Document ID: EPA-HQ-OW-2002-0043-0180
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-08-11T04:00Z

Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
1
Estimated
by
assuming
a
body
weight
of
0.180
kg
and
0.124
kg
for
males
and
females,
respectively,
and
food
consumption
of
0.018
kg/
day
and
0.014
kg/
day
for
males
and
females,
respectively
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

D­
1
EPA/
OW/
OST/
HECD
Final
draft
APPENDIX
D.
CYANAMIDE
I.
HEALTH
EFFECTS
IN
ANIMALS
A.
Short­
Term
Exposures
Toxicity
studies
for
cyanamide
are
summarized
in
Table
D­
1.
No
specific
short­
term
studies
of
cyanamide
by
the
inhalation
or
dermal
routes
were
located.
However,
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).
No
studies
that
identified
an
LD
50
were
located.

NCI
(
1979)
evaluated
the
short­
term
toxicity
of
calcium
cyanamide
in
F344
rats
and
B6C3F1
mice
in
a
study
designed
to
find
the
appropriate
dose
range
for
a
chronic
bioassay
(
see
Tables
D­
2
and
D­
3).
F344
rats
(
5/
sex/
group)
received
calcium
cyanamide
in
the
diet
for
7
weeks
at
concentrations
of
0,
400,
600,
800,
900,
1000,
1200,
1500,
3000,
4000,
8000,
10,000,
16,000,

or
30,000
ppm.
These
are
equivalent
to
cyanamide
doses
of
0,
21,
31,
42,
47,
52,
63,
79,
157,

210,
420,
525,
839,
and
1574
mg
cyanamide/
kg­
day
for
males,
and
0,
24,
36,
47,
53,
59,
71,
89,

178,
237,
474,
592,
948,
and
1777
mg
cyanamide/
kg­
day
for
females.
1
B6C3F1
mice
received
calcium
cyanamide
in
the
diet
for
seven
weeks
at
concentrations
of
0,
1500,
3000,
4000,
8000,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
2
Estimated
by
assuming
a
body
weight
of
0.0316
kg
and
0.0246
kg
for
males
and
females,
respectively,
and
food
consumption
of
0.0057
kg/
day
and
0.0048
kg/
day
for
males
and
females,
respectively
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

D­
2
EPA/
OW/
OST/
HECD
Final
draft
10,000,
16,000,
or
30,000
ppm.
These
are
equivalent
to
doses
of
0,
142,
284,
379,
757,
946,

1514,
and
2839
mg
cyanamide/
kg­
day
for
males
and
0,
154,
307,
409,
819,
1024,
1636,
and
3071
mg
cyanamide/
kg­
day
for
females.
2
Clinical
signs
and
body
weight
were
recorded.

Histopathologic
analysis
was
conducted
on
all
major
tissues
and
organs,
and
on
all
gross
lesions.

In
rats,
100%
mortality
was
observed
at
doses
of
8000
ppm
and
higher
in
both
males
and
females.

Body
weight
decreases
>
10%
were
observed
in
males
at
doses

600
ppm
and
in
females
at
doses

900
ppm
.
Bile­
duct
hyperplasia
was
observed
in
males
and
females
at
doses

1500
ppm,
and
thyroid
hyperplasia
was
observed
in
males
and
females
at
doses

600
ppm.

In
mice,
100%
mortality
was
observed
in
the
high
dose
for
both
males
and
females;

however,
at
the
next
lowest
dose
(
16,000
ppm)
there
was
no
effect
on
mortality.
A
decrease
in
body
weight
of
more
than
10%
was
observed
in
male
mice
at
doses

8,000
ppm
and
in
female
mice
in
all
dose
groups.
Both
male
and
female
mice
in
the
two
highest
dose
groups
developed
bile­
duct
hyperplasia,
vacuolation
and
hepatic
necrosis.
However,
the
livers
were
normal
in
all
lower
dose
groups.
Based
on
thyroid
hyperplasia
in
both
sexes
and
decreased
body
weight
in
males,
the
NOAEL
in
this
study
for
rats
was
400
ppm
(
21
mg
cyanamide/
kg­
day
for
males
and
24
mg
cyanamide/
kg­
day
for
females)
and
a
LOAEL
of
600
ppm
(
31
mg
cyanamide/
kg­
day
for
males
and
36
mg
cyanamide/
kg­
day
for
females).
The
lowest
dose
tested
(
1500
ppm,
or
154
mg
cyanamide/
kg­
day)
was
a
LOAEL
in
female
mice,
based
on
decreased
body
weight.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
3
EPA/
OW/
OST/
HECD
Final
draft
Summary.
Only
one
study
on
the
short­
term
toxicity
of
cyanamide
was
located.
NCI
(
1979)
exposed
rats
and
mice
to
calcium
cyanamide
in
the
diet
for
seven
weeks.
Effects
in
rats
included
decreased
body
weight,
bile­
duct
hyperplasia,
and
thyroid
hyperplasia.
Effects
in
mice
included
decreased
body
weight,
bile­
duct
hyperplasia,
and
liver
vacuolation
and
necrosis.

Decreased
body
weight
appears
to
be
the
critical
effect;
the
NOAEL
for
this
effect
is
21
mg
cyanamide/
kg­
day
and
the
LOAEL
is
31
mg
cyanamide/
kg­
day.

B.
Long­
Term
Exposures
Obach
et
al.
(
1985)
evaluated
the
toxicity
of
cyanamide
in
rats
following
oral
exposure.

Sprague­
Dawley
rats
(
20/
sex/
group)
received
cyanamide
by
gavage
(
vehicle
not
reported)
at
doses
of
0,
2,
7,
or
25
mg/
kg­
day
for
six
months.
Body
weights
were
recorded.
At
the
end
of
the
treatment
period,
blood
was
collected
and
analyzed
for
serum
chemistry
and
enzymes.
Livers
were
evaluated
histopathologically;
no
other
toxicologic
endpoints
were
evaluated.
Final
body
weights
of
both
male
and
female
rats
treated
with
doses
of
7
mg/
kg­
day
or
higher
were
statistically
significantly
decreased
compared
with
controls.
In
males,
bilirubin
was
significantly
increased
compared
with
controls
7
mg/
kg­
day
and
higher;
bilirubin
was
significantly
increased
in
females
only
at
the
mid­
dose.
The
authors
attributed
this
to
a
hemolytic
effect
resulting
from
cyanamide
treatment.
Liver
vacuolation
and
fatty
metamorphosis
was
observed
in
all
groups,

including
the
controls,
but
was
more
prominent
in
high­
dose
females.
In
contrast
to
the
results
of
Guillen
and
Vazquez
(
1984)
described
below,
no
inclusion
bodies
were
observed
at
any
dose.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
4
EPA/
OW/
OST/
HECD
Final
draft
Although
the
statistical
significance
of
the
liver
effects
were
not
reported,
the
authors
noted
that
the
effects
were
prominent
in
the
high­
dose
females.
Based
on
decreased
body
weight
and
increased
bilirubin,
the
2
mg/
kg­
day
dose
is
considered
to
be
a
NOAEL
and
the
7
mg/
kg­
day
dose
is
considered
to
be
a
LOAEL.

In
a
follow­
up
study,
Obach
et
al.
(
1986b)
evaluated
the
role
of
cyanamide
on
brain
biochemistry
and
body
weight.
Sprague­
Dawley
rats
(
14­
19
males/
group)
received
cyanamide
by
oral
gavage
(
vehicle
not
reported)
at
doses
of
0,
2,
8,
or
25
mg/
kg­
day
for
six
months.
Body
weight,
food
consumption,
and
water
consumption
were
recorded.
After
sacrifice,
whole
brains
were
removed
and
analyzed
for
the
following
neurotransmitters
and
their
metabolites:
3­

methoxy­
4­
hydroxy­
phenylethyleneglycol
sulphate
(
MOPEG­
SO4,
a
metabolite
of
noradrenaline),

noradrenaline,
dopamine,
tryptophan,
5­
hydroxytryptamine,
and
5­
hydroxyindolacetic
acid.
No
other
toxicologic
endpoints
were
evaluated.
Treatment
with
cyanamide
resulted
in
dosedependent
decreases
in
both
food
consumption
and
body
weight.
The
decrease
in
body
weight
was
statistically
significant
at
25
mg/
kg­
day
beginning
in
week
3,
and
at
8
mg/
kg­
day
beginning
in
week
20.
In
addition,
the
brain
concentration
of
MOPEG­
SO4
was
significantly
increased
in
the
high­
dose
group.
The
authors
concluded
that
a
central
action
of
cyanamide
on
brain
catecholamines
resulted
in
an
anorexic
effect,
depressing
food
consumption
and
body
weight.

