacrificed
on
day
70.
A
control
group
received
nondisinfected
water.
No
significant
increases
in
incidence
of
gamma­
glutamyltranspeptidase
foci
were
observed.

In
Kurokawa
et
al.
(
1984)
chlorite
was
not
shown
to
increase
tumor
incidences
in
rats
and
mice;
these
studies
are
considered
inadequate
for
assessing
human
carcinogenicity
because
the
exposure
was
for
less
than
a
lifetime,
a
high
incidence
of
Sendai
virus
was
found
in
the
rats,
and
mortality
was
high
in
the
mouse
control
group
because
of
excessive
fighting.

These
data
do
not
definitively
characterize
the
carcinogenicity
of
chlorine
dioxide
or
chlorite,
and
additional
studies
may
be
required.

6.0
FQPA
Considerations
6.1
Developmental
Toxicity
Study
Conclusions
Page
17
of
32
Increased
susceptibility
to
effects
of
chlorine
dioxide
have
been
observed
in
the
two­
generation
reproduction
toxicity
study
in
rats
(
CMA,
1996)
as
well
as
from
the
Orme
et
al.
(
1985)
study.
In
the
two­
generation
reproduction
toxicity
study,
significant
changes
were
observed
in
maximum
response
in
startle
amplitude
and
absolute
brain
weight
in
F1
rat
pups
at
a
dose
of
3
mg/
kg/
day.
In
the
Orme
et
al.
developmental
toxicity
study,
neurobehavioral
deficits
in
offspring
were
observed
also
at
a
dose
of
14
mg/
kg/
day
administered
to
maternal
rats.
These
deficits
in
pups
were
observed
in
the
absence
of
significant
maternal
toxicity.

A
developmental
toxicity
study
in
rabbits
(
Harrington
et
al.,
1995)
showed
no
evidence
of
increased
susceptibility
when
chlorite
was
administered
to
mated
female
New
Zealand
White
rabbits
at
dose
levels
of
0,
200,
600,
or
1200
ppm
in
drinking
water.

6.2
Reproductive
Toxicity
Study
Conclusions
There
was
no
evidence
of
a
primary
effect
of
reproduction
based
on
the
available
data
for
chlorine
dioxide.

6.3
Information
from
Literature
Sources
The
Office
of
Pesticide
Programs
has
also
decided
to
rely
upon
available
published
data
to
characterize
the
hazard
of
chlorine
dioxide,
as
the
data
are
from
peer­
reviewed
journals
and
also
are
consistent
with
regard
to
the
effect
levels
observed
and
the
type(
s)
of
toxicity
observed.
These
data
include
the
IRIS
Toxicological
Review
of
Chlorine
dioxide
and
Chlorite
(
EPA,
2002),
Toxicological
Profile
for
Chlorine
dioxide
(
ATSDR,
2004),
The
US
EPA
National
Primary
Drinking
Water
Regulations
(
EPA,
1998),
and
the
US
EPA
Office
of
Water
drinking
Water
Health
Advisory
for
Chlorine
dioxide,
Chlorite,
and
Chlorate
(
EPA
1996).

6.4
Pre­
and/
or
Postnatal
Toxicity
A.
Determination
of
Susceptibility
Developmental
delays
have
been
observed
in
animal
studies
following
in
utero
and
postnatal
exposure
to
ingested
chlorine
dioxide
or
chlorite,
suggesting
that
infants
and
children
may
be
more
likely
than
adults
to
experience
adverse
effects
following
exposure
to
these
chemicals,
although
the
reasons
for
this
increased
sensitivity
are
not
fully
understood.
It
is
well
recognized
that
neurological
development
continues
after
birth
and
that
gastrointestinal
uptake
of
many
nutrients
and
chemicals
is
greater
in
the
neonate
than
the
adult.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
At
the
time
of
the
original
toxicity
endpoint
assessment,
the
HIARC
concluded
that
an
extra
10x
uncertainty
factor
under
the
Food
Quality
Protection
Act
should
be
considered
in
risk
assessments
conducted
for
chlorine
dioxide.
This
recommendation
was
based
upon
evidence
of
susceptibility
in
a
two­
generation
reproduction
toxicity
study
in
rats
and
evidence
of
susceptibility
from
Page
18
of
32
scientific
literature
reports.

Since
the
time
of
this
1999
recommendation,
policy
guidance
was
issued
in
September
of
2001
through
the
Health
Effects
Division,
Office
of
Pesticide
Programs
regarding
the
determination
of
the
appropriate
FQPA
safety
factor
in
tolerance
assessment.
This
guidance
states
that
whereas
in
the
past
"...
OPP
has
routinely
applied
an
additional
FQPA
safety
factor
where
data
on
a
pesticide
shows
increased
susceptibility
or
sensitivity
(
either
qualitative
or
quantitative)
in
the
developing
organism,"
It
is
now
the
intent
that
"...
OPP
will
now
put
greater
emphasis
on
analyzing
the
degree
of
concern
and,
rather
than
apply
an
additional
safety
factor
based
solely
on
the
identification
of
heightened
sensitivity
or
susceptibility,
will
conduct
a
case­
by­
case
weight
of
evidence
approach
that
qualitatively
examines
the
level
of
concern
for
sensitivity
/
susceptibility
and
assess
whether
traditional
uncertainty
factors
already
incorporated
into
the
risk
assessment
are
adequate
to
protect
the
safety
of
infants
and
children.
Using
this
approach,
in
many
cases
the
concerns
regarding
pre­
and
postnatal
toxicity
can
be
addressed
when
a
Reference
Dose
(
RfD)
or
Margin
of
Exposure
(
MOE)
is
based
on
the
pre­
or
postnatal
endpoints
in
the
offspring."

