,,,..__ Environme.iiai Pfoiec:ion ,__
lAJH|. Agency Hay, 1991
Revised January 199?
Research and
Development
DRINKING WATER CRITERIA DOCUMENT
FOR CYANIDE
^ Prepared for
cy
HEALTH AND ECOLOGICAL CRITERIA DIVISION
OFFICE OF SCIENCE AND TECHNOLOGY
OFFICE OF WATER
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
U.S. EPA Headquarters Lib
Mail code aaoi "
1200 Pennsylvania Avent,,
Washington DC 20460
CM
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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to
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DISCLAIMER
This document has been reviewed 1n accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement
recommendation for use.
or
11
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FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking-Water Act, as amended 1n
1986, requires the Administrator of the Environmental Protection Agency to
publish maximum contaminant level goals (HCLGs) and promulgate National
Primary Drinking Water Regulations for each contaminant, which, 1n the
judgment of the Administrator, may have an adverse effect on public health
and which 1s known or anticipated to occur 1n public water systems. The
MCLG Is nonenforceable and Is set at a level at which no known or antici-
pated adverse health effects In humans occur and which allows for an
adequate margin of safety. Factors considered 1n setting.the MCLG Include
health effects data and sources of exposure other than drinking water.
This document provides the health effects basis to be considered in
establishing the MCLG. To achieve this objective, data on pharmacoklnetlcs,
human exposure, acute and chronic toxldty to animals and humans, epidemi-
ology and mechanisms of toxldty are evaluated. Specific emphasis 1s placed
on literature data providing dose-response Information. Thus, while the
literature search and evaluation performed In support of this document has
been comprehensive, only the reports considered most pertinent In the deri-
vation of the MCLG are cited 1n the document. The comprehensive literature
data base In support of this document Includes Information published up to
March 1987;'however, more recent data may have been added during the review
process. Health effects and toxlcoklnetlc data provided In this document
are limited to HCN and free CN (CN~).
When adequate health effects data exist, Health Advisory values for less
than lifetime exposures (1-day, 10-day and longer-term, -1054 of an
Individual's lifetime) are Included In this document. These values are not
used In setting the MCLG, but serve as Informal guidance to municipalities
and other organizations when emergency spills or contamination situations
occur.
Tudor Davles
Office of Science and
Technology
James Elder, Director
Office of Groundwater
and Drinking Water
111
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DOCUMENT DEVELOPMENT
Linda R. Papa, M.S., Document Manager
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Helen H. Ball, M.S., Project Officer
Environmental Criteria and Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Authors
Dlpalc K. Basu, Ph.D.
Michael W. Neal, Ph.D.
Sharon B, Wilbur, M.S.
Syracuse Research Corporation
Syracuse, New York
(EPA Contract #68-03-3112)
Editorial Reviewers
Judith Olsen, B.A.
Environmental Criteria and
Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Scientific Reviewers
Cynthia,. Son1ch-Mull1n M.S'.
Michael L. Dourson, Ph.D.
Environmental Criteria and
Assessment Office, Cincinnati
U.S. Environmental Protection Agency
Ernest C. Foulkes, Ph.D.
Ketterlng Laboratory
Department of Environmental Health
University of Cincinnati
Cincinnati, Ohio
(EPA Contract #68-03-3234,
Eastern Research Group)
Nancy H. Ch1u, Ph.D.
James 0. Murphy, Ph.D.
Edward V. Ohanlan, Ph.D.
Office of Science and Technology
U.S. Environmental Protection Agency
Julio A. Salinas, Ph.D.
1372 High Street
Hestwood, MA
(EPA Contract #68-03-3234.
Eastern Research Group)
Document Preparation
Offl?i"cin?lSKtl Servkes Staffl £nv1r°>ental Criteria and Assessment
1v
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TABLE OF CONTENTS
Page
I. SUMMARY 1-1
II. PHYSICAL AND CHEMICAL II-l
STRUCTURE AND IDENTIFICATION II-l
PHYSICAL AND CHEMICAL PROPERTIES II-l
ENVIRONMENTAL FATE IN AQUATIC MEDIA II-5
SUMMARY II-8
III. TOXICOKINETICS III-l
ABSORPTION III-l
DISTRIBUTION Ill-4
METABOLISM 111-10
EXCRETION . ! III-17
SUMMARY . . 111-19
IV. HUMAN EXPOSURE IV-1
V. HEALTH EFFECTS IN ANIMALS V-l
GENERAL TOXICITY ' V-l
Acute Exposure V-2
Subchronlc Exposure V-15
Chronic Exposure .- V-24
TARGET ORGAN TOXICITY :. V-26
Central Nervous System V-26
Heart «V-28
Thyroid V-28
OTHER EFFECTS V-28
Cardnogenldty V-28
Mutagenlclty ; ...,.-......'... V-29
Teratogen1c1ty and Other Reproductive Effects . . . V-30
SUMMARY ' V-35
VI. HEALTH EFFECTS IN HUMANS VI-1
ACUTE EXPOSURE VI-1
Oral VI-1
Inhalation VI-4
Dermal VI-7
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TABLE OF CONTENTS (cont.
. Page
SUBCHRQNIC ANC CHRONIC EXPOSURE. . . VI-7
Oral VI-7
Inhalation VI-8
Occupational Exposure VI-9
EpIdemlologU Studies VI-10
HIGH RISK SUBPOPULATIONS VI-13
SUMMARY VI-13
VII. MECHANISMS OF TOXICITY VII-1
ACUTE VII-1
CHRONIC VII-2
SYNERGISM VII-4
ANTAGONISM VII-4
SUMMARY VI1-6
VIII. QUANTIFICATION OF TOXICOLOGIC EFFECTS VIII-1
INTRODUCTION VIII-1
NONCARCINOGENIC EFFECTS VIII-6
Short-Term Exposure VIII-7
Long-Term Exposure VIII-14
QUANTIFICATION OF NONCARCINOGENIC EFFECTS VIII-16
Derivation of 1-Day HA VIII-16
Derivation of 10-Day HA VIII-17
Derivation of Longer-Term HA VIII-18
Assessment of Lifetime Exposure and Derivation
of a DWEL VIII-18
CARCINOGENIC EFFECTS VIII-20
. QUANTIFICATION OF CARCINOGENIC EFFECTS VIII-20
EXISTING GUIDELINES, RECOMMENDATIONS AND STANDARDS . . . VIII-21
SPECIAL GROUPS AT RISK VIII-22
SUMMARY VIII-23
IX. REFERENCES. . .- IX-1
v1
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LIST OF TABLES
No. Title . Page
II-l Structure and Identification Symbols of
Selected Cyanides . . II-2
II-2 Physical and Chemical Properties of the Selected Cyanides . II-3
III-l Mean Levels and Ranges of Cyanide Ion Concentration In
Human Organs 1n Cases of Fatal Poisoning JII-6
III-2 Cyanide Levels 1n Human Tissues and Fluids After Fatal
Cyanide Poisoning III-7
III-3 Cyanide Concentrations In Various Organs of Rats Treated
with NaCN Orally (A) or HCN by Inhalation (B) HI-8
III-4 Comparison of Cyanide Concentrations In Tissues
from Rabbits Killed by HCN with Concentrations In
Tissues from Rabbits Killed with KCN. . . | III-ll
III-5 Rhodanese Activity In Tissues of the Dog, Rhesus
Monkey, Rabbit and Rat (mg CN" converted to CNS/g
111-13
V-1
V-2
V-3
V-4
;
V-5
V-6
VI-1
VI-2
VI-3
VIII-1
VIII-2
Single-Dose LDso Values for Cyanides. .
Acute Toxlclty of Cyanides In Laboratory Animals
Sensitivity of Various Species to Inhalation
Exposures of HCN
Effects of Subchronlc Exposure of Laboratory Animals.
to Cyanide
Effects of Chronic Exposure of Laboratory Animals to
Cyanide
Fetotoxlc and Teratogenlc Effects of NaCN In Hamsters ...
Fatal Oral Doses of Cyanide Compounds
Reported (Estimated) Human Responses to Various
Concentrations of HCN Vapors '
Summary of Ep1dem1olog1c Studies of Cyanide Exposure. . . .
Acute LDso Values for Cyanides.
Summary of Quantification of Toxlcologlc Effects
V-4*
V-7
V-16
V-1 7
V-25
V-31
VI-2
VI-5
vi-n
VIII-8
VIII-24
vll
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CNS
CuCN
DUEL
EEC
EKG
GI
HA
HCN
l.p.
1.ro.
KCN
LOAEL
MF
NaCN
NOAEL
RfO
s.c.
TSH
UF
UV
LIST OF ABBREVIATIONS
Central Nervous System
Copper cyanide
Drinking water equivalent level
Electroencephalogram
Electrocardiogram
Gastrointestinal
Health Advisory
Hydrogen cyanide (hydrocyanic add)
Intraperltoneal
Intramuscular
Potassium cyanide
Dose lethal to SOX of receplents
Concentration lethal to 50% of receplents
Lowest-observed-adverse-effect level
Modifying Factor
Sodium cyanide
No-observed-adverse-effect level
Reference Dose
Subcutaneous
Thyroid stimulating hormone
Uncertainty Factor
Ultraviolet
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I. SUMMARY
Cyanides are a group of organic and Inorganic .compounds that contain the
cyano (CN) radical. Free cyanide 1s defined as the sum of cyanide present
as HCN and cyanide 1on as CN~. In water, hydrogen cyanide and the
alkali-metal cyanides are very soluble and dissociate Into their respective
anlons and cations 1n water and, except for HCN, are only slightly soluble
In organic solvents. The alkaline earth metal cyanides, 1n general, are not
very soluble 1n water. HCN Is volatile, and In aqueous solution Is a very
weak add. At pH below 8, most of HCN 1n an aqueous media Is present 1n the
nondlssoclated form. As the pH Increases, HCN will dissociate Into CN".
CN~ 1n water may form simple or complex cyanides depending on whether
there 1s an excess of cyanide or metal present In the aqueous media. The
metal cyanides can be oxidized to Isocyanate and ultimately to CO- and
' -*
N. 1n the presence of strong oxidizing agents.
The fate of cyanides In the aquatic media may vary widely. Hydrogen
cyanide and the most common alkali-metal cyanides may be lost from aquatic
media primarily through the volatilization process. Some of these cyanides
may also be lost through m1crob1al degradation 1n aquatic media and sorptlon
to partlculate matters In water. However, both these processes are less
significant than volatilization.
The sparingly soluble metal cyanides, such as CuCN 1n addle waters
(pH <7) may form some HCN that may subsequently volatilize from water. But
the predominant fate of these compounds Is sedimentation and mlcroblal
degradation.
02670 1-1 01/24/92
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The fate of water soluble complex metal cyanides, such as ferrocyanlde
and ferrlcyanldes, with respect to blodegradatlon 1s not known with cer-
tainty. In the absence of destabilizing factors In water (high temperature,
sunlight, extreme pH conditions), these complexes are expected to have long
lifetimes and can be transported In the aquatic media.
The simple metal cyanides and HCN do not bloaccumulate In aquatic organ-
Isms. The water soluble complex metal cyanides may bloaccumulate to some
extent 1n aquatic organisms although the bloaccumulatlon factors for such
compounds are not known.
Cyanide Is readily absorbed from the lungs, the GI tract and the skin.
Inhalation exposure to HCN provides the most rapid route of entry, resulting
In the most rapid onset of toxic effects. Cyanide enters erythrocytes and
1s found In the blood at low levels In normal humans. Transplacental
transfer can also occur. Cyanide 1s detoxified by an Intramltochondrlal
enzyme, rhodanese, which catalyzes the transfer of sulfur from a donor to
cyanide to form the less toxic thlocyanate. Thlocyanate 1s excreted 1n the
urine. Rhodanese Is widely distributed throughout the body; the highest
levels are found In the liver. Minor detoxification pathways Include
spontaneous reaction with cystlne to form 2-1mino-4-th1azol1d1ne-carboxyl1c
acid, and the reaction with hydroxycobalamlri (vitamin BI?) to form
cyanocobalamln. Both products are excreted In urine. The major route of
cyanide elimination 1s via thlocyanate 1n the urine, although some cyanide
can enter 1-carbon-compound metabolic pathways and be eliminated as C0_ 1n
expired air. A small amount of unchanged HCN Is eliminated 1n expired air.
02670 1-2 01/24/92
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Signs of acute poisoning by cyanide Include Tapld breathing, gasping,
tremors, convulsions and death. The severity and rapidity of onset of
effects depend on route, dose, duration of exposure and compound adminis-
tered. Inhalation exposure results 1n the most rapid absorption and appear-
" " *
ance of toxic signs. Oral exposure to cyanide salts results In slower GI
absorption, passage to the liver and faster detoxification. The acute oral
(gavage) LD5Q for cyanide Is 4 rag CN"/kg bw In rats and 3.4 mg CN"/kg
In mice. The IC5Q for Inhaled HCN by mice Is 1J8A mg/m*. Species differ
with respect to sensitivity with the dog being the most sensitive. Cyanide
1s less toxic when administered subchronlcally,and chronically In the diet.
t
Subchronlc and chronic subcutaneous administration of cyanide to rats
results In hlstopathologlc damage to the brain and spinal cord. Subchronlc
oral exposure to cyanide 1n capsules has resulted ,1n hlstopathologlc lesions
1n the CNS of dogs. The results of chronic oral administration reveal no"
evidence of cardnogenlclty. Negative results for KCN 1n the reverse
mutation assay were obtained 1n five strains of Salmonella typhlmuMum with
or without metabolic activation. A marginally positive response was found
for HCN gas 1n strain TA100 of S. typhlmurlum. Cyanide was negative 1n a
modified rec assay 1n Bacillus subtllls. Severe teratogenlc effects were
observed following the administration of high doses 'of NaCN by subcu-
taneously Implanted osmotic mini pumps 1n hamsters.
*
Ingestlon of cyanide by humans at doses of 0.5-3.5 mg/kg bw was found to
'f
be fatal following acute axposure. Death, which 1s preceded by
hyperventllatlon, vomiting, unconsciousness, convulsions, rapid heart rate,
gasping and vascular collapse, occurs within 20 minutes of Ingestlon. A
no-effect level for Ingestlon by humans Is 0.06 mg CN"/kg bw. The
02670 1-3 05/20/91
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estimated l-m1nute LC5Q for Inhalation of HCN by humans Is 3763 mg/m3.
Inhalation of -2000 mg/m3 result In dyspnea, followed by rapid breathing,
then apnea, gasping and death within minutes. Many people are unable to
smell cyanide, which has the odor of bitter almond, due to a sex-linked
recessive gene. Sublethal concentrations produce dizziness, headache,
confusion, nausea and numbness! Chronic oral exposure to HCN, KCN or NaCN
1n humans has not been described. Ingestlon of cyanogenlc plants, In
combination with dietary deficiencies In protein, vitamin B._ and
rlboflavln, may result In neuropathies. Ingestlon of cyanogenlc chemicals
combined with Iodine deficiency may be associated with the etiology of
goiter and cretinism. Other disorders associated with defective cyanide
metabolism Include tobacco amblyopla, retrobulbar neuritis and Leber's
hereditary optic atrophy. Smoking during pregnancy may result In birth of
low-weight Infants. This may be partly due to the cyanide content of
tobacco smoke. Case studies and epidemlologic studies of workers
occupatlonally exposed to cyanide describe effects such as headache,
dizziness, nausea and thyroid enlargement.
Cyanide exerts Its toxic effects by reacting with ferric Iron (Fe }
1n cytochrome oxldase, the enzyme that catalyzes the terminal step In the
electron transport chain, thereby preventing utilization of oxygen by cells.
The CNS and the heart are particularly sensitive to this hlstotoxic hypoxla.
If the exposure to cyanide Is high enough, the detoxification mechanism via
rhodanese may be overloaded and toxic signs occur. Chronic or repeated
exposure to high doses may result In repeated hypoxlc Insult to the CNS and
degenerative changes In the CNS of rats and dogs.
02670 1-4 05/20/91
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Synerg1st1c effects may occur 1f cyanide exposure Is accompanied by
exposure to other Inhibitors of cytochrome oxldase, such as azlde and
sulflde. Treatments for cyanide poisoning are based on the generation or
administration of compounds that can compete with cytochrome oxldase for
cyanide. Sodium nitrite can generate methemoglobln that binds cyanide. Any
compound that can act as a sulfur donor for ;rhodanese, such as sodium
thlosulfate, can be an effective antidote. Cobalt-containing compounds can
compete with cytochrome oxldase for cyanide and are also effective antidotes.
The. available data are Insufficient to develop a 1-day, 10-day or
longer-term HAs for cyanide. It 1s recommended that the DWEL of .0.7 mg/i
be adopted for the adult longer-term HA and the adjusted DHEL of 0.2 mg/i,
be adopted for the child 1-day, 10-day and longer-term HAs. The available
human and animal cancer studies are Inadequate to determine the carcinogenic
potential of cyanide and hence cyanide 1s accorded a Group D weight of-
evidence according to EPA's cancer risk assessment procedures. *
02670 1-5 05/20/91
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II. PHYSICAL AND CHEMICAL PROPERTIES
Structure and Identification ;
Cyanides are a group of organic and Inorganic compounds that contain the
cyano (CN) radical. Free cyanide Is defined as the sum of cyanide present
as HCN and as CN". A large number of Inorganic cyanides are used Indus-
trially, both as simple salts or as complex cyanides. The usefulness of
cyanides stems from the tendency of these compounds to form strong complexes
with most metals. Organic cyanides known as nHrlles can dissociate to
yield CN~ or HCN. Compounds such as acrylonltrlle and adlponltrlle are
the main cyanides produced In the United States (Towlll et al.. 1978). In
this section, only a few widely used Industrial Inorganic cyanides will be
discussed. The structure, molecular formula, molecular weight, Chemical
Abstract Services (CAS) Registry number, and Registry of Toxic Effects of
Chemical Substances (RTECS) number of selected cyanides are given In
Table II-l.
Physical and Chemical Properties
Physical and chemical properties {Heast, 1980;, Towlll et al., 1978) of
selected cyanides are given In Table II-2.
Hydrogen cyanide Is a colorless, flammable liquid or gas that 1s
misdble with ethanol and water but Is only slightly soluble In ether
(Towlll et al., 1978). Liquid HCN Is unstable and can .polymerize violently
1n the absence of stabilizers. In aqueous solutions, UV light may Induce
polymerization of HCN. Among the many polymerized products of HCN are the
trlmer, tetramer and other high molecular weight polymers (Cotton and
Wilkinson, 1980).
02680
II-l
10/06/87
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TABLE II-1
Structure and Identification Symbols of Selected Cyanides*
Compound
Hydrogen cyanide;
hydrocyanic add;
prusslc add; forrno
nltrlle
Sodium cyanide
Potassium cyanide
Copper (1) cyanide;
cuprlcln; cuprous
cyanide
Potassium ferrlcyanlde;
Tripotasslum hexa-
cyanoferrate
Molecular
Formula
HCN
NaCN
KCN
CuCN
K3Fe(CN)6
Molecular
Weight
27.03
49.01
65.12
89.56
326.27
CAS No.
74-90-8
143-33-9
151-50-8
544-92-3
13746-66-2
RTECS
No.
MW6825000
VZ7525000
TS8750000
-GL71 50000
U8225000
'Source: NIOSH, 1981
02660
II-2
10/06/87
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In aqueous solution, HCN Is a very weak acid having a pK (dlssoda-
el
tlon constant) value of 9.21 at 25flC (Cotton and Wilkinson, 1980). The
relationship of pH to percent undlssoclated HCN In aqueous solutions at 25"C
Is shown below (Callahan et al., 1979):
pH % undlssoclated HCN
<7
e
9
10
>99
93.3
58
13
Therefore, at pH below 8, most of HCN In aqueous media Is present In the
undlssoclated' form.
Simple cyanides are represented by the formula A(CN) , where A Is an
alkali (sodium, potassium) or a metal. The alkali-metal cyanides, NaCN and
KCN, are less soluble In ethanol and methanol than In water (Weast, 1980).
Since these compounds are 1on1c, their solubility In less polar and nonpolar
organic solvents may be even lower than In alcohols. Both NaCN and KCN are
strongly hydrolyzed In aqueous media, producing basic solutions. In the
presence of strong mineral acids, the salts will liberate HCN from aqueous
solutions (TowHl et al., 1978).
