Document ID: EPA-HQ-OW-2002-0043-0179
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-08-11T04:00Z

Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
1
EPA/
OW/
OST/
HECD
Final
draft
APPENDIX
C.
CYANATE
I.
Health
Effects
in
Animals
A.
Short­
Term
Exposure
Cyanate.
Toxicity
studies
for
cyanate
are
summarized
in
Table
C­
1.
No
specific
shortterm
studies
of
cyanate
by
the
inhalation
or
dermal
route
of
exposure
were
located.
However,

cyanic
acid
(
HOCN)
is
described
as
highly
irritating
to
the
eyes,
skin,
and
mucous
membranes
(
O'Neil
et
al.,
2001).
The
LD
50
of
sodium
cyanate
by
gavage
is
1,500
mg/
kg
(
corresponding
to
975
mg
cyanate/
kg).
This
is
five
times
greater
than
that
administered
intraperitoneally,
310
mg
sodium
cyanate/
kg
(
202
cyanate/
kg)
(
Haut
et
al.,
1975).
Haut
et
al.
(
1975)
also
reported
that
guinea
pigs
appeared
to
be
more
sensitive
than
rats
to
sodium
cyanate.

Haut
et
al.
(
1975)
conducted
a
series
of
experiments
investigating
the
effects
in
rats
of
exposures
to
cyanate
for
increasing
durations,
and
comparing
the
effects
in
rats
and
guinea
pigs.

Haut
et
al.
(
1975)
evaluated
the
short­
term
effects
of
sodium
cyanate
in
male
albino
rats.

Rats
(
Walter
Reed
Carworth
Farm
strain;
27
treated
animals)
received
sodium
cyanate
by
gavage
at
doses
of
0
or
400
mg
sodium
cyanate/
kg­
day
(
260
mg
cyanate/
kg­
day)
for
3
to
5
days.
After
sacrifice,
the
livers
were
removed
and
evaluated
histopathologically
and
biochemically.
Sixteen
of
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
2
EPA/
OW/
OST/
HECD
Final
draft
the
27
rats
treated
died
within
three
to
five
days.
The
rats
that
died
developed
convulsions
15
to
30
minutes
after
dosing.
Livers
of
the
remaining
treated
animals
demonstrated
increased
glycogen
deposits
and
significantly
decreased
glucose­
6­
phosphatase
activity
in
the
livers
compared
to
controls.
Based
on
increased
mortality,
the
dose
of
260
mg
cyanate/
kg­
day
is
considered
to
be
a
frank
effect
level
(
FEL).

Haut
et
al.
(
1975)
evaluated
the
short­
term
effects
of
sodium
cyanate
in
guinea
pigs
(
strain
and
sex
not
specified).
Guinea
pigs
received
sodium
cyanate
by
gavage
at
doses
of
100
mg/

kgday
(
65
mg
cyanate/
kg­
day)
for
7
days
or
200
mg/
kg­
day
(
130
mg
cyanate/
kg­
day)
for
3
days
(
9
and
5
animals/
group,
respectively).
After
sacrifice,
the
livers
were
evaluated
histopathologically
and
biochemically.
Four
of
the
nine
animals
in
the
65
mg
cyanate/
kg­
day
group
died
following
treatment.
The
livers
of
the
animals
receiving
this
dose
demonstrated
inflammatory
infiltration
and
patchy
necrosis.
All
animals
receiving
the
higher
dose
showed
signs
of
neurotoxicity
characterized
by
paralysis
and
lethargy.
Based
on
increased
mortality,
the
dose
of
100
mg/
kg­
day
(
65
mg
cyanate/
kg­
day)
is
considered
to
be
a
FEL.

Haut
et
al.
(
1975)
investigated
the
effects
of
administering
0
or
200
mg
sodium
cyanate/
kg­
day
(
130
mg
cyanate/
kg­
day)
by
gavage
for
10
days
to
male
albino
rats
(
Walter
Reed
Carworth
Farm
strain;
3
treated
groups
of
10­
15
animals,
numbers
of
controls
not
specified).

Body
weight
gain,
food
consumption,
and
clinical
signs
were
recorded.
Blood
was
collected
for
analysis
of
serum
chemistry.
After
sacrifice,
livers
were
removed
and
evaluated
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
3
EPA/
OW/
OST/
HECD
Final
draft
histopathologically
and
biochemically.
Body
weight
gain
and
food
consumption
were
decreased
in
treated
animals
compared
with
controls;
however,
no
information
was
presented
on
the
statistical
significance
of
these
findings.
Treated
rats
showed
signs
of
neurotoxicity:
one­
half
of
the
rats
developed
neuromuscular
paralysis
of
their
hind
legs
and
nearly
all
showed
marked
lethargy
compared
to
controls.
Treated
rats
had
statistically
significantly­
decreased
blood
sugar
and
increased
serum
glutamic
oxaloacetic
transaminase
(
SGOT)
levels
compared
with
controls.

Livers
of
treated
rats
were
characterized
by
perinuclear
vacuolization,
glycogen
deposits,
and
increased
mitotic
activity.
In
addition,
the
activities
of
glucose­
6­
phosphatase
and
glucose­
6­

phosphate
dehydrogenase
(
G6PD)
in
the
livers
were
significantly
decreased.
Based
on
neurotoxicity
and
liver
toxicity,
a
LOAEL
of
200
mg/
kg­
day
(
130
mg
cyanate/
kg­
day)
was
identified.

Haut
et
al.
(
1975)
also
administered
sodium
cyanate
by
gavage
at
doses
of
0
and
50
mg/
kg­
day
(
32
mg
cyanate/
kg­
day)
to
male
albino
rats
(
Walter
Reed
Carworth
Farm
strain,

number
not
specified)
for
8
weeks.
Body­
weight
gain,
food
consumption,
and
clinical
signs
were
recorded.
Blood
was
collected
for
analysis
of
serum
chemistry.
After
sacrifice,
livers
were
removed
and
evaluated
histopathologically
and
biochemically.
Administration
of
sodium
cyanate
had
no
effect
on
body­
weight
gain
or
food
consumption.
No
differences
were
observed
between
treated
animals
and
controls
in
serum­
chemistry
parameters.
Treated
animals
displayed
a
mild
lethargy.
Livers
of
treated
animals
appeared
normal
under
light
microscopy,
but
showed
a
slight
increase
in
glycogen
deposits.
The
authors
noted
that
this
dose
of
cyanate
was
well
tolerated.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
4
EPA/
OW/
OST/
HECD
Final
draft
Based
on
this,
50
mg/
kg­
day
(
32
mg
cyanate/
kg­
day)
was
identified
as
the
NOAEL.
It
should
be
noted,
however,
that
mild
lethargy
was
observed,
and
more
sensitive
indicators
of
neurotoxicity
were
not
evaluated.