Based
on
decreased
body
weight,
the
NOAEL
is
determined
to
be
2
mg/
kg­
day
and
the
LOAEL
to
be
8
mg/
kg­
day.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
3
Note
­
This
study,
and
all
of
the
animal
studies
except
NCI
(
1979)
used
Colme
®
for
the
cyanamide
dosing
and
"
pure"
calcium
cyanamide
as
a
comparison.
NCI
(
1979)
dosed
the
rats
and
mice
with
calcium
cyanamide.
However,
the
newer
human
studies
(
1997­
1999)
say
that
Colme
®
is
calcium
cyanamide.
It
is
unclear
whether
all
of
the
studies
reviewed
for
this
document
were
conducted
with
calcium
cyanamide
(
in
which
case,
there
is
nothing
to
the
different
toxicities
of
the
two
compounds),
or
whether
the
formulation
of
Colme
®
changed
recently.

D­
5
EPA/
OW/
OST/
HECD
Final
draft
Valerdiz
and
Vaquez
(
1989)
investigated
the
apparent
differences
in
liver
toxicity
between
cyanamide
and
calcium
cyanamide.
3
(
See
Table
II­
1
for
the
differences
in
structure
between
these
two
compounds.)
Male
Wistar
rats
(
20/
group)
received
either
16
mg/
kg­
day
of
cyanamide
or
30
mg/
kg­
day
of
calcium
cyanamide
(
equivalent
to
16
mg/
kg­
day
cyanamide)
by
gavage
in
Tween
80
for
25
weeks.
Control
animals
received
vehicle
only.
Body
weights
were
recorded.
At
sacrifice,

blood
was
collected
for
analysis
of
serum
chemistry
and
the
liver
was
evaluated
by
both
light
and
electron
microscopy.
No
other
toxicologic
endpoints
were
evaluated.
Both
cyanamide
and
calcium­
cyanamide
treatment
resulted
in
significantly
decreased
body
weights.
All
of
the
animals
treated
with
cyanamide
demonstrated
inclusion
bodies
in
the
liver
cells.
In
contrast,
none
of
the
animals
treated
with
calcium
cyanamide
showed
any
histopathologic
changes
of
the
liver.

Therefore,
cyanamide
appears
to
be
more
toxic
to
the
liver
than
calcium
cyanamide.
However,

based
on
decreased
body
weight,
a
dose
of
16
mg
cyanamide/
kg­
day
is
considered
to
be
a
LOAEL
for
both
forms.

NCI
(
1979)
reported
the
results
of
a
chronic
bioassay
on
calcium
cyanamide
in
F344
rats
and
B6C3F1
mice.
F344
rats
(
50/
sex/
group)
received
calcium
cyanamide
in
the
diet
for
107
weeks
at
doses
of
0,
100
or
200
ppm
(
0,
4.1,
and
8.3
mg
cyanamide/
kg­
day)
for
males
and
0,
100,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
4
Estimated
by
assuming
a
body
weight
and
food
consumption
of
0.38
kg
and
0.03
kg/
day,
respectively
for
males,
and
0.229
kg
and
0.021
kg/
day,
respectively
for
females
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

5
Estimated
by
assuming
a
body
weight
and
food
consumption
of
0.037
kg
and
0.0064
kg/
day,
respectively
for
males
and
0.035
kg
and
0.0061
kg­
day,
respectively
for
females
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

D­
6
EPA/
OW/
OST/
HECD
Final
draft
or
400
ppm
(
0,
4.8,
or
19
mg
cyanamide/
kg­
day4)
for
females.
B6C3F1
mice
(
50/
sex/
group)

received
calcium
cyanamide
in
the
diet
for
107
weeks
at
doses
of
0,
500,
and
2000
ppm
(
0,
45
and
180
mg
cyanamide/
kg­
day
for
males
and
0,
45,
and
181
mg
cyanamide/
kg­
day
for
females5).

Survival,
body
weight
and
clinical
signs
were
recorded.
Histopathological
analysis
was
conducted
on
all
major
tissues
and
organs
and
on
gross
lesions.
In
rats,
no
treatment­
related
effects
were
observed
on
survival,
body
weight,
or
histopathology.
In
mice,
decreased
survival
was
observed
in
high­
dose
males.
No
treatment­
related
effects
on
body
weight
or
histopathology
were
observed
in
males
or
females.
The
high
dose
in
male
rats,
200
ppm
(
8.3
mg
cyanamide/
kg­
day)

was
a
freestanding
NOAEL.
Based
on
decreased
survival
in
male
mice,
the
NOAEL
was
determined
to
be
500
ppm
(
45
mg
cyanamide/
kg­
day)
and
the
LOAEL
to
be
2000
ppm
(
180
mg/
kg­
day).

Guillen
and
Vazquez
(
1984)
evaluated
the
effects
of
cyanamide
on
liver
toxicity
in
rats.

Wistar
rats
(
5
males/
group)
received
daily
doses
of
0,
8,
or
16
mg/
kg
cyanamide
administered
intraperitoneally
for
up
to
27
weeks.
Water
consumption
and
body
weight
were
measured;
at
sacrifice,
the
livers
were
evaluated
by
both
light
and
electron
microscopy.
No
other
toxicologic
endpoints
were
evaluated.
In
both
treated
groups,
water
consumption
and
body
weights
were
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
7
EPA/
OW/
OST/
HECD
Final
draft
significantly
decreased
compared
to
controls.
By
the
seventh
week
of
treatment,
morphologic
changes
were
observed
in
the
livers
of
all
treated
animals
that
were
not
observed
in
controls.

These
lesions
included
increased
glycogen
deposition
and
inclusion
bodies.
However,
the
incidence
of
the
lesions
and
the
statistical
significance
of
these
lesions
compared
to
control
animals
was
not
reported.
This
study
is
limited
for
risk
assessment
purposes
due
to
the
small
number
of
animals,
use
of
an
exposure
route
not
relevant
to
environmental
exposure,
and
the
incomplete
reporting.
However,
based
on
the
observation
of
liver
pathology,
the
low
dose
of
8
mg/
kg­
day
could
be
considered
as
a
LOAEL.

Summary.
No
long­
term
studies
of
cyanamide
by
the
inhalation
or
dermal
routes
are
available.
Several
subchronic
studies
of
cyanamide
by
gavage
are
available
in
rats
(
Guillen
and
Vazquez,
1984;
Obach
et
al.,
1985;
Obach
et
al.,
1986b).
All
three
studies
demonstrated
decreased
food
consumption
accompanied
by
decreased
body
weight
at
doses
of
7­
8
mg/
kg­
day,

with
Obach
et
al.
(
1985,
1986b)
reporting
corresponding
NOAELs
of
2
mg/
kg­
day.
Both
Guillen
and
Vazquez
(
1984)
and
Obach
et
al.
(
1985)
observed
liver
toxicity,
characterized
by
glycogen
deposits,
inclusion
bodies,
and
vacuolation
at
doses
of
8
mg/
kg­
day.
These
studies
are
all
limited
for
risk
assessment
because
they
did
not
evaluate
any
organs
or
tissues
other
than
liver.
Valerdiz
and
Vaquez
(
1989)
determined
that
cyanamide
is
more
toxic
than
calcium
cyanamide
to
the
liver.

The
only
chronic
oral
bioassay
of
cyanamide
(
NCI,
1979)
was
conducted
in
rats
and
mice
using
calcium
cyanamide.
No
treatment­
related
noncancer
effects
were
observed
in
either
rats
or
mice.

The
study
identified
a
free­
standing
NOAEL
in
rats
of
8.3
mg
cyanamide/
kg­
day.
The
dose
of
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
8
EPA/
OW/
OST/
HECD
Final
draft
180
mg
cyanamide/
kg­
day
was
a
LOAEL
in
mice,
based
on
decreased
survival,
with
a
corresponding
NOAEL
of
45
mg/
kg­
day.
However,
in
light
of
the
observation
of
Valerdiz
and
Vaquez
(
1989)
that
cyanamide
is
more
toxic
than
calcium
cyanamide,
it
is
possible
that
the
NCI
(
1979)
study,
which
used
calcium
cyanamide,
may
have
missed
liver
effects
that
would
have
been
observed
with
cyanamide.