C.
Proposed
Hazard­
based
Special
FQPA
Safety
Factor(
s):

In
the
case
of
chlorine
dioxide,
the
endpoint
selected
for
both
dietary
and
non­
dietary
exposures
was
based
upon
adverse
effects
observed
in
offspring
from
developmental
and
reproductive
toxicity
data.
Consistent
with
the
approach
used
by
the
EPA's
Office
of
Water
for
use
of
chlorine
dioxide
as
a
drinking
water
disinfectant
(
Federal
Register
Vol.
63,
No.
61,
pages
15673­
15692,
March
31,
1998)
and
the
updated
guidance
on
selection
of
a
safety
factor
under
FQPA,
the
endpoint
selected
for
assessment
of
risk
from
dietary
and
non­
dietary
exposure
to
chlorine
dioxide
is
felt
to
be
protective
of
potentially
susceptible
populations
including
children,
based
upon
the
selection
of
an
endpoint
and
effects
observed
in
offspring
and
the
use
of
an
NOAEL
value
based
on
those
effects.
Therefore
it
can
be
concluded
that
an
additional
safety
factor
under
FQPA
is
not
necessary
in
this
case
and
that
the
traditional
uncertainty
factor
(
MOE)
of
100
for
intraspecies
and
interspecies
variation
will
support
the
safety
standard
of
`
reasonable
certainty
of
no
harm'
as
required
by
the
FQPA
statute
for
food­
use
pesticides.

6.5
Recommendation
for
a
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
is
not
recommended,
based
upon
the
examination
of
these
endpoints
in
the
two­
generation
reproduction
toxicity
study
submitted
by
the
Chemical
Manufacturers
Association
(
1996)
and
the
use
of
these
data
in
support
of
the
toxicity
endpoints
selected
for
chlorine
dioxide.

7.0
Summary
of
Toxicological
Doses
and
Endpoints
for
Chlorine
dioxide/
sodium
chlorite
for
Use
in
Human
Risk
Assessment
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
(
Table
2)
Page
19
of
32
Table
2:
Summary
of
Toxicological
Doses
and
Endpoint
Selection
for
Chlorine
dioxide/
sodium
chlorite
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
UF/
MOE
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
An
acute
dietary
endpoint
was
not
identified
in
the
database
for
chlorine
dioxide.
This
risk
assessment
is
not
required.

Chronic
Dietary
NOAEL
=
3
mg/
kg/
day
UF
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

Chronic
PAD
=
0.03
mg/
kg/
day
Two­
generation
reproduction
toxicity
study
(
CMA,
1996)
­
decreases
in
absolute
brain
and
liver
weight,
and
lowered
auditory
startle
amplitude
at
LOAEL
of
6
mg/
kg/
day
Developmental
Toxicity
­
Rat
(
Orme
et
al.,
1985)­
neurobehavioral
and
exploratory
deficits
in
rat
pups
at
LOAEL
of
14
mg/
kg/
day
Incidental
Oral
(
short­
and
intermediate­
term)
NOAEL
=
3
mg/
kg/
day
MOE
=
100
See
summary
for
dietary
assessment
Short­
Term
Dermala
(
1­
30
days)
NOAEL
=
3
mg/
kg/
day
MOE
=
100
See
summary
for
dietary
assessment
Intermediate­
Term
Dermala
(
30­
days­
6
months)
NOAEL
=
3
mg/
kg/
day
MOE
=
100
See
summary
for
dietary
assessment
Long­
Term
Dermala
(
>
6
months)
NOAEL
=
3
mg/
kg/
day
MOE
=
100
See
summary
for
dietary
assessment
Inhalation
(
occupational
and
homeowner
shortterm
See
text
for
explanation
of
NOAEL/
LOAEL
values
chosen
Occupational
`
RfC'
=
0.009
mg/
m3
(
0.003
ppm)
b
Homeowner
short­
term
`
RfC'
=
0.14
mg/
m3
(
0.05
ppm)
b
Inhalation
toxicity
studies­
Rat
homeowner
short­
term:
Dalhamn,
1957
[
LOAEL
of
28
mg/
m3
(
10
ppm)]

occupational
exposure:
Paulet
and
Debrousses,
1970,
1972
using
LOAEL
of
1.0
ppm
(
2.8
mg/
m3);
Dalhamn,
1957
using
NOAEL
of
0.1
ppm
(
0.28
mg/
m3).
Inhalation
(
homeowner
longterm
Agency
RfC
methodology
used
to
derive
an
RfC
value
of
2
x
10­
4
mg/
m3
(
USEPA,
2000)
(
Paulet
and
Desbrousses,
1970,
1972)
selected
as
cocritical
studies
(
USEPA,
2000)

a
Based
on
the
use
of
an
oral
endpoint
for
dermal
risk
assessments
and
the
lack
of
a
dermal
absorption
study,
a
dermal
absorption
value
of
100%
as
a
default
will
be
used.
b
unit
conversion:
1
ppm
ClO2
x
67.46/
24.45
=
2.8
mg/
m3
8.0
Toxicity
Profile
Tables
8.1
Acute
Toxicity
Profile
Table
(
Table
3).
Page
20
of
32
Table
3.
Acute
Toxicity
Profile
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
Chlorine
dioxide
­
Oxine
(
purity
not
reported)
MRID
41919701
Unacceptable
0,
2720,
3340,
4110,
or
5050
mL/
kg
(
assume
100%,
thus
0,
2720,
3340,
4110,
or
5050
mg/
kg)
administered
via
intubation
Rats
(
5/
sex/
dose)
Toxicity
Category
III
LD50
=
4560
mg/
kg
(
males)
=
4150
mg/
kg
(
females)

There
were
no
deaths
in
males
or
females
at
the
two
lowest
doses
(
2720
and
3340
mg/
kg).
At
4110
mg/
kg,
there
were
three
female
deaths
during
the
first
day
and
one
male
death
on
day
2.
At
the
high
dose
(
5050
mg/
kg),
there
were
4
male
deaths
and
3
female
deaths.