Graziano
et
al.
(
1973)
evaluated
the
effect
on
thyroid
function
of
short­
term
oral
exposure
to
sodium
cyanate.
Female
Sprague­
Dawley
female
rats
(
10/
group)
were
fed
either
stock
diet
or
diet
containing
0.33%
sodium
cyanate
for
one
month
(
assuming
a
body
weight
of
0.204
kg
and
a
daily
food
consumption
of
0.02
kg/
day
[
U.
S.
EPA,
1988],
this
is
equivalent
to
a
dose
of
209
mg
cyanate/
kg­
day).
The
authors
measured
the
distribution
of
125I
among
thyroid
hormones
and
the
ability
of
the
thyroid
to
concentrate
125I.
Administration
of
sodium
cyanate
had
no
effect
on
thyroid
function.
Based
on
this,
209
mg
cyanate/
kg­
day
was
identified
as
a
NOAEL.

Teisseire
et
al.
(
1986)
injected
albino
rats
(
strain
and
sex
not
specified)
intraperitoneally
with
0
or
60
mg
sodium
cyanate/
kg­
day
(
39
mg
cyanate/
kg­
day)
5
times
a
week
for
either
3
weeks
(
15/
group)
or
6
weeks
(
10/
group).
After
the
3­
week
treatment,
the
animals
were
anesthetized
and
evaluated
for
oxygen
transport
and
hemodynamic
parameters.
The
animals
were
then
sacrificed
and
the
heart
excised
and
weighed.
The
animals
treated
for
6
weeks
were
weighed
weekly,
had
blood
drawn
at
regular
intervals,
and
were
evaluated
for
hematological
parameters.

Treated
rats
had
statistically
significantly
decreased
body
weight,
decreased
relative
heart
weight,

and
decreased
right­
ventricle
weight
compared
to
control
rats.
By
21
days
of
treatment,
the
treated
rats
had
significantly
increased
hematological
parameters
compared
with
controls,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
5
EPA/
OW/
OST/
HECD
Final
draft
including
hematocrit,
hemoglobin
concentration,
number
of
red
blood
cells,
and
mean
cell
volume.

The
study
authors
concluded
that
chronic
sodium
cyanate
treatment
produced
hypoxia­
like
effects
(
i.
e.,
induced
polycythemia,
pulmonary
hypertension,
right­
ventricular
hypertrophy,
and
blunted
pulmonary­
pressor
response
to
acute
hypoxia).
Based
on
the
decreased
body
weight
and
decreased
relative
heart
weight,
a
LOAEL
of
39
mg/
kg­
day
was
identified.
However,
this
study
was
conducted
using
intraperitoneal
injection,
a
route
of
exposure
that
is
not
relevant
to
environmental
exposure.
Therefore,
this
study
provides
an
understanding
of
the
potential
hazard
posed
by
cyanate,
but
is
not
suitable
for
dose­
response
assessment.

Summary.
The
short­
term
toxicity
of
cyanate
has
been
evaluated
in
rats
(
Haut
et
al.,

1975;
Graziano
et
al.,
1973;
Teisseire
et
al.,
1986)
and
guinea
pigs
(
Haut
et
al.,
1975).
Guinea
pigs
appear
to
be
more
sensitive
to
cyanate
than
rats.
A
dose
of
260
mg
cyanate/
kg­
day
for
3
to
5
days
resulted
in
increased
mortality
in
rats,
while
a
dose
of
only
65
mg
cyanate/
kg­
day
for
7
days
resulted
in
increased
mortality
in
guinea
pigs
(
Haut
et
al.,
1975).
Short­
term
exposure
to
cyanate
resulted
in
severe
weight
loss
and
signs
of
neurotoxicity
(
convulsions,
lethargy,
and
limb
paralysis)
and
liver
toxicity
(
vacuolization
and
glycogen
deposits).
An
oral
dose
of
130
mg
cyanate/
kg­
day
for
10
days
was
a
LOAEL
in
rats,
based
on
neurotoxicity
and
liver
toxicity.
An
oral
gavage
dose
of
32
mg
cyanate/
kg­
day
for
8
weeks
was
a
NOAEL
in
rats
(
Haut
et
al.,
1975),

but
mild
lethargy
was
observed
at
this
dose
and
no
sensitive
evaluation
of
neurotoxicity
was
conducted.
Oral
exposure
to
cyanate
at
a
dose
of
209
mg
cyanate/
kg­
day
had
no
effect
on
thyroid
function
(
Graziano
et
al.,
1973).
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
6
EPA/
OW/
OST/
HECD
Final
draft
B.
Long­
Term
Exposure
Cyanate.
In
an
18­
month
study,
Tellez­
Nagel
et
al.
(
1977)
fed
15
Sprague­
Dawley
rats
a
diet
containing
0.3%
sodium
cyanate
by
weight
(
based
on
an
average
food
factor
of
0.075
kg/
day
for
male
and
female
Sprague­
Dawley
rats
in
a
chronic
study
[
U.
S.
EPA,
1988],
equivalent
to
a
dose
of
145
mg
cyanate/
kg­
day).
The
rats
were
examined
and
weighed
bi­
weekly
and
half
of
the
controls
and
treated
rats
were
sacrificed
at
18
months.
The
rats
were
sacrificed
by
perfusionfixation
and
the
fixed
brain,
spinal
cord,
dorsal
and
ventral
spinal
roots,
sciatic,
peroneal,
tibial
and
plantar
nerves
were
examined
by
light
and
electron
microscopy.
All
treated
rats
failed
to
gain
as
much
weight
as
the
controls
and
showed
marked
weakness
of
the
hind
limbs,
which
progressed
to
involve
the
upper
extremities
as
well.
A
peripheral
neuropathy
involving
mostly
the
lumbar
roots
and
sciatic
nerves
was
found
along
with
vacuolization
of
myelin.
The
myelin
sheaths
were
distended.
Macrophages
were
actively
splitting
the
myelin
and
phagocytizing
the
myelin
remnants.
Axoplasmic
changes
were
subtle
and
consisted
of
accumulation
of
glycogen
within
vacuoles
and
occasional
adaxonal
invaginations
of
Schwann­
cell
cytoplasm.
Based
on
the
demyelination
of
the
peripheral
axons,
a
LOAEL
of
145
mg/
kg­
day
was
identified.

Kern
et
al.
(
1977)
fed
a
total
of
15
beagle
dogs
(
11
females,
4
males)
doses
of
30
to
170
mg
sodium
cyanate/
kg­
day
(
20
to
111
mg
cyanate/
kg­
day)
5
days/
week
for
12
to
39
months.
The
administered
dose
varied
depending
on
whether
the
dogs
exhibited
toxic
effects.
The
dogs
were
examined
and
weighed
monthly.
Blood
was
obtained
for
a
complete
analysis;
carbamylation
was
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
7
EPA/
OW/
OST/
HECD
Final
draft
evaluated
based
on
levels
of
hydantoin
residues.
Ocular
examinations
were
performed
and
at
sacrifice
the
eyes
were
measured
for
cation
concentration,
reduced
glutathione,
and
lens
water.

Extracellular
space
was
calculated
and
expressed
as
a
percentage
of
total
water
in
the
lens.