C.
Reproductive/
Developmental
Toxicity
Valles
et
al.
(
1987)
reported
the
results
of
a
two­
generation
reproduction
study
of
cyanamide
in
the
rat.
Sprague­
Dawley
rats
(
20
males
and
40
females/
group)
received
cyanamide
at
doses
of
0,
2,
7,
or
25
mg/
kg­
day
by
oral
gavage
(
vehicle
not
reported).
Parental
males
were
treated
for
a
total
of
70
days.
Parental
females
were
treated
for
15
days
prior
to
mating,
through
gestation
and
lactation.
The
F1
generation
was
treated
from
weaning
of
the
F1
pups
through
weaning
of
the
F2
generation.
Twenty
dams
per
group
were
sacrificed
on
day
13
of
gestation
and
were
evaluated
for
the
number
of
embryos,
the
number
of
implantation
sites,
and
the
number
of
embryos
undergoing
resorption.
The
remaining
dams
were
allowed
to
litter
normally,
and
litters
were
evaluated
for
size,
number
of
dead
and
living
neonates,
and
gross
anomalies.
The
F1
pups
were
evaluated
for
behavioral
and
developmental
parameters.
In
order
to
determine
which
sex
was
affected
by
cyanamide,
the
high­
dose
males
from
the
parental
generation
and
twenty
new
females
treated
with
25
mg/
kg­
day
were
mated
to
an
equal
number
of
untreated
females
and
males,
respectively.
Histopathologic
evaluation
of
brain,
hypophysis,
and
reproductive
organs
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
9
EPA/
OW/
OST/
HECD
Final
draft
was
conducted
on
the
parental
and
F1
generation
animals.
A
statistically
significant
decrease
in
the
fertility
percentage
was
observed
in
the
high­
dose
group.
This
decrease
in
fertility
percentage
was
observed
when
treated
males
were
mated
with
untreated
females,
but
not
when
treated
females
were
mated
with
untreated
males.
These
results
suggested
that
cyanamide
was
affecting
male
reproduction.
For
the
parental
dams
sacrificed
on
gestation
day
13,
statistically
significant
decreases
in
weight
gain,
number
of
corpora
lutea,
and
number
of
implantations
was
observed
in
the
high­
dose
group.
In
the
dams
allowed
to
deliver
naturally,
there
was
also
a
decrease
in
weight
gain,
number
of
implantations,
and
live
pups.
In
the
parental
generation,
significant
decreases
in
relative
epididymis
and
prostrate
weights,
as
well
as
testicular
atrophy
was
observed
in
the
25
mg/
kg­
day
dose
group.
Cyanamide
exposure
had
no
effect
on
any
reproductive
or
developmental
parameters
in
the
F1
generation.
Based
on
reproductive
toxicity
in
the
parental
generation,
the
NOAEL
in
this
study
is
determined
to
be
7
mg/
kg­
day,
and
the
LOAEL
is
determined
to
be
25
mg/
kg­
day.

Ali
and
Persaud
(
1987)
evaluated
the
developmental
effects
of
cyanamide
administered
intraperitoneally
to
rats.
Pregnant
Sprague­
Dawley
rats
(
number
not
specified)
received
0
or
40
mg/
kg­
day
of
cyanamide
on
gestation
days
9
to
12.
On
gestation
day
12,
the
embryos
were
removed
and
evaluated
for
morphological
alterations.
In
addition,
crown­
rump
length
and
head
length
were
also
recorded
for
each
embryo.
Complete
resorption
occurred
in
two
animals
treated
with
cyanamide.
However,
since
no
information
was
provided
on
the
number
of
animals
in
each
group
or
the
statistical
significance
of
this
finding,
it
cannot
be
determined
if
resorption
of
litters
is
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
10
EPA/
OW/
OST/
HECD
Final
draft
an
adverse
effect
of
cyanamide.
Cyanamide
treatment
had
no
effect
on
any
of
the
morphological
parameters
evaluated
in
the
embryos.
This
study
is
inadequate
for
risk­
assessment
purposes
due
to
the
use
of
a
route
of
exposure
that
is
not
environmentally
relevant,
and
incomplete
reporting.

Summary.
The
available
data
on
the
reproductive
and
developmental
toxicity
of
cyanamide
are
limited
to
a
developmental
toxicity
study
in
rats
conducted
by
intraperitoneal
injection
and
a
two­
generation
toxicity
study
in
rats
exposed
via
gavage.
In
the
two­
generation
reproduction
study,
Valles
et
al.
(
1987)
observed
effects
on
reproduction
in
the
parental
generation,
but
not
the
F1
generation,
of
rats
exposed
to
25
mg
cyanate/
kg­
day
by
gavage;
the
NOAEL
was
7
mg/
kg­
day.
There
was
a
significant
decrease
in
fertility
percentage
in
parentalgeneration
rats.
A
crossover
study
(
in
which
treated
males
were
mated
with
untreated
females
and
vice
versa)
showed
that
the
decreased
fertility
was
due
to
an
effect
on
male
reproduction,
and
female
fertility
was
not
affected.
Treated
parental
males
had
significant
decreases
in
epididymis
weights
and
testicular
atrophy.
For
treated
parental
dams,
there
was
a
significant
decrease
in
the
number
of
corpora
lutea
and
implantations.
Also,
treated
dams
allowed
to
deliver
naturally
had
a
significant
decrease
in
the
number
of
live
pups.
Ali
and
Persaud
(
1987)
administered
40
mg
cyanamide
to
rats
on
gestation
days
9­
12
by
intraperitoneal
injection.
Complete
resorption
of
litters
was
observed
in
treated
dams;
no
gross
abnormalities
or
alterations
in
crown­
rump
or
head
length
were
observed
in
pups.
However,
no
information
is
given
on
the
statistical
significance
of
the
resorption
incidence
and
the
authors
did
not
perform
a
complete
analysis
of
skeletal
and
softtissue
abnormalities
or
variations
in
pups.
These
weaknesses,
combined
with
the
use
of
a
non­
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
11
EPA/
OW/
OST/
HECD
Final
draft
environmentally
relevant
route
of
exposure,
make
this
study
inadequate
for
risk
assessment
purposes.
These
studies
suggest
that
cyanamide
is
a
male
reproductive
toxicant
and
affects
developmental
endpoints;
the
only
NOAEL
identified
is
7
mg/
kg­
day.

D.
Mutagenicity
and
Genotoxicity
Only
limited
information
on
the
mutagenicity
of
cyanamide
is
available.
Cyanamide
was
negative
in
both
gene
mutation
and
chromosome
damage
assays;
the
positive
result
in
one
strain
of
Salmonella
was
not
supported
by
testing
in
a
related
strain.
Cyanamide
at
a
concentration
of
300

g/
mL
inhibited
both
growth
and
cell
division
in
Saccharomyces
cerevisiae
(
Loveless
et
al.,

1954).
Calcium
cyanamide
at
doses
of
1000
or
2000
ppm
was
nonmutagenic
in
the
Drosophila
sex­
linked
recessive
lethal
test
(
Yoon
et
al.,
1985).
Calcium
cyanamide
was
positive
with
strain
TA1535,
but
negative
with
strains
TA98,
TA100,
and
TA1537,
in
the
Salmonella
mutagenicity
assay.
It
was
not
reported
whether
the
positive
result
occurred
with
or
without
metabolic
activation
(
Zeiger,
1987).
The
negative
result
in
strain
TA100,
which
detects
the
same
changes
as
strain
TA1535
but
is
more
sensitive,
casts
doubt
on
the
reliability
of
the
positive
result
in
strain
TA1535.
Cyanamide
at
concentrations
of
0.03
to
3
mM
did
not
induce
single­
strand
DNA
breaks
in
rat
hepatocytes
in
vitro
(
Sina
et
al.,
1983).
Cyanamide
at
doses
of
10
to
247
mg/
kg
by
gavage
did
not
increase
the
incidence
of
micronucleated
polychromatic
erythrocytes
in
the
bone
marrow
of
mice
(
Menargues
et
al.,
1984).
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
6
Estimated
by
assuming
a
body
weight
and
food
consumption
of
0.38
kg
and
0.03
kg/
day,
respectively
for
males
and
0.229
kg
and
0.021
kg­
day,
respectively
for
females
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

7Estimated
by
assuming
a
body
weight
and
food
consumption
of
0.037
kg
and
0.0064
kg/
day,
respectively
for
males
and
0.035
kg
and
0.0061
kg/
day,
respectively
for
females
(
U.
S.
EPA,
1988).
The
resulting
dose
was
then
multiplied
by
the
ratio
of
the
molecular
weights
of
cyanamide
to
calcium
cyanamide.

D­
12
EPA/
OW/
OST/
HECD
Final
draft
Summary.
Cyanamide
was
negative
in
bacterial
gene
mutation
assays
(
Loveless
et
al.,

1954;
Zeiger
et
al.,
1987),
a
Drosophila
sex­
linked
recessive
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).

E.
Carcinogenicity
NCI
(
1979)
reported
the
results
of
a
chronic
bioassay
on
calcium
cyanamide
in
F344
rats
and
B6C3F1
mice.
F344
rats
(
50/
sex/
group)
received
calcium
cyanamide
in
the
diet
for
107
weeks
at
doses
of
0,
100,
or
200
ppm
(
0,
4.1,
and
8.3
mg
cyanamide/
kg­
day)
for
males
and
0,

100,
or
400
ppm
(
0,
4.8,
and
19
mg
cyanamide/
kg­
day6)
for
females.
B6C3F1
mice
(
50/
sex/
group)
received
calcium
cyanamide
in
the
diet
for
107
weeks
at
doses
of
0,
500,
or
2000
ppm
(
0,
45,
and
180
mg
cyanamide/
kg­
day
for
males
and
0,
45,
or
181
mg
cyanamide/
kg­
day
for
females7).
Survival,
body
weight
and
clinical
signs
were
recorded.
Histopathological
analysis
was
conducted
on
all
major
tissues
and
organs
and
on
gross
lesions.
NCI
(
1979)
concluded
that
no
tumor
at
any
site
in
the
rats
was
clearly
associated
with
administration
of
calcium
cyanamide.