Effects
observed
include
GI
distress,
nosebleed,
dark
urine,
polyuria,
or
cyanosis.
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
Chlorine
dioxide
purity
 
79%
a.
i.
MRID
43558601
Acceptable
0,
18.0,
40.9,
149.4,
180.0,
or
225.0
mg/
kg
(
males)
and
0,
25.0,
56.8,
207.5,
250.0,
or
312.5
mg/
kg
(
females)
administered
via
gavage
Rats
(
6/
sex/
dose)
Toxicity
Category
II
LD50
=
292
mg/
kg
(
males)
=
340
mg/
kg
(
females)

Toxic
signs
first
appeared
2­
4
hours
after
dosing
in
Dose­
Group
3
females
(
207.5
mg/
kg)
and
Group
4
males
(
180
mg/
kg),
as
decreased
activity,
with
increasing
severity
at
higher
doses.
These
signs
were
accompanied
by
rapid/
labored
breathing,
abdominal
respiration,
depilation,
and
weight
loss,
leading
to
death
at
the
highest
dosages
in
both
sexes.
Post­
mortem
examination
of
animals
revealed
hyperemic
internal
organs
(
liver,
spleen,
kidney,
lung).
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
Chlorine
dioxide
purity
 
2%
a.
i.
MRID
43441901
Acceptable
0,
2000,
4000,
5050,
or
5500
administered
via
intubation
Rats
(
5/
sex/
dose)
Toxicity
Category
III
LD50
=
3455
mg/
kg
(
males)
=
2773
mg/
kg
(
females)
=
3084
mg/
kg
(
combined)

Clinical
signs
of
toxicity
preceding
death
included
piloerection,
diarrhea,
polyuria,
ptosis,
lacrimation,
decreased
activity,
nasal
and
ocular
discharge,
salivation,
whole
body
tremors,
emaciation,
blanching,
corneal
opacity,
dehydration,
prolapsed
penis,
crusted
eyes/
nose/
mouth,
discolored
fur,
pale
mucous
membranes,
necrotic
tails,
and
general
cachexia.
Body
weight
in
survivors
appeared
unaffected,
but
those
that
died
lost
between
25
and
35
g
prior
to
death.
Gross
necropsy
examinations
revealed
signs
of
chromodacryorrhea;
discolorations
of
thymus,
lungs,
pancreas,
lymph
nodes,
fatty
tissues,
mesentery,
kidneys,
and
urine;
discoloration
of
the
contents
of
the
stomach,
bladder,
small
intestine,
and
pleural
cavity;
GI
tract
distended
with
"
gas;"
swollen/
undersized
lungs;
discolored/
enlarged
heart;
and
constricted
blood
vessels.
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
Chlorine
dioxide
purity
 
5%
a.
i.
Accession
40168701
MRID
Supplemental
Doses
not
reported.
Toxicity
Category
III
LD50
=
1550
mg/
kg
870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rabbits
Chlorine
dioxide
­
Oxine
(
purity
not
reported)
MRID
41919702
Unacceptable
0
or
1.91
mL/
kg
(
assume
100%,
thus
0
or
2020
mg/
kg)

Rabbits
(
5/
sex/
dose)
Toxicity
Category
III
LD50>
2020
mg/
kg
No
animals
died,
and
all
survived
to
termination
in
apparently
normal
health.
Page
21
of
32
Table
3.
Acute
Toxicity
Profile
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rabbits
Sodium
chlorite
 
80%
a.
i.,
Lot
#
220984­
15
Accession
40168704
MRID
Core
minimum
Aqueous
paste
containing
2
g/
kg
sodium
chlorite
Rabbits
(
5/
sex)
Toxicity
Category
III
LD50>
2000
mg/
kg
No
animals
died,
and
no
adverse
clinical
effects
were
noted
during
the
observation
period.
Body
weight
gain
was
normal
for
both
sexes
(
6.7%
for
males,
5.9%
for
females),
and
no
pathological
changes
were
attributed
to
the
test
compound.
870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rabbits
Chlorine
dioxide
 
Oxine
(
2%
a.
i.)
MRID
43441902
Acceptable
0
or
2020
mg/
kg,
applied
to
at
least
10%
of
body
surface
Rabbits
(
5/
sex)
Toxicity
Category
III
LD50>
2020
mg/
kg
No
animals
died.
Occasional
evidence
of
decreased
defacation
and/
or
diarrhea,
or
nasal
discharge
in
one
or
two
animals,
was
manifest
during
the
14­
day
study
period.
One
male
displayed
discolored
stomach
contents,
with
the
stomach,
cecum,
and
rectum
distended
with
gas;
two
females
showed
discolored
(
gray)
edges
of
several
lung
lobes.

Dermal
irritation
was
minimal,
and
included
Grades
1
to
2
erythema
and/
or
edema
or
desquamation,
but
no
undue
thickening
or
fissuring.
None
of
these
skin
effects
persisted
to
Day
14.
870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Chlorine
dioxide
­
Oxine
(
purity
not
reported)
MRID
41919703
Unacceptable
Rats
were
exposed
to
0,
4.54,
or
5.75
mg/
L
for
4
hours.

Rats
(
5/
sex/
dose)
Toxicity
Category
IV
LC50
>
5.75
mg/
L
(
highest
dose
tested)

There
were
no
deaths.
Gross
necropsy
revealed
no
observable
abnormalities
at
either
concentration.

870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Chlorine
dioxide
­
purity
not
reported
Accession
40168707
MRID
Core­
supplemental
Rats
were
exposed
to
0,
1.51
or
2.80
mg/
L
for
1
hour.

Rats
(
5/
sex/
dose)
Toxicity
Category
III
LC50
>
2.8
mg/
L
(
1­
hour)

No
animals
died
and
no
clinical
signs
of
irritation
were
evident
in
either
test
group.
Body
organs
appeared
to
be
grossly
normal,
and
weights
of
heart,
liver,
and
kidneys
were
within
normal
ranges
for
this
strain.

Testing
guideline
criteria
not
met
include:
1.
Only
1­
hour
exposure;
4
hours
required.
2.
Exposure
chamber
inadequately
described.
Particle
sizing
is
not
reported.
4.
Concentrations
too
low
to
determine
LC50.
5.
Only
nominal
concentrations
were
reported.
870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Chlorine
dioxide
 
100%
a.
i.
MRID
43558602
Unacceptable
Rats
were
exposed
to
260
ppm
(
0.72
mg/
L)
for
4
hours.

