Drinking
Water
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for
Cyanogen
Chloride
and
Potential
Metabolites
E­
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Final
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APPENDIX
E.
HYDROGEN
CHLORIDE
I.
Health
Effects
in
Animals
A.
Short­
Term
Exposures
Using
the
toxicity
of
HCl
to
evaluate
the
toxic
potential
of
cyanogen
chloride
is
somewhat
problematic.
As
discussed
in
Chapter
3,
essentially
all
pathways
for
cyanogen
chloride
metabolism
result
in
the
production
of
HCl.
However,
using
the
toxicity
of
ingested
HCl
to
estimate
the
toxicity
of
HCl
formed
in
the
body
from
cyanogen
chloride
is
problematic,
in
light
of
the
acidic
pH
of
the
stomach
and
our
lack
of
quantitative
knowledge
of
the
percentage
of
ingested
HCl
that
is
absorbed
from
the
stomach.
HCl
could
form
in
the
blood
from
reaction
of
glutathione
with
cyanogen
chloride,
resulting
in
a
toxic
effect
from
the
lowered
pH,
but
quantitatively
evaluating
that
toxic
potential
is
difficult.
This
latter
issue
was
addressed
further
in
Chapter
7
of
the
main
document
and
in
Section
3
of
this
appendix.

Oral
toxicity
studies
for
HCl
are
summarized
in
Table
E­
1,
and
inhalation
studies
are
summarized
in
Table
E­
2.
HCl
is
highly
irritating
and
corrosive.
The
primary
target
of
inhalation
exposure
is
the
nasal
tract,
although
high
exposures
can
also
damage
the
lungs.
Sensory
irritation
and
pulmonary
irritation
have
also
been
observed.
The
only
short­
term
study
of
oral
exposure
to
HCl
was
a
study
of
HCl
used
in
the
water
mixed
with
feed
for
14
days
(
Throssell
et
al.,
1996).
Drinking
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No
studies
on
the
effects
in
animals
of
acute
exposure
to
HCl
via
the
oral
or
dermal
routes
were
located,
but
sufficiently
high
concentrations
would
be
expected
to
be
corrosive
at
the
site
of
contact
(
e.
g.,
the
trachea
for
oral
exposure
and
the
skin
for
dermal
exposure).

Throssell
et
al.
(
1996)
investigated
the
renal
effects
of
metabolic
acidosis
on
groups
of
12
female
Wistar
rats.
The
animals
were
fed
a
powdered
diet
containing
20%
casein
as
a
paste
mixed
with
water
(
1/
1
w/
w)
and
2%
methylcellulose
for
a
2­
week
induction
period
prior
to
dosing.
The
control
animals
received
plain
water
mixed
with
the
feed
for
the
rest
of
the
study,

while
the
experimental
group
then
received
the
same
feed
mixed
with
0.8
M
HCl
for
14
days.

Twenty­
four
hour
urine
samples
were
collected
at
7
and
14
days.
The
study
authors
calculated
that
the
rats
received
a
mean
daily
HCl
dose
of
19.7
mmol.
Using
the
reported
body
weight
of
200
g,
this
corresponds
to
a
dose
of
approximately
3600
mg/
kg­
day.
There
was
a
statistically
significant,
5­
fold
increase
in
urine
volume
in
the
acidotic
animals
compared
to
baseline.
Urine
pH
decreased
slightly
and
nonsignificantly,
while
there
was
a
marked,
statistically­
significant
increase
in
urinary
protein
excretion,
as
well
as
in
daily
excretion
of
lysozyme,
N­
acetyl
glucosaminidase
(
NAG),
and
albumin,
with
a
smaller
rise
in
immunoglobulin
G
(
IgG)
excretion.

Acidosis
was
confirmed
by
arterial
blood­
gas
measurements.
Body
weight
of
the
acidotic
rats
was
comparable
to
controls
at
baseline,
but
was
significantly
lower
(
by
15%)
after
two
weeks;

kidney
weights
were
increased
by
15%.
There
were,
however,
no
structural
lesions
apparent
on
histopathologic
examination
of
the
kidney,
although
the
density
of
tubular
nuclei
was
significantly
decreased.
Among
the
acidotic
rats,
staining
of
tubular
cells
with
antibody
to
the
Tamm­
Horsfall
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protein
(
THP)
was
less
prominent
than
in
controls,
but
THP­
positive
tubular
casts
were
observed,

suggesting
tubular
injury.
The
study
authors
interpreted
the
decreased
tubular
nuclear
density
as
suggesting
that
tubular­
cell
hypertrophy
was
the
predominant
mechanism
of
the
increased
kidney
size.
Overall,
the
results
indicated
that
the
renal
tubule
was
the
primary
target
of
acidosis
in
the
kidney.

In
an
attempt
to
determine
the
HCl
hazard
at
a
missile
test­
firing
site,
Darmer
et
al.
(
1974)

calculated
30­
minute
LC
50
values
for
Sprague­
Dawley­
derived
CFE
rats
and
ICR­
derived
CF­
1
mice
of
4701
and
2644
ppm
(
7018
and
3947
mg/
m3),
respectively.
The
LC
50
values
for
5­
minute
exposures
were
40,989
(
rat)
and
13,745
ppm
(
mice)
(
corresponding
to
61,190
and
20,519
mg/
m3).
The
animals
were
monitored
for
7
days
after
the
exposure.
Thus,
it
appeared
that
mice
are
2
to
3
times
more
sensitive
than
rats
to
the
lethal
effects
of
HCl
exposure.
Similar
LC
50
values
were
calculated
for
rats
and
mice
exposed
to
a
fine
aerosol
of
HCl
(
64%
of
droplets

1

m,

99.9%
of
droplets

5

m).
Histopathological
examination
revealed
lesions
of
the
respiratory
tract,
including
the
lung
and
nose,
but
not
other
tissues.

In
a
short­
term
study,
lightly
anesthetized
baboons
(
3
males/
group)
were
exposed
to
nominal
concentrations
of
0,
500,
5000,
or
10,000
ppm
HCl
(
0,
746,
7460,
or
14,900
mg/
m3)
for
15
minutes
and
observed
for
3
months
(
Kaplan,
1987;
Kaplan
et
al.,
1988).
A
concentrationrelated
increase
in
respiratory
frequency
and
minute
volume
was
observed
during
exposure,
but
the
tidal
volume
was
unaffected.
Despite
the
increased
minute
volume,
the
two
higher
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concentrations
caused
decreased
arterial
PO
2
during
exposure
and
for
at
least
10
minutes
postexposure
but
follow­
up
pulmonary
function
and
blood­
gas
measurements
at
3
days
or
3
months
following
exposure
did
not
show
any
abnormalities.
The
study
authors
noted
that
no
mortality
was
observed
in
this
study,
while
much
lower
concentrations
are
lethal
to
mice.
In
light
of
the
similarity
of
the
structure
and
complexity
of
the
upper
airways
of
the
baboon
and
the
human
child,

baboons
would
be
expected
to
resemble
humans
more
than
mice
would.
(
The
complexity
of
the
upper
airways
is
related
to
the
degree
of
scrubbing
of
inhaled
irritants,
and
increases
with
age
in
humans.)
On
the
other
hand,
the
study
authors
noted
the
contrast
between
the
increased
respiratory
rate
seen
in
baboons
and
the
reflex
inhibition
of
respiratory
rate
due
to
trigeminalnerve
stimulation
seen
in
rodents.
In
a
separate
experiment
(
Kaplan,
1987),
baboons
(
1
animal/
concentration)
were
exposed
to
one
of
eight
concentrations
of
HCl
ranging
from
190
to
17,290
ppm
(
284
to
25,800
mg/
m3)
for
5
minutes,
and
then
tested
for
avoidance/
escape
performance.
No
effect
on
this
endpoint
was
observed
in
the
baboons,
or
in
rats
exposed
for
5
minutes
at
one
of
12
concentrations
(
1
rat/
concentration)
ranging
from
11,800
ppm
(
17,600
mg/
m3)
to
a
lethal
concentration
of
76,730
ppm
(
114,500
mg/
m3).
The
baboons
exposed
to
the
two
highest
concentrations
died
of
bacterial
pneumonia
several
weeks
after
exposure.

Several
studies
evaluated
the
concentrations
at
which
HCl
causes
sensory
irritation.

Sensory
irritation
is
defined
as
the
stimulation
of
the
trigeminal­
nerve
endings
in
the
cornea
and
nasal
mucosa,
causing
a
stinging
sensation.
In
laboratory
animals,
sensory
irritation
causes
a
short
pause
in
breathing
following
each
inspiration,
resulting
in
decreased
respiratory
rate
and
a
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lengthened
expiratory
phase.
By
contrast,
pulmonary
irritation
includes
an
initial
increase
in
respiratory
rate
followed
by
a
decreased
rate.
The
decreased
respiratory
rate
with
pulmonary
irritation
is
due
to
a
pause
following
each
expiration,
as
a
result
of
stimulation
of
irritant
receptors
within
the
lung.
Sensory
irritation
is
appropriate
as
an
indication
of
a
chemical's
potential
for
respiratory­
tract
irritation,
but
not
for
dose­
response
assessment
(
U.
S.
EPA,
1994).

Burleigh­
Flayer
et
al.
(
1985)
exposed
groups
of
4­
8
male
English
smooth­
haired
guinea
pigs
to
0,
320,
680,
1040,
or
1380
ppm
HCl
(
0,
480,
1015,
1550,
or
2060
mg/
m3)
for
30
minutes,

and
measured
respiratory
rate
and
induction
of
sensory
or
pulmonary
irritation.
Deaths
were
observed
in
3/
8
animals
at
the
high
concentration
and
in
2/
8
animals
(
after
exposure
termination)

at
1040
ppm.
For
sensory
irritation,
the
concentration­
duration­
response
relationship
was
not
linear
with
time.
Sensory
irritation
appeared
at
6
minutes
at
320
ppm
(
480
mg/
m3),
but
occurred
almost
immediately
at
all
higher
concentrations
(
680­
1380
ppm).
By
contrast,
time
to
pulmonary
irritation
decreased
linearly
with
concentration.
Guinea
pigs
exposed
to
1040
ppm
were
sacrificed
at
2
and
15
days
post­
exposure.
In
contrast
to
the
results
of
Buckley
et
al.
(
1984),
lung
injury
was
observed
at
this
lethal
concentration,
including
multifocal
acute
alveolitis,
congestion,
and
squamous
metaplasia
with
loss
of
cilia
in
the
larger
conducting
airways
at
2
days
post­
exposure.

Mild
bronchitis
and
lymphoid
hyperplasia
were
observed
at
15
days
post­
exposure.
Corneal
opacities
were
also
observed.
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Barrow
et
al.
(
1977)
evaluated
sensory
irritation
in
a
similar
study,
conducted
in
male
Swiss­
Webster
mice
(
4/
group).
The
concentration
eliciting
a
50%
decrease
in
respiratory
rate
(
i.
e.,
the
RD
50)
was
309
ppm
(
461
mg/
m3).
Histopathological
analysis
was
not
conducted
as
part
of
this
study.