Hemangiosarcomas
were
observed
in
male
mice
with
incidence
of
1/
20,
2/
50,
and
10/
50
for
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
13
EPA/
OW/
OST/
HECD
Final
draft
control,
mid­
and
high­
dose
groups,
respectively.
Statistical
analysis
indicated
a
significant
doserelated
trend
for
these
tumors;
however,
neither
dose
group
was
statistically
significant
when
compared
with
controls.
Malignant
lymphomas
were
observed
in
female
mice
with
incidences
of
1/
20,
11/
46,
and
16/
50
for
control,
mid­,
and
high­
dose
groups
respectively.
Statistical
analysis
indicated
a
significant
dose­
related
trend
for
these
tumors.
In
addition,
the
incidence
in
the
highdose
group
was
statistically
significant
compared
with
controls.
However,
NCI
(
1979)
reported
that
the
historical
control
incidence
for
this
tumor
type
in
B6C3F1
mice
was
21%.
Therefore,
the
incidence
of
5%
in
the
matched
control
group
may
have
been
abnormally
low.
NCI
(
1979)

concluded
that
neither
of
these
tumor
types
were
clearly
related
to
administration
of
calcium
cyanamide.

Summary.
One
standard
cancer
bioassay
on
cyanamide
was
located.
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.
Hemangiosarcomas
were
observed
in
male
mice
with
a
significant
dose­
related
trend.
However,
neither
dose
group
was
statistically
significant
when
compared
with
controls.
Malignant
lymphomas
were
observed
in
female
mice.

Statistical
analysis
indicated
a
significant
dose­
related
trend
for
these
tumors
and
a
significant
increase
in
incidence
in
the
high­
dose
group
compared
with
controls.
However,
NCI
(
1979)

indicates
that
the
historical
control
incidence
for
this
tumor
type
in
B6C3F1
mice
was
21%;

therefore,
the
incidence
in
the
matched
control
group
may
be
abnormally
low.
NCI
(
1979)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
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D­
14
EPA/
OW/
OST/
HECD
Final
draft
concluded
that
neither
of
these
tumors
were
clearly
related
to
administration
of
calcium
cyanamide.

II.
Health
Effects
in
Humans
A.
Case
Reports
and
Clinical
Studies
Cyanamide
is
used
in
the
treatment
of
alcoholics.
Accordingly,
there
are
several
clinical
studies
of
the
effects
of
ingested
cyanamide
(
see
Table
D­
1).
Several
clinical
case
studies
also
demonstrate
that
people
exposed
to
cyanamide
by
either
the
dermal
or
oral
routes
can
develop
contact
dermatitis.
No
inhalation
studies
of
human
exposure
to
cyanamide
were
located.

Goday­
Bujan
et
al.
(
1994)
reported
three
cases
in
which
the
patients
who
handled
cyanamide
at
work
developed
contact
dermatitis
on
their
hands.
The
dermatitis
cleared
up
when
the
patients
were
away
from
work.
The
dose
to
which
these
patients
was
exposed
was
not
reported.
In
all
three
cases,
patch
tests
confirmed
an
allergic
reaction
to
cyanamide.
Conde­

Salazar
et
al.
(
1981)
also
report
a
case
of
contact
dermatitis
following
dermal
exposure
to
cyanamide.
The
patient
was
an
assistant
in
a
psychiatric
ward
where
he
dispensed
a
medication
containing
cyanamide.
He
developed
dermatitis
on
the
fingers
of
his
right
hand;
the
dermatitis
improved
when
the
patient
was
away
from
work.
The
dose
to
which
the
patient
was
exposed
was
not
reported.
Patch
tests
confirmed
an
allergic
reaction
to
cyanamide.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
15
EPA/
OW/
OST/
HECD
Final
draft
Several
case
studies
report
the
development
of
an
allergic
dermatitis
in
patients
who
were
ingesting
cyanamide
as
a
medication
for
treating
alcoholism
(
Abajo
et
al.,
1999;
Kawana,
1997;

Ajima
et
al.,
1997).
A
total
of
nine
cases
are
reported;
in
all
cases,
the
patients
had
been
ingesting
cyanamide
as
a
drug
used
for
treating
alcoholism.
For
one
case,
the
reported
dose
was
100
mg/
day
(
1.4
mg/
kg­
day,
assuming
a
body
weight
of
70
kg)
and
the
onset
of
skin
lesions
occurred
three
weeks
after
initiation
of
cyanamide
treatment
(
Ajima
et
al.,
1997).
For
seven
cases,
the
reported
dose
was
7
mL/
day
of
a
1%
carbimide
solution
(
1
mg/
kg­
day
assuming
1%

weight/
volume
solution
and
body
weight
of
70
kg);
however,
it
was
not
clear
if
the
carbimide
solution
was
free
cyanamide
or
calcium
cyanamide
(
Kawana,
1997).
Kawana
(
1997)
reported
that
the
interval
between
the
initiation
of
cyanamide
therapy
and
the
onset
of
dermatitis
lesions
ranged
from
10
days
to
3
months
(
10
days
in
one
patient,
14
days
in
two
patients,
2­
3
months
for
four
patients).
However,
the
cyanamide
dose
that
resulted
in
an
onset
of
lesions
in
10
days
was
not
reported.
In
all
cases,
the
dermatitis
resolved
once
cyanamide
treatment
was
stopped,
and
in
all
cases
but
one,
patch
testing
confirmed
the
allergic
reaction
to
cyanamide.

Vazquez
et
al.
(
1983)
report
the
results
of
liver
biopsies
conducted
on
ten
chronic
alcoholic
patients
who
had
been
treated
with
Colme
®
(
a
form
of
cyanamide)
for
durations
ranging
from
4
months
to
7
years.
The
reported
doses
were
45
to
180
mg/
day
(
0.6­
2.6
mg/
kg­
day,

assuming
a
70­
kg
body
weight).
A
total
of
four
of
the
patients
received
doses
of
0.6­
0.7
mg/

kgday
although
one
of
these
was
also
being
treated
with
disulfiram.
Four
of
the
patients
received
doses
of
0.9
mg/
kg­
day.
Two
patients
received
doses
of
1.9
and
2.6
mg/
kg­
day,
respectively,
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
16
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OW/
OST/
HECD
Final
draft
although
the
patient
receiving
1.9
mg/
kg­
day
was
also
treated
with
disulfiram.
Six
of
the
patients
were
still
being
treated
with
Colme
®
at
the
time
of
the
biopsy.
In
the
remaining
patients,
Colme
®
therapy
had
been
stopped
3­
7
years
prior
to
the
biopsy.
Hepatomegaly
was
observed
in
six
patients.
Inclusion
bodies
were
observed
in
hepatocytes
from
all
but
one
patient;
altered
hepatocytes
were
observed
predominantly
in
the
periportal
area.
The
patient
who
did
not
have
inclusion
bodies
had
only
been
treated
with
0.6
mg/
kg­
day
cyanamide
for
4
months
and
had
been
off
cyanamide
treatment
for
3
years.
This
patient
showed
fatty
changes
in
the
liver,
which
could
have
been
the
result
of
alcohol
consumption.
The
remaining
patients
treated
with
0.6­
0.7
mg/

kgday
all
had

5%
of
hepatocytes
bearing
inclusion
bodies,
except
for
the
patient
who
was
being
treated
concurrently
with
disulfiram.
The
patients
treated
with
0.9
mg/
kg­
day
had
5­
50%
(
mean
26%)
of
their
hepatocytes
with
inclusion
bodies.
The
patients
treated
with
1.9
and
2.6
mg/
kg­
day
had
50%
and
40%
of
their
hepatocytes
with
inclusion
bodies,
respectively.
This
limited
exposureresponse
data
supports
the
association
of
the
inclusion
bodies
with
the
Colme
®
treatment,
rather
than
the
previous
consumption
of
alcohol,
although
alcohol
may
have
enhanced
the
observed
effects.
This
conclusion
is
supported
by
studies
in
rats
(
see
Guillen
and
Vazquez,
1984,
in
Chapter
5),
which
demonstrated
inclusion
bodies
in
the
livers
of
rats
exposed
to
cyanamide,
but
not
alcohol.
There
is
not
enough
information
in
the
study
to
determine
if
the
hepatomegaly
observed
in
these
patients
was
due
to
Colme
®
treatment
exclusively,
or
whether
alcohol
consumption
contributed
to
this
effect.
Based
on
liver
toxicity
as
evidenced
by
>
5%
inclusion
bodies,
a
dose
of
0.6
mg/
kg­
day
is
considered
a
NOAEL
and
a
dose
of
0.9
mg/
kg­
day
is
a
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
17
EPA/
OW/
OST/
HECD
Final
draft
LOAEL.
Conclusions
from
this
study
are
limited,
however,
by
the
small
number
of
patients
receiving
the
lowest
doses.

