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Chapter
VII.
Mechanism
of
Toxicity
and
Sensitive
Populations
A.
Biochemical
Basis
of
Toxicity
No
studies
have
been
conducted
describing
the
mechanism
of
toxicity
for
cyanogen
chloride.
However,
since
cyanogen
chloride
in
the
blood
is
almost
immediately
metabolized,
it
is
likely
that
the
systemic
toxicity
of
cyanogen
chloride
is
due
to
activity
of
metabolites
rather
than
the
parent
compound.
In
contrast,
irritation
effects
observed
at
the
portal­
of­
entry
following
inhalation
exposure
may
be
due
to
cyanogen
chloride
itself.
As
discussed
in
Chapter
3,
toxic
effects
of
ingested
cyanogen
chloride
and
a
plausible
mode
of
action
can
be
proposed
based
on
consideration
of
cyanogen
chloride
biochemistry
and
the
biochemistry
of
its
known
and
putative
metabolites.

Data
from
humans
and
laboratory
animals
shows
that
exposure
to
cyanogen
chloride
vapor
results
in
irritation
of
the
eyes,
throat,
and
respiratory
tract
(
Flury
and
Zernick,
1931;

Prentiss,
1937;
Michigan
Department
of
Public
Health,
1977;
Reed,
1920;
Aldridge
and
Evans,

1946;
Haymaker
et
al.,
1952).
The
irritation
occurred
within
less
than
a
minute
after
the
initiation
of
exposure
(
Flury
and
Zernick,
1931).
Although
it
is
possible
that
the
irritation
is
due
to
HCl
formed
by
glutathione­
mediated
reduction
to
cyanide
and
HCl
(
which
is
a
very
rapid
reaction
in
blood),
the
glutathione
concentration
in
the
eyes,
throat,
and
respiratory
tract
may
not
be
sufficiently
high
to
result
in
sufficiently
rapid
reduction
of
cyanogen
chloride
and
production
of
HCl.
Similarly,
formation
of
HCl
by
cyanogen
chloride
hydrolysis
or
reactions
with
other
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nucleophiles
is
slow
at
neutral
pH.
These
considerations
suggest
that
the
irritation
is
due
to
the
parent
cyanogen
chloride,
rather
than
one
of
its
metabolites.

Regardless
of
whether
the
parent
or
a
metabolite
is
responsible
for
cyanogen
chloride
irritation,
results
from
exposure
to
cyanogen
chloride
vapor
indicate
that
ingestion
of
large
quantities
of
cyanogen
chloride
may
also
cause
irritation
to
the
mucous
membranes
of
the
mouth
and
throat.
Such
irritant
effects
are
likely
to
be
concentration­
dependent
(
rather
than
dosedependent
and
so
unlikely
to
occur
at
environmentally­
relevant
doses.

As
discussed
in
Chapter
3,
it
is
plausible
that
ingested
cyanogen
chloride
is
absorbed
as
the
parent
compound,
in
light
of
the
pH­
dependence
of
cyanogen
chloride
hydrolysis
and
reaction
with
nucleophiles.
It
appears
that
formation
of
cyanate
and
cyanamide
in
the
gastrointestinal
tract
would
occur
relatively
slowly,
although
reaction
with
other
physiological
nucleophiles
may
occur.

Absorbed
cyanogen
chloride
(
or
its
metabolites)
would
enter
the
blood
stream
either
via
the
portal
vein
or
directly
from
the
intestine.
Rapid
glutathione­
mediated
reduction
of
cyanogen
chloride
to
cyanide
and
HCl
would
be
expected
to
occur,
based
on
injection
and
in
vitro
studies
showing
rapid
reactivity
of
cyanogen
chloride
via
this
pathway
in
blood,
and
the
high
glutathione
concentration
in
the
liver.
Cyanide
produced
in
the
portal
vein
or
liver
would
likely
be
converted
to
thiocyanate
by
the
rhodanese
enzyme
in
the
liver.
Cyanide
formed
in
the
blood
following
intestinal
absorption
of
cyanogen
chloride
would
be
metabolized
by
rhodanese
found
elsewhere
in
the
body,
or
by
mercaptopyruvate
sulfurtransferase,
which
is
concentrated
in
blood
cells.
This
hypothesized
metabolic
pathway
would
suggest
that
HCl
production
would
result
in
transient
pH
decreases,
which
are
at
least
somewhat
localized
to
the
portal
vein
and
liver.
Systemic
acidosis
is
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unlikely
at
environmental
exposures,
as
shown
by
the
calculations
in
Section
III
of
Appendix
E.

This
hypothesis
suggests
that
the
primary
effects
of
ingested
cyanogen
chloride
would
be:
(
1)

systemic
effects
due
to
cyanide
and
thiocyanate,
(
2)
possible
liver
effects
due
to
HCl
and
decreased
pH,
and
(
3)
at
very
high
concentrations,
irritation
of
the
mouth,
throat,
and
possibly
other
portions
of
the
gastrointestinal
tract.
As
noted,
no
ingestion
data
are
available
to
test
the
hypothesized
endpoints.
The
observation
of
nervous
system
effects
from
injection
and
inhalation
exposure
to
cyanogen
chloride
supports
the
prediction
of
systemic
effects
due
to
cyanide.

In
contrast,
the
proposed
liver
effects
would
be
specific
to
first­
pass
metabolism
following
cyanogen
chloride
ingestion.
Ideally,
the
potential
for
liver
effects
could
be
analyzed
by
evaluating
the
local
buffering
capacity
of
the
liver
and
comparing
that
to
HCl
concentrations
produced
by
cyanogen
chloride
metabolism,
but
data
on
the
liver's
buffering
capacity
were
not
located.
In
the
absence
of
such
data,
a
rough
evaluation
can
be
made
by
comparison
with
studies
of
HCl
ingestion.
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
injury
(
SGOT,

SGPT),
at
drinking
water
doses
of
approximately
36
mg/
kg­
day
in
rats
and
25
mg/
kg­
day
in
rabbits.
Comparison
of
these
results
with
cyanogen
chloride
ingestion
is
reasonable,
since
both
involve
exposure
in
drinking
water
and
issues
related
to
first­
pass
metabolism.
Uncertainties
remain
as
to
how
differences
in
the
rate
or
degree
of
absorption
from
the
stomach
would
affect
the
peak
hydrogen
ion
concentration
in
the
liver,
and
the
relative
degree
of
absorption
in
the
stomach
versus
intestine.
In
particular,
the
degree
of
HCl
absorption
at
this
relatively
low
dose
is
unknown.
Liver
effects
were
not
investigated
in
the
feed
studies
that
provided
higher
doses
of
HCl
(
Throssell
et
al.,
1995,
1996),
but
liver
damage
is
not
one
of
the
effects
associated
with
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acidosis
(
Bookallil,
2001),
suggesting
that
the
liver
is
resistant
to
moderate
changes
in
blood
pH.

Overall,
the
data
suggest
that
HCl
produced
from
metabolism
of
cyanogen
chloride
would
not
be
sufficient
to
damage
the
liver,
but
there
are
a
number
of
uncertainties
in
the
data.

The
primary
uncertainties
in
the
proposed
cyanogen
chloride
metabolic
pathway
(
and
associated
predictions
of
toxicity)
are
the
identity
of
other
metabolites
or
reaction
products,
the
degree
to
which
other
metabolites
are
formed,
the
form
in
which
cyanogen
chloride
is
absorbed,

the
degree
of
absorption
in
the
stomach
versus
the
intestine,
and
the
kinetics
of
HCl
formation
and
neutralization.
There
are
also
uncertainties
in
the
overall
quantification
of
cyanogen
chloride
metabolism
to
cyanide
and
thiocyanate,
and
whether
cyanogen
chloride
is
metabolized
directly
to
thiocyanate
in
vivo.

No
in
vitro
studies
evaluating
cyanogen
chloride
toxicity
were
located.
In
the
only
in
silico
(
modeling)
study
evaluating
cyanogen
chloride
toxicity,
Moudgal
et
al.
(
2000)
evaluated
relationships
between
the
structure
of
244
disinfectant
byproducts,
including
21
nitriles,
and
potential
developmental
toxicity
using
a
rat
oral
developmental
toxicity
submodel
of
TOPKAT
®
,
a
quantitative
structure
toxicity
relationship
(
QSTR)
prediction
tool.
Based
on
individual
structural
descriptors,
model
probabilities
were
used
to
derive
qualitative
estimates
as
follows:
0.0
to
0.3
negative,
0.3
to
0.7
indeterminate,
0.7
to
1.0
positive.
The
probability
estimate
is
independent
of
the
potency
or
severity
of
developmental
effects
that
could
be
induced,
and
would
be
interpreted
as
the
likelihood
that
the
chemical
can
cause
developmental
toxicity
in
rats
following
oral
dosing.

As
a
group,
the
nitrile
disinfectant
byproducts
were
characterized
as
having
a
high
probability
of
developmental
toxicity.
Of
the
21
individual
nitrile
compounds,
13
were
positive,
5
were
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negative,
and
for
3
the
model
did
not
make
a
prediction.
Cyanogen
chloride
was
predicted
as
positive
for
developmental
toxicity
using
this
system.
The
effects
of
individual
structural
moieties
were
also
examined
by
the
software
for
various
structural
classes
of
compounds.
The
nitrile
moiety,
chlorine
atom,
and
bromine
atom
were
identified
as
contributing
most
significantly
to
the
developmental
toxicity
predictions
for
the
group
of
20
nitriles.
The
importance
of
the
nitrile
group
in
the
developmental
toxicity
predictions
is
consistent
with
cyanide
as
a
causal
factor
in
the
developmental
toxicity
of
these
compounds
in
vivo,
although
cyanide
itself
has
not
been
shown
to
be
a
developmental
toxicant.