Buckley
et
al.
(
1984)
attempted
to
determine
the
potential
for
pathologic
damage
following
exposure
to
sensory
irritants
at
the
RD
50.
Based
on
the
mouse
RD
50
for
HCl
of
309
ppm,
a
group
of
16­
24
male
Swiss
Webster
mice
were
exposed
for
3
days,
6
hours/
day
to
a
timeweighted
average
concentration
of
304
ppm
(
range
295­
310
ppm)
HCl
(
454
mg/
m3).
(
The
study
reported
the
results
for
a
number
of
different
chemicals,
and
it
was
unclear
how
many
animals
were
tested
with
HCl.)
Half
the
group
was
sacrificed
immediately
after
the
termination
of
exposure,
and
half
were
necropsied
3
days
post­
exposure;
the
respiratory
tract
was
examined
histopathologically
in
both
groups.
Only
three
exposures
were
conducted
(
as
opposed
to
five
for
other
irritants),
because
of
a
high
incidence
of
deaths;
all
of
the
mice
died
or
were
found
moribund
by
the
end
of
the
study.
The
severity
of
lesions
was
highest
in
the
anterior
portion
of
the
nasal
cavity.
Severe
necrosis
and
exfoliation
of
the
respiratory
epithelium
were
observed
along
with
minimal
necrosis
of
the
olfactory
epithelium.
No
abnormalities
were
noted
in
the
trachea
or
lungs.

Stavert
et
al.
(
1991)
compared
the
acute
toxicity
of
HCl
in
nose­
breathing
male
Fisher
344
rats
and
in
rats
breathing
through
an
endotracheal
tube
("
mouth
breathers").
After
baseline
ventilatory
parameters
were
measured,
the
rats
were
exposed
for
30
minutes
to
approximately
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1300
ppm
HCl
(
1940
mg/
m3)
or
to
clean
air
(
8/
group).
Mortality
was
~
6%
among
the
nose
breathers
and
46%
among
the
mouth
breathers.
As
expected,
the
nose
breathers
had
significant
nasal
histopathology,
including
necrosis,
exudate,
and
inflammation,
while
nasal
sections
of
the
mouth
breathers
were
generally
normal.
Mild
epithelial
necrosis
of
the
trachea
was
observed
in
nose
breathers
exposed
to
HCl,
and
somewhat
more
severe
tracheal
necrosis
was
seen
in
mouthbreathing
rats
exposed
to
air
(
compared
to
the
normal
nose­
breathing
controls).
The
mouth
breathers
exposed
to
HCl
had
a
severe
diffuse
ulcerative
tracheitis
with
necrosis
of
the
mucosa
and
submucosa
and
fibrin
and
neutrophilic
exudate.
These
lesions
were
more
severe
than
in
the
mouth­
breathing
controls.
Nose
breathers
exposed
to
HCl
had
no
lung
lesions,
but
similarlyexposed
mouth
breathers
had
increased
neutrophils
in
the
alveoli,
and
some
necrosis
of
the
larger
bronchi
with
PMN
infiltrations,
but
the
latter
lesion
was
not
statistically
increased
over
the
mouthbreathing
controls.
Lung
wet
weight
was
slightly,
but
significantly,
increased
in
the
mouth
breathers,
but
not
in
the
nose
breathers.
A
stronger
degree
of
weight
loss
was
seen
in
the
nose
breathers.

As
part
of
the
90­
day
study
described
under
the
section
on
longer­
term
studies,

ToxiGenics,
Inc.
(
1984)
conducted
an
interim
sacrifice
after
short­
term
exposure.
In
this
study,

groups
of
31
males
and
21
females
for
each
strain/
species
of
B6C3F1
mice
and
Sprague­
Dawley
and
Fisher
344
rats
were
exposed
to
HCl
at
0,
10,
20,
or
50
ppm
(
0,
15,
30,
or
75
mg/
m3,

respectively)
for
6
hours/
day.
Adjusting
for
the
6
hour/
day
exposure
results
in
adjusted
daily
exposure
concentrations
of
0,
3.7,
7.5,
and
19
mg/
m3.
Ten
animals/
group
were
sacrificed
on
day
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5
(
after
4
exposures).
The
high­
concentration
male
and
female
mice
lost
weight
as
compared
to
their
pre­
exposure
levels;
in
comparison,
the
controls,
low­
and
mid­
concentration
groups
gained
weight.
The
body­
weight
increase
in
the
high­
concentration
male
and
female
Fisher
344
rats
and
the
high­
concentration
male
Sprague­
Dawley
rats
was
statistically
significantly
lower
than
in
the
corresponding
controls;
there
was
no
significant
effect
on
body
weight
in
the
female
Sprague­

Dawley
rats.
Histological
examination
found
that
lesions
were
limited
to
the
nose.
In
both
Fisher
344
and
Sprague­
Dawley
rats,
there
was
minimal­
to­
mild
rhinitis
of
the
anterior
portion
of
the
nasal
cavity,
with
the
males
being
more
affected.
Fisher
344
rats
also
had
occasional
hyperkeratosis.
No
treatment­
related
histological
lesions
were
seen
in
mice
of
either
sex.
(
See
Tables
E­
3.)

In
an
evaluation
of
the
potential
for
subtle
neurological
effects
of
HCl,
Einhorn
and
Moore
(
1990)
exposed
Long­
Evans
rats
(
4/
exposure,
sex
not
reported)
to
0,
75,
150,
or
300
ppm
(
0,

112,
224,
448
mg/
m3)
for
5­
15
minutes,
and
conducted
neurophysiology
evaluations.
They
observed
a
decreased
brainstem
auditory­
evoked
response
(
BAER)
at
all
exposure
levels.
In
addition,
the
electroencephalogram
(
EEG)
was
altered
at
150
and
300
ppm.
The
biological
significance
of
these
subtle
changes
is
unclear,
and
was
not
addressed
by
the
authors.

Summary.
In
the
only
study
of
the
effects
in
animals
of
short­
term
oral
exposure
to
HCl,
metabolic
acidosis,
decreased
body
weight,
and
increased
kidney
weight
were
observed
in
rats
provided
feed
mixed
with
acidified
water
(
Throssell
et
al.,
1996).
No
other
studies
on
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
9
EPA/
OW/
OST/
HECD
Final
draft
short­
term
effects
of
oral
exposure,
and
no
studies
on
the
effects
of
dermal
exposure
of
animals
to
HCl
were
located,
but
toxicity
at
the
site
of
contact
would
be
expected
to
result
from
exposure
to
sufficiently
high
concentrations.
Several
studies
evaluated
the
effects
of
inhalation
exposure
to
HCl.
As
expected,
exposure
to
the
acid
resulted
in
sensory
irritation,
nasal
inflammation
and
necrosis
(
Burleigh­
Flayer
et
al.,
1985;
ToxiGenics,
Inc.,
1984).

B.
Long­
Term
Exposures
Long­
term
ingestion
of
relatively
large
quantities
of
HCl
results
in
metabolic
acidosis.

Due
to
the
corrosive
effect
of
concentrated
HCl,
these
long­
term
studies
have
administered
the
HCl
in
dilute
solutions.
The
total
doses
of
HCl
needed
to
cause
this
condition
are
relatively
large
due
to
the
natural
secretion
of
HCl
by
the
stomach,
and
are
estimated
at
several
times
the
amount
of
free
HCl
secreted
by
the
stomach.
Metabolic
acidosis
is
a
well­
characterized
condition
with
a
variety
of
causes
(
reviewed
in
Chan,
1983;
Robertson,
1989).
The
physiological
response
to
metabolic
acidosis
includes
a
rapid
increase
in
the
respiratory
rate.
This
is
followed
by
stepwise
increments
of
net
acid
excretion
that
occur
over
a
period
of
3­
4
days
until
maximal
renal
acidification
occurs.
Studies
in
laboratory
animals
found
that
prolonged
exposure
to
high
levels
of
HCl
resulted
in
decreased
body
weight
and
increased
kidney
weight
(
Throssell
et
al.,
1995,

1996).
Urinary
excretion
of
proteins
increased
and
then
returned
to
normal,
indicating
that
compensatory
changes
occurred
and
the
damage
was
transient
(
Throssell
et
al.,
1995).
Weanling
mice
may
be
more
sensitive
than
adult
mice
to
the
effects
of
acidified
water,
with
water
at
pH
2­
3
Drinking
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Document
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Cyanogen
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E­
10
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HECD
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draft
causing
decreased
weight
gains
(
reported
only
in
an
abstract,
as
cited
by
Tober­
Meyer
et
al.,

1981),
and
severe
intestinal
irritation
at
pH
1.7
(
McDougall
et
al.,
1987).
Exposure
to
acidified
drinking
water
for
2
years
caused
dentine
erosion
in
rats
(
Tober­
Meyer
et
al.,
1981).
However,

neither
effects
of
HCl
on
the
stomach
nor
on
the
teeth
are
likely
to
be
relevant
to
HCl
produced
endogenously
from
the
metabolism
of
cyanogen
chloride,
since
they
result
from
high
acidity
at
the
portal
of
entry.
Several
of
the
studies
of
acidified
drinking
water
were
published
only
as
abstracts
or
only
in
German,
and
so
were
not
reviewed.

Tober­
Meyer
et
al.
(
1981)
administered
normal
or
acidified
drinking
water
(
pH
2.3­
2.5)
to
groups
of
10
male
Han:
Wistar
rats
for
7
months.
The
authors
estimated
the
HCl
concentration
at
6.14
mmol
HCl/
L,
corresponding
to
a
dose
of
36
mg/
kg­
day
for
rats
(
using
a
drinking
water
consumption
of
0.16
L/
kg­
day
for
a
subchronic
study
in
female
Wistar
rats,
U.
S.
EPA,
1988).

Parameters
evaluated
included
red
blood
cell
count,
differential
blood
cell
count,
hemoglobin,

blood
glucose
and
other
typical
serum
biochemistry
endpoints
(
including
the
electrolytes
sodium,

potassium,
and
calcium),
blood­
gas
analysis,
serum
protein,
SGOT,
serum
glutamic
pyruvic
transaminase
(
SGPT),
body
weight,
liver
and
kidney
weights,
and
histopathological
analysis
of
major
organs.
Urinary
proteins
were
not
evaluated.
Blood
was
drawn
in
weeks
5,
9,
13,
17,
21,

25,
and
29.
In
a
similar
study,
groups
of
8
male
New
Zealand
White
rabbits
were
treated
with
normal
or
acidified
water
(
doses
of
0
or
approximately
25
mg/
kg­
day
for
rabbits,
using
a
drinking
water
consumption
of
0.11
L/
kg­
day);
blood
was
sampled
in
weeks
4,
8,
12,
17,
21,
and
26.
The
endpoints
evaluated
were
the
same
as
in
the
rat
study.
No
significant
effects
were
observed
in
Drinking
Water
Criteria
Document
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Cyanogen
Chloride
and
Potential
Metabolites
E­
11
EPA/
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OST/
HECD
Final
draft
either
rats
or
rabbits.
The
study
authors
calculated
that
the
rats
ingested
approximately
1/
4
of
the
free
HCl
secreted
by
the
stomach.