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

C.
Summary
of
Human
Studies
There
is
some
limited
clinical
information
on
oral
and
dermal
exposure
to
cyanamide,

based
on
its
use
in
the
treatment
of
alcoholism.
Contact
dermatitis
has
resulted
from
both
oral
(
Abajo
et
al.,
1999;
Kawana,
1997;
Ajima
et
al.,
1997)
and
dermal
(
Bujan
et
al.,
1994;
Conde­

Salazar
et
al.,
1981)
exposure
to
cyanamide.
A
dose
was
available
for
only
one
case
(
1.4
mg/

kgday
Ajima
et
al.,
1997);
exposures
were
for
1­
4
months.
One
study
(
Vazquez
et
al.,
1983)

reported
the
results
of
a
liver
biopsy
of
10
chronic
alcoholics
treated
with
Colme
®
for
4
months
to
7
years.
The
primary
observations
were
inclusion
bodies
in
hepatocytes
and
altered
hepatocytes
in
the
periportal
area,
which
were
observed
in
all
patients
except
for
the
one
with
the
shortest
treatment
time.
A
NOAEL
of
0.6
mg/
kg­
day
and
a
LOAEL
of
0.9
mg/
kg­
day
can
be
identified
from
this
study,
based
on
the
incidence
of
hepatocytes
with
inclusion
bodies
by
study
subject.
Hepatomegaly
was
also
observed
in
6/
10,
and
one
patient
had
fatty
changes,
but
these
effects
could
have
resulted
from
the
chronic
alcohol
ingestion.
No
studies
on
the
effects
of
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
18
EPA/
OW/
OST/
HECD
Final
draft
inhalation
exposure
to
cyanamide,
and
no
epidemiological
studies
of
cyanamide
exposure
via
any
route
were
located.

III.
Quantification
of
Toxicological
Effects
Methods
for
the
quantification
of
toxicological
effects
are
described
in
Section
VIII.
A.

Health
Advisories
for
cyanamide
are
summarized
in
Table
D­
2.

A.
Noncarcinogenic
Effects
A.
1.
One­
day
Health
Advisory
No
studies
of
suitable
duration
were
located.
In
the
absence
of
adequate
data,
the
Ten­
day
HA
value
is
recommended
as
a
conservative
estimate
of
an
appropriate
one­
day
HA
value.

A.
2.
Ten­
day
Health
Advisory
The
only
animal
study
suitable
for
derivation
of
a
10­
day
HA
is
a
7­
week
dietary
study
of
calcium
cyanamide
in
rats
and
mice
(
NCI,
1979).
This
study
identified
a
NOAEL
in
rats
of
21
mg/
kg­
day,
and
a
LOAEL
of
31
mg/
kg­
day
based
on
decreased
body
weight
in
male
rats
and
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
8A
health
advisory
based
on
dermatitis
would
typically
be
chosen
to
protect
people
from
becoming
sensitized
to
the
chemical,
rather
than
the
lower
dose
that
avoids
a
dermatitis
reaction
in
people
who
are
already
sensitized.
This
is
because
once
someone
is
sensitized,
that
person
may
react
to
doses
orders
of
magnitude
lower
than
the
sensitizing
dose.
In
the
case
of
cyanamide,
it
is
likely
that
the
subjects
were
initially
sensitized
by
the
high
pharmacologically
active
dose
given
in
the
clinical
studies,
since
that
dose
would
have
dominated
their
total
cyanamide
exposure.
Therefore,
the
clinical
doses
are
appropriate
for
the
development
of
health
advisories.

D­
19
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Final
draft
thyroid
hyperplasia
in
both
sexes.
This
study
is
limited
by
the
fact
that
it
was
conducted
using
calcium
cyanamide,
which
may
be
less
toxic
to
the
liver
than
cyanamide.
Human
studies
of
subjects
with
alcoholism
treated
with
cyanamide
for
durations
of
10
days
to
>
1
year
have
found
that
dermatitis
can
result
from
oral
exposure
to
cyanamide
(
Abajo
et
al.,
1999;
Kawana,
1997;

Ajima
et
al.,
1997).
Doses
reported
to
result
in
dermatitis
were
in
the
range
of
1
to
1.4
mg/

kgday
administered
for
10
days
to
3
months
(
Kawana,
1997;
Ajima
et
al.,
1997).
Several
of
these
studies
confirmed
the
allergic
reaction
to
cyanamide
using
patch
tests.
The
NOAEL
of
0.6
mg/
kg­
day
identified
by
Vazquez
et
al.
(
1983)
for
development
of
liver
effects
in
subjects
being
treated
for
alcoholism
for
4
months
to
7
years
is
not
appropriate
as
the
basis
for
the
10­
day
Health
Advisory
for
two
reasons.
First,
the
liver
effects
would
be
expected
to
progress
with
increasing
duration,
and
might
not
be
expected
to
develop
after
only
10
days.
Second,
the
duration
of
these
studies
was
longer
than
appropriate
for
a
Ten­
day
Health
Advisory.
Based
on
these
considerations,
the
ten­
day
Health
Advisory
is
derived
based
on
case
reports
of
dermatitis,
with
similar
LOAELs
of
1
mg/
kg­
day
and
1.4
mg/
kg­
day
(
Kawana,
1997;
Ajima
et
al.,
1997,

respectively).
8
An
uncertainty
factor
of
3
is
used
to
protect
sensitive
populations,
since
the
case
studies
of
people
who
develop
dermatitis
appear
to
already
constitute
a
sensitive
population,
but
variability
in
toxicokinetics
needs
to
be
taken
into
account.
Because
the
dermatitis
was
identified
as
being
a
specific
allergic
reaction
to
cyanamide,
it
is
reasonable
to
expect
that
the
individuals
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
20
EPA/
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OST/
HECD
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draft
with
dermatitis
had
increased
sensitivity
to
the
effects
of
cyanamide
(
toxicodynamic
differences),

rather
than
being
more
sensitive
due
to
toxicokinetic
differences.
An
uncertainty
factor
of
10
was
used
for
extrapolation
from
a
LOAEL.
The
composite
uncertainty
factor
is
30,
based
on
a
factor
of
3
for
human
variability
and
a
factor
of
10
for
extrapolation
from
a
LOAEL.

(
1
mg/
kg­
day)
(
10
kg)
Ten­
day
HA
(
for
a
child)
=
=
0.33
mg/
L,
rounded
to
0.3
mg/
L
(
30)
(
1
L/
day)
where:

1
mg/
kg­
day
=
LOAEL,
based
on
the
development
of
dermatitis
in
human
subjects
administered
cyanamide
for
1
days
to
3
months
(
Kawana,
1997),
supported
by
a
LOAEL
of
1.4
mg/
kg­
day
reported
by
Ajima
et
al.
(
1997).

10
kg
=
assumed
body
weight
of
a
child.

30
=
composite
uncertainty
factor,
based
on
a
factor
of
10
for
extrapolation
from
a
LOAEL,
and
a
factor
of
3
to
protect
sensitive
subpopulations,
since
the
individuals
developing
dermatitis
appear
to
constitute
a
sensitive
population,
but
variability
in
toxicokinetics
needs
to
be
taken
into
account
1
L/
day
=
assumed
daily
water
consumption
by
a
10­
kg
child.

A.
3
Longer­
term
Health
Advisory
There
are
a
number
of
human
studies
of
subjects
with
alcoholism
treated
with
cyanamide.

As
noted
in
the
context
of
the
development
of
the
Ten­
day
Health
Advisory,
these
studies
have
found
that
exposure
to
1­
1.4
mg/
kg­
day
for
10
days
to
>
1
year
can
result
in
dermatitis
from
oral
exposure
to
cyanamide
(
Kawana,
1997;
Ajima
et
al.,
1997).
In
the
one
study
that
investigated
health
effects
of
human
exposure
for
longer
durations,
Vazquez
et
al.
(
1983)
conducted
a
case
study
of
a
total
of
10
patients
treated
for
alcoholism
with
doses
ranging
from
0.6
to
2.6
mg/
kg­
Drinking
Water
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Document
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HECD
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draft
day
for
4
months
to
7
years.
Hepatomegaly
was
observed
in
6/
10
subjects,
and
inclusion
bodies
consisting
of
glycogen
deposits
were
observed
in

5%
of
hepatocytes
from
patients
receiving
0.6­

0.7
mg/
kg­
day,
in
an
average
of
26%
of
hepatocytes
from
patients
receiving
0.9
mg/
kg­
day,
and
in
40­
50%
of
hepatocytes
from
patients
receiving
1.9­
2.6
mg/
kg­
day.
Based
on
these
data,
it
appears
that
the
NOAEL
for
liver
effects
is
0.6
mg/
kg­
day
and
the
LOAEL
is
0.9
mg/
kg­
day.

