CYANIDES
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
-------
CRITERION DOCUMENT
CYANIDE
CRITERIA
Aquatic Life
For free cyanide (expressed as CN) the criterion to protect '
<•>
freshwater aquatic life as derived using the Guidelines is 1.4 ug/1
as a 24-hour average and the concentration should not exceed 38 ug/1
at any time.
For saltwater aquatic life, no criterion for free cyanide can
be derived using the Guidelines, and there are insufficient data to
estimate a criterion using other procedures.
Human Health
For the protection of human health from the toxic properties
of cyanide ingested through water and through contaminated aquatic
organisms, the ambient water quality criterion is determined to be
200 ug/1.
-------
Introduction
Cyanide exists in water in the free form (CN~ and HCN)
which is extremely toxic or bound to organic or inorganic
moieties in which it is less toxic. Free and complex forms
of cyanide can be converted one to the other under conditions
found in the aquatic environment. The criterion is based
on free cyanide, since that is the principle toxic moiety
(Broderius, 1979; Smith, et al. 1979; Smith, et al. 1979).
Cyanide is lethal to freshwater fishes at concentrations
as low as about 50 jug/1 and has been shown to adversely
affect invertebrates and fishes at concentrations of about
10 jug/1. Very few saltwater data have been generated.
Because of the volatility of HCN, it tends to escape
from the water column. In addition, it is readily degraded
by microorganisms and by animal metabolism. For these reasons
it is not expected to bioconcentrate in aquatic organisms.
Cyanides are known to be degraded by human liver to
the less toxic thiocyanate and despite their high levels
of acute toxicity, are not known to be chronically toxic
to humans.
A-l
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REFERENCES
Boderius, S.J., et al. 1977. Relative toxicity of free
cyanide and dissolved sulfide forms to the fathead minnow,
Pimephales promelas. Jour. Fish. Res. Board (insert).
35: 2323.
Smith, L.L., Jr. et al. 1979. Acute and chronic toxicity
of HCN to fish and invertebrates. U.S. Environ. Prot. Agency.
Ecological Report Series. EPA-600/3-79-009.
Smith, L.L., et al. 1978. Acute toxicity of hydrogen cyanide
to freshwater fishes. Arch. Environ. Contam. Toxicol. 7: 325.
A-2
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Compounds containing the cyanide group (CN) are used and
readily formed in many industrial processes and can be found in a
variety of effluents, such as those from the steel, petroleum,
metal plating, mining, and chemical industries. Cyanide commonly
occurs in water as hydrocyanic acid (HCN), the cyanide ion
(CN~), simple cyanides, metallocyanide complexes, or as simple
chain and complex ring organic compounds. "Free cyanide" is
defined as the sum of the cyanide present as either HCN or CN~.
The alkali metal salts such as potassium cyanide (KCN) and sodium
cyanide (NaCN) are very soluble in aqueous solutions and the
resulting cyanide ions readily hydrolyze with water to form HCN.
The extent of HCN formation is dependent upon temperature and pH.
At 20° C and a pH of 8 or below the fraction of free cyanide
existing as HCN is at least 0.96.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506-
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The
following tables contain the appropriate data that were found in
the literature, and at the bottom of each table are the calcula-
tions for deriving various measures of toxicity as described in
the Guidelines.
B-l
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The cyanide ion (CN~) can combine with various heavy metal
ions to form metallocyanide complex anions, whose stability is
highly variable. Zinc and cadmium cyanide complexes, when
diluted with water, are known to rapidly and nearly completely
dissociate to form HCN. Some of the other metallocyanide anions,
such as those formed with copper, nickel, and iron, demonstrate
varying degrees of stability. The hexacyanoferrate (II) and
(III) complexes are subject to direct photolysis by natural
light. The release of cyanide ion by this phenomenon may be
important in relatively clear receiving waters.
The toxicity to aquatic organisms of most simple cyanides
and metallocyanide complexes is due mostly to the presence of HCN
as derived from ionization, dissociation, and photodecomposition
of cyanide-containing compounds (Doudoroff, 1976; Smith et al.,
1979), although the cyanide ion (CN~) is also toxic (Broderius
et al., 1977). In most cases the complex ions themselves have
relatively low toxicity. Cyanide affects animals by inhibiting
utilization of available oxygen for metabolism at the cellular
level of respiration.
Since both HCN and CN~ are toxic to aquatic life and since
the vast majority of free cyanide usually exists as the more
toxic HCN, and since almost all existing CN~ can be readily
converted to HCN at pH values that commonly exist in surface
waters, the cyanide criterion will be stated in terms of free
cyanide expressed as CN. Free cyanide is a much more reliable
index of toxicity than total cyanide since the ratio of free to
total may be quite variable in natural waters.
B-2
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All of the cyanide concentrations given herein are free
cyanide expressed as CN. Data reported as ug HCN/1 were adjusted
to free cyanide as CM as follows:
Free cyanide (ug CN/1) = (^ HCN^}pK x mOl'Wt- CN
1/(1+10PH~PKHCN nol. wt. HCN
where pKHCN = 1-3440 + 2347.2 (izatt et al., 1962).
T ( °K)
Acute Toxicity
In Table 1 the LC50 values based on tests with nine fish
species are summarized. The greatest number of tests were
conducted with brook trout, bluegill and fathead minnows. Eighty
percent of the data resulted from studies conducted by Smith et
al. (1978) and Broderius et al. (1977). All of their tests were
conducted under flow-through conditions with the reported HCN
levels calculated from measured free cyanide concentrations.
Certain life stages and species of fish appear to be more
sensitive to cyanide than others. Eggs, sac fry, and warmwater
species tended to be the most resistant. A review of pertinent
data indicates that free cyanide concentrations in the range from
about 50 to 200 ug/1 have eventually proven fatal to most species
of the more sensitive fish with concentrations much above 200
ug/1 being rapidly fatal to most fish specie^,
A number of authors have reported an in---rase in toxicity of
cyanide with reduction in dissolved oxygen below the 100 percent
saturation level. The tolerance of fish to cyanide solutions
that are rapidly lethal has been observed to decrease with a rise
of temperature. However, long term lethality tests have
B-3
-------
demonstrated (Smith et al., 1978) that fish are more susceptable
to cyanide with a reduction in temperature. No pronounced
relationship has been observed between the acute toxicity of
cyanide to fish and alkalinity, hardness, and pH below about
8.3.
When the geometric mean of the acute values is divided by
the sensitivity factor (3.9), a Final Fish Acute Value of 38 ug/1
is obtained. Since no adjusted values from Table 1 are below
this value, the sensitivity factor (from the Guidelines) appears
to be slightly conservative. For comparison, the lowest 96 hour
LC50 value from a flow-through test with measured concentrations
is 52 ug/1 (Smith ot al. 1978).
The results of 11 acute tests with 6 invertebrate species
are given in Table 2. With two exceptions (Oseid and Smith, in
press), all results are based on static tests with unmeasured
concentrations. The geometric mean of the adjusted values (Table
2) divided by the sensitivity factor (21) gives a Final
Invertebrate Acute Value of 60 ug/1. None of the corrected LC50
values are lower than this value. Because the Final Fish Acute
Value is lower than the comparable value for invertebrate species,
the Final Acute Value is 38 ug/1.
Chronic Toxicity
Results from only a few sublethal and partial life cycle
chronic tests with fish have been reported (Table 3). Based on
long-term survival from an embryo-larval test with bluegills and
reproduction by brook trout and fathead minnows, the geometric
B-4
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mean of the chronic effects listed in Table 3 is 9.6 ug/1. This
value divided by the sensitivity factor (6.7) yields a Final Fish
Chronic Value of 1.4 ug/1. This value is about 30 times lower
than the Final Fish Acute Value.
Two invertebrate life cycle tests (Table 4) were conducted;
one with isopods and the other with the scud, Gammarus
pseudolimnaeus. The chronic values were 34.1 and 18.3 ug/1,
respectively. When the geometric mean of these two values is
divided by the sensitivity factor (5.1), it results in a Final
Invertebrate Chronic Value of 4.9 ug/1 which is about 14 times
lower than the Final Invertebrate Acute Value. Since the Final
Fish Chronic Value is lower than the Final Invertebrate Chronic
Value, the Final Chronic Value is 1.4 ug/1.
Plant Effects
Only one plant test has been reported (Table 5). According
to Fitzgerald et al. (1952) 90 percent of the blue-green alga,
Micrccystis aerusinoss, was killed when exposed to a free cyanide
concentration of 7,790 ug/1. Thus, the Final Plant Value is
7,790 ug/1.
Residues
No residue data were found for cyanide.
Miscellaneous
Table 6 contains no data that would alter the selection of
1.4 ug/1 as the Final Chronic Value. In fact, there are some
additional studies that are supportive of this value.
B-5
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Several authors (Neil, 1957; Broderius, 1970; Dixon, 1975;
Lesniak, 1977; Leduc, 1978; Oseid and Smith, in press; Ruby and
Dixon, manuscript) reported adverse effects due to cyanide at
concentrations as low as 10 ug/1. In another study, Kimball et
al. (1978) reported that adult bluegills exposed to 5.2 ug/1
for 289 days exhibited no reproduction. Thus, the Final Chronic
Value of 1.4 ug/1, based on fish chronic data, does not appear to
be unrealistic in view of these studies and the results of the
invertebrate chronic tests.
B-6
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
All concentrations herein are for free cyanide expressed
as CN. The concentrations below have been rounded to two
significant figures.
Final Fish Acute Value = 38 jug/1
Final Invertebrate Acute Value = 60 A»g/l
Final Acute Value = 38 jug/1
Final Fish Chronic Value = 1.4 jug/1
Final Invertebrate Chronic Value = 4.9 jug/1
Final Plant Value = 7,790 /ig/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 1.4 >ug/l
0.44 x Final Acute Value = 17 jug/1
The maximum concentration of free cyanide is the Final
Acute Value of 38 /ag/1 and the 24-hoqr concentration is
the Final Chronic Value of 1.4 jug/1. No important adverse
effects on freshwater aquatic organisms have been reported
to be caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For free cyanide (expressed as CN) the
criterion to protect freshwater aquatic life as derived
using the Guidelines is 1.4 ;ug/l as a 24-hour average and
the concentration should not exceed 38 >ug/l at any time.