4
rats
One
of
the
four
treated
rats
died
during
the
first
hour
of
exposure,
and
all
four
rats
displayed
ocular
discharges
and
epistaxis
(
nosebleed).
The
three
survivors
were
sacrificed
immediately
after
termination
of
the
two­
hour
exposure,
and
presented
evidence
of
pulmonary
edema,
and
"
circulatory
engorgement."
Page
22
of
32
Table
3.
Acute
Toxicity
Profile
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Sodium
chlorite
 
80.6%
a.
i.
MRID
42484101
Core
Minimum
Rats
were
exposed
to
0,
0.29,
0.30,
0.35,
0.7,
or
1.6
mg/
L
for
4
hours.

Rats
(
5/
sex/
dose)
Toxicity
Category
II
LC50
=
0.29
mg/
L
(
4­
hour)

Death
before
termination
of
the
study
occurred
in
all
groups
except
in
the
0.3
mg/
L
group,
usually
within
2
to
6
days
of
exposure,
preceded
by
labored
respiration
and
lethargy
and/
or
ataxia.
Survivors
to
14
days
lost
weight
during
the
first
post­
exposure
week,
but
partially
regained
it
during
the
second
week
(
although
mean
weights
remained
markedly
depressed).

In
contrast
to
grossly
normal
internal
organs
in
the
0.3
mg/
L
animals,
a
number
of
rats
in
the
other
test
groups
exhibited
either
congestion
or
discoloration
of
the
lungs.
870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
Chlorine
dioxide
­
Oxine
(
purity
not
reported)
MRID
41919704
Unacceptable
Rabbits
were
exposed
to
0.1
mL
of
undiluted
test
article
instilled
directly
into
conjunctival
sac
of
left
eye
(
right
as
control).
Eyes
in
3/
9
animals
were
washed
with
water.

Rabbits
(
3/
sex/
dose)
Toxicity
Category
III
The
maximum
average
irritation
score
(
PIS)
24
hours
after
treatment
was
4.3
for
non­
washed
eyes
and
5.3
for
washed
eyes.
These
scores
correspond
to
"
minimally
irritating"
and
"
mildly
irritating."

Since
conjunctival
irritation
was
cleared
by
Day
7,
oxine
is
assigned
a
Tox
III.

870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
Chlorine
dioxide
­
Oxine
(
2%
a.
i.)
MRID
43441903
Acceptable
Rabbits
were
exposed
to
0.1
mL
of
undiluted
test
article
instilled
directly
into
conjunctival
sac
of
left
eye
(
right
as
control).
Eyes
in
3
males
were
washed
with
water.

Rabbits
(
6
males,
3
females)
Toxicity
Category
III
PIS
=
7.0
(
unwashed
at
24
hours)
=
4.0
(
unwashed
at
1
hour)

Neither
the
washed
nor
the
unwashed
eyes
stained
positive
for
fluorescein.
All
effects
cleared
by
Day
4.
Test
substance
is
considered
"
mildly
irritating."

870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
Chlorine
dioxide
 
5%
a.
i.
Accession
40168705
MRID
Supplemental
Unspecified
amount
of
test
substance
instilled
into
the
eye.

2
rabbits
Toxicity
Category
III
Test
substance
is
a
mild
ocular
irritant,
producing
mild
conjunctivitis
lasting
for
2
days
(
completely
resolved
by
Day
3).

870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
Chlorine
dioxide
 
Oxine
(
purity
not
reported)
MRID
41919705
Unacceptable
0.5
mL
undiluted
test
material;
wrappings
were
removed
and
test
sites
were
washed
with
tap
water
after
4
hours.

Rabbits
(
3/
sex)
Toxicity
Category
IV
Irritation
scores
ranged
from
0.3
observed
90
minutes
after
washing)
to
0.2
at
24
hours.
No
irritation
(
0.0)
was
encountered
at
48
and
72
hours.
The
test
article
is
classified
as
"
practically
not
an
irritant."

870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
Sodium
chlorite
 
80%
a.
i.,
Lot
#
220984­
15
Accession
40168704
MRID
Core
minimum
Aqueous
paste
containing
2
g/
kg
sodium
chlorite
Rabbits
(
5/
sex)
Toxicity
Category
II
Draize
primary
irritation
score
(
PIS)
 
7.3,
thus
sodium
chlorite
is
considered
a
primary
skin
irritant.
Page
23
of
32
Table
3.
Acute
Toxicity
Profile
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
Chlorine
dioxide
 
5%
Accession
40168706
MRID
Core
minimum
Unspecified
amount
of
test
material
applied
to
four
areas
of
skin
in
2
animals.

Rabbits
(
2
animals,
sex
not
specified)
Toxicity
Category
IV
No
dermal
irritation
reported.

870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
Chlorine
dioxide
 
Duozon
100­
L
(
0.3
ppm
a.
i.)
MRID
43503201
Acceptable
0.5
mL
of
0.3
ppm,
covered.
After
4
hours,
dressing
and
residual
material
removed.

3
Rabbits
Toxicity
Category
IV
All
indices
of
irritation
were
zero;
PII
score
was
0.0
for
all
time
periods
up
to
7
days.
This
formulation
is
considered
non­
irritating.

