Document ID: EPA-HQ-OW-2002-0043-0185
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-08-11T04:00Z

Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
1
Chapter
I.
Executive
Summary
A.
Introduction
Cyanogen
chloride
is
a
drinking
water
disinfection
byproduct
formed
in
the
presence
of
chloramine
and
ammonia.
This
document
summarizes
the
toxicity
and
exposure
data
on
cyanogen
chloride.
Because
the
data
on
cyanogen
chloride
are
very
limited,
the
data
on
known
and
potential
metabolites
were
also
considered.
This
document
is
an
update
and
expansion
of
the
Rough
Final
Draft
for
the
Drinking
Water
Criteria
Document
on
Haloacetonitriles,
Chloropicrin
and
Cyanogen
Chloride
(
U.
S.
EPA,
1987).
The
section
on
cyanide
is
an
update
and
extension
of
the
Drinking
Water
Criteria
Document
for
Cyanide
(
U.
S.
EPA,
1992),
and
the
section
on
thiocyanate
is
an
update
and
extension
of
an
Issue
Paper
prepared
by
U.
S.
EPA's
Superfund
Health
Risk
Technical
Support
Center
(
U.
S.
EPA,
1997a).
Full
literature
searches
were
conducted
in
December
1999
on
the
toxicity
of
cyanogen
chloride,
cyanide,
thiocyanate,
cyanate,

cyanamide,
and
HCl,
and
on
exposure
to
cyanogen
chloride
and
cyanide.
These
searches
were
supplemented
by
selected
key
references
identified
after
the
search.

Toxicity
data
on
cyanogen
chloride
are
extremely
limited.
Toxicity
studies
are
limited
to
three
acute
toxicity
studies
conducted
prior
to
the
advent
of
modern
toxicology
methods
(
Reed,

1920;
Aldridge
and
Evans,
1946;
Haymaker
et
al.,
1952).
These
studies
are
unsuitable
even
for
the
development
of
short­
term
risk­
assessment
values,
because
key
information
about
doses
and
study
design
was
not
reported.
In
addition,
the
studies
tended
to
be
descriptive
of
observations,

rather
than
providing
such
objective
measures
as
body
weights
or
histopathology
findings.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
2
Due
to
this
lack
of
toxicity
data
on
cyanogen
chloride,
surrogates
were
considered
as
the
basis
for
the
cyanogen
chloride
assessment.
Toxicokinetics
data
show
that
dosing
with
cyanogen
chloride
results
in
elevated
tissue
levels
of
cyanide
and
thiocyanate,
two
chemicals
for
which
considerably
more
toxicity
information
is
available.
Hydrogen
chloride
(
HCl)
would
also
be
produced
in
those
reactions,
but
its
production
has
not
been
evaluated.
Water
chemistry
data
also
suggest
that
cyanogen
chloride
can
react
to
form
cyanate,
and
cyanamide,
although
these
compounds
have
not
been
identified
in
animals
dosed
with
cyanogen
chloride,
or
even
in
in
vitro
studies
of
metabolism.
Unfortunately,
no
mass
balance
toxicokinetics
studies
of
cyanogen
chloride
have
been
conducted,
so
no
quantitative
identification
of
metabolites
is
possible.

Nonetheless,
the
toxicity
and
toxicokinetics
of
the
identified
and
possible
metabolites
of
cyanogen
chloride
are
summarized
in
this
document,
to
aid
in
the
evaluation
of
the
toxic
potential
of
cyanogen
chloride.

B.
Toxicokinetics
No
data
were
located
regarding
the
absorption
of
cyanogen
chloride
by
the
oral
or
dermal
routes
of
exposure,
although
cyanogen
chloride
appears
to
be
rapidly
absorbed
following
inhalation
exposure
(
Aldridge
and
Evans,
1946).
The
absorption
of
known
or
potential
metabolites
of
cyanogen
chloride
is
not
of
concern,
since
these
would
be
formed
after
cyanogen
chloride
has
already
been
absorbed.
No
data
were
located
regarding
the
distribution
of
cyanogen
chloride.
Both
cyanide
and
thiocyanate
appear
to
distribute
freely
through
the
body
following
absorption.
Following
absorption
via
all
routes
of
exposure,
cyanide
has
been
found
in
lung,

heart,
blood,
liver,
brain,
spleen,
and
kidney
(
ATSDR,
1997).
Thiocyanate
does
not
cross
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
3
blood­
brain
barrier
(
Wood,
1975),
but
can
cross
the
placenta
(
Kreutler
et
al.,
1978).
Very
little
data
are
available
on
the
distribution
of
cyanate
and
cyanamide.
Both
compounds
were
detected
in
the
blood
within
minutes
of
administration
in
mice,
rats,
or
dogs
(
Johnson
et
al.,
1985;
Obach
et
al.,
1985).
However,
the
calcium
form
of
cyanamide
appears
to
distribute
more
slowly,

peaking
in
the
blood
by
1
hour
following
oral
administration
(
Loomis
and
Brien,
1983).

Early
studies
of
cyanogen
chloride
(
Aldridge
and
Evans,
1946;
Aldridge,
1951)
indicate
that,
in
animals
exposed
to
cyanogen
chloride
by
either
intravenous
injection
or
inhalation,

cyanogen
chloride
was
not
detected
in
the
blood,
but
cyanide
(
CN
­)
was
detected
as
soon
as
1
minute
following
the
start
of
exposure.
Further
studies
characterizing
the
reaction
products
showed
that
cyanogen
chloride
is
rapidly
reduced
to
cyanide
by
glutathione
in
the
blood
(
Aldridge,
1951).
In
addition,
thiocyanate
(
SCN
­)
was
detected
at
double
the
background
levels
and
in
saliva.
These
early
studies
concluded
that
approximately
30­
40%
of
the
cyanogen
chloride
had
been
converted
to
cyanide
at
higher
doses,
while
60­
80%
is
converted
to
cyanide
at
lower
doses
(
Aldridge
and
Evans,
1946;
Midwest
Research
Institute,
1997).
However,
the
authors
did
not
determine
how
much
of
cyanogen
chloride
had
been
converted
to
thiocyanate.
In
addition,

the
authors
did
not
determine
if
the
total
amount
of
cyanide
and
thiocyanate
accounted
for
the
total
cyanogen
chloride
dose
or
if
additional,
unidentified
metabolites
were
present.
The
degree
of
conversion
of
cyanogen
chloride
to
cyanide
at
environmentally­
relevant
doses
is
not
known,

but
it
would
be
expected
that
conversion
to
cyanide
at
these
lower
doses
would
be
>
80%.