B-7
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Table 1. Freshwater fish acute values for cyanide
Organism
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Y Salvelinus
00
Brook trout
Salvelinus
Brook trout
Salvelinus
Brcok trout
Salvelinus
Brook trout
S;ilvel inua
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Brook trout
Salvelinus
Bicussay
Hfctnod"
(sac fry) , FT
fontinalis
(sac fry) ,
fontinalis
(sac fry) ,
fontinalis
(sac fry),
fontinalis
(swim-up) ,
fontinalis
(swim-up) ,
fontinalis
(swim-up) ,
fontinalis
(swim-up) ,
fontinalis
(swim-up) ,
fontinalis
(juvenile) ,
fontina] is
(juvenile) ,
fontinalis
(juvenile) ,
fontinalis
(juvenile) ,
fontinalis
(juvenile) ,
fontinalis
(juvenile) ,
fontinalis
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
Test
Cone .**
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
Time
(hrs)
96
96
96
96
96
96
96
96
96
96
96
96
96
96
96
LCbo
(U'i/i)
105
342
507
252
84
54.4
86.5
104
90.3
73.5
83.0
75.0
86.4
91.9
99.0
Adjusted
LCbo
(uq/i)
105
342
507
252
84
54.4
86.5
104
90.3
73.5
83.0
75.0
86.4
91.9
99.0
Keteiei
Smith,
1978
Smith,
1S7S
Smith,
197ft
Smith,
1970
Smith,
1978
Smith,
1978
Smith,
1978
Smith,
1978
Smith,
1978
Smith.
197S
Smith.
1978
Smith,
1978
Smith,
1978
Smith,
1978
Smith,
1978
,c.
et
et
et
et
et
et
et
et
et
et
et
et
et
et
et
nl.
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
al.
-------
Table 1. (Continued)
Organism Method*
Brook trout (juvenile), FT
Salvelinus fontinalis
Brook trout (juvenile),
Salvelinus fontinalis
Brook trout (juvenile),
Salvelinus fontinalis
Brook trout (juvenile),
Salvelinus fontinalis
Brook trout (juvenile),
Salvelinus fontinalis
Brook trout (juvenile),
Salvelinus fontinalis
03
' Brook trout (juvenile) ,
Snlvelinus fontinalis
Brook trout (juvenile) ,
Salvelinus fontinalis
Brook trout (adult),
Salvelinus fontinalis
Rainbow trout,
Salmo gairdneri
Rainbow trout ''rvei lie),
Salmo gairdner
Goldfish (juvenile),
Carassius auratus
Fathead minnow (embryo),
Pimephales promelas
Fathead minnow (embryo),
I'imaphales promelas
Fathead minnow (embryo) ,
Pimephales promelas
Fathead minnow (embryo),
Pirncphdles promelas
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
Test
Cone.**
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
Time
jnrs)
96
96
96
96
96
96
96
96
96
48
96
96
96
96
96
96
LCbv.
96.7
112
52
60.2
66.8
71.4
97.0
143
156
68
57
318
347
272
201
123
Adjusted
LCbo
(uq/J.)
96.7
112
52
60.2
66.8
71.4
97.0
143
156
55
57
318
347
272
201
123
Keterence
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al .
1978
Smith, et al.
1978
Oardwell, et al
1976
Brown, 1968
Smith, et al.
1978
Cardwell. et al
1976
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
-------
Table 1. (Continued)
Adjusted
bioassay Test
Organism Method'-" Cone .**
Fathead minnow (embryo), FT M
Pimo[>halej3 promelas
Fathead minnow (embryo), FT M
Pimeghales promelas
Fathead minnow (embryo) , FT M
Pimephales promelas
Fathead minnow (fry) , FT M
Pimephales promelas
Fathead minnow (fry) , FT M
Pimephales promelas
Fathead minnow (fry), FT M
CO . Pimephales promelas
1
^ Fathead minnow (fry), FT M
Pimephales promelas
Fathead minnow (fry) , FT ' M
Pimephales promelas
Fathead minnow FT M
(juvenile) ,
Pimephales promelas
Fathead minnow FT M
(juvenile) ,
Pimephales promelas
Fathead minnow FT M
(juvenile) ,
Pimephales promelas
Fathead minnow FT M
(juvenile) ,
Pimephales promelas
Time
Ints)
96
96
96
96
96
96
96
96
96
96
96
96
LCbu
(u.i/1)
186
200
206
120
98.7
81.8
110
116
119
126
81.5
124
LCbU
(liq/H
186
200
206
120
98.7
81.8
110
116
119
126
81.5
124
keterence
Smith,
1973
Smith,
1978
Smith .
1978
Smith,
1978
Smith,
1978
Smith.
1978
Smith,
1978
Smith.
1978
Smith,
1978
Smith.
1978
Smith,
1973
Smith,
1978
et al
et al
et al
et al
et al
et al
et al
et al
et al
et al
et al
et al
Fathead minnow
(juvenile),
Pimophales promelas
FT
96
137 137 Smith, et al.
1978
-------
Table I. (Continued)
Adjusted
m
i
Organism
Fathead minnow
(juvenile),
Pimephalcs promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
Pimophales promelas
Fathead minnow
(juvenile).
Pimephales promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(juvenile),
P_ime£hale_s promelas
Fathead minnow
(juvenile).
Bioabsay Test
Method" Cone.**
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
M
Time
i"")
96
96
96
96
96
96
96
96
96
96
96
LCbo
131
105
119
131
122
161
188
175
163
169
230
LCbO
(uq/i)
131
105
119
131
122
161
188
175
163
169
125.7
Keterence
Smith, et al
1978
Smith, et al
1978
Smith, et al
1978
Smith, et al
1978
Smith, et al
1978
Smith, et al
1978
Smith, et al
1978
Smith, et al
1973
Smith, et al
1978
Smith, et al
1978
Doudoroff ,
1956
-------
Table 1. (Continued)
Adi us ted
Organism
Fathead minnow
(juvenile) ,
Pimephales gromelas
Fathead minnow
(juvenile) ,
Pimephales promelas
Fathead minnow
(juvenile) ,
Pimephales promelas
Fathead minnow
(juvenile) ,
Pimephales promelas
& Fathead minnow,
(_, Pimephales promelas
ro
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Black-nosed dace,
Rhinichthys atratulus
Mosquitofish,
Camhusia affinis
Guppy (adult) ,
Poecilia reticulata
Bluegill (fry).
Lepomis macrochirus
Bluegill (fry).
Lcponiis macrochirus
Blue-gill (fry),
l.opomis macrochirus
Bluegill (fry),
Lepomis macrochirus
Uioabsay
Method"
FT
FT
FT
FT
S
S
S
FT
S
FT
FT
FT
FT
FT
Test
cone.""
M
M
M
M
M
M
M
M
U
M
M
M
•
M
M
Time
(nr:;)
96
96
96
96
96
96
48
24
96
96
96
96
96
96
LOfc
|u.]/i)
120
113
128
128
350
230
240
220
639
147
364
232
279
273
LCSO
(IIIJ/D
120
113
128
128
248
163
138
145
350
147
364
232
279
273
Keierence
Broderius ,
at al. 1977
Broderius,
et al. 1977
Broderius ,
et al. 1977
Broderius ,
et al. 1977
Henderson,
et al. 1961
Henderson ,
et al. 1961
Black, et al.
1957
Llpschuetz &
Cooper, 1955
Wallen, et al
1957
Anderson ft
Weber, 1975
Smith, et al.
1Q78
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
-------
Table 1. (Continued)
Dioausay Test
Method* cone.
w
i
M
co
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile) ,
Lepomis macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Bluegill (juvenile) ,
Lepomis macrochirus
Bluegill (adu!:) ,
Lepomis macroihirus
Bluegill (juvenile) ,
Lepomis macrochirus
Bluegill (juvenile) ,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill (juvenile),
FT
FT
FT
FT
FT
FT
FT
FT
FT
S
S
FT
FT
S
S
M
M
M
M
M
M
M
M
M
U
M
M
M
U
U
Lupomis macrochirus
'ime
nris)
96
96
96
96
96
96
96
96
96
96
48
48
72
96
48
LCbi.
(u-l/I )
81
85.7
74
100
107
99.0
113
121
126
180
160
134
154
180
280
Adjusted
LCbl)
jug/ 1| _
81
85.7
74
100
107
99.0
113
121
126
98
92
108
142
98
124
Keterence
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al .
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Smith, et al.
1978
Cairns &
Scheier, 1958
Cairns, et al
1965
Cardwell,
et al. 1976
Doudorof f ,
et al. 1966
Patrick,
et al. 1968
Turnbull ,
et al. 1954
-------
TaMe 1. (Continued)
00
1
\->
*>•
bioassay Test
Qrqjnisin Method"' Cone ,**
Bluegill (juvenile) , S M
Lepomis macrochirus
Biuegill (juvenile), S M
l.eporai s macrochi.rus
Yellow perch (embryo), FT M
Perca flavescens
Yellow perch (fry), FT M
Perca flavescens
Yellow perch (fry) , FT M
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Yellow perch FT M
(juvenile) ,
Perca flavescens
Time
(lira)
96
96
96
96
96
96
96
96
96
96
96
Adjusted
LCbv. LC50
fu.j/l) (uq/i| kererence
150 106 Henderson,
et al. 1961
160 114 cairns &
Scheier, 1963
281 281 Smith, et al.
1978
288 288 Smith, et al.
1978
330 330 Smith, et al.
1978
88.9 88.9 Smith, ec al.
197G
93 93 Smith, et al.
1978
74.7 74.7 Smith, et al.