Throssell
et
al.
(
1995)
investigated
the
renal
effects
in
female
Wistar
rats
of
prolonged
metabolic
acidosis.
The
rats
were
fed
a
powdered
diet
containing
20%
casein
as
a
paste
mixed
with
water
(
1/
1
w/
w)
and
2%
methylcellulose
throughout
the
study,
and
for
a
2­
week
induction
period
prior
to
dosing.
A
group
of
21
pair­
fed
controls
received
plain
water
mixed
with
the
feed,

while
the
experimental
group
of
32
rats
received
the
same
feed
mixed
with
0.5
M
HCl
for
14
weeks.
The
study
authors
calculated
that
the
rats
received
a
mean
daily
HCl
dose
of
10.3
mmol.

Using
the
average
of
the
initial
and
final
body
weights
(
225
g),
this
corresponds
to
a
dose
of
approximately
1670
mg/
kg­
day.
All
of
the
rats
had
free
access
to
tap
water.
Food
consumption
was
measured
daily,
body
weights
were
measured
weekly,
and
24­
hour
urine
samples
were
collected
every
other
week.
The
glomerular
filtration
rate
(
GFR)
was
measured
at
14
weeks,
and
then
the
rats
were
sacrificed,
weighed,
and
the
kidneys
were
weighed
and
fixed.
Body
weight
in
the
acidotic
rats
was
decreased
throughout
the
study,
with
a
final
body
weight
at
80%
of
the
control
value,
even
though
food
consumption
was
slightly
higher
in
the
acidotic
rats.
Kidney
weight
was
slightly,
but
not
significantly
increased,
and
relative
kidney
weight
was
significantly
increased.
Urine
volume
was
significantly
increased
at
14
weeks,
and
urine
pH
was
significantly
decreased.
Total
urinary
protein,
lysozyme,
and
albumin
peaked
at
week
8,
and
were
at
or
near
baseline
levels
by
week
12­
14.
Only
a
slight
increase
in
immunoglobulin
G
(
IgG)
in
urine
was
observed.
Mean
arterial
pH
at
sacrifice
was
lower
in
the
acid­
supplemented
group,
but
there
was
Drinking
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Document
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E­
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draft
no
effect
on
GFR
or
serum­
creatinine
concentration.
Microscopic
examination
found
no
histopathologic
effects
in
the
kidney,
and
specialized
stains
found
no
increase
in
macrophage
infiltration.
Based
on
the
absence
of
histological
effects
or
effects
on
GFR,
and
on
the
recovery
in
urinary
protein
levels,
the
study
authors
concluded
that
metabolic
acidosis
neither
causes
nor
exacerbates
chronic
renal
injury.
The
authors
suggested
that
the
resolution
of
the
proteinuria
was
due
to
either
transient
tubular
damage
that
resolved
before
sacrifice,
or
to
a
short­
term
reduction
of
endocytosis
or
intralysosomal
degradation
of
tubular
proteins.
Nonetheless,
based
on
the
transient
kidney
effects,
1670
mg/
kg­
day
was
a
LOAEL
in
this
study.

Clausing
and
Gottschalk
(
1989)
provided
male
Ico/
Shoe:
WIST
rats
(
8­
10/
group)
with
untreated
drinking
water
(
controls),
or
drinking
water
acidified
to
pH
2
or
pH
3
with
HCl
for
21
weeks.
Based
on
the
pH,
HCl
was
in
the
drinking
water
at
approximately
0,
0.01,
or
0.001
M,

corresponding
to
doses
of
0,
5.4,
and
54
mg/
kg­
day,
assuming
a
default
water
consumption
of
0.147
L/
kg­
day.
There
were
no
effects
on
hematology,
or
on
serum
creatinine,
blood
urea
nitrogen
(
BUN),
or
alkaline
phosphatase.
The
urine
volume
was
decreased
in
a
dose­
related
fashion
at
13
weeks,
and
the
decrease
was
statistically
significant
at
21
weeks.
The
study
authors
attributed
the
decrease
to
altered
kidney
function.
By
contrast,
drinking­
water
intake
in
the
pH
3
group
was
elevated
over
the
control
levels.
(
Drinking­
water
intake
data
were
not
reported
for
the
pH
2
group.)
The
authors
did
not
report
whether
the
animals
exhibited
evidence
of
water
retention,
which
would
indicate
a
kidney
effect.
Alternatively,
the
rats
may
have
been
"
playing"

with
the
drinking­
water
dispenser
due
to
poor
palatability,
so
that
the
actual
intake
was
lower
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
13
EPA/
OW/
OST/
HECD
Final
draft
than
reported.
Decreased
protein
excretion
(
statistically
significant
at
21
weeks),
decreased
protein
concentration
in
urine,
and
decreased
phenol­
red
excretion
after
i.
v.
injection
were
also
observed,
although
there
was
no
dose­
response
for
the
effects
on
protein
at
21
weeks.
This
study
is
limited
by
internal
inconsistencies
and
inconsistencies
with
similar
studies,
as
well
as
limited
reporting
of
results.

In
an
attempt
to
rid
a
mouse
colony
(
strain
not
reported)
of
Pseudomonas
aeruginoasa,

McDougall
et
al.
(
1987)
acidified
the
drinking
water
to
0.02
M
or
0.005
M
with
HCl
(
pH
1.7
and
2.3,
respectively).
They
noted
that
"
a
large
number
of
weanling
mice
kept
on
the
higher
level
of
acid
developed
severe
intestinal
irritation."
This
irritation
was
not
observed
at
the
lower
HCl
dose.
The
authors
noted
that
a
viral
origin
of
the
irritation
could
not
be
ruled
out.
However,
the
lack
of
irritation
at
the
lower
HCl
concentration
suggests
a
relationship
to
the
HCl
dosing.
The
duration
of
exposure
and
number
exposed
were
not
reported,
and
other
endpoints
of
toxicity
were
apparently
not
evaluated.
Since
the
effect
observed
was
at
the
portal
of
entry,
the
concentration
of
the
exposure
at
the
LOAEL
(
i.
e.,
0.02
M)
may
have
been
more
important
than
the
total
daily
dose
(
254
mg/
kg­
day,
assuming
a
daily
water
intake
of
0.3483
L/
kg,
based
on
the
average
across
strains
and
sexes
[
U.
S.
EPA,
1988]).
At
the
NOAEL
of
0.005
M,
the
estimated
dose
is
64
mg/
kg­
day.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
14
EPA/
OW/
OST/
HECD
Final
draft
Inhalation
studies
in
animals
include
studies
up
to
chronic
duration,
and
found
that
the
primary
targets
of
long­
term
inhalation
exposure
are
the
nasal
epithelium,
along
with
the
larynx
and
trachea.

In
an
unpublished
90­
day
inhalation
study
using
B6C3F1
mice
and
Sprague­
Dawley
and
Fisher
344
rats
(
ToxiGenics,
Inc.,
1984),
groups
of
31
males
and
21
females
of
each
strain/
species
were
exposed
to
HCl
at
10,
20,
or
50
ppm
(
0,
15,
30,
or
75
mg/
m3,
respectively)
for
6
hours/
day,

5
days/
week
for
90
days.
The
duration­
adjusted
concentrations
were
0,
2.7,
5.3,
and
13
mg/
m3.

Several
animals
died
during
the
study;
however,
the
deaths
did
not
appear
to
be
exposure
related.

Ten
males
and
ten
females
per
group
were
sacrificed
after
four
exposures,
as
described
above
in
the
section
on
short­
term
exposures,
and
10
animals/
sex/
group
were
sacrificed
and
evaluated
after
90
days.
Body
weights
in
male
and
female
mice
at
the
high
exposure
were
decreased
compared
to
the
control
by
~
10%
(
statistically
significant).
High­
concentration
male
Fisher
344
rats
also
had
sporadic
instances
of
significantly
lower
body
weight.
There
was
no
effect
on
hematology,

clinical
chemistry,
or
urinalysis.
The
histopathology
examination
included
an
extensive
list
of
organs,
including
the
nasal
turbinates
(
four
sections),
trachea,
larynx,
and
lung.
All
tissues
were
examined
from
the
control
and
high­
concentration
groups,
and
only
the
nasal
turbinates,
trachea,

lungs,
and
any
gross
lesions
from
the
low­
and
mid­
concentration
groups.
Histologic
examination
showed
minimum­
to­
mild
rhinitis
in
both
strains
of
rats
(
Table
E­
4).
Lesions
occurred
in
the
anterior
portion
of
the
nasal
cavity
and
were
concentration­
and
time­
related.
In
mice
exposed
to
50
ppm,
there
was
cheilitis
and
accumulation
of
macrophages
in
the
perioral
tissues
after
90
days.
Drinking
Water
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Document
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Cyanogen
Chloride
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E­
15
EPA/
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OST/
HECD
Final
draft
"
Eosinophilic
globules"
in
the
epithelial
lining
of
the
nasal
tissues
were
also
observed
in
female
mice
at
all
concentrations
and
high­
exposure
male
mice.
Congestion
was
also
observed
in
the
mice,
but
was
not
concentration­
related;
there
was
no
nasal
or
other
respiratory
tract
inflammation
in
mice.
The
low
concentration
was
the
LOAEL
in
all
three
species/
strains.
Based
on
the
more
sensitive
sex,
the
LOAEL(
HEC)
was
0.24
mg/
m3
in
male
Fisher­
344
rats,
0.34
mg/
m3
in
male
Sprague­
Dawley
rats,
and
0.25
mg/
m3
in
female
mice.

In
a
chronic
inhalation
study
in
rats,
male
Sprague­
Dawley
rats
(
100/
group)
were
exposed
to
0
or
10
ppm
(
0
or
15
mg/
m3)
HCl
for
6
hours/
day,
5
days/
week
(
duration­
adjusted
concentration,
2.5
mg/
m3)
for
their
lifetimes.
Because
the
animals
were
not
exposed
on
holidays,

in
addition
to
other
days
of
no
exposure,
exposures
were
for
4.7
days/
week
on
average.
Interim
results
were
reported
by
Albert
et
al.
(
1982),
and
the
full
study
was
reported
by
Sellakumar
et
al.