The
identification
of
the
NOAEL
is
limited,
however,
by
the
small
number
of
subjects.
(
Since
a
total
of
only
four
patients
were
exposed
to
the
apparent
NOAEL
of
0.6­
0.7
mg/
kg­
day,
it
is
possible
that
this
dose
would
have
been
considered
a
LOAEL
if
the
sample
size
were
larger).
The
results
of
the
study
are
supported
by
animal
studies,
which
reported
liver
vacuolation
and
fatty
changes
in
rats
administered
7
mg/
kg­
day
cyanamide
by
gavage
for
6
months
(
NOAEL
of
2
mg/
kg­
day)
(
Obach
et
al.,
1985);
inclusion
bodies
in
rats
administered
16
mg/
kg­
day
cyanamide
by
gavage
in
Tween
80
for
25
weeks
(
no
NOAEL
identified)
(
Valerdiz
and
Vazquez,
1989);
and
glycogen
deposits
in
rats
administered
8
mg/
kg­
day
intraperitoneally
for
27
weeks
(
Guillen
and
Vazquez,
1984).
Two
lines
of
reasoning
indicate
that
the
effects
in
the
human
subjects
were
not
due
to
their
consumption
of
alcohol.
First,
inclusion
bodies
were
also
seen
in
rats
that
had
received
cyanamide,
but
not
ethanol
(
Guillen
and
Vazquez,
1984).
Second,
there
is
some
doseresponse
data
for
cyanamide
and
these
inclusion
bodies,
as
described
above.
It
is
unknown,

however,
whether
alcohol
consumption
increases
susceptibility
to
cyanamide­
induced
inclusion
bodies.
Based
on
these
considerations,
the
longer­
term
HA
is
based
on
the
NOAEL
of
0.6
mg/
kg­
day
reported
by
Vazquez
et
al.
(
1983)
for
liver
effects
in
human
subjects.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
22
EPA/
OW/
OST/
HECD
Final
draft
In
the
absence
of
data
on
variability
in
human
toxicokinetics
and
toxicodynamics,
a
factor
of
10
is
used
to
account
for
variability
in
the
human
population.
Although
alcohol
consumption
may
have
enhanced
the
sensitivity
of
the
subject
population,
no
quantitative
information
is
available
regarding
this
possibility,
and
so
the
default
factor
of
10
is
used
as
a
conservative
approach.
The
supporting
database
includes
subchronic
and
chronic
studies
in
rats
and
mice
(
Obach
et;
al.,
1985,
1986b;
NCI,
1979).
In
a
two­
generation
study,
Valles
et
al.
(
1987)
observed
effects
on
reproduction
in
the
parental
generation,
but
not
the
F1
generation,
of
rats
exposed
to
25
mg
cyanate/
kg­
day
by
gavage;
the
NOAEL
was
7
mg/
kg­
day.
No
developmental
toxicity
studies
using
environmentally­
relevant
routes
of
exposure
were
located.
The
only
available
developmental
toxicity
data
is
from
an
abstract
of
a
study
in
which
pregnant
rats
were
administered
40
mg/
kg­
day
cyanamide
on
gestation
days
9­
12
(
Ali
and
Persaud,
1987).
An
increased
incidence
of
total
resorption
of
litters
was
reported,
although
there
was
no
information
on
the
statistical
significance
of
the
findings.
Based
on
these
database
deficiencies,
and
taking
into
account
the
uncertainty
in
the
human
NOAEL
due
to
the
small
sample
size
(
1­
4
per
dose
level),

an
uncertainty
factor
of
3
is
used
for
an
incomplete
database.
Using
a
factor
of
3
for
database
deficiencies
and
a
factor
of
10
for
human
variability
results
in
a
composite
uncertainty
factor
of
30.

Two
alternative
approaches
for
the
derivation
of
the
Longer­
term
Health
Advisory
might
be
considered.
One
would
be
to
use
the
NOAEL
of
2
mg/
kg­
day
for
liver
vacuolation
and
fatty
changes
in
a
6­
month
study
in
rats
(
Obach
et
al.,
1985).
Uncertainty
factors
of
10
each
would
be
Drinking
Water
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Document
for
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Chloride
and
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D­
23
EPA/
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HECD
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used
for
interspecies
extrapolation
and
intraspecies
variability.
A
database
uncertainty
factor
of
1
would
be
used,
since
the
adjustments
for
small
sample
size
in
the
Vazquez
et
al.
(
1983)
study
would
not
apply.
A
composite
uncertainty
factor
of
100
would
result,
and
the
calculated
health
advisory
would
be
similar
to
that
calculated
based
on
the
Vazquez
et
al.
data.
Another
alternative
would
be
to
use
the
LOAEL
of
1.0
mg/
kg­
day
for
dermatitis
in
subjects
treated
with
cyanamide
for
10
days
to
>
1
year
(
Abajo
et
al.,
1999;
Kawana,
1997;
Ajima
et
al.,
1997).
As
noted
in
the
context
of
the
Ten­
day
value,
this
effect
is
seen
in
a
sensitive
population
(
people
who
are
susceptible
to
sensitization
to
cyanamide)
and
so
an
intraspecies
uncertainty
factor
of
3
would
be
used.
In
addition,
the
database
for
dermatitis
is
more
robust
than
the
database
for
hepatic
effects
in
people,
so
a
database
factor
of
1
would
be
used
with
the
dermatitis
endpoint.
Using
an
uncertainty
factor
of
10
for
extrapolation
from
a
LOAEL,
a
composite
uncertainty
factor
of
30
would
be
used
with
the
dermatitis
endpoint,
resulting
in
a
health
advisory
less
conservative
than
one
based
on
the
liver
endpoint.

Based
on
these
considerations
,
the
Longer­
term
Health
Advisory
is
derived
based
on
the
liver
endpoint,
with
a
composite
uncertainty
factor
of
30.

(
0.6
mg/
kg­
day)
(
10
kg)
Longer­
Term
HA
(
for
a
child)
=
=
0.2
mg/
L
(
30)(
1
L/
day)
where:

0.6
mg/
kg­
day
=
NOAEL,
with
a
corresponding
LOAEL
of
0.9
mg/
kg­
day
for
glycogen
deposits
in
inclusion
bodies
and
hepatomegaly
in
human
subjects
exposed
to
cyanamide
for
5
months
to
7
years
(
Vazquez
et
al.,
1983).

10
kg
=
assumed
body
weight
of
a
child.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
24
EPA/
OW/
OST/
HECD
Final
draft
30
=
composite
uncertainty
factor,
chosen
to
account
for
inter­
individual
variability
in
humans
and
insufficiencies
in
the
database,
including
the
lack
of
developmental
toxicity
data
and
very
small
sample
size
in
the
principal
study
(
n=
1­
4/
dose).

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

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

(
0.6
mg/
kg­
day)
(
70
kg)
Longer­
Term
HA
(
for
an
adult)
=
=
0.7
mg/
L
(
30)(
2
L/
day)

where:

0.6
mg/
kg­
day
=
NOAEL,
with
a
corresponding
LOAEL
of
0.9
mg/
kg­
day
for
glycogen
deposits
in
inclusion
bodies
and
hepatomegaly
in
human
subjects
exposed
to
cyanamide
for
5
months
to
7
years
(
Vazquez
et
al.,
1983).

70
kg
=
assumed
body
weight
of
an
adult.

30
=
composite
uncertainty
factor,
chosen
to
account
inter­
individual
variability
in
humans
and
insufficiencies
in
the
database,
including
very
small
sample
size
in
the
principal
study
(
n=
1­
4/
dose).