One
way
to
infer
mechanism(
s)
of
toxicity
for
cyanogen
chloride
is
by
comparing
known
toxic
effects
and
target
organs
of
cyanogen
chloride
with
those
of
known
or
potential
metabolites
to
find
similarities.
It
appears
that
cyanogen
chloride
and
cyanide
produce
similar
effects
in
the
central
nervous
system
(
CNS).
As
will
be
discussed
below,
some
of
the
effects
produced
by
cyanogen
chloride,
namely
severe
weight
loss
and
peripheral
neurotoxicity,
are
also
similar
to
those
produced
by
cyanate.
It
is
plausible
that
the
eye
and
respiratory
tract
irritation
and
pulmonary
edema
observed
following
exposure
to
cyanogen
chloride
vapor
are
due
to
the
parent
chemical,
although
HCl
formed
from
cyanogen
chloride
may
also
contribute.
This
initial
examination
of
endpoints
suggests
that
cyanide
can
account
for
the
primary
effects
of
cyanogen
chloride,
but
not
all
of
cyanogen
chloride
toxicity.
In
addition,
no
direct
information
is
available
on
the
effects
of
long­
term
exposure
to
cyanogen
chloride.
In
order
to
further
aid
in
identifying
the
mechanism
of
toxicity
for
cyanogen
chloride,
mechanisms
of
the
known
and
potential
metabolites
of
cyanogen
chloride
are
discussed
in
the
following
paragraphs.
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Cyanide.
The
mechanism
of
toxicity
for
cyanide
has
been
described
in
detail
by
ATSDR
(
1997)
and
is
summarized
here.
The
CNS
is
the
primary
target
of
cyanide
toxicity,
particularly
following
acute
exposure.
Symptoms
of
CNS
toxicity
following
cyanide
exposure
include
respiratory
depression,
convulsions,
coma,
and
death.
Cyanide
appears
to
exert
its
acute
toxic
effects
by
binding
with
cytochrome
c
oxidase,
which
then
becomes
unable
to
catalyze
the
reactions
that
transfer
electrons
from
reduced
cytochrome
c
to
oxygen.
As
a
result,
cellular
oxygen
use
is
impaired
and
aerobic
metabolism
stops.
As
anaerobic
metabolism
proceeds,
blood
levels
of
pyruvic
acid,
lactic
acid
and
NADPH
rise;
the
ATP/
ADP
ratio
decreases.
One
of
the
reasons
that
the
CNS
is
a
primary
target
of
cyanide
toxicity
may
be
the
high
energy
demand
in
nervous
tissue.
The
inhibition
of
oxygen
use
by
cells
causes
oxygen
tension
to
rise
in
the
peripheral
tissues,
which
results
in
a
decrease
in
the
unloading
gradient
for
oxyhemoglobin.
Thus,

oxyhemoglobin
is
present
in
the
venous
blood.
In
addition
to
cytochrome
c
oxidase,
cyanide
binds
to
other
metalloenzymes
that
contain
ferric
iron,
including
catalase,
peroxidase,

methemoglobin,
and
hydroxocobalmin;
this
binding
also
contributes
to
the
symptoms
of
cyanide
toxicity.
Cyanide
also
stimulates
the
release
of
secondary
neurotransmitters
and
catecholamines
from
the
adrenal
glands
and
adrenergic
nerves.
Thus,
the
cardiac
effects
and
the
peripheral
autonomic
responses
observed
following
cyanide
exposure
appear
to
be
due
to
the
increase
of
plasma
catecholamine
levels.
CNS
necrosis
and
demyelination
caused
by
cyanide
may
be
due
to
vasoconstriction
and
low
blood
flow
in
the
brain
resulting
from
low
carbon
dioxide
levels.

Alternatively,
the
decreased
ATP/
ADP
ratio
may
alter
energy­
dependent
calcium
homeostasis
in
nerve
cells.
Thus,
the
acute
effects
of
cyanide
result
primarily
from
the
interruption
of
aerobic
metabolism
and
from
the
release
of
secondary
neurotransmitters
and
catecholamines,
and
include
altered
respiration,
vomiting,
nausea,
and
weakness;
and
ultimately,
convulsions,
coma,
and
death.
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Although
the
CNS
effects
of
cyanide
are
well­
known,
no
definitive
statement
regarding
whether
cyanide
also
causes
peripheral
neuropathy
is
possible
at
this
time.
The
weakness
observed
in
the
epidemiology
study
of
El
Ghawabi
et
al.
(
1975)
could
be
due
to
either
peripheral
or
central
nervous
system
effects,
and
no
objective
measurements
(
such
as
of
nerve
conduction
velocity)

were
performed.

Since
cyanide
is
a
known
metabolite
of
cyanogen
chloride,
and
the
histological
evidence
of
CNS
toxicity,
including
necrosis
and
demyelination,
is
virtually
identical
for
cyanogen
chloride
and
cyanide,
it
is
likely
that
cyanogen
chloride
toxicity
to
the
CNS
is
mediated
through
cyanide.

The
thyroid
and
male
reproductive
system
are
also
target
organs
of
cyanide
toxicity,

particularly
following
longer­
term
exposure.
Cyanide's
effects
on
the
thyroid
are
mediated
by
its
metabolite
thiocyanate;
the
mechanism
of
thiocyanate
toxicity
is
discussed
below.
No
data
were
located
that
indicate
that
cyanide
acts
directly
on
the
thyroid.
No
data
were
located
that
describe
the
mechanism
of
cyanide's
toxicity
on
the
male
reproductive
system,
although
NTP
(
1993)

suggested
that
the
effects
may
be
related
to
perturbations
in
hormonal
balance.
The
available
data
are
insufficient
to
determine
whether
cyanogen
chloride
affects
the
thyroid
or
the
male
reproductive
system.
Only
minimal
data
were
located
on
the
potential
developmental
toxicity
of
cyanide,
and,
for
that
reason,
extrapolation
to
cyanogen
chloride
is
not
possible.
As
discussed
in
greater
detail
in
Section
VII.
C.
2,
Tewe
and
Maner
(
1981)
found
no
evidence
of
cyanide
developmental
toxicity
at
parental
doses
up
to
21.6
mg
CN/
kg­
day.
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Thiocyanate.
There
is
no
question
that
the
thyroid
is
the
primary
target
organ
for
thiocyanate
toxicity;
however,
although
no
toxicity
studies
have
thoroughly
evaluated
other
organs
and
tissues,
toxicity
to
other
targets
cannot
be
ruled
out.
Thiocyanate
acts
by
blocking
the
active
transport
of
iodide
into
the
thyroid
gland.
Because
its
ionic
size
is
similar
to
that
of
iodide,

thiocyanate
is
a
competitive
inhibitor
with
iodide
for
the
Na+/
I­
symporter
protein
that
concentrates
iodide
in
the
thyroid
gland.
In
fact,
the
symporter
has
a
greater
affinity
for
thiocyanate
than
for
iodide
(
Wolff,
1998).
In
addition
to
blocking
iodide
uptake
by
the
thyroid,

thiocyanate
also
causes
iodide
already
accumulated
in
the
thyroid
to
be
discharged
(
Wolff,
1998).

Once
thiocyanate
has
blocked
iodide
uptake
by
the
thyroid,
the
feedback
mechanisms
that
regulate
balance
of
the
thyroid­
pituitary
axis
are
disrupted,
resulting
in
the
classic
symptoms
of
thyroid
toxicity
produced
by
thiocyanate.
Specifically,
by
blocking
iodide
uptake,
thiocyanate
causes
the
thyroid
to
decrease
production
and
secretion
of
the
hormones
triiodothyronine
(
T3)

and
thyroxine
(
T4)
(
Hill
et
al.,
1989).
As
the
blood
levels
of
these
hormones
drop,
the
hypothalamus,
through
the
release
of
thyrotropin
releasing
hormone
(
TRH),
stimulates
the
pituitary
gland
to
produce
thyroid
stimulating
hormone
(
TSH).
TSH
then
interacts
with
receptors
on
the
cell
surface
of
thyroid
follicular
cells
to
stimulate
increased
iodide
uptake
and
production
of
thyroid
hormones.
Under
normal
circumstances,
increasing
blood
levels
of
thyroid
hormones
serves
as
a
negative
feedback
mechanism
on
the
thyroid­
pituitary
axis
and
the
system
equilibrates.

However,
when
thiocyanate
is
present
at
levels
that
completely
block
iodide
uptake,
the
thyroid
cannot
produce
T3
and
T4,
and
so
TSH
levels
in
the
blood
remain
elevated.
As
a
result,
the
thyroid
is
subject
to
excessive
TSH
stimulation,
causing
an
increase
in
thyroid
weight
and
size
as
thyroid
epithelial
cells
increase
in
volume
and
vascularity
and
colloid
is
resorbed
from
the
follicular
lumen
(
Hill
et
al.,
1989).
With
continued
TSH
stimulation,
thyroid
changes
progress
to
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follicular­
cell
hyperplasia,
characterized
by
increased
mitotic
activity
and
in
the
number
of
follicular
cells
per
gland.
Eventually,
prolonged
TSH
stimulation
can
lead
to
thyroid
cancer
in
animals,
although
it
is
not
clear
if
this
progression
occurs
in
humans
(
Hill
et
al.,
1989).
Therefore,

the
symptoms
of
thiocyanate
toxicity,
including
decreased
T3
and
T4
blood
levels,
increased
TSH
blood
levels,
increased
thyroid
weight
and
thyroid
hyperplasia,
are
all
directly
related
to
its
ability
to
block
iodide
uptake
by
the
thyroid.

Thiocyanate
is
a
known
metabolite
of
cyanogen
chloride
and
of
cyanide.
The
thyroid
effects
of
cyanide,
which
are
generally
observed
following
longer­
term
exposure,
are
mediated
through
its
metabolism
to
thiocyanate.
Since
cyanogen
chloride
is
also
metabolized
to
both
cyanide
and
thiocyanate,
and
these
metabolites
are
available
for
distribution
to
the
thyroid,

cyanogen
chloride
would
also
be
expected
to
cause
effects
on
the
thyroid
following
longer­
term
exposure.
No
data
have
been
generated
on
the
thyroid
effects
of
cyanogen
chloride;
additional
research
is
needed
in
this
area.