1975
94.7 94.7 Smith, et al . ,
1978
101 101 Smith, et al. ,
1978
107 107 Smith, et al . ,
1978
* S = static. FT = flow-through
** I) = unmeasured, M = measured .,.. ^
Geometric mean of adjusted values = 147.9 wg/1 "3 g~~ ~ -^ >'8/l
Lowest value from a flow-through test with measured concentrations = 52 ug/1
-------
Table 2. Freshwater inx'ertebrate acute values for cyanide
Adjusted
CO
1
I-1
tn
Bitxissay Test
organism Method* Cone .**
Snail. S U
Goniobasis livescens
Snail (embryo), S U
Lyiflnaea spp^
Snail, S U
Lymnaea emarginata
Snail, S U
Physa heterostropha
Snail. S U
Physa heterostropha
Snail, S U
Phy_sa integra
Cladoceran, S U
Daphnin pulex
Isopod, FT M
Asellus communis
Scud, FT M
Gaminarus pseudol imnaeus
Mayfly. S U
Stcnonoma rubrum
Caddisfly, S U
Hydropsyche spp
Time
Itirs)
48
96
48
96
96
48
48
96
96
48
48
LCbo
760,000
51.900
3,300
432
431
1.350
83
2,326
167
500
2,000
Si)
276,800
44,000
1,202
366
. 365
492
70
2,326
167
182
728
Kfeierence
Cairns ,
et al. 1976
Dowden &
Bennett, 1965
. Cairns ,
et al. 1976
Patrick,
et al. 1968
Cairns ft
Scheier, 1958
Cairns ,
et al. 1976
Lee, 1976
Oseid &
Smith, In press
Oseid &
Smith, In press
Roback. 1965
Roback, 1965
* S = static. FT = flow-through
** U = unmeasured, M = measured
Geometric mean of adjusted values = 1,252 |ig/l
1.252
Mg/1
Lowest value from a flow-through test with measured concentrations = 167 pg/1
-------
3. Freshwater fish chronic values for cyanide
Organism Test*
Brook trout, LC
Salvelinus fontinalis
Fathead minnow. LC
Pimephales pronielas
Bluegill. E-L
Lepomis macrochirus
Chronic
Limits Value
fug/1)
5.6-11.0 7.9
13.3-20.2 16.4
9.3-19.8 6.8
Befprencc
Koenst, et al. 1977
Lind. et al. 1977
Kimball. et al..1973
03
I
* LC - life cycle or partial life cycle; E-L = embryo-larval test
Geometric mean of chronic values •= 9.6 pg/1
Lowest chronic value =6.8 yg/1
-------
Table A. l-'rcsliwiiior invertebrate chronic values for cvanlde
Chronic
Limits Value
Organism Tfcst.* (ug/i^ (ug/11
Isopod. LC 29-40 34.1
Asellus comraunis
ScuU, LC 16-21 18.3
Garriinnrus pseudolimnaeus
Reference
Oseid t Smith, In press
Oseid & Smith, In press
* LC = life cycle or partial life cycle
Geometric mean of chronic values «• 25 iig/1
Lowest chronic value -18.3 vig/1
25
4.9 ug/1
03
I
-------
w
I
M
00
Table 5. Freshwater plant effects for cyanide
Concentration
Organ! HIII Ettect (ug/il Reference
Blue-Rrccn alpa. 90% ki.ll 7,790 Fitzgerald, et al. 1952
Mici'ucysLJ s aeruginosa
Lowest plant value =7,790 jig/1
-------
Table 6. Other freshwater data for cyanide
Organism
Scud,
Gammarus
pstuJoTrmnaeus
Cladoceran,
Daphnia niapna
Coho salmon.
Oncorhynchus kisutch
Chinook salmon
(juvenile) ,
Oncorhynchus tshavjytscha
Atlantic salmon,
Salmo salar
™ Brook trout (fry).
j_, Salvelinus foncinalis
vo
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout (fry),
Salvelinus fon.innlis
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout (fry) ,
Salvelinus fontinalis
Brook trout (fry) ,
Salvelinus foncinalis
Brook trout
Test
Duration
98 days
96 hrs
2 hrs
64 days
58 days
15.2 min
10.8 min
11.7 min
26 min
58 min
210 min
130 hrs
27 days
3.6 days
Ettect
Competition with
Asellus affects
HCS toxicity
LC50
Swimming speed
reduced
27% reduction in
biomass
Teratogenic effects
Co embryos
Death
Death
Death
Death
Death
Death
Death
100% survival
Lethal
Result
Juq/H
9
160
10
20
10
8,640
4.290
2,130
853
392
217
50
20
80
Relei eiict
Oseid & Smith, In pres
Dowden & Bennett, 1965
Broderius, 1970
Negilski, 1973
Leduc, 1978
Karsten. 1934
Karsten, 1934
Karsten. 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
KarsLcn, 1934
Neil , 1957
(juvenile) ,
Salvelinus fontinalis
-------
Table. 6. (continued)
DO
1
N)
O
Test
Organism Duration
Brook trout 40 days
(juvenile)
Salvelinus fontinal.is
Brook trout 25.5 tnin
(juvenile) ,
Salvelinus fontinalis
Rainbow trout 250 tnin
(juvenile) ,
Sal mo gairdneri
Rainbow trout 20 days
(juvenile) ,
Salmo gairdneri
Rainbow trout (adult), 2 min
Salmo gairdneri
Rainbow trout (adult) , 8 -min
Salmo gairdneri
Rainbow trout (adult), 12 min
Salmo gairdneri
Rainbow trout (adult) , 12 min
Salmo gairdneri
Rainbow trout (adult) , 24 min
Salmo gairdneri
Rainbow trout (adult) , 72 min
Salmo gairdneri
Rainbow trout (adult), 90 min
Salmo gairdneri
Rainbow trout 2,525 min
(adult),
Salmo gairdneri
Kainbow trout 1,617 min
(adult).
Sa]mo gairdneri
Rainbow trout 3,600 min
(adult),
Salmo gairdneri
Result
Effect Jug/n
Not lethal 50
75% reduction in 10
swimming endurance
Approximate median 200
survival time
Abnormal oocyte 10
development
Mean survival time 2,000
Mean survival time 300
Mean survival time 250
Mean survival time 200
Mean survival time 180
Mean survival time 160
Mean survival time 140
Mean survival time 100
Mean survival time 90
Mean survival time 80
Reference
Neil, 1957
Neil. 1957
Dep. Sci. Ind. Res. , 1956
Lesniak, 1977
Herbert & Merkens , 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
Herbert & Merkens. 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
Herbert & Merkens, 1952
-------
Table 6. (Continued)
I
to
Organism
Rainbow trout
(adult).
Sajjno gairdnerl
Rainbow trout
(juvenile),
SaImp gairdneri
Rainbow trout
(juvenile),
Salmo gairdneri
Rainbow trout
(juvenile).
Salmo gairdneri
Rainbow trout
(yearling),
Salmo gairdneri
Rainbow trout
(yearling).
Salmo gairdneri
Rainbow trout,
Siin!0. gairdneri
Rainbow trout,
Salmo gairdneri
Brown trout
(juvenile),
Salmo trutta
Brown trout
(juvenile),
Sa_lmo trutta .
Brown trout
(juvenile),
Salmo trutta
Brown trout
(juvenile)
Salmo Lnjtta
Result
fug/i.)
Test
Duration Fttect
A,441 min Mean survival time
9 days Weight gain reduced
4 days Increased respiration
rate
9 days Liver damage
(necrobiosis)
21 days 65% reduction in
weight gain
21 days 75% reduction in
swimming ability
18 days Production of spermato-
gonia reduced to 87%
18 days Production of sperroato-
gonia reduced to 51%
6.58 min Geometric mean time to 1,006
death
15 min Geometric mean time to
death
70 Herbert & Merkens, 1952
10 Dixon, 1975
10 Dixon, 1975
10 Dixon, 1975
20 Speyer, 1975
20 Speyer, 1975
10 Ruby & Dixon, Manuscript
30 Ruby & Dixon, Manuscript
Burdick, et al. 1958
510 Burdick, et al. 1958
30.1 min Geometric mean time to
death
320 Burdick, et al. 1958
5 hrs Oxygen uptake Inhibited 25 Carter, 1962
-------
Table 6. (Continued)
03
IsJ
NJ
Brown trout (fry),
Sal mo trutta
Brown trout (fry),
Salmo trutta
Brown trout (fry) ,
Salmo trutta
Brown trout (fry),
Salmo trutta
Fathead minnow
(juvenile),
Pimephales promelas
Channel catfish
(juvenile),
Ictalurus punctatus
Guppy (juvenile),
Lebistes reticulatus
Stickleback,
Gasterosteus aculeatus
Threespine stickleback
(adult).
Gasterosteus aculeatus
Threespine stickleback
(adult) ,
Gasterosteus aculeatus
Threespine stickleback
(adult),
Gasterosteus aculeatus
Bluegill (adult),
Lepomis macrochirus
Bluegill (adult),
l.cppmi s macrochirus
Bluegill (juvenile),
Lepomis macrochirus
Test
Duration Kttect
8.2 min Death
8.9 min Death
8.2 roin Death
140 min Death
5 days LC50
26 hrs LC50
Result
(uu/il
8,030
4,140
2.070
217
120
Ret ereiicfc
Karsten. 1934
Karsten, 1934
Karsten, 1934
Karsten, 1934
Cardwell, et al. 1976
161 Cardwell. et al. 1976
120 hrs Threshold concentration 236
90 min Depressed respiration 1.040
rate
824 min Median survival time 134
642 min Median survival time
412 min Median survival time 237
289 days Survival reduced 67.8
289 days No reproduction 5.4
202 min Median survival time 190
Chen, 1968
Jones, 1947
Broderius, 1973
170 Broderius, 1973
Broderius, 1973
Kimball, et al. 1970
Kimball, et al. 1978
Broderius, 1973
-------
Table 6. (Continued)
Orgjniam
Test
Duration tttect
Result
(uci/l) Ketereiicfc
CD
I
to
Rainbow trout
(adult).
Salmo gairdneri
Rainbow trout
(juvenile).
Salmo gairdneri
Rainbow trout
(juvenile).
Salmo gairdneri
Rainbow trout
(juvenile),
Salmo gairdneri
Rainbow trout
(yearling),
Salmo gairdneri
Rainbow trout
(yearling) ,
Salmo gairdneri
Rainbow trout,
Sa^lmo gairdneri
Rainbow trout,
Salmo gairdneri
Brown trout
(juvenile),
Salmo trutta
Brown trout
(juvenile) ,
Salmo trutta
Brown trout
(juvenile) ,
Salmo trutta
Brown trout
(juvenile)
Salmo Lnacta
4,441 min Mean survival time
9 days Weight gain reduced
4 days Increased respiration
rate
9 days Liver damage
(necrobiosis)
21 days 65% reduction in
weight gain
21 days 75% reduction in
swimming ability
18 days Production of spermato-
gonia reduced to 87%
18 days Production of spermato-
gonia reduced to 51%
6.58 min Geometric mean time to 1,006
death
70 Herbert & Merkens, 1952
10 Dixon, 1975
10 Dixon, 1975
15 min Geometric mean time to 510
death
10 Dixon, 1975
20 Speyer. 1975
20 Speyer, 1975
10 Ruby & Dixon, Manuscript
30 Ruby ft Dixon, Manuscript
Burdick. et al. 1958
Burdick, et al. 1958
30.1 min Geometric mean time to
death
320 Burdick, et al. 1958
5 hrs Oxygen uptake inhibited 25 Carter, 1962
-------
Table 6. (Continued)
CO
I
Brown trout (fry),
Sa1mo true La
Brown trout (fry),
Salmo trutta
Brown trout (fry),
Salmo trutta
Brown trout (fry),
SaImo trutta
Fathead minnow
(juvenile),
Pimephales promelas
Channel catfish
(juvenile),
Ictalurus punctatus
Guppy (juvenile),
Lebistes reticulatus
Stickleback,
Gastcrosteus aculeatus
Threespine stickleback
(adult).