Many simple metal cyanides (CaCn, AgCN) are sparingly soluble or almost
Insoluble. Copper (I) cyanide has a solubility product of only 3.2xlO"20
In aqueous solution at ambient temperature (NIOSH, 1976); H Is soluble 1n
HC1 and also In KCN and NH4OH, with the formation of complexes (Cotton and
Wilkinson. 1980). In acidic solution, CuCN will form HCN, which may be
released from the aqueous phase. At a pH of 3, 78X of the cyanide may be
02680
II-4
01/24/92
-------
removed from a 52 ppm CuCN solution 1n 30 minutes by the application of
vacuum (Watson, 1973). . ,
sHmple metal cyanides can form a variety of highly soluble, complex
metal cyanides 1n the presence of alkali cyanides: A H(CN) . In" this
y *
formula, A represents the alkali, M the heavy metal (ferrous and ferric
Iron, cadmium, copper, nickel, silver, zinc, or others). Initial
dissociation of each of these soluble, alkali-metallic, complex cyanides
yields an anlon that 1s the radical MICN)'. This may dissociate
further, depending on several factors, with the liberation of CN and
consequent formation of HCN. The degree of dissociation of the various
metallocyanlde complexes at equilibrium, which may not be attained for a
long time. Increases with decreased concentration and decreased pH, and Is
i*
Inversely related to their highly variable stability. The zinc- and
'**
*
cadmium-cyanide complexes are dissociated almost totally 1n very dilute
solutions; thus these complexes can result In acute toxlclty to fish at
.ordinary pH. In equally dilute solutions there Is much less dissociation
for the nickel-cyanide complexes and more stable cyanide complexes formed
with copper and silver. Acute toxldty (to fish) of dilute solutions
containing copper- or silver -cyanide complex anlons can be mainly due to the
toxlclt'y of the complex Ions, and not HCN. The Iron-cyanide complex Ions
are very stable.
Potassium ferrlcyanlde Is less soluble In ethanol than In water (Towlll
et al.,- 1978). The aqueous solution Is unstable and decomposes slowly on
standing. This compound normally does not produce HCN or cyanide ions 1n
water, but may produce HCN when exposed to sunlight or UV radiation (Towlll
et al.. 1978).
02680 ' II-5 > 01/24/9?
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The metal cyanides can be oxidized to Isocyanate and ultimately to CO-
and N? 1n the presence of strong oxidizing agents such as Cl, gas, 0.
i 23
gas, catalytic 02 and peroxides. In fact, such processes, 1n addition to
electrolytic decomposition, Ionizing radiation, heat, activated carbon
adsorption. Ion floatation and .liquid-liquid extraction are suitable for the
treatment of cyanide wastes (Watson, 1973).
Environmental Fate In Aquatic Media
The three likely chemical processes that may cause loss of simple cyan-
Ides In aquatic media are oxidation, hydrolysis and photolysis. Cyanides
are known to be oxidized to Isocyanates by strong oxidizing agents. The
Isocyanates may then hydrolyze to amlne and C0? (Towlll et al., 1978).
Whether such oxidation and subsequent hydrolysis of Isocyanates will signif-
icantly occur In natural waters known to contain peroxy radicals has not yet
been determined.
The hydrolysis of alkali-metal cyanides proceeds rapidly 1n aquatic
media, with production of HCN and alkali-metal hydroxides. The HCN produced
may undergo further hydrolysis according to the following reaction (Callahan
et al.. 1979):
HEM -p^HE"- ^ >H,CO-I»^_ >MH + HC(
The reaction rate for the alkaline and acidic hydrolysis of HCN at the
normal pH region (6-9) encountered In natural aquatic media Is too slow
{Callahan et al., 1979) to be significant 1n determining the fate of
cyanides In aquatic media.
02680 H-6 01/24/92
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The photolysis of HCN and cyanide Ions In aqueous solution was studied
by Frank and Bard (1977). These compounds were found to be very resistant
to photolysis with available sunlight. However, in the presence of T102
powder, more than 99X of the 26 mg CN~/l of solution was oxidized In 2
days with sunlight Irradiation (Frank and Bard, 1977}, presumably through a
heterogeneous photocatalytlc oxidation process. However, such photocata-
lytlc oxidation may not be very significant 1n natural aquatic systems
because of significant light reduction at Increasingly greater depths below
the surface.
The photodecompos!tlon of aqueous ferrocyanlde and ferrlcyanlde solution
In sunlight, with the resultant production of HCN, has been observed
(Callahan et al.,- 1979). A 5-hour sunlight exposure of 100 mg/i potassium
ferrocyanlde produced cyanide Ions at a concentration of 6 mg/i {Callahan
et al., 1979). While H Is known that such compounds will photolytlcall.y
produce HCN In sunlight, the Importance of this .photodecomposltlon process
1n determining the fate of ferrocyanlde and ferrlcyanlde In aquatic" media
cannot be determined unless the rate constants for these processes are known.
Several Investigators have demonstrated that cyanides In aquatic media
can be blodegraded at low concentrations by both single and mixed micro-
organisms (Callahan et .al., 1979). Both aerobic and anaerobic mlcroblal
degradation of cyanide during sewage treatment plant operations have also
been demonstrated (Callahan et al., 1979). It Is evident from the'litera-
ture that cyanides at low concentrations can be blodegraded 1n 'natural
surface waters. However, additional data are needed to assess the relative
Importance of this process In determining the fate of aquatic cyanides: -.The
02680 H-7 01/24/92'
-------
studies -by Raef et al. (T977a,b) Indicate that volatilization of HCN from
aquatic media may be a far more significant process for cyanides than
blodegradatlon.
The two physical processes that contribute to the loss of cyanides from
aquatic media are volatilization and sorptlon. In most natural waters,
cyanides will be present both as CN~ and HCN. As has been shown 1n the
Physical and Chemical Properties Section, the percent of HCN 1n aqueous
solution Increases with decreasing pH of the solution.
Since the pH of most natural waters ranges between 6 and 9, a large
percent of dissociated cyanide anlon will be present In the form of HCN.
Hydrogen cyanide being extremely volatile, the undlssodated HCN 1s likely
to volatilize from aquatic media. It has been shown that the half-life of
HCN evaporation from solutions at concentrations of 25-200 vg/i ranges
from 22-110 hours In the laboratory. When the experiments were performed
outdoors at moderate wind-speed, the rate of HCN loss Increased by a factor
of 2-2.5 {Callahan et al.. 1979).
Hydrogen cyanide and alkali-metal cyanides are not likely to be strongly
sorbed onto sediments because of high water solubilities. It was shown by
Raef et al. (1977b), In an aerobic mlcroblal blodegradatlon study of 3
cyanide, that the biological sol Ids removed very Utt'le cyanide from solu-
tion through adsorption. From this result and the results of adsorption
studies of other Investigators (Callahan et al., 1979), It appears that
sorptlon may not be an Important reaction of water soluble cyanides in
aquatic media.
02680
II-8
01/24/92
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There are no data available to Indicate bloconcentratlon of cyanide 1n
aquatic organisms. Using the equation of Ve.Uh-et al. {1979} for the
bloconcentratlon factor (BCF) of a chemical In whole fish (log BCF = 0.76
log K ) and the value of K given 1n Table II-2, BCF values of 1.9 and
0.27 can be calculated for HCN and NaCN, respectively. According to U.S.
EPA {I960}, cyanides are not bloaccumulated In aquatic organisms, and the
concentration of cyanides In tissues Is considered the same as the concen-
tration of cyanide In the surrounding media. However, there Is some
evidence of bloaccumulatlon of metal cyanide complexes In fish, although the
actual bloaccumulatlon factors are not known. It Is difficult to assess the
environmental significance of bloaccumulatlon of cyanide complexes since
they are far less toxic than soluble HCN, NaCN and KCN.
Summary .«*
Hydrogen cyanide and the alkali-metal cyanides are very soluble In water^
and except for HCN are not very soluble In organic solvents. The alkaline-*
earth metal cyanides, In general, are not very soluble In water. Hydrogen
cyanide Is highly volatile, and In aqueous solution 1s a very weak acid.
The alkali-metal salts of .cyanides are easily hydrolyzed In an aqueous
solution. The metal cyanides can be oxidized to Isocyanate and ultimately
to CO- and N- In the presence of strong oxidizing agents. Some of the
complex metal cyanides, such as the ferrocyanldes and ferrlcyanldes,
liberate HCN when the solutions are exposed to sunlight."
The fate of cyanides 1n aquatic media may vary widely. Hydrogen cyanide
and the most common alkali-metal cyanides may be lost from aquatic media
primarily through volatilization. Some of these cyanides may also be lost
02680
II-9
01/24/92
-------
through .,.»,.,
-------
III. TOXICOKINETICS
Absorption
The cyanides are rapidly absorbed by animals and humans, whether expo-
sure occurs by Inhalation of HCN gas, by Ingestlon of the cyanide salts KCN
or NaCN, or by dermal exposure to HCN gas or to aqueous solutions of KCN,
KCN and NaCN.
Gettler and Balne (1938) reported some early Observations of quantHa-
i
tWe absorption data In dogs and humans. Three dogs received single gavage
doses of KCN equivalent to 1.57. 4.42 and 8.40 mg HCN/kg bw corresponding to
amounts of 20, 50 and 100 mg HCN, respectively. The dogs died within 155,
21 and 8 minutes, respectively, after dosing. At necropsy, the amount of
HCN remaining 1n the GI tract was measured. The difference between the
amount administered and the amount remaining 1n trie GI tract was considered
' .&
to represent the amount absorbed. According to this definition, the
low-dose dog absorbed 14.4 mg of the administered 20 mg or 1.13 mg/kg bw
(72%). The dog that received 50 mg HCN absorbed 12 mg or 1.06 mg/kg bw
F
(24%). The dog that received 100 mg HCN absorbed 16.6 mg or 1.39 mg/kg bw
(16.6%). In 3 cases of fatal human poisoning, Gettler and Balne (1938)
estimated the total absorbed dose of cyanide as 228.1 (15.7X), 101.0 (18.7%)
and 59.9 (19.5%) mg HCN. The actual time of death for these cases was
unknown. In a fourth case 1n which the time of death occurred 3 hours after
t
the Ingestlon of 29.8 mg HCN, the amount of HCN absorbed was estimated to be
24.4 mg {81.9X). :
Llebowltz and Schwartz (1948) reported a case of attempted suicide In
which an 80 kg man had Ingested an estimated 3-5 g (37.5-62.5 mg/kg bw) KCN
and recovered. He vomited 0.5 hour following Ingestlon, and gastric lavage
02690 III-l 04/13/88
-------
was performed Immediately on admission to a hospital. Two hours after
Ingestlon the concentration of HCN In blood was 200 mg/i, giving an
estimated total of 1200 mg HCN 1n blood (assuming a volume of 6 I of
blood) and 2400 mg HCN In the whole body. These HCN concentrations
correspond to 192 mg CN~/l blood, and an estimated total of 1152 mg
CN~ In blood and 2304 mg CN~ In the whole body.
Absorption of HCN across the 61 mucosa proceeds rapidly because 1t Is a
weak acid with a pK of 9.2. The acidic environment In the stomach favors
a
the nonlonlzed form of HCN and, hence, facilitates the absorption. The
physiologic pH of body tissues also favors the undlssoclated species (U.S.
EPA, 1980; Callahan et a!., 1979).
Quantitative data on absorption of HCN by Inhalation In dogs was
reported by Gettler and Balne (1938). The HCN gas was generated Into an
Inhalation apparatus from a tube containing a solution of hydrocyanic add.
Exhaled cyanide was bubbled through a solution of sodium hydroxide. The
amount of absorbed HCN was estimated by subtracting the amount of cyanide
remaining In the apparatus from the Initial amount 1n the tube. Although
the original amount of HCN In the tube was not reported, one dog was calcu-
lated to have absorbed 16.0 mg [1.55 mg/kg bw) and the -other dog 10.1 mg
(1.11 mg/kg bw). These doses were fatal to the dogs In 15 and 10 minutes,
respectively.
Absorption of low levels of cyanide by humans following Inhalation can
be Inferred from data on blood levels of thlocyanate In cigarette smokers
compared with nonsmokers (Wilson and Matthews, 1966). Although plasma
levels of cyanide did not differ significantly between the two groups.
02690
II1-2
05/20/91
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smokers had significantly (p<0.001) higher levels of thlocyanate, presumably
formed from metabolism of Inhaled cyanide 1n cigarette smoke, than did non-
smokers.
The air concentrations of HCN resulting 1n certain blood levels 1n
humans were tabulated by Knowles and Bain (1968). At >300 ppm {330
mg/ms), blood levels reached >10 mg/i. Concentrations of >200 ppm (220
mg/m3), >110 ppm (111 mg/m3) and >50 ppm (55 mg/m3} 1n air resulted In
blood levels of 8-10, 3-8 and 2-4 mg/i, respectively. It was emphasized
that wide variations exist, and the values were presented as examples.
Humans retained -60% of HCN 1n the lungs, following the Inhalation of HCN
(0.0005-0.02 mg/i). through normal breathing by mouth (Landahl and
Herrmann, 1950).
t
t<
Cyanides can also be absorbed by the dermal route. Walton and Wither-
v<
spoon (1926) held a test tube of 1-Inch diameter containing liquid HCN
against the shaved bellies of guinea pigs and observed signs of toxldty.
Dogs that were exposed to HCN gas In a chamber that allowed their heads to
be excluded from exposure also developed toxic signs.
Drinker (1932) reported that three men working In an atmosphere of 2%
(v/v) (20,000 ppm or 22,000 mg/m3) HCN gas for 8-10 minutes developed
symptoms of dizziness, weakness and throbbing pulse, despite the fact that
they were wearing gas masks. Potter (1950) described a case of an HCN
process worker who entered the chamber wearing a gas mask and protective
clothing: While attempting to take a sample of hydrocyanic add, he removed
one glove, and some of the acid ran over his hand. WHhln 5 minutes, he
became dizzy, had difficulty breathing and became unconscious.
02690
III-3
02/04/85
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Hydrogen cyanide, either liquid or gas, Is more readily absorbed
dermally than are the cyanide salts (Wolfsle and Shaffer, 1959}, although
cases of toxIcUy 1n humans have resulted from dermal exposure to solutions
of KCN {NIOSH, 1976). Since HCN can be generated from solutions of KCN and
NaCN, some absorption may be attributed to Inhalation exposure {see
Chapter II).
Distribution
Once cyanide 1s absorbed It Is rapidly distributed by the blood through-
out the body. H1th1n the blood, a greater concentration of cyanide was
found in erythrocytes than 1n plasma when HCN was administered (McMillan and
Svoboda, 1982); however, this was not the case when KCN was administered
(Farooqul and Ahmed, 1982). Farooqul and Ahmed (1982) studied the Incorpo-
ration of radioactivity 1n the erythrocytes of rats treated orally with
K14CN (5 mg/kg). Levels of radioactivity declined rapidly from whole
blood and plasma with a small Increase 1n erythrocytes over 24 hours.
Following hemolysls, the majority of the radioactivity (94.32*) 1n the
erythrocytes was found 1n the hemolysate rather than the membranes. The
heme fraction contained 10% of the radioactivity while 14-25X and 5-1054 were
found In the globtn and cell membrane, respectively. Since cyanide reacts
readily .with Iron In the ferric state (Fe*++) (Hartung, 1982; NIOSH,
1976), the accumulation of cyanide within erythrocytes Is mainly due to the
binding of the cyanide 1on to Fe 1n met hemoglobin to form the nontoxlc
complex cyanomethemoglobln (Chen and Rose, 1952).
Feldsteln and Klendshoj (1954) reported blood levels of cyanide 1n
normal humans that ranged from 0-0.107 ng/mi with an average of 0.048'
02690 I!M. 03/26/85
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Tissue levels of cyanide 1n humans fatally poisoned with cyanide have
been obtained at autopsy (Ansell and Lewis, 1970; Gettler and Balne, 1938;
Flnck, 1969). In examining the data, two Issues should be noted. First,
when the concentration found equals zero, a loss of HCN from the sample must
be suspected. This could occur by volatilization between the time of death
and the time of assay, or by metabolism of CN~ to SCN~ (which was not
assayed). Secondly, the time between exposure and death depends on the dose
of cyanide, which In these cases was unknown. If death occurred very
rapidly, H 1s possible that the tissue distribution of cyanide was not
complete and, therefore, tissue levels of cyanide could be Irrelevant.
Ansell and Lewis (1970) tabulated the mean levels of cyanide found \n
postmortem samples of tissues (Table III-l). The highest concentrations of
cyanide were found 1n the spleen and blood. Gettler and Balne (1938),
however, found high cyanide levels 1n brains and livers of three humans who
"S
had Ingested fatal doses of cyanide. The Importance of analyzing many
tissues to determine the route of exposure was emphasized by Flnck (1969).'
Table III-2 presents the distribution of cyanide In tissues of three fatally
poisoned humans. For case one, no lung tissue had been submitted to the
toxlcologlst for analysis. Based on low levels of cyanide 1n the gastric
contents, cyanide Inhalation may be suspected. Cases two and three,
however, demonstrated high levels In stomach contents following Ingestlon.
The differences In cyanide distribution following-the oral and Inhala-
tion exposures 1n rats were examined by Yamamoto et al. (1982). Rats were
treated by gavage with NaCN to give a dose of 7 and 21 mg CN'/kg bw.
Another group of rats Inhaled HCN at concentrations that averaged 356 and
1180 ppm (392 and 1298 mg/m3, respectively). The results are presented In
Table III-3. Since little difference 1n distribution was observed with
02690
III-5
04/13/88
-------
TABLE III-l
Mean Levels and Ranges of Cyanide Ion Concentration 1n
Human Organs In Cases of Fatal Po1son1nga«b
Tissue
Blood
Brain
Liver
Kidney
Spleen
Stomach Contents
Urine
No. of Cases
with Quantitative
Levels Available
58
34
48
34
22
49
17
Mean
(nig X)
2.39
1.20
1.62
0.51
3.77
160.0
0.08
Range
(mg X)
0-5.3
0-19.9
0-25.0
0-2.8
0-37.5
0.2-2800
0-0.96
aSource: Adapted from Ansel 1 and Lewis, 1970
&Note: for variable routes of exposure
02690
III-6
02/04/85
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TABLE III:2
Cyanide Levels in Human Tissues and Fluids
After Fatal Cyanide Poisoning*
Cyanide Content {mq/100 q or mq/100 mi)
Samp 1 e
Gastric contents
Lung
Blood
Liver
Kidney
Muscle
Brain
Urine
Fat
Case Ib1
0.03
NA.
0.50
0.03
0.11
NA
0.07
0.20
NA
Case 2^
15
0.90
0.75
0.40
0.35
0.30
0.25
0.20
0,20
Case 3C
20
0.70
0.80
0.50
0.40
NA
0.06
NA
NA
aSource: Adapted from Flnck, 1969
bDeath from Inhalation of cyanide gas
C0eath from Ingestlon of cyanide salt
NA = Not analyzed
02690
III-7
08/07/84
-------
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02690
I1I-8
08/30/88
-------
respect to dose or concentrations, the authors, combined the data. Although
these combined data are provided In Table 111-3, one must examine the
appropriateness of doing so. The results of time to death Indicate that
animals receiving 21 mg/kg bw or 1298 mg/ra3 died within significantly less
time (average 3.3 and 5.4 minutes, respectively) than those receiving 7
mg/kg bw or 392 mg/m3 (average time to death 10.3 and 9.6 minutes,
respectively). This suggests that a uniform body distribution of cyanide
may not have been reached at the time of death of the animals receiving the
higher dose. . In order to compare the distributions for the two routes of
t
administration, the organ levels of cyanide were examined and expressed as
percentage of the respective blood levels. Following oral administration,
cyanide levels 1n the liver were higher than those Vn the blood, and were
dependent on. the dose Ingested. No differences were observed In the lungs.
Following Inhalation exposure, cyanide levels In both the liver and lungs
did not differ from that observed 1n the blood and were unrelated to the
concentration In the air. In the spleen, cyanide levels were higher
following oral administration than inhalation regardless of the dose or
concentration. These results suggest that body distribution of cyanide
depends primarily on the route of administration.
The pattern of distribution of cyanide may also depend on the type of
compound administered. Ballantyne et al. (1972) compared the tissue
distribution of cyanide from KCN and HCN In rabbits fallowing Intramuscular
Injection. For either case, the administered dose of cyanide was 8 mg/kg.
Levels of cyanide were measured In tissues of two groups of rabbits
(6/group) at 0.5 hours after death. In another two groups of rabbits, the
organs were perfused with saline In order to measure the actual tissue
levels without Interference from blood cyanide levels 1n the tissues. The
02690 111-9 05/20/91
-------
results are presented 1n Table III-4. The higher levels of cyanide 1n blood
and tissues following HCN rather than KCN administration were presumably due
to the more rapid absorption and distribution of HCN. High levels of
cyanide were found In perfused brain, spinal cord and liver.