(
1985).
All
animals
were
observed
daily,
weighed
monthly,
and
allowed
to
die
naturally
or
killed
when
moribund,
with
the
study
ending
at
week
128.
Complete
necropsies
were
performed
on
all
animals,
with
particular
attention
given
to
the
respiratory
tract.
Histologic
sections
were
prepared
from
the
head
(
four
sections),
lung
(
one
section
from
each
lobe),
trachea,
larynx,
liver,
kidneys,

testes,
and
other
organs
where
gross
pathological
signs
were
present.
However,
neither
study
discussed
histopathological
events
in
organs
other
than
the
respiratory
tract.
HCl­
exposed
animals
showed
no
differences
in
body
weights
or
survival
when
compared
with
air
controls.
No
nasal
tumors
were
observed.
Epithelial
or
squamous
hyperplasia
was
observed
in
the
nasal
mucosa
(
location
not
specified)
of
62/
99
exposed
animals,
compared
to
51/
99
in
the
concurrent
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
16
EPA/
OW/
OST/
HECD
Final
draft
control
group
(
Table
E­
5).
The
incidence
of
squamous
metaplasia
of
the
nasal
mucosa
was
9/
99
and
5/
99
in
the
exposed
and
control
rats,
respectively.
Rhinitis
was
observed
in
>
70%
of
the
exposed
and
control
animals.
In
the
laryngeal­
tracheal
segments,
hyperplasia
was
observed
in
the
larynx
in
22/
99
exposed
rats,
and
in
the
trachea
in
26/
99
exposed
rats,
compared
with
2/
99
and
6/
99
controls,
respectively.
Squamous
metaplasia
was
not
reported
in
the
larynx
or
trachea.
The
authors
did
not
report
any
grading
of
the
severity
of
any
of
these
changes,
although
they
stated
that
no
"
serious
irritating
effects"
in
the
nasal
epithelium
were
observed.
Based
on
these
results,

the
10
ppm
(
15
mg/
m3)
concentration
can
be
considered
a
LOAEL
(
LOAEL(
HEC)
=
6.1
mg/
m3).

This
study
is
limited
for
the
purpose
of
evaluating
carcinogenic
potential
due
to
the
testing
of
only
one
exposure
level.

No
studies
on
the
effects
of
long­
term
dermal
exposure
to
HCl
were
located.

Summary.
Several
studies
have
evaluated
the
longer­
term
effects
of
ingested
HCl,

primarily
as
part
of
investigations
of
the
effect
of
metabolic
acidosis
(
Throssell
et
al.,
1995;

Clausing
and
Gottschalk,
1989).
Other
studies
evaluated
the
effects
of
drinking
water
that
was
acidified
as
part
of
a
disinfection
effort
(
Tober­
Meyer
et
al.,
1981;
McDougall
et
al.,
1987).
The
studies
of
acidosis
found
that
the
kidney
was
the
primary
target,
although
one
study
(
Throssell
et
al.,
1995)
found
that
the
effects
on
the
kidneys
had
reversed
by
the
end
of
the
study,
due
to
the
kidney
adapting
to
the
acidosis.
In
the
only
study
of
HCl
ingestion
that
examined
the
liver
(
Tober­
Meyer
et
al.,
1981),
no
effect
was
seen
on
liver
weight
or
serum
enzymes
indicating
liver
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
17
EPA/
OW/
OST/
HECD
Final
draft
injury
(
SGOT,
SGPT),
at
drinking
water
doses
of
36
mg/
kg­
day
in
rats
and
25
mg/
kg­
day
in
rabbits.
The
studies
on
the
effects
of
acidified
water
indicate
that
pH
1.7
water
can
cause
stomach
irritation
in
weanling
rats,
but
pH
2
water
results
in
minimal
or
no
effects
(
Tober­
Meyer
et
al.,
1981;
McDougall
et
al.,
1987;
Clausing
and
Gottschalk,
1989).
The
data
are
insufficient
to
determine
whether
weanlings
are
more
sensitive,
or
whether
the
difference
between
these
two
concentrations
identifies
a
NOAEL/
LOAEL
boundary.
Either
way,
the
effects
of
HCl
on
the
stomach
are
of
questionable
relevance
to
the
effects
of
cyanogen
chloride
and
its
metabolites,

since
the
stomach
would
not
be
expected
to
be
the
primary
site
of
cyanogen
chloride
metabolism
and
HCl
production.
The
potential
for
metabolic
acidosis
resulting
from
HCl
production
from
cyanogen
chloride
is
probably
of
greater
relevance.

Longer­
term
inhalation
studies
of
HCl
found
hyperplasia
of
the
nasal
mucosa,
and
in
the
trachea
and
larynx,
and
nasal
rhinitis
(
Sellakumar
et
al.,
1985;
Albert
et
al.,
1982;
ToxiGenics,

Inc.,
1984).
Rats
were
more
sensitive
than
mice
to
the
same
exposure
concentration,
or
when
the
concentration
was
normalized
by
the
HEC.
The
studies
are
limited
by
the
testing
of
only
a
single
concentration
(
Sellakumar
et
al.,
1985;
Albert
et
al.,
1982)
or
by
incomplete
reporting
and
histopathology;
no
NOAEL
has
been
identified.
No
longer­
term
studies
of
dermal
effects
of
HCl
were
identified.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
18
EPA/
OW/
OST/
HECD
Final
draft
C.
Reproductive/
Developmental
Toxicity
Les
(
1968)
investigated
the
effect
on
mouse
reproduction
of
disinfecting
water
with
sodium
hypochlorite
and
HCl.
As
part
of
preparing
new
matings
in
the
Jackson
Laboratory
production
colony,
mice
from
the
inbred
strains
C3H/
HeJ
and
C57BL/
6J
(
168
cages/
strain/
condition)
were
provided
either
tap
water
(
pH
9.2­
9.8)
or
water
to
which
sodium
hypochlorite
and
HCl
had
been
added
to
achieve
10­
13
ppm
residual
chloride
and
pH
2.5.

Matings
were
either
in
pairs
or
trios
(
1
male
and
2
females).
Matings
were
continued
for
6
months.
For
the
C3H/
HeJ
strain,
the
numbers
of
mice
born,
mice
weaned,
and
the
number
born/
dam
and
weaned/
dam
were
statistically
significantly
higher
in
the
treated
group
than
the
control
group.
Similar
results
were
obtained
with
the
C57BL/
6J
strain,
although
a
much
stronger
improvement
was
observed
in
the
trios
than
in
the
pair­
mated
cages.
Thus,
the
groups
drinking
disinfected
water
had
better
reproductive
performance.
Although
the
mice
were
exposed
to
a
mixture,
the
data
suggest
that
drinking
water
of
pH
2.5
alone
would
have
no
adverse
effect
on
reproductive
performance
in
these
strains.

The
only
developmental
toxicity
data
for
HCl
are
two
low­
quality
studies
conducted
via
the
inhalation
route.
Pavlova
(
1976)
exposed
groups
of
8­
15
female
Wistar
rats
to
0
or
302
ppm
(
450
mg/
m3)
HCl
via
inhalation
for
1
hour.
One
group
was
exposed
12
days
prior
to
mating,
and
the
other
group
on
day
9
of
gestation.
One­
third
of
the
exposed
rats
died,
with
signs
of
severe
dyspnea
and
cyanosis.
Survivors
had
decreased
oxygen
saturation,
hyperchloruria,
and
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
19
EPA/
OW/
OST/
HECD
Final
draft
hyperproteinuria.
Fetal
mortality
was
significantly
higher
in
rats
exposed
during
pregnancy.
Fetal
body
weight
at
age
4
weeks
was
significantly
decreased
compared
to
controls
in
the
rats
exposed
prior
to
mating.
When
the
progeny
were
subjected
to
an
additional
exposure
of
35
ppm
HCl
(
52
mg/
m3)
at
the
age
of
2­
3
months,
functional
abnormalities
in
the
organs
of
the
progeny
were
similar
to
those
found
in
the
mothers
(
i.
e.,
in
the
lungs
and
kidney).
No
general
conclusion
regarding
the
developmental
toxicity
of
HCl
is
possible
from
this
study,
because
it
did
not
use
standard
developmental
toxicity
exposure
methods
or
methods
for
evaluation
of
effects,
and
tested
a
very
high
exposure
concentration.

In
another
study
from
the
same
laboratory
(
GEOMET
Technologies,
Inc.,
1981),
female
rats
were
exposed
to
302
ppm
(
450
mg/
m3)
HCl
for
1
hour
prior
to
mating.
Exposure
killed
20­

30%
of
the
rats.
In
rats
surviving
6
days
after
exposure,
a
decrease
in
blood­
oxygen
saturation
was
noted,
as
was
kidney,
liver,
and
spleen
damage.
In
addition,
treatment
altered
the
estrus
cycles.
In
rats
mated
12­
16
days
postexposure
and
killed
on
day
21
of
pregnancy,
fewer
live
fetuses,
a
decrease
in
fetal
weight,
and
an
increase
in
relative
lung
weights
of
the
fetuses
were
observed.
(
It
is
not
clear
if
this
is
really
a
separate
study,
or
just
a
separate
reporting
of
the
same
data
as
reported
by
Pavlova
[
1976]).

Summary.
Studies
of
reproductive
and
developmental
toxicity
of
HCl
are
limited
to
a
single
study
investigating
the
effect
on
reproductive
performance
of
disinfecting
drinking
water
with
sodium
hypochlorite
and
HCl
(
Les,
1968),
and
two
low­
quality
inhalation
studies
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
20
EPA/
OW/
OST/
HECD
Final
draft
investigating
the
effects
of
exposure
for
one
hour
to
a
concentration
that
produced
some
deaths
in
rats,
either
prior
to
mating
or
on
gestation
day
9
(
Pavlova,
1976;
GEOMET
Technologies,
Inc.,

1981).
There
was
no
adverse
effect
on
reproductive
performance
in
the
drinking
water
study.

Increased
fetal
mortality
and
altered
organ
function
of
the
progeny
were
observed
in
the
inhalation
study,
but
these
effects
may
have
been
secondary
to
the
high
maternal
toxicity.

D.
Mutagenicity
and
Genotoxicity
No
effect
on
mutation
rate
was
observed
in
S.
typhimurium
strains
TA97,
TA98,
TA100,

TA102,
or
TA1535
using
the
standard
plate
incorporation
assay
and
buffered
solutions
down
to
pH
5.5
in
the
presence
and
absence
of
S9
(
Cipollaro
et
al.,
1986).
Although
HCl
itself
was
not
tested,
this
study
evaluated
the
effects
of
increased
hydrogen
ion
concentrations.
Decreased
viability
was
observed
at
pH
5,
and
complete
lethality
at
lower
pH
values.

Morita
et
al.
(
1989)
evaluated
the
potential
of
HCl
to
produce
chromosome
aberrations
in
Chinese
hamster
ovary
(
CHO­
K1)
cells
at
concentrations
up
to
16
mM
(­
S9)
or
12
mM
(+
S9).