Gasterosteus aculeatus
Threespine stickleback
(adult),
Gasterosteus aculeatus
Threespine stickleback
(adult),
Gasterosteus aculeatus
Bluegill (adult),
Lepomis macrochirus
Bluegill (adult),
l.cponus macrochirus
Bluegill (juvenile),
Lcpomis macrochirus
Test Result
Duration li:ttect
8.2 min Death
8.9 min Death
8.2 min Death
140 min Death
5 days LC50
26 hrs LC50
120 hrs Threshold concentration
90 min Depressed respiration
rate
824 min Median survival time
J
8
4
2
1
u
-------
Table 6. (Continued)
Onianism
Test
Duration
Result
(ug/ll
Bluegill (juvenile),
macrochirus
B)
I
N>
00
260 min
Bluegill (juvenile) , 351 min
l.epomis macrochtrus
Bluegill (juvenile) , 258 min
Lepomis. macrochirus
Bluegill (juvenile), 352 min
Lepomis macrochirus
Bluegill (juvenile), 655 min
Lepomis macrochirus
Smallmouth bass 7.8 min
(juvenile) ,
Micropterus dolomieui
Smal Imouth bass 12. A min
(juvenile) ,
Micropterus dolomieui
Smallmouth bass 15.4 min
(juvenile) ,
Micropterus dolomieui
Smallmouth bass 30.6 min
(juvenile) ,
Micropterus dolomieui
Smallmouth bass 42.8 min
(juvenile) ,
Micropterus dolomieui
Smallmouth bass 80.5 min
(juvenile) ,
Micropterus dolomieui
Smallmouth bass 133 min
(juvenile) ,
Micropccrus dolomieui
Sniiil ImouLh bass 290 min
(juvenile) ,
Micropterus dolomieui
Median survival time
Median survival time
Median survival time
Median survival time
Median survival time
Geometric mean time
to death
Geometric mean time
to death
Geometric mean time
to death .
Geometric mean time
to death
Geometric mean time
to death
Geometric mean time
to death
Geometric mean time
to death
Geometric mean time
to death
194 Broderius, 1973
165 Broderius. 1973
165 Broderius, 1973
144 Broderius, 1973
127 Broderius, 1973
1,980 Burdick, et a\. 1958
1,430 Burdick, ct al. 1958
978 Burdick, et al. 1958
755 Burdick, et al. 1958
478 Burdick, et al. 1958
338 Burdick, et al. 1958
243 Burdick, et al. 1958
175 Burdick, et al. 1958
-------
03
I
to
Table 6. (Continued)
Test Result
Organism Duration fttect fug/1)
Largemouth bass 2 days Significant increases 40 Morgan ft Kiihn, 1974
(juvenile), in opercular rate
f'icropterus salmoides
-------
SALTWATER ORGANISMS
Introduction
The data base for the effects of cyanide on saltwater
organisms is limited to a few studies on algae and an oyster.
Plant Effects
Two saltwater algal species (Webster and Hackett, 1965;
Nelson and Tolbert, 1970) have been exposed to cyanide and there
was an inhibition of respiration in Prototheca zopfi at 3,000
ug/1 and enzyme inhibition in Chlorella sp. at 30,000 ug/1 (Table
7). The Final Plant.JValue is 3,000 ug/l°
Miscellaneous
A short exposure of an.oyster to cyanide (Usuki, 1956)
resulted in the observation of a suppression in activity after 10
minutes of exposure to 150 ug/1 (Table 8). After 3 hours there
was an inhibition in activity at 30,000 ug/1.
B-25
-------
CRITERION FORMULATION
Saltwater-Aquatic Life
Summary of Available Data
All values are for free cyanide expressed as CN. The
concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = not available
Final Invertebrate Acute Value = not available
Final Acute Value = not available
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 3,000 ;ug/l
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 3,000 ;ug/l
0.44 x Final Acute Value = not available
No saltwater criterion can be derived for free cyanide
using the Guidelines because no Final Chronic Value for
either fish or invertebrate species or a good substitue
for either value is available, and there are insufficient
data to estimate a criterion using other procedures.
B-26
-------
ro
i
to
-J
Table 7. Marine plant effects for cyanide
Concentration
Organism Ettect (uq/ll Reference
Green alga. Respiration 3.000 Webster & Hackect, 1965
Prototheca zopfi inhibition
Green alga, Enzyme inhibition 30,000 Nelson & Tolberc. 1970
Chlorella sp
Lowest plant value = 3,000 pg/1
-------
w
I
to
oo
Table 8. Other marine data for cvantdt (Usuki. 1956)
Orqani sm
Oyster,
Crassostrea sp.
Oyster,
Crassostrea sp.
Test
Duration Ettfrct
10 mins Activity suppression
3 hrs Activity inhibition
Result
(uq/1)
150
30,000
-------
REFERENCES
Anderson, P., and L. Weber. 1975. Toxic response as a
quantitative function of body size. Toxicol. Appl. Pharmacol.
33: 471.
Black, H.H., et al. 1957. Industrial waste guide—by-product
coke. Proc. llth Ind. Waste Conf. Purdue Univ. 41: 494.
Broderius, S.J. 1970. Determination of molecular hydro-
cyanic acid in water and studies of the chemistry and toxicity
to fish of the nickelocyanide complex. M.S. thesis. Oregon
State University, Corvallis.
Broderius, S.J. 1973. Determination of molecular hydro-
cyanic acid in water and studies of the chemistry and toxicity
to fish of metal-cyanide complexes. Ph.D. thesis. Oregon
State University, Corvallis.
Broderius, S., et al. 1977. Relative toxicity of free
cyanide and dissolved sulfide forms to the fathead minnow,
Pimephales promelas. Jour. Fish. Res. Board Can. 34: 2323.
Brown, V.M. 1968. The calculation of the acute toxicity
of mixtures of poisons to rainbow trout. Water Res. 2: 723.
Burdick, G.E., et al. 1958. Toxicity of cyanide to brown
trout and smallmouth bass. N.Y. Fish Game Jour. 5: 133.
B-29
-------
Cairns, J. Jr., and A. Scheier. 1958. The effect of periodic
low oxygen upon toxicity of various chemicals to aquatic
organisms. Proc. 12th Ind. Waste Conf. Purdue Univ. Eng.
Ext. Ser. No. 94, Eng. Bull. 42: 165.
Cairns, J. Jr., and A. Scheier. 1963. Environmental effects
upon cyanide toxicity to fish. Notulae Naturae, Acad. Natural
Sci., Philadelphia, No. 361.
Cairns, J. Jr., et al. 1965. A comparison of the sensi-
tivity to certain chemicals of adult zebra danios Brachydanio
rerio (Hamilton-Buchanan) and zebra danio eggs with that
of adult bluegill sunfish Lepomis macrochirus Raf. Notulae
Naturae, Acad. Natural Sci., Philadelphia, No. 381.
Cairns, J., Jr., et al. 1976. Invertebrate response to
thermal shock following exposure to acutely sub-lethal con-
centrations of chemicals. Arch. Hydrobiol. 77: 164.
Cardwell, R., et al. 1976. Acute toxicity of selected
toxicants to six species of fish. EPA 600/3-76-008. U.S.
Environ. Prot. Agency
Carter, L. 1962. Bioassay of trade wastes. Nature 196: 1304.
Chen, C.W. 1968. A kinetic model of fish toxicity thresh-
old. Ph.D. thesis. University of California, Berkeley.
B-30
-------
Department of Scientific and Industrial Research. 1956.
Water pollution research 1955. H.M. Stationery Off. London.
Dixon, D.G. 1975. Some effects of chronic cyanide poisoning
on the growth, respiration and liver tissue of rainbow trout.
M.S. thesis. Concordia University, Montreal.
Doudoroff, P. 1956. Some experiments on the toxicity of
complex cyanides to fish. Sewage Ind. Wastes 28: 1020.
Doudoroff, P., et al. 1966. Acute toxicity to fish of
solutions containing complex metal cyanides, in relation
to concentrations of molecular hydrocyanic acid. Trans.
Am. Fish. Soc. 95: 6.
Dowden, B.P., and H.J. Bennett. 1965. Toxicity of selected
chemicals to certain animals. Jour. Water Pollut. Control
Fed. 37: 1308.
Fitzgerald, G.P., et al. 1952. Studies on chemicals with
selective toxicity to blue-green algae. Sewage Ind. Wastes
24: 888.
Henderson, C. , et al. 1961. The effects of soire organic
cyanides (nitriles) on fish. Proc. 15th Ind. Waste Conf.
Purdue Univ. Eng. Ext. Ser. No. 106. Eng. Bull. 45: 120.
B-31
-------
Herbert, D.W.M., and J.C. Merkens. 1952. The toxicity
of potassium cyanide to trout. Jour. Exp. Biol. 29: 632.
Izatt, R.M., et al. 1962. Thermodynamics of metal-cyanide
coordination. I. pK, H°, and S° values as a function
of temperature for hydrocyanic acid dissociation in aqueous
solution. Inorg. Chem. 1: 828.
Jones, J.R.E. 1947. The oxygen consumption of Gasterosteus
aculeatus L. in toxic solutions. Jour. Exp. Biol. 23: 298.
Karsten, A. 1934. Investigations of the effect of cyanide
on Black Hills trout. Black Hills Eng. 22: 145.
Kimball, G., et al. 1978. Chronic toxicity of hydrogen cyanide
to bluegills. Trans. Am. Fish. Soc. 107: 341i
Koenst, W., et al. 1977. Effect of chronic exposure of
brook trout to sublethal concentrations of hydrogen cyanide.
Environ. Sci. Technol. 11: 883.