Cyanide does not accumulate In blood and tissues following chronic
exposure. Howard and Hanzal (1955) treated rats with dietary concentrations
of HCN of 100 and 300 ppm (mg/kg diet) for 2 years. At the end of the
2-year period, virtually no cyanide was found 1n plasma or kidneys. Low
levels were found In erythrocytes (mean of 1.97 yg/100 ml). Increased
levels of thlocyanate, the less toxic primary metabolite of cyanide (see
Metabolism Section) were found 1n plasma (1123 jig/100 mi), erythrocytes
(246 pg/100 ml). liver (665 vg/100 g) and kidney {1188 ,,9/100 g}.
Transplacental transfer of cyanide presumably occurs. Doherty et al.
(1962) reported that administration of solutions of NaCN to pregnant
hamsters by subcutaneous Infusion using osmotic mini pumps resulted In
malformed fetuses (see TeratogenVcUy and Other Reproductive Effects Section
In Chapter V); this finding, however, does not prove occurrence of trans-
placental transfer.
Metabolism
The major metabolite of cyanide Is the less toxic Urlocyanate (U.S. EPA,
1980; Ansel! and Lewis, 1970; Williams, 1959; de Duve et al., 1955). formed
by the transfer of sulfur from a sulfur donor to the cyanide 1on by the
02690
111-10
08/30/88
-------
TABLE III-4
1
Comparison of Cyanide Concentrations 1n Tissues from Rabbits
Killed by HCN with Concentrations In Tissues from
Rabbits Killed wHh KCNa-b
Cyanide concentration
mean > standard errorc
Tissue
Skeletal muscle
Kidney
Liver
Spinal cord
Brain
Whole blood
Serum
Skeletal muscle
-Kidney
Liver
Spinal cord
Brain
Whole blood
Serum
HCN
Containing
35.0 * 5.2
74.7 * 10.3
148.7 i 32.3
48.5 * 4.9
145.3 + 37.2
685.0 * 83.0
275.0 ± 18.0
Perfused with
9.3 * 2.7
11.0 f 4.3
43.7 ± 13.5
49.8 * 14.7
289.0 * 67.7
761.0 + 129.0
261.0 * 48.0
KCN
blood
29.6 +
52.0 t
82.0 *
36.8 *
106,5 *
453,0 +
161.0 *
saline .
7.8 +
2-3 f
6.5 *
22:5 ±
98.0 +
438.0 *
134^0 i
2.4
11.0
8.0
3.5
12.4
34.0
21.0
2.4
1.1
0.8
3.8
5.0
8.0
8.0
Pd
<0.5
<0.1
<0.1
<0.1
<0.1
<0.05
<0.005
<0.7
<0,1 .
<0.025
<0.2
<0.02
<0.05
<0.05
aSource: Ballantyne et al., 1972
,
bFor both compounds the dose was equivalent to 8 mg CN'/kg bw
concentrations expressed as vg CNV100 g tissue wet weight or wg
CN/100 mi blood or serum
^Significance of difference 1n cyanide concentrations between animals
killed with HCN and those killed wUh KCN
02690
III-ll
08/30/88
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enzymatic action of rhodanese (Lang, 1933). fihodanese Is the trivial name
for thlosulfate: cyanide sulfurtransferase, EC 2.8.1.1. or 3-mercapto-
pyruvate:cyan1de sulfurtransferase EC 2.8.1.2. (Pettlgrew and Fell. 1973).
The species and tissue distribution of rhodanese were Investigated by
HlmwUh and Saunders (1948); the results are presented In Table III-5. The
activity of the enzyme was highly variable among species and tissues. In
the dog, the highest activity of rhodanese was found In the adrenal gland,
-2.5 times greater than the activity In liver. Monkeys, rabbits and rats
had highest activity 1n liver and kidney, with relatively low levels of
rhodanese In adrenals. It should be noted that the enzyme activity In the
livers of monkeys, rabbits and rats was -10-20 times higher than the
activity 1n the liver of dogs, and that total activity In the other species
was higher than that 1n dogs. Dogs are particularly sensitive to the acute
effects of cyanide {see General Toxlclty Section In Chapter V), Similar
activities of the enzyme among the species were found for brain, testes,
lungs, spleen and .muscle. The ubiquitous nature of the enzyme was
demonstrated 1n the dog for which low levels of rhodanese activity were also
measured 1n erythrocytes, anterior pituitary, thyroid, pancreas, lymph
nodes, salivary glands, optic nerve, eye, Intestine and heart.
The activities of different compounds as sulfur-donors have been
studied. Klmwlch and Saunders (1948) found that sodium thlosulfate (100%
relative activity) was the best sulfur donor when -compared with sodium
sulflde (4%), thlourea (4.5X), <*-naphthylth1ourea (4.6X), thlouracll (IX)
and cysteine (IX). No activity was measured when thlodlglycol. dlphenyl
sulflde or dlphenyldlsulflde were tested. Sorbo (1953) found that p-toluene
thlosulfonate was -4.5 times more active as a sulfur donor than thlosulfate,
while ethyl thlosulfate, ethyl xanthate, d1ethyld1th1ocarbamate and
02690
111-12
08/30/88
-------
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02690
111-13
08/30/88
-------
2
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I !
hydrosulfHe were relatively Inactive. The structural requirements,
therefore, were for a .free sulfur to be adjacent to another sulfur atom In
the molecule. Since the greatest activity of rhodanese 1s found In mito-
chondria (de Duve et al.,.1955), and rhodanese Is widely distributed among
tissues (H1mw1ch and Saunders, 1948), the rate limiting factor for cyanide
detoxification to thlocyanate 1s the Intracellular, and especially Intra- .
mHochondrlal, availability of an appropriate endogenous sulfur donor. The
nature of the endogenous sulfur donor 1s unknown {U.S. EPA, 1980). Westly
(1983) hypothesized that the sulfone carrier 1s albumin. Radlolsotope
studies have Indicated that albumin does Interact with elemental sulfur and
that this complex can react with cyanide.
Pettlgrew and Fell (1973) Investigated cyanlde-thlocyanate Interconver-
slon by administering KCN 1.p. to Wlstar rats fed either a normal diet or a
vitamin 8,2-defIdent diet. Both groups received a dally dose of 9.2;:
vmole (0.6 mg). CN~/100 g bw, 5 days/week for 3 weeks. This dose ap-
proximates, the minimum dose that has previously been shown (Lessen, 1971}
to produce neurologic disturbances In rats. Among the vitamin 8,--defi-
cient rats, the mean whole blood CN~ concentrations rose 6-fold while the
mean plasma thlocyanate concentration rose 8-fold. Among the normally fed
rats, blood was sampled at various Intervals following the Injection. The
whole blood CN~ concentration rose quickly reaching a maximum -20 minutes
post-injection and then fell rapidly to minimal levels.- -2 hours postlnjec-
tlon. Conversely, the plasma thlocyanate levels Increased slowly, reaching
a maximum between 1 and 4 hours postlnjectlon .after which It decreased
gradually.
02690 111-15 05/20/91
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A detoxification rate of 0.076 mg/kg/m1niite was determined In guinea
pigs during continuous Intravenous Infusion of cyanide (Lendle, 1964). The
estimated detoxification rate In humans has been estimated as 0.017 mg/kg/
i
minute (McNamara, 1976). This estimate was based on a study In men Injected
Intravenously with HCN.
The overall rate of conversion of cyanide to thlocyahate will depend
upon the rate of conversion of thlocyanate to cyanide. The rhodanese
reaction was shown to be nonreverslble'; however, conversion of thlocyanate
to cyanide was found to be mediated by a different enzyme, thlocyanate
oxldase, which has been found In erythrocytes of humans, dogs, rabbits and
rats (Goldstein and Rleders, 1951, 1953). A minor activity of the
glutath1one-S-transferases 1n converting organic thtocyanates to cyanide was
reported by Hablg etal. (1975).
The overall rate of detoxification of cyanide will also depend upon the
contribution of minor pathways. Cyanide can react spontaneously with
cystlne to yield 2-am1noth1azollne-4-carboxyllc acid, which tautomeMzes to
2-1m1no-4-th1azol1d1necarboxyl1c add (Wood and Cooley, 1956). Rats
pretreated with 38S-cyst1ne excreted 16X of a subcutaneous dose of NaCN as
35S-labe1ed 2-lm1no-4-th1azol1d1ne-carboxyl1c .acid In the urine. Thlo-
cyanate In urine accounted for BOX of the cyanide dose.
Another minor route of cyanide detoxification Is via the reaction of
cyanide with the B12 vitamin, hydroxocobalamln, to yield cyanocobalamln, a
complex .that Is an essential element, 1s nontoxlc, and Is excreted 1n urine
(Brink et al.. 1950; Boxer and Rlckards, 1951) and bile (Herbert, 1975). A
metabolic pathway Involving the oxidation of cyanide to CO- and formate
02690
111-16
05/20/91
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was studied by Boxer and Rlckards (I952b). A dog Injected with -0.1 mg
14CN~/kg, once an hour for 5 hours, excreted 0.007% of the dose as
formate and 92% as thlocyanate over 2 days. Rats similarly treated with
14CN~ (215 Wg/rat/1nject1on), excreted 1.7% of the dose 1n the expired
air. Of this amount of radioactivity, 10% was H14CN and 90% was
14CO_. Thus, carbon, derived from cyanate can enter one-carbpn-compound
metabolic pathways. The various pathways of cyanide blotransformatlon are
summarized In Figure III-l.
Excretion
By far the major route of cyanide elimination from the body Is via
urinary excretion of thlocyanate. Rats eliminated 80% of subcutaneously-
Injected cyanide as thlocyanate 1n the urine, while 16% was eliminated as.
urinary 2-1m1no-4-th1azol1d1ne-carboxyl1c acid (Wood and Cooley, 1956). A
man who had Ingested 3-5 g KCN (1.2 g HCN was estimated In blood, assuming
6 i blood, 2 hours later) eliminated a total of 237.14 mg of thlocyanate.
In 72-hour urine (LVebowltz and Schwartz, 1948). Hal1szewsk1 and Bass
(1955) found Increased levels of thlocyanate In the urine, saliva and
1
perspiration of cigarette smokers compared with nonsmokers. Okoh (1983)
reported the pattern of elimination of 14C 1n rats maintained on a diet of
KCN (-2 mg CN~/rat/day) for 6 weeks, and then Injected subcutaneously with
Na14CN. Over 57% of the administered radioactivity was excreted In the
24-hour urine compared wHh 4.9% 1n expired air and 1.7% In feces. Thlo-
cyanate accounted for 78.8% and cyanide for 1.3% of the urinary radioactiv-
ity. Of the radioactivity In expired air. 89.5% was 14C02 and 9.4% was
14CN". In a similar study, Okoh and PHt (1982) also found radioactiv-
ity excreted 1n feces following IntraperHoneal Injection of Na14CN, This
finding, along with relatively high levels of radioactivity 1n the stomach
02690 111-17 08/30/88
-------
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02690
111-18
03/26/85
-------
wall and stomach contents compared with other tissues, suggested that GI
reclrculatlon was occurring. Approximately 80% of the radioactivity In the
stomach contents was In the form of thlocyanate.
The finding of low levels of unchanged HCN In expired air of rats and
humans was reported by Boxer and Rlckards (1952a). Guinea pigs eliminated
"1-2% of Intravenously-Infused HCN as unchanged gas 1n* the expired air
(Frledberg and Schwarzkopf, 1969). Ohsy et al. (1987) found that >50% of an
admlnlsterd dose of cyanide was excreted In the urine of hens as thlocyanate
within 6 hours. Little cyanide was excreted directly and the rate of
thlocyanate excretion closely paralleled plasma thlocyanate concentrations.
As mentioned previously 1n the Metabolism Section, cyahocobalamln Is
excreted In urine (Boxer and Rlckards, 1951). Additionally, In humans, 3-8
vg of cyanocobalamln are excreted Into the GI tract, mainly In the bile.
All but 1 v9 of this excreted cyanocobalamln Is reabsorbed by the
Intrinsic factor mechanism at the level of the Heum, thus allowing
effective enterohepatlc reclrculatlon of vitamin B,- (Herbert, 1975).
Summary
Cyanides are readily absorbed from the lungs, the GI tract and skin
(U.S. EPA, 1980). Following uptake by blood, cyanide Is rapidly distributed
throughout the body. Cyanide accumulates -within erythrocytes (Farooqul and
Ahmed, 1982; McMillan and Svoboda, 1982) where It combines with Fe+** of
methemoglobln (Chen and Rose. 1952) and the heme moiety of hemoglobin
(Farooqul and Ahmed, 1982). Cyanide can be detected at low levels 1n blood
of normal humans (Feldsteln and Klendshoj, 1954). Relatively high levels of
cyanide have been found 1n spleen, brain and liver at autopsy of humans
fatally poisoned with cyanide. Distribution patterns differ with respect to
02&90 111-19 08/30/88
-------
route of exposure (Mnck, 1969; Yamamoto et al., 1982} and compound (Bal-
lantyne et al., 1972). Cyanide and thlocyanate accumulate 1n blood and
tissues following chronic exposure {Howard and Hanzal, 1955). The major
route of metabolism and detoxification of cyanide Is via rhodanese
(th1osu!fate:cyan1de sulfurtransferase), which catalyzes the transfer of
sulfur from thlosulfate to cyanide to yield thlocyanate (Lang, 1933; Sorbo,
1953). Rhodanese Is widely distributed and the activity 1s highly variable
among tissues and species; high levels are found 1n the liver and kidneys of
monkeys, rabbits and rats and In the adrenals of dogs (Hlmwlch and Saunders,
1948). The greatest activity of rhodanese 1s located In mitochondria (de
Duve et al., 1955), and the enzyme 1s specific for a sulfur donor with a
free sulfur atom adjacent to another sulfur atom In the molecule (Sorbo,
1953). The rate of detoxification In guinea pigs has been estimated at
0.076 mg/kg/mlnute (Lendle, 1964) and In humans as 0.017 nig/kg/minute
(McNamara, 1976). Minor detoxification pathways Include the spontaneous
reaction of cyanide with cystlne to form 2-1m1no-4-th1azo11d1necarboxyl1c
acid (Wood and Cooley, 1956), and the reaction of cyanide with
hydroxocobalamln (vitamin 8-12a^ to y1e^ cyanocobalamln (vitamin B,_)
'(Brink et al., 1950; Boxer and Rlckards, 1951). Both of these compounds are
excreted 1n urine. Cyanide can also be oxidized to CO. and formate (Boxer
and Rlckards, 1952b). The major route of cyanide elimination Is via urinary
excretion of thlocyanate (Wood and Cooley, 1956; Okoh, 1983). Small
percentages of radioactivity derived from Na14CN administered
IntraperHoneally to rats were excreted In expired air and feces (Okoh,
1983). The fecal, excretion, coupled with the detection of radioactivity 1n
the stomach wall and contents following 1ntraper1toneal Injection of 14CN,
suggested GI reclrculatlon (Okoh and P1tt, 1982).
02690 TIT On
111-zo . 08/30/88
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IV. HUMAN EXPOSURE
This chapter will be submitted by the Science and Technology Branch.
Criteria and Standards Division, Office of Drinking Water.
02700 IV-l 01/28/85
-------
-------
IV. HUMAN EXPOSURE
Humans may be exposed to chemicals such as cyanide from a variety of
sources, Including drinking water, food, ambient air, occupational settings
and consumer products. This analysis of human exposure to cyanide 1s lim-
ited to drinking water, food and ambient air because those media are con-
sidered to be sources common to all Individuals. Even 1n limiting the
analysis to these three sources, H must be recognized that Individual expo-
sure will vary widely based on many personal choices and on several factors
over which there 1s little control. Where one lives, works and travels,
what one eats, and physiologic characteristics related to age, sex and
health status can all profoundly affect dally exposure and Intake. Indi-
viduals living 1n the same neighborhood or even 1n the same household can
experience vastly different exposure patterns.
In the Exposure Estimation Section of this chapter, available informa-
tion 1s presented on the range .of human exposure and intake for cyanide from
drinking water, food and ambient air for the 70 kg adult male. It 1s not
possible to provide an estimate of the number of Individuals experiencing
specific combined exposures from those three sources.
Exposure Estimation
Drinking Hater. Essentially no Information ; was obtained Indicating
the occurrence of cyanide In drinking water supplies. Only one of the
Federal surveys [the 1969 Community Hater Survey (CWSS)] Included cyanide as
an analyte.
02700 IV-1 01/16/85
-------
The CWSS (McCabe et al., 1970) examined 120 surface water supplies, 613
groundwater supplies, 152 supplies with mixed water or purchased sources and
84 special systems (trailer parks, tourist and other Institutions) 1n the
United States 1n 1969. Samples were analyzed for various chemicals Includ-
ing cyanide. A total of 2595 distribution water samples were collected.
The U.S. Public Health Service mandatory drinking water limit for cyanide 1n
effect at the time of this study was 0.01 mg/i. Cyanide concentrations 1n
all samples were below this limit. The maximum cyanide concentration
reported was 0.008 mg/i.
According to U.S. EPA (1980), cyanide 1s an uncommon pollutant 1n U.S.
water supplies. Levels 1n excess of the U.S. Public Health Service man-
datory limit (McCabe et al., 1970} were not documented 1n U.S. EPA (1980).
Apparently, the general recognition of the high toxldty of cyanide has made
Its removal standard practice 1n Industry. As reported 1n U.S. EPA (1980),
accidental perturbations have resulted 1n fish kills, livestock death and
other environmental damage. Approximately 1500 drums (30 and 55 gallon}
containing cyanides disposed near Byron, IL caused significant environmental
damage and livestock death. Surface water runoff from the area was reported
to contain up to 365 mg/l of cyanide (Towlll et al., 1978).
Given the lack of Information on cyanide In public drinking water sup-
plies, human Intake of cyanide from drinking water could not be evaluated.
Diet. Although It 1s uncommon to find cyanide 1n foods In the United
States, certain nUMles naturally occur 1n plants such as soybeans, lima
beans and cassava (U.S. EPA, 1980; Honlg et al., 1963). Honlg et al. (1983)
02700 IV-2 01/16/85
-------
found levels of cyanide <0.1 mg/kg In raw soybean meal and <1.5 mg/kg ^n
soybean product samples tested under standard conditions. Honlg and
r
coworkers maintained that, according to the Food Protein Council (1978),
i
consumption of edible soy protein products 1n the United States Is >1 bil-
lion pounds annually, which 1s equivalent to <3>g of proteln/person/day.
The authors, therefore, concluded that soybean cyanide levels do not appear
to be of nutritional significance.
Although the Uma bean has been studied more than any other cyanogenetlc
plant food consumed by man (Lelner, 1966), none of these studies have
focused on cyanide levels 1n Uma beans consumed In the United States. Simi-
larly, the cassava plant 1s used to produce tapioca, a food Infrequently
eaten 1n the United States; no studies have been conducted In the United
States on cyanide levels In cassavas (Honlg et al., 1983).
*'
No data are available from the Food and Drug Administration (FDA) on the
occurrence of cyanide In foods nor Is any Information available on the dally
dietary Intake of cyanide.
A1r. No Information 1s" available on the levels of cyanide In ambient
air.
Summary
Insufficient Information was available to assess human exposure to cyan-
ide or to determine the relative source contribution to total exposure by
the three common media (drinking water, food and ambient air).
02700 IV-3 01/16/85
-------
References
Food Protein Council. 1978. Soy protein Improving our food system. Food
Protein Council, Washington, DC. {Cited 1n Honlg et al., 1983J
Honlg, D.H., M.E. Hockrldge, R.M. Gould and J.J. Rackis. 1983. Determina-
tion of cyanide 1n soybeans and soybean products. J. Agrlc. Food Chem.
31(2): 272-275.
Lelner. I.E. 1966. Cyanogenetlc glycosldes. In: Toxicants occurring
naturally In foods. Food Protection Committee, Food and Nutrition Board,
Natl. Acad. Sc1., Washington, DC. p. 58-61.
McCabe, L.J., J.M. Symons, R.D. Lee and G.G. Robeck. 1970. Survey of com-
munity water supply systems. J. Am. Water Works Assoc. 62: 670-687.
Towlll, I.E., et al. 1978. Reviews of the environmental effects of pol-
lutants: V. Cyanide. U.S. EPA. (Cited 1n U.S. EPA, 1980)
U.S. EPA. 1980. Ambient Water Quality Criteria for Cyanides. Environ-
mental Criteria and Assessment Office, Cincinnati, OH. EPA-440/5-80-037.
NTIS PB 81-117483.