Metabolism
of
cyanogen
chloride
to
cyanide
exhibits
a
clear
dose­
dependence,
although
interspecies
differences
are
also
observed.
Based
on
limited
information
regarding
the
aqueous
chemistry
of
cyanogen
chloride,
other
potential
metabolites
of
cyanogen
chloride
include
cyanate
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
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HECD
Final
draft
I­
4
(­
OCN),
cyanamide
(
H
2
NCN),
and
chloride
ion
(
Cl­).
Note,
however,
that
no
studies
have
been
conducted
to
determine
if
these
compounds
would
be
detected
following
cyanogen
chloride
administration.
The
major
metabolic
pathway
for
cyanide
is
conversion
to
thiocyanate
by
either
rhodanese
or
3­
mercaptopyruvate
sulfur
transferase.
This
pathway
accounts
for
60­
80%
of
a
cyanide
dose.
Minor
pathways
include
incorporation
into
a
1­
carbon
metabolic
pool
or
conversion
to
2­
aminothiazoline­
4­
carboxylic
acid
(
ATSDR,
1997).
Rhodanese
is
a
mitochondrial
enzyme
that
is
widely
distributed
throughout
the
body.
It
has
been
found
in
liver,

lung,
nasal
passages,
kidney,
and
muscle
(
Sylvester
and
Sander,
1990;
Devlin
et
al.,
1989a,
b;

Lewis
et
al.,
1991),
although
the
distribution
of
rhodanese
among
tissues
varies
widely
in
different
species
(
Himwich
and
Saunders,
1948;
Drawbaugh
and
Marrs,
1987).
Cyanide
appears
to
be
in
equilibrium
with
thiocyanate
in
the
body.
Although
the
action
of
rhodanese
is
not
reversible,
there
is
an
enzyme
system,
thiocyanate
oxidase,
that
catalyzes
the
reaction
of
thiocyanate
and
hydrogen
peroxide
to
form
cyanide
and
sulfate
(
Wood,
1975).
Cyanate
appears
to
be
hydrolyzed
to
carbon
dioxide
and
ammonia
by
the
enzyme
cyanase,
which
is
located
in
the
kidney,
liver,
and
red
blood
cells
(
Johnson
et
al.,
1985).
The
primary
metabolic
pathway
for
cyanamide
acetylation
is
to
form
N­
acetylcyanamide
(
Mertschenk
et
al.,
1991).
A
second
pathway
has
been
demonstrated
in
vivo,

but
not
in
vitro.
In
this
pathway,
the
enzyme
catalase
facilitates
the
interaction
of
cyanamide
and
hydrogen
peroxide
to
form
an
unstable
intermediate,
which
spontaneously
decomposes
to
form
cyanide
and
nitroxyl
(
Shirota
et
al.,
1987).

No
information
is
available
regarding
the
excretion
of
cyanogen
chloride.
Cyanide
is
primarily
excreted
in
the
urine
as
thiocyanate,
although
a
small
amount
appears
to
be
excreted
in
expired
air
as
carbon
dioxide
(
ATSDR,
1997).
The
elimination
half­
life
in
rats
following
acute
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
5
oral
administration
has
been
estimated
to
be
14
minutes,
with
an
undetermined
longer
half­
life
following
subchronic
exposure
(
Leuschner
et
al.,
1991).
Data
in
monkeys
suggest
a
longer
halflife
based
on
the
slow
decrease
in
blood
levels
following
a
30­
minute
inhalation
exposure
(
Purser
et
al.,
1984).
Thiocyanate
appears
to
be
excreted
in
the
urine
unchanged
(
Wood
et
al.,
1975).

Thiocyanate
has
a
long
half­
life;
it
was
still
detectable
in
the
blood
one
week
following
exposure
(
Anderson
and
Chen,
1940).
The
half­
life
in
nonpregnant
goats
was
16
hours
(
Boulos
et
al.,

1973).
Cyanate
is
primarily
excreted
in
expired
air
as
carbon
dioxide,
with
a
half­
life
of
43
minutes
(
Johnson
et
al,
1985).
Cyanamide
is
primarily
excreted
in
the
urine
as
Nacetylcyanamide
although
a
small
amount
is
excreted
in
expired
air
as
carbon
dioxide
(
Dietrich
et
al.,
1976).
The
elimination
half­
life
is
reported
to
be
62
minutes
in
dogs,
and
27
minutes
in
rats
following
oral
exposure
(
Obach
et
al.,
1989).
No
information
was
available
on
the
half­
life
of
cyanate
or
cyanamide
following
repeated
exposures.
Overall,
these
data
suggest
the
potential
for
some
degree
of
thiocyanate
retention
after
repeated
exposure
to
sufficiently
high
levels
of
cyanogen
chloride.
Information
on
body
burden
was
available
only
for
cyanide
and
its
metabolite
thiocyanate.
Concentrations
of
cyanide
and
its
metabolite
thiocyanate
in
blood
serum
and
plasma,

urine,
and
saliva
have
been
used
as
indicators
of
cyanide
exposure,
and
are
elevated
in
cigarette
smokers
and
populations
consuming
large
quantities
of
food
containing
cyanide
(
e.
g.,
improperly
processed
cassava).