Cyanate.
The
toxicological
effects
of
cyanate
are
described
in
detail
in
Appendix
C,
but
the
biochemical
mechanisms
are
summarized
here
to
provide
a
context
for
cyanogen
chloride
toxicity.
Cyanate
is
a
biologically
active
molecule
that
forms
irreversible
carbamyl
bonds
with
terminal
amino
groups
of
amino
acids
(
Nicholson
et
al.,
1976).
Although
this
action
of
cyanate
is
relatively
nonspecific
and
can
affect
any
protein,
cyanate
has
a
particular
affinity
for
the
terminal
valine
of
hemoglobin,
forming
a
carbamylated
hemoglobin
molecule
that
has
greater
affinity
for
oxygen
than
noncarbamylated
hemoglobin.
This
property
of
cyanate
led
to
its
use
in
clinical
trials
in
the
1970s
as
a
therapeutic
agent
for
sickle­
cell
anemia.
Carbamylated
hemoglobin
was
thought
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to
reduce
sickling
by
shifting
the
oxygen
dissociation
curve
to
the
left,
thereby
increasing
oxygen
affinity
and
decreasing
the
formation
of
deoxyhemoglobin
S
(
Haut
et
al.,
1975).

The
primary
toxic
effects
of
cyanate
include
severe
weight
loss,
cataracts,
peripheral
neuropathy,
and
liver
toxicity
characterized
by
altered
glycogen
metabolism.
The
mechanism
of
at
least
two
of
these,
cataracts
and
liver
toxicity,
appear
to
be
related
to
the
ability
of
cyanate
to
carbamylate
protein.
Cyanic
acid
(
HOCN)
is
also
described
as
highly
irritating
to
the
eyes,
skin,

and
mucous
membranes
(
O'Neil
et
al.,
2001),
an
effect
that
might
also
be
related
to
carbamylation.
Charache
et
al.
(
1975)
found
that
there
was
considerable
retention
of
carbamylated
residues
in
the
eyes
of
rats
administered
a
single
dose
of
300
mg
potassium
cyanate
by
gavage.
In
addition,
the
lenses
of
rabbits
incubated
with
cyanate
in
vitro
developed
opacities
and
demonstrated
inhibition
of
the
lens
cation
pump
(
Nicholson
et
al.,
1976;
Kern
et
al.,
1977).

Therefore,
it
appears
that
carbamylation
of
either
the
lens
structural
proteins
or
enzymes
that
maintain
ion
fluxes
is
responsible
for
the
development
of
cataracts.
Haut
et
al.
(
1975)

demonstrated
that
cyanate
inhibits
several
liver
enzymes
associated
with
glycogen
metabolism,

including
phosphorylase,
glucose­
6­
phosphatase,
G6PD,
and
UDPG­
pyrophosphorylase.
This
enzyme
inhibition
could
account
for
the
accumulation
of
glycogen
deposits
associated
with
cyanate
exposure.

Less
information
is
available
regarding
the
mechanism
of
the
weight
loss
and
peripheral
neuropathy
caused
by
cyanate.
The
peripheral
neuropathy
is
well­
characterized
as
such
by
objective
measures
such
as
decreased
nerve
conduction
velocity
and
elevated
sensation
threshold
(
Ohnishi
et
al.,
1975;
Charache
et
al.,
1975).
Charache
et
al.
(
1975)
observed
retention
of
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carbamylated
residues
in
the
spinal
cord
of
rabbits
administered
a
single
dose
of
300
mg
potassium
cyanate
by
gavage,
but
no
information
was
provided
on
peripheral
nerves.
It
is
possible
that
cyanate
directly
carbamylates
proteins
in
the
myelin
membrane
or
carbamylates
enzymatic
proteins
associated
with
maintaining
ion
flux
in
the
nerves,
as
was
observed
for
lens
tissue.
However,
no
data
have
been
located
confirming
these
potential
mechanisms.

Alternatively,
the
effects
on
weight
loss
and
nervous
tissue
could
be
mediated
through
the
cyanate­
induced
increase
in
oxygen
affinity
of
hemoglobin.
Teisseire
et
al.
(
1986)
found
that
rats
treated
with
cyanate
for
three
weeks
developed
hypoxia­
like
effects
characterized
by
decreased
body
weight,
increased
oxygen
affinity
of
hemoglobin,
and
altered
red­
blood­
cell
morphology.

The
authors
noted
that
the
weight
loss
was
similar
to
that
observed
in
animals
maintained
in
a
hypobaric
chamber
for
4
weeks,
and
that
the
mechanism
could
be
an
impairment
of
oxygen
diffusion
from
capillaries
to
tissues.

Cyanamide.
The
toxicological
effects
of
cyanamide
are
described
in
detail
in
Appendix
D,
but
the
biochemical
mechanisms
are
summarized
here
to
provide
a
context
for
cyanogen
chloride
toxicity.
Little
is
known
about
the
mechanism
of
toxicity
of
cyanamide.
Cyanamide
is
described
as
having
the
potential
to
cause
irritation
of
the
eyes,
skin,
and
respiratory
system,
as
well
as
salivation
(
O'Neil
et
al.,
2001),
but
the
mechanism
of
these
effects
is
not
known.

Cyanamide
inhibits
the
enzyme
aldehyde
dehydrogenase
(
ALDH)
and
has
been
widely
used
in
Europe
as
a
drug
to
treat
chronic
alcoholism.
When
taken
with
alcohol,
cyanamide
has
an
aversive
effect
caused
by
the
increased
levels
of
aldehyde
in
the
blood
(
Obach
et
al.,
1986b;
Valles
et
al.,

1987).
Toxic
effects
observed
in
humans
and
animals
following
cyanamide
exposure
include
severe
weight
loss,
liver
toxicity
characterized
by
glycogen
deposits,
allergic
dermatitis,
and
male
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reproductive
effects.
Of
these,
only
the
male
reproductive
effects
may
be
related
to
the
action
of
cyanamide
as
an
ALDH
inhibitor.
Valles
et
al.
(
1987)
note
that
ALDH
is
widely
distributed
in
the
body,
especially
in
the
gonads.
Increased
levels
of
acetaldehyde
have
been
shown
to
have
a
toxic
effect
on
the
gonads,
and
other
compounds
that
inhibit
ALDH
have
also
been
associated
with
testicular
toxicity
(
Valles
et
al.,
1987).
The
effect
of
cyanamide
on
weight
loss
appears
to
be
an
anorectic
effect
on
the
CNS
similar
to
that
of
amphetamine­
like
drugs
and
unrelated
to
its
action
as
an
ALDH
inhibitor.
Obach
et
al.
(
1986b)
observed
that
cyanamide
exposure
increased
the
brain
concentration
of
MOPEG­
SO
4,
a
metabolite
of
noradrenaline,
a
change
also
see
with
amphetamines
that
induce
anorexia.
The
mechanism
of
liver
toxicity
is
unknown.
Guillen
and
Vazquez
(
1984)
observed
the
presence
of
inclusion
bodies
(
apparently
containing
glycogen)
in
the
livers
of
rats
that
had
been
exposed
to
cyanamide,
but
had
never
been
exposed
to
ethanol.
The
authors
concluded
that
these
findings
exclude
the
possibility
that
liver
toxicity
seen
in
the
human
studies
is
due
to
accumulation
of
acetaldehyde
or
to
chronic
ethanol
exposure.
They
speculated
that
cyanamide
may
also
have
an
action,
as
yet
unidentified,
on
enzymes
involved
with
glycogen
metabolism.

Relationship
of
Metabolite
Data
to
Cyanogen
Chloride.
In
summary,
all
of
the
toxic
effects
observed
following
cyanogen
chloride
exposure
can
be
accounted
for
by
the
known
or
potential
metabolites.
The
toxic
effects
observed,
together
with
information
about
their
mechanism,
can
also
be
used
to
address
whether
all
of
the
toxic
effects
of
cyanogen
chloride
are
due
to
the
known
metabolites
(
cyanide
and
thiocyanate),
or
whether
other
potential
metabolites
could
also
be
contributing
to
cyanogen
chloride
toxicity.
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As
described
above,
it
is
plausible
that
the
eye
and
lung
irritation
observed
following
exposure
to
cyanogen
chloride
vapor
is
due
to
the
parent
chemical.
It
is
also
possible
that
these
effects
may
be
due
to
HCl,
cyanate,
or
cyanamide
formed
from
hydrolysis
of
cyanogen
chloride
or
reaction
with
ammonia
or
other
amines,
since
all
of
these
latter
chemicals
are
themselves
irritating.

However,
hydrolysis
of
cyanogen
chloride
to
HCl
and
cyanate
would
likely
be
slow
under
the
neutral
to
slightly
acidic
conditions
at
the
contact
sites
of
the
eyes
and
respiratory
tract.

Cyanogen
chloride
might
also
react
with
cellular
constituents
to
produce
HCl
and
substituted
cyanamides,
thiocyanates,
or
cyanates.
However,
it
is
unclear
whether
HCl,
cyanate,
and
cyanamide
would
be
formed
quickly
enough
following
exposure
to
cyanogen
chloride
vapor
to
explain
the
observed
irritation.
Similarly,
the
kinetics
of
their
formation
following
ingestion
exposure
to
cyanogen
chloride
is
unknown,
although
increased
local
concentrations
of
HCl
(
i.
e.,

decreased
pH)
may
occur
in
the
liver
and
portal
vein.
Inhalation
of
hydrogen
cyanide
has
not
been
reported
to
cause
pulmonary
edema
or
eye
irritation,
indicating
that
cyanogen
chloride
itself,

or
a
different
metabolite,
is
responsible
for
the
observed
irritation.

Effects
on
the
nervous
system
constitute
the
second
major
class
of
effects
seen
with
cyanogen
chloride.
The
observed
symptoms
include
muscle
weakness
in
humans
(
Reed,
1920)

and
tremors,
muscle
rigidity,
and
limb
paralysis
in
dogs
(
Haymaker
et
al.,
1952).
The
available
data
and
methods
used
were
not
specific
enough
to
differentiate
between
effects
on
the
central
and
peripheral
nervous
systems,
although
the
limb
paralysis
suggests
that
the
peripheral
nervous
system
may
have
also
been
affected.
Cyanide
is
known
to
affect
the
central
nervous
system;

effects
on
the
peripheral
nervous
system
might
also
occur,
but
the
data
are
not
specific
enough
to
identify
such
effects.
By
contrast,
cyanate
is
known
to
affect
the
peripheral
nervous
system,
based
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on
objective
measures
such
as
nerve
conduction
velocity
(
Ohnishi
et
al.,
1975;
Charache
et
al.,

1975).
A
finding
that
cyanogen
chloride
affects
the
peripheral
nervous
system
would
suggest
that
cyanate
may
be
the
toxic
agent,
but
an
effect
of
cyanide
could
not
be
ruled
out.
Production
of
cyanide
would
be
expected
following
ingestion
exposure
to
cyanogen
chloride,
but
it
is
not
known
whether
cyanate
would
be
produced.
Following
ingestion
of
cyanogen
chloride,
cyanide
that
is
not
detoxified
in
the
liver
as
part
of
first­
pass
metabolism
would
be
expected
to
be
distributed
widely
in
the
body,
including
distribution
to
the
nervous
system.