The
highest
concentration
tested
in
the
absence
or
presence
of
S9
was
cytotoxic.
Chromosome
aberrations
were
increased
at
14
mM
HCl
­
S9
(
measured
pH
of
5.5
initially,
and
pH
6.7
after
24
hours)
and
10
mM
HCl
+
S9
(
pH
5.8
immediately
and
6.3
after
6
hours).
The
aberrations
were
primarily
chromatid
breaks
and
chromatid
exchanges.
The
observed
effects
were
primarily
due
to
the
low
pH,
rather
than
the
HCl
per
se,
since
similar
effects
were
seen
with
organic
buffers
at
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
21
EPA/
OW/
OST/
HECD
Final
draft
acidic
pHs.
Cell
survival
at
the
clastogenic
concentrations
was
not
reported.
Levis
and
Majone
(
1981)
found
that
HCl
at
0.01
or
0.025
N
had
no
effect
on
the
production
of
chromosome
aberrations
in
CHO
cells,
apparently
in
the
absence
of
S9.

In
a
report
on
EPA's
Gene­
Tox
Program,
Heidelberger
et
al.
(
1991)
reported
that
HCl
at
concentrations
of
31­
500

g/
mL
was
negative
for
cell
transformation
in
SA7/
SHE
cells.
The
basis
for
the
choice
of
concentrations
tested
was
not
provided,
but
testing
sufficiently­
high
doses
was
included
in
the
criteria
for
an
acceptable
assay.
This
assay
measures
the
ability
of
chemicals
to
enhance
adenovirus­
induced
transformation.

HCl
was
negative
in
a
microsuspension
adaptation
of
the
Bacillus
subtilis
"
rec"
assay
that
used
E.
coli
DNA
repair­
deficient
strains
(
McCarroll
et
al.,
1981a).
The
strains
tested
were
WP2,

WP2
uvrA­,
WP67
uvrA­
polA­,
CM611
uvrA­
recA­,
W3110polA+,
and
p3478
polA­.
The
endpoint
in
this
assay
is
whether
the
chemical
causes
preferential
kill
of
repair­
deficient
strains,
and
thus
the
assay
measures
primary
DNA
damage.
Similarly,
HCl
was
negative
in
a
microsuspension
adaptation
of
the
"
rec"
assay
that
used
B.
subtilis
strains
M45
rec­
and
H17
rec+
(
McCarroll
et
al.,

1981b).

In
a
test
of
a
number
of
leather
tannins
and
the
materials
used
to
dissolve
them,
Venier
et
al.
(
1985)
found
no
effect
on
the
induction
of
sister
chromatid
exchanges
(
SCEs)
in
CHO
cells
by
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
22
EPA/
OW/
OST/
HECD
Final
draft
HCl
concentrations
up
to
0.01
N.
Levis
and
Majone
(
1981)
also
found
that
HCl
at
0.01
or
0.025
N
(
apparently
in
the
absence
of
S9)
had
no
effect
on
the
production
of
SCEs
in
CHO
cells.

Summary.
Genotoxicity
studies
of
HCl
include
gene
mutation
assays
in
S.
typhimurium
(
Cipollaro
et
al.,
1986),
chromosome
aberration
assays
in
CHO
cells
(
Morita
et
al.,
1989;
Levis
and
Majone,
1981),
an
assay
for
cell
transformation
in
SA7/
SHE
cells
(
Heidelberger
et
al.,
1991),

and
several
assays
for
DNA
damage
(
McCarroll
et
al.,
1981a,
1981b;
Venier
et
al.,
1985;
Levis
and
Majone,
1981).
These
studies
found
that
HCl
was
not
genotoxic.
The
one
positive
study
found
an
increase
in
chromosome
aberrations
in
CHO
cells,
a
finding
that
was
attributed
to
the
low
pH
and
resulting
cell
stress,
rather
than
genotoxicity
of
HCl
per
se
(
Morita
et
al.,
1989).

E.
Carcinogenicity
As
discussed
in
the
section
on
longer­
term
toxicity,
Sellakumar
et
al.
(
1985)
and
Albert
et
al.
(
1982)
reported
on
a
chronic
inhalation
study
conducted
in
male
Sprague­
Dawley
rats
(
100/
group)
exposed
to
0
or
10
ppm
(
0
or
15
mg/
m3)
HCl
for
6
hours/
day,
5
days/
week
(
duration­
adjusted
concentration,
2.5
mg/
m3)
for
their
lifetimes.
Complete
necropsies
were
performed
on
all
animals,
with
particular
attention
given
to
the
respiratory
tract.

Histopathological
effects
were
reported
only
for
the
respiratory
tract.
HCl­
exposed
animals
showed
no
differences
in
body
weights
or
survival
when
compared
with
air
controls.
No
treatment­
related
tumors
were
observed,
although
the
treated
group
had
an
elevated
incidence
of
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
23
EPA/
OW/
OST/
HECD
Final
draft
epithelial
or
squamous
hyperplasia
of
the
nasal
mucosa
and
hyperplasia
of
the
larynx
and
trachea.

This
study
is
limited
for
the
purpose
of
evaluating
carcinogenic
potential,
due
to
the
testing
of
only
one
exposure
level.

Summary.
The
only
available
study
on
HCl
carcinogenicity
study
in
animals
is
an
inhalation
assay
(
Sellakumar
et
al.,
1985;
Albert
et
al.,
1982).
The
one
concentration
tested
produced
respiratory
tract
hyperplasia
but
no
tumors.
This
study
is
limited
for
the
purpose
of
evaluating
carcinogenic
potential,
due
to
the
testing
of
only
one
exposure
level.

II.
Health
Effects
in
Humans
A.
Case
Reports
and
Clinical
Studies
Case
reports
of
dermal
or
oral
exposure
to
HCl
were
not
identified,
but
irritation
and
necrosis
at
the
sites
of
contact
would
be
expected,
based
on
the
caustic
effect
of
HCl.
The
relevance
of
such
effects
to
cyanogen
chloride
is
questionable.
Oral
toxicity
studies
for
HCl
are
summarized
in
Table
E­
1,
and
inhalation
studies
are
summarized
in
Table
E­
2.

Deschamps
et
al.
(
1994)
reported
on
a
case
of
a
woman
with
no
preexisting
respiratory
complaints,
who
developed
asthma
after
she
accidentally
inhaled
a
mixture
of
sodium
hypochlorite
and
hydrogen
chloride.
The
subject
was
atopic
at
initial
evaluation
a
few
days
after
the
accident,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
24
EPA/
OW/
OST/
HECD
Final
draft
with
a
positive
reaction
to
aeroallergens
and
increased
IgE.
Her
first
asthma
attack
was
44
days
after
the
accident,
and
then
attacks
occurred
periodically
for
at
least
2
years
after
the
accident.

Bronchial
histologic
examination
showed
partial
to
total
epithelial
destruction
and
a
slight
inflammatory
response.
The
authors
suggested
that
the
asthma
resulted
from
epithelial
destruction
impeding
the
release
of
bronchodialator
neuropeptides.

Adults
(
age
18­
25)
with
mild
asthma
(
5/
sex)
were
exposed
to
0,
0.8
and
1.8
ppm
HCl
(
0,

1.2,
and
2.7
mg/
m3)
for
45
minutes,
and
pulmonary­
function
tests
performed
immediately
after
exposure
were
compared
to
baseline
levels
(
Stevens
et
al.,
1992).
Each
subject
was
exposed
to
each
concentration
in
a
double­
blind
fashion,
with
exposures
separated
by
at
least
a
week.
The
exposure
periods
consisted
of
15
minutes
treadmill
walking,
15
minutes
rest,
and
15
minutes
walking.
A
half­
face
mask
was
used
to
allow
nose
and
mouth
breathing,
but
to
eliminate
ocular
exposure.
No
exposure­
related
effects
were
observed
in
subjective
symptoms
or
in
pulmonaryfunction
tests,
including
forced
expiratory
volume
in
1
second
(
FEV
1),
forced
vital
capacity
(
FVC),
maximal
flow
at
50%
and
75%
of
vital
capacity
(
V
max50
and
V
max75),
respiratory
resistance,

and
peak
flow.
This
is
the
only
available
controlled
human
exposure
study
of
HCl.

B.
Epidemiological
Studies
Data
on
the
long­
term
effects
of
acute,
high­
level
exposure
to
HCl
are
limited,
and
no
studies
evaluated
the
noncancer
effects
of
long­
term
human
exposure
to
HCl
via
the
oral,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
25
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draft
inhalation,
or
dermal
routes.
However,
Kilburn
(
1996)
reported
on
a
20­
month
follow­
up
of
a
population
accidentally
exposed
to
unspecified
levels
of
HCl
fumes
in
an
accident.
The
study
was
initiated
because
the
officer
initially
responding
to
the
spill
developed
impaired
balance,
decreased
memory,
headaches,
and
respiratory
illnesses.
No
study
was
conducted
immediately
after
the
spill,
although
the
investigating
officer
and
exposed
residents
reported
tearing
eyes,
burning
throats,
headache,
chest
pain,
shortness
of
breath,
and
flu­
like
symptoms.
The
subjects
completed
questionnaires
on
respiratory
symptoms,
neurologic
disorders,
other
symptoms,
and
exposure;

completed
a
profile
of
mood
states
(
POMS),
and
underwent
physiologic
and
psychologic
testing
and
spirometry.
The
exposed
group
consisted
of
45
adults
and
24
children
who
occupied
the
mobile­
home
park
where
the
accident
occurred.
A
referent
population
of
56
adults
and
39
children
were
recruited
from
a
nearby
mobile­
home
park,
and
an
attempt
was
made
to
match
referents
to
the
exposed
group
for
age
and
educational
characteristics,
although
the
education
level
was
still
significantly
lower
in
the
exposed
group.
Statistically
significant
effects
were
seen
among
the
adults
for
a
number
of
endpoints,
with
the
strongest
effects
on
reaction
time,
digit
symbol
(
a
measure
of
cognitive
function),
and
POMS
scores.
Significant
effects
were
also
seen
on
scores
of
balance
and
perceptual
motor
speed,
and
the
frequency
for
a
number
of
subjective
symptoms.
The
effect
was
stronger
when
only
women
(
who
were
more
likely
to
be
home
at
the
time
of
the
initial
exposure)
were
analyzed,
and
effects
on
balance,
pulmonary
midflow,
and
reaction
time
were
more
abnormal
among
the
subjects
who
lived
closest
to
the
spill.
Covariance
analysis
with
adjustments
for
potential
confounders
(
including
education
level)
found
that
effects
on
reaction
time,
balance,
and
digit
symbol
were
statistically
significantly
associated
with
Drinking
Water
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Document
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exposure.
Statistically
significant
effects
were
also
seen
for
reaction
time
and
balance
in
the
children
(
ages
8­
17).
Spirometry
measurements
were
reduced
compared
to
predicted
in
both
the
exposed
and
referent
groups.
Significant
decreases
compared
to
the
referents
were
seen
in
1­

second
forced
expiratory
volume
(
FEV
1)
and
forced
expiratory
midflow
rate
at
25­
75%
of
vital
capacity
(
FEF
25­
75),
but
it
is
unclear
whether
these
decreases
occurred
in
adults
or
children,
due
to
inconsistencies
between
the
text
and
table.
The
study
author
noted
that
the
exposed
group
had
a
higher
occupational
exposure
to
chemical
refining
and
to
solvents,
but
that
these
exposures
did
not
contribute
to
the
observed
variation.
No
further
details
on
the
analysis
were,
however,

reported.
The
study
author
also
noted
that
he
had
found
evidence
of
chlorine
neurotoxicity
in
a
separate
study.