Fourteen
dogs
developed
cataracts.
Five
animals
developed
corneal
lesions.
Nearly
all
animals
that
developed
cataracts
showed
signs
of
weight
loss
and
nervous
system
(
tremors,
seizure)
or
gastrointestinal
(
vomiting,
diarrhea)
involvement.
Younger
animals
appeared
more
susceptible
to
cataractogenic
effect
than
older
animals.
Biochemical
changes
in
the
involved
lens
included
an
increase
in
intracellular
sodium
with
a
decrease
in
potassium,
which
the
authors
believed
indicated
increased
leakiness
of
plasma
membranes.
Lens
instability
was
also
evidenced
by
a
61%
increase
in
extracellular
space.
There
was
similarly
a
34%
decrease
in
intracellular
lens
glutathione,
cation
leakage,
and
a
12%
increase
in
lactate
leakage.
Carbamylation
was
greater
in
dogs
with
corneal
lesions
than
the
cataractous
group
as
a
whole.
A
single
dog
received
only
the
lowest
dose
of
20
mg
cyanate/
kg­
day.
The
only
effect
seen
at
this
dose
was
tremors;
no
lens
effects
were
observed.

At
the
next
higher
dose
of
58
mg
cyanage/
kg­
day,
weight
loss,
tremors,
diarrhea,
and
lens
effects
were
seen.
Since
animals
that
did
not
exhibit
signs
of
toxicity
at
lower
doses
were
given
higher
doses,
it
is
reasonable
to
conclude
that
most
of
the
dogs
did
not
exhibit
signs
of
toxicity
at
20
mg
cyanate/
kg­
day,
and
the
single
animal
receiving
the
lowest
dose
can
be
considered
a
sensitive
subject
for
clinical
signs.
Similarly,
since
this
"
sensitive"
animal
did
not
have
weight
loss
or
lens
effects,
it
appears
reasonable
to
suggest
that
the
lens
effects
occurs
at
higher
levels
than
tremors
do
in
the
sensitive
population.
Therefore,
based
on
the
tremors
in
this
dog,
supported
by
weight
loss
and
cataracts
at
higher
doses,
a
LOAEL
of
20
mg
cyanate/
kg­
day
was
identified
in
a
sensitive
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
8
EPA/
OW/
OST/
HECD
Final
draft
population.

Tellez
et
al.
(
1979)
administered
0,
15,
25,
or
35
mg
sodium
cyanate
(
0,
10,
16,
or
23
mg
cyanate/
kg­
day)
to
11
adult
pigtailed
monkeys
(
sex
not
reported)
by
subcutaneous
injection
for
2,

4,
or
6
months.
Following
sacrifice,
the
fixed
tissues
of
the
cerebrum,
brain
stem,
cerebellum,
and
spinal
cord
were
examined
by
light
and
electron
microscopy.
The
animals
receiving
16
or
23
mg/
kg­
day
developed
a
predominantly
demyelinating
lesion
in
the
pyramidal
tracts
of
the
spinal
cord.
This
was
characterized
by
distension
of
the
myelin
sheaths
and
the
presence
of
large
intramyelinic
spaces
formed
by
myelin
breakdown.
No
neuronal
changes
were
observed
in
the
motor
cortex,
basal
ganglia,
midbrain,
medulla
or
anterior­
horn
cells
of
the
spinal
cord.
There
was
no
peripheral
neuropathy,
and,
except
for
an
occasional
distended
fiber
with
dense
bodies
and
whorls
of
neurofilaments,
there
was
no
axoplasmic
damage.
The
controls
and
the
monkeys
maintained
at
10
mg/
kg­
day
displayed
no
clinical
or
anatomical
abnormality
associated
with
cyanate
exposure.
The
authors
concluded
that
cyanate
produces
myelin
damage
similar
to
that
observed
in
the
peripheral
nervous
system
of
the
rat.
However,
in
the
monkey,
this
damage
is
located
in
the
pyramidal
tracts
of
the
spinal
cord.
Based
on
the
demyelinating
lesions
of
the
spinal
cord,
a
NOAEL
of
10
mg
cyanate/
kg­
day
and
a
LOAEL
of
16
mg
cyanate/
kg­
day
were
identified.

However,
this
study
was
conducted
using
subcutaneous
injection,
a
route
of
exposure
that
is
not
relevant
to
environmental
exposure.
Therefore,
this
study
provides
an
understanding
of
the
potential
hazard
posed
by
cyanate,
but
is
not
suitable
for
dose­
response
assessment.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
9
EPA/
OW/
OST/
HECD
Final
draft
Summary.
Long­
term
studies
of
cyanate
by
the
oral
route
of
exposure
are
available
in
monkeys
(
Tellez
et
al.,
1979),
rats
(
Tellez­
Nagel
et
al.,
1977),
and
dogs
(
Kern
et
al.,
1977).
No
data
on
the
long­
term
effects
of
cyanate
by
inhalation
or
dermal
exposure
are
available.
These
studies
are
all
limited
for
risk­
assessment
purposes
because
they
all
only
evaluated
limited
endpoints
(
either
neurotoxicity
or
cataracts).
In
addition,
the
monkeys
were
dosed
by
subcutaneous
injection,
which
is
not
an
environmentally­
relevant
route
of
exposure.
Nonetheless,

these
studies
confirm
results
observed
in
human
case
studies
that
long­
term
exposure
to
cyanate
results
in
severe
weight
loss,
demyelination
of
either
spinal
cord
(
monkeys)
or
peripheral
nerves
(
rats),
and
cataracts
(
dogs).
However,
no
data
are
available
to
rule
out
toxicity
in
other
organ
systems.
The
lowest
LOAEL
observed
was
20
mg
cyanate/
kg­
day
in
dogs
(
Kern
et
al.,
1977).

C.
Reproductive/
Developmental
Toxicity
Graziano
et
al.
(
1973)
examined
the
effects
of
cyanate
on
the
reproductive
capacity
of
mice.
C57BL/
6J
mice
(
6
male/
female
pairs/
group)
were
fed
1%
sodium
cyanate
by
weight
(
assuming
an
average
food
factor
of
0.19
for
males
and
0.20
for
females
[
U.
S.
EPA,
1988],
this
is
equivalent
to
a
dose
of
approximately
1235
and
1312
mg
cyanate/
kg­
day
for
males
and
females,

respectively).
The
doses
were
administered
beginning
on
the
day
of
cohabitation,
the
day
of
cervical
plug
(
gestation
day
0),
or
7
or
14
days
after
the
cervical
plug.
The
authors
observed
the
number
of:
successful
matings,
young
born
in
each
litter,
young
weaned;
and
the
length
of
the
estrus
cycle.
The
birth
weights
of
the
litter
were
recorded
and,
at
the
conclusion
of
the
study,
a
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
10
EPA/
OW/
OST/
HECD
Final
draft
histological
examination
was
performed.
There
were
no
significant
effects
on
the
number
of:

successful
matings,
young
born
and
weaned,
or
the
birth
weight
of
the
pups.
In
addition,
there
were
no
gross
abnormalities
in
the
pups.
However,
the
cyanate­
fed
females
did
not
have
any
further
pregnancies
while
maintained
on
the
cyanate
treatment.
These
mice
had
a
prolonged
anestrus
cycle
and
came
into
estrus
only
occasionally
and
sporadically.
The
authors
concluded
that
this
block
in
reproductive
capacity
was
reversible,
since
normal
pregnancies
and
litters
were
observed
following
resumption
of
a
regular
diet.
Histological
examination
revealed
no
lesions
in
the
ovaries
or
testes.
No
other
endpoints
were
evaluated.
Based
on
a
reduced
reproductive
capacity,
a
LOAEL
of
1235
mg
cyanate/
kg­
day
was
identified.