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

A.
4
Reference
Dose,
Drinking
Water
Equivalent
Level,
and
Lifetime
Health
Advisory
The
only
chronic
animal
study
of
cyanamide
is
the
chronic
bioassay
of
calcium
cyanamide
in
rats
and
mice
conducted
by
NCI
(
1979).
Male
mice
in
the
high­
dose
group
had
decreased
survival
relative
to
controls.
No
treatment­
related
nonneoplastic
effects
were
observed
in
either
rats
or
mice.
The
study
identified
a
NOAEL
of
8.3
mg
cyanamide/
kg­
day
in
rats,
and
a
NOAEL
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
25
EPA/
OW/
OST/
HECD
Final
draft
of
45
mg
cyanamide/
kg­
day
in
mice.
As
noted
by
Valerdiz
and
Vazquez
(
1989),
calcium
cyanamide
appears
to
be
less
toxic
to
the
liver,
on
a
mg
cyanamide/
kg­
day
basis.
Liver
effects
were
also
reported
by
Vazquez
et
al.
(
1983)
in
a
case
study
of
10
patients
treated
for
alcoholism
with
0.9­
2.6
mg/
kg­
day
cyanamide
for
5
months
to
7
years;
no
effects
were
observed
in
patients
receiving
doses
of
0.6­
0.7
mg/
kg­
day.
As
noted
for
the
Longer­
term
Health
Advisory,
this
endpoint
is
supported
by
animal
studies,
which
reported
liver
vacuolation
and
fatty
changes
in
rats
administered
7
mg/
kg­
day
cyanamide
by
gavage
for
6
months
(
NOAEL
of
2
mg/
kg­
day)
(
Obach
et
al.,
1985),
inclusion
bodies
in
rats
administered
16
mg/
kg­
day
cyanamide
by
gavage
in
Tween
80
for
25
weeks
(
no
NOAEL
identified)
(
Valerdiz
and
Vazquez,
1989),
and
glycogen
deposits
in
rats
administered
8
mg/
kg­
day
intraperitoneally
for
27
weeks
(
Guillen
and
Vazquez,
1984).
In
addition,
use
of
the
human
data
is
preferred
when
possible,
and
is
more
health­
protective
in
this
case.
Therefore,
the
RfD
is
based
on
the
NOAEL
of
0.6
mg/
kg­
day
for
the
development
of
inclusion
bodies
in
patients
treated
for
alcoholism
for
5
months
to
7
years
(
Vazquez
et
al.,
1983).

An
uncertainty
factor
of
10
is
used
for
protection
of
sensitive
human
populations.
Although
the
human
studies
were
based
on
exposure
of
7
years
or
less,
the
animal
data
suggest
that
a
reduced
uncertainty
factor
for
extrapolation
from
subchronic
duration
is
appropriate.
Decreased
body
weight
was
seen
in
rats
exposed
to
16
mg/
kg­
day
cyanamide
as
calcium
cyanamide
for
25
weeks,

and
rats
exposed
to
16
mg/
kg­
day
cyanamide
for
the
same
duration
had
decreased
body
weight
and
hepatocytic
inclusion
bodies
(
Valerdiz
and
Vazquez,
1989),
but
there
were
no
effects
on
body
weight
or
on
the
liver
in
rats
exposed
to
doses
up
to
11.5
mg/
kg­
day
as
calcium
cyanamide
(
NCI,

1979).
Although
the
use
of
calcium
cyanamide
in
the
chronic
study
is
a
complicating
factor,
the
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
26
EPA/
OW/
OST/
HECD
Final
draft
animal
data
suggest
that
there
is
minimal
progression
with
cyanamide
as
the
exposure
duration
increases
from
subchronic
to
chronic.
Therefore,
a
partial
factor
of
3
is
used
for
subchronic­

tochronic
extrapolation.
A
factor
of
3
is
used
for
an
incomplete
database,
as
described
for
the
Longer­
term
Health
Advisory.
A
composite
uncertainty
factor
of
100
results.

Step
1:
Determination
of
a
RfD
for
Cyanamide
RfD
=
0.6
mg/
kg­
day
=
0.006
mg/
kg­
day
(
100)

where:

0.6
mg/
kg­
day
=
NOAEL,
with
a
corresponding
LOAEL
of
0.9
mg/
kg­
day
for
glycogen
deposits
in
inclusion
bodies
and
hepatomegaly
in
human
subjects
exposed
to
cyanamide
for
5
months
to
7
years
(
Vazquez
et
al.,
1983).

100
=
composite
uncertainty
factor,
chosen
to
protect
sensitive
subpopulations,
to
account
for
extrapolation
from
subchronic
to
chronic
duration,
and
insufficiencies
in
the
database,
including
very
small
sample
size
in
the
principal
study.

Step
2:
Determination
of
a
Drinking
Water
Equivalent
Level
(
DWEL)
for
Cyanamide
DWEL
=
(
0.006
mg/
kg­
day)
(
70kg)
=
0.21
mg/
L
(
rounded
to
0.2
mg/
L)
(
2
L/
day)

where:

0.006
mg/
kg­
day
=
RfD
70
kg
=
assumed
body
weight
of
an
adult
2
L/
day
=
assumed
drinking­
water
consumption
of
a
70­
kg
adult
Step
3:
Determination
of
Lifetime
HA
for
Cyanamide
Lifetime
HA
=
(
0.21
mg/
L)
(
20%)
=
0.04
mg/
L
(
40

g/
L)

where:
0.21
mg/
L
=
DWEL
(
prior
to
rounding)
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
27
EPA/
OW/
OST/
HECD
Final
draft
20%
=
assumed
relative
source
contribution
from
water
B.
Carcinogenic
Effects
One
standard
cancer
bioassay
on
cyanamide
was
located.
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.
Hemangiosarcomas
were
observed
in
male
mice
with
a
significant
dose­
related
trend.
However,
the
tumor
incidence
was
not
statistically
significant
in
either
dose
group
when
compared
with
controls.
Malignant
lymphomas
were
observed
in
female
mice.
Statistical
analysis
indicated
a
significant
dose­
related
trend
for
these
tumors
and
a
significant
increase
in
incidence
in
the
high­
dose
group
compared
with
controls.

However,
NCI
(
1979)
reported
that
the
historical
control
for
this
tumor
type
in
B6C3F1
mice
was
21%;
therefore,
the
incidence
of
5%
in
the
matched
control
group
may
have
been
abnormally
low.

NCI
(
1979)
concluded
that
neither
of
these
tumors
was
clearly
related
to
administration
of
calcium
cyanamide.
Except
for
a
positive
result
in
Salmonella
strain
TA
1535
(
Zeiger,
1987),

cyanamide
was
negative
in
bacterial
gene­
mutation
assays
(
Loveless
et
al.,
1954;
Zeiger,
1987),
a
Drosophila
sex­
linked
recessive
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).

Based
on
these
considerations,
cyanamide
is
classified
as
Group
D,
Not
Classifiable
as
to
Human
Carcinogenicity,
using
the
U.
S.
EPA
(
1986)
guidelines.
Using
the
U.
S.
EPA
(
1999)
Draft
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
D­
28
EPA/
OW/
OST/
HECD
Final
draft
Guidelines
for
Carcinogen
Risk
Assessment,
the
data
are
inadequate
for
an
assessment
of
the
human
carcinogenic
potential
of
cyanamide.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
D­
29
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
One­
Day
HA
None
located
Ten­
Day
HA
Human
(
1
male)
Ajima
et
al.,

1997
1.4
mg/
kg­
day
Oral
3
weeks
Granulocytopenia
and
dermatitis
None
1.4
mg/

kgday
Case
report
of
a
patient
being
treated
for
alcoholism.
Patch
tests
confirm
allergic
reaction
to
cyanamide.

Co­
basis
of
10­
day
HA
in
this
Critieria
Document
Human
(
6
patients)
Kawana,

1997
7
mL/
day
of
a
1%
carbimide
solution
(
1
mg/
kg­
day
assuming
1%

weight/
volume
solution
of
cyanamide
and
body
weight
of
70
kg
Oral
10
days­
3
months
Dermatitis
N/
A
1
mg/

kgday
Case
report
of
6
patients
being
treated
for
alcoholism.
Patch
tests
confirm
allergic
reaction
to
cyanamide.

Co­
basis
of
10­
day
HA
in
this
Critieria
Document
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
30
Rat,
F344
(
5/
sex/
group)
NCI,
1979
0,
400,
600,

800,
900,
1000,

1200,
1500,

3000,
4000,

8000,
10000,

16000,
30000
ppm
(
0,
21,
31,

42,
47,
52,
63,

79,
157,
210,

420,
525,
839,

1574
(
males);
0,

24,
36,
47,
53,

59,
71,
89,
178,

237,
474,
592,

948,
1777(
females)

mg
cyanamide/

kg­
day)
Diet
7
weeks
Dec
bw
males

600
ppm,
females

900
ppm.
Thyroid
hyperplasia
in
both
sexes

600
ppm
400
ppm
(
21
mg
cyanamide/

kg­
day)
600
ppm
(
31
mg
cyanamide/

kg­
day)
Dose­
range
finding
study
for
chronic
study.

Study
conducted
with
calcium
cyanamide.

Doses
calculated
based
on
average
subchronic
body
weights
and
food
intake
for
F344
rats
(
U.
S.
EPA.,
1988)

Bile
duct
hyperplasia

1500
ppm.
100%

mortality

8000
ppm.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
31
Mouse,
B6C3F1
(
5/
sex/
group)
NCI,
1979
0,
1500,
3000,

4000,
8000,

10000,
16000,

30000
ppm
(
0,

142,
284,
379,

757,
946,
1514,

2839
(
males);
0,

154,
307,
409,

819,
1024,

1636,
3071
(
females)
mg
cyanamide/

kgday
Diet
7
weeks
Dec
bw
females

1500
ppm.
None
1500
ppm
(
154
mg/
kg­
day)
Dose­
range
finding
study
for
chronic
study.