There
are
several
epidemiology
studies
evaluating
the
potential
carcinogenicity
of
inhaled
HCl.
Bond
et
al.
(
1991)
conducted
a
case­
control
study
of
lung
cancer,
nested
in
a
cohort
of
19,608
male
chemical­
manufacturing
employees
employed
by
Dow
Chemical
Company
in
Texas.

The
case
group
consisted
of
all
308
subjects
who
died
from
cancer
of
the
trachea,
bronchus,
or
lungs
in
the
period
1940­
1980.
The
controls
were
individually
matched
based
on
race,
year
of
birth,
and
year
of
hire.
Two
control
groups
were
chosen
­
one
a
decedent
control
and
the
other
a
"
living
series,"
chosen
from
all
of
the
other
members
of
the
cohort
without
lung
cancer.
HCl
exposure
was
estimated
from
knowledge
of
the
chemical
processes
and
limited
monitoring
data.

The
subjects
were
grouped
by
estimated
8­
hour
TWA
HCl
exposure
into
workers
exposed
to
0,

0.2­
0.3
ppm,
0.9­
2.0
ppm,
and
2.2­
5.1
ppm
(
0.3­
0.4,
1.3­
3,
and
3.3­
7.6
mg/
m3).
Cumulative
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
27
EPA/
OW/
OST/
HECD
Final
draft
exposure
scores
were
also
calculated
for
each
subject
using
the
midpoint
of
the
TWA
range
for
each
job,
and
were
grouped
into
four
categories
(
0,
0.1­
3.9,
4.0­
12.4,
and

12.5
ppm­
years).

Smoking
histories
were
available
for
70.8
of
the
cases
and
75.5%
of
the
controls
from
telephone
interviews.
Other
exposures
at
the
plant
included
asbestos,
benzene,
beryllium,
carbon
tetrachloride,
sulfur
dioxide,
and
wood
dust.
Similar
results
were
obtained
with
both
control
groups,
so
the
results
were
pooled
to
increase
statistical
power.
HCl
exposure
had
no
effect
on
the
lung
cancer
risk
based
on
a
comparison
of
the
cases
and
controls
(
relative
risk
[
RR]
of
1.0,

95%
confidence
interval
[
CI]
of
0.8­
1.3).
Allowing
for
a
15­
year
latency
from
first
exposure
to
HCl
resulted
in
a
slightly
lower
RR
of
0.9
(
95%
CI,
0.7­
1.2).
There
was
no
association
between
increasing
cancer
risk
and
several
measures
of
HCl
exposure,
including
the
exposure
duration,

cumulative
exposure
to
HCl,
and
the
highest
average
exposure.
However,
in
light
of
other
exposures
of
the
cohort
to
lung
cancer­
inducing
agents,
a
smaller
effect
of
HCl
might
have
been
missed.
IARC
(
1992)
stated
that
the
use
of
Mantel­
Haenszel
adjusted
relative
risks
in
this
study
"
may
not
have
been
optimal."
Further
details
were
not
provided.

Siemiatycki
(
1991,
as
cited
by
IARC,
1992)
conducted
a
case­
control
study
of
histologically­
confirmed
cases
of
lung
cancer
among
male
residents
of
Montreal,
Canada.
The
study
included
3,730
cancer
patients
and
533
population
controls
from
an
age­
stratified
sample
of
the
general
population.
An
additional
control
group
consisted
of
cases
of
cancer
at
other
sites
(
cancer
control).
Detailed
lifetime
job
histories
and
data
on
potential
confounders
were
obtained,

and
this
information
was
converted
into
occupational
exposures.
The
293
most
common
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
28
EPA/
OW/
OST/
HECD
Final
draft
occupational
exposures
were
evaluated
as
potential
risk
factors
for
cancer.
Cumulative
exposure
indices
were
estimated,
based
on
duration,
concentration,
frequency,
and
degree
of
certainty
in
the
exposure
assessment.
Those
exposed
were
classified
as
"
any"
or
"
substantial,"
a
subset
of
"
any."
The
analysis
was
repeated
for
the
French­
Canadian
subset
of
the
population
(
about
60%

of
the
total
sample).
There
was
no
association
between
all
cancers
of
the
lung
and
HCl
exposure.

The
odds
ratio
for
oat
cell
carcinoma
of
the
lung
was
1.6
compared
to
the
cancer
controls
(
19
cases,
90%
CI,
1.0­
2.6);
for
workers
exposed
at
the
"
substantial"
level,
the
odds
ratio
was
2.1
(
8
cases,
90%
CI
1.0­
4.5).
In
an
analysis
restricted
to
the
French­
Canadian
subset
and
population
controls,
the
odds
ratio
for
non­
Hodgkins
lymphoma
was
1.6
(
18
cases,
90%
CI
1.0­
2.5),
and
the
odds
ratio
for
rectal
cancer
was
1.9
(
18
cases,
90%
CI
1.1­
3.4).

A
cohort
study
of
1,165
male
steel­
pickling
workers
exposed
for
at
least
6
months
during
the
period
1940­
1964
(
Beaumont
et
al.,
1987)
included
a
subset
of
workers
exposed
to
mists
of
acids
other
than
sulfuric
acid.
[
Exclusion
of
sulfuric
acid
exposure
is
particularly
important,

because
sulfuric
acid
is
a
human
carcinogen
(
IARC,
1992).]
The
primary
acid
to
which
these
workers
were
exposed
was
HCl.
This
study
found
an
excess
risk
for
lung
cancer,
with
a
standardized
mortality
ratio
of
2.24
(
9
deaths,
95%
CI,
1.20­
4.25).
The
excess
persisted
when
workers
who
had
been
employed
in
1950­
1954
were
evaluated,
using
other
steelworkers
as
a
control
for
socioeconomic
and
lifestyle
factors
such
as
smoking
(
SMR,
2.00,
95%
CI,
1.06­
3.78).
Drinking
Water
Criteria
Document
for
Cyanogen
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and
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E­
29
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draft
C.
Summary
of
Human
Studies
HCl
is
a
strong
acid,
so
acute
high­
level
exposures
cause
corrosion
at
the
portal
of
entry
via
the
oral,
inhalation,
or
dermal
routes.
Human
studies
and
reports
of
accidental
exposures
have
generally
been
limited
to
acute
(
e.
g.,
1­
hour)
inhalation
exposures,
and
have
found
that
the
observed
effects
include
nasal
edema,
throat
irritation,
coughing,
and,
at
increasing
concentrations,
bronchitis,
pulmonary
edema
and
death.
A
clinical
study
of
asthmatic
adults
exposed
to
a
maximum
concentration
of
1.8
mg/
m3
HCl
for
45
minutes
found
no
effects
on
pulmonary
function
(
Stevens
et
al.,
1992).
There
have
been
some
reports
of
long­
term
sequalae
to
acute
exposures
of
humans,
including
a
case
report
of
asthma
(
Deschamps
et
al.,
1994)
and
an
epidemiology
study
that
found
decrements
in
pulmonary
function
and
in
neurological
function
(
decreased
balance
and
reaction
time)
one
year
after
an
accident
resulting
in
exposure
of
a
community
(
Kilburn,
1996).
Adjustments
were
made
for
other
exposures,
but
insufficient
details
were
provided
for
an
independent
evaluation.

Human
data
regarding
the
carcinogenicity
of
HCl
are
mixed,
and
include
one
US
cohort
study
showing
excess
lung
cancer
risk
(
Beaumont
et
al.,
1987)
and
one
Canadian
case­
control
study
finding
a
borderline
increased
risk
for
oat­
cell
carcinoma,
but
no
effect
on
other
histological
types
of
lung
cancer
(
Siemiatycki,
1991).
A
large
American
case­
control
study
found
no
excess
risk
of
lung,
brain,
or
kidney
cancer
(
Bond
et
al.,
1991).
Since
the
positive
findings
were
at
the
point
of
contact,
the
relevance
to
cyanogen
chloride
carcinogenicity
is
questionable.
Drinking
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III.
Quantification
of
Toxicological
Effects
Methods
for
the
quantification
of
toxicological
effects
are
described
in
Section
VIII.
A.

A.
Noncarcinogenic
Effects
A.
1.
One­
day
Health
Advisory
No
studies
of
suitable
duration
were
located.
In
the
absence
of
adequate
data,
the
health
advisory
for
the
next­
longer
duration
is
usually
recommended
as
a
conservative
estimate
of
an
appropriate
one­
day
HA
value.
However,
as
described
in
the
following
sections,
no
health
advisories
are
derived
for
HCl.

A.
2.
Ten­
day
Health
Advisory
The
only
study
of
a
duration
and
route
appropriate
for
a
10­
day
HA
is
a
14­
day
study
in
which
liquid
hydrochloric
acid
was
mixed
with
the
feed
of
rats
(
Throssell
et
al.,
1996).
This
study
identified
a
LOAEL
in
rats
of
3600
mg/
kg­
day
based
on
metabolic
acidosis
that
resulted
in
decreased
body
weight,
increased
kidney
weight,
and
kidney
histopathology
detectable
only
using
special
stains.
Although
the
acidosis
is
a
systemic
effect,
these
data
cannot,
however,
be
directly
extrapolated
to
cyanogen
chloride,
due
to
differences
in
the
toxicokinetics
of
ingested
HCl
and
Drinking
Water
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Document
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Cyanogen
Chloride
and
Potential
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E­
31
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draft
HCl
formed
from
cyanogen
chloride
metabolism.
For
example,
ingested
HCl
is
added
to
the
HCl
in
the
stomach,
and
must
be
absorbed
systemically
to
cause
acidosis,
while
cyanogen
chloride
ingestion
results
primarily
in
the
production
of
HCl
in
the
blood
and
liver.
Therefore,
a
Ten­
day
HA
is
not
derived.