Summary.
No
standard
multigeneration
or
developmental­
toxicity
studies
of
cyanate
are
available.
In
the
only
study
of
reproductive
effects,
Graziano
et
al.
(
1973)
found
that
a
dose
of
approximately
1200
­
1300
mg
cyanate/
kg­
day
in
the
diet
of
male
and
female
mice
had
no
effect
on
the
number
of
successful
matings,
the
number
of
live
pups
born,
or
the
birth
weight
of
pups.

However,
females
maintained
on
this
diet
following
the
first
pregnancy
had
a
prolonged
anestrus
cycle
and
did
not
have
any
further
pregnancies
while
exposed
to
cyanate.
This
effect
was
reversible;
females
were
able
to
conceive
after
exposure
to
cyanate
stopped.

D.
Mutagenicity
and
Genotoxicity
Only
one
study
regarding
the
mutagenicity
of
cyanate
was
located.
Melzer
et
al.
(
1983)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
11
EPA/
OW/
OST/
HECD
Final
draft
determined
that
although
potassium
cyanate
was
cytotoxic
at
concentrations

0.3
mM,
it
does
not
induce
ouabain­
resistant
mutants
in
Chinese
Hamster
V79
cells
at
any
concentration.

E.
Carcinogenicity
No
studies
on
the
carcinogenicity
of
cyanate
by
any
route
of
exposure
were
located.

II.
Health
Effects
in
Humans
A.
Case
Reports
and
Clinical
Studies
A
number
of
human
clinical
studies
on
orally­
administered
cyanate
are
available,
because
cyanate
underwent
clinical
trials
in
the
1970'
s
as
a
therapeutic
agent
to
treat
sickle­
cell
anemia.

These
studies
are
summarized
in
Table
C­
1.
No
studies
on
the
dermal
or
inhalation
effects
of
cyanate
were
located.

Peterson
et
al.
(
1974)
and
Ohnishi
et
al.
(
1975)
examined
the
effects
of
sodium
cyanate
administered
to
patients
with
sickle­
cell
anemia.
Peterson
et
al.
(
1974)
evaluated
nerve
conduction
in
27
patients
who
were
treated
with
cyanate
to
treat
sickle
cell
anemia
for
periods
ranging
from
47
days
to
749
days.
The
authors
measured
the
maximum
motor
conduction
velocities
of
the
median,
ulnar,
common
peroneal,
and
posterior
tibial
nerves;
sensory
latency
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
12
EPA/
OW/
OST/
HECD
Final
draft
time;
and
cutaneous
sensation
(
measured
in
two
cases
prior
to
sural
nerve
biopsy).
In
16
of
the
27
patients,
the
results
of
the
nerve­
conduction
study
were
consistent
with
polyneuropathy.

These
patients
exhibited
marked
weakness
of
the
upper
and
lower
extremities,
with
distal
weakness
greater
than
proximal
and
right­
sided
effects
more
prominent
than
the
left.
There
was
a
decrease
in
touch
pressure,
joint
position,
and
vibration
sensations
in
the
hands
and
feet.
Patients
had
a
broad­
based
gait
characteristic
of
foot
drop.
The
proximal
and
distal
muscles
showed
spontaneous
fibrillations
and
a
moderate
to
marked
reduction
of
voluntary
recruited
motor
unit
potentials,
some
of
which
were
irregular
and
slightly
larger
in
amplitude.
Twelve
of
the
16
patients
showing
nerve
conduction
abnormalities
showed
a
severe
weight
loss.
Children
appeared
to
have
a
higher
incidence
of
subnormal
conduction
velocities.
The
effects
were
reversible
upon
cessation
of
treatment.
The
authors
concluded
that
the
adverse
effects
were
related
to
both
the
peak
dose
and
total
exposure
time.
In
the
16
patients
with
nerve
conduction
abnormalities,
the
sodium
cyanate
dose
ranged
from
32­
49
mg/
kg­
day,
with
a
mean
of
38
mg/
kg­
day
(
25
mg
cyanate/
kg­
day).
In
the
11
patients
without
nerve
conduction
abnormalities,
the
sodium
cyanate
dose
ranged
from
28
to
45
mg/
kg­
day,
with
a
mean
of
33
mg/
kg­
day
(
21
mg
cyanate/
kg­
day).

Therefore,
based
on
the
incidence
of
polyneuropathy
and
weight
loss,
the
dose
of
38
mg/
kg­
day
(
25
mg
cyanate/
kg­
day)
can
be
considered
a
LOAEL.

Ohnishi
et
al.
(
1975)
conducted
fascicular
biopsies
in
two
patients
with
sickle­
cell
anemia
who
had
been
treated
with
sodium
cyanate
at
doses
of
41
and
44
mg/
kg­
day
(
26
and
28
mg
cyanate/
kg­
day)
for
440
and
600
days,
respectively.
The
biopsies
revealed
a
slight
decrease
in
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
13
EPA/
OW/
OST/
HECD
Final
draft
density
of
large
and
small
myelinated
fibers.
One
of
the
two
patients
had
an
occasional
fiber
with
axonal
enlargement
and
thin
myelin
sheath.
The
most
common
abnormality
in
the
patient
who
had
an
abnormally
elevated
touch­
pressure
sensation
threshold
was
segmental
demyelination.
The
most
common
abnormality
in
the
patient
with
normal
touch­
pressure
sensation
threshold
was
the
presence
of
linear
rows
of
myelin
ovoids.
Ohnishi
et
al.
(
1975)
concluded
that
axonal
degeneration
is
the
main
pathological
change
in
the
sural
nerves
of
patients
with
polyneuropathy
resulting
from
cyanate
ingestion.

In
a
drug
trial,
Charache
et
al.
(
1975)
treated
six
sickle­
cell
anemia
patients
with
oral
doses
of
20­
30
mg
sodium
cyanate/
kg­
day
(
13­
19
mg
cyanate/
kg­
day)
for
approximately
3
to
7
months.
Hematologic
and
chemical
determinations
were
conducted,
irreversibly­
sickled
cells
were
counted,
and
measurements
of
valine
hydantoin
were
made.
Four
of
the
six
patients
exhibited
signs
of
definite
or
suspected
toxicity.
One
patient
developed
a
worsening
of
an
underlying
psychiatric
disorder.
Another
exhibited
severe
weight
loss
and
a
peculiar
taste
in
her
mouth.
Two
patients
had
decreased
nerve­
conduction
velocity
after
6
and
7
months
of
treatment.