02700
IV~4 01/16/85
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HEALTH EFFECTS IN ANIMALS
General Toxldty
There are numerous studies on the toxic effects>of the cyanides adminis-
tered to animals by a variety of routes. In the current discussion, studies
employing the oral route of administration are emphasized. No attempt was
made to review all the studies employing other routes of exposure; however.
several representative reports are Included for the sake of. completeness.
An Important consideration In evaluating oral toxlclty of cyanides Is
not only the total amount administered but also the rate of Us absorption.
This follows .from the fact that the liver Is the major site of cyanide
detoxification; like any other enzymatlcally catalyzed reaction this detoxi-
fication reaches a maximum rate 1n the presence of excess substrate. If
cyanide absorption proceeds too fast, the capacity of the liver to form,
f
thlocyanate upon first pass of mesenterlc blood 'through the organ may be
exceeded. In contrast, slow absorption of the same total oral load of the
poison may allow complete metabolism by the liver. For the most part,
cyanide Is readily absorbed from the GI tract, especially since at physio-
logic pH It Is present mostly In the highly diffusible nonlonlzed- form.
However, the rate of absorption may be Influenced by factors such as the
composition and volume of the Intestinal contents and. by the rate of
peristalsis. .
An additional factor, which occurs during cyanide feeding studies. Is
the likely loss of this substance by volatilization of HCN before the food
Is consumed. .Even If attempts are made to chemically determine total
cyanide loss, average concentrations of cyanide In food cannot be computed
unless It 1s known whether such loss follows zero or first-order kinetics.
02710 V-l 05/20/91
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i .
Two Important conclusions follow from these considerations: use of
feeding studies as the basis for the setting of water standards Introduces
an uncertainty In the case of cyanide, which must be accounted for.
Secondly, toxlclty of cyanide may differ greatly depending upon the route of
administration; after Inhalation the poison reaches, the liver at a rate
quite different from that following 1ngest1on. Use of data other than oral
for setting permissible drinking water standards for cyanide Introduces
additional uncertainties.
Acute Exposure. The lethal effects of cyanide exposure by any route
are well known; however, the severity of effects and the time course depend
upon the route, the dose, the duration and the compound administered. By
far. Inhalation of the HCN gas results In the most rapid absorption and,
hence, the most rapidly appearing signs of toxlclty. Gastrointestinal
absorption of the salts, NaCN and KCN, Is slower and results In passage
through the portal system Into the liver. Rhodanese, the enzyme(s)
responsible for converting the cyanide 1on Into thlocyanate, Is found 1n
tissues throughout the body, but the major site 1n most species Is the
liver. Therefore, first passage of cyanide Into the liver following GI
absorption results In a greater degree of detoxification than If cyanide 1s
absorbed from the lungs. Cyanide exerts Us toxic effect by reacting with
the ferric 1on (Fe***) In mltochondrlal cytochrome oxldase, thereby
Interfering with cellular respiration (see Chapter VII)'.'
02710
V-2
05/20/91
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Single-dose ID5Q values for cyanides are presented 1n Table V-l. For
the sake of comparison, all doses are represented as the dose of the admin-
istered compound, as well as the equivalent dose of cyanide Ion. Ballantyne
et al. {1971, 1972) demonstrated that Intramuscular administration of HCN to
rabbHs resulted 1n lower LD5Qs than did Intramuscular administration of
KCN to rabbits with the LD5Q for HCN 1n female rabbits being significantly
lower; however, when expressed as dose of cyanide Ion, the Lnens were
approximately equivalent. Oral LD^' values are available for NaCN and
KCN. For NaCN, a human oral LD5Q of 2.86 mg NaCN/kg bw (1.52 mg CN~/kg
bw) and a rat oral LD5Q of 6.44 mg NaCN/kg bw (3.41 mg CN~/kg bw) are
reported {NIOSH, 1976). for KCN, oral LD50's" are reported as follows: 10
mg KCN/kg bw (4 mg CN~/kg bw) for rats (Galnes, 1969; Hayes, 1967), 8.5 mg
KCN/kg bw (3.4 mg CN~/kg bw) for mice (Sheeny and Hay, 1968), 5 mg KCN/kg
bw (2 mg CN~/kg bw) for rabbits (NIOSH, 1976) and 2.86 mg KCN/kg bw (1.14.
mg CN~/kg bw) for humans (NIOSH, 1976). Note that In the case of.cyanide,,
such determinations differ from the classical determination of an ID
(I.e., counting of deaths during 14 days after dose administration) since
cyanide 1s extremely acutely toxic. For the LD50 determination 1n mice,
the animals were observed for 24 hours because many mice that appeared to be
moribund recovered. The LD5« for Vntraperltoneal NaCN In mice (Kruszyna
et al., 1982) 1s essentially the same as that for oral KCN In mice (Sheeny
and May, 1968), when expressed In terms of cyanide Ion (3.2 vs. 3.4). KCN
and NaCN have been administered IntraperHoneally or subcutaneously to mice
and dogs 1n order to determine the effects of antidotal treatment on the
LO (Kruszyna et al., 1982; Hay et al., 1966,'1972; Isom and Way, 1973;
Chen and Rose, 1952}. Strelcher (1951) demonstrated that an Increase 1n
temperature decreased the toxlclty of KCN. The LC5Q for Inhalation (not
02710 V-3 05/20/91
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Included In Table V-l) of HCN In Swiss-Webster mice for a 30-mlnute exposure
and a 10-m1nute recovery period was determined to be 166 ppm (182.6 mg
HCN/m3) (Matljak-Schaper and AlaMe, 1982).
Table V-2 Is a summary of studies of acute toxlclty other than L05Q
determinations. For the purposes of this review, durations ranging from a
single exposure up to 14 dally doses are considered to be acute. Time to
death depends upon dose and rapidity of absorption. Three dogs receiving
oral doses of KCN of 3.8, 10.7 and 20.2 mg KCN/kg bw (1.5. 4.3 and 6.1 mg
CN"/kg bw, respectively) died 1n 155, 21 and 8 minutes, respectively
(Gettler and Balne, 1938). Oral doses of 10 and 15 mg KCN/kg bw (4 and 6 mg
CN~/kg bw, respectively) were fatal to rats and mice, respectively; the
Incidence of mortality depended on the amount administered (Ferguson,
1962). Basu (1983) found that an oral dose of 8 mg KCN/kg bw, (3.2 mg
CN"/kg bw) resulted 1n no signs of toxldty In five guinea pigs, and
slight tremors with complete recovery In three guinea pigs. This dose 1s
approximately equal to the L05_ 1n mice (see Table V-l). Kreutler et al.
(1978) studied the effect of KCN administered In the diet of rats 1n
relation to protein content and Iodine deficiency. The rats tolerated a
much higher dose of cyanide (80 mg CN~/kg bw/day) when It. was mixed 1n the
diet than when administered by gavage. All of the rats on the low protein
diet lost body weight, regardless of other treatments. KCN-treated rats on
a low protein diet deficient In Iodine had Increased thyroid weight,
Increased thyroid-to-body weight ratio and Increased levels of plasma
'thyroid stimulating hormone (TSH). Addition of Iodine to the diet protected
the rats from the effects on the thyroid. Rats on high protein diets gained
02710
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body weight regardless of treatment. Although these diets were not supple-
mented by Iodine, no effects on the thyroid were observed from cyanide
exposure. Ingestlon of cyanogen glycoslde-contalnlng foods, along with
nutritional deficiencies, Is suspected of having a goltrogenlc effect In
humans (Ermans et al., 1972).
Effects of acute Inhalation exposure of dogs and rats to HCN are also
summarized In Table V-2. A dog receiving a bolus of 3.8 mg KCN/kg bw (1.5
mg CN~/kg bw) by gavage died 1n 155 minutes, while a dog Inhaling a total
of 1.55 mg/kg bw (1.5 mg CN~/kg bw) died In 15 minutes (Settler and Balne.
1938). Correlation of duration of exposure and concentration with lethal
effect 1s difficult because of the wide range of sensitivity among species
and the small number of animals exposed/group. This phenomenon was demon-
strated In dogs by Haymaker et al. (1952) (see Table V-2). Hlstopathologlc
lesions to the gray matter of the brain were observed when the dogs were
necropsled. Moss et al. (1951) reported a minimum lethal concentration of
55 mg HCN/m3 for <20 minutes In female rats. Rats tolerated repeated
acute Inhalation exposures (one !2.5-m1nute exposure every 4 days) to HCN of
220 mg/m3 (O1Flaherty and Thomas, 1982). During the experimental period,
the rats had Increased activities of cardiac specific creatlne phosphoMnase
(an Index of myocardlal damage) and Increased numbers of ectoplc heart beats
In response to noreplnephrlne. The rats were killed and necropsled within 2
weeks of the last exposure. No consistent Increase In. Incidence of lesions
to the myocardium was observed.
Barcroft (1931) compared the sensitivities of a variety of species to
HCN. Animals were exposed by Inhalation to 1000 mg/m3 HCN and the time at
02710
V-14
05/20/91
-------
which death occurred was recorded. The results are presented In Table V-3.
The species were also compared wHh respect to the highest concentration
that the animals could breathe "Indefinitely." It was not clear as to how
this determination was made, but the reported concentrations ranged from
100-400 mg HCN/m3. The order of sensitivities to these nonlethal
concentrations, from, the most sensitive to the least sensitive species was
dog = rat > mouse > rabbit = monkey * cat > goat > guinea pig.
Toxic effects of cyanides administered by other routes are described In
Table V-2. Dermal absorption of HCN gas resulted 1n death In dogs and
guinea pigs (Walton and HHherspoon, 1926). A, dose-response for toxic
effects of KCN administered IntraperUoneally to mice was defined by Isom et
al. (1982). Such signs as rapid breathing, agitation, loss of coordination
and convulsions were rare at doses of 1 and 2 mg KCN/kg bw (0.4 and 0.8 mg
>T
CN'/kg bw. respectively). At 3, 4 and 5 mg KCN/kg bw (1.2. 1.6 and 2.0 mg
CN~/kg bw, respectively), these effects were observed within 2-3 minutes.
At 6 mg JCCN/kg bw (2.4 mg CN~/kg bw), there, was 20% mortality 1n 4
minutes. Subcutaneous administration of NaCN to rats resulted 1n signifi-
cantly Increased acetylchollnesterase activity In the cerebral cortex,
hippocampus and mldbraln compared with controls (Owasoyo and Iramaln, 1980).
Intravenous administration of 1 mg NaCN/kg bw (0.5 mg CN~/kg bw) to dogs
resulted In EEG, EKG and blood pressure changes (Burrows et al., 1973).
Subchronlc Exposure. A summary of the effects following subchronlc
exposure of animals to cyanides was provided 1n Table V-4. The Intermittent
Ingestlon of low doses over a day appears to allow for sufficient
detoxification to account for the sublethal effects. Rats tolerated 25
02710 V-15 05/20/91
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TABLE V-3
Sensitivity of Various Species to Inhalation Exposures of HCN*
Species
(number/species
not given)
Lethal time of exposure to a
Concentration of 1000 mg HCN/m3
(minutes)
Dog
Mouse
Cat
Rabbit
Rat
Guinea pig
Goat
Monkey
0.8
1.0
1.0
1.0
2.0
2.0
3.0
3.5
*Source: Barcroft, 1931
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V-20
05/20/91
-------
dally doses of KCN, each of which were equal to the acute oral L05Q (10 mg
KCN/kg bw or 4 rag CN~/kg bw), when the chemical was mixed 1n the diet
(Hayes, 1967). In a second experiment, 90 dally doses that were equal to 25
times the LD5Q did not result In mortality when administered 1n the diet
(Hayes, 1967}. Rats appeared to tolerate a higher oral dose of KCN (-30 mg
KCN/kg bw/day or 12 tug CN~/kg bw/day for 21 days) that was administered 1n
drinking water (Palmer and Olson, 1979), than when KCN was administered In a
bolus by gavage with water as the vehicle (Hayes, 1967; Galnes, 1969). The
rats that had received KCN 1n the drinking water had significantly Increased
liver weights when compared with controls (Palmer and Olson, 1979). Rats
receiving KCN 1n the diet for 21 days (20 mg KCN/kg bw/day or 8 mg CN~/kg
bw/day) did not have Increased liver weights, but>the doses were lower than
when KCN was added to the drinking water. Other parameters were not
examined (Palmer and Olson, 1979).
Tewe (1982) studied the effects of dietary KCN, administered for 84
days, 1n the African giant rat (8/group). The concentration In the diet
(2500 mg KCN/kg diet) was approximately equivalent to 90 mg KCN/kg bw/day
(36 mg CN~/kg bw/day). The effects 1n the African giant rat were slightly
reduced food consumption, slightly reduced body weight gain and an Increase
In serum urea. The differences from control were significant only for serum
urea. The brain was not examined hlstologlcally; although It Is a.target
organ for subcutaneously administered cyanide In rats .(Smith et al.f 1963;
Lessen, 1971).
Tewe and Maner (1980, 1982) conducted studies In Yorkshire pigs and
Sprague-Dawley rats to determine the Interrelationships of cyanide, dietary
02710 V-21 05/20/91
-------
protein and Iodine on the physiologic performance. Only those portions of
the reports where pigs and rats were maintained on standard diets with or
without KCN are discussed here. ' There were no significant differences
between treated rats (750 ppm CN~ In diet for 56 days) and controls when
compared for food consumption, body weight gain, food efficiency (food
Intake/body weight gain), protein efficiency ratio (body weight gain/protein
Intake} and liver and kidney weight-to-body weight ratios {Tewe and Maner,
1982). Klstologlc examinations were not performed. Treated pigs (500 ppm
CN~) had slightly reduced food consumption; however, body weight gain was
not affected (Tewe and Maner, 1980). Hlstologic examination of the pigs
revealed no pathologic changes In thyroid, hypophysis, stomach, liver,
cardiovascular tissue, spleen, tonsils, thymus, Intestinal mesentery,
kidney, eye, brain, spinal cord, neural ganglia or bone. Organ-to-body
weight ratios.of thyroid, liver, kidney, spleen and heart were not different
from controls.
The American Cyanamld Co. (1959) conducted a study 1n beagles on the
effects of NaCN mixed with their food. The dogs consumed 3 mg CN~/kg
bw/day for 30-32 days. There were no clinical signs of toxlclty or effects
on food consumption, body weight gain or hematologlc parameters. Hlsto-
logic examination was extensive and Included tongue, tonsils, cervical lymph
node, salivary gland, thyroid, trachea, myocardium, aorta, lung, thymus,
liver, gall bladder, pancreas, esophagus, stomach, duodenum, jejunum, lleum,
colon, cecum, rectum, mesenteMc lymph node, spleen, adrenal, kidney,
ureter, urinary bladder, skeletal muscle, cerebellum, cerebrum, spinal cord,
pituitary, testls, prostate, ovary, uterus and vagina. No treatment-related
abnormalities were found. There were no differences 1n organ-to-body weight
02710 V-22 05/20/91
-------
ratios of submaxlllary glands, thyroid, heart; lung, liver, adrenal,
pancreas, spleen, kidney, brain, pituitary, testls or ovary. The dose had ,
been chosen on the basis of the concentration of NaCN 1n the food that the
dogs would accept and eat completely. Dogs receiving doses of >1.0 mg
NaCN/kg bw/day (0.5 mg CN~/kg bw/day) for up to 15 months had signs of
Intoxication Immediately after each dosing, but they recovered 1n <0.5 hour
(Meriting et al., I960). The NaCN was administered In a capsule.
Degenerative changes 1n ganglion cells of the CNS were observed 1n all three
treated dogs. The lowest exposure was 0.27 mg CN~/kg bw/day.
i
Effects of subchronlc exposure to cyanide by other routes are also
Included In Table V-4. Rabbits exposed to 0.55 mg HCN/ma air for 28 days
had no treatment-related changes 1n the ultrastructure of the myocardium
(Hugod, 1981). Rats treated subcutaneously 3 days/week for 90 days with
NaCN In TWA (time-weighted average) doses of 0.61*. 1.31 and 1.72 mg CN'/kg:
bw/day had high rates of mortality and hlstopathologlc damage to the brain
(Lessell, 1971). The damage consisted of necrotic lesions In the corpus
callosum and the optic nerve. A no-effect level was a TWA dose of 0.11 mg
CN"/kg bw/day for 90 days. Smith et al. (1963) also found hlstopathologlc
damage to the brains of .rats treated once weekly for 22 weeks with
subcutaneous Injections of 0.57 mg CN~/kg bw. Hurst (1940) found necrotlc
i
lesions In white and gray matter of the brains of rhesus monkeys treated
with lethal Intramuscular TWA doses of KCN (0.76-15..2 mg CN"/kg bw/day)
for 17-103 days. Baboons treated subcutaneously' for 42 months with 1 mg
NaCN/kg bw (0.4 mg CN~/kg bw) 5 days/week, had Increased hemoglobin and
decreased MCU and MCHC values compared with controls (Crampton et al..
1979). There was no effect on body weight gain, and the treated animals
02710 V-23 05/20/91
-------
appeared to be 1n good health throughout the experiment. Animal studies
have shown that repeated Injections of cyanide can cause CNS damage,
particularly to the white matter (levlne, 1967).
Chronic Exposure. Only two studies were found that provided
Information on the effects of long-term exposure of animals to cyanide.
Details of the studies are presented In Table VT5.
In the study of Howard and Hanzal (1955), groups of 10 male and 10
female Carworth Farms rats were maintained for 104 weeks on diets that had
been fumigated with HCN. It was necessary to measure the loss of HCN due to
evaporation from the chow and to prepare fresh rations every other day to
nominal concentrations of 100 and 300 mg HCN/kg diet. Results of the analy-
sis of residues over the 2-year duration of the study Indicated an average
drop In the dietary concentration of HCN over 2 days from 100 mg/kg diet to
51.9 mg/kg diet (48X loss} for the low-dose level and from 300 mg/kg diet to
80.1 mg/kg diet {73X loss), for the high-dose level. Thus, the average
concentrations are 76 mg/kg diet for the low-dose level and 190 mg/kg'diet
for the high-dose level.
During the 2 years of this study, the growth curves for all groups did
not vary as a result of treatment. Food consumption, hematologlc values and
survival were also similar Vn all groups. At termination of the study, the
only pathologic lesions observed were those associated with aging. The only
effects of treatment were Increased CN~ level 1n the red blood cells, and
Increased thlocyanate levels In the plasma, red blood cells, liver and
kidneys .of animals from both treatment groups.
02710 V-24 05/20/91
-------
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Phllbrick et al. (1979) mixed KCN 1n the diet at a concentration of 1500
rag/kg diet and maintained groups of 10 male weanling rats (strain not speci-
fied) on this diet for 11.5 months. When expressed 1n terms of cyanide,
this dietary concentration Is higher than the concentration of cyanide In
the food of the rats In the Howard and Hanzal (1955) study. Positive
controls received a diet containing 10% casein supplemented with 0.3%
Dl-methlonlne, Kl and vitamin B
12'
Two groups received this diet plus
either 1500 ppm KCN or 2240 KSCN. Negative controls received the 10% casein
diet supplemented with methlonamlne but with no added KI or vitamin B,~.
Two additional groups received this negative control diet plus either 1500
ppm KCN or 2240 ppm KSCN. Thus, of those two groups receiving KCN, one
received a complete diet whereas the other was restricted In Iodine and
vitamin B,_. No deaths occurred nor were there any gross signs of
toxIc'Hy. Effects were reduced body weight gain, decreased plasma thyroxlne
levels and decreased rate of thyroxlne secretion. The effects appeared
greater 1n the animals oh the deficient diet, although the difference was
not always significant. There were no definitive hlstopathologlc lesions 1n
the optic or CNS tissue, thyroid or sciatic tissue; however, vacuollzatlon
and myelln degeneration were observed In spinal cord sections.
Target Organ Toxic1ty
Central Nervous System. Several studies discussed 1n the General
Toxlclty Section described hlstopathologlc damage .to brain tissues.
Haymaker et al. (1952) found lesions In the gray matter of brains of dogs 28
hours after fatal Inhalation exposure to 690 mg/m3 HCN for 2 minutes. The
damage Included necrosis, of the cerebral cortex, caudate nucleus and
putamen, substantla nlgra, globus pallldus, pulvlnar of the thalamus and
027TO
V-26
05/20/91
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cerebellum cortex. Dogs given subchronlc oral doses of >1.0 mg/kg/day NaCN
showed degenerative changes In ganglion cells, especially Purklnje cells of
the cerebellum (Meriting et al., 1960). EEG changes such as low electrical
activity and depressed wave amplitude were observed In dogs given a single
dose of 1 mg NaCN/kg bw Intravenously (Burrows et al., 1973).