Based
on
consideration
of
cyanogen
chloride
biochemistry
and
that
of
its
known
and
putative
metabolites,
it
is
plausible
that
ingested
cyanogen
chloride
is
absorbed
from
the
stomach
and/
or
intestine
as
the
parent
compound,
and
that
most
of
its
metabolism
occurs
in
the
gastrointestinal
tract
and
liver.
Metabolism
in
the
blood
after
absorption
from
the
intestine
is
also
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
6
possible,
as
is
reaction
with
nucleophiles
in
the
intestine,
or
its
contents.
The
high
concentration
of
rhodanese
in
the
liver
would
enhance
the
rate
of
conversion
to
thiocyanate
from
cyanide
that
is
produced
in
the
portal
vein
or
liver.
HCl
production
might
result
in
transient
pH
decreases,
but
it
appears
that
systemic
acidosis
would
be
unlikely
at
environmentally­
relevant
doses.

Given
the
available
kinetic
data
for
cyanogen
chloride,
it
is
reasonable
to
assume
that
the
toxicity
of
cyanogen
chloride
is
likely
to
be
due
to
metabolites
rather
than
the
parent
compound.

Therefore,
it
is
reasonable
to
use
metabolites
as
surrogates
for
the
development
of
toxicity
values,

given
the
lack
of
toxicity
data
on
cyanogen
chloride
itself.
Since
cyanide
and
thiocyanate
are
known,
observed
metabolites
of
cyanogen
chloride,
these
chemicals
were
considered
as
possible
surrogates,
even
though
the
exact
quantitative
relationship
between
cyanogen
chloride
and
cyanide
or
thiocyanate
production
has
not
been
adequately
determined.
The
health­
protective
nature
of
this
approach,
and
associated
uncertainties,
are
discussed
in
the
context
of
the
quantitation
in
Chapter
8,
and
the
risk
characterization
in
Chapter
9.
It
is
also
plausible
that
additional
metabolites
are
formed
following
cyanogen
chloride
exposure,
in
light
of
the
limited
available
quantitative
data
on
metabolism.
However,
other
potential
metabolites
(
e.
g.,
cyanate,

cyanamide,
HCl)
have
not
been
identified
experimentally,
and
so
were
not
considered
as
potential
surrogates.
Toxicity
data
for
these
chemicals
as
development
of
toxicity
values
is
summarized
in
Appendices
C,
D,
and
E.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
7
C.
Human
Exposure
Cyanogen
chloride
is
formed
in
raw
water
during
chlorination
and
increases
when
ammonium
chloride
is
added
prior
to
chlorination
(
Ohya
and
Kanno,
1987)
or
if
ammonia
is
present
in
the
source
water
(
WHO,
2000).
Most
cyanide
in
waters
commonly
occurs
as
HCN
(
ATSDR,
1997).

Cyanogen
Chloride.
The
ICR
database
(
U.
S.
EPA,
2000b)
contains
some
information
on
concentrations
of
cyanogen
chloride
in
drinking­
water
systems,
and
on
how
those
concentrations
vary
with
input­
water
characteristics
and
treatment
methods.
The
database
contains
information
from
6
quarterly
samples
from
7/
97
to
12/
98,
from
approximately
300
large
systems
covering
approximately
500
plants.
The
mean
concentrations
of
cyanogen
chloride
in
the
distribution
system
at
the
maximum
point
for
drinking
water
derived
from
surface
water
and
groundwater
were
3.02
and
1.63
µ
g/
L,
respectively.
The
mean
concentration
of
cyanogen
chloride
in
finished
water
and
the
mean
distribution
system
maximum
were
significantly
higher
in
treated
surface
water
(
at
p
=
0.05)
than
their
respective
concentrations
in
treated
groundwater.

Because
cyanogen
chloride
is
formed
when
chlorine
reacts
with
organic
material
in
the
presence
of
ammonia,
only
plants
that
used
chloramine
as
a
primary
or
secondary
disinfectant
were
required
to
monitor
for
cyanogen
chloride.
In
the
ICR
database,
35%
of
the
surface­
water
plants
and
23%
of
the
groundwater
plants
reported
cyanogen
chloride
observations
(
U.
S.
EPA,
2000c).

The
National
Occupational
Exposure
Survey
(
NOES)
conducted
by
NIOSH
from
1980
to
1983
estimated
that
1393
workers
were
exposed
to
cyanogen
chloride.
Drinking
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I­
8
There
is
no
information
in
the
available
literature
on
the
concentration
of
cyanogen
chloride
in
the
air
and
no
information
in
the
available
literature
on
dermal
exposure
to
cyanogen
chloride.
Cyanogen
chloride
body
burden
is
expected
to
be
negligible,
in
light
of
its
rapid
metabolism.
There
is
no
quantitative
data
on
dietary
levels.
Although
one
investigator
found
that
cyanogen
chloride
may
be
produced
from
the
reaction
of
instant
tea
with
water
containing
chloramine
residual,
no
quantification
of
cyanogen
chloride
concentration
was
provided.

Cyanogen
chloride
was
not
included
among
the
analytes
measured
in
the
current
FDA
Market
Basket
Study
(
U.
S.
FDA,
2002).

Due
to
the
lack
of
data,
no
estimate
can
be
made
on
average
daily
exposure
to
cyanogen
chloride.
An
RSC
of
20%
is
used
for
cyanogen
chloride
to
account
for
the
likelihood
of
exposure
to
cyanogen
chloride
or
cyanide
from
sources
other
than
tap
water,
such
as
ambient
air
and
food,

in
the
absence
of
adequate
data.

Hydrogen
cyanide.
The
latest
information
on
concentrations
of
cyanide
in
public
water
supplies
drinking
water
comes
from
the
latest
quarterly
reporting
(
updated
April
28,
2000)
of
the
NCOD,
which
contains
information
from
thousands
of
drinking­
water
systems.
Cyanide
was
detected
in
7%
of
the
plants
(
3%
of
the
samples)
using
surface
water
as
a
source,
and
in
3%
of
the
plants
(
2%
of
the
samples)
using
groundwater
as
a
source.
Although
the
average
cyanide
concentrations
in
treated
surface
water
were
reported
as
2844

g/
L,
and
the
average
concentrations
in
treated
groundwater
were
reported
as
2194

g/
L,
there
was
no
statistically
significant
difference
between
the
two
cyanide
concentrations.
Average
cyanide
concentrations
in
surface
water
and
groundwater
were
calculated
only
for
those
samples
where
cyanide
was
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
9
detected.
Non­
detects
were
not
included
in
the
calculation
of
average
concentrations.
Therefore,

the
calculated
averages
may
not
accurately
reflect
the
cyanide
concentrations
to
which
populations
served
by
these
water
systems
are
exposed.
Medians
were
not
available
from
the
NCOD
survey.