However,
no
baseline
was
established
prior
to
initiation
of
the
treatment.
Of
the
two
patients
with
decreased
nerve­
conduction
velocity,
one
was
profoundly
disabled
by
motor
neuropathy
that
primarily
affected
his
legs.
In
this
patient,
the
neuropathy
was
reversible,
since
he
regained
the
use
of
his
legs
after
cyanate
treatment
was
stopped.
Based
on
peripheral
neuropathy,
a
LOAEL
of
13
mg
cyanate/
kg­
day
was
identified.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
14
EPA/
OW/
OST/
HECD
Final
draft
Nicholson
et
al.
(
1976)
evaluated
two
patients
who
had
been
treated
with
orallyadministered
sodium
cyanate
at
30
or
35
mg/
kg­
day
(
19
or
23
mg
cyanate/
kg­
day)
for
six
months.

Both
patients
developed
bilateral
posterior
subcapsular
cataracts.
In
one
of
the
patients,
the
opacity
of
the
lens
regressed
spontaneously
3
month
after
treatment
was
discontinued.
By
experimental
design,
one
patient
was
crossed
over
to
placebo
therapy
for
6
months,
followed
by
another
6­
month
treatment
course.
Following
the
first
treatment,
no
subjective
change
in
visual
function
and
acuity
was
noted,
although
small
axial
posterior
subcapsular
cataracts
were
noted.

In
addition,
the
patient
experienced
a
7%
weight
loss.
During
the
second
course
of
treatment,
the
patient
developed
cataracts,
but
maintained
his
body
weight.
The
authors
also
noted
that
the
patient's
nerve
conduction
was
normal
throughout
treatment.
No
other
toxicity
endpoints
were
discussed.
Based
on
the
development
of
cataracts,
a
LOAEL
of
19
mg
cyanate/
kg­
day
was
identified.

B.
Epidemiological
Studies
No
epidemiological
studies
of
cyanate
were
located.

C.
Summary
of
Human
Studies
There
are
several
clinical
studies
of
oral
exposure
to
cyanate,
because
sodium
cyanate
has
been
used
to
treat
sickle­
cell
anemia.
The
primary
target
of
cyanate
exposure
is
the
peripheral
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
15
EPA/
OW/
OST/
HECD
Final
draft
nervous
system,
resulting
in
peripheral
neuropathy
(
Peterson
et
al.,
1974;
Ohnishi
et
al.,
1975;

Charache
et
al.,
1975).
This
effect
was
characterized
by
decreased
nerve
conduction
velocity,

altered
gait,
weakness,
and
decreased
sensation
in
the
hands
and
feet.
Severe
weight
loss
was
also
reported.
All
of
the
published
studies
tested
only
one
dose
and
reported
an
effect
at
that
dose.
Exposures
were
to
13­
29
mg
cyanate/
kg­
day,
for
47­
749
days.
Cataract
formation
has
also
been
associated
with
ingestion
of
cyanate,
at
20
mg
cyanate/
kg­
day
for
6
months
(
Nicholson
et
al.,
1976).
No
data
on
the
effects
of
dermal
or
inhalation
exposure
to
cyanate
were
located.

No
epidemiological
studies
of
cyanate
were
located.

III.
Quantification
of
Toxicological
Effects
Methods
for
the
quantification
of
toxicological
effects
are
described
in
Section
VIII.
A
of
the
main
document.
Health
Advisories
for
cyanate
are
summarized
in
Table
C­
2.

A.
Noncarcinogenic
Effects
A.
1.
One­
day
Health
Advisory
Cyanate.
No
suitable
studies
were
located.
The
available
studies
are
not
appropriate
as
the
basis
for
the
One­
day
HA,
because
only
frank­
effect
levels
(
causing
paralysis
and
death)
were
identified
(
Haut
et
al.,
1975).
In
the
absence
of
adequate
data,
the
Ten­
day
HA
value
is
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
16
EPA/
OW/
OST/
HECD
Final
draft
recommended
as
a
conservative
estimate
of
an
appropriate
one­
day
HA
value.

A.
2.
Ten­
day
Health
Advisory
Haut
et
al.
(
1975)
observed
mild
lethargy
and
a
slight
increase
in
liver
glycogen
deposits
in
rats
exposed
by
gavage
for
8
weeks
to
32
mg
cyanate/
kg­
day.
In
light
of
the
minimal
and
nonadverse
nature
of
these
effects,
this
dose
can
be
considered
a
NOAEL.
Graziano
et
al.
(
1973)

found
no
effect
on
thyroid
function
in
rats
administered
209
mg/
kg­
day
for
1
month
in
diet.

Although
the
single
dose
tested
was
a
NOAEL,
the
likely
target
organ
(
nervous
system)
was
not
evaluated,
limiting
the
reliability
of
the
NOAEL.
There
are
several
human
studies
in
which
a
single
dose
level
of
cyanate
was
tested
for
periods
ranging
from
3
months
to
1
year
as
a
treatment
in
people
with
sickle­
cell
anemia
(
Peterson
et
al.,
1974;
Ohnishi
et
al.,
1975;
Charache
et
al.,

1975;
Nicholson
et
al.,
1976).
These
studies
identified
LOAELs
of
13­
25
mg/
kg­
day,
based
on
severe
weight
loss
and
peripheral
neuropathy.
None
of
these
studies
indicated
the
minimum
duration
of
exposure
at
which
these
symptoms
began
to
appear.
It
is
unclear
whether
weight
loss
and
neuropathy
began
to
appear
as
early
as
after
10
days
to
a
month
of
exposure,
which
is
the
appropriate
study
duration
for
developing
the
10­
day
HA.
However,
human
data
are
preferred
over
animal
data
as
the
basis
for
the
ten­
day
Health
Advisory,
therefore
the
Charache
et
al.
(
1975)

is
judged
as
the
most
appropriate
option
for
the
derivation
of
the
10­
day
HA.
Furthermore,
the
same
Health
Advisory
would
be
developed
if
it
were
decided
to
default
to
the
Longer­
term
Health
Advisory
for
the
ten­
day
value.
Thus,
the
Ten­
day
Health
Advisory
is
based
on
a
LOAEL
of
13
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
17
EPA/
OW/
OST/
HECD
Final
draft
mg
cyanate/
kg­
day
reported
by
Charache
et
al.
(
1975)
in
a
case
study
of
three
sickle­
cell
anemia
patients
administered
sodium
cyanate
for
3­
7
months.
Although
there
were
only
a
few
subjects
in
this
study,
the
identified
LOAEL
is
supported
by
a
LOAEL
of
25
mg
cyanate/
kg­
day
in
a
study
of
27
people
exposed
for
a
year
(
Peterson
et
al.,
1974;
Ohnishi
et
al.,
1975);
no
corresponding
NOAELs
were
identified.
An
uncertainty
factor
of
10
is
used
to
account
for
the
use
of
a
LOAEL,

and
a
factor
of
10
is
used
to
protect
sensitive
populations.
Neither
the
metabolism
of
cyanate
nor
the
mechanism
of
action
of
cyanate
appear
to
be
related
to
hemoglobin,
and
so
there
is
no
reason
to
expect
sickle­
cell
anemia
patients
to
constitute
a
sensitive
population.