Smith et al. (1963} found that subcutaneous administration of 1.43 mg
KCN/kg bw to rats once weekly for 22 weeks resulted In degeneration of
pyramidal cells In the cerebral cortex, degeneration of the cerebellum
(Purklnje cells) and hippocampus, degenerating neurons 1n the brain and
pallor of myelln In the corpus callosum. Lessell (1971) described necrotlc
lesions In the corpus callosum and optic nerves of rats treated
* ' ~ ' '
subcutaneously with >1.16 mg NaCN/kg/day. Focal constriction of the optic
nerve was observed 1n severely affected rats. In a subsequent study, 1n
*
which the doses of NaCN were adjusted 1n order to keep rats In a coma for
225-260 minutes, there were severe ultrastructural pathologic changes In the1
optic nerve, particularly 1n the retrobulbar zone (Lessell and Kuwabara,
1974). The optic, nerve lesions Included edema, enlarged astrocytes,
clumping of myelln, nerve fiber degeneration and necrotlc and swollen axons
that had few mlcrotubules. Owasoyo and Iramain (1980) found. Increased
activity of acetylchollnesterase In the cerebral, cortex, hippocampus and
t
mldbraln of rats given subcutaneous doses of NaCN. Ferraro (1933) studied
the CNS hlstopathology of cats and monkeys given. Increasing doses of KCN.
The damage Included demyellnatlon In white matter of the frontal, occipital,
parietal and temporal lobes, the corpus callosum, the cerebellum, the spinal
cord and optic nerve. Degeneration of axis cylinder, gllosls, hypertrophy
and vacuollzatlon of ollgodendroglla were also observed. PhUbrlck et al.
02710 V-27 . 05/20/91
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(1979) reported vacuolUatlon and myelln degeneration 1n the white matter of
the spinal cord In rats fed diets containing 75 mg KCN/kg bw (30 mg CN/kg
bw).
Heart. O'Flaherty and' Thomas (1982) found that Inhalation of HCN by
rats resulted 1n Increased activity of plasma cardiac specific creatlne
phosphoklnase, an Indicator of myocardlal damage, although there was no
consistent Increase In the incidence of lesions to the myocardium. Hugod
(1981) also failed to detect changes 1n the ultrastructure of the myocardium
of rabbits after HCN inhalation. Purser et al. (1984) exposed cynomolgus
monkeys to concentrations of HCN ranging from 100-172 ppm and observed
bradycardla with arrhythmias and T-wave abnormalities, followed by rapid
recovery. EKG changes observed following Intravenous Injections of NaCN In
dogs Included sinus pause, bradycardla and elevated or blphaslc T waves
(Burrows et al., 1973). There was also a marked Increase In systolic.
dlastollc and venous blood pressures.
Thyroid. Kreutler et al. (1978) administered KCN orally (2000 ppm 'in
the diet) for 14 days. Decreases In thyroid weights and plasma levels of
TSH In rats were Inhibited by addition of Iodine to the diet, or by
providing adequate levels of protein 1n the diet. However, Phllbrlck et al.
(1979) reported'decreased thyroxlne levels and decreased rates of thyroxlne
secretion 1n rats treated chronically with standard diets containing KCN.
Other Effects
Cardnogenlclty. Pertinent data regarding the carclnogenlclty of HCN,
KCN and NaCN were not located In the available literature; HCN and KCN are
02710
V-28
05/20/91
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not scheduled for testing by the National Toxicology Program {NTP, 1991).
Short-term toxlclty studies for NaCN have, been completed and are -currently
undergoing review (NTP, 1991). Perry (1935) foundi that Inhalation exposure
of rats to hydrogen cyanide retarded the growth of Implanted Jensen rat
sarcomas, but .effective concentrations were very near the lethal
concentrations. Bown et al. (1960) found that Intraperltoneal Injections of
cyanide prolonged the lives of mice with transplanted Ehrllch ascltes tumors
and Sarcoma 180. Human patients with advanced cancers 1n the pelvic region
tolerated pelvic perfuslons of cyanide without evidence of toxlclty. Other
studies onthe anti-tumor activity of cyanide' and the controversial
t
cyanogenlc glycoslde, amygdalln (laetrlle), which releases cyandle on
enzymatic hydrolysis, have been reviewed elsewhere (Towlll et al., 1978).
t
Hutagenlclty. Most of the, assays of cyanides for mutagenlclty and
effects on ONA synthesis have been negaltve. De Flora (1981) and DeFlora et
al. (1984) found that KCN.was negative for reverse mutation 1n Salmonella
typhlmurlum strains TA1535, TA1537, TA1538, TA97, TA98, TATOO and TA102,
using both the spot test and plate Incorporation application technique, up
to a dose of 3xlO~3 nmoles/plate. This was the highest dose tested due to
bacterial toxlclty. Addition of the S-9 mix. prepared from livers of
Aroclor-lnduced rats, had no effect on the response. Kushl et al. (1983)
reported that HCN gas was marginally mutagenlc to S. typhlmurlum strain
TA100 In doses <5 mg/plate. Addition of S-9 mix decreased the mutagenlc
response. Negative results were obtained In strain TA98. DeFlora et al.
(1984) also found that KCN was negative for Inducing ONA damage In
repair-deficient EscherUhla coll strains WP67, CM871 and WP2. Karube et
al. (1981) tested cyanide, a known Inhibitor of cellular respiration (see
02710 V-29 05/20/91
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Chapter VII), by a method employing the rec assay In Bacillus subtnis
strains M45 Rec~ and H17 Rec*. The technique Involved the use of two
m1crob1al electrodes consisting of Immobilized bacteria on oxygen electrodes
to -measure the preferential death of the Rec" strain 1n response to
decreased respiration by the DMA-damaged bacteria. If the test chemical
damaged'the DNA, then the -Rec* strain could repair the damage, and the
rate of current Increase at the Rec* electrode would be slower than at the
electrode of the repair-deficient Rec~ strain. Cyanide Increased the rate
of current at both electrodes equally (dose-related), since the Inhibition
of cytochrome oxldase, rather than DNA damage, was responsible for the
decrease In cellular respiration {see Chapter VII).
TeratooenlcltY and Other Reproductive Effects. Doherty et al. {1982}
studied the teratogenldty of NaCN 1n pregnant Golden Syrian hamsters. On
day 6 of gestation, osmotic m1n1pumps were Implanted subcutaneously at the
back of the necks of 5-7 animals/group. The pumps delivered doses of NaCN
of 0, 0.126, 0.1275 or 0.1295 mmoles/kg bw/hour (0, 148.2, 149.9 or 152.3 mg
NaCN/kg bw/day or 0, 78.5, 79.4 or 80.7 mg CN'/kg bw/day, respectively)
from days 6-9 of gestation, at which time the pumps were removed. The
hamsters- were killed on day 11 of gestation. The osmotic mlnlpump method of
administration was chosen 1n order to approximate the slow release of
cyanide from nHrlles during \n_ vivo metabolism. It was believed that the
leratogenlc effect of nHrlles and cyanogenk glycosldes, e.g., laetrUe
(Hmmte et al., 1981; HlllhUe, 1982. 1983) was due to In vivo release of
cyanide. The results are presented In Table V-6. Severe teratogenlc
effects were observed at all three doses. In addition, mild maternal
toxlclty was observed at 148.2 and 149.9 mg/kg/day, and more severe effects
were seen at 152.3 mg/kg day. Toxic signs Included shortness of breath.
02710
V-30
05/20/91
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1ncoord1nat1on, reduced body temperature and ' loss of body weight.
Preliminary range-finding experiments revealed that a dose of 0,126
mmole/kg/hour (148.0 mg/kg/day) resulted 1n no fetal abnormalities, while a
dose of 0.133 mmole/kg/hour (156.4 mg/kg/day} resulted In 100% resorptlons
and death to some of the dams. In experiments with pair-fed controls, It
was shown that the loss of body weight, 1n Itself, was not related to the
fetal abnormalities. No significant relationship between maternal toxlclty
and the Incidence of fetal malformations was found by analysis of variance
of the transformed data (p>0.05). When thlosulfate was co-administered with
cyanide, no teratogenlc effect was found. The Investigators stated that the
results do not Imply a dose-response relationship because the variability In
certified pump rates of Individual mini pumps 1s larger than the percentage
difference among doses. Furthermore, the pumping rates cannot be verified
1H vivo.
Tewe and Maner (1981a) studied the effect of KCN added at a concentra-
tion of 500 ppm as the cyanide 1on {500 mg CN~/kg diet or 1250 mg KCN/kg
diet) to a basal diet containing low-HCN cassava (21 mg HCN/kg) meal on the
reproductive performance of female Wlstar rats. Control rats were fed the
basal diet (which contained 12 mg HCN/kg diet) 1n quantities that were equal
to the diet consumed by treated rats. The KCN-treated rats were fed the
test diet from 19.7*0.8 days before pregnancy, through lactation and during
t
the post-weaning period. The controls were fed the control diet from
16.3+1.1 days before pregnancy and through post-weaning. Hale rats did not
receive the diets. Prior to parturition, the pregnant rats were separated,
so that half the treated dams would remain on the test diet, the other half
on the basal diet. Controls were separated similarly. At weaning, two rats
02710 V-33 05/20/91
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from each Utter were selected and assigned at random to control and treat-
ment groups for a 28-day post-weaning period. No significant differences
were found among the various treated and control groups wUh respect to
weight gain during gestation, litter size, birth weight of pups, feed
consumption and body weight change during lactation, weights of maternal
liver and kidney, weanling weights or mortality of offspring. The offspring
that were continued on the diets during the post-weaning period consumed
significantly less food and grew at a significantly slower rate than the
basal diet offspring, regardless of previous cyanide exposure {$t± utero
and/or In milk and/or 1n diet). The protein efficiency ratio of rats
exposed \n utero and fed cyanide during the post-weaning phase was
significantly reduced compared with basal diet rats. Assuming that a
weanling rat weighs approximately 45 g and consumes food equivalent to 10%
of Us body weight, then the rats fed diets with added KCN consumed
approximately 50 mg CN~/kg/day.
In a similar study, Tewe and Maner (1981b) studied the effect of cyanide
on the reproductive performance of pregnant Yorkshire pigs. Cassava
(containing a low level of HCN) was supplemented wUh protein, minerals and
vitamin mix to which was added KCN. The groups, consisting of six pigs
each, received the basal diet of low cyanide (30.3 mg CN~/kg diet) or the
basal diet plus cyanide, which provided total CN" levels of 276.6 and
520.7 mg CN~/kg diet. The concentrations as mg CN~/kg diet were
calculated by the Investigators. The diets were started on the day after
breeding and continued until parturition. Two pregnant pigs/group were
killed on day 110 of gestation; the remaining pigs were fed their respective
diets until parturition and then fed standard diets (no cyanide) during the
02710 V_34
05/20/91
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56 days of lactation. The piglets were not fed any cyanide. No differences
were found with respect to litter size, IHter size at weaning, .birth weight
of piglets, dally feed Intake of sows or piglets. In the pigs that were
killed on day 110 of gestation, no significant differences were found among
groups for body weight, body weight gain during gestation, organ-to-body
weight ratios of thyroid, spleen, liver, kidney and heart, number of
fetuses/litter, weight of fetuses, weight of fetal 'liver .or kidney. The
thyrold-tp-body weight ratios of fetuses from sows receiving 276.6 mg
CN~/kg diet- were significantly reduced (p<0,05) compared with the
low-cyanide group (30.3 mg CN~/kg diet), but the high-cyanide (520.7 mg
CN /kg diet) group was not different from the low-cyanide group. Fetal
spleen-to-body weight ratio was significantly reduced (p<0.05) In the
high-cyanide group compared with both other groups. The fetal heart-to-body
weight ratio of the high-cyanide group was significantly reduced (p<0.05)
compared with the low-cyanide group. Hlstopathologlc examination of two*
killed pigs/group on -day 110 of gestation Indicated hyperplasla of kidney
glbmerular cells in one sow from each of the low- and medium-cyanide groups
and In both sows of the high-cyanide group. Both h1gh-cyan1de sows had an
accumulation of colloid and folUcular cells of low height In the thyroid.
No difference 1n hypophysis, adrenal, pancreas, tongue, esophagus, stomach,
liver, cardiovascular tissues, lymphoretlcular system of the spleen,
tonsils, thymus, Intestinal mesenteries, eye, brain or spinal cord were
observed between the treatment groups.
Summary
Signs of acute poisoning by cyanide Include rapid breathing, gasping,
tremors, convulsions and death. The speed of onset and the severity of the
02710 V-35 05/20/91
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effects depend upon the route, the dose, the duration of exposure and the
compound administered. Inhalation of HCN results 1n the fastest absorption
and appearance of toxic signs. Gastrointestinal absorption of the cyanide
salts results In passage Into the liver, the major site of detoxification.
Cyanide exposure, results In death because the cyanide Ion reacts with
cytochrome oxldase, blocking cellular respiration. If enough cyanide Is
detoxified before death occurs, the animal may recover.
The acute oral LD5Q for KCN was 10 mg/kg bw (4 mg CN~/kg bw} 1n rats
(Galnes. 1969; Hayes, 1967} and 8.5 mg KCN/kg bw (3.4 mg CN*/kg bw) In
mice (Sheehy and Way, 1968). Intraperltoneal Injection of NaCN In mice
results In a similar LD5Q as orally administered KCN when expressed as
cyanide (3.2 mg CN~/kg bw) (Kruszyna et al., 1982). The dose-response for
Intraperltoneally administered KCN In mice Indicated that 1 or 2 mg KCN/kg
bw (0.4 or 0.8 mg CN"/kg bw) had minimal or no effects, while 3-5 nig
KCN/kg bw (1.2-2.0 mg CN'/kg bw) resulted In signs of toxlclty (convul-
sions, agitation) (Isom et al., 1982). A dose of .6 mg KCN/kg bw (2.4 mg
CN~/kg bw) resulted In 20% mortality. Doses that are fatal to one species
may be harmless to others. An oral dose of 3.8 mg KCN/kg bw (1.5 mg
CN~/kg bw) was fatal to a dog In 155 minutes (Settler and Balne. 1938) but
a higher dose of 8 mg KCN/kg bw (3.2 mg CN~/kg bw}, equal to the LD5Q 1n
mice, had only minimal effects on guinea pigs (Basu, 1983). Rats tolerated
much higher doses of cyanide (80 mg CN~/kg bw/day) when mixed In the diet
(Kreutler et al., 1978) than when administered by gavage at 4.0 mg CN"/kg
bw (Ferguson, 1962}.
02710
V-36
05/20/91
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The LC50 1n mice for inhaled HCN was 184 mg/ra3 for 30 minutes
(Matjak-Schaper and Alarle, 1982). Correlation of concentration and
duration of exposure with effect was difficult due to the high variability
In response even within the same species, In which some animals recovered
from doses that were fatal to others {Haymaker et al., 1952). When the
concentration of HCN was kept at 1000 mg/m3, the time H took for dif-
ferent species to die decreased 1n the order: monkey > goat > guinea pig =
rat > rabbit ~ cat = mouse > dog (Barcroft, 1931).' Therefore, monkeys were
least sensitive; dogs were most sensitive.
Animals tolerated higher doses of cyanide when administered 1n the diet
or In the drinking water during subchronlc exposure {Hayes, 1967; Palmer and
Olson, 1979). Rats receiving -12 mg CN~/kg bw/day In drinking water had
significantly Increased liver weights compared with controls, while rats
receiving -8 mg CN'/kg bw/day In the diet did not (Palmer and Olson,
1979). No clinical signs of toxlclty, effects on body weight, hematology
and no hlstopathologlc lesions were found 1n beagles that consumed 3 mg
CN~/kg bw/day (calculated from body weight data and amount of CN consumed)
1n the diet for 30 days (American Cyanamld Co.1, 1959). However, dogs
receiving >0.27 mg CN~/kg bw/day, administered In 'a capsule for 15 months,
had degenerative changes " In ganglion cells of the CNS (Herttlng et al.,
1960). Subchronlc exposure to cyanide by subcutaneous and Intramuscular
routes has resulted In hlstopathologlc lesions In the Brain and spinal cord
of rats and monkeys (Lessell,.1971; Smith et al., 1963; Hurst, 1940) and
changes 1n hematologlc parameters 1n baboons (Crampton et al., 1979).
(
Chronic 'dietary exposure to cyanides (-3.2 and 4.3 mg CN~/kg bw/day)
resulted 1n no effects clinically or h1stolog1cally (Howard and Hanzal,
02710 V-37 05/20/91
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1955), but dally doses of -30 mg CN~/kg bw/day 1n the diet of rats
resulted In changes In thyroid homeostasls, reduced.body weight gain and
moderate demyeHnatlon 1n the spinal cord (PhUbrlck et al., 1979).
Pertinent data regarding the carclnogenldty of cyanides were not
located In the available literature. Cyanide may have ant Humor activity
(Perry, 1935; Brown et al., 1960). Negative results for KCN were obtained
for mutagenlclty 1n Salmonella typhlmurlum strains TA1535, TA1537, TA1538,
. TA97, TA98, TA100 :and TA102, wHh and without metabolic activation (De
Flora, 1981; OeFlora et aK, 1984); although In a study by Kushl et al.
(1983) mutagenlc activity of HCN,gas was found 1n S. typhlmurlum strain
TA100. Cyanide was negative In a modified rec assay In Bacillus subtnis
(Karube et al., 1981). .NaC.N Induced severe teratogenlc effects In hamsters
when administered by subcutaneously Implanted osmotic mini pumps that
delivered cyanide at a rate of 3.3-3.4 mg ClT/kg bw/hour (79.2-81.6 mg
CN'/kg bw/day) from days 6-9 of gestation (Doherty et al., 1982). There
were no effects of dietary cyanide 1n a concentration of 500 mg CfT/kg
" diet on the reproductive performance of pregnant rats fed KCN throughout
gestation and lactation (Tewe and Maner, 1981a). Offspring that were
continued on the test diet after weaning consumed less food and grew at a
significantly reduced rate compared with control offspring. The effects on
the reproductive performance of pigs maintained on diets containing cyanide
{30.3, 276.6 and 520.7 mg CN~/kg diet) throughout ges-tatlon and lactation
Included reduced piglet organ-to-body weight ratios of the thyroid. In the
medium-dose group relative to the low-dose group, of the spleen In the
high-dose group relative to the medium- and low-dose groups and of the heart
In the high-dose group relative to the low-dose group of fetuses (Tewe and
02710 V-38 05/20/91
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Maner, 1981b). Treated sows had hyperplasla of kidney glomerular cells and
accumulation of colloid and morphologic changes In follkular cells of the
thyroid.
02710 V-39 05/20/91
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-------
VI. HEALTH EFFECTS IN HUMANS
Acute Exposure
The acute effects of cyanide exposure 1n humans have been well docu-
mented. Several reviews have described the effects of Ingestlon and Inhala-
tion of HCN, KCN and NaCN (DIPalma, 1971, Gosselln et a!., 1976; NIOSH,
1976; Hartung, . 1982). In addition, systemic toxldty following dermal
exposure has been described.
Oral. Acute exposure to cyanide by the oral route has usually
occurred from suicide attempts (NIOSH, 1976). Reports of fatal oral doses
are In good agreement. These data are summarized 1n Table VI-1. Gettler
and St. George (1934) estimated a lethal dose of cyanide, as hydrocyanic
acid '{HCN} to be 50 mg (0.71 mg/kg bw for a 70 kg human). Gettler and Balne
(1938) reported that the minimum lethal oral dose! of HCN was 0.5 mg/kg bw.