There
was
no
information
presented
in
the
ATSDR
(
1997)
Toxicological
Profile
for
Cyanide
on
the
concentration
of
HCN
in
soil
or
sediments.
However,
because
of
its
highly
volatile
nature
and
its
expected
tendency
to
biodegrade
and
leach
out
of
the
soil,
HCN
is
not
expected
to
be
present
in
soil
in
any
appreciable
amount.

Based
on
information
presented
in
the
ATSDR
(
1997)
Toxicological
Profile
for
Cyanide,

between
1981
and
1983,
4005
workers
were
potentially
exposed
to
HCN.
In
addition
to
HCN
concentrations
in
drinking
water,
there
are
some
limited
data
on
HCN
concentrations
in
air
and
food.

Based
on
an
atmospheric
concentration
of
170
ppt
(
188
ng/
m3)
and
a
daily
average
inhalation
rate
of
20
m3,
the
ATSDR
(
1997)
Toxicological
Profile
for
Cyanide
estimated
an
inhalation
exposure
to
the
general
U.
S.
non­
urban,
nonsmoking
population
of
3.8

g
cyanide/
day.

Although
concentrations
of
HCN
in
foods
are
expected
to
be
low,
one
author
estimated
that
intake
from
food
would
exceed
HCN
intake
from
inhalation
of
air
and
ingestion
of
drinking
water
(
Fiksel
et
al,
1981).
However,
estimates
of
the
HCN
concentration
in
the
total
diet
were
not
located
in
the
available
literature.
Cyanide
was
not
included
among
the
analytes
measured
in
the
current
FDA
Market
Basket
Study
(
U.
S.
FDA,
2002).
Therefore,
no
independent
estimate
of
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
10
daily
HCN
intake
from
food
could
be
made.
An
RSC
of
20%
accounts
for
the
likelihood
of
exposure
to
cyanide
from
sources
other
than
tap
water,
such
as
ambient
air
and
food,
in
the
absence
of
adequate
data.

HCN
is
a
metabolite
of
a
number
of
industrial
chemicals
(
acetonitrile,
propionitrile,

acrylonitrile,
n­
butyronitrile,
maleonitrile,
and
succinonitrile).
As
a
result,
occupational
or
environmental
exposure
to
these
chemicals
could
contribute
to
the
background
levels
of
HCN
in
biological
fluids.
HCN
is
also
a
metabolite
of
pharmaceuticals
such
as
Laetrile
and
a
drug
used
to
reduce
high
blood
pressure,
and
clinical
use
of
these
compounds
could
induce
a
body
burden
of
HCN.

Thiocyanate.
Since
the
health
advisories
for
cyanogen
chloride
are
based
on
cyanide,
as
described
below,
exposure
to
thiocyanate
as
not
evaluated.

D.
Health
Effects
in
Animals
Short­
term
Studies.
Only
four
old
short­
term
studies
of
cyanogen
chloride
were
located
(
Reed,
1920;
Aldridge
and
Evans,
1946;
Haymaker
et
al.,
1952;
Flury
and
Zernik,
1931).
Rats,

cats,
dogs,
and
a
goat
were
exposed
by
either
inhalation
or
injection.
These
studies
are
unsuitable
for
risk
assessment
because
key
information
about
doses
and
study
design
are
not
reported.

However,
the
studies
do
help
to
identify
the
potential
health
effects
of
cyanogen
chloride,
which
include
neurotoxicity
(
depressed
reflexes,
muscular
tremors,
rigidity
and
weakness
of
limbs,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
11
convulsions,
necrosis
in
brain),
weight
loss,
cardiac
irregularities,
and
pulmonary
congestion
and
edema.
Cyanogen
chloride
also
irritates
the
respiratory
passages
and
eyes.

Only
limited
information
regarding
the
short­
term
effects
of
cyanide
in
animals
is
available.

LD
50
s
(
either
oral
or
dermal)
for
cyanide
range
from
about
3
to
9
mg/
kg;
inhalation
LC
50
s
range
from
154
to
543
mg/
m3.
Inhalation
exposure
of
rats
or
monkeys
for
30
minutes
resulted
in
signs
of
neurotoxicity
(
loss
of
muscle
tone
and
reflexes,
convulsions),
decreased
and
arrhythmic
heart
rate,
and
alterations
in
respiration
(
increased
air
flow,
decreased
respiratory
rate,
compliance,
and
minute
volume)
(
Purser
et
al.,
1984;
Bhattacharya
et
al.,
1994).
Two­
week
oral
exposure
of
rats
to
87
mg
CN/
kg­
day
resulted
in
thyroid
toxicity
(
decreased
TSH
and
increased
thyroid
weights)

in
animals
that
were
protein­
and
iodine­
deficient
(
Kreutler
et
al.,
1978).
Increased
liver
weight
was
observed
in
Sprague­
Dawley
rats
administered
14
mg
CN/
kg­
day
in
drinking
water
for
21
days
(
Palmer
and
Olson,
1979).
No
effects
were
observed
in
animals
with
an
adequate
protein
diet.
Supplementation
of
protein­
deficient
rats
with
iodine
also
eliminated
the
effects
of
cyanide
on
thyroid.