Other
effects
associated
with
the
known
or
putative
metabolites
of
cyanogen
chloride
involve
endpoints
that
are
either
nonspecific
(
e.
g.,
weight
loss),
or
have
not
been
investigated
following
cyanogen
chloride
exposure
(
e.
g.,
reproductive,
thyroid
effects).
In
the
absence
of
data
on
distribution
following
cyanogen
chloride
exposure,
it
is
plausible
that
metabolites
of
cyanogen
chloride
are
widely
distributed,
and
so
reach
the
target
tissues.
The
parent
cyanogen
chloride
would
be
expected
to
react
quickly
once
it
reaches
the
blood,
and
so
would
not
be
distributed
to
the
target
tissues.

Severe
weight
loss
and
decreased
appetite
were
also
observed
in
workers
chronically
exposed
to
cyanogen
chloride
vapor
(
Reed,
1920).
Severe
weight
loss,
accompanied
by
vomiting
and
diarrhea,
was
also
observed
in
dogs
exposed
to
cyanogen
chloride
via
inhalation
for
2
weeks
(
Haymaker
et
al.,
1952).
Of
the
metabolites
and
potential
metabolites
described
in
this
document,

severe
weight
loss
is
most
closely
associated
with
cyanate
and
cyanamide
(
Haut
et
al.,
1975;
NCI,

1979).
However,
weight
loss
has
also
been
associated
with
chronic
exposure
to
cyanide
(
Wolfsie
and
Shaffer,
as
cited
by
ACGIH,
1996),
although
cases
of
weight
loss
were
not
reported
in
the
Drinking
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cyanide
studies
reviewed
for
this
document.
In
addition,
the
observation
of
Teisseire
et
al.
(
1986)

that
hypoxia
can
cause
weight
loss
supports
the
presumption
that
weight
loss
could
also
result
from
exposure
to
cyanide.
Thus,
the
weight
loss
seen
following
repeated
exposure
to
cyanogen
chloride
suggests
that
cyanate
or
cyanamide
could
be
involved,
but
this
effect
might
also
be
due
to
cyanide.

Male
reproductive
toxicity
has
also
been
observed
in
animals
exposed
to
cyanide
(
NTP,

1993)
or
cyanamide
(
Valles
et
al.,
1987),
and
thyroid
effects
result
from
chronic
exposure
to
cyanide
or
thiocyanate.
In
addition,
liver
toxicity
results
from
exposure
to
cyanate
or
cyanamide.

These
effects
have
not
been
observed
with
cyanogen
chloride,
but
only
limited
toxicity
testing
has
been
conducted
to
date,
and
specific
studies
to
evaluate
reproductive
or
thyroid
effects
of
cyanogen
chloride
have
not
been
conducted.
Therefore,
these
endpoints
do
not
shed
further
light
on
the
issue
of
the
toxic
agents
resulting
from
exposure
to
cyanogen
chloride.

B.
Mechanism
of
Carcinogenesis
There
are
no
cancer
bioassays
of
cyanogen
chloride
or
cyanide;
therefore,
no
conclusion
can
be
made
regarding
their
carcinogencity,
and
any
considerations
of
mode
of
action
are
speculative.
The
limited
genotoxicity
data
for
these
chemicals
(
De
Flora
1981;
De
Flora
et
al.,

1984;
Painter
and
Howard,
1982;
Melzer
et
al.,
1983;
NTP,
1993)
also
indicate
that
genotoxicity
is
not
of
concern,
although
none
of
these
chemicals
has
been
fully
evaluated.
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Moudgal
et
al.
(
2000)
evaluated
relationships
between
the
structure
of
244
disinfectant
byproducts,
including
21
nitriles,
and
potential
carcinogenicity
using
mouse
and
rat
oral
submodels
of
TOPKAT
®
,
a
quantitative
structure
toxicity
relationship
(
QSTR)
prediction
tool.

As
a
group,
the
nitrile
disinfectant
byproducts
were
characterized
as
having
a
low
probability
of
carcinogenicity
and
cyanogen
chloride
was
predicted
as
negative
in
male
and
female
rats
and
mice.

The
carcinogenic
potential
of
thiocyanate
is
also
unknown.
Information
on
thiocyanate
carcinogenicity
is
limited
to
two
oral
carcinogenicity
studies
in
rats
conducted
in
the
same
laboratory
(
Lijinsky
and
Reuber,
1982;
Lijinsky
and
Kovatch,
1989).
The
only
effect
in
the
first
study
was
an
increase
in
liver
tumors,
and
this
was
not
confirmed
at
the
higher
dose
tested
in
the
second
study.
The
second
study
suggested
an
increase
of
thyroid
tumors
in
treated
animals.

Although
the
increase
was
not
statistically
significant,
it
is
consistent
with
thiocyanate's
mode
of
action.
Limitations
of
these
studies
include
the
testing
of
only
a
single
dose,
use
of
an
insufficient
number
of
animals,
and
incomplete
evaluation
of
key
information.
In
addition,
the
thoroughness
of
the
histopathological
evaluation
(
and
whether
the
thyroid
was
evaluated)
is
unclear,
since
the
authors
only
stated
that
major
organs
and
all
lesions
were
evaluated.
Potassium
thiocyanate
does
not
have
any
structural
alerts
for
genotoxicity
(
Rosenkranz
and
Klopman,
1990),
and
genotoxicity
data
are
limited
to
marginal
results
in
a
S.
typhimurium
mutagenicity
assay
(
Kier,
1988,
as
reported
by
Rosenkranz
and
Klopman,
1990).

However,
the
biochemical
activity
of
thiocyanate
suggests
that,
at
sufficiently
high
doses,

thiocyanate
could
cause
thyroid
tumors.
A
similar
supposition
would
apply
to
cyanide,
since
it
is
metabolized
to
thiocyanate.
As
described
in
greater
detail
in
Section
VII.
A,
thiocyanate
acts
by
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blocking
the
active
transport
of
iodide
into
the
thyroid
gland,
resulting
in
decreased
levels
of
the
thyroid
hormones
T3
and
T4,
and
increased
production
of
TSH
(
Hill
et
al.,
1989).
Since
sufficiently
high
thiocyanate
levels
block
the
negative­
feedback
regulation
of
TSH,
the
increased
TSH
levels
in
the
blood
can
result
in
increased
thyroid
weight,
follicular­
cell
hyperplasia,
and
ultimately
cancer.
This
mode
of
action
is
well­
established
for
chemicals
that
alter
thyroid
hormone
homeostasis,
and
indicates
that
thiocyanate
(
and,
therefore,
cyanide)
can
cause
thyroid
tumors
in
rats.
It
is
unknown,
however,
whether
they
actually
do
cause
tumors
at
nonlethal
doses.
In
addition,
because
rats
lack
thyroxine­
binding
globulin,
resulting
in
a
much
shorter
T4
half­
life
than
in
humans
(
12­
24
hours,
in
contrast
to
6­
7
days
in
humans),
humans
are
less
sensitive
than
rats.
It
is
not
clear
if
the
progression
from
decreased
levels
of
thyroid
hormones
to
thyroid
tumors
occurs
in
humans
(
Hill
et
al.,
1989).
Finally,
if
thiocyanate
or
cyanide
did
cause
thyroid
tumors
via
this
mode
of
action,
protection
against
changes
in
TSH
levels
would
protect
against
cancer,
and
so
extrapolation
to
low
doses
would
be
using
the
margin
of
exposure
approach.

The
carcinogenicity
of
cyanamide
also
cannot
be
determined.
In
the
only
standard
cancer
bioassay
on
cyanamide,
NCI
(
1979)
evaluated
the
carcinogenicity
of
calcium
cyanamide
in
drinking
water
to
F344
rats
and
B6C3F1
mice.
No
tumors
related
to
treatment
were
observed
in
rats.
The
incidence
of
hemangiosarcomas
was
elevated
in
male
mice,
and
the
incidence
of
malignant
lymphomas
was
elevated
in
female
mice.
However,
NCI
(
1979)
did
not
consider
either
of
these
tumors
to
be
clearly
related
to
administration
of
calcium
cyanamide,
because
the
incidence
of
hemangiosarcomas
was
not
significantly
different
from
controls,
and
the
incidence
of
malignant
lymphomas
was
within
the
range
of
historical
controls.
Based
on
negative
results
in
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bacterial
gene­
mutation
assays
(
Loveless
et
al.,
1954;
Zeiger
1987),
a
Drosophila
sex­
linked
recessive
gene­
mutation
assay
(
Yoon
et
al.,
1985),
an
assay
of
DNA
damage
in
mammalian
cells
(
Sina
et
al.,
1983),
and
a
micronucleus
assay
in
mice
(
Menargues
et
al.,
1984),
cyanamide
is
not
expected
to
be
genotoxic.

C.
Interactions
and
Susceptibilities
This
section
focuses
on
the
metabolic
pathway
in
which
cyanogen
chloride
is
metabolized
to
cyanide
and
thiocyanate,
since
these
are
the
only
metabolites
that
have
been
identified
in
vivo.

Cyanate
is
also
addressed,
since
cyanide
can
also
be
converted
to
cyanate.

1.
Potential
Interactions
No
data
were
located
on
the
potential
interactions
between
cyanogen
chloride
or
its
metabolites
and
other
chemicals.
However,
since
cyanide
and
thiocyanate
are
known
metabolites
of
cyanogen
chloride,
it
would
be
expected
that
the
effects
of
cyanogen
chloride
would
be
additive
with
the
effects
of
cyanide
and
thiocyanate.
In
addition,
additive
effects
would
be
expected
for
any
other
chemicals
that
act
through
similar
mechanisms.