A range of doses of 0.5-3.5 mg HCN/kg bw taken orally was quoted by Ermans
et al. (1972). This range Includes the 60-90 mg (0.86-1.29 mg/kg bw) range
cited by Gosselln et al. (1976) equivalent to -1 teaspoon of a 2%
hydrocyanic acid solution. Ingestlon of 50-100 mg (0.71-1.42 mg/kg bw} of
NaCN or KCN can result In Immediate collapse and respiratory arrest
{Hartung, 1982). The minimum lethal dose of cyanide salts was quoted by
DIPalma (1971) as 200 mg for adults (2.9 mg/kg bw), although suicide
attempts usually Involved Ingestlon of >l-6 g corresponding to "a spoon-
ful." When this amount of cyanide Is Ingested, -3.5 mg/kg bw had been
absorbed before death resulted. Gastrointestinal absorption of Inorganic
cyanide salts 1s slower than pulmonary absorption of HCN, and the onset and
severity of symptoms are delayed and diminished. The time-course of
responses has been described by DIPalma (1971). 'within 1-5 minutes after
02720 VI-1 05/20/91
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TABLE VI-1
Fatal Oral Doses of Cyanide Compounds
Compound
mg
HCN . 50
HCN
CN salts . 200
HCN
HCN 60-90
NaCN or KCN 50-100
Oose
mg CN'/kg bw
0.71
0.5
2.9
0.5-3.5
0.86-1.29
0.71-1.42
Reference
Gettler and St. George, 1934
Gettler and Balne, 1938
DIPalma, 1971
Ermans et al. , 1972
Gosselln et al.,-1976
Hartung, 1982
02720
VI-2
03/26/85
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Ingestlon, chemoreceptor stimulation results In hyperventllatlon, the
stomach lining becomes Irritated and vomiting may occur. At 5-20 minutes,
unconsciousness, convulsions, muscular contraction of the Jaw. flushed and
dry skin, rapid and Irregular pulse and gasping occur. Vascular collapse,
dilation of the pupils and cyanosis follow. Bodansky and Levy (1923)
administered KCNS or KCN In a gelatin capsule on two consecutive days to 25
human subjects. On the first day, the subjects received 15 mg KCNS, and on
the second day, 10 mg KCN. Assuming the average weight of a human to be -70
kg, these amounts represent doses of 0.14 mg KCN/kg bw and 0.21 mg KCNS/kg
bw (both equivalent to -0.06 mg CN~/kg bw). All subjects effectively
detoxified these doses, as determined by thlocyanate level measurements.
Llebowltz and Schwartz (1948) reported a case of a 60-year-old,' 80 kg
man who had attempted suicide by Ingesting an estimated 3-5 g of KCN. At
one-half hour after Ingestlon, he vomited. One-half hour later, on admis-
sion to the hospital, he was comatose, and gastric lavage was performed.
One-half hour after lavage, he regained consciousness; 8 hours after
admission he had short-lived lingering effects, of nausea and weakness.
Subsequently he recovered fully. The blood level of cyanide at 2 hours
after admission was 0.2 mg HCN/mi. Assuming a blood volume of 6 i, the
Investigators calculated that 1.2 g (15 mg/kg bw): of HCN was present 1n the
circulating blood. This absorbed dose Is at least 5 times the lethal dosr-
of Ingested KCN, and yet, the patient recovered. No apparent reason for his
recovery, was discovered; however, recovery from Ingestlon of cyanide salts
Is not unprecedented. UebowUz and Schwartz (1948) cited 22 cases of
recovery, Utt1 et al. (1985) reported a case 1n which an 18-year-old man
Ingested 975-1300 mg KCN (13.9-18.5 mg KCN/kg bw), was treated and survived.
02720 VI-3 ' 05/20/91
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Shortly after recovery, the man developed severe Parklnsonlan syndrome and
died 19 months after the cyanide Ingestlon. The cllnlcopathologic findings
Indicated that the Parklnsonlsm was the result of cyanide poisonings.
Inhalation. Inhalation of HCN gas results In the most rapid onset of
poisoning, producing almost Immediate collapse, respiratory arrest and death
within minutes (DIPalma, 1971}. Although cyanide has a characteristic odor
of bitter almond, In human, the ability to smell cyanide 1s controlled by a
sex-linked recessive gene (K1rk and Stenhouse, 1953). NIOSH (1976) compiled
data from human case reports and animal studies to estimate concentration-
response effects for humans (Table VI-2). These data Indicated that air-
borne concentrations of HCN of 99-528 mg/m3 are fatal 1n 30-60 minutes.
However, some reports Indicated no Injury at concentrations as high as 550
mg/m3 for "l minute, while others reported that 297 mg/m3 was Immediately
fatal. Discrepancies may be due to Individual variations and, 1n some
cases, the problems Inherent 1n extrapolating data from animal experiments
In order to predict human responses.
Barcroft (1931) placed a man (70 kg) and a dog (12 kg) in an Inhalation
chamber and exposed them simultaneously to HCN at concentrations of 550-688
mg/m3. After 50 seconds, the dog became unsteady; at 1.25 minutes, the
dog collapsed and was unconscious; at 1.5 minutes, the dog had tetanic
convulsions. One second later (91. seconds of exposure), the man emerged
from the chamber, and put on a respirator, but felt no symptoms. Two
seconds later, the dog was believed to be dead (It recovered, and was
walking around the next morning). Within a few minutes after exposure, the
man was briefly nauseated and had difficulty concentrating.
02720 VI-4 05/20/91
-------
TABLE VI-2
Reported (Estimated) Human Responses, to Various
Concentrations of HCN Vapors3
Reponses Concentration (mg/m3)b
Fatal 1n 6-8 minutes
Fatal after 30 minutes
Fatal after 10 minutes
Fatal after 30 minutes
Fatal after 30-60 minutes
Fatal after 30-60 minutes
Fatal after 60 minutes
Tolerated for 30-60 minutes without Immediate >
or after effects
Complaints of headache, nausea, vomiting.
cardiac symptoms
Minimal symptoms after several hours of exposure
Effects after several hours of exposure
No observed effect
Fatigue, headache, body weakness, tremor, pain,
nausea
Headache, weakness, changes In taste and smell,
throat Irritation, nausea, effort dyspnea.
enlarged thyroids, changes 1n blood chemistry
Increased thlocyanate excretion 1n urine, but
to a lesser extent than In cigarette smokers;
no other effects noted
Slight decrease 1n leukocytlc activity of cytochrome'
oxldase, peroxldase and succlnate dehydrogenase after
an average of 5.4 years of exposure
. 297 .
243-528
199
149
121-149
110-264
99
50-59 ';;
50
22-44
20-40
0-19;
mean 5.4
5.5-14.3
4.6-13.6;
mean, 9.1
2.2-8.8;
mean 5.5
0.25
02720
VI-5
08/30/88
-------
TABLE VI-2 (cent.)
Reponses
Concentration (mg/m3)b
No effects
No symptoms after 6 hours
No serious consequences 1n 1 minute
No Injury In 1 minute
No Injury 1n 1.5 minutes
Nausea and difficulty concentrating after
91-second exposure
0.11-0.99
20-40
550
550
413
550-688
aSource: NIOSH, 1976
bThe concentrations In mg/m3 were calculated from concentrations ex-
pressed 1n ppm by multiplying by 1.1.
02720
VI-6
08/30/88
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According to DIPalma (1971), acute exposure of humans to-Inhalation of
-2200 mg HCN/m3 results first 1n shortness of breath, local Irritation to
the throat and a feeling of warmth.- Following a'period of rapid breathing
and sometimes an outcry, apnea, gasping, collapse, convulsions and often
cardiac arrest occur within minutes. It was estimated that rapid death
.results from an absorbed dose of as IHtle as 0.7 mg HCN/kg bw. At lower
airborne concentrations (-5-50 mg/m3) (see Table VI-2), symptoms Include
dizziness, numbness, weakness, headache,, nausea and vomiting, confusion,
rapid breathing and rapid pulse (NIOSH, 1976; Kartung, 1982). Wexler et al.
(1947) found that Intravenous Injection of 0.11-0.2 mg NaCN/kg bw (roughly
equivalent to 0.06-0.11 mg HCN/kg bw absorbed ifollowing Inhalation, as
estimated by ratio of molecular weights) In humans resulted In sinus pause
and Irregularly slowed heart rate, followed by an' Increased pulse above
control. . i
t
Dermal. Absorption of HCN or solutions of cyanide salts through the
skin may result 1n effects similar to the sublethal effects of Inhalation
exposure {Potter, 1950). Local effects to the skin such as dermatitis and
rash may also result (Drinker, 1932; NIOSH, 1976). An LD5Q for dermal
absorption of HGN, which 1s much slower than pulmonary absorption, was esti-
mated as 100 mg/kg bw (DIPalma, 1971).
Subchronlc and Chronic Exposure
Oral. Pertinent data regarding chronic ora.l exposure of humans to
hydrocyanic acid. KCN and NaCN were not located In the available literature.
There Is a body of literature on the etiology 'of thyroid disorders and
neuropathies characterized by optic atrophy, nerve deafness and spinal
02720 VI-7 , 05/20/91
-------
ataxla in people living In certain tropical areas of Africa, where the
staple, diet consists largely of cassava (Monekosso and Wilson, 1966; Osun-
tokun, 1968, 1972; Osuntokun et al., 1969, 1970; Makene and Wilson, 1972;
Ermans et al., 1972; Delange and Ermans, 1971). Cassava Is a root food that
contains a high level of the cyanogenlc glycoslde, UnamaMn. Llnamarln
releases cyanide on metabolism or add hydrolysis in yVvo; therefore, expo-
sure Vs not to cyanide per se. Tropical neuropathies have also been associ-
ated with such factors as Infections, protein deficiency, Mboflavln defi-
ciency, vitamin B12 "(cobalamln) deficiency or defective B,- metabolism
(Osuntokun, 1968; Osuntokun et al., 1969; Makene and Wilson, 1972). Inges-
tlon of cassava, In combination with Iodine deficiency, has been associated
with high Incidences of goiter and cretinism 1n Zaire {Delange and Ermans,
.1971; Ermans et al., 1972).
Inhalation.
Cigarette Smoke Inhalation exposure to cyanide 1n tobacco smoke
by heavy smokers has been associated with the condition of tobacco amblyo-
p1a, characterized by a loss of visual acuity; Leber's hereditary optic
atrophy, a similarly manifested disorder; and with retrobulbar neuritis
complicating pernicious anemia and optic atrophy (Mokes, 1958; Pettlgrew and
Fell, 1972, 1973; Wilson and Matthews, 1966; Foulds et al., 1968; Wilson,
1983). These disorders appear to Involve-defective metabolism of cyanide to
thlocyanate, as well as a deficiency In vitamin B._-or defective vitamin
B,_ metabolism.
Smoking during pregnancy Is associated with a higher risk of giving
birth to low body weight Infants and of perinatal death {Andrews, 1973).
02720
VI-8
05/20/91
-------
Andrews (1973) compared plasma thlocyanate levels 1,n maternal and cord blood
taken at delivery from 21 women who.had smoked during pregnancy and from 22
women who had not. For both maternal and cord blood, smokers (>10 ciga-
rettes/day) had significantly (p<0.001) higher levels of thlocyanate than
did nonsmokers. Although no differences were found for Infant weight,
duration of gestation or onset of labor, group sizes were small -(21 smokers,
22 nonsmokers). This study does demonstrate, however, the potential for
Intra-uteMne exposure. The use of low-tar, low-nicotine or filter ciga-
rettes does not reduce the HCN concentration 1n cigarette smoke (Way, 1984).
Occupational Exposure.
Case Studies Chronic exposure to the cyanides by the Inhalation
and dermal routes Involves occupational exposure of persons engaged 1n case
hardening and .polishing of metals and photographic materials workers.
Sandberg (1967) described a case of a goldsmith apprentice. In the course-
of his work, the man cleaned goldware 5-10 times dally for 4 years. The
cleaning solution was prepared by adding 15 g KCN to a liter of water, heat-
Ing to boiling and adding 50 ml of hydrogen peroxide. This procedure
caused spattering on .the skin. His symptoms Included headaches, listless-
ness, partial paralysis of his left arm and left leg, a grayish pallor and
partial loss of vision 1n the left eye. Hardy, et al. (1950) described a
case hardener who had been consistently exposed to HCN In his work. His
>
symptoms Included headaches, episodes of dizziness, ' confusion, muscular
weakness, poor vision, slurred speech, abdominal cramps, tremor, body rash
and an enlarged thyroid. In another case, a man who had been frequently
(
exposed to cyanide for 5 months while working as a machinist developed a
goiter. The thyroid enlargements \n these two cases were presumed to be a
02720 VI-9 05/20/91
-------
result of the action of thlocyanate formed upon metabolism of cyanide. Many
additional cases of chronic occupational exposure to cyanide.of Individuals
who developed similar conditions have been reviewed by NIOSH (1976).
Ep1dem1o1oq1c Studies. NIOSH (1976) reviewed several epldemlologlc
studies that have been published 1n various countries around the world (Sa1a
et al., 1970; Carmelo. 1955; Dlnca et al., 1972; and Radojldc, 1973),
Including one conducted In Egypt (El Ghawabl et al., 1975) and one In India
(Chandra et al.t 1980). These studies are summarized In Table VI-3.
Typical symptoms and manifestations of cyanide poisoning were observed In
each study, with the exception of the study by Dlnca et al. (1972), which
studied enzyme activity only. NIOSH (1976) questioned the validity of the
techniques In measuring enzyme activity. Blood smears were stained for
detection of enzyme granules In neutrophUH leukocytes. In the study of
Carmelo (1955), the original exposed cohort had consisted of 600 fumlgators
who had experienced acute episodes of Intoxication. Their symptoms were
typical. In the study of El Ghawabl et al. (1975), the study groups had
been Instructed to avoid foods containing cyanogenlc and thlocyanogenlc
glucosldes (e.g., cabbage-Uke -vegetables) (Ermans et al., 1972). The
Increased mean uptake of 131I by the exposed workers, who had not been at
work for 2 days prior to the determination, was explained as a response to
acute cyanide withdrawal. Chandra et al. (1980) also Instructed the
subjects to avoid cyanogenlc foods. In addition, data from smokers and
nonsmokers were analyzed separately. Smokers showed higher levels of
cyanide and thlocyanate 1n their blood and urine.
02720
VI-10
05/20/91
-------
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High Risk Subpopulatlons
Pregnant women who smoke may Increase the susceptibility of their
Infants to toxic effects of cyanide. Smoking during pregnancy has been
linked to low-weight of Infants and perinatal death, and higher plasma thlo-
cyanate levels were found In cord blood of smokers than nonsmokers {Andrews,
1973).
A metabolic disturbance In the conversion of cyanide to thlocyanate and
vitamin B,- deficiency have been associated with such conditions as
tobacco amblyopla, Leber's hereditary optic atrophy and retrobulbar neuritis
In people who are exposed to excess cyanide In tobacco smoke (Wilson,- 1983).
Excess exposure to cyanide and Iodine deficiencies has been associated with
thyroid abnormalities, such as goiter and cretinism (Oelange and Ermans,
1971; Ermans et al., 1972}.. Neuropathies have been associated with
Increased cyanide exposure due to chronic dietary Intake of cassava as a
staple food, 1n combination with protein deficiency, rlboflavln and vitamin
B,- deficiencies and Infections (Osuntokun et al., 1969; Osuntokun, 1968;
Hakene and Wilson, 1972). Therefore, .Individuals with a metabolic defect 1n
the rhodanese system (the enzyme that transfers sulfur to cyanide, see
Metabolism Section 1n Chapter III}, a vitamin B12 deficiency or defective
B,- metabolism or Iodine deficiency, and fetuses .exposed in utero. are at
a higher risk to the toxic effects of excessive' cyanide Intake than the
general population.
(
Summary
Acute oral exposure to cyanide has usually occurred from suicide
attempts. Fatal orally absorbed doses range from 0.5-3.5 mg HCN/kg bw
02720 VI-13 05/20/91
-------
(Gett.ler and St. George, 1934; Gettler and Balne, 1938; Ermans et al., 1972;
Gosselln et al., 1976). The minimum lethal dose of orally Ingested cyanide
salts 1s -2.9 mg/kg.bw (OlPalma, 1971)., When 1-6 g ("a spoonful") Is
Ingested, ~3;5 mg/kg bw has been absorbed by the time of death. Within 20
minutes of exposure to fatal doses, events progress from hypervehtHatlon,
vomiting, unconsciousness, convulsions, rapid and Irregular heart rate,
gasping, vascular collapse and cyanosis, to death. Several cases of
recovery have been reported after 1ngest1on of cyanide at doses that have
proved fatal In other cases (Llebowltz and Schwartz, 1948; Utt1 et al.,
1985).
Inhalation of HCN 1s the most rapid route of fatal exposure and poison-
ing. Acute exposure of humans to -2200 mg HCN/m3 results In shortness of
breath, Irritation to the throat and warmth followed by rapid breathing, an
outcry, apnea, gasping, collapse, convulsions and death In minutes (DIPalma,
1971). As little as 0.7 mg HCN/kg bw absorbed after Inhalation may result
In rapid death. Sublethal concentrations {5-50 mg/m3) result In dizzi-
ness., confusion, headache, nausea, numbness and hyperventllatlon (NIOSH.
1976). Acute dermal exposure produces similar effects, although much more
slowly (Potter, 1950; DIPalma, 1971).
Chronic oral exposure to HCN, KCN or NaCN has not been described.
People living 1n tropical areas of Africa consume cassava as a staple food,
which contains high levels of Unamarln, a cyanogenlc glycoslde that
releases cyanide on metabolism or acid hydrolysis Jm vivo (Osuntokun et al.,
1969; Osuntokun, 1968; Makene and Wilson, 1972). These people have high
Incidences of neuropathies associated with cyanide, vitamin 8,- defi-
ciency, protein deficiency and Infections. Ingestlon of cassava, together
02720
VJ-14
05/20/91
_
-------
with Iodine deficiency, has been associated with the. etiology of goiter and
cretinism (Ermans et a"!., 1972, Oelange and Ermans, 1971).
Chronic exposure to cyanide has been associated with tobacco amblyopla
1n heavy cigarette smokers, Leber's hereditary optic atrophy and retrobulbar
neuritis (WHson, 1983). A defect 1n cyanide metabolism and vitamin IL-
deficiency appear to be Involved In these disorders. Smoking during
pregnancy may result 1n low birth-weight Infants (Andrews, 1973).
Case studies and ep1dem1o1ogk studies of metal case hardeners and HCN
/
fumlgators occupatlonally exposed to cyanide fumes, describe effects 1n
workers typical of sublethal cyanide poisoning, Including headache, dizzi-
ness and thyroid enlargement (NIOSH. 1976).
02720 VI-15 05/20/91
-------
-------
VII. MECHANISHS OF TOXICITY
Acute
The mechanism by which cyanide exerts Its acute toxic effects 1s well
understood and has been reviewed 1n numerous reports. The following discus-
sion 1s based on reviews by DIPalma (1971), Gosselln et al. (1976), U.S. EPA
(1980), Solomonson (1981), Hartung (1982) and Way.(1984).
i
The cyanide 1on can be formed ^ vivo by dissociation of HCN, KCN, NaCN
and any other cyanogenlc compounds. The 1on has a high affinity for many
biologically active metal Ions. It forms a stable complex with Iron In the
ferric state (Fe **). Cytochrome oxldase, the -terminal enzyme In the
mitochondrlal electron transport chain. Is Inhibited by HCN complexlng with
the heavy metal Ions contained 1n the enzyme {Hay, 1984). The Inactivated
enzyme Is unable to catalyze the reaction:
cytochrome
oxldase
Fe^-cytochrome * 0.5 0 X Fe3±-cytochrome +'.0.502'
resulting 1n Inhibition of cellular respiration, the Inhibition results 1n
a hlstotoxlc hypoxla since cells are unable to utilize oxygen. Ox1 datWe
phosphorylatlon Is unable to proceed, and there 1s a shift to anaerobic
metabolism with resultant accumulation of. lactate,. The cells cannot use
oxygen delivered by oxyhemoglobln, thus, venous blood appears bright red
since hemoglobin continues to carry oxygen. Since CNS and the heart are
particularly sensitive to hypoxla, toxic effects are manifested. The time
course for these events 1s very rapid and deat'h can ensue In minutes
(DIPalma, 1971). . :
02730 VII-1 08/30/88
-------
Cyanide 1s capable of' complexlng with many enzymes and compounds that
contain Fe ** Including catalase, peroxldase and methemoglobln. Cyanide
can also form complexes with compounds that contain metals other than Iron
such as hydroxycobalamln (vitamin B12a), phosphatase, tyroslnase, ascorbic
add-ox1dase, xanthlne oxldase and sucdnlc dehydrogenase (DIPalma, 1971).
However, the reaction with cytochrome oxldase 1s the most Important for the
onset of the acute toxic effects.
As discussed 1n Chapter III. cyanide Is detoxified by the action of the
enzyme rhodanese '(Lang, 1933), the trivial name for cyanide sulfurtransfer-
ase. The enzyme transfers sulfur from a sulfur donor to cyanide to form the
less toxic thlbcyanate, which 1s excreted In the urine (Williams, 1959).
The major site of rhodanese activity 1n most species (rat, rabbit, monkey)
Is the liver (Hlmwlch and Saunders, 1948), with particular localization 1n
mitochondria (de Ouve et a!., 1955). The rate-limiting factor In cyanide
detoxlcatlon, therefore, Is the availability of an 1ntram1tochondr1al sulfur
donor.