Although
there
is
a
relatively
large
number
of
animal
studies
on
the
effects
of
thiocyanate
in
animals,
most
of
the
studies
concentrated
on
the
key
target
organ,
the
thyroid,
rather
than
evaluating
a
range
of
endpoints.
More
importantly,
many
of
the
studies
tested
only
a
single
dose,

so
a
dose­
response
could
not
be
evaluated,
and
often
a
NOAEL
could
not
be
identified.
The
animal
studies
consistently
reported
decreased
plasma­
T4
levels
and
increased
thyroid
weight;

effects
on
T3
were
inconsistent.
Other
studies
reported
decreased
mammary
development
at
similar
doses
(
possibly
secondary
to
thyroid
effects),
and
decreased
hemoglobin.
Short­
term
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
12
animal
toxicity
data
are
available
from
rats
(
Wolff
et
al.,
1946;
Rawson
et
al.,
1944;
De
Groot
et
al.,
1991)
and
guinea
pigs
(
Taubman
and
Heilborn,
1930).
No
NOAEL
was
identified
in
any
of
the
studies.
The
lowest
reliable
LOAEL
was
123
mg
SCN/
kg­
day,
based
on
decreased
T4,

increased
thyroid
weight,
and
activation
of
thyroid
follicles
(
De
Groot
et
al.,
1991).
Decreased
hemoglobin
was
also
observed
in
guinea
pigs
following
2
doses
of
120
mg
SCN/
kg/
dose
(
Taubman
and
Heilborn,
1930).

Long­
term
Studies.
No
long­
term
toxicity
studies
of
cyanogen
chloride
are
available.

Subchronic
toxicity
data
for
cyanide
by
oral
exposure
are
available
in
rats
(
NTP,
1993;
Philbrick
et
al.,
1979),
mice
(
NTP,
1993),
dogs
(
Kamalu,
1993),
and
miniature
pigs
(
Jackson,
1988).
The
only
chronic
study
(
Howard
and
Hanzal,
1955)
of
cyanide
identified
a
free­
standing
NOAEL
of
10.8
mg
CN/
kg­
day.
No
data
on
the
effects
of
subchronic
or
chronic
exposure
to
cyanide
by
the
inhalation
or
dermal
routes
were
located.
Earlier
studies
of
cyanide
(
Philbrick
et
al.,
1979;

Jackson,
1988)
established
that
the
CNS
and
thyroid
are
targets
of
long­
term
cyanide
toxicity.

Philbrick
et
al.
(
1979)
observed
demyelination
of
the
spinal
cord,
decreased
plasma­
T4
levels,
and
increased
thyroid
weights
in
rats
ingesting
cyanide
(
44
mg
CN/
kg­
day)
in
the
diet
for
11.5
months.
Jackson
(
1988)
observed
behavioral
changes
and
decreased
levels
of
T3
and
T4
in
pigs
who
received
cyanide
in
water
for
24
weeks,
with
a
NOAEL
of
0.7
mg
CN/
kg­
day
and
a
LOAEL
of
1.2
mg
CN/
kg­
day.
However,
this
study
is
limited
by
the
small
group
size,
the
lack
of
information
on
the
biological
significance
of
the
hormone
changes,
and
the
lack
of
thyroid
histopathology
data
that
would
confirm
that
cyanide
is
having
an
adverse,
rather
than
adaptive,

effect
on
the
thyroid
at
these
doses.
Kamalu
(
1993)
observed
histopathological
changes
in
kidney,
adrenal,
and
testis
of
dogs
who
received
cyanide
(
1.04
mg
CN/
kg­
day)
in
the
diet
for
14
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
13
weeks.
In
particular,
this
study
suggests
that
cyanide
may
be
a
male
reproductive
toxicant,
based
on
the
presence
of
abnormal
cells
and
sloughing
of
germ
cells
in
the
seminiferous
tubules
and
a
decreased
percentage
of
tubules
in
stage
8
of
the
spermatogenic
cycle.
However,
Kamalu
(
1993)

did
not
conduct
histopathology
on
the
CNS
or
thyroid
tissue
and
did
not
measure
thyroid
hormones.
Therefore,
it
is
not
possible
to
rule
out
the
CNS
and
thyroid
as
target
organs
based
on
this
study,
or
to
evaluate
the
relative
sensitivities
of
the
thyroid,
CNS,
and
male
reproductive
tract.
In
addition,
dogs
have
low
levels
of
rhodanese,
so
they
are
not
good
models
for
human
toxicity
(
ATSDR,
1997).
Male
reproductive
effects,
characterized
by
decreased
epididymis
and
testis
weights,
were
also
observed
in
rats
and
mice
exposed
to
cyanide
in
drinking
water
for
13
weeks
(
NTP,
1993).
The
NOAEL
was
4.5
mg
CN/
kg­
day
in
rats,
and
8.6
mg
CN/
kg­
day
in
mice;

the
corresponding
BMDLs
(
lower
95%
confidence
limits
on
the
benchmark
doses)
were
0.79
mg
CN/
kg­
day
in
rats
and
12
mg
CN/
kg­
day
in
mice.
This
study
did
not
observe
histopathological
changes
in
brain
or
thyroid
tissue,
but
did
not
measure
plasma
levels
of
thyroid
hormones
or
measure
thyroid
weight.
Although
evidence
of
thyroid
hyperplasia
would
be
needed
to
determine
that
a
given
dose
of
cyanide
is
adverse
to
the
thyroid,
it
is
possible
that
this
study
did
not
detect
early
signs
of
adaptive
effects
in
the
thyroid.

Long­
term
toxicity
data
for
thiocyanate
are
available
from
mice
(
Nagasawa
et
al.,
1980)

and
rats
(
Pyska,
1977;
Philbrick
et
al.,
1979;
Kanno
et
al.,
1990)
exposed
to
thiocyanate
via
the
diet
and
drinking
water.
No
data
on
the
effects
of
inhalation
or
dermal
exposure
were
located.

As
for
the
short­
term
studies,
no
subchronic
or
chronic
studies
were
located
that
meet
EPA
test
guidelines
(
including
serum
biochemistry
for
a
number
of
endpoints
and
histopathology
of
an
extensive
list
of
tissues
and
organs).
Nonetheless,
there
is
fairly
good
support
that
the
target
Drinking
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Document
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I­
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organ
(
the
thyroid)
has
been
identified,
and
a
number
of
studies
have
focused
on
effects
on
that
organ.
None
of
the
studies
that
evaluated
thyroid
endpoints
identified
a
NOAEL.
The
lowest
LOAEL
was
identified
by
Philbrick
et
al.
(
1979),
who
reported
a
statistically
significant
decrease
in
plasma
T4
and
increased
thyroid
weight
(
but
no
thyroid
histopathology)
in
rats
administered
98
mg
SCN/
kg­
day
in
diet
for
11.5
months;
plasma
T4
was
increased
at
this
dose
after
4
months
of
exposure.
Pyska
et
al.
(
1977)
also
reported
decreased
plasma
protein­
bound
iodine
(
a
measure
of
plasma
T3
and
T4)
in
rats
administered
100
mg
SCN/
kg­
day
for
approximately
10
weeks
in
drinking
water.