Data
are
available
to
suggest
that
carbon
monoxide,
carbon
dioxide
and
ascorbic
acid
may
increase
the
toxicity
of
cyanide.
Levin
et
al.
(
1987)
evaluated
the
interactions
between
exposure
to
hydrogen
cyanide
and
carbon
monoxide
or
carbon
dioxide
in
rats
at
exposure
levels
near
the
hydrogen
cyanide
LC
50.
Co­
exposure
to
hydrogen
cyanide
and
carbon
monoxide
resulted
in
approximately
additive
effects
on
lethality.
Co­
exposure
to
hydrogen
cyanide
with
carbon
dioxide
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at
the
nonlethal
concentration
of
5%
decreased
the
LC
50
to
75
ppm,
compared
with
110
ppm
for
hydrogen
cyanide
alone,
suggesting
a
more
than
additive
effect
on
lethality.
Basu
et
al.
(
1983)

reported
that
pretreatment
of
guinea
pigs
with
ascorbic
acid
potentiated
the
toxic
effects
of
oral
dosing
with
potassium
cyanide.
Only
3/
8
of
the
guinea
pigs
exhibited
slight
tremors
following
exposure
to
3.2
mg/
kg
cyanide
as
potassium
cyanide
alone,
but
severe
tremors
and
convulsions
were
seen
in
all
animals
that
were
pretreated
for
3
days
with
300
mg
ascorbic
acid
(
approximately
1.3
mg/
kg)
and
received
the
same
dose
of
cyanide.
The
authors
suggested
that
ascorbic
acid
competes
with
cyanide
for
cysteine,
decreasing
the
detoxification
of
cyanide.
Compounds
that
inhibit
cytochrome
c
oxidase,
such
as
sulfide
or
azide,
would
also
be
expected
to
interact
with
cyanide.

Chemicals
that
interfere
with
cyanide
toxicity
have
been
extensively
studied
as
part
of
the
identification
of
antidotes
(
reviewed
in
ATSDR,
1997).
Compounds
that
act
as
sulfane
sulfur
donors
include
thiosulfates
and
polythionates.
These
chemicals
aid
in
the
detoxification
of
cyanide
by
rhodanese.
The
other
major
class
of
cyanide
antagonists
produce
compounds
that
compete
with
cytochrome
c
oxidase
for
binding
to
cyanide.
Chemicals
in
this
class
include
sodium
nitrite,
amyl
nitrite,
and
hydroxylamine,
all
of
which
form
methemoglobin.

Methemoglobin
interacts
with
cyanide
to
form
cyanomethemoglobin,
preventing
the
cyanide
from
binding
to
cytochrome
c
oxidase
and
exerting
its
toxic
effects.
Cobalt
may
also
act
as
an
antagonist
by
forming
a
stable
complex
directly
with
cyanide.
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2.
Childhood
Susceptibility
Cyanide.
Data
are
limited,
but
there
is
no
indication
that
children
or
fetuses
are
particularly
susceptible
to
the
acute
effects
of
cyanide.
Rather,
as
discussed
in
the
next
section,

the
limited
data
suggest
that
young
animals
may
be
less
susceptible
than
older
animals
to
the
acute
effects
of
cyanide
(
McMahon
and
Birnbaum,
1990).
In
support
of
this
possibility,
a
study
of
an
epidemic
of
konzo
(
spastic
paraparesis
associated
with
cassava
consumption
and
associated
cyanide
exposure)
found
no
cases
in
children
under
4
years
of
age
out
of
72
cases
examined
(
Cliff
et
al.,
1997).
It
does
not
appear
that
the
method
of
case
identification
(
through
community
notice)
would
have
excluded
young
children,
but
the
degree
of
exposure
of
young
children
was
not
addressed
in
the
article.
A
prolonged
period
of
breast
feeding
may
have
reduced
exposure
for
the
children.
In
contrast,
Rosling
(
1987,
as
cited
in
ATSDR,
1997)
reported
that
children
and
women
may
be
more
susceptible
to
spastic
paraparesis.
As
described
in
Section
VII.
C.
3,
the
limited
available
data
on
age­
related
differences
in
acute
toxicity
and
in
the
expression
of
enzymes
that
metabolize
cyanide
suggest
that
susceptibility
increases
with
old
age,
at
least
partially
because
of
decreased
activity
of
the
detoxifying
enzyme
rhodanese
(
McMahon
and
Birnbaum,

1990).

While
higher
levels
of
rhodanese
in
young
animals
would
decrease
the
acute
toxicity
of
cyanide,
it
would
increase
the
thiocyanate
levels
in
the
body,
and
thus
increase
the
susceptibility
to
thyroid
effects,
including
neurodevelopmental
effects
secondary
to
thyroid
effects.
In
addition,

the
effects
of
decreased
thyroid
hormone
levels
can
be
more
adverse
in
fetuses.
While
hypothyroidism
in
adults
typically
results
in
goiter
(
an
enlarged
thyroid),
congenital
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hypothyroidism
is
associated
with
stunted
bodily
growth
and
mental
development.
Because
the
youngest
animals
evaluated
in
the
McMahon
and
Birnbaum
(
1990)
study
were
2­
3
months
old,

and
the
late
gestational
and
early
neonatal
periods
constitute
the
critical
time
window
for
the
effects
of
thyroid­
hormone
levels
on
neurodevelopment
(
Porterfield,
1994;
Porterfield,
2000),
the
results
of
that
study
are
not
informative
with
regard
to
the
effects
of
age­
related
differences
in
metabolism
on
relative
sensitivity
to
any
neurodevelopmental
effects
of
cyanide
(
or
cyanogen
chloride).
Since
the
thyroid
effects
of
cyanide
result
from
its
conversion
to
thiocyanate,
they
are
discussed
below
in
further
detail
in
the
context
of
thiocyanate.

Data
on
the
developmental
toxicity
of
cyanide
are
limited
to
one
dietary
study
in
rats.

Tewe
and
Maner
(
1981)
observed
no
effects
on
pup
weights,
litter
size,
or
pup
mortality
in
the
offspring
of
dams
exposed
to
21.6
mg
CN/
kg­
day
as
KCN
throughout
mating,
gestation,
and
lactation.
There
was,
however,
a
significant
decrease
in
food
consumption
and
growth
rate,
and
an
increase
in
the
ratio
of
food
consumption
to
body
weight
gain
in
weanling
rats.
The
single
dose
tested
in
this
study
is
approximately
5­
fold
the
NOAEL
of
4.5
mg
CN/
kg­
day
for
male
reproductive
effects
(
and
almost
30
times
the
corresponding
BMDL)
that
is
the
basis
for
the
cyanide
RfD
presented
in
Chapter
VIII.
However,
since
no
internal
examination
was
conducted,

the
teratogenic
potential
of
cyanide
is
unknown,
although,
presumably,
the
authors
would
have
noted
overt
external
malformations.
Although
the
NOAELs
for
other
endpoints,
such
as
the
male
reproductive
toxicity
seen
with
cyanide
exposure,
are
lower
than
those
identified
for
changes
in
serum
levels
of
thyroid
hormones
in
developmental
toxicity
studies,
neurodevelopmental
effects
and
sensitive
markers
of
a
hypothyroid
state
(
e.
g.,
brain
levels
of
thyroid
hormones)
have
not
been
evaluated
in
any
study
of
cyanide
toxicity.
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Thiocyanate.
Limited
data
were
located
that
directly
investigated
age­
related
differences
in
the
systemic
toxicity
of
thiocyanate.
In
the
only
study
addressing
this
issue
with
dose­
response
information,
Kreutler
et
al.
(
1978)
evaluated
thyroid
weight
in
rat
pups
and
their
dams
in
a
study
where
the
groups
of
4­
7
pregnant
dams
were
administered
sodium
thiocyanate
in
drinking
water
during
gestation
through
postpartum
day
10.
As
described
further
in
Section
V.
C,
the
estimated
doses
were
0,
6.3,
12.6,
and
25.3
mg
SCN/
kg­
day.
Thyroid
weights
of
the
dams
(
relative
to
body
weight)
were
significantly
increased
at
all
doses
at
5
days
postpartum,
but
only
at
the
high
dose
at
10
days
postpartum.
In
the
pups,
there
were
dose­
related
increases
in
thyroid
weights
that
were
statistically
significant
at
all
doses
on
day
5,
but
only
at
the
two
top
doses
on
day
10.
Some
of
the
difference
between
the
results
in
the
dams
on
days
5
and
10
postpartum
may
be
an
artifact
of
the
small
sample
size,
since
the
control
relative
thyroid
weight
was
much
lower
at
day
5
than
day
10.

However,
the
magnitude
of
the
effect
on
thyroid
weight
was
also
higher
in
the
pups
at
each
dose
level.
These
results
suggest
that
the
pup
is
more
sensitive
than
the
dam
to
the
thyroid
effects
of
thiocyanate,
particularly
since
the
plasma­
thiocyanate
levels
were
much
lower
in
the
pups.

However,
the
absence
of
an
evaluation
of
other
endpoints
of
thyroid
toxicity
(
e.
g.,
thyroid
hormone
levels,
histopathology)
makes
it
difficult
to
determine
whether
the
increased
thyroid
weight
in
the
pups
was
adaptive
or
adverse.
T4
levels
were
evaluated
by
Bala
et
al.
(
1996)
in
dams
exposed
to
thiocyanate
in
the
diet
for
8
weeks,
from
weaning
through
conception,

pregnancy,
and
lactation,
and
in
their
pups
at
weaning.
Serum
T4
levels
were
significantly
decreased
in
both
the
dams
and
pups.
The
absolute
T4
levels
were
similar
in
both
groups,

although
the
control
levels
were
lower
in
the
pups,
so
the
magnitude
of
the
decrease
was
lower
in
the
pups.
Only
one
dietary
level
of
thiocyanate
was
tested.
In
addition,
the
amount
transferred
to
the
pups
is
not
known;
therefore,
comparisons
cannot
be
done
on
a
mg/
kg­
day
basis.
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Limited
human
data
support
the
suggestion
that
fetuses
and
neonates
may
be
more
susceptible
to
thyroid
effects
of
cyanide
and
its
metabolite
thiocyanate.
Ermans
et
al.
(
1980)

reported
that
congenital
hypothyroidism
occurs
at
an
elevated
incidence
(
e.
g.,
5.5%
in
one
region)

in
newborns
in
areas
where
cassava
is
a
staple
food.
Cassava
contains
cyanogenic
glycosides,
and
can
be
a
significant
dietary
source
of
cyanide.
Although
goiter
is
observed
in
adults
under
similar
conditions,
the
effects
of
hypothyroidism
in
infants
(
stunted
growth
and
mental
development)
are
more
severe.