Chronic
The effects of chronic low-level exposure to cyanide are neurologic In
nature. Repeated Insults to neurologic tissue resulting 1n hlstotoxlc
hypoxla may be responsible for the demyellnatlon and necrosis of many
tissues of the CNS, Including the optic'nerve (Ferraro,- 1933; Lessen, 1971;
Lessell and Kuwabara. 1974; Smith et al., 1963). Wilson (1983) has reviewed
the role of cyanide In human diseases. Tobacco amblyopla, associated with
heavy smoking and vitamin B|2 depletion, and retrobulbar neuritis may be
the result of abnormal cyanide and vitamin B.J. metabolism (Wilson, 1983;
02730 VII-2 . 05/20/91
-------
Wokes, 1958). These conditions are effectively treated with hydroxy-
cobalamln (vitamin B,?), which can react with cyanide to form cyanoco-
balamln (Wilson et al., 1971). If there were a defect In cyanide conversion
to thlocyanate, .or Insufficient vitamin B.J. to 'detoxify -the accumulated
cyanide, neurologic disorders may occur. Similar Interrelationships may be
Involved 1n the etiology of such disorders as ieber's hereditary optic
atrophy (Wilson,- 1983). Neuropathies and amblyoplas among people living In
the tropical areas may also Involve vitamin B,- deficiency. This Is
especially true 1n Africa, where cassava, a root food rich 1n the cyanogenlc
glycosldes, Unamarln and lotaustralln, 1s a dietary staple. In these
disorders, many complicating -factors, such as protein and other vitamin
deficiencies, may also be Involved (Wilson, 1983). The Interrelationships
between cyanide, thlocyanate, vitamin B,- and Inherent defects 1n the
metabolic control of the conversions are not completely understood. One
suggestion was- that cyanide, formed |ri vivo from thlocyanate by the'?
enzymatic action of thlocyanate oxldase 1n red blood cells {Goldstein and"
Rleders, 1953) may reach levels that are chronically toxic If there 1s a
deficiency 1n vitamin B,«. Therefore, vitamin B,? may play a role In
the regulation of cyanide metabolism. Increased blood levels of thlocyanate
resulting from 1ngest1on of cyanogenlc foods. In combination with Iodine
deficiency, may play a role 1n the etiology of. goiter and cretinism among
Inhabitants of the tropics (Ermans et al., 1972; Delange and Ermans, 1971).
Thlocyanate 1s known competitively to Inhibit the uptake of Iodide by the
thyroid.
02730 VII-3 05/20/91.
-------
Synergism
Other chemicals known to Inhibit cytochrome oxldase are sulflde and
azlde (Smith and Gosseltn, 1979; Smith et al.. 1977). and they may as such
have a synergUtlc or additional effect on cyanide toxiclty. Sulflde Is a
more potent Inhibitor of cytochrome oxldase than Is cyanide, and may act by
the same mechanism .{Nlcholls, 1975; Smith et al., 1977). Basu (1983). found
that guinea pigs pretreated with ascorbate prior to oral administration of
KCN developed a 1QOX Incidence of severe tremor, ataxla, muscle twitches,
paralysis and convulsion compared with only slight tremors In 38% of the
animals treated only with KCN. It was postulated' that ascorbate ties up
cystelne so that 1t cannot act as a sulfur donor for the enzymatic action of
rhodanese to convert cyanide to tMocyanate. Administration of cystelne had
a protective effect on the enhanced toxiclty of ascorbate plus cyanide. In
a recent paper. Levin et al. (1987) examined the effects of exposure to a
variety of gases Including HCN and low oxygen levels that could be produced
by fires. Thirty-minute studies on the lethal effects of carbon monoxide
and HCN Indicated they act 1n an additive fashion. Exposure to 5% CO
reduced the LC_. value for HCN exposure In rats from 110 ppm to 75 ppm.
Antagonism
Since cyanide acts by Inhibiting cytochrome.oxldase, thereby Inhibiting
the cellular utilization of oxygen, oxygen 1s not an antagonist of cyanide
toxiclty (U.S. EPA, 1980). Since cyanide can bind- to Fe***t methemo-
globln, which contains the ferric 1on, can compete with cytochrome oxldase
for cyanide, forming cyanomethemoglobln (Hartung, 1982; Hay 1981, 1984).
The use of sodium nitrite, hydroxylamlne, amyl nitrite and other compounds
capable of generating methemoglobln as antidotes to acute cyanide poisoning
02730 VII-4 05/20/91
-------
has Us basis 1n this reaction {Smith and Olson, 1973; Way, 1981, 1984).
Hethylene blue has been used as an antidote In the past (Trautman, 1930),
and Its use may still be advocated by some physicians; however, H does not
form met hemoglobin as readily as the nitrites (Hay, 1961)..
!
Although oxygen In Hself Is nol an antagonist, numerous studies have
found that oxygen enhances the antidotal efficacy of the combination of
sodium thlosulfate (a sulfur donor for the rhodanese reaction) and sodium
nitrite (a methemoglobln generator) {Way et al., 1966; Burrows et al., 1973;
Isom and Way. 1974; Sheehy and Way, 1968). Schwartz et al. {1979} found
that pretreatment of mice with pyruvate had a protective effect against
cyanide poisoning. Pyruvate enhanced the antidotal effect of sodium
i
thlosulfate, but not of sodium nitrite. When used 1n combination with
sodium thlosulfate and sodium nitrite, maximum antidotal efficacy was
V!
observed.
c
Administration of compounds that can serve as sulfur donors for
rhodanese may be a useful antidotal approach. Sorbo (1953) compared the
effectiveness of many sulfur containing compounds and concluded that the
structural requirements were for a free sulfur atom to be adjacent to
another sulfur atom In the molecule. Frankenberg (1980) Injected mice
.Intravenously with bovine liver rhodanese and a sulfur donor, following the
administration of cyanide and found the enzyme to have an antidotal effect
on cyanide poisoning. Dlsulfonlc add (DIDS) has been found to reduce
cyanide-Induced contractions In vitro by blocking 1on1c channel mechanisms
that facilitate the entry of cyanide .Into vascular smooth muscle cells
(Robinson et al.. 1985).
02730 VII-5 ' 05/20/91
-------
Cobalt and cobalt containing' compounds, such as vitamin B,. (hydroxo-
cobalamln) (Mushett et al., 1952), cobalt-EDTA (Oavlson, 1969; Frledberg and
Schwarzkopf, 1969) and cobaltous hlstldlne (Frledberg and Schwarzkopf, 1969)
have been used as effective antidotes to cyanide toxldty because of the
affinity of cyanide for cobalt.
Summary
Cyanide exerts Us acute toxic effect by forming a complex with Fe**+
In cytochrome oxldase, the terminal enzyme 1n the mitochondria! electron
transport chain, thereby Inhibiting utilization of oxygen by cells (01-
Palma, 1971). The Inhibition results In hlstotoxlc hypoxla, preventing
oxldatlve phosphorylatlon. There Is a shift to anaerobic metabolism. The
CMS and the heart are particularly sensitive to hypoxla, and toxldty 1s
manifested.. Cyanide can complex with other compounds that contain metals,
but the reaction with cytochrome oxldase Is the most Important, toxlco-
loglcally. Cyanide 1s detoxified by the enzymatic activity of rhodanese,
which transfers sulfur from a donor molecule to cyanide to form thlocyanate.
Chronic cyanide exposure may contribute to the etiology of neurologic
and optical disorders (tobacco amblyopla, tropical neuropathy, Leber's
hereditary optic atrophy), since repeated Insults of hypoxla to neurologic
tissue results 1n demyellnatlon and necrosis of.'many tissues of the CNS,
Including the optic nerve In animals (Ferraro, 1933; lessen, 1971; Lessen
and Kuwabara, 1974; Smith et al., 1963). Defects In cyanide metabolism,
along with nutritional deficiencies of protein and vitamin BI?, are
believed to be Involved (Wilson, 1983). The goltrogenic effect of cyanide
may be due to thlocyanate, which Inhibits the uptake of Iodine by the
thyroid (Erriians et al., 1972).
02730 vi-I-6 05/20/91
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Synerglstlc effects may occur If cyanide exposure is accompanied by
>
exposures to other substances known to Inhibit cytochrome oxldase, such as
sulflde and azlde (Smith and Gosselln, 1979). Ascorbate potentiated the
toxldty of cyanide In guinea pigs, perhaps by reacting with cystelne and
thereby preventing cystelne from acting as a sulfur donor for rhodanese
(Basu, 1983).
Cyanide poisoning can be antagonized by methemoglobin, or any compound
that can generate methemoglobin U» vivo, such as sodium nitrite {Way, 1981,
1984). .Oxygen enhances the antidotal efficacy of sodium thlosulfate and
sod.lum nitrite (Hay, 1981). as does pyruvate (Schwartz et al.t 1979).
Cyanide probably reacts with the carbonyl group of pyruvate to yield a
cyanohydMn. Any compound that can act as a sulfur donor for rhodanese
would be a cyanide antagonist (Sorbo, 1953), and treatment with rhodanese
y
Itself was an effective antidote {Frankenberg, 1980). Cobalt containing^
*
compounds have also been used as effective anUdo,U-s to cyanide poisoning .
(Mushett et al... 1952; Davlson, 1969; Frledberg and Schwarzkopf, 1969).
02730 VII-7 05/20/91
-------
-------
VIII. QUANTIFICATION OF TOXICOLOGIC EFFECTS
Introduction
The quantification of tpxlcologlc effects of a chemical consists of
separate assessments of noncardnogenlc and. carcinogenic health effects.
Chemicals that do not produce carcinogenic effects5 are believed to have a
threshold dose below which no adverse, noncarclnogenlc health effects occur,
while carcinogens are assumed to act without a threshold.
In the quantification of noncardnogenlc effects, a Reference Dose
(RfD), (formerly termed the Acceptable Dally Intake (ADI)] 1s calculated.
The RfO Is an estimate (with uncertainty spanning perhaps an order of magni-
tude) of a dally exposure to the human population (Including sensitive
subgroups) that Is likely to be without an appreciable risk of deleterious
health effects during a lifetime. The RfD 1s derived from a no-observed-
adverse-effect level (NOAEL), or lowest-observed-adverse-effect level
(LOAEL), Identified from a subchronlc or chronic study, and divided by an
uncertainty factor(s) times a modifying factor. The RfD 1s calculated as
follows:
RfD . ("OAEL or LOAEL> = . mg/kg bw/day
[Uncertainty Factor(s) x Modifying Factor]
Selection of the uncertainty factor (UF) to be employed 1n the
calculation of the RfD Is based upon professional judgment, while
considering the entire data base of toxlcologlc effects for the chemical.
In order to ensure that uncertainty factors are selected and applied 1n a
consistent manner, the U.S. EPA (1991) employs a modification to the
02740 VIII-1 05/20/91
-------
guidelines proposed by the National Academy of Sciences (NAS, 1977, 1980) as
follows: . .
Standard Uncertainty Factors (UFs)
Use a 10-fold factor when extrapolating from valid experimental
results from studies using prolonged exposure to average healthy
humans. This factor 1s Intended to account for the variation
1n sensitivity among the members of the human population. [10H]
Use an additional 10-fold factor when extrapolating from valid
results of long-term studies on experimental animals when
results of studies of human exposure are not available or are .
Inadequate. This factor 1s Intended to account for the uncer-
tainty In extrapolating animal data to the case of humans.
[IDA]
Use an additional 10-fold factor when extrapolating from less
than chronic results on experimental animals when there Is no
useful long-term human data. This factor Is Intended to
account for . the uncertainty In extrapolating from less than
chronic NOAELs to chronic NOAELs. [10S]
Use an additional 10-fold factor when deriving an RfD from a
LOAEL Instead of a NOAEL. This factor 1s Intended to account
for the uncertainty In extrapolating from LOAELs to NOAELs.
, POL] .
Modifying Factor (MF)
Use professional Judgment to determine another uncertainty
factor (MF) that 1s greater than zero and less than or equal to
TO. The magnitude of the MF depends upon the professional
assessment of scientific uncertainties of the study and data
base not explicitly treated above, e.g., the completeness of
the overall data base and the number of species tested. The
default value for the MF Is 1.
The uncertainty factor used for a specific risk assessment 1s based
principally upon scientific judgment rather than scientific fact and
accounts for possible 1ntra- and Interspedes differences. Additional
considerations not Incorporated In the NAS/ODW guidelines for selection of
an uncertainty factor Include the use of a less than lifetime study for
deriving an RfD, the significance of the adverse health effects and the
counterbalancing of beneficial effects.
02740
VIII.-2
08/31/88
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From the RfD, a Drinking Water Equivalent Level (DWEL) can be calcu-
lated. The DWEL represents a medium specific , (I.e., drinking water)
lifetime exposure at which adverse, noncarclnogenlc health effects are not
anticipated to occur. The DWEL assumes 100% exposure from drinking water.
The DWEL provides the noncardnogenlc health effects basis for establishing
a drinking water standard. For 1ngest1on data, the DWEL Is derived as
.follows: ,
DWEL = (RfD) x (Bo(*y weight In kg) _
Drinking Water Volume In 4/day ~ -
where:
Body weight = assumed to be 70 kg for an adult
Drinking water volume = assumed to be 2 l/day for an adult
In addition to the RfD and the DWEL, Health Advisories (HAs) for expo-
i
sures of shorter duration (1-day, 10-day and longer-term) are determined.^
The HA values are used as Informal guidance to municipalities and other
organizations when emergency spills or contamination situations occur. The"
HAs are calculated using an equation similar to the RfD and DWEl; however,
the NOAELs or LOAELs are Identified from acute or suochronlc studies. The
HAs are derived as follows:
HA (HOAEL or LOAEL) x (bw) "
HA « ' - * =.____ mg/i
(UF) x ( _ i/day)
Using the above equation, the following drinking water HAs are developed
for noncardnogenlc effects:
1. 1-day HA for a 10 kg child Ingesting 1 I water per day.
2. 10-day HA for a 10 kg child Ingesting 1 i water per day.
3. Longer-term HA for. a 10 kg child Ingesting V I water per day.
4. Longer-term HA for a 70 kg adult Ingesting 2.1 water per day.
02740 VIII-3 09/22/87
-------
The 1-day HA calculated for a 10 kg child assumes a single acute
exposure to the chemical and Is generally derived from a study of
-------
estimates usually come from lifetime exposure studies using animals. In
order to predict the risk for humans from an.lmal data, animal doses must be
converted to equivalent human doses. This conversion Includes correction
for noncontlnuous exposure, less than lifetime studies and.for differences
1n size. The factor that compensates for the size difference Is the cube
root of the ratio of the animal and human body weights. It Is assumed that
the average adult human body weight 1s 70 kg and that the average water
consumption of an adult human.1s 2 a of water per day.
For contaminants with a carcinogenic, potential, chemical levels are
correlated with a carcinogenic risk estimate by employing a cancer potency
(unit risk) value together with the assumption for lifetime exposure from
Ingestlon of water. The cancer unit risk Is usually derived from a linear-
ized multistage model with a 95% upper confidence limit providing a low dose
estimate; that 1s, the true risk, to humans, while not Identifiable, Is not
likely to exceed the upper limit estimate and, 1n fact, may be lower.
Excess cancer risk estimates may also be calculated using other models such
as ,the one-hit, .Helbull, loglt and probH, There. 1s Uttle basis In the
current understanding of the biological mechanisms Involved In cancer to
suggest that any one of these models Is able to predict risk more accurately
than any other. Because each model 1s based upon, differing assumptions, the
estimates derived for each model can differ by several orders of magnitude.
The scientific data base used to calculate and. support the setting of
cancer risk rate levels has an Inherent uncertainty that Is due to the
systematic and random errors In scientific measurement. In most cases, only
studies using experimental animals have been performed. Thus, there Is
02740 VIII-5 09/22/87
-------
uncertainty when the data are extrapolated to humans. When developing
cancer risk rate levels, several other areas of uncertainty exist, such as
the Incomplete knowledge concerning the health effects of contaminants 1n
drinking water, the .Impact of the experimental animal's age, sex and
species, the nature of the target organ system(s) examined and the actual
rate of exposure of the Internal targets In experimental animals or humans.
Dose-response data usually are available only for high levels of exposure
and not for the lower levels of exposure closer to where a standard may be
set. When there Is exposure to more than one contaminant, additional
uncertainty results from a lack of Information about possible synerglstlc or
antagonistic effects.
Noncarclnoqenlc Effects
Cyanides are readily absorbed from the lungs, the 61 tract and the skin
by animals and humans. Inhalation exposure to HCN provides the most rapid
rate of entry, resulting In the most rapid onset of toxic effects. Absorp-
tion also occurs rapidly by 1ngest1on of the cyanide salts, KCN and NaCN, by
dermal exposure to HCN, aqueous solutions of HCN (hydrocyanic add), KCN and
NaCN.
Several studies reported quantitative absorption data In animals and
humans (Settler and Balne, 1938; L1ebow1tz and Schwartz, 1948; Lendle, 1964;
McNamara, 1976). These studies suggest that the absolute amount absorbed
was relatively constant and not related to the time between administration
and death.
02740
VIII-6
05/20/91
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The main site, of cyanide detoxification 1s In the liver via the
enzymatic action of rhodanese (the detoxifying enzyme 1n the liver) to form
the less toxic thlocyanate. Differences among species with respect to
distribution of rhodanese may account In part for .their differences 1n
sensitivity to cyanide. Dogs were found to have very low levels of
rhodanese. Monkeys, rabbits and rats had hepatic levels -10-18 times higher
t
than dogs (Hlmwlch and Saunders, 1948). Total levels of the enzyme 1n all
tissues, except the adrenals, were lower In dogs than In the other species.
Levels of rhodanese 1n other species, Including humans, have not been
reported.
The major route of cyanide elimination from the body 1s via urinary
excretion of thlocyanate. Rats eliminated 80% of subcutaneously-lnjected
cyanide as thlocyanate 1n the urine, while 15X was eliminated as urinary:
2-1m1no-4-th1azol1d1ne carboxyllc acid (Hood and Cooley, 1956). A man who=i-
had Ingested 3-5 g (at least 1.2 g HCN was present- In blood 3 hours later)T
eliminated a total of 237 mg thlocyanate In 72-hour urine (Uebowltz and
Schwartz, 1948). ; .
Short-Term Exposure. -In animals, acute LD5Q values for cyanide
range from -0.91 mg CN~/kg by Intramuscular administration 1n rabbits, to
6.3 mg CN~/kg by oral Ingestlon In mice. Acute ID values are summa-
rized In Table VIII-1. For comparison purposes all doses are presented as
the dose of the administered compound as well as the equivalent dose of
cyanide 1on (CN~).
A dermal LD5Q for HCN In humans has been estimated to be 100 mg/kg
(DIPalma, 1971).
02740 VIII-7 08/31/88
-------
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Most of the studies on the health effects of oral exposure to cyanides
In animals have been conducted using KCN, although NaCN has also been admin-
istered 1n some studies. Few studies on acute oral toxldty of cyanides
providing dose-response data were encountered. Oral {via gastric Intuba-
tion) doses of KCN equivalent to 4.0 and 6.0 mg CfT/kg were fatal to rats
and mice, respectively (Ferguson, 1962). Increasing the volume of water 1n
which the dose was administered had the effect of Increasing the Incidence
of death 1n the animals. Data are not available that Indicate an effect of
vehicle volume at sublethal doses.
Of 8 guinea pigs administered a single oral dose of KCN equivalent to
3.2 mg CN~/kg, 5 had no signs of toxldty; the other 3 had slight tremors
from which they recovered within 15 minutes (Basu, 1983). It should be
noted that this low effect level In guinea pigs Is .equal to. the LD5Q In
mice.
Rats can tolerate higher doses of cyanide when administered 1n the diet
than when administered orally by gavage. The GI absorption following
Intermittent Ingestlon of low doses of cyanide over a day may allow for
sufficient detoxlcatlon to occur (see Chapter V). Sherman rats survived 25
dally doses of 4 mg CN"/kg bw when given as KCN mixed with the food
(Hayes, 1967). This dally dose 1s equal to the acute oral LD5Q In aqueous
vehicle in the same strain of rats.