Reproductive/
Developmental
Effects.
No
studies
on
the
reproductive
or
developmental
toxicity
of
cyanogen
chloride
by
any
route
of
exposure
were
located.
No
standard
multigeneration
or
developmental
toxicity
studies
of
cyanide
are
available.
Cyanide
appears
to
be
a
male
reproductive
toxicant
in
rats,
mice,
and
dogs,
as
discussed
in
the
previous
section
(
NTP,

1993;
Kamalu,
1993).
Tewe
and
Maner
(
1981)
found
no
effects
on
litter
size,
birth
weight
of
pups,
or
pup
mortality
in
the
offspring
of
female
rats
receiving
cyanide
in
the
diet
throughout
mating,
gestation,
and
lactation,
although
daily
body
weight
gain
was
decreased
in
weanlings.

No
standard
multigeneration
reproduction
study
of
thiocyanate
by
any
route
was
located.

A
multigeneration
study
(
Raghunath
and
Bala,
1998)
was
conducted
in
rats
administered
108
mg
SCN/
kg­
day
in
feed,
and
decreased
serum
T4
was
observed
at
the
single
dose
tested,
with
a
somewhat
stronger
effect
in
the
F2
generation.
In
addition,
there
was
no
developmental
toxicity
study
that
included
morphological
evaluation
of
the
pups.
Two
studies
reported,
however,
that
mammary
gland
development
of
young
females
is
inhibited
at
doses
at
or
above
those
that
cause
Drinking
Water
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Document
for
Cyanogen
Chloride
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Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
15
thyroid
effects
(
Pyska,
1977;
Nagasawa
et
al.,
1980).
No
standard
developmental
toxicity
studies
were
identified,
although
Nagasawa
et
al.
(
1980)
found
no
effect
on
fertility,
litter
size,
fetal
viability,
or
pup
weight
when
mice
were
administered
thiocyanate
in
drinking
water
up
to
488
mg
SCN/
kg­
day.
Decreased
litter
weight
was
observed
in
the
offspring
of
rats
administered
approximately
156
or
260
mg
SCN/
kg­
day
in
drinking
water,
but
not
52
mg
SCN/
kg­
day
(
Pyska,

1977).
Several
studies
evaluated
thyroid
effects
in
pups
that
were
exposed
to
thiocyanate
during
gestation
and
lactation
(
Bala
et
al.,
1996;
Raghunath
and
Bala,
1998;
Kreutler
et
al.,
1978),
but
no
NOAEL
was
identified.
Kreutler
et
al.
(
1978)
included
the
lowest
doses,
testing
rats
down
to
6.3
mg
SCN/
kg­
day
in
drinking
water.
Unfortunately,
these
authors
only
evaluated
relative
thyroid
weight,
and
increases
in
thyroid
weight
may
be
adaptive
or
adverse,
depending
on
the
effects
on
thyroid
hormones
and
histopathology.
Using
the
most
conservative
interpretation,
the
low
dose
of
6.3
mg
SCN/
kg­
day
in
the
Kreutler
et
al.
(
1978)
study
can
be
considered
an
equivocal
LOAEL.
The
next­
lowest
developmental
LOAEL
was
108
mg
SCN/
kg­
day,
identified
by
Bala
et
al.
(
1996)
and
Raghunath
and
Bala
(
1998),
based
on
decreased
serum
T4
in
pups.

In
general,
the
reproductive
and
developmental
database
for
cyanogen
chloride
and
its
known
or
potential
metabolites
is
incomplete.
The
available
studies
suggest
that
cyanide
is
a
male
reproductive
toxicant,
and
thiocyanate
appears
to
alter
thyroid
function
in
pups
exposed
during
gestation
and
lactation.

Genotoxicity.
No
data
are
available
on
the
genotoxicity
of
cyanogen
chloride.
Although
the
data
for
some
known
or
potential
metabolites
of
cyanogen
chloride
are
limited,
overall
the
available
data
suggest
that
none
of
the
metabolites
are
genotoxic.
Overall,
cyanide
has
been
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
16
negative
in
bacterial
mutagenicity
assays
(
De
Flora,
1981;
De
Flora
et
al.,
1984;
NTP,
1993)
and
assays
of
DNA
damage
and
repair
(
De
Flora
et
al.,
1984;
Painter
and
Howard,
1982);
although
a
positive
result
was
obtained
in
one
strain
of
Salmonella
with
and
without
S9
activation
(
Kushi
et
al.,
1983).
No
assays
of
mammalian
gene
mutation
or
chromosome
aberration
are
available.

Genotoxicity
data
on
thiocyanate
are
limited
to
marginal
results
in
a
S.
typhimurium
mutagenicity
assay
(
Kier,
1988,
as
reported
by
Rosenkranz
and
Klopman,
1990).
Potassium
thiocyanate
does
not
have
any
structural
alerts
for
genotoxicity
(
Rosenkranz
and
Klopman,
1990).

Carcinogenicity.
There
are
no
cancer
bioassays
of
cyanogen
chloride
or
cyanide.
Two
oral
carcinogenicity
studies
in
rats
were
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
higher
doses
of
SCN
may
be
associated
with
increased
incidence
of
thyroid
tumors.
Although
the
increase
of
thyroid
tumors
was
not
statistically
significant,
the
observation
of
thyroid
tumors
in
consistent
with
what
is
known
about
the
SCN
mode
of
action
on
the
thyroid.

However,
these
studies
suffer
from
a
number
of
limitations.
Only
a
single
dose
was
tested
in
each
study,
limited
numbers
of
animals
were
tested
(
20/
group
first
study;
20/
sex/
group
second
study),

and
the
studies
did
not
provide
a
complete
report
of
the
information
needed
to
adequately
assess
SCN
carcinogenicity.