(
13
mg/
kg­
day)
(
10
kg)
Ten­
day
HA
(
for
a
child)
=
=
1.3
mg/
L,
rounded
to
1
mg/
L
(
100)(
1
L/
day)

where:

13
mg/
kg­
day
=
LOAEL,
based
on
the
finding
of
severe
weight
loss
and
peripheral
neuropathy
in
case
studies
of
sickle­
cell
anemia
patients
administered
sodium
cyanate
for
3­
7
months
(
Charache
et
al.,
1975).

10
kg
=
assumed
body
weight
of
a
child.

100
=
composite
uncertainty
factor,
chosen
to
account
for
extrapolation
from
a
LOAEL
in
humans
and
to
protect
sensitive
subpopulations.

1
L/
day
=
assumed
daily
water
consumption
by
a
10­
kg
child.

A.
3
Longer­
term
Health
Advisory
No
studies
of
suitable
duration
via
an
appropriate
route
of
exposure
that
identified
a
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
18
EPA/
OW/
OST/
HECD
Final
draft
NOAEL
were
located
in
either
humans
or
animals.
However,
there
is
a
series
of
case
studies
in
people
with
sickle­
cell
anemia
treated
with
cyanate
at
oral
doses
ranging
from
13
to
25
mg
cyanate/
kg­
day
for
3
months
to
one
year
(
Peterson
et
al.,
1974;
Ohnishi
et
al.,
1975;
Charache
et
al.,
1975;
Nicholson
et
al.,
1976).
The
adverse
effects
included
peripheral
neuropathy
characterized
by
demyelination
and
cataracts.
In
all
cases,
these
symptoms
were
preceded
by
severe
weight
loss.
These
findings
are
supported
by
a
6­
month
study
in
monkeys
treated
by
subcutaneous
injection
which
identified
a
NOAEL
of
10
mg/
kg­
day
and
a
LOAEL
of
16
mg/

kgday
based
on
demyelination
of
the
spinal
cord
(
Tellez
et
al.,
1979).
No
subchronic
animal
studies
of
cyanate
conducted
via
the
oral,
inhalation,
or
dermal
routes
were
identified.
Therefore,
these
human
studies
can
be
used
to
develop
a
Longer­
term
Health
Advisory,
based
on
a
the
lowest
human
LOAEL
of
13
mg
cyanate/
kg­
day
(
Charache
et
al.,
1975).
An
uncertainty
factor
of
10
is
used
to
extrapolate
from
the
LOAEL
to
a
NOAEL,
and
a
factor
of
10
is
used
to
protect
sensitive
individuals,
in
light
of
the
absence
of
available
data
on
human
variability
in
toxicokinetics
and
toxicodynamics.
In
addition
to
the
human
data,
the
database
for
animal
toxicity
studies
with
cyanate
via
environmentally­
relevant
routes
includes
chronic
oral
studies
in
rats
(
Tellez­
Nagel
et
al.,
1977)
and
dogs
(
Kern
et
al.,
1977).
There
is
also
a
subchronic
monkey
study
conducted
by
injection
(
Tellez
et
al.,
1979).
There
are,
however,
no
reproductive
or
developmental
toxicity
studies
of
cyanate.
Based
on
these
considerations,
an
uncertainty
factor
of
3
is
included
for
database
deficiencies.
The
resulting
composite
uncertainty
factor
is
300.

(
13
mg/
kg­
day)
(
10
kg)
Longer­
Term
HA
(
for
a
child)
=
=
0.43
mg/
L
(
rounded
to
0.4
mg/
L)
(
300)(
1
L/
day)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
19
EPA/
OW/
OST/
HECD
Final
draft
where:

13
mg/
kg­
day
=
LOAEL,
based
on
finding
of
severe
weight
loss
and
peripheral
neuropathy
in
case
studies
of
sickle­
cell
anemia
patients
administered
sodium
cyanate
for
3­
7
months
(
Charache
et
al.,
1975).

10
kg
=
assumed
body
weight
of
a
child.

300
=
composite
uncertainty
factor,
chosen
to
account
for
extrapolation
from
a
LOAEL,
for
protect
sensitive
subpopulations,
and
insufficiencies
in
the
database
(
lack
of
reproductive
and
developmental­
toxicity
studies).

1
L/
day
=
assumed
daily
water
consumption
by
a
10­
kg
child.

The
Longer­
term
HA
for
a
70­
kg
adult
consuming
2
L/
day
of
water
is
calculated
as
follows:

(
13
mg/
kg­
day)
(
70
kg)
Longer­
Term
HA
(
for
an
adult)
=
=
1.5
mg/
L
(
rounded
to
2
mg/
L)
(
300)(
2
L/
day)

where:

13
mg/
kg­
day
=
LOAEL,
based
on
finding
of
severe
weight
loss
and
peripheral
neuropathy
in
case
studies
of
sickle­
cell
anemia
patients
administered
sodium
cyanate
for
3­
7
months
(
Charache
et
al.,
1975).

70
kg
=
assumed
body
weight
of
an
adult.

300
=
composite
uncertainty
factor,
chosen
to
account
for
extrapolation
from
a
LOAEL,
for
protection
of
sensitive
subpopulations,
and
insufficiencies
in
the
database
(
lack
of
reproductive
and
developmental­
toxicity
studies).

2
L/
day
=
assumed
daily
water
consumption
by
a
70­
kg
adult.

A.
4
Reference
Dose,
Drinking
Water
Equivalent
Level,
and
Lifetime
Health
Advisory
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
20
EPA/
OW/
OST/
HECD
Final
draft
No
adequate
studies
of
suitable
duration
conducted
via
an
appropriate
route
of
exposure
that
identified
a
NOAEL
were
located
in
either
humans
or
animals.
However,
there
is
a
series
of
case
studies
in
people
with
sickle­
cell
anemia
treated
with
cyanate
at
oral
doses
ranging
from
13
to
25
mg
cyanate/
kg­
day
for
3
months
to
one
year
(
Peterson
et
al.,
1974;
Ohnishi
et
al.,
1975;

Charache
et
al.,
1975;
Nicholson
et
al.,
1976).
The
adverse
effects
included
peripheral
neuropathy
characterized
by
demyelination
and
cataracts.
In
all
cases,
these
symptoms
were
preceded
by
severe
weight
loss.
An
18­
month
rat
study
(
Tellez­
Nagel
et
al.,
1977)
confirmed
the
effects
of
severe
weight
loss
and
peripheral
neuropathy,
but
the
only
dose
tested,
145
mg
cyanate/
kg­
day,
was
an
order
of
magnitude
greater
than
the
doses
causing
similar
effects
in
humans.
A
chronic
oral
study
of
dogs
administered
cyanate
in
capsules
5
times/
week
for
12­
38
months
(
Kern
et
al.,
1977)
also
demonstrated
tremors
in
a
single
dog
at
20
mg
cyanate/
kg­
day.