Leduc, G. 1978. Deleterious effects of cyanide on early
life stages of Atlantic salmon (Salmo salar). Jour. Fish.
Res. Board Can. 35: 166.
Lee, D. 1976. Development of an invertebrate bioassay
to screen petroleum refinery effluents discharged into fresh-
water. Ph.D. thesis. Virginia Polytechnic Inst. State University,
Blacksburg.
B-32
-------
Lesniak, J.A. 1977. A histological approach to the study
of sublethal cyanide effects on rainbow trout ovaries.
M.S. thesis. Concordia University, Montreal.
Lind, D., et al. 1977. Chronic effects of hydrogen cyanide
on the fathead minnow. Jour. Water Pollut. Control Fed.
49: 262.
Lipschuetz, M., and A.L. Cooper. 1955. Comparative toxi-
cities of potassium cyanide and potassium cuprocyanide to
the western blacknosed dace (Rhinichtys atratulus meleagris).
N.Y. Fish Game Jour. 2: 194.
Morgan, W.S.G., and P.C. Kuhn. 1974. A method to monitor
the effects of toxicants upon breathing rates of largemouth
bass (Micropterus salmoides Lacepede). Water Res. 8: 67.
Negilski, D.S. 1973. Individual and combined effects of
cyanide pentachlorphenol and zinc on juvenile chinook salmon
and invertebrates in model stream communities. M.S. thesis.
Oregon State University, Corvallis.
Neil, J.H. 1957. Some effects of potassium cyanide on
speckled trout (Salvelinus fontinalis) . Pages 74-96 in_
Papers presented at 4th Ontario Ind. Waste Conf. Water Pollut.
Adv. Comm., Ontario Water Resour. Comm., Toronto.
Nelson, E.B., and N.E. Tolbert. 1970. Glycolate dihydro-
genase in green algae. Arch. Biochem. Biophys. 141: 102.
B-33
-------
Oseid, D. , and L. Smith. The effects of hydrogen cyanide
on Asellus communis and Gammarus pseudolimnaeus and changes
in their competitive response when exposed simultaneously.
Bull. Environ. Contam. Toxicol. (In press).
Patrick, R., et al. 1968. The relative sensitivity of
diatoms, snails, and fish to twenty common constituents
of industrial wastes. Prog. Fish-Cult. 30: 137.
Roback, S.S. 1965. Environmental requirements of Trichoptera,
Pages 118-126 in Biological problems in water pollution.
3rd Seminar (1962), R.A. Taft Sanit. Eng. Center, Cincinnati,
Ohio. • . •
Ruby, S.M., and D.G. Dixon. Influence of sublethal concen-
trations of cyanide on early stages of spermatogenesis in
rainbow trout, Salmo gairdneri. Water Pollut. Res Lab.,
Concordia University, Montreal. (Manuscript.)
Smith, L., .et al. 1978. Acute toxicity of hydrogen cyanide
to freshwater fishes. Arch. Environ. Contam. Toxicol. 7: 325.
Smith, L.L. Jr., et al. 1979. Acute and chronic toxicity
of HCN to fish and invertebrates.. Ecol. Rep. Ser. EPA-600/3-
79-009. U.S. Environ. Prot. Agency.
B-34
-------
Speyer, M.R. 1975. Some effects of chronic combined arsenic
and cyanide poisoning on the physiology of rainbow trout.
M.S. thesis. Concordia University, Montreal.
Turnbull, H., et al. 1954. Toxicity of various refinery
materials to fresh-water fish. Ind. Eng. Chem. 46: 324.
Usuki, I. 1965. A comparison of the effects of cyanide
and azide on the ciliary activity of the oyster gill. Sci.
Rep. Tohoku University, Fourth Sci. 22: 137.
Wallen, I.E., et al. 1957. Toxicity to Gambusia affinis
of certain pure-chemicals in turbid waters. Sewage Ind.
Wastes 29: 695.
Webster, D.A., and D.P. Hackett. 1965. Respiratory chain
of colorless algae. I. Chlorophyta and Euglenophyta.
Plant Physiol. Lancaster. 40: 1091.
B-35
-------
CYANIDES
Mammalian Toxicology and Human Health Effects
Summary
Cyanides are defined as hydrogen cyanide (HCN) and
its salts. The toxicological effects of cyanides are based
upon their potential for rapid conversion by mammals to
HCN. Various organic compounds containing the CN moiety
which may have a potential for conversion to HCN in vivo
will not be considered in this document. Cyanides have
long been feared for their high lethality and their fulmina-
ting action. At the present time, however, cyanides do
not constitute ,an. important or widespread environmental
health problem. Almost all examples of human cyanide poisoning
or adverse environmental effects in the past have involved
occupational exposures or relatively localized sources of
pollution. Cyanides are uncommon in U.S. water supplies
and in the atmosphere. Although some food plants clearly
can cause acute cyanide poisoning if ingested in sufficient
amount, the evidence associating cyanide compounds in other
plants with chronic neuropathies is not convincing.
Some evidence suggests that the uses of cyanide in
the U.S. are increasing, and, therefore, continued vigilance
in the form of monitoring is indicated. However a number
of properties and characteristics of cyanide indicate that
it will probably remain only a potential pollutant or one
of secondary concern. For example, cyanide has a low degree
of persistence in the environment and it is not accumulated
or stored in any mammalian species that has been studied.
C-l
-------
In keeping with the latter, a sizeable body of experimental
evidence suggests that cyanide has an unusually low degree
of chronic toxicity. It does not appear to be mutagenic,
teratogenic, or carcinogenic.
No new evidence was encountered to suggest that the
P.H.S. drinking water standard for cyanide set in 1962 should
be lowered (Natl. Inst. Occup. Safety Health, 1969).
C-2
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EXPOSURE
Introduction
Cyanides are defined as hydrogen cyanide (HCN) and
its salts. The toxicological effects of cyanides are based
upon their potential for rapid conversion by mammals to
HCN.
Cyanide production in the U.S. is now over 700 million
pounds per year and it appears to be increasing steadily
(Towill, et al. 1978). The sources and industrial uses
of cyanide compounds in the United States have recently
been reviewed exhaustively (Natl. Inst. Occup. Safety Health
1976; Towill, et al. 1978). Briefly, the major industrial
users of cyanide in the U.S. are the producers of steel,
plastics, synthetic fibers and chemicals, and the electroplating
and metallurgical industries. In addition to these industries
(see Table 1) cyanide wastes are discharged into the environment
from the pyrolysis of a number of synthetic and natural
materials and from chemical, biological, and clinical labora-
tories. Although wool, silk, polyacryionitrile, nylon,
polyurethane, and paper are all said to liberate HCN on
combustion, the amounts vary widely with the conditions.
As yet there is no standardized fire toxicity test protocol
in the U.S. (Terrill, et al. 1978).
Despite numerous potential sources of pollu. :.on, cyanide
is relatively uncommon in most U.S. water supplies. A survey
of 969 U.S. public water supply systems in 1970 revealed
no cyanide concentrations above the mandatory limit (McCabe,
et al. 1970). In 2,595 water samples, the highest cyanide
C-3
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TABLE 1 INORGANIC CYANIDE WASTES
Source and
Mrifprisl —
Bureau of
I II III IV
the Census
V
regions
VI VII VIII
Total
IX
Annual waste production (Ib/year)
Cyanides from , , , fifififififi a
electroplating 2.78 x 10° 6.07 x 10° 6.86 x 10° 0.96 x 10° 1.04 x 10° 0.49 x 10° 0.77 x 10° 0.15 x 10° 2.20 x 10° 21.32 x 10°
Paint sludge
cyanides 1,000 9,900 13,800 2,900 3,850 2,150 3,350 550 7,300 44,900
sludge 0.92 x 106 8.12 x 106 11.32 x 106 2.40 x 106 3.16 x 106 1.76 x 106 2.74 x 106 0.44 x 106 5.97 x 106 36.83 x 106
n
•f- Paint residue ,. ,. ^ c c r
cyanides 0.18 x 105 0.57 x 103 0.62 x 103 0.23 x 103 0.47 x 103 0.20 x 103 0.30 x 103 0.13 x 10° 0.41 x 103 3.1i x 103
old paint 13 x 106 41 x 106 44 x 106 16 x 106 34 x 106 14 x 106 21 x 106 9 x 106 29 x 106 221 x 106
Stored wastes (Ib)
Sodium cyanide 1,400
Calcium cyanide
Copper cyanide 100
Potassium cyanide
Silver cyanide
Potassium
ferr icyanide
Potassium
ferrocyanide
16 1,416
180 25 205
32 132
2 2
16 10 26
,
4 4
12 12
Source: Ottinger, et al. 1973, Table 1.
-------
concentration found was 8 ppb and the average concentration
was 0.09 ppb (Towill, et al. 1978). In part, this must
be ascribed to the volatility of undissociated hydrogen
cyanide which would be the predominant form in all but highly
alkaline waters. Also, in part, cyanide ion would have
a decided tendency to be "fixed" in the form of insoluble
>
or undissociable complexes by trace metals. In view of
the increased production and uses of cyanide in the U.S.,
however, continued vigilance in the form of monitoring is
certainly indicated particularly in the proximity of known
potential sources of pollution. Techniques for monitoring
have been reviewed elsewhere . (Natl. Inst. Occup. Safety
Health, 1976; Towill, et al. 1978).
C-5
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Ingestion from Water
As noted above, cyanide is an uncommon pollutant in
most U.S. water supplies and documented examples of levels
in excess of the 1962 P.H.S. limits (U.S. Pub. Health Serv.
1962) are extremely rare. No human cases of illness or
death due to cyanide in water supplies are known. The lack
of such documentation, of course, cannot be accepted compla-
cently. It is entirely possible that pulse discharges of
industrial wastes result in high localized concentrations
which have escaped detection, but general recognition of
the high toxicity of cyanide has made its removal standard
practice in most industries (Reed, et al. 1971). Fortunately,
known methods for cyanide removal including alkaline chlorina-
tion, hypochlorite treatment, reaction with aldehydes, electro-
lytic decomposition, exposure to ionizing radiation, and
heating are effective and relatively economical (Lawes,
1972; Watson,1973).
A few accidents have resulted in massive fish kills,
some livestock deaths, and environmental damage. Cyanide,
unknowingly released from a sewage plant in Oak Ridge, Tenn.,
was responsible for the death of 4,800 fish in Melton Hill
Lake near the sewage outfall (The Oak Ridge, 1975). About
1,500 55- and 30-gallon drums containing cyanides disposed
of near Byron, 111. resulted in long-range environmental
damage and livestock death. Surface water runoff from the
area contained up to 365 ppm cyanide (Towill, et al. 1978).