Based
on
these
considerations,
cyanogen
chloride,
cyanide,
and
thiocyanate
would
all
be
classified
as
Group
D,
Not
Classifiable
as
to
Human
Carcinogenicity,
using
the
U.
S.
EPA
(
1986)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
17
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
these
compounds.

E.
Health
Effects
in
Humans
Cyanogen
chloride
was
used
as
a
poison
gas
during
World
War
I,
with
rapid
lethality
resulting
from
sufficiently
high
exposures.
Acute
exposure
to
lower
concentrations
resulted
in
irritation
of
the
eyes,
throat,
and
lungs
(
Flury
and
Zernick,
1931;
Prentiss,
1937;
Michigan
Department
of
Public
Health,
1977).
Only
one
epidemiology
study
of
the
human
health
effects
of
cyanogen
chloride
exposure
was
located.
Reed
(
1920)
reported
on
symptoms
in
a
group
of
14
men
at
a
plant
that
manufactured
cyanogen
chloride.
No
exposure
levels
were
available,
but
the
symptoms
reported
during
periods
of
high
exposure
included
dizziness,
nausea,
and
prostration
that
lasted
several
hours.
Chronic
symptoms
included
weakness,
lassitude,
and
eye,
nose
and
throat
irritation.
The
observed
symptoms
are
consistent
with
those
seen
following
cyanide
exposure.
The
irritative
effects
and
lung
congestion
were
attributed
to
co­
exposure
to
chlorine.

Case
reports
of
accidental
exposure
to
cyanide
and
hydrogen
cyanide
indicate
that
exposure
via
the
oral,
inhalation,
and
dermal
routes
are
of
concern.
The
reported
symptoms
include
dizziness,
weakness,
nausea,
and
a
rapid
pulse;
these
symptoms
can
progress
to
convulsions,
unconsciousness,
and
death
(
Saincher
et
al.,
1994;
Liebowitz
and
Schwartz,
1948;

Potter,
1950;
Drinker,
1932).
Similar
symptoms
were
reported
for
all
three
routes
of
exposure.

Symptoms
characteristic
of
parkinsonism
have
been
reported
among
subjects
who
recover
from
acute
cyanide
poisoning
(
Uitti
et
al.,
1985;
Carella
et
al.,
1988;
Rosenberg
et
al.,
1989;
and
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
18
Grandas
et
al.,
1989).
The
only
epidemiology
study
of
long­
term
exposure
to
cyanide
was
conducted
in
Egypt
with
36
workers
exposed
to
cyanide
in
the
electroplating
industry;
air
concentrations
were
monitored.
Reported
symptoms
included
headache,
weakness,
throat
irritation,
and
vomiting.
A
small
percentage,
who
were
exposed
to
the
highest
concentrations,

reported
neurological
disorders.
Mild
to
moderate
thyroid
enlargement
was
reported
in
56%
of
the
workers,
although
none
of
the
workers
had
clinical
evidence
of
hypo­
or
hyper­
thyroidism.

This
study
identified
a
LOAEL
of
7.2
mg
CN/
m3,
corresponding
to
a
LOAEL(
HEC)
of
2.6
mg
CN/
m3.

No
relevant
inhalation
or
dermal
toxicity
studies
of
thiocyanate
exposure
of
humans
were
identified.
There
is
a
significant
amount
of
data
on
thiocyanate
orally
administered
to
humans,

because
thiocyanate
was
used
for
many
years
to
treat
hypertension.
However,
data
on
the
effects
in
normotensive
humans
is
limited.
Adverse
effects
observed
included
weakness,
nervous­
system
effects
(
including
slurred
speech,
disorientation,
and
hallucinations),
and
enlarged
thyroid.
Some
of
the
observed
effects
may
have
been
due
to
a
rapid
decrease
in
blood
pressure.
While
the
decreased
blood
pressure
was
a
beneficial
effect
for
the
hypertensive
subjects,
the
same
change
could
be
adverse
in
normotensive
subjects,
although
it
is
unclear
if
the
drop
in
blood
pressure
would
be
as
large
in
normotensive
subjects.
Doses
were
reported
inconsistently,
but
doses
of
1.7­
2.8
mg
SCN/
kg­
day
used
to
treat
hypertension
had
a
relatively
low
incidence
of
adverse
effects.

Two
studies
evaluated
thyroid
effects
of
thiocyanate
in
normotensive
populations.

Dahlberg
et
al.
(
1984)
found
no
effect
on
serum
T
3,
T
4,
or
thyrotropic
hormone,
or
the
T
3:
T
4
ratio
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
1
OSCN
is
not
reported
one
of
the
ions
which
are
known
to
inhibit
iodine
transport
in
the
thyroid
(
Wolff,
1998).

EPA/
OW/
OST/
HECD
Final
draft
I­
19
in
37
volunteers
administered
8
mg/
day
thiocyanate
in
milk
(
0.11
mg
SCN/
kg­
day)
for
12
weeks.

Maximum
serum
thiocyanate
levels
were
0.78
mg/
100
mL
in
non­
smokers
and
1.07
mg/
100
mL
in
smokers.
Banerjee
et
al.
(
1997)
evaluated
thyroid
hormone
levels
in
35
women
in
India
who
ingested
thiocyanate
and
hydrogen
peroxide
as
a
bacteriocide
in
milk
for
at
least
5
years,

compared
with
matched
women
ingesting
raw
milk.
The
exposed
women
ingested
approximately
0.19
mg
SCN/
kg­
day.
The
average
serum
level
of
thiocyanate
was
230

mol/
L
(
1.3
mg/
100
mL)