Other
dogs
apparently
tolerated
this
dose,
and
so
were
given
higher
doses
of
58
mg
cyanate/

kgday
and
higher,
and
exhibited
weight
loss,
tremors,
diarrhea,
and
cataracts.
The
RfD
is
based
on
the
Charache
et
al.
(
1975)
study,
in
light
of
the
variability
of
doses
administered
to
the
dogs,
and
because
it
is
more
appropriate
to
base
the
RfD
on
human
studies,
when
possible.
Therefore,
the
cyanate
RfD
is
based
on
the
lowest
human
LOAEL
of
13
mg
cyanate/
kg­
day
(
Charache
et
al.,

1975).
A
total
of
four
uncertainty
factors
was
used
with
this
LOAEL.
A
factor
of
10
each
was
used
to
account
for
human
variability
and
use
of
a
LOAEL.
A
factor
of
3
was
used
to
account
for
the
fact
that
people
in
the
studies
had
a
less­
than­
lifetime
exposure.
This
partial
uncertainty
factor
was
determined
to
be
sufficient
for
subchronic
to
chronic
extrapolation,
given
the
support
of
the
chronic
dog
study,
which
identified
a
LOAEL
in
an
apparent
sensitive
population
that
is
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
21
EPA/
OW/
OST/
HECD
Final
draft
comparable
to
the
LOAELs
seen
in
the
human
studies.
An
additional
factor
of
3
was
used
to
account
for
deficiencies
in
the
database
(
the
lack
of
reproductive
and
developmental
toxicity
studies
of
cyanate).
A
factor
of
3
is
appropriate
to
account
for
the
absence
of
reproductive
and
developmental
studies,
in
the
presence
of
systemic
toxicity
studies
in
multiple
species.
A
composite
uncertainty
factor
of
1000
results.

Step
1:
Determination
of
a
RfD
for
Cyanate
RfD
=
13
mg/
kg­
day
=
0.013
mg/
kg­
day,
rounded
to
0.01
mg/
kg­
day
1000
where:

13
mg/
kg­
day
=
LOAEL,
based
on
finding
of
severe
weight
loss
and
peripheral
neuropathy
in
case
studies
of
sickle­
cell
anemia
patients
administered
sodium
cyanate
for
3­
7
months
(
Charache
et
al.,
1975).

1000
=
composite
uncertainty
factor
for
use
of
a
LOAEL,
for
protection
of
sensitive
individuals,
use
of
a
less­
than­
lifetime
study
and
incomplete
database
(
lack
of
reproductive
and
developmental
toxicity
studies).

Step
2:
Determination
of
a
Drinking
Water
Equivalent
Level
(
DWEL)
for
Cyanate
DWEL
=
(
0.013
mg/
kg­
day)
(
70kg)
=
0.46
mg/
L
(
rounded
to
0.5
mg/
L)
(
2
L/
day)

where:

0.013
mg/
kg­
day
=
RfD
(
before
rounding)
70
kg
=
assumed
body
weight
of
an
adult
2
L/
day
=
assumed
drinking
water
consumption
of
a
70­
kg
adult
Step
3:
Determination
of
Lifetime
HA
for
Cyanate
Lifetime
HA
=
(
0.46
mg/
L)
(
20%)
=
0.092
mg/
L
(
rounded
to
90

g/
L)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
C­
22
EPA/
OW/
OST/
HECD
Final
draft
where:
0.46
mg/
L
=
DWEL
(
before
rounding)
20%
=
assumed
relative
source
contribution
from
water
B.
Carcinogenic
Effects
There
are
no
cancer
bioassays
of
cyanate.
Cyanate
was
negative
in
the
only
genotoxicity
study
located,
a
mammalian
gene­
mutation
assay
(
Melzer
et
al.,
1983).
Due
to
this
lack
of
data,

cyanate
is
classified
as
Group
D,
Not
Classifiable
as
to
Human
Carcinogenicity,
using
the
U.
S.

EPA
(
1986)
guidelines.
Using
the
U.
S.
EPA
(
1999)
Draft
Guidelines
for
Carcinogen
Risk
Assessment,
the
data
are
inadequate
for
an
assessment
of
the
human
carcinogenic
potential
of
cyanate.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
C­
23
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
One­
Day
HA
Rat,
Carworth
Farm
(
27
males/
group)
Haut
et
al.,

1975
0,
400
mg
Na
cyanate/
kg­
day
(
260
mg
cyanate/
kg­
day)
Gavage
3­
5
days
Inc
mortality,

convulsions,

inc
liver
glycogen
and
dec
liver
G6P
activity
None
260
(

FEL)
None
Guinea
Pig
(
strain
and
sex
not
specified,

5/
group)
Haut
et
al.,

1975
0,
200
mg
Na
cyanate/
kg­
day
(
130
mg
cyanate/
kg­
day)
Gavage
3
days
Paralysis
and
lethargy
None
200
mg/
kg­
day
(
130
mg
cyanate/

kg­
day,

FEL)
None
Ten­
Day
HA
Rat
(
15/
group;

strain
and
sex
not
specified)
Teisseire
et
al.,
1986
0,
60
mg
Na
cyanate/
kg­
day
(
39
mg
cyanate/
kg­
day)
i.
p.
injection
5x/
week
for
3
or
6
weeks
Dec
body
weight,
dec
relative
heart
weight
None
60
mg/

kgday
(
39
mg
cyanate/

kg­
day)
Route
of
exposure
not
relevant
to
environmental
exposure,
but
provides
information
on
hazard
characterization
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
EPA/
OW/
OST/
HECD
Final
draft
C­
24
Guinea
Pig
(
strain
and
sex
not
specified,

9/
group)
Haut
et
al.,

1975
0,
100
mg
Na
cyanate/
kg­
day
(
65
mg
cyanate/
kg­
day)
Gavage
7
days
Death
in
4/
9;

liver
inflammatory
infiltration
and
necrosis
None
100
mg/
kg­
day
(
65
mg
cyanate/

kg­
day)
None
Rat,
Carworth
Farm
(
males,

30­
45)
Haut
et
al.,

1975
0,
200
mg
Na
cyanate/
kg­
day
(
130
mg
cyanate/
kg­
day)
Gavage
10
days
Dec
body
weight
gain
and
food
consumption.

lethargy
and
hindlimb
paralysis.

liver
vacuolation
and
glycogen
deposits
None
200
mg/
kg­
day
(
130
mg
cyanate/

kg­
day)
None
Rat,
Carworth
Farm
(
males,

numbers
not
specified)
Haut
et
al.,

1975
0,
50
mg
Na
cyanate/
kg­
day
(
32
mg
cyanate/
kg­
day)
Gavage
8
weeks
Mild
lethargy,

slight
inc
in
liver
glycogen
deposits
50
mg/

kgday
(
32
mg
cyanate/

kg­
day)
None
None
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
EPA/
OW/
OST/
HECD
Final
draft
C­
25
Rat,
Sprague­