8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
4)

Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
(
§
82­
1)
90­
Day
Oral
(
Drinking
water)
 
Rat
Chlorine
Dioxide
purity
not
reported
Daniel,
et
al.
1990
0,
25,
50,
100,
or
200,
mg/
L
(
Male:
0,
2,
4,
6,
or
12
mg/
kg/
day)
(
Female:
0,
2,
5,
8,
or
15
mg/
kg/
day)
NOAEL
<
2
mg/
kg/
day
(
lowest
dose
tested)
LOAEL
=
2
mg/
kg/
day,
based
on
nasal
lesions,
and
organ
weight
decrease
(
spleen
and
liver)

No
exposure­
related
deaths
were
reported.
Exposure
to
200
mg/
L
resulted
in
significant
reductions
in
terminal
body
weights
and
body
weight
gain.
Significant
reductions
in
water
consumption
were
observed
in
the
males
and
females
exposed
to
 
50
mg/
L
and
 
25
mg/
L,
respectively.
Absolute
liver
weights
were
decreased
in
males
at
 
50
mg/
L.
Absolute
spleen
weights
were
decreased
in
females
at
 
25
mg/
L.
Serum
lactate
dehydrogenase
and
aspartate
aminotransferase
levels
were
decreased
and
serum
creatinine
levels
were
increased
in
the
males
exposed
to
 
100
mg/
L.
A
significant
increase
in
incidence
of
nasal
lesions
was
found
in
males
exposed
to
 
25
mg/
L
and
in
females
at
 
100
mg/
L.
These
lesions
may
be
a
result
of
rats
inhaling
chlorine
dioxide
vapors
at
the
drinking
water
sipper
tube
or
from
vapors
off­
gassing
after
drinking
the
water.
Page
24
of
32
Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
(
§
82­
1)
90­
Day
Oral
(
Gavage)
 
Rat
Sodium
Chlorite
purity
not
reported
Harrington,
et
al.
(
1995a)
0,
10,
25,
or
80
mg/
L
(
0,
7.4,
19,
or
60
mg/
kg/
day)
NOAEL
=
7.4
mg/
kg/
day
LOAEL
=
19
mg/
kg/
day,
based
on
stomach
lesions
and
increases
in
spleen
and
adrenal
weights
Body
weight
and
food
consumption
were
not
affected
by
treatment.
The
following
was
noted
in
the
high­
dose
group:
(
1)
four
animals
died
during
treatment;
(
2)
both
sexes
exhibited
salivation,
significantly
decreased
erythrocyte
counts
and
morphologic
changes
in
erythrocytes,
and
decreased
total
serum
protein
levels;
(
3)
males
exhibited
significantly
decreased
hematocrit
and
hemoglobin
levels
and
increased
met
hemoglobin
and
neutrophil
levels,
whereas
female
met
hemoglobin
levels
were
significantly
decreased;
(
5)
relative
adrenal
and
spleen
weights
increased
in
both
sexes
and
absolute
adrenal
and
spleen
weights
and
relative
liver
and
kidney
weights
were
increased
in
females;
and
(
6)
both
sexes
displayed
squamous
epithelial
hyperplasia,
hyperkeratosis,
ulceration,
chronic
inflammation,
and
edema
in
the
stomachs.

In
the
19
mg/
kg­
day
dose
group,
the
following
observations
were
made:
(
1)
in
males,
occasional
salivation,
increased
met
hemoglobin
levels
and
neutrophil
counts,
decreased
lymphocyte
counts,
and
histologic
alterations
in
the
stomach
of
two
males;
and
(
2)
in
females,
increased
relative
and
absolute
spleen
and
adrenal
weights.

Non­
guideline
Subchronic
Inhalation
Toxicity­
Rat
and
Rabbit
Chlorine
Dioxide
purity
not
reported
Dalhamn
(
1957)

Study
1:
Decreasing
concentrations
for
3
minutes,
once
a
week.
3400
ppm
(
Week
1),
1100
ppm
(
Week
2),
and
800
ppm
(
Week
3)
(
9500,
3000,
and
2200
mg/
m3).

Study
2:
0
or
260
ppm
(
0
or
720
mg/
m3)
for
2
hours.

Study
3:
0
or
10
ppm
(
0
or
28
mg/
m3),
4
hours/
day
for
9
days
in
13­
day
period.

Study
4:
0
or
0.1
ppm
(
0
or
0.28
mg/
m3),
5
hours/
day
for
10
weeks.
NOAEL
=
0.1
ppm
(
0.28
mg/
m3),
rats
exposed
5
hours/
day
for
10
weeks
LOAEL
=
10
ppm
(
28
mg/
m3),
rats
exposed
4
hours/
day
for
2
weeks,
based
on
respiratory
tract
irritation.

Study
1:
Respiratory
distress
and
decreased
body
weight
were
observed.
Bronchopneumonia
and
hyperemia
of
the
renal
corticomedullary
junction
were
observed
in
exposed
rats
(
2/
3);
renal
hyperemia
was
also
observed
in
the
control
group
(
2/
3).

Study
2:
Ocular
discharge,
epistaxis,
death
(
1/
4
rats),
pulmonary
edema,
and
circulatory
engorgement
were
observed.

Study
3:
Death
(
3/
5
rats),
rhinorrhea,
"
embarrassed
respiration,"
weight
loss,
and
respiratory
infection
with
acute
renal
and
hepatic
congestion
were
observed
in
the
exposed
rats.

Study
4:
No
effects
on
body
weight
gain
were
observed
and
no
histologic
alterations
were
observed
in
the
lungs,
kidneys,
or
liver.
Page
25
of
32
Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Non­
guideline
Subchronic
Inhalation
­
Rat
and
Rabbit
Chlorine
Dioxide
purity
not
reported
Paulet
and
Desbrousses
(
1970)

Group
1:
5
male
and
5
female
rats
exposed
to
10
ppm
(
28
mg/
m3),
2
hours/
day
for
30
days.

Group
2:
10
male
rats,
10
female
rats,
and
4
rabbits
exposed
to
5
ppm
(
14
mg/
m3),
2
hours/
day
for
30
days.

Group
3:
10
male
and
10
female
rats
exposed
to
2.5
ppm
(
6.9
mg/
m3),
7
hours/
day
for
30
days.

Group
4:
8
rabbits
exposed
to
2.5
ppm
(
6.9
mg/
m3),
4
hours/
day
for
45
days.
LOAEL
=
2.5
ppm
(
6.9
mg/
m3)
based
on
thoracic
effects
in
rats
(
7
hours/
day
for
30
days)
and
pulmonary
effects
in
rabbits
(
4
hours/
day
for
45
days).