Ingestion from Foods
Except for certain naturally occurring organonitriles
in plants, it is uncommon to find cyanide in foods in the
C-6
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U.S. In higher plants the major group of organonitrlies
are the cyanogenic glycosides and at least 20 distinct compounds
are known. Perhaps the best known of this group is the
compound, amygdalin, which is found in many parts of the
cherry laurel and the seeds of cherries, plums, peaches,
apricots, apples, and pears. Amygdalin is the chief ingredient
in Laetrile. Both Laetrile and amygdalin-containing fruit
pits have been implicated as causes of acute cyanide poison-
ing in humans (Braico, et al. 1979; Gosselin, et al. 1976).
The release of free cyanide from cyanogenic glycosides can
be effected by acid hydrolysis or most rapidly by^-gluco-
sidases, enzymes present in plants and in the intestinal
microflora of mammals but found in only trace amounts in
animal tissues (Conchie, et al. 1959).
Another naturally occurring group of organonitriles
are called the pseudocyanogenic glycosides of which the
best known example is cycasin from the Cycadaceae species.
As implied by the name, cyanide release from these compounds
is unlikely to occur iri vivo since alkaline hydrolysis is
required (Miller, 1973). Cycasin and related glycosides
are highly toxic and their ingestion along with foodstuffs
has been implicated in a variety of so-called "tropical
neuropathies" and amblyopias (Osuntokun, 1968) . A -hough
these neurological disturbances have frequently been cited
in the literature (Towill, et al. 1978) as examples of "chronic
cyanide poisoning," the evidence for that extrapolation
is indirect and inconclusive. The failure of repeated attempts
to produce similar syndromes with pure hydrogen cyanide
or its salts (below), strongly suggests that the neuropathies
C-7
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produced by cycasin-containing foods are due to other unrecog-
nized toxins, to the cycasin per se, or to uncharacterized
toxic metabolites rather than to cyanide.
Other organonitriles found in plants include the lathyro-
genic compounds, such as^\-glutamyl-^-cyanoalanine, the
glucosinolates such as glucobrassicin, and the cyanopyridine
alkaloids such as ricinine and indoleacetonitrile (Towill,
et al. 1978). Although many of these are toxic to mammals,
no evidence links their toxicity to cyanide poisoning.
Inhalation
Hydrogen cyanide vapor is absorbed rapidly through
the lungs (Gettler and St. George, 1934). Because HCN has
a pKa of 9.2 and exists primarily as the acid under biological
conditions, absorption across the alveolar membrane should
be rapid (Wolfsie and Shaffer, 1959). Human inhalation
of 270 ppm HCN vapor brings death immediately, while 135
ppm is fatal after 30 minutes (Dudley, et al. 1942).
Cyanide absorption following inhalation of very low
concentrations is indicated by the observation that smokers
have higher thiocyanate levels in plasma and other biological
fluids than do nonsmokers (Wilson and Matthews, 1966).
Cyanide levels usually are not significantly different in
smokers as compared with non-smokers (Pettigrew and Fell,
1973; Wilson and Matthews, 1966), since cyanide absorbed
from inhaled tobacco smoke is rapidly converted to thiocya-
nate (Johnstone and Plimmer, 1959; Pettigrew and Fell, 1973).
Inhalation of cyanide salt dusts is also dangerous because
the cyanide will dissolve on contact with moist mucous mem-
branes and be absorbed into the bloodstream (Davison, 1969;
C-8
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Knowles and Bain, 1968).
The so-called distinctive odor of bitter almonds ascribed
to HCN does not necessarily serve as a warning of exposure.
The ability to smell hydrogen cyanide appears to be a geneti-
cally determined trait. Individuals vary widely from not
being able to detect the odor, at all to extreme sensitivity
(Kirk and Stenhouse, 1953).
Dermal
Hydrogen cyanide in either liquid or vapor form is
absorbed through the skin (Drinker, 1932; Potter, 1950;
Tovo, 1955; Walton and Witherspopn, 1926). Absorption is
probably increased if the skin is cut, abraded, or moist.
Many accidents involving skin contamination also involve
inhalation exposure; the contribution due to skin absorption
in these cases is difficult to assess. Potter (1950) described
a case in which liquid HCN ran over the bare hand of a worker
wearing a fresh air respirator. Cyanide inhalation was
prevented, but the worker collapsed into deep unconsciousness
within five minutes, suggesting significant percutaneous
absorption.
PHARMACOKINETICS
Absorption
Probably the common inorganic cyanides of ccnunerce
are rapidly absorbed from the stomach and duodenum. Certainly,
the human experience in regard to the rapidly lethal effects
(Gosselin, et al. 1976) of ingested cyanides is in accord
with the above, but experimental studies which actually
define quantitatively the rates of penetration are not available,
C-9
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Hydrogen cyanide is a weak acid with a pK of 9.2.
a
Thus, the acid milieu of the stomach would greatly favor
the undissociated species, HCN, which should further hasten
absorption. Even at the physiological pH of 7.4, however,
cyanide would exist predominantly as the unionized moiety
which would serve to facilitate its transfer among various
body compartments (see above). In accord with the theory
of non-ionic diffusion cyanide would be predicted to accumulate
in body compartments which are at a higher pH (more alkaline)
than blood. At present, no evidence can be cited to substan-
tiate directly that prediction.
It has long been common knowledge that hydrogen cyanide
gas or vapor-s are rapidly absorbed via the lungs producing
reactions within a few seconds and death within minutes
(Gosselin, et al. 1976). Hydrogen cyanide was used as the
instrument of execution for convicted criminals in some
U.S. States primarily because of its rapid lethal effects
on inhalation of high concentrations.
Hydrogen cyanide gas or solutions are absorbed through
the intact skin much more readily than are the ionized salts
which are less lipid soluble (Wolfsie and Shaffer, 1959).
Absorption is probably increased in both cases if the skin
has been cut or abraded. Alleged cases of human skin absorp-
tions, however, are often complicated by the possibility
of concomitant inhalation of cyanide gas (see also Dermal,
above) . Again, quantitative estimates of the rate of penetrar-
tion of skin by various forms of cyanide are not available.
C-10
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Distribution
Cyanide is distributed to all organs and tissues via
the blood where its concentration in red cells is greater
than that in plasma by a factor of two to three. Presumably,
the accumulation of cyanide in erythrocytes is a reflection
of its binding to methemoglobin which is found normally
in the blood of non-smokers in concentrations amounting
to as much as two percent of the total circulating pigment
(Smith and Olson, 1973). However, there may be other factors
as yet unrecognized which favor the accumulation of cyanide
in red cells. Cyanide may also accumulate locally in body
cells because of binding to metalloproteins or enzymes such
as catalase or cytochrome c oxidase (Smith, et al. 1977).
The possibility of concentration differences due to pH gradients
between body compartments was mentioned above. Certainly,
one would predict that cyanide would readily cross the placenta,
but again quantitative data are lacking.
Metabolism
By far, the major pathway for the metabolic detoxication
of cyanide involves its conversion to thiocyanate via the
enzyme rhodanese (de Duve, et al. 1955). Rhodanese is widely
distributed in the body, but the highest activity is found
in mammalian liver (Table 2). The rate of the rhodanese
reaction in vivo is limited by the availability of the endo-
genous sulfur containing substrate, the identity of which
is still unknown. Thiosulfate can serve as a substrate
for rhodanese with a high degree of efficiency both in vivo
and In vitro (Chen and Rose, 1952; Himwich and Saunders,
1948) .
C-ll
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TABLE 2
RHODANESE ACTIVITY IN TISSUES OF THE DOG, RHESUS MONKEY, RABBIT, AND RAT
(rag CN converted to CNS per gram of tissue)
Dog
Tissue
Suprarenals
whole
cortex
medulla
i Liver
H
to
Brain
cortex
caudate nucleus
midbrain
cerebellum
medulla
Spinal cord
cervical
lumbar
sacral
Heart
Kidney
Testes
Epidydymis
Ovaries
Lung
Spleen
Muscle
Intestine
duodenum
: jejunum
I Eye
Optic nerve
Range3
2.14-3.60
(5.46, 4.50)
2.86-5.62
0.27-1.12
0.78-1.46
(4.91, 6.28)
0.34-0.92
0.27-1.06
0.52-1.35
0.21-1.22
0.38-1.52
0.15-1.08
0.12-0.84
0.16-1.41
0.11-0.14
0.42-0.74
0.32-0.41
0.29
0.42
0.16-0,17
0.10-0.14
0.03-0.19
0.05-0.11
0.04
0.02
0.35
Number
of
observations
6
2
2
7
7
7
6
7
7
7
4
4
6
6
5
1
1
3
2
6
3
1
1
1
Rhesus
Range
0.14-1.35
10.98-15.16
(5.98)
0.27
0.34-0.50
0.22-0.80
0.33
0.49-0.85
0.56-0.57
0.20-0.42
0.23-0.28
0.48-0.82
2.46-3.58
0.38-0.46
0.11-0.21
0.12-0.34
0.23-0.57
Monkey
Number
of
observations
3
4
1
2
2
1
2
2
2
2
3
4
3
2
2
3
Rabbit Rat
Range
1.24-3.94
7.98-18.92
1.41-1.44
0.13-0.18
1.17-1.39
0.63-1.24
0.91
0.89-0.90
0.35-1.74
0.59-1.10
6.20-7.69
0.32-0.36
0.30
0.40
0.20
0.18
Number
of Range
observations
2 0.27-0.41
9 14.24-28.38
2 0.70-0.72
2
2 0.73-1.13
2
1
2 0.16-0.18
2 0.23-0.27
3 0.56-0.74
3 10. 44-11.08
2 1.24-1.61
1
1
1
1
Number
of
observations
2
9
2
2
2
2
2
2
2
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TABLE 2 (Cont.)
O
I
Tissue
Salivary gland, parotid
Lymph node
Pancreas
Thyroid
Anterior pituitary
Whole blood
Erythrocytes
Plasma
Range3
.