Developmental
toxicity
studies
of
thiocyanate
have
found
that
the
primary
effects
were
decreased
litter
weight
(
Pyska,
1977)
or
growth
retardation
(
Heydens,
1985);
no
teratogenicity
was
observed
(
Heydens,
1985).
In
one
study
(
Pyska,
1977),
the
maternal
LOAEL
for
thyroid
effects
was
the
pup
NOAEL
for
decreased
litter
weight,
although
neither
thyroid
effects
in
pups
nor
other
standard
developmental
toxicity
endpoints
were
evaluated.
In
another
study
(
Heydens,

1985),
the
dams
were
not
evaluated
and
there
was
no
pup
NOAEL,
but
the
pup
LOAEL
of
55
mg/
kg­
day
was
comparable
to
LOAELs
reported
in
other
studies
for
thyroid
effects
in
adults.

Potential
neurodevelopmental
toxicity
is
a
key
unresolved
issue
for
both
thiocyanate
and
cyanide
(
since
cyanide
is
metabolized
primarily
to
thiocyanate)
because
they
have
the
potential
for
inducing
hypothyroidism
in
fetuses
and
neonates.
Hypothyroidism,
defined
by
increased
serum
levels
of
TSH
and
decreased
levels
of
T3
and
T4,
has
been
associated
with
neurodevelopmental
delay
in
both
humans
and
rats.
In
humans,
congenital
hypothyroidism,
or
cretinism,
is
characterized
by
long­
term
effects
on
behavior,
locomotor
ability,
speech,
hearing
and
cognition
(
Chan
and
Kilby,
2000).
Prompt
supplementation
of
neonates
with
thyroid
hormone
can
restore
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
VII­
24
neurodevelopmental
function.
In
rats,
hypothyroidism
has
been
associated
with
anatomical
alterations
in
the
cerebellum
including
reduction
of
growth
and
branching
of
Purkinje
cells,

delayed
proliferation
and
migration
of
granule
cells,
delayed
myelination,
and
changes
in
synaptic
connection
among
cerebellar
neurons
(
Koibuchi
and
Chin,
2000).
These
changes
appear
to
be
mediated
by
circulating
T4,
which
is
converted
in
the
astrocytes
to
T3.
It
is
not
clear,
however,
if
there
is
a
direct
correlation
between
serum
T3
levels
and
brain
T3
levels.
Brain
T3
then
appears
to
bind
to
nuclear
thyroid­
hormone
receptors
and
regulate
gene
expression
(
Koibuchi
and
Chin,

2000).
However,
it
is
not
clear
whether
thyroid
hormones
exert
their
effect
by
directly
regulating
genes
that
encode
for
peptides
crucial
for
cerebellar
development,
or
whether
thyroid
hormones
regulate
the
expression
of
genes
encoding
other
transcription
factors
(
Koibuchi
and
Chin,
2000).

The
degree
of
decrease
in
serum
T4
levels
that
result
in
neurodevelopmental
effects
is
also
not
known.

Maternal
hypothyroidism
during
pregnancy
can
also
affect
the
long­
term
mental
development
of
the
child.
Haddow
et
al.
(
1999)
demonstrated
that
children
whose
mothers
had
diagnosed
hypothyroidism
during
pregnancy
were
four
times
more
likely
to
average
85
or
less
on
I.
Q.
tests.
Morreale
de
Escobar
et
al
(
2000)
conducted
a
comparative
analysis
of
5
studies
evaluating
neurodevelopment
in
children
of
hypothyroid
mothers
by
normalizing
the
IQ
scores
to
a
scale
of
100
and
estimating
the
frequency
of
IQ
scores

85.
For
the
control
populations
in
all
five
studies,
the
frequency
of
IQ

85
ranged
from
5
to
18%
and
the
frequency
of
IQ

70
ranged
from
1
to
2.3%.
In
contrast
the
frequency
of
IQ

85
ranged
from
19
to
50%
in
children
born
to
hypothyroid
mothers.
Frequency
of
IQ

70
ranged
from
5
to
14%
in
these
same
children.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
VII­
25
Morreale
de
Escobar
et
al
(
2000)
suggest
that
it
is
the
levels
of
maternal
T4
that
are
critical
to
proper
neurodevelopment
of
child,
not
levels
of
T3
or
TSH.

No
information
was
located
on
age­
related
differences
in
expression
of
thiocyanate
oxidase,
the
enzyme
that
converts
thiocyanate
back
to
cyanide.
Thiocyanate
oxidase
also
converts
thiocyanate
to
OSCN­,
which
reacts
nonenzymatically
with
cyanide
to
form
cyanate.

Cyanate.
No
data
were
located
on
potential
age­
related
differences
in
the
systemic
toxicity
of
cyanate.
Similarly,
no
standard
developmental
toxicity
studies
of
cyanate
were
located.

Graziano
et
al.
(
1973)
conducted
a
study
investigating
the
effects
of
cyanate
on
reproductive
capacity
of
mice
(
6
male/
female
pairs
per
group)
fed
either
0
mg
or
approximately
1,200­
1300
(
depending
on
the
sex)
mg
cyanate/
kg­
day.
This
study
is
limited
by
the
small
sample
size
and
the
limited
number
of
endpoints
evaluated.
Nevertheless,
there
was
no
effect
on
pup
birth
weight
and
no
gross
abnormalities,
although
the
cyanate
exposure
altered
the
estrus
cycle
after
the
first
pregnancy.
No
information
was
located
on
age­
related
differences
in
expression
of
cyanase,
the
enzyme
that
hydrolyzes
cyanate
to
ammonia
and
carbon
dioxide.

Implications
for
Cyanogen
Chloride.
There
are
no
data
on
potential
age­
related
differences
in
the
toxicity
or
toxicokinetics
of
cyanogen
chloride
itself.
Data
on
age­
related
differences
of
the
metabolites
is
also
limited,
but
suggest
that
acute
toxicity
and
developmental
toxicity
(
excluding
neurodevelopmental
toxicity)
would
not
occur
at
doses
below
those
that
cause
systemic
toxicity
in
adults.
The
data
suggest
that
young
rats
and
animals
(
and
possibly
humans)

are
more
susceptible
to
effects
of
thiocyanate
on
thyroid
weight,
but
there
was
insufficient
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
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OW/
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HECD
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VII­
26
associated
information
on
thyroid
hormone
changes
to
determine
if
the
effects
on
thyroid
weight
were
adaptive
or
adverse.
Epidemiology
data
support
the
suggestion
that
cyanide
exposure
of
fetuses
from
maternal
consumption
of
cassava
can
lead
to
altered
physical
and
mental
development
at
doses
that
only
cause
goiter
in
adults.
It
has
been
long
known
that
decreased
T4
levels
in
neonates,
if
left
untreated,
lead
to
severe
neurological
deficits.
A
newly
emerging
body
of
data
demonstrates
that
children
born
to
women
who
had
decreased
T4
during
pregnancy
also
suffer
long­
term,
permanent
cognitive
impairment.
The
data
strongly
demonstrate
that
decreased
T4
in
both
pregnant
women
and
fetuses/
neonates
results
in
neurodevelopmental
effects.
The
key
outstanding
issue
is
whether
thiocyanate
(
and,
by
implication,
cyanide
and
cyanogen
chloride)
can
cause
enough
of
a
decrease
in
T4
to
result
in
neurodevelopmental
effects,
and
if
so,
at
what
doses
those
effects
occur.
This
endpoint
is
of
concern
because
neurodevelopmental
effects
are
known
to
result
from
decreased
T4
levels.

3.
Other
Potential
Susceptible
Populations
People
with
a
defect
in
the
enzyme
systems
that
convert
cyanide
to
thiocyanate
(
rhodanese
and
mercaptopyruvate
sulfurtransferase)
may
be
more
susceptible
to
the
toxic
effects
of
cyanide.

For
example,
people
with
amyotrophic
lateral
sclerosis
possess
a
disorder
in
cyanide
metabolism
that
may
result
in
an
increased
susceptibility
to
cyanide
(
Kato
et
al.,
1985,
cited
in
ATSDR,

1997).
Similarly,
a
deficiency
in
rhodanese
has
been
associated
with
Leber's
hereditary
optic
atrophy
(
Wilson,
1983).
Vitamin
B
12
deficiency
increases
the
susceptibility
to
tobacco
amblyopia,

a
disease
associated
with
abnormalities
in
both
cyanide
and
vitamin
B
12
metabolism
(
Wilson,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
VII­
27
1983).
As
noted
in
Section
III,
cyanide
can
be
metabolized
by
conversion
to
vitamin
B
12
,

cyanocobalamin.

People
with
protein
or
iodine
deficiency
may
be
more
sensitive
to
the
thyroid
effects
of
cyanide
that
are
caused
by
the
metabolite
thiocyanate.
Kreutler
et
al.
(
1978)
observed
that
rats
on
a
low
protein
diet
(
2%
casein)
demonstrated
increased
plasma
TSH
and
thyroid
weights
following
potassium
cyanide
administration;
rats
on
a
normal
protein
diet
(
20%
casein)
that
were
exposed
to
the
same
concentrations
of
cyanide
did
not
develop
these
effects.
When
the
rats
were
administered
iodine
concurrently
with
cyanide,
the
thyroid
effects
were
not
observed.
Studies
in
human
populations
that
eat
cyanide­
containing
foods,
such
as
cassava,
also
suggest
that
an
increased
susceptibility
to
thyroid
effects
may
be
associated
with
deficiencies
of
protein,
iodine,

vitamin
B
12,
or
other
vitamins,
although
an
etiological
agent
other
than
cyanide
has
been
proposed
as
the
cause
of
the
tropical
neuropathies
(
reviewed
in
ATSDR,
1997).