Hale Sprague-Dawley rats (70 g, 7 rats/group) tolerated KCN at a level
of 0.08 mg CN"/ma when KCN was dissolved 1n the drinking water for 21
days {Palmer and Olson, 1979). This dose can be calculated as 12 mg
CN /kg/day by assuming that a young growing rat consumes an amount of
02740
VIII-10
05/20/91
-------
water equal to -15X of Us body weight each day. The 1ngest1on of water by
rats 1s Intermittent, thus GI absorption Is Intermittent, as In the case of
dietary doses. There was no effect on body weight gain, but there was a
significant Increase In the average liver weight when compared with controls
(p<0.05). When the KCN was mixed 1n the food at a concentration equivalent
to 80 mg CN~/kg feed, a dally dose of 8 mg CN'/kg bw (calculated by
assuming that a young growing rat. In a subchronlc study, consumes an amount
of food equal to -10X of Its body weight per day), did not result 1n
Increased liver weight. Potassium cyanide In the diet may have been more
slowly absorbed than KCN In water due to physical 'Interference with
absorption or possible Influence of chemical Interactions of cyanide with
components of the food. The Sprague-Dawley rats used In this study (Palmer
and Olson, 1979) were not examined historically,: but African giant rats
(Crlcetomys gamblanus. Haterhouse), maintained on diets containing 1000 mg
CN~/kg diet (dally dose of 36 mg CN"/kg bw) forj 84 days did not have
hlstopathologlc lesions 1n the thymus, kidney, liver and spleen (Tewe,
1982}. Thus, a dally dose of 8 'mg CN~/kg bw administered orally 1n food
(Palmer and Olson, 1979) is a NOAEL for Increased Hyer weight 1ri rats.
In a dietary study conducted by the American Cyanamld Co. (1959), three
male and two female beagle dogs received NaCN mixed with food for 30-32
days. One male and one female dog served as controls. Each meal, which the
dogs consumed completely, contained 24 mg CN~. The average weight of the
dogs was 7.6 kg; therefore, the dally dose was ~3 mg CN~/kg bw. There
were no effects during the dietary study on body weight, hemoglobin content,
hematocrlt or differential white cell count. No treatment-related hlsto-
pathologlc lesions or organ-to-body weight ratio changes were . observed
during exhaustive histologic examinations. A single gavage dose at this
02740 VIII-11 08/31/88
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level in dogs resulted In death in another study (Gettler and Balne, 1938).
/
Dogs receiving 1.5, 4.3 and 8.1 mg CN~/kg bw as, single oral doses of KCN
died In 155, 21 and 8.minutes, respectively. In the American Cyanamld study
the dogs tolerated the higher dose because absorption may have been slowed
due to the presence of food In the stomach.
Isom et al. (1982) studied the dose-response relationship of Intraperl-
toneally administered KCN 1n male Swiss-Webster mice (4/group}. The dose-
dependent toxic signs Included agitation, uncoordinated movement; gasping,
Irregular breathing, convulsion, respiratory arrest and death. At doses of
KCN equivalent to 0.4 and 0.8 mg CN"/kg bw, these" signs were "barely
detectable.". At doses of 1.2, 1.6 and 2.0 mg CN"/kg bw, the mice started
gasping,.and had irregular respiration and convulsions within 2-3 minutes of
cyanide administration. At 2.4 mg CN~/kg bw, the toxic signs were more
severe and 20% of the mice died. At doses >2.4 mg CN~/kg bw (not speci-
fied), all the mice died within 4 minutes. Assuming that "barely detect-
able" means that the mice were slightly agitated and breathed slightly more
rapidly, 0.8 mg CN~/kg bw may represent a LOAEL and 0.4 mg CN~/kg bw
probably represents a NOAEL for 1ntraper1tonea1ly administered cyanide In
mice. Because cyanide 1s rapidly absorbed from the 61 tract and Is rapidly
detoxified on first passage through the liver, the effects of 1ntraper1to-
neal administration may well be equivalent to the effects of oral admini-
stration. Data shown 1n Table VIII-1 indicate that the Intraperltoneal
L050 and the oral L05Q In mice (3.2 and 3.4 mg CN~/kg bw, respec-
tively) are essentially equivalent.
02740
VIII-12
08/31/88
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The administration of NaCN by osmotic mlnlpumps, Implanted subcutane-
ously 1n pregnant hamsters on days 6-9 of gestation, -resulted 1n severe
teratogenlc effects (Ooherty et al., 1982). The pumps delivered NaCN at
rates of -0.1275 mmole NaCN/kg bw or a dally dose of 150 mg NaCN/kg bw (80
mg CN'/kg bw). This study has little relevance to: the risk assessment due
to the high dose of cyanide and the method of administration, which was
chosen In order to mimic the slow release of cyanide from nltrlles during In
vivo metabolism.
In an acute study, a man and a dog were exposed1 to HCN gas (between 500
and 625 ppm) simultaneously In an Inhalation chamber (Barcroft, 1931). The
man mimicked the movements of the dog, to approximate the same degree of
activity, until the dog collapsed and went Into convulsion. The man then
exited the chamber with no symptoms except mild nausea and a sense of con-
fusion. The dog was removed from the chamber and was believed to be dead,
but subsequently recovered. !
Information on the acute effects of Ingestlon of cyanides 1n humans has
t
been obtained from case reports of suicide attempt's^. For HCN taken orally,
absorbed doses of 0.5-3.5 mg HCN/kg bw (0.48-3.4 mg CN~/kg bw} are fatal
(Gettler and St. George; 1934; Gosselln et al., 1976; Ermans et al., 1972).
Lethal doses of NaCN or KCN were reported to range from 50-200 mg or 0.7-2.9
mg/kg bw for a 70 kg human (-0.3-1.5 mg CN~/kg' bw) (Hartung, 1982;
DlPalma, 1971). However, a case was reported 1n which a man recovered, fol-
lowing Ingestlon of 3-5 g of KCN (-15 mg CN"/kg bw was absorbed)
(LlebowHz and Schwartz, 1948). '. ' '
02740 VIII-13 08/31/88
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Bodansky and Levy (.1923) administered cyanide orally In a capsule to 25
human subjects on 2 consecutive days. The capsules contained 15 mg of KCNS
on the first day and 10 mg KCN on the second day. Assuming that the average
body weight of humans Is 70 kg, the doses were 0.21 mg KCNS and 0.14 mg
KCN/kg bw or 0.06 mg CN~/kg bw. The subjects effectively detoxified these
doses as determined from measurements of thlocyanate levels In saliva. The
subjects did not complain of any symptoms. While a dally .dose of 0,06 mg
CN~/kg bw thus exerted no acute oral effect In humans, It does not
necessarily represent the maximum no-effect level.
Long-Term Exposure. In a 2-year dietary study, Carworth Farms rats
(10 anlmals/sex/group) were administered diets fumigated with HCN (Howard
and Hanzal, 1955). Diets contained 0, 100 or 300 mg HCN/kg. Results of the
residue analyses (done to measure evaporation loss) Indicated that In 2 days
the dietary concentration of HCN fell, on an average, from 100 to 51.9 mg/kg
diet for the low-dose level and from 300 to 80.1 mg/kg diet for the high-
dose level. The average dally low and high concentrations were -76 and 190
mg HCN/kg diet (73 and 183 mg. CN~/kg diet), repectlvely. From data on
reported food consumption and body weight, the estimated dally doses were
3.6 and 4.6 mg CN~/kg bw for the low-dose males and females, respectively,
and 7.5 and 10.8 mg CN~/kg bw for the high-dose males and females, respec-
tively. There were no treatment-related effects on growth rate, no gross
signs of toxldty, nor any effects on organ-to-body weight ratios for liver,
kidney, spleen, brain, heart, adrenals or gonads. There were no hlstopatho-
loglc lesions of the heart, lung, liver, spleen, stomach, Intestines,
kidney, adrenal, testes, uterus, ovary, cerebrum or cerebellum. The number
of animals hlstologlcally examined was not specified, but H was stated as a
02740
VIII-14
08/31/88
-------
"representative" number. Thus, the dally doses of 3.6 and 7.5 mg CN~/kg.
bw (for males) and 4.6 and 10.8 mg CN~/kg bw (for females) appear to be
no-adverse-effect levels for 2-year cyanide feeding to rats.
Phllbrlck et al. (1979) fed KCN In the diet to a group of 10 male rats
(strain not specified) for 11.5 months at a concentration of 1500 mg KCN/kg
diet (600 mg CN~/kg diet). Another group of 10 rats served as the con-
trol. Assuming that a rat 1n a long-term feeding study consumes a quantity
of food equal to -5% of Us body weight, the dietary level corresponds to a
dally dose of -30 mg CN~/kg bw. When compared with controls, the treated
rats had-a 40% reduction In mean body weight gain, 53% decrease 1n plasma
thyroxlne levels'and .68% decrease 1n t'hyroxlne secretion rates. There were
no definitive hlstopathologlc lesions to thyroid, sciatic, optic or other
neural tissue. M1ld degenerative changes 1n the my'eHn of the spinal cord
were observed. Thus, a dally dose of 30 mg CN~/kg bw was a LOAEL for
dietary cyanide 1n rats. ;
Herttlng et al. (1960) treated three dogs orally with NaCN'ln a gelatin
capsule for up to 14.5 months. There was one control dog. Treatments were
as 'follows: dog I received a dally dose of 0.27!mg CN~/kg bw for 13.5
months; dog II received a dally dose of 0.53 mg CN'/kg bw for 16 weeks and
then . a dally dose of 2.2 mg CN~/kg bw for -10.5 months longer; dog III
received a dally dose of 1.1 mg CN~/kg bw for 14.5 months. When dally
doses XJ.53 -mg CN~/kg bw -were administered, there were signs of acute
Intoxication Immediately after dosing; however, recovery occurred In <0.5
hours. In all treated dogs, hlstologk examination revealed degeneration of
CNS ganglion cells and necrosis and Inflammation of Purklnje cells of the
02740 VIII-15 08/31/88
-------
cerebellum. Thus, a no-effect level In dogs cannot be Identified. The
finding of hlstologlc damage to the CMS of dogs following subchronlc.oral
dosing with low levels of cyanide may reflect the greater, sensitivity of
dogs to cyanide poisoning. Dogs have a decreased ability to detoxify
cyanide since levels of rhodanese are very low 1n the dog, especially 1n the
liver, when compared with rats, rabbits and monkeys (H1mw1ch and Saunders,
1948).
No Information was available on chronic oral exposure of humans to HCN,
KCN or NaCN. Chronic 1ngest1on of cyanogenlc plants, such as cassava, a
root food that forms the staple diet of people living In certain tropical
areas of Africa, has been associated with the etiology of neuropathies and
thyroid disorders (Osuntokun, 1972; Delange and Ermans, 1971). Exposure,
however, was to llnamarln and lotaustralln, cyanogenlc glycosldes contained
In cassava, 1n addition to cyanide per se. Other complicating factors, such
as vitamin B,?, protein and Iodine deficiencies also played a role
(Wilson, .1983).
Quantification of Noncardnoqenlc Effects
Derivation of 1-Day HA. No suitable study was Identified from which
to calculate a 1-day health advisory. The results of Bodansky and Levy
(1923) refer to one arbitrarily chosen low dose of cyanide and provide
little Indication of permissible loads. Indeed, If these results were used,
the resultant 1-day HA would actually fall below those criteria estimated
from the more extensive results for more prolonged exposure. Thus, It Is
recommended that the 1-day HA be set at the same level as the 10-day HA.
02740
VIII-16
08/31/88
-------
Derivation of 10-Day HA. The study by Palmer and Olson (1979) could
be used for the derivation of the 10-day HA. Using this data, the 10-day HA
for a 10 kg child could be calculated as follows:
10 dav HA _ (8 mg CN /kg bo/dav) (10 kg)
(1 i/day) (100} (5)
= 0.16 mg CN~/i (rounded 0.2 rag CN/l)
I
where: .
8 mg CNVkg bw/day = NOAEL for effects on liver weight
or body weight 1n rats following a
21 day exposure via food (Palmer and
Olson, 1979)
10 kg = assumed weight of a child
1 i/day = assumed water consumption by a child
100 = uncertainty factor. An uncertainty
factor of 100 1s selected based upon
U.S. EPA (1991) andiNAS/ODW guide-
lines In which a NOAEL from an .
animal study Is used.
5 = modifying factor. A modifying
factor of 5 1s selected because of
the possible problems associated
with the use of a dietary study to
estimate a drinking water criterion.
However, H 1s recommended that the DHEL of 0.7 mg/t be used for the child
1-day and 10-day HAs. The NOAEL of 10.8 mg/kg/day used for the DHEL comes
from, a study where the animals were exposed for ,2 years; the 8 mg/kg/day
NOAEL Is from a study where animals were exposed for only 21 days.
Therefore, because there were no adverse effects when the exposure was for a
longer time at higher levels, the DWEL of 0.7 mg/i would be protective for
the child 1-day and 10-day exposures also. The; corresponding 1-day and
10-day HAs for a 10 kg child consuming 1 l of water would be 0.2 mg/l.
02740 VIII-17 05/20/91
-------
. Derivation of Longer-Term HA. The .available data are Insufficient to
develop longer-term HAs for cyanide. It Is recommended that the OWEL of 0.7
mg/a be used as the longer-term HA for the 70 kg adult and the modified
DWEL of 0.2 mg/i (adjusted for a 10 kg child) be used for the longer-term
HA for a 10 kg child.
Assessment of lifetime Exposure and Derivation of a OHEL. The study
by Howard and Hanzal (1955) has been selected to serve as the basis for an
RfD and lifetime DWFl because H Is the only long-term study for which a
NOAEL was Identified. In this study female rats (Cartworth Farm) exposed to
4.6 or 10.8 mg CN/kg bw for 2 years experienced no adverse effects. An RfD
of 0.02 mg/kg/day was verified (verification date 03/23/88) by the Agency-
wide RfD Workgroup using the 10.8 mg/kg bw dose as a NOAEL (U.S. EPA, 1991}.
In deriving dally doses, certain assumptions and decisions are made as
follows:
1. The HCN concentrations reported by the authors are converted to
CN" concentrations on a molecular weight basis.
2. The body weight data presented by the authors are used rather
than employing the assumption that a rat weighs an average of
350 g over Us Ufespan (45 FR 79352, November 28, 1980). The
average body weights for all exposure groups are estimated from
the growth charts using linear Interpolation to estimate miss-
Ing data points.
3. The food consumption data presented by the -authors are used
rather than assuming an .average food consumption for all dose.
groups.
4. Average CN~ concentrations over the life of the experiment
are estimated from the data presented by the authors and by
assuming that the rate of loss of HCN can be described by a
first-order process.
02740
VIII-18
05/20/91
-------
5. It 1s Inappropriate to use a net absorption coefficient to
account for presumed differences In the absorption of CN~ 1n
food vs. drinking water. However, there Is a given measure of
uncertainty associated with the use of a dietary study to
estimate a drinking water criterion, thus, an additional 5-fold
uncertainty factor 1s used.
Thus, the data are:
Average Food
Dose Group Average Concentration Consumption Body Weight
(mg CNVkg diet) (av. g/rat/day) (g)
Low male
High male
Low female
High female
73
183
73
183
19.46
18.50
14.69
17.24
390
394
232
255
Average dally doses are calculated as follows:
i
low dose male:
(73 mg CNVkg diet x 0.01946 kg)/0.390 kg = 3.6 mg CNVkg bw/day
high dose male:
(183 mg CNVkg diet x 0.01850 kg)/0.394 kg *!7.5 mg CNVkg bw/day
low dose female: t
(73 mg CNVkg diet x 0.01469 kg)/0.232 kg = 4.6 mg CNVkg bw/day
high dose female:
(183 mg CNVkg diet x 0.01724 kg)/0.255 kg = 10.8 mg CNVkg bw/day
;
Step 1 - RfD Derivation
RfD
(10.8 mq CN /ko bwl
(100) (5)
0.022 mg/kg/day (rounded to 0.02 mg/kg/day)
where: 10.8 mg CNVkg bw
NOAEL for absence of clinical- and
hlstologlc effects 1n a 2-year
dietary study In rats (Howard and
Hanzal, 195b). j
02740
VIII-19
05/20/91
-------
100
uncertainty factor. An uncertainty
factor of TOO Is selected based upon
U.S. EPA (1991) and NAS/ODW guide-
lines In which a NOAEL from an
animal study 1s used.
modifying factor. A modifying
factor of 5 Is selected due .to
possible problems associated with
the use of a dietary study to
estimate a drinking water criterion.
Step 2 - DUEL Derivation
nun 0.02 mo/ka/day x 70 ko
DHEL = -
ng/l (70°
where:
0.02 mg/kg/day = RfD
2 I/day = assumed water consumption by an adult
70 kg = assumed body weight of an adult
This DWEL calculation assumes 100X of the human exposure derives from
drinking water. The DWEL may be modified upon the availability of relative
source contribution data providing human exposure estimates from food, air
and possibly the occupational environment. The ultimate goal 1s to estab-
lish a DUEL so that human exposure from all sources does not exceed the RfD.
Carcinogenic Effects
Potassium cyanide was negative for reverse mutation In five strains of
Salmonella typhlmurlum. with and without metabolic activation (De Flora,
1981). A marginally positive response was obtained 1n strain TA100 with HCN
gas (Kushl et a!., 1983). Cyanide was also negative in a modified rec assay
In Bacillus sufatllls (Karube et al., 1981).
02740
VIII-20
05/20/91
-------
Quantification of Carcinogenic Effects
Studies ipyarcHng the cardnogenUHy of cyanide were not located 1n the
available literature. The lack of information concerning the carcinogenic
potential of cyanide precludes any further analysis of carcinogenic
potential. The International Agency for Research on Cancer (IARC) has not
evaluated the carcinogenic potential of cyanide (WHO, 1982). Applying the
criteria described In U.S. EPA (1986) Guidelines for Carcinogen Risk
Assessment, cyanide has been classified 1n Group 0: not classifiable In this
case due to a lack of bloassay studies. This category 1s for agents with
Inadequate or Insufficient human and animal studies for carclnogenldty.
Existing Guidelines. Recommendations and Standards ;
The ambient water quality criterion has been proposed at 3.77 mg
CN~/a assuming that a 70 kg human consumes 2 I of water and 6.5 g of...
<&
fish per day with a bloconcentratlon factor of 1.0 (U.S. EPA, 198?).
The U.S. Public Health Service (1962) recommended that concentrations of
cyanide In water supplies not exceed .0.2 mg CN~/a. In order to protect
human health. The value appears to be calculated'from the TLV, which gives
a water level of -19 mg/i followed by the application of a 100-fold uncer-
tainty factor. This uncertainty factor was used due to the steep dose-
effect relationship observed for cyanide when body levels exceed detoxifi-
cation capacity. The U.S. Public Health Service (1962) also it-commended
that, concentrations 1n drinking water be kept b'elow 0.01 mg CN'/i since
this level or lower can be achieved by proper treatment.
027.40 . VIII-21 ! 05/20/91
-------
A TLV for alkali cyanides In workroom air of 5 mg CN~/m3 Is recom-
mended "by the ACGIH (1980) based upon Irritation to the respiratory -system
as well as protection from the effects of chronic exposure. The TLV of 5 mg
CN"/m3 was also recommended by NIOSH (1976} and adopted by OSHA (1981).
Special Group at Risk
The* only special considerations Identified for cyanide exposure were the
potential effects to high risk subpopulatlons. Infants and fetuses may be
at higher risk to cyanide. Pregnant hamsters exposed to high doses (>78
mg/kg) of cyanide experienced severe teratogenlc effects (Doherty et a!.,
1982). Andrews (1973) found that pregnant women who smoke have higher
levels of plasma thlocyanate In blood than nonsmokers. It has been
suggested that cyanide exposure may result In low body weight Infants.
A metabolic disturbance 1n the conversion of cyanide to thlocyanate and
vitamin 8.. deficiency has been associated with such conditions as tobacco
amblyopla and Leber's hereditary optic atrophy 1n persons who are exposed to
excess cyanide 1n tobacco smoke (Wilson, 1983). Iodine deficiency, along
with excess exposure to cyanide, may be Involved 1n the etiology of such
thyroid disorders as goiter and cretinism (Delange and Ermans, 1971; Ermans
et a!., 1972). Protein deficiencies, vitamin B.. and Mboflavln deficien-
cies may subject people 1n the tropics who eat cassava, a cyanogenlc plant,
to Increased risks of tropical neuropathies (Osuntokun, 1972; Osuntokun et
al., 1969; Makene and Wilson, 1972). Therefore, Individuals with a meta-
bolic defect 1n the rhodanese system, a vitamin B,- deficiency or
defective B,. metabolism, Iodine deficiency, protein deficiency as well as
fetuses exposed J[n utero. are at a higher risk to the toxic effects of
cyanide exposure than the general population.
02740
VIII-22
05/20/91
-------
Additional groups at a higher risk may be strict vegetarians who may
become vitamin BI? deficient and people unable to smell cyanide;
Summary
The recommended values for the 1-day and 10-day HAs for the child and
longer-term HAs for both adults and children and the OHEL are summarized In
Table VIII-2.
02740
VIII-23
05/20/91
-------
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