0.05-0.36
0.08-0.13
0.14-0.28
0.05-0.94
0.26
0.01-0.02
0.01-0.02
0.01
Dog Rhesus
Number
of Range
observations
3 0.99
2
4 0.12-0.44
3
1
2
2
1
Monkey Rabbit
Number Number
of Range of
observations observations
1
2
Rat
Number
Range of
observations
aFigures in parentheses are single observations falling outside the normal range.
Source: Adapted from Himwich and Saundecs, 1948, Table 1, p. 351. Reprinted by permission of the publisher,
-------
Alternative minor metabolic pathways for cyanide metabolism-
include conjugation with cysteine to form 2-iminothiazolidene-
4-carboxylic acid, a reaction that is said to proceed nonenzyma-
tically (Figure 1). In rats given a total dose of 30 mg
over an eight-day period, this pathway accounts for no more
than 15 percent of the total cyanide (Wood and Cooley, 1956).
A very small fraction of the total cyanide is bound by hydroxo-
cobalamin, probably less than 1 percent (Brink, et al. 1950).
A small amount (about one to two percent) is excreted unchang-
ed as HCN via the lungs (Friedberg and Schwarzkopf, 1969).
By reactions that are not well understood, cyanide gains
access to metabolic pathways for one carbon compounds and
it is converted to formate and to carbon ,dioxide.
Excretion
As estimated in rats given 30 mg sodium cyanide intra-
peritoneally over a period of eight days, 80 percent of
the total cyanide is excreted in the urine in the form of
thiocyanate (Wood and Cooley, 1956). Because the fate of
cyanide is largely determined by a single metabolic pathway,
one would predict that it would fit a relatively simple
pharmacokinetic model, e.g., first order kinetics in plasma,
but such detailed analyses have not been made. Cyanide
does not appear to accumulate significantly in any body
compartment with repeated doses or chronic exposures.
Because the liver contains the highest activity of
rhodanese, it is possible that pre-existing liver disease
might slow the rate of cyanide metabolism, but no studies
appear to address this question. No inhibitors of rhodanese
are known which are active in vivo.
C-14
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CN-
Major path
CNS- -
2-imino-thiazolidine-
4-carboxylic acid
~ pool
Excretion
', cyanocobalamin
HCN
in expired air
H
CC
1CNO HCC
), sorr
ii
)OH - me
oni
COl
te excreted
i urine
one-carbon
compounds
Figure i. Fate of cyanide ion in the body. Source: Williams,
1959, p. 393. Reprinted by permission of the publisher.
C-15
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EFFECTS
Acute, Sub-acute and Chronic Toxicity
Hydrogen cyanide and its alkali metal salts are chemicals
of high inherent lethality to man and other mammals. The
mean lethal dose of these substances by mouth in human adults
is in the range of 50 to 200-mg (1 to 3 mg/kg), and death
is rarely delayed more than an hour (Gosselin, et al. 1976) .
In respiratory exposures to hydrogen cyanide gas, death
occurs in 10 to 60 minutes at ambient concentrations of
0.1 to 0.3 mg/1 or 100 to 300 ppm (Table 3). In non-fatal
poisonings recovery is generally rapid and complete.
The acute effects of cyanide poisoning in all obligate
aerobic species can be ascribed directly or indirectly to
a single specific biochemical lesion, namely the inhibition
of cytochrome c oxidase (Gosselin, et al. 1976). Inhibition
of this terminal enzyme complex in the respiratory electron
transport chain of mitochondria impairs both oxidative metabo-
lism and the associated process of oxidative phosphorylation
(Lehninger, 1975). The ensuing syndrome has been well charac-
terized in man and in laboratory animals (e.g., Gosselin,
et al. 1976) . In its major features cyanide poisoning resembles
the effects of acute hypoxia whether the latter is due to
airway obstruction or to the absence of oxygen (anoxic hypoxia),
carbon monoxide poisoning (anemic hypoxia) or shock (stagnant
or hypokinetic hypoxia), all of which result in a decreased
supply of oxygen to peripheral tissues.
Cyanide poisoning differs from other types of hypoxia
in that the oxygen tension in peripheral tissues usually
remains normal or may even be elevated (Brobeck, 1973).
C-16
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TABLE 3
HUMAN RESPONSE TO INHALED CYANIDE AND CYANIDE-CONTAINING COMPOUNDS
Compound
Cyanide concentration
Response
conjunctiva and the mucous
membranes of the respiratory
system
Reference
Hydrogen cyanide
Cyanogen
o
i Cyanogen chloride
H-1
Cyanogen bromide
(nig/liter)
0.3
0.2
0.15
0.12-0.15
0.40
0.120
0.005
0.0025
0.40
0.035
0.006
(ppm)
270
181
135
110-135
16
159
48
2
1
92
8
1.4
Immediately fatal
Fatal after 10-min exposure
Fatal after 30-min exposure
Fatal after % to 1 hr or
later, or dangerous to life
Nasal and eye irritation after
6 to 8 min
Fatal after 10-min exposure
Fatal after 30-min exposure
Intolerable concentration,
10-min exposure
Lowest irritant concentration,
10-min exposure
Fatal after 10-min exposure
Intolerable concentration
Greatly irritating to
Prentiss,
Prentiss,
Prentiss,
Fassett,
McNerney
Schrenk
Prentiss,
Fassett,
Fassett,
Fassett,
Prentiss,
Prentiss,
Prentiss,
1937
1937
1937
1963
and
, 1960
1937
1963
1963
1963
1937
1937
1937
-------
This paradoxical difference arises because the effect of
cyanide is to block the utilization of oxygen by aerobic
cells, a novel condition referred to as histotoxic hypoxia.
The organ systems most profoundly affected, however, are
the same as those impaired in any hypoxia irrespective of
etiology, namely the brain and the heart because of their
high dependence on oxidative metabolism. Two signs associated
with cyanide poisoning in man (e.g., Gosselin, et al. 1976)
follow from the preceding: 1) The failure to utilize molecular
oxygen in peripheral tissues results in abnormally high
concentrations of oxyhemoglobin in the venous return which
accounts' for a flush or brick-red color of the skin; and
2) attempts to compensate for the inhibition of oxidative
metabolism leads to increased demands on glycolysis which
accounts for a metabolic (lactic) acidosis.
A special but less unique effect of cyanide is stimula-
tion of the chemoreceptors of the carotid body which elicits
a characteristic pattern of reflex activity (Heymans and
Neil, 1958). Since the nature of these chemoreceptors is
unknown, it is possible that the effect of cyanide on them
is due also in some way to the inhibition of cytochrome
c oxidase. Stimulation of the carotid body chemoreceptors
by cyanide results in an immediate, well-sustained, and
marked augmentation of the respiration. Circulatory effects
which often accompany the increase in ventilation include
a transient rise in blood pressure which is probably secondary
to a reflex sympathetic discharge. The rise in blood pressure
is often accompanied by a bradycardia which some authorities
insist is not due to the common baroreceptor reflex via
C-18
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the vagus nerves. The pressor response is followed by a
fall in blood pressure to hypotensive levels from which
the victim may not recover (Heymans and Neil, 1958).
The other prominent effect of cyanide on the respiration
is a direct depression or fatal arrest which is the result
of an action of cyanide at the level of the brain stem nuclei
responsible for the control of breathing. In poisoned victims,
the heart beat invariably outlasts breathing movements.
The cardiac irregularities often noted may be secondary
to respiratory embarrassment, but direct histotoxic effects
of cyanide on myocardial cells are an even more likely mechanism.
Massive doses by mouth or concentrated respiratory
exposures may result in a sudden loss of consciousness which
may simply represent fainting secondary to the late fall
in blood pressure noted above. Presumably, the histotoxic
hypoxia triggers a massive peripheral vasodilation resulting
in orthostatic hypotension and collapse. The sequence of
events is slower on exposure to lower concentrations (Table 3)
and victims may experience anxiety, confusion, vertigo,
and giddiness before loss of consciousness. Unconsciousness
is followed by asphyxial convulsions which may be violent
and generalized. Opisthotonus, trismus, and incontinence
are common. The seizures may be followed by a brief period
of paralysis or rigidity with death in apnea (Gosselin,
et al. 1976).
Despite the high lethality of large single doses or
acute respiratory exposures to high vapor concentrations
of cyanide, repeated sublethal doses do not result in cumula-
tive adverse effects. Thus, cyanide is an example of a
C-19
-------
chemical which has a high acute toxicity, but an unusually
low degree of subacute or chronic toxicity. Hertting, et
al. (1960) gave once or twice each day to dogs doses (0.5
to 2 mg/kg) of sodium cyanide that usually resulted in acute
toxic signs but from which the animals recovered completely
within half an hour. This regimen was continued over a
period of 15 months with no evident pathophysiologic changes
in organ function or permanent alteration in intermediary
metabolism. Similarly, rats tolerated the equivalent of
an acute oral LD of potassium cyanide each day for 25
days when it was mixed with their regular diet (Hayes, 1967).
Workers at American Cyanamid (1959) fed to beagle dogs
a diet containing 150 ppm sodium cyanide for 30 days without
observing a significant effect on their food consumption,
hematologic parameters, behavioral characteristics, or micro-
scopic changes in their organs or tissues. Howard and Hanzal
(1955) fed a diet that had been fumigated with cyanide gas
and contained the equivalent of 100 to 300 ppm hydrogen
cyanide to rats for two years also with essentially negative
findings. The conclusion that cyanide in substantial but
sublethal intermittent doses can be tolerated for long periods
of time and perhaps indefinitely seems inescapable.
It seems reasonable to assume that continuous exposure
to some as yet undefined but low concentration of hydrogen
cyanide gas will lead inevitably to an exhaustion of the
reserve capacity of mammals to inactivate and detoxify cyanide.
The rate at which cyanide can be inactivated acutely has
been measured in guinea pigs. By continuously infusing
cyanide solutions intravenously at different rates Lendle
C-20
-------
(1964) showed that at a rate of 0.076 mg kg"1 min"1 about
90 percent of the single lethal dose as determined by "bolus"
injection could be detoxified over the course of an hour.
When the rate of administration was slowed, multiple lethal
doses could be tolerated. Extrapolation to a dose rate
that could be tolerated indefinitely, however, does not
seem justified with such a highly artificial model system.