Study
conducted
with
calcium
cyanamide.

Doses
calculated
based
on
average
subchronic
body
weights
and
food
intake
for
B6C3F1
mice
(
U.
S.
EPA.,
1988)

Dec
bw
males

8000
ppm.
Liver
hyperplasia,
vacuolation,
necrosis

16000
Subchronic
Human
Goday­
Bujan
et
al.,
1994
Not
reported
Dermal
3
months
to
>
1
year
Contact
dermatitis
N/
A
N/
A
Case
reports
of
occupational
exposure
to
a
drug
used
for
treating
alcoholism
(
Colme
®
)
that
contains
6
g/
100
ml
of
cyanamide.
Patch
tests
confirm
allergic
reaction
to
cyanamide.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
32
Human
(
1
male)
Conde­
Salazar
et
al.,

1981
Not
reported
Dermal
4
months
Contact
dermatitis
N/
A
N/
A
Case
reports
of
occupational
exposure
to
a
drug
used
for
treating
alcoholism
(
Colme
®
)
that
contains
6
g/
100
ml
of
cyanamide.
Patch
tests
confirm
allergic
reaction
to
cyanamide.

Human
(
1
male)
Abajo
et
al.,

1999
Not
reported
Oral
3
months
Allergic
dermatitis
N/
A
N/
A
Case
report
of
a
patient
being
treated
for
alcoholism
with
Colme
®
.
Patch
tests
confirm
allergic
reaction
to
cyanamide.

Human
(
8
males,
2
females)
Vazquez
et
al.,
1983
0.6­
2.6
mg/

kgday
Oral
4
months
to
7
years
Hepatomegaly,

inclusion
bodies
in
hepatocytes,
fatty
change
in
liver
0.6
mg/

kgday
0.9
mg/

kgday
Case
report
of
10
patients
being
treated
for
alcoholism.
Liver
biopsy
was
only
endpoint
evaluated.

Basis
of
longer­
term
HA
and
RfD
in
this
Criteria
Document.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
33
Rat,
Wistar
(
5
males/
group)
Guillen
and
Vazquez,

1984
0,
8,
16
mg/

kgday
i.
p.
27
weeks
Inc
water
consumption,
dec
body
weight,
liver
histopathology
None
8
mg/

kgday
No
data
given
on
incidence
of
liver
effects
or
statistical
significance
of
findings.

Rat,
Sprague­

Dawley
(
20/
sex/
group)
Obach
et
al.,

1985
0,
2,
7,
25
mg/
kg­
day
Gavage
(
vehicle
not
reported)
6
months
Inc
serum
bilirubin,

dec
body
weight
2
mg/

kgday
7
mg/

kgday
Body
weight
and
bilirubin
statistically
significant
at
LOAEL.

Rat,
Sprague­

Dawley
and
Wistar
(
20­
65
males/
group)
Obach
et
al.,

1986b
0,
2,
8,
25
mg/
kg­
day
Gavage
(
vehicle
not
reported)
6
months
Dec
body
weight,

food
and
water
consumption.
2
mg/

kgday
8
mg/

kgday
No
other
endpoints
evaluated,
except
for
levels
of
neurotransmitters
and
their
metabolites
in
brain.

Rat,
Wistar
(
16
males
/
group)
Valerdiz
and
Vazquez,

1989
0,
16
mg/
kg­
day
(
as
cyanamide)
Gavage
(
in
Tween
80)
25
weeks
Significantly
dec
body
weight.
hepatocytic
inclusion
bodies.
None
16
mg/

kgday
Liver
was
only
endpoint
evaluated.
Purpose
of
study
was
to
compare
toxicity
of
cyanamide
with
calcium
salt.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
34
Rat,
Wistar
(
16
males
/
group)
Valerdiz
and
Vazquez,

1989
0,
30
mg/
kg­
day
(
as
calcium
cyanamide,

equivalent
to
16
mg/
kg­
day
cyanamide)
Gavage
(
in
Tween
80)
25
weeks
Significantly
decr
body
weight.
No
effects
on
liver.
None
30
mg/

kgday
calcium
salt
(
16
mg/
kg
cyanamideday
Liver
was
only
endpoint
evaluated.
Purpose
of
study
was
to
compare
toxicity
of
cyanamide
with
calcium
salt.

Calcium
salt
less
toxic
to
liver.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
35
Chronic
Rat,
F344
(
50/
sex/
group)
NCI,
1979
Males:
0,
100,

200
ppm
calcium
cyanamide
(
0,

4.1,
8.3
mg
cyanamide/

kgday
females:
0,
100,

400
ppm
calcium
cyanamide
(
0,

4.8,
19
mg
cyanamide/

kgday
Oral,
diet
107
weeks
No
treatment
related
effects.
200
ppm
(
8.3
mg/
kg­
day)
None
NCI
concluded
that
cyanamide
is
not
carcinogenic
to
rats.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
36
Mouse,
B6C3F1
(
50/
sex/
group)
NCI,
1979
0,
500,
2000
ppm
calcium
cyanamide
(
0,

45,
180
mg
cyanamide/

kgday
in
males;
0,

45,
181
mg
cyanamide/

kgday
in
females)
Oral,
diet
107
weeks
Dec
survival
in
highdose
males.
No
treatment
related
nonneoplastic
effects.

Hemangiosarcomas
and
lymphomas.
500
ppm
(
45
mg/

kgday
2000
ppm
(
180
mg/
kg­
day)
Hemangiosarcomas
in
males
had
sig.
trend
but
dose
groups
not
sig.

compared
with
controls.

Lymphomas
in
females
sig.
for
both
trend
and
pairwise
comparison.

However,
control
incidence
sig.
lower
than
historical
controls.

NCI
concluded
that
tumors
not
clearly
related
to
administration
of
cyanamide.

Reproductive
and
Developmental
Rat,
pregnant
females
(
strain
and
number
not
specified)
Ali
and
Persaud,
1987
0,
40
mg/
kg­
day
i.
p.
Gestation
day
9­
12
Inc
incidence
of
total
resorption
of
litters
None
40
mg/

kgday
Abstract
only;

incomplete
reporting.

No
information
on
statistical
significance
of
findings.
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
Table
D­
1.
Summary
of
Oral
Toxicity
Studies
for
Cyanamide.

Strain,
Species,
Sex
Reference
Dose
Route
Duration
Response
at
LOAEL
NOAEL
mg/

kgday
LOAEL
mg/

kgday
Comments
EPA/
OW/
OST/
HECD
Final
draft
D­
37
Rat,
Sprague­

Dawley
(
20
males/
group;

40
females/

group)
Valles
et
al.,

1987
0,
2,
7,
25
mg/
kg­
day
Gavage
(
vehicle
not
reported)
2­
generation
study.
F0
generation
­

70
days;
F1
generation
­

entire
lifetime
F0:
dec
fertility
percentage,
dam
weight
gain,
number
of
corpora
lutea
and
implantations.
Dec
epididymis
and
prostrate
weights.

Testicular
atrophy.

F1:
No
effects
7
mg/

kgday
25
mg/

kgday
Dec
fertility
observed
when
treated
male
rats
were
mated
with
untreated
females.
No
dec
fertility
when
treated
females
were
mated
with
untreated
males.

Dec
=
decreased;
Inc
=
increased;
i.
p.
=
Intraperitoneal;
N/
A
=
Not
applicable;
sig
=
Significant
Drinking
Water
Criteria
Document
for
Cyanogen
Chloride
and
Potential
Metabolites
EPA/
OW/
OST/
HECD
Final
draft
D­
38
Table
D­
2.
Summary
of
Development
of
the
Health
Advisories
for
Cyanamide
Principal
Study
Critical
Effect
NOAEL/

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

Ten­
day
Kawana,
1997;

Ajima
et
al.,

1997
Allergic
dermatitis
None
1.0
30
(
3H,
10L)
N/
Ab
0.3
Longer­
term
Vazquez
et
al.,

1983
Liver
toxicity
(
glycogen
deposits
in
inclusion
bodies
and
hepatomegaly)
0.6
0.9
30
(
10H,
3D)
N/
A
0.2
(
child)

0.7
(
adult)

Lifetime
Vazquez
et
al.,

1983
Liver
toxicity
(
glycogen
deposits
in
inclusion
bodies
and
hepatomegaly)
0.6
0.9
100
(
10H,
3S,
3D)
0.006
0.04
a.
Areas
of
uncertainty
addressed
by
uncertainty
factors
are:
animal
to
human
extrapolation
(
A);
intrahuman
variability
and
protection
of
sensitive
subpopulations
(
H);
extrapolation
from
a
LOAEL
to
a
NOAEL(
L);
extrapolation
from
a
subchronic
to
chronic
exposure
(
S);
and
lack
of
a
complete
database
(
D)

b.
N/
A
=
not
applicable