in
the
exposed
group,
and
91

mol/
L
(
0.53
mg/
100
mL)
for
matched
control
women.
The
thiocyanate­
exposed
group
had
significantly
lower
levels
of
serum
T
4
and
higher
levels
of
TSH
than
the
non­
exposed
group.
Together,
these
two
studies
identify
an
apparent
NOAEL/
LOAEL
pair.
The
primary
uncertainty
in
that
identification
is
whether
the
Indian
population
was
more
susceptible
to
the
effects
of
thiocyanate,
due
to
the
potential
for
low
protein
intake.
Another
uncertainty
is
whether
OSCN
(
to
which
the
Indian
women
were
exposed)
is
more
toxic
than
the
equivalent
amount
of
SCN.
1
Since
the
thyroid
responds
rapidly
to
changes
in
iodine
or
related
ions,
progression
of
the
effect
with
increased
exposure
duration
from
12
weeks
to
5
years
would
not
be
expected.
The
NOAEL/
LOAEL
pair
is
supported
by
the
study
of
Beamish
et
al.
(
1954),

who
observed
thyroid
toxicity
(
decreases
in
protein­
bound
plasma­
iodine
concentration
and
thyroid
uptake
of
iodine)
in
hypertensive
subjects
with
blood
thiocyanate
levels
(
1.3­
5
mg/
100
mL)
similar
to
those
reported
by
Banerjee
et
al.
(
1997).
However,
no
data
on
amount
of
thiocyanate
ingested
were
available
from
the
Beamish
et
al.
(
1954)
study.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
20
F.
Mechanism
of
Action
Almost
all
of
the
toxic
effects
observed
following
cyanogen
chloride
exposure
can
be
accounted
for
by
the
known
or
potential
metabolites.
The
sole
exception
is
the
irritative
effects
from
exposure
to
cyanogen
chloride
vapor,
which
appear
to
be
due
to
the
parent
compound.

Based
on
consideration
of
cyanogen
chloride
biochemistry
and
that
of
its
known
and
putative
metabolites,
a
toxicokinetic
pathway
and
mechanism
of
action
can
be
proposed.
It
is
plausible
that
ingested
cyanogen
chloride
is
absorbed
as
the
parent
compound,
and
that
essentially
all
of
its
metabolism
occurs
in
the
gastrointestinal
tract
and
liver.
Metabolism
in
the
blood
after
absorption
from
the
intestine
is
also
possible,
as
is
reaction
with
nucleophiles
in
the
intestine,
or
its
contents.
Rapid
glutathione­
mediated
reduction
to
cyanide
and
HCl
would
be
expected
to
occur
in
the
portal
vein
and
in
the
liver
during
first­
pass
metabolism,
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.
The
rhodanese
enzyme
in
the
liver
would
then
convert
the
cyanide
formed
to
thiocyanate.
Formation
of
thiocyanate
directly
from
cyanogen
chloride,
and/
or
formation
of
other
metabolites,
may
also
occur.
This
hypothesized
metabolic
pathway
would
suggest
that
HCl
production
would
result
in
localized
pH
decreases
in
the
portal
vein
and
liver.

Systemic
acidosis
is
unlikely
at
environmental
exposures,
as
shown
by
the
calculations
in
Chapter
VIII.
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
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
21
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.

The
potential
liver
effects
of
cyanogen
chloride
would
be
specific
to
first­
pass
metabolism
following
cyanogen
chloride
ingestion,
and
would
not
apply
to
the
available
inhalation
and
injection
studies
of
cyanogen
chloride.
The
limited
available
data
indicate
that
liver
damage
is
not
an
effect
of
increased
hydrogen
ion
concentrations
at
doses
that
cause
acidosis
(
Bookallil,
2001).

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

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).
People
with
hypothyroid
disorders,
and
protein
or
iodine
deficiency
may
be
more
sensitive
to
the
thyroid
effects
of
cyanide
that
are
caused
by
the
metabolite
thiocyanate.
Protein
deficiency
is
rare
in
the
Western
world
(
U.
S.
FDA,
1999),
but
approximately
5%
of
the
U.
S.
population
may
have
iodine
deficiencies
(
Hollowell
et
al.,
1998).
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
22
G.
Quantification
The
human
and
animal
data
on
cyanogen
chloride
are
insufficient
for
the
derivation
of
Health
Advisories
or
an
RfD.
Therefore,
the
cyanogen
chloride
Health
Advisories
and
RfD
were
derived
using
cyanide
as
a
surrogate,
based
on
the
fact
that
it
is
a
known
metabolite
that
represents
a
major
portion
of
the
cyanogen
chloride
dose.
Table
I­
1
presents
the
Health
Advisories
derived
for
cyanogen
chloride,
all
based
on
cyanide
as
a
surrogate,
and
adjusting
for
molecular
weight.
The
data
were
insufficient
for
derivation
of
a
one­
day
HA,
and
so
the
Ten­
day
HA
is
used
in
its
place.

Table
I­
1.
Summary
of
Health
Advisory
Values
for
Cyanogen
Chloride
Basis
One­
day
HA
mg/
L
Ten­
day
HA
mg/
L
Longer­
term
HA
Child
mg/
L
Longer­
term
HA
Adult
mg/
L
Lifetime
HA
mg/
L
RfD
mg/
kg­
day
Cyanide
NOAEL
0.3
0.3
0.1
0.4
0.08
0.01
Cyanide
BMDL
N/
A
N/
A
0.02
0.07
0.01
0.002
There
are
no
cancer
bioassays
of
cyanogen
chloride
or
cyanide.
No
data
are
available
on
the
genotoxicity
of
cyanogen
chloride,
although
a
QSTR
analysis
predicted
that
cyanogen
chloride
was
negative
for
carcinogenicity
in
rats
and
mice
of
both
sexes
(
Moudgal
et
al.,
2000).
Although
the
data
for
some
known
or
potential
metabolites
of
cyanogen
chloride
are
limited,
the
available
data
suggest,
overall,
that
none
of
the
metabolites
is
genotoxic.
Based
on
these
considerations,

cyanogen
chloride,
cyanide
and
thiocyanate
are
all
classified
as
Group
D,
Not
Classifiable
as
to
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
I­
23
Human
Carcinogenicity,
using
the
U.
S.
EPA
(
1986)
guidelines.
Using
the
U.
S.
EPA
(
1999)
Draft
Guidelines
for
Cancer
Risk
Assessment,
the
data
are
inadequate
for
an
assessment
of
the
human
carcinogenic
potential
of
these
compounds.