Dawley
(
10
females/

group)
Graziano
et
al.,
1973
0,
0.33%
Na
cyanate
(
209
mg
cyanate/

kgday
a
Diet
1
month
No
effect
on
thyroid
function
(
iodine
uptake
or
distribution
of
hormones)
209
mg/
kg­
day
None
No
other
endpoints
evaluated
in
these
animals;
no
information
on
possible
neurological
effects
Dose
calculated
assuming
a
body
weight
of
0.204
kg
and
a
daily
food
consumption
of
0.02
kg/
day
[
U.
S.
EPA,

1988]

Subchronic
Human
(
27
patients)
Peterson
et
al.,
1974;

Ohnishi
et
al,

1975
28­
49
mg
sodium
cyanate/
kg­
day,

(
18­
32
mg
cyanate/
kg­
day)

dose
range
for
affected
and
unaffected
subjects
Oral
Approximatel
y
1
year
Peripheral
neuropathy
characterized
by
demyelination
and
axonal
degeneration
None
38
mg/

kgday
(
25
mg
cyanate/

kg­
day),

based
on
mean
max.
dose
of
affected
group
Case
studies
of
people
being
treated
with
cyanate
for
sickle
cell
anemia.
16
of
27
people
included
in
study
developed
neuropathy.
Symptoms
preceded
by
severe
weight
loss.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
EPA/
OW/
OST/
HECD
Final
draft
C­
26
Human
(
3
males,
3
females)
Charache
et
al.,
1975
20­
30
mg
sodium
cyanate/
kg­
day
(
13­
19
mg
cyanate/
kg­
day)
Oral
Approximatel
y
3­
7
months
Peripheral
neuropathy
None
20
mg/

kgday
(
13
mg
cyanate
/
kg­
day)
Case
studies
of
3
patients
treated
for
sickle
cell
anemia
with
cyanate.
Symptoms
preceded
by
severe
weight
loss.
Basis
of
10­
day
HA,

longerterm
HA
and
RfD
in
this
Criteria
Document.

Human
(
2
males)
Nicholson
et
al.,
1976
30,
35
mg
sodium
cyanate/
kg­
day
(
19,
23
mg
cyanate/
kg­
day)
Oral
6
months
Cataracts
None
30
mg/

kgday
(
19
mg
cyanate/

kg­
day)
Case
studies
of
2
patients
treated
for
sickle
cell
anemia
with
cyanate.
Symptoms
preceded
by
severe
weight
loss.

Monkey,
pigtailed
Tellez
et
al,

1979
0,
15,
25,
35
mg
Na
cyanate/
kg­
day
(
0,
10,
16,
23
mg
cyanate/

kgday
Subcutaneous
injection
2,
4,
or
6
months
Demyelination
in
spinal
cord.

Lesions
appeared
earlier
at
higher
doses.
15
mg/

kgday
(
10
mg
cyanate/

kg­
day)
25
mg/

kgday
(
16
mg
cyanate/

kg­
day)
Route
of
exposure
not
relevant
to
environmental
exposure,
but
provides
infomation
on
hazard
characterization
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
EPA/
OW/
OST/
HECD
Final
draft
C­
27
Chronic
Rat,
Sprague­

Dawley
(
15/
group,
sex
not
specified)
Tellez­
Nagel
et
al.,
1977
0.3%
sodium
cyanate
(
167
mg
cyanate/

kgday
Diet
18
months
Dec
body
weight
gain,

weakness
and
motor
deficit
of
limbs,

100%
incidence
of
peripheral
neuropathy
characterized
by
demyelination
None
167
mg/
kg­
day
Dose
calculated
based
on
an
average
food
factor
of
0.075
kg/
day
for
male
and
female
Sprague­
Dawley
rats
in
a
chronic
study
[
U.
S.
EPA,
1988]

Dog,
beagle
(
11
females,
4
males)
Kern
et
al.,

1977
30­
170
mg
Na
cyanate/
kg­
day
(
20­
111
mg
cyanate/
kg­
day)
Capsules
5x/
week,
12­

39
months
Weight
loss,

vomiting
and
diarrhea,

seizures
and
tremors,
cataracts
(
in
all
but
the
1
dog
on
30
mg/
kg­
day)
None
30
mg/

kgday
(
20
mg
cyanate/

kg­
day)
Methods
also
describe
rats
exposed
to
0.3%

diet
for
12
months
and
monkeys
exposed
orally
to
50­
100
mg/
kg/
day
for
36
months.
Report
indicates
no
effects
in
these
other
species,

but
no
data
presented.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
C­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanate.

Strain,
Species,

Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg
cyanate/

kg­
day
LOAEL
mg
cyanate/

kg­
day
Comments
EPA/
OW/
OST/
HECD
Final
draft
C­
28
Reproductive
and
Developmental
Mouse,
C57BL/
6J
(
6
mated
pairs/

group)
Graziano
et
al.,
1973
0,
1%
Na
cyanate
(
1235
mg
cyanate/

kgday
for
males
and
1312
mg
cyanate/
kg­
day
for
females)
Diet
Animals
started
on
test
diet
either
on
the
day
of
cohabitation,

GD
0,
GD
7,

or
GD
14
and
continued
throughout
pregnancy
No
effect
on
#

of
successful
matings,
#

pups/
litter,

litter
weight,

or
pup
gross
abnormalities.

Prolonged
anestrus
and
no
subsequent
litters.
None
1235
mg
cyanate/

kg­
day
No
other
endpoints
evaluated
in
this
group;
no
information
on
signs
of
neurotoxicity.
Dose
calculated
assuming
an
average
food
factor
of
0.19
for
males
and
0.20
for
females
(
U.
S.

EPA,
1988)

a
assuming
a
body
weight
of
0.35
kg
and
food
consumption
of
0.03
kg/
day;
ratio
of
cyanate
to
sodium
cyanate
is
0.65
Dec
=
decrease;
FEL
=
frank
effect
level;
GD
=
gestation
day;
Inc
=
Increase.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
C­
29
Table
C­
2.
Summary
of
Development
of
the
Health
Advisories
for
Cyanate
Principal
Study
Critical
Effect
NOAEL/

BMDL
LOAEL
Uncertainty
Factorsa
RfD
(
mg/
kg/
day)
Health
Advisory
(
mg/
L)

Ten­
day
Charache
et
al.,

1975
Severe
weight
loss,
peripheral
neuropathy,
cataracts
None
13
100
(
10H,
10L)
a
N/
A
1
Longer­
term
Charache
et
al.,

1975
Severe
weight
loss,
peripheral
neuropathy
None
13
300
(
10H,
3D,
10L)
N/
A
Child:
0.4
Adult:
2
Lifetime
Charache
et
al.,

1975
Severe
weight
loss,
peripheral
neuropathy,
cataracts
None
13
1000
(
10H,
3D,
10L,

3S)
0.01
0.09