A.
3
Longer­
term
Health
Advisory
Only
limited
data
appropriate
for
derivation
of
a
longer­
term
HA
are
available,
and
these
studies
consist
of
two
types.
The
NOAELs
and
LOAELs
identified
in
the
studies
in
which
drinking
water
was
acidified
appeared
to
be
lower
on
a
body­
weight
basis
than
those
in
studies
in
which
acidified
water
was
used
to
moisten
feed
and
produce
metabolic
acidosis.
This
conclusion
is
limited,
however,
by
the
paucity
of
studies
that
identified
both
a
NOAEL
and
a
LOAEL.
Thus,

free­
standing
NOAELs
of
25­
36
mg/
kg­
day
were
identified
in
rats
and
rabbits
provided
drinking
water
at
pH
2.3­
2.5
for
7
months
(
Tober­
Meyer
et
al.,
1981),
compared
with
a
free­
standing
LOAEL
of
1670
mg/
kg­
day
for
decreased
body
weight
and
metabolic
acidosis
when
acidified
water
was
used
to
moisten
feed
in
a
rat
study
(
Throssell
et
al.,
1995).
The
endpoints
evaluated
by
Tober­
Meyer
et
al.
(
1981)
included
both
kidney
and
liver
effects.
Improved
reproductive
performance
was
observed
in
a
continuous­
mating
reproduction
study
in
mice
exposed
for
6
months
to
drinking
water
containing
HCl
at
pH
2.5
and
sodium
chlorite
(
approximately
29
mg/

kgday
(
Les,
1968),
making
this
dose
a
NOAEL.
The
only
drinking­
water
study
in
which
an
effect
was
seen
was
a
study
of
unspecified
duration,
in
which
weanling
rats
were
provided
acidified
Drinking
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draft
water
of
pH
2.3
or
1.7;
severe
stomach
irritation
was
seen
at
the
lower
pH
(
McDougall
et
al.,

1987).
The
corresponding
estimated
daily
doses
were
64
mg/
kg­
day
(
NOAEL)
and
254
mg/

kgday
(
LOAEL).
However,
the
relevance
of
these
drinking­
water
studies
to
cyanogen
chloride
is
questionable,
since
ingested
HCl
is
delivered
directly
to
the
stomach,
while
cyanogen
chloride
ingestion
results
primarily
in
the
production
of
HCl
in
the
blood
and
liver.
Similarly,
although
acidosis
is
a
systemic
effect,
information
on
HCl
doses
in
feed
that
result
in
acidosis
cannot
be
directly
extrapolated
to
cyanogen
chloride,
due
to
uncertainties
regarding
the
relative
rate
and
amount
of
HCl
and
cyanogen
chloride
absorption
from
the
stomach
and
intestines.
Therefore,
a
Longer­
term
HA
is
not
derived.

A.
4
Reference
Dose,
Drinking
Water
Equivalent
Level,
and
Lifetime
Health
Advisory
As
discussed
above,
differences
in
the
toxicokinetics
of
HCl
and
cyanogen
chloride
make
it
inappropriate
to
extrapolate
from
HCl
toxicity
to
cyanogen
chloride.
For
example,
ingested
HCl
is
added
to
the
HCl
in
the
stomach,
and
must
be
absorbed
systemically
to
cause
acidosis,

while
cyanogen
chloride
ingestion
results
in
the
production
of
HCl
in
the
blood
and
liver.

Therefore,
a
Lifetime
Health
Advisory
is
not
derived
for
HCl.

B.
Carcinogenic
Effects
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
E­
33
EPA/
OW/
OST/
HECD
Final
draft
The
only
available
study
on
HCl
carcinogenicity
study
in
animals
is
an
inhalation
assay
(
Sellakumar
et
al.,
1985;
reported
also
as
Albert
et
al.,
1982).
The
one
concentration
tested
produced
respiratory
tract
hyperplasia
but
no
tumors.
This
study
is
limited
for
the
purpose
of
evaluating
carcinogenic
potential,
due
to
the
testing
of
only
one
exposure
level.
Human
data
regarding
the
carcinogenicity
of
HCl
are
mixed,
and
include
one
US
cohort
study
showing
excess
lung
cancer
risk
(
Beaumont
et
al.,
1987)
and
one
Canadian
case­
control
study
finding
a
borderline
increased
risk
for
oat­
cell
carcinoma,
but
no
effect
on
other
histological
types
of
lung
cancer
(
Siemiatycki,
1991).
A
large
American
case­
control
study
found
no
excess
risk
of
lung,
brain,
or
kidney
cancer
(
Bond
et
al.,
1991).
Since
the
positive
findings
were
at
the
point
of
contact,
the
relevance
to
cyanogen
chloride
carcinogenicity
is
questionable.
Therefore,
no
carcinogenicity
assessment
of
HCl
was
conducted
as
part
of
the
cyanogen
chloride
assessment.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
EPA/
OW/
OST/
HECD
Final
draft
E­
34
Table
E­
1.
Summary
of
Oral
Toxicity
Studies
for
HCl.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
One­
Day
HA:
None
Ten­
Day
HA
Wistar
Rat
(
12
females/

group)
Throssell
et
al.,
1996
0,
feed
mixed
with
0.8
M
HCl
intake:
19.7
mmol
HCl/
day
0,
3600
mg/
kg­
day
Water
used
to
moisten
feed
14
days
Metabolic
acidosis,

including
inc
urine
volume,
dec
body
weight,
inc
kidney
weight,
but
kidney
histopathology
limited
to
tubular
casts
None
3600
Study
was
conducted
to
investigate
the
renal
effects
of
metabolic
acidosis;
rats
had
free
access
to
tap
water
for
drinking.

Dose
calculated
using
reported
body
weight
of
200
g
Subchronic
Mouse
Weanlings
(
Number
and
strain
NS)
McDougall
et
al.,
1987
0.02
M
or
0.005
M
HCl
(
pH
1.7
or
pH
2.3
64
or
254
mg/
kg/
day
Drinking
water
NS
­
but
evaluated
as
weanlings
Severe
stomach
irritation
0.005
M
0.02
M
NOAEL
reported
as
concentration,
since
the
effect
at
the
site
of
contact
suggests
a
concentrationrelated
(
rather
than
total
dose­
related)
effect
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
1.
Summary
of
Oral
Toxicity
Studies
for
HCl.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
E­
35
Wistar
Rat
(
32
females
exposed,

21
pair­
fed
female
controls)
Throssell
et
al.,
1995
0,
feed
mixed
with
0.5
M
HCl
intake:
10.3
mmol
HCl/
day
0,
1670
mg/
kg­
day
Water
used
to
moisten
feed
14
weeks
Inc
food
consumption
but
dec
body
weight,

inc
kidney
weight,

urine
volume.
Urinary
protein,
lysozyme,

albumin
peaked
at
week
8,
but
returned
to
baseline
by
end
of
study.
None
1670
Rats
had
free
access
to
tap
water
for
drinking.
No
effect
on
GFR
or
kidney
histopathology.
Authors
suggested
that
there
was
transient
tubular
damage,
but
the
kidney
adapts
to
the
metabolic
acidosis.

Dose
calculated
using
average
of
initial
and
final
body
weights,
225
g
Ico/
Shoe:

WIST
Rat
(
8­
10
males/
group)
Clausing
and
Gottschalk,

1989
0,
drinking
water
acidified
to
pH
2
or
pH
3
with
HCl
Approximately
0.01M
or
0.001
M
HCl
0,
5.4,
54
Drinking
water
21
weeks
Dec
urine
volume,

protein
excretion,

protein
concentration
in
urine
N/
A
N/
A
Study
limited
by
internal
inconsistencies
and
inconsistencies
with
similar
studies,
as
well
as
limited
reporting
of
results.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
1.
Summary
of
Oral
Toxicity
Studies
for
HCl.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
E­
36
Han:
Wistar
Rat
(
10
males/
group)
Tober­

Meyer
et
al.,

1981
0,
drinking
water
acidified
to
pH
2.3­
2.5
with
HCl
Estimated
at
6.14
mmol
HCl/
L
max
0,
36
mg/
kg­
day
Drinking
water
7
months
No
effect
on
the
liver,

kidney,
or
hematological
parameters
36
None
Authors
estimated
that
the
rats
ingested
almost
1/
4
of
the
free
HCl
secreted
by
their
stomachs.
Doses
calculated
using
a
drinking
water
factor
of
0.16
for
male
Wistar
rats
in
a
subchronic
study
(
U.
S.
EPA,
1988)

New
Zealand
White
Rabbit
(
8
M/
group)
Tober­

Meyer
et
al.,

1981
0,
drinking
water
acidified
to
pH
2.3­
2.5
with
HCl
Estimated
at
6.14
mmol
HCl/
L
max
0,
25
mg/
kg­
day
Drinking
water
7
months
No
effect
25
None
None.
Doses
calculated
using
a
drinking
water
factor
of
0.11L/
kg
for
New
Zealand
rabbits
in
a
subchronic
study
(
U.
S.
EPA,
1988)

Reproductive
and
Developmental
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
1.
Summary
of
Oral
Toxicity
Studies
for
HCl.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
E­
37
C3H/
HeJ
or
C57BL/
6J
mouse
(
168
cages/

strain/
condition)
Les,
1968
Tap
water
(
pH
9.2­
9.8)
or
drinking
water
to
which
Na
hypochlorite
and
HCl
added
to
10­

13
ppm
residual
chloride
and
pH
2.5
Approximately
29
mg/
kg­
day
Drinking
water
6
months
continuous
matings
Improved
reproductive
performance
(
in
number
born/
dam
and
number
weaned/
dam)
29
None
Mice
mated
in
pairs
or
1
M
and
2
Fs
Improved
performance
considered
due
to
disinfectant
activity
of
hypochlorite
and
HCl.

Doses
calculated
using
the
average
water
consumption
across
mouse
strains
and
sexes
of
0.2649
L/
kg­
day
(
U.
S.
EPA,
1988)

Dec
=
decreased;
Inc
=
increased;
NS
=
Not
Specified;
GFR
=
glomerular
filtration
rate;
M
=
male;
F
=
female
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
E­
38
EPA/
OW/
OST/
HECD
Final
draft
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
One­
Day
HA
Human
(
45
adults
and
24
children
exposed;
56
adult
and
39
children
controls)
Kilburn,

1996
Accidental
exposure,

not
estimated
Few
hours­

1
day
N/
A
Dec
pulmonary
function
and
neurological
scores
(
balance
and
reaction
time
were
particularly
affected)

20
months
postexposure
N/
A
N/
A
Although
no
exposure
level
available,
this
study
is
useful
for
hazard
identification.

Effects
were
stronger
among
those
expected
to
have
higher
exposure.

Effects
apparent
after
adjustment
for
occupational
solvent
exposure,
but
details
not
provided.

Asthmatic
adults
(
5/
sex)
Stevens
et
al.,
1992
0,
1.2,
2.7
(
0,
0.8,
1.8
ppm)
45
min.

(
15'
walking,

15'
rest,
15'

walking)
N/
A
No
effects
on
subjective
symptoms
or
pulmonary
function
tests
2.7/
None
2.7/
None
Study
done
doubleblind
with
each
subject
exposed
to
each
concentration,
separated
by
at
least
a
week.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
39
Baboon
(
3
males/

group)
Kaplan,

1987;
Kaplan
et
al.,
1988
0,
746,

7460,
14,900
(
0,
500,

5000,
10,000
ppm)
15
minutes
N/
A
Inc
respiratory
frequency
and
minute
volume
during
exposure;
no
effect
on
pulmonary
function
at
3
days
or
3
months
None/

746
N/
A
None
English
Guinea
pig
(
4­
8
males/
group)
Burleigh­

Flayer
et
al.,

1985
0,
480,

1015,
1550,

2060
(
0,
320,
680,

1040,
1380
ppm)
30
minutes
N/
A
Sensory
irritation
resulting
in
decreased
respiratory
rate
at
all
concentrations.