Protein
deficiency
is
not
common
in
the
Western
world,
although
it
does
occur
in
Third
World
countries
(
U.
S.
FDA,
1999).
By
contrast,
iodine
deficiency
is
more
common
in
the
United
States.
Hollowell
et
al.
(
1998)
evaluated
the
iodine
excretion
data
from
the
National
Health
and
Nutrition
Examination
Surveys
III
(
NHANES
III)
conducted
in
1988­
1994,
and
determined
that
the
median
urinary
iodine
(
I)
excretion
in
the
total
U.
S.
population
was
124.6

g
I/
g
creatinine.

They
also
found
that
7.5%
of
the
total
U.
S.
population
had
urinary
iodine
excretion
lower
than
50

g
I/
g
creatinine,
a
value
that
the
National
Research
Council
(
NRC,
1989)
determined
to
be
"
adequate"
for
normal
thyroid
function.
Hollowell
et
al.
(
1998)
reported
that
urinary
iodine
excretion
below
the
level
determined
by
the
NRC
to
be
"
adequate"
was
observed
in
9.0%
of
U.
S.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
VII­
28
males
and
6.1%
of
U.
S.
females.
Among
U.
S.
women,
urinary
iodine
excretion
below
"
adequate"

levels
was
observed
in
5.1%
of
pregnant
women,
and
8.2%
of
women
of
child­
bearing
age
(
15­

44
years).
People
with
less
than
adequate
levels
of
iodine
excretion
are
at
increased
risk
of
hypothyroidism.
Note
that
the
"
adequacy"
is
reported
here
in
terms
of
excretion,
which
is
easier
to
measure
than
intake.
In
order
to
maintain
an
"
adequate"
level
of
iodine
excretion,
a
minimum
dietary
iodine
of
50
to
75

g/
day
is
needed
for
members
of
the
general
population.
To
provide
an
extra
margin
of
safety,
the
recommended
iodine
allowance
for
adults
of
both
sexes
is
set
at
150

g/
day.
An
extra
25

g/
day
intake
is
recommended
for
pregnant
women,
and
an
extra
50

g/
day
is
recommended
for
lactating
women,
in
order
to
cover
the
extra
demands
of
the
fetus
and
infant.

Since
the
extra
iodine
is
provided
to
the
fetus
or
infant
through
the
placenta
or
mother
milk,
only
iodine
used
by
the
mother
will
be
excreted
in
the
mother's
urine.
Therefore,
urinary
iodine
excretion
is
a
good
indicator
of
an
"
adequate"
intake,
even
for
pregnant
or
lactating
women.

Age­
related
differences
in
the
amounts
of
rhodanese
and
the
kinetics
of
cyanide
suggest
that
the
elderly
have
an
increased
sensitivity
to
the
acute
toxic
effects
of
cyanide.
McMahon
and
Birnbaum
(
1990)
evaluated
age­
related
differences
in
cyanide
toxicity
in
male
C57Bl/
6N
mice
aged
2­
3
months,
10­
12
months,
and
25­
30
months.
Mice
(
10/
age
group)
were
treated
with
single
doses
of
0,
1,
2,
4,
or
6
mg/
kg
potassium
cyanide
by
gavage
and
were
monitored
for
clinical
signs
of
toxicity
(
prostration,
labored
breathing,
tremors)
for
2
hours.
The
same
animals
were
used
for
each
dose
level
with
a
2­
week
recovery
period
between
exposures.
After
treatment
with
the
high
dose,
the
mice
were
allowed
to
recover,
were
sacrificed,
and
the
liver
and
brain
were
evaluated
for
activity
of
rhodanese,
mercaptopyruvate
sulfurtransferase
(
MPST),
and
cytochrome
oxidase.
In
a
separate
experiment,
2­
3
month
and
10­
12
month
old
mice
were
treated
Drinking
Water
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Document
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Cyanogen
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Potential
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orally
with
a
single
dose
of
6
mg/
kg
potassium
cyanide,
and
groups
of
3­
4
mice
were
evaluated
for
blood,
liver,
and
brain
levels
of
cyanide
at
time
points
ranging
from
2.5
minutes
to
25
minutes
after
exposure.

At
a
dose
of
6
mg/
kg,
the
incidence
of
labored
breathing
was
statistically
significantly
increased
in
both
the
10­
12
month
mice
and
the
25­
30
month
mice
compared
with
the
2­
3
month
mice,
suggesting
that
cyanide
was
more
toxic
in
the
older
animals.
Similar
age­
dependent
toxicity
was
observed
in
the
4
mg/
kg
dose
group;
lower
doses
were
apparently
not
toxic.
To
evaluate
the
reasons
for
the
age­
dependent
differences,
the
authors
evaluated
the
levels
of
rhodanese,
the
primary
enzyme
responsible
for
cyanide
metabolism,
in
the
livers
and
brains
of
the
mice.
Liver
rhodanese
exhibited
the
highest
activity
(
both
on
a
protein
weight
basis
and
on
a
tissue
weight
basis)
in
the
10­
12
month
mice.
By
contrast,
brain
rhodanese,
as
measured
by
activity/
g
tissue,

was
significantly
lower
in
10­
12
month
mice
and
25­
30
month
mice,
compared
with
the
2­
3
month
mice.
In
addition,
both
the
peak
concentration
of
cyanide
in
the
brain
and
the
area
under
the
curve
(
AUC)
were
significantly
higher,
and
the
time
to
peak
concentration
in
the
brain
was
shorter
in
10­
12
month
mice
compared
with
the
2­
3
month
mice.
No
significant
effects
of
age
on
cyanide
levels
in
the
blood
or
liver
were
seen.
(
Tissue
levels
of
cyanide
were
not
measured
in
the
aged
mice.)
The
authors
also
investigated
age­
related
changes
in
the
inhibition
of
cytochrome
oxidase
(
the
primary
cellular
target
of
cyanide)
in
the
liver
and
brain,
but
found
no
significant
effect.
Activity
of
MPST
in
the
brain
and
liver
was
higher
in
the
10­
12
month
and
25­
20
month
mice.
Because
MPST
supplies
the
sulfur
for
detoxification
of
cyanide
by
rhodanese,
one
might
have
expected
increased
toxicity
to
be
associated
with
decreased
MPST
activity.
Since
increased
toxicity
was
instead
associated
with
increased
MPST
activity,
the
authors
concluded
that
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
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OW/
OST/
HECD
Final
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VII­
30
older
mice
were
more
sensitive
to
the
acute
toxic
effects
of
cyanide,
and
suggested
that
this
resulted
from
slower
reactivation
of
cytochrome
oxidase
due
to
lower
rhodanese
levels
in
the
brain.
Other
possible
mechanisms
suggested
by
the
authors
included
age­
related
decreases
in
enzymes
involved
in
antioxidant
defense,
or
alterations
in
the
"
sink"
of
reversible
cyanide
binding
to
unknown
tissue
constituents.
The
study
authors
(
McMahon
and
Birnbaum,
1990)
noted
that
other
authors
have
reported
that
the
experimental
manipulation
of
hepatic
rhodanese
level
does
not
always
result
in
the
expected
change
in
cyanide
toxicity.
Therefore,
the
implications
of
this
study
are
unclear.
There
is
much
more
liver
rhodanese
than
brain
rhodanese,
so
liver
accounts
for
a
much
higher
percentage
of
the
total
body
detoxifying
capacity,
but
it
is
possible
that
brain
rhodanese
is
important
in
determining
acute
neurotoxicity.

People
with
hypothyroidism
may
also
represent
a
susceptible
population
because
their
thyroid
status
is
already
compromised
and
they
have
less
capacity
to
adapt
to
an
additional
challenge
to
the
thyroid.
As
described
by
the
American
Association
of
Clinical
Endocrinologists
(
2002),
hypothyroidism
is
of
primary
concern
in
two
populations:
neonates
and
women
over
35.

Congenital
hypothyroidism
in
the
US
occurs
in
about
1
in
4,000
children.
Women
are
5
to
8
times
more
likely
than
men
to
develop
thyroid
disease.
Incidence
of
hypothyroidism
increases
with
age;
peak
onset
of
hypothyroidism
occurs
between
ages
35
and
60.
One
in
ten
women
aged
65
or
older
has
hypothyroidism.
In
addition,
hypothyroidism
appears
to
be
linked
with
diabetes:

hypothyroidism
occurs
in
about
36%
of
the
diabetic
population,
compared
with
about
6%
of
the
general
population.
Finally,
pregnancy
appears
to
alter
thyroid
function
resulting
in
an
increased
likelihood
of
developing
hypothyroidism.
One
of
50
women
in
the
U.
S.
is
diagnosed
with
hypothyroidism
during
pregnancy.
Up
to
10%
of
women
are
diagnosed
with
postpartum
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
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Metabolites
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OW/
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Final
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VII­
31
thyroiditis
within
1
year
following
delivery
and
about
50%
of
these
will
develop
permanent
hypothyroidism
within
5
years
of
diagnosis.

No
data
were
located
on
polymorphisms
in
any
genes
related
to
the
metabolism
of
cyanide,
thiocyanate,
or
cyanate.

D.
Summary
Since
data
on
cyanogen
chloride
toxicity
and
mechanism
of
action
are
very
limited,
data
on
the
known
toxic
effects
and
target
organs
of
cyanogen
chloride
were
compared
with
those
of
its
known
or
potential
metabolites
(
along
with
the
available
information
on
cyanogen
chloride
biochemistry
and
toxicokinetics)
to
provide
information
on
the
potential
mechanism(
s)
of
action
of
cyanogen
chloride
toxicity.
The
primary
target
of
acute
exposure
to
cyanide
is
the
CNS.