Group
1:
Adverse
effects
observed
in
exposed
rats
include:
nasal
discharge
and
red
eyes,
localized
bronchopneumonia
with
desquamation
of
the
alveolar
epithelium,
and
significantly
increased
blood
erythrocyte
and
leukocyte
levels.

Group
2:
Similar
effects
to
those
observed
in
Group
1
rats
were
noted
in
this
study.
There
were
no
alterations
in
erythrocyte
or
leukocyte
levels
at
this
concentration.

Group
3:
Lymphocyte
infiltration
of
the
alveolar
spaces,
alveolar
vascular
congestion,
hemorrhagic
alveoli,
epithelial
erosions,
and
inflammatory
infiltrations
of
the
bronchi
were
observed
in
exposed
rats.
Body
weight
gain
was
"
slightly
slowed"
(
data
not
presented)
and
the
erythrocyte
and
leukocyte
levels
were
85%
and
116%
of
controls,
respectively
(
statistical
analysis
not
reported),
in
exposed
rats.

Group
4:
In
exposed
rabbits,
hemorrhagic
alveoli
and
congested
capillaries
were
observed
in
the
lungs.
Body
weight
gain
was
not
adversely
affected,
and
erythrocyte
and
leukocyte
levels
were
80%
and
116%
of
controls
(
statistical
analysis
not
reported).

Non­
guideline
Subchronic
Inhalation
 
Rat
Chlorine
Dioxide
purity
not
reported
Paulet
and
Desbrousses
(
1972)
1
ppm
(
2.8
mg/
m3),
5
hours/
day,
5
days/
week
for
2
months
LOAEL
=
1
ppm
(
2.8
mg/
m3),
based
on
respiratory
effects.

Weight
gain
and
erythrocyte
and
leukocyte
levels
were
not
affected,
but
concurrent
control
data
was
not
presented.
Vascular
congestion
and
peribronchiolar
edema
were
observed
in
the
lungs
of
exposed
rats;
no
alterations
in
the
epithelium
or
parenchyma
were
observed.

Non­
guideline
Subchronic
Inhalation
­
Rat
and
Rabbit
Chlorine
Dioxide
purity
not
reported
Paulet
and
Desbrousses
(
1974)
5,
10,
or
15
ppm
(
14,
28,
or
41
mg/
m3),
for
15
minutes,
2
or
4
times/
day
for
1month
NOAEL
=
5
ppm
(
14
mg/
m3)
LOAEL
=
10
ppm
(
28
mg/
m3),
based
on
lung
damage.

At
15
ppm,
1/
10
and
1/
15
rats
exposed
two
or
four
times/
day,
respectively,
died;
body
weight
loss
was
observed
in
both
groups.
Histologic
alterations
observed
in
the
high­
dose
groups
included
nasal
and
ocular
inflammation
and
discharge,
bronchitis,
and
catarrhous
lesions
of
the
alveoli
with
peribronchiolar
infiltrations
(
more
pronounced
in
the
4
times/
day
group).
The
alveolar
lesions
were
reversible;
15
days
after
exposure
termination,
the
lung
histology
was
similar
to
that
of
controls.
No
histologic
alterations
were
observed
in
the
liver.
At
10
ppm,
alveolar
irritation
and
decreases
in
body
weight
gain
were
observed.
No
adverse
effects
on
clinical
signs,
body
weight
gain,
or
histopathology
of
the
lungs
were
observed
at
5
ppm.
Exposure
to
chlorine
dioxide
did
not
adversely
affect
hematologic
parameters.
Page
26
of
32
Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Developmental­
Rabbit
Sodium
chlorite
purity
80.58%
Acceptable
 
Guideline
MRID
41715701
Females
(
16­
17/
dose)
exposed
in
drinking
water
0,
200,
600,
or
1200
ppm
(
0,
12­
14,
36­
42,
or
76­
84
mg/
kg/
day)
from
GD
7­
19
Maternal
Toxicity
NOAEL
=
200
ppm
(
12­
14
mg/
kg/
day)
LOAEL
=
600
ppm
(
36­
42
mg/
kg/
day)
Developmental
Toxicity
NOAEL
=
200
ppm
(
12­
14
mg/
kg/
day)
LOAEL
=
600
ppm
(
36­
42
mg/
kg/
day),
based
on
decreased
fecal
output,
food
consumption,
and
water
intake.

Drinking
water
administration
of
sodium
chlorite
to
pregnant
NZW
does
during
the
dosing
period
of
major
organogenesis
caused
dose­
related
reductions
in
water
consumption
(
due
to
decreased
palatability
at
600
and
1200
ppm)
as
well
as
consequential
decreases
in
food
consumption
and
body
weight
gain,
especially
early
in
treatment.
Despite
these
maternal
effects,
no
evidence
of
embryolethality,
fetotoxicity,
or
teratogenicity
was
found.
There
was
a
slight
effect
on
embryonic
growth
of
mid­
and
high­
dose
levels,
but
no
clear
dose­
response
was
evident,
hence
any
association
between
treatment
at
600
or
1200
ppm
and
retardation
was
considered
inconclusive.

Non­
Guideline
Developmental­
Rat
Chlorine
dioxide
purity
not
reported
Orme
et
al.
(
1985)

Group
1:
Females
exposed
in
drinking
water
0,
1,
20,
or
100
mg/
L
(
0,
1,
3,
or
14
mg/
kg/
day)
2
weeks
prior
to
mating
and
throughout
gestation
and
lactation.

Group
2:
5­
day
old
pups
exposed
via
gavage
0
or
14
mg/
kg/
day,
postnatal
days
5­
20.
Developmental
Toxicity
NOAEL
=
20
mg/
L
(
3
mg/
kg/
day)
LOAEL
=
100
mg/
L
(
14
mg/
kg/
day)
for
neurobehavioral
effects
in
offspring
of
rats
exposed
in
drinking
water.

No
significant
alterations
in
pup
weight
were
observed
in
the
pups
exposed
in
utero;
the
postnatally
exposed
pups
weighed
significantly
less
than
controls
on
postnatal
days
14 
21.
Age
of
eye
opening
was
not
affected
by
chlorine
dioxide
exposure.
There
was
a
significant
correlation
between
T4
levels
and
locomotor
activity.