1040
ppm
and
higher
caused
mortality
­

histopath
included
acute
alveolitis
and
lung
congestion
None/
480
N/
A
Concentration­
duration
response
not
linear.

Irritation
at
6
min
at
320
ppm,
but
almost
immediately
at
higher
concentrations
Fisher
344
Rats
(
8
males/
group)
Stavert
et
al.,

1991
0,
1940
(
0,
1300
ppm)
30
minutes
N/
A
Nasal
necrosis,

exudate,
inflammation
6%
mortality
N/
A
N/
A
The
study
also
exposed
rats
via
an
endotracheal
tube
"
mouth
breathers".
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
40
Long
Evans
Rat
(
4/
exposure,

sex
NS)
Einhorn
and
Moore,
1990
0,
112,
224,

448
(
0,
75,
150,

300
ppm)
5­
15
minutes
N/
A
Dec
brainstem
auditory
evoked
response
(
BAER)
at
all
levels;
EEG
affected
at
150
and
300
ppm
N/
A
N/
A
Adversity
of
changes
unclear
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
41
Wistar
Rat
(
8­
15)
Pavlova,

1976
0,
450
(
0,
302
ppm)
1
hour
GD
9
N/
A
One­
third
of
the
animals
died,
with
signs
of
severe
dyspnea
and
cyanosis.
Survivors
had
dec
oxygen
saturation,
hyperchloruria,
and
hyperproteinuria.

Fetal
mortality
was
significantly
elevated.
When
the
progeny
were
subjected
to
an
additional
exposure
of
35
ppm
(
52
mg/
cu.
m)
at
the
age
of
2­
3
months,

functional
abnormalities
in
the
organs
of
the
progeny
were
similar
to
those
found
in
the
mothers.
None
450
No
effect
on
hypoxic
challenge
of
progeny
at
age
2­
3
months.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
42
Wistar
Rat
(
8­
15)
Pavlova,

1976
0,
450
(
0,
302
ppm)
1
hour
Once,

12
days
before
mating
N/
A
One­
third
of
the
animals
died,
with
signs
of
severe
dyspnea
and
cyanosis.
Survivors
had
dec
oxygen
saturation,
hyperchloruria,
and
hyperproteinuria.

When
the
progeny
were
subjected
to
an
additional
exposure
of
35
ppm
(
52
mg/
m3)
at
the
age
of
2­
3
months,

functional
abnormalities
in
the
organs
of
the
progeny
were
similar
to
those
found
in
the
mothers.
None
450
No
effect
on
hypoxic
challenge
of
progeny
at
age
2­
3
months.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
43
Swiss
Webster
mouse
(
16­
24
males,
#

unclear)
Buckley
et
al.,
1984
454
TWA
(
304
ppm)
6
hours/
day
3
days
113
Severe
necrosis
and
exfoliation
of
the
respiratory
epithelium
were
observed,
along
with
minimal
necrosis
of
the
olfactory
epithelium.
None/
454
N/
A
All
of
the
mice
died
or
were
found
moribund
by
the
end
of
the
study.

Fisher­
344
Rat
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
4
days
0,
3.7,
7.5,

19
(
exposure
only
4
d,
so
no
days/
wk
adjustment
Minimal
to
mild
rhinitis,
and
occasional
hyperkeratosis,
of
anterior
portion
of
nasal
cavity
(
Males
more
affected)
3.7/
7.5
N/
A
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days
­

see
subchronic
section
Sprague­

Dawley
Rat
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
4
days
0,
3.7,
7.5,

19
(
exposure
only
4
d,
so
no
days/
wk
adjustment
Minimal
to
mild
rhinitis
of
anterior
portion
of
nasal
cavity
(
Males
more
affected.)
3.7/
7.5
N/
A
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days
­

see
subchronic
section
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
44
B6C3F1
Mouse
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
4
days
0,
3.7,
7.5,

19
(
exposure
only
4
d,
so
no
days/
wk
adjustment
Body
weight
dec
compared
to
preexposure
at
high
concentration
7.5/
19
N/
A
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days
­

see
subchronic
section
Ten­
Day
HA:
None
Subchronic
Fisher­
344
Rat
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
5
d/
week
90
days
0,
2.7,
5.3,

13
Minimal
to
mild
rhinitis,
and
occasional
hyperkeratosis,
of
anterior
portion
of
nasal
cavity
(
Males
more
affected)
None/
2.7
None/
0.24
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days
Sprague­

Dawley
Rat
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
5
d/
week
90
days
0,
2.7,
5.3,

13
Minimal
to
mild
rhinitis
of
anterior
portion
of
nasal
cavity
(
Males
more
affected.)
None/
2.7
None/
0.34
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
metabolites
Table
E­
2.
Summary
of
Inhalation
Toxicity
Studies
for
HCl.

Strain
Species,

Sex
Reference
Exposure
mg/
m3
Duration
Duration­

Adjusted
mg/
m3
Response
NOAEL/

LOAEL
mg/
m3
NOAEL/

LOAEL
(
HEC)

mg/
m3
Comments
EPA/
OW/
OS/
HECD
Final
draft
E­
45
B6C3F1
Mouse
(
31
males,
21
females/
grou
p)
Toxigenics,

Inc.,
1984
0,
15,
30,
75
(
0,
10,
20,

50
ppm)
6
hr/
day
5
d/
week
90
days
0,
2.7,
5.3,

13
Eosinophilic
globules
in
nasal
turbinates,
congestion
(
females
more
affected)
None/
2.7
(
F)
None/
0.25
10
animals/
sex/
group
killed
on
day
5,

10/
sex/
group
killed
and
evaluated
at
90
days.

No
nasal
or
respiratory
tract
inflammation.

Chronic
Sprague­

Dawley
Rat
(
100
males)
Sellakumar
et
al.,
1985;

Albert
et
al.,

1982
0,
15
(
10
ppm)
6
hr/
d
5
d/
week
for
lifetime
0,
2.5
Hyperplasia
of
nasal
mucosa,
and
in
trachea
and
larynx
None/
2.5
None/
6.51
Only
one
concentration
tested;
no
severity
grading,
no
reporting
on
extrarespiratory
histopathology.
Basis
for
EPA's
current
RfC
1The
HEC
presented
on
IRIS
was
used.

Dec
=
Decreased;
Inc
=
Increased;
N/
A
=
Not
applicable;
NS
=
not
specified;
GD
=
gestation
day;
TWA
=
time­
weighted
average;
d
=
days
DrinkingWater
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OS/
HECD
Final
draft
E­
46
Table
E­
3.
Histopathology
Results
Following
Acute
Inhalation
Exposure
to
HCl.

Lesion
Exposure
Concentration
(
ppm)

Males
Females
0
10
20
50
0
10
20
50
Fisher
344
Rats
Acute
Rhinitis
(
Level
A
nasal
turbinate)
0/
10
0/
10
1/
10
4/
10
0/
10
0/
10
0/
10
4/
10
Hyperkeratosis
(
Level
A
nasal
turbinate)
0/
10
0/
10
2/
10
2/
10
0/
10
0/
10
2/
10
2/
10
Subacute
Rhinitis
(
Level
A
nasal
turbinate)
0/
10
0/
10
3/
10
2/
10
0/
10
0/
10
2/
10
3/
10
Levels
B,
C,
D
No
lesions
reported
Sprague­
Dawley
Rats
Acute
Rhinitis
(
Level
A
nasal
turbinate)
0/
10
0/
10
3/
10
5/
10
0/
10
0/
10
1/
10
4/
10
Levels
B,
C,
D
No
lesions
reported
Mice
No
treatmentrelated
lesions
reported
Adapted
from
ToxiGenics,
Inc.
(
1984)
EPA/
OW/
OS/
HECD
Final
draft
E­
47
Table
E­
4.
Histopathology
Results
Following
Subchronic
Inhalation
Exposure
to
HCl.

Lesion
Exposure
Concentration
(
ppm)

Males
Females
0
10
20
50
0
10
20
50
Fisher
344
Rats
Hyperkeratosis
(
Level
A
nasal
turbinate)
0/
10
0/
10
0/
10
2/
10
0/
10
0/
10
1/
10
1/
10
Acute
rhinitis
(
Level
A
nasal
turbinate)
0/
10
3/
10
7/
10
9/
10
0/
10
3/
10
5/
10
6/
10
Levels
B,
C,
D:
No
lesions
reported
Sprague
Dawley
Rats
Congestion
(
Level
A
nasal
turbinate)
1/
10
0/
10
0/
10
1/
10
0/
10
0/
10
0/
10
0/
10
Subacute
rhinitis
(
Level
A
nasal
turbinate)
3/
10
4/
10
7/
10
7/
10
2/
10
4/
10
6/
10
6/
10
Congestion,
Level
B
1/
10
0/
10
0/
10
1/
10
0/
10
0/
10
0/
10
0/
10
Congestion,
Level
C
1/
10
0/
10
1/
10
1/
10
0/
10
0/
10
0/
10
0/
10
Congestion,
Level
D
1/
10
0/
10
0/
10
2/
10
0/
10
0/
10
0/
10
0/
10
Mice
Nasal
turbinate
congestion,
Level
A
0/
10
4/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
11
Eosinophilic
globules
in
nasal
turbinate,
Level
A
0/
10
0/
10
0/
10
2/
10
0/
10
1/
10
0/
10
5/
11
Congestion,
Level
B
0/
10
4/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
11
Eosinophilic
globules
in
nasal
turbinate,
Level
B
0/
10
0/
10
0/
10
2/
10
0/
10
3/
10
6/
10
6/
11
Eosinophilic
globules
in
nasal
turbinate,
Level
C
0/
10
0/
10
0/
10
1/
10
0/
10
0/
10
0/
10
1/
11
Congestion,
Level
C
0/
10
4/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
11
Focal
Hemorrhage,
Level
D
1/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
11
Congestion,
Level
D
0/
10
4/
10
0/
10
0/
10
0/
10
0/
10
0/
10
0/
11
EPA/
OW/
OS/
HECD
Final
draft
E­
48
Adapted
from
ToxiGenics,
Inc.
(
1984)
EPA/
OW/
OS/
HECD
Final
draft
E­
49
Table
E­
5.
Respiratory
Tract
Histopathology
in
Rats
Chronically
Exposed
to
HCl.

Observation
HCl
Air
Control
Colony
Control
Number
of
animals
examined
99
99
99
Larynx
Hyperplasia
22
2
2
Trachea
Hyperplasia
26
6
2
Nasal
Rhinitis
81
72
70
Epithelial
or
squamous
hyperplasia
62
51
45
Squamous
metaplasia
9
5
6
Adapted
from
Sellakumar
et
al.
(
1985)