Cyanide
acts
by
binding
with
cytochrome
c
oxidase,
interfering
with
cellular
oxygen
use.
It
is
likely
that
cyanogen
chloride
toxicity
to
the
CNS
is
mediated
through
cyanide.
Chronic
exposure
to
cyanide
results
in
effects
on
the
thyroid
and
the
male
reproductive
system.
The
mechanism
for
the
reproductive
effects
is
not
known,
but
the
thyroid
effects
result
from
chronic
exposure
to
the
cyanide
metabolite
thiocyanate.
Thiocyanate
acts
by
blocking
the
active
transport
of
iodide
into
the
thyroid
gland,
disrupting
the
feedback
mechanisms
that
regulate
balance
of
the
thyroidpituitary
axis.
As
documented
for
a
number
of
other
chemicals
exerting
similar
effects
on
the
thyroid,
this
results
in
decreased
production
and
secretion
of
the
hormones
T3
and
T4,
and
increased
levels
of
TRH
and
TSH.
Prolonged
increases
in
TSH
can
result
in
increased
thyroid
weight,
follicular
cell
hyperplasia,
and
cancer.
Decreased
T3
and
T4
levels,
and
increased
thyroid
Drinking
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weight,
have
been
observed
in
toxicity
studies
with
thiocyanate.
However,
follicular
cell
hyperplasia
and
cancer
have
not
been
observed
following
exposure
to
thiocyanate,
although
it
is
unclear
whether
the
relevant
studies
fully
evaluated
the
thyroid.
Decreased
T4
levels
in
pregnant
women
and
in
fetuses/
neonates
have
been
demonstrated
to
result
in
neurodevelopmental
effects
in
children.
Based
on
the
mode
of
action
of
thiocyanate,
and
altered
hormone
levels
in
exposed
pups,
it
would
also
be
useful
to
evaluate
the
potential
neurodevelopmental
toxicity
of
thiocyanate,

but
such
studies
have
not
been
conducted.
Based
on
the
observed
in
vivo
metabolism
of
cyanogen
chloride
to
thiocyanate,
the
effects
seen
with
thiocyanate
may
also
occur
following
chronic
exposure
to
cyanogen
chloride.

Cyanate
is
also
produced
from
the
metabolism
of
cyanide,
although
cyanate
has
not
been
identified
as
a
metabolite
of
cyanogen
chloride.
The
primary
toxic
effects
of
cyanate
include
irritation
of
the
eyes,
skin,
and
respiratory
tract
(
following
inhalation
exposure),
severe
weight
loss,
cataracts,
peripheral
neuropathy,
and
liver
toxicity
characterized
by
altered
glycogen
metabolism.
The
mechanism
of
at
least
two
of
these,
cataracts
and
liver
toxicity,
appear
to
be
related
to
the
ability
of
cyanate
to
carbamylate
protein.
Taking
advantage
of
the
affinity
of
cyanate
for
hemoglobin,
cyanate
was
used
in
clinical
trials
as
a
therapeutic
agent
for
sickle­
cell
anemia.
Peripheral
neuropathy
caused
by
cyanate
may
be
due
to
carbamylation
of
proteins
in
the
myelin
membrane
or
proteins
associated
with
maintaining
ion
flux
in
the
nerves.
It
has
also
been
proposed
that
the
effects
on
weight
loss
and
nervous
tissue
could
be
mediated
through
the
increased
oxygen
affinity
of
hemoglobin
induced
by
cyanate.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
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HECD
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draft
VII­
33
Cyanamide
inhibits
the
enzyme
aldehyde
dehydrogenase
(
ALDH)
and
has
been
widely
used
in
Europe
as
a
drug
to
treat
chronic
alcoholism.
Toxic
effects
observed
in
humans
and
animals
following
cyanamide
exposure
include
irritation
of
the
eyes,
skin,
and
respiratory
system
(
following
inhalation
exposure),
severe
weight
loss,
liver
toxicity
characterized
by
glycogen
deposits,
allergic
dermatitis,
and
male
reproductive
effects,
but
only
the
male
reproductive
effects
may
be
related
to
the
action
of
cyanamide
as
an
ALDH
inhibitor.

All
of
the
toxic
effects
observed
following
cyanogen
chloride
exposure
can
be
accounted
for
by
the
known
or
potential
metabolites.
It
is
plausible
that
the
eye
and
lung
irritation
observed
following
exposure
to
cyanogen
chloride
vapor
is
due
to
the
parent
chemical.
It
is
also
possible
that
these
effects
may
be
due
to
HCl,
cyanate,
or
cyanamide
formed
from
hydrolysis
of
cyanogen
chloride
or
reaction
with
ammonia
or
other
amines,
although
it
appears
less
likely
that
these
reactions
occur
sufficiently
rapidly
in
vivo
following
inhalation
exposure.
Similarly,
the
kinetics
of
formation
of
these
metabolites
following
ingestion
exposure
to
cyanogen
chloride
is
unknown,

although
transient
increased
concentrations
of
HCl
(
decreased
pH)
may
occur,
particularly
in
the
liver
and
portal
vein.
It
is
plausible
to
expect
that
ingested
cyanogen
chloride
will
be
reduced
by
glutathione
to
cyanide
and
HCl
as
part
of
first­
pass
metabolism,
resulting
in
elevated
HCl
levels
in
the
blood
that
is
part
of
enterohepatic
circulation,
and
in
the
liver.

Nervous
system
effects
of
cyanogen
chloride
can
be
attributed
to
cyanide.
If
cyanogen
chloride
were
also
to
cause
peripheral
nervous
system
effects,
this
could
suggest
a
role
of
cyanate,

although
such
effects
might
also
be
due
to
cyanide.
Severe
weight
loss
and
decreased
appetite
have
been
seen
in
workers
chronically
exposed
to
cyanogen
chloride
(
Reed,
1920)
and
in
exposed
Drinking
Water
Criteria
Document
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Cyanogen
Chloride
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VII­
34
animals
(
Haymaker
et
al.,
1952).
This
rather
nonspecific
effect
is
most
closely
associated
with
cyanate
and
cyanamide
(
Haut
et
al.,
1975;
NCI,
1979),
but
has
also
been
seen
following
chronic
exposure
to
cyanide
(
Wolfsie
and
Shaffer,
1958,
as
cited
by
ACGIH,
1996).

The
carcinogenic
potential
of
cyanogen
chloride,
cyanide,
and
thiocyanate
cannot
be
determined
from
available
data.
QSTR
analysis
suggests
that
cyanogen
chloride
is
not
carcinogenic
(
Moudgal
et
al.,
2000).
Adequate
carcinogenicity
studies
are
lacking
for
most
of
these
chemicals,
although
the
mode
of
action
of
thiocyanate
on
the
thyroid
suggests
that
it
could
cause
thyroid
cancer
in
rats
via
a
nongenotoxic
mode
of
action.
Although
none
of
these
compounds
have
been
completely
tested,
the
available
data
do
not
indicate
that
any
of
the
compounds
are
genotoxic.

Additive
interactions
would
be
expected
between
cyanogen
chloride
and
its
metabolites,

cyanide
and
thiocyanate.
Cyanide
also
exhibited
additive
interactions
with
carbon
monoxide,
and
synergism
with
ascorbic
acid,
and
there
is
some
evidence
for
synergism
with
carbon
dioxide.
A
number
of
compounds
have
been
identified
that
inhibit
the
toxicity
of
cyanide.

The
only
information
on
populations
particularly
susceptible
to
cyanogen
chloride
is
based
on
extrapolation
from
its
metabolites.
The
limited
data
do
not
indicate
that
children
or
fetuses
are
particularly
susceptible
to
the
acute
effects
of
cyanide;
rather,
the
limited
data
suggest
that
young
animals
are
less
susceptible
than
older
animals
to
the
acute
effects
of
cyanide
(
McMahon
and
Birnbaum,
1990).
A
QSTR
analysis
(
Moudgal
et
al.,
2000)
suggests
that
cyanogen
chloride
is
a
developmental
toxicant,
but
the
model
does
not
provide
information
on
the
potency
of
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
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HECD
Final
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VII­
35
chemical
or
the
severity
of
effects
predicted.
Although
the
limited
data
indicate
that
standard
developmental
effects
of
cyanide
occur
at
doses
higher
than
those
that
cause
thyroid
effects,
the
potential
for
neurodevelopmental
effects
resulting
from
the
thyroid
effects
of
thiocyanate
is
of
concern,
and
has
not
been
investigated.
Congenital
hypothyroidism
is
associated
with
stunted
bodily
growth
and
mental
development.
In
addition,
young
animals
have
higher
levels
of
rhodanese,
decreasing
the
acute
toxicity
of
cyanide,
but
increasing
the
thiocyanate
levels
in
the
body,
and
thus
potentially
the
susceptibility
to
thyroid
effects.
Limited
data
from
a
study
in
which
thyroid
hormone
levels
were
measured
in
pups
and
dams
following
exposure
of
pregnant
and
lactating
dams
(
Kreutler
et
al.,
1978)
suggests
that
rat
pups
are
more
sensitive
than
dams
to
the
thyroid
effects
of
thiocyanate.

Other
potentially
susceptible
populations
include
people
with
a
defect
in
the
enzyme
systems
that
convert
cyanide
to
thiocyanate
(
rhodanese
and
mercaptopyruvate
sulfurtransferase),

who
may
be
more
susceptible
to
the
acute
effects
of
cyanide.
Vitamin
B
12
deficiency
would
also
increase
susceptibility
to
cyanide,
while
hypothyroid
disorders
and
protein
or
iodine
deficiency
may
increase
sensitivity
to
cyanide
and
its
metabolite
thiocyanate.
Hypothyroidism
occurs
at
a
higher
incidence
among
the
elderly,
diabetics,
and
pregnant
women.
The
elderly
may
also
be
more
susceptible
to
the
acute
toxicity
of
cyanide,
possibly
due
to
slower
reactivation
of
cytochrome
oxidase,
due
to
lower
rhodanese
levels
in
the
brain;
liver­
rhodanese
level
was
not
correlated
with
acute
toxicity.

Other
than
the
age­
related
differences
in
rhodanese
levels,
no
information
was
located
on
age­
related
differences
in
the
expression
of
any
of
the
genes
related
to
the
metabolism
of
cyanide
Drinking
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Document
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Final
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36
or
thiocyanate.
No
data
were
located
on
polymorphisms
in
any
genes
related
to
the
metabolism
of
cyanide
or
thiocyanate.