Group
1:
Locomotor
activity
was
consistently
decreased
in
the
100
mg/
L
group,
but
the
decrease
was
not
statistically
significant.
There
was
a
significant
decrease
in
T3
and
T4
levels
In
all
groups.
T4
levels
were
not
significantly
altered
in
exposed
dams.

Group2:
Activity
was
significantly
decreased
in
exposed
rats
on
postnatal
days
18 
19;
on
days
15 
17
and
20,
activity
levels
were
similar
to
controls.
T4
levels
were
also
significantly
decreased
in
exposed
rats.

Non­
Guideline
Reproduction
(
Drinking
water)
 
Rat
Sodium
chlorite
purity
81.4%
CMA
(
1996)
F0:
0,
3,
5.7,
or
21
mg/
kg/
day
(
males)
0,
3.9,
7.6,
or
29
mg/
kg/
day
(
females)
F1:
0,
2.9,
or
23
mg/
kg/
day
(
males)
0,
3.9,
8,
or
29
mg/
kg/
day
(
females)
NOAEL
=
2.9
mg/
kg/
day
LOAEL
=
5.7
mg/
kg/
day,
based
on
low
auditory
startle
response
amplitude
and
hematotoxicity
on
postnatal
day
24.

Significant
alterations
related
to
treatment
at
high­
dose
included
reduced
absolute
and
relative
liver
weight
in
F1
males
and
females,
reduced
pup
survival,
and
reduced
body
weight
at
birth
and
throughout
lactation
in
F1
and
F2
rats,
lower
thymus
and
spleen
weight
in
both
generations,
decreased
absolute
brain
weight
for
F1
and
F2
females,
delayed
sexual
development
in
F1
and
F2
males
and
females,
and
lowered
red
blood
cell
parameters
and
white
blood
cell
counts
in
F1
rats.
In
the
mid­
dosed
groups,
reduced
absolute
and
relative
liver
weight
in
F1
males
was
observed.
In
addition,
a
significant
decrease
in
maximum
response
to
an
auditory
startle
stimulus
was
noted
in
mid­
and
high­
dose
groups
on
postnatal
day
24,
but
not
on
postnatal
day
60.
Page
27
of
32
Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.4100
(
§
83­
1)
Chronic
Toxicity­
Rat
Chlorite
purity
not
reported
Haag
(
1949)
0,
1,
2,
4,
8,
100,
or
1000
mg/
L
chlorite
for
2
years
(
0,
0.09,
0.18,
0.35,
0.7,
9.3,
or
81
mg/
kg/
day)
NOAEL
=
8
mg/
L
(
0.7
mg/
kg/
day)
LOAEL
=
100
mg/
L
(
9.3
mg/
kg/
day),
based
on
renal
effects.
Animals
exposed
to
chlorite
concentrations
 
100
mg/
L
exhibited
treatment­
related
renal
pathology,
characterized
by
distention
of
the
glomerular
capsule
and
appearance
of
a
pale
pinkish
staining
material
in
the
renal
tubules.

Non­
Guideline
Carcinogenicity­
Mouse
Chlorite
purity
not
reported
Robinson
et
al.
(
1986)

Study
1:
5
dorsally
shaved
females
in
chambers
filled
with
0,
1,
10,
100,
300,
or
1000
ppm
liquid
chlorine
dioxide,
10
min/
day
for
4
days.

Study
2:
40
mice
immersed
in
0
or
1000
ppm
chlorine
dioxide
for
10
minutes.
Study
1:
A
significant
increase
in
interfollicular
epidermal
thickness
was
observed
in
the
1,000
ppm
group,
but
not
at
the
lower
concentrations.
Increases
in
total
cell
numbers
and
basal
cell
numbers
in
skin
sections
were
observed
in
both
the
300
and
1,000
ppm
groups.

Study
2:
A
significant
increase
in
interfollicular
epidermis
thickness
was
observed
at
all
time
periods,
with
the
highest
values
at
10
and
12
days
postexposure.

The
authors
concluded
that
even
short­
term
dermal
exposure
to
high
concentrations
of
chlorine
dioxide
is
capable
of
inducing
hyperplastic
responses
in
the
mouse
skin.

Non­
Guideline
Carcinogenicity­
Mouse
and
Rat
Chlorite
purity
not
reported
Kurokawa
et
al.
(
1984)

Study
1:
20
dorsally
shaved
females
exposed
to
20
mg/
mL
sodium
chlorite
in
acetone
(
100
mg/
kg
sodium
chlorite
per
application)
twice
a
week
for
51
weeks.

Study
2:
20
mice
exposed
to
20
µ
mol
DMBA
followed
by
51­
week
exposure
to
sodium
chlorite.
Study
1:
Sodium
chlorite
did
not
result
in
increased
tumor
incidence.

Study
2:
Tumor
incidence
was
6/
20
(
30%)
compared
with
0/
20
in
mice
that
received
DMBA
followed
by
acetone
treatments
for
51
weeks.
Squamous
cell
carcinomas
were
observed
in
5/
20
animals
in
the
chlorite
group.
Results
were
not
statistically
significant.