Synergism and/or Antagonism
Since cyanide acts by inhibiting cytochrome c oxidase,
it is reasonable to presume that any other established inhibitor
of the same enzyme would have toxic effects synergistic
with (or additive to) those of cyanide. An established
example of such a substance is sulfide which is encountered
as hydrogen sulfide gas or as the alkali metal salts (Smith
and Gosselin, 1979). Sulfide is even more potent than is
cyanide as an inhibitor of cytochrome c oxidase, and similar-
ities between sulfide and cyanide inhibition suggest that
they act by similar mechanisms (Nicholls, 1975; Smith, et
al. 1977). No specific experimental studies can be cited,
however, on the combined effects of cyanide and sulfide
in either in vitro or j.n vivo systems.
The only other established inhibitor of cytochrome
c oxidase is azide (given either as hydrazoic acid or its
alkali metal salts). Azide is a much weaker inhibitor of
cytochrcme c oxidase than is cyanide or sulfide, and it
appears to act by a different inhibitory mechanism (Smith,
et al. 1977). Again, no specific studies can be cited to
establish whether azide has synergistic or additive effects
in combination with cyanide.
C-21
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Although cyanide produces the cellular equivalent of
hypoxia, there is no reason to suppose that other causes
of hypoxia would have effects additive to or synergistic
with those of cyanide. By coincidence one cause of anemic
hypoxia (Brobeck, 1973), namely, methemoglobinemia, is a
specific antagonist to cyanide (below). Oxygen has no effect
on cyanide inhibition of cytochrome c oxidase ii± vitro,
and it does not reverse the course of cyanide poisoning
in vivo. Since cyanide blocks the utilization of molecular
oxygen in peripheral tissues, its effects on oxygen tension
are opposite in direction to those of "true" hypoxia. Since
cytochrome c oxidase has a very high affinity for molecular
oxygen, it seems unlikely that the oxygen tension in peripheral
tissues in cyanide poisoning is ever a limiting parameter.
Cyanide poisoning is specifically antagonized by any
chemical agent capable of rapidly generating methemoglobin
in vivo such as sodium nitrite, hydroxylamine, amyl nitrite,
and a large number of aromatic amino- and nitro-compounds
such as aniline, p-aminopropiophenone and nitrobenzene (Smith
and Olson, 1973). Methemoglobin binds cyanide tightly in
the form of the biologically inactive complex, cyanmethemo-
globin. From a therapeutic standpoint there are several
disadvantages to the induction of methemoglobinemia despite
its established efficacy. Cyanmethemoglobin is a dissociable
complex and eventually the dissociation of free cyanide
from it may result in a recurrence of symptoms. The procedure
is limited by the concentration of methemoglobin that can
be tolerated by the victim, and the chemicals used to generate
C-22
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methemoglobin have toxic side effects of their own (Gosselin,
et al. 1976).
A second therapeutically useful approach to the antagonism
of cyanide poisoning is to provide an exogenous substrate
for the enzyme rhodanese, which converts cyanide to the
considerably less toxic form of thiocyanate. The endogeneous
substrate for rhodanese is not known, but p-toluene thiosul-
fonate (CH3CgH4-S02-S~)is 4.5 times more active than thio-
sulfate as a substrate in vitro (Sorbo, 1953). Ethyl thiosulfate
(C2H5-S-S03-0~), ethyl xanthate (C2H5OCS2~), diethyl dithio-
carbamate (C2H5)2NCS2~), hydrosulfite (S204=)and colloidal
sulfur are all inactive as substrates for rhodanese (Sorbo,
1953). It is probable that other sulfur compounds as yet
untested can also serve as substrates for rhodanese.
A variety of cobalt compounds effectively antagonize
cyanide poisoning presumably by reacting chemically with
free cyanide, e.g., cobaltous chloride, hydroxocobolamine,
cobalt EDTA. The latter two compounds have been used in
humans (Gosselin, et al. 1976). Although oxygen alone has
no effect on cyanide poisoning, it is said to potentiate
the anti-cyanide actions of thiosulfate and particularly
the thiosulfate-nitrite combination (Way, et al. 1966).
Teratogenicity, Mutagenicity, Carcinogenicity
There are no data on teratogenic, mutagenic, or carcino-
genic effects of cyanide nor do there appear to be any published
studies with analagous compounds from which one might postulate
the possible adverse effects of long-term, low-level exposure.
As previously indicated, above a number of studies designed
to show chronic or cumulative adverse ef.cjcts yielded only
C-23
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negative findings. It is possible that cyanide has antineo-
plastic activity; at least one study (Perry, 1935} reported
a low therapeutic index for cyanide against rat sarcomas.
In contrast, thiocyanate, the major product of cyanide
detoxification in_ vivo has produced developmental abnormalities
in the chick (Nowinski and Pandra, 1946) and ascidian embryo
(Ortolani, 1969) at high concentrations. Unfortunately,
these studies with thiocyanate cannot be extrapolated to
man nor can those of Hrizu, et al. (1973) who reported a
cytostatic effect of thiocyanate on human KB cells in culture
as well as an increased survival rate in mice inoculated
with Ehrlich ascites tumor cells. Again, the amounts used
preclude any meaningful extrapolation to human patients.
Thus, there is no evidence that chronic exposure to cyanide
results in teratogenic, mutagenic, or carcinogenic effects.
C-24
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CRITERION FORMULATION
Existing Guidelines and Standards
The U.S. Public Health Service Drinking Water Standards
of 1962 established 0.2 mg CN~/1 as the acceptability criterion
for water supplies. In addition to defining the 0.2 rag/1
criterion for cyanide the PHS set forth an "objective" to
achieve concentrations below 0.01 mg CN~/1 in water "because
proper treatment will reduce cyanide levels to 0.01 mg/1
or less" (U.S. Pub. Health Serv. 1962). The Canadian
government has recently adopted criterion and objective
concentrations of 0.2 mg CN~/1 and 0.02 mg CN~/1, respectively.
The latter figure represents the lower limit of detection
by colorimetric methods (Health Welfare Can. 1977) .
The U.S. PHS criterion was based on cyanide toxicity
to fish and not to man. Obviously, a disparity exists between
the exposure condition for man and for fish. The human
experience cited involved discrete single doses by mouth
whereas the fish data are derived from continuous total
body exposure. The latter conditions are not a very realistic
model from which to assess the human hazard. Even chronic
occupational exposures of men to hydrogen cyanide gas allows
for respite at the end of each working day. No data were
encountered which compared single acute oral LD "oses
in fish to ambient concentrations in their watr •' ich produced
death within a specified interval.
Current Levels of Exposure
Since cyanide is encountered only infrequently in water
supplies or in the atmosphere and since long-term and large-
scale monitoring has not been carried out, insufficient
C-25
-------
data exist to estimate current levels of exposure of the
general population. A number of factors contribute to the
rapid disappearance of cyanide from water. Bacteria and
protozoa may degrade cyanide by converting it to carbon
dioxide and ammonia (Leduc, et al. 1973). Cyanide is converted
to cyanate during chlorination of water supplies (Rosehart
and Chu, 1974). An alkaline pH favors the oxidation by
chlorine, whereas an acid pH favors volatilization of HCN
into the atmosphere. As cited, cyanide concentrations above
8 ppb were not found in a survey of 2,595 water samples
collected throughout the United States (Towill, et al. 1978).
Thus, these concentrations were well below the objective
levels established by the PHS.
Special Groups at Risk
Although it was speculated that the elderly and the
debilitated individuals in our population may be at special
risk with respect to cyanide, no experimental or epidemiologi-
cal studies can be cited to prove the point.
Basis and Derivation of Criterion
As shown in Table 4, the criterion of 0.2 mg CN~/1
allows for safety factors ranging from 41 to 2100. El Ghawabi,
et al. (1975) studied the effects of chronic cyanide exposure
in the electroplating sections of three Egyptian factories.
A total of 36 male employees with exposures up to 15 years
were studied and compared with a control group of 20 normal,
non-smoking males. Only minimal differences with respect
to thyroid gland size and function were found. The El Ghawabi
study was given considerable weight in formulating the NIOSH
C-26
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TABLE 4
Basis and Derivation of Cyanide Criterion
o
1
to
-j
Exposure
Levels
9.2 mg/m
2.5 mg/m3
12 mg/kg
3NOAEL
Route
Inhalation
Inhalation
Oral
Species
Man
Man
Rat
Calculated
Daily Exposure
60.8 mgb
16.5 mgb
840 mgc
Margin , of
Safety0
152
41
2100
Investigator
El Ghawabi, et al. 1975
NIOSH, 1976
Howard and
Hanzal, 1955
Based on 100% retention and on alveolar exchange of 6.6m for 8 hours.
Rat data converted to human equivalent assuming food consumption of 60 g/kg for rats and 70
kg human.
Daily exposure compared with 0.4 mg/day exposure from the consumption of 2 1 water containing
0.2 mg/1.
-------
recommendations for occupational exposure which gives a
safety factor of 41 when applied to drinking water by the
usual extrapolations (Table 4). Finally, a safety factor
of 2,100 is obtained using the results of a two year chronic
feeding study in rats. When fed at the rate of 12 mg/kg
per day over the equivalent of a lifetime, these rats showed
t
no overt signs of cyanide poisoning, and heir.atological values
were normal. Gross and microscopic examinations of tissues
revealed no abnormalities. The only abnormality found was
an elevation of thiocyanate levels in the liver and kidneys.
Consequently the ADI for man is derived by taking the no
observable adverse effect level in mammals (12 mg/kg/day)
multiplied by the weight of the average man (70 kg) and
dividing by a safety factor of 100. Thus,
ADI = 12 mg/kg/day x 70 kg t 100 =8.4 mg/day.
The equation for calculating the criterion for the
cyanide content of water given an Acceptable Daily Intake is
2X + ["(0.0187) (F) (X)] = ADI
Where
2 = amount of drinking water, I/day
X = cyanide concentration in water, mg/1
0.0187 = amount of fish consumed, kg/day
F = bioconcentration factor, mg cyanide/kg fish
per mg cyanide/1 water
ADI = limit on daily exposure for a 70 kg person = 8.4 mg/day
2X + (0.0187) (2.3)X =8.4
X = 4.11 :ng/l .
Thus, the current and recommended criteria (0.2 mg/1)
has a margin of safety of 20.6 (4.11 -r 0.2).
C-28
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No new additional evidence was encountered to suggest
that the 1962 PHS Drinking Water Standard for cyanide should
be lowered. The concentration of 0.2 mg/1 or less is easily
achieved by proper treatment and concentrations in excess
of that amount have been encountered only on rare occasions
in U.S. water supplies. The experience since 1962 suggests
that 0.2 mg CN~/1 is a safe criterion for man.
C-29
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