870.5100
(
§
84­
2)
Bacterial
reverse
Chlorine
dioxide
purity
not
reported
Miller
et
al.
(
1986)

TA98
and
TA100,
400­
fold
drinking
water
concentration
chlorine
dioxide
(
with
and
without
metabolic
activation)

TA98,
4000­
fold
drinking
water
concentration
chlorine
dioxide
(
with
and
without
metabolic
activation)
400­
fold:
Negative
(
with
or
without
metabolic
activation)

4000­
fold:
Positive
(
without
metabolic
activation)

870.5300
(
§
84­
2)
Acceptable
 
Guideline
In
Vivo
Mouse
cell
gene
mutation
test
Chlorine
dioxide
purity
not
reported
Accession
No.
265867
4
hours
to
a
range
of
7
concentrations
(
1.32
to
36.9
µ
g/
mL)
in
the
absence
of
metabolic
activation
and
(
6.73
to
65.2
µ
g/
mL)
in
the
presence
of
metabolic
activation
Positive
(
in
the
absence
and
presence
of
metabolic
activation)

870.5300
(
§
84­
2)
In
Vivo
Mouse
cell
gene
mutation
test
Chlorine
dioxide
purity
not
reported
Meier
et
al.
(
1985)
0.1­
0.4
mg
via
gavage
for
5
consecutive
days
Negative
870.5375
(
§
84­
2)
In
Vivo
mammalian
chromosome
aberration
test
­
Mouse
Chlorine
dioxide
purity
not
reported
Accession
No.
265867
10,
15,
or
50
µ
g/
mL
(
in
the
presence
and
absence
of
metabolic
activation)
Positive
(
in
the
absence
and
presence
of
metabolic
activation)

870.5380
(
§
84­
2)
Mammalian
spermatogonial
chromosomal
aberration
test
­
Rat
Chlorine
dioxide
purity
not
reported
Meier
et
al.
(
1985)
0.1­
0.4
mg
via
gavage
for
5
consecutive
days
(
0,
3.2,
8,
or
16
mg/
kg/
day)
Negative
870.5385
(
§
84­
2)
In
Vivo
bone
marrow
chromosome
aberration
test
­
Mouse
Chlorine
dioxide
purity
not
reported
Meier
et
al.
(
1985)
0.1­
0.4
mg
via
gavage
for
5
consecutive
days
Negative
Page
28
of
32
Table
4:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
Chlorine
Dioxide/
Sodium
Chlorite.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.8800
Morphologic
transformations
of
cells
in
culture
Chlorine
dioxide
purity
not
reported
Accession
No.
265867
to
cytotoxic
levels
Negative
for
increased
transform
foci.

a
Converted
from
ppm
to
mg/
kg/
day
using
a
reference
body
weight
of
0.0316
kg
and
water
intake
of
0.0078
L/
day.
Page
29
of
32
9.0
REFERENCES
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1984.

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MRID
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Masumi.
"
Can
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40168701
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Rat
[
EPA
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MA),
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Inc.
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Number
NA,
February
13,
1976.

40168704
(
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LD50
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15.
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Fairfield,
NJ),
Internaltional
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Number
GBL
024065,
April
23,
1985.

40168705
(
Accession
#):
Primary
Eye
Irritation
 
Rabbit
[
EPA
"
Report
of
Analysis"
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5H28,
Anthium
Dioxcide
(
EC),
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Chlorine
Dioxide,
5%].
Air
and
Hazardous
Materials
Division,
EPA,
Region
1
(
Boston,
MA),
International
Dioxcide,
Inc.
Study
Number
NA,
February
13,
1976.

40168707
(
Accession
#):
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Inhalation
Toxicity,
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Research
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Herndon,
VA),
International
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Inc.
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NA,
August
8,
1968.

41715701
(
MRID
#):
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21,
1990.

41919701
(
MRID#):
Rat
Acute
Oral
Toxicity:
Oxine
 
New
Powerful
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and
Sanitizer.
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Inc.,
Houston,
TX,
Lab.
Project
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3347­
84,
August
3,
1984.

41919702
(
MRID
#):
Rat
Acute
Dermal
Toxicity:
Oxine
 
New
Powerful
Bacteriostat
and
Sanitizer.
Stillmeadow,
Inc.,
Houston,
TX,
Lab.
Project
No.
3348­
84,
July
11,
1984.

41919703
(
MRID
#):
Rat
Acute
Inhalation
Toxicity:
Oxine
 
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Deodorizer
(
AKA
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Inc.,
Houston,
TX,
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Project
No.
4777­
87,
June
10,
1987.

41919704
(
MRID
#):
Rabbit
Eye
Acute
Irritation:
Oxine­
New
Powerful
Bacteriostat
and
Sanitizer.
Stillmeadow,
Inc.,
Houston,
TX,
Lab.
Project
No.
3349­
84,
June
26,
1984.

41919705
(
MRID
#):
Rabbit
Skin
Irritation:
Oxine
 
New
Powerful
Bacteriostat
and
Sanitizer.
Stillmeadow,
Inc.,
Houston,
TX,
Lab.
Project
No.
3350­
84,
June
26,
1984.
Page
30
of
32
42484101
(
MRID
#):
Acute
Inhalation
Toxicity
Evaluation
in
Rats.
International
Research
and
Development
Corporation
(
IRDC),
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MI.
Lab.
Project
No.
632­
001,
August
14,
1992.

43441901
(
MRID
#):
Acute
Oral
Toxicity
Study
in
Rats.
Stillmeadow,
Inc.,
Sugar
Land,
TX,
Lab.
Project
No.
1439­
94,
October
26,
1994.

43441902
(
MRID
#):
Acute
Dermal
Toxicity
Study
in
Rabbits.
Stillmeadow,
Inc.,
Sugar
Land,
TX,
Lab.
Project
No.
1440­
94,
October
10,
1994.

43441903
(
MRID
#):
Primary
Eye
Irritation
Study
in
Rabbits.
Stillmeadow,
Inc.,
Sugar
Land,
TX,
Lab.
Project
No.
1441­
94,
October
11,
1994.

43503201
(
MRID
#):
Irritant
Effects
of
Duozon
100­
1
As
a
concentration
of
0.3
ppm
relating
to
chlorine
dioxide
(
CLO2)
on
rabbit
skin.
Pharmatox,
Landkreis,
Hannover,
Germany,
Lab.
Project
No.
Not
Available,
July,
1994.

43558601
(
MRID
#):
Abdel­
Rahman,
et
al.,
"
Toxicity
of
Alcide,"
published
in
J.
Appl.
Toxicol.
2(
3):
160­
164,
1982.

43558602
(
MRID
#):
Dalhamn,
T.,
"
Chlorine
Dioxide:
Toxicity
in
Animal
Experiments
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Industrial
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published
in
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107,
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al.
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(
2004):
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(
1997):
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Daniel,
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Haag,
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