Toxicity Profiles
Toxicity Summary for CYANIDE
NOTE:
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were correct at the time they were produced, these values are subject to change.
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Toxicity Value Database
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- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
February 1994
Prepared by Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.
Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under
Contract No. DE-AC05-84OR21400
EXECUTIVE SUMMARY
Cyanide most commonly occurs as hydrogen cyanide and its salts--sodium and potassium
cyanide. Cyanides are both man-made and naturally occurring substances. They are found in
several plant species as cyanogenic glycosides and are produced by certain bacteria, fungi, and
algae. In very small amounts, cyanide is a necessary requirement in the human diet. Cyanides
are released to the environment from industrial sources and car emissions (ATSDR, 1989).
Cyanides are readily absorbed by the inhalation, oral, and dermal routes of exposure. The
central nervous system (CNS) is the primary target organ for cyanide toxicity. Neurotoxicity has
been observed in humans and animals following ingestion and inhalation of cyanides. Cardiac and
respiratory effects, possibly CNS-mediated, have also been reported. Short-term exposure to high
concentrations produces almost immediate collapse, respiratory arrest, and death (Hartung, 1982;
EPA, 1985). Symptoms resulting from occupational exposure to lower concentrations include
breathing difficulties, nervousness, vertigo, headache, nausea, vomiting, precordial pain, and
electrocardiogram (EKG) abnormalities (Carmelo, 1955; El Ghawabi et al., 1975; Sandberg, 1967;
Wuthrich, 1954). Thyroid toxicity has been observed in humans and animals following oral and
inhalation exposure to cyanides (Philbrick et al., 1979; EPA, 1984). In animal studies, cyanides
have produced fetotoxicity and teratogenic effects, including exencephaly, encephalocele, and rib
abnormalities (Doherty et al., 1982; Frakes et al., 1986; Tewe and Maner, 1981b; Willhite, 1982).
Reference doses (RfDs) have been calculated for subchronic and chronic oral exposure to
cyanide and several cyanide compounds (EPA, 1990a-e; 1991a-e). The values, derived from a
single study, are based on a no-observed-adverse-effect level (NOAEL) of 10.8 mg/kg/day for
cyanide in a 2-year dietary study with rats (Howard and Hanzal, 1955). The subchronic and
chronic oral RfDs are 0.02 mg/kg/day for cyanide; 0.04 mg/kg/day for sodium cyanide, calcium
cyanide, and cyanogen; 0.05 mg/kg/day for potassium cyanide, chlorine cyanide, and zinc
cyanide; 0.1 mg/kg/day for silver cyanide; and 0.2 mg/kg/day for potassium silver cyanide. Data
were insufficient to derive a reference concentration (RfC) for cyanide.
No suitable cancer bioassays or epidemiological studies are available to assess the
carcinogenicity of cyanide. Therefore, EPA (1991b) has placed cyanide in weight-of-evidence
group D, not classifiable as to human carcinogenicity.
1. INTRODUCTION
Cyanide (CN-, CAS No. 57-12-5) most commonly occurs as hydrogen cyanide (HCN, CAS
No. 74-90-8) and its salts--sodium cyanide (NaCN, CAS No. 143-33-9) and potassium cyanide
(KCN, CAS No. 151-50-8). Cyanides are ubiquitous in nature, arising from both natural and
anthropogenic sources. Cyanogenic glycosides, producing hydrogen cyanide upon hydrolysis, are
found in a number of plant species. Cyanides are also produced by certain bacteria, fungi, and
algae. Minute amounts of cyanide in the form of vitamin B12 (cyanocobalamine) are a necessary
requirement in the human diet (ATSDR, 1989). Hydrogen cyanide, a colorless liquid with a
characteristic odor of bitter almonds (Verschueren, 1983), has a molecular weight of 27.03 and
a boiling point of 25.6C. It is miscible with water and alcohol and slightly soluble in ether
(Budavari et al., 1989).
Cyanide is released to the environment from numerous sources. Metal finishing and organic
chemical industries as well as iron and steel production are major sources of cyanide releases to
the aquatic environment. More than 90% of emissions to the air are attributed to releases in automobile exhaust. Workers in a wide variety of occupations may be exposed to cyanides. The
general population may be exposed to cyanides by inhalation of contaminated air, ingestion of contaminated drinking water, and/or consumption of a variety of foods (ATSDR, 1989).
2. METABOLISM AND DISPOSITION
2.1 ABSORPTION
Hydrogen cyanide is rapidly absorbed by the gastrointestinal and respiratory tract; the liquid
and possibly the concentrated vapor are absorbed directly through the intact skin (Hartung, 1982;
EPA, 1984). Hydrogen cyanide, a weak acid with a pKa of 9.2, is more rapidly absorbed from
the gastrointestinal tract than cyanide salts (EPA, 1984). Gettler and Baine (1938) calculated that
dogs treated with 20, 50, or 100 mg/kg potassium cyanide by gavage absorbed 72, 24, or 17% of
the administered dose. Absorption of cyanide from smoke inhaled by cigarette smokers is inferred
by higher plasma levels of thiocyanate (a metabolite) in smokers compared to nonsmokers (EPA,
1984). Landahl and Herrmann (1950) reported that humans retained 57-77% of inhaled hydrogen
cyanide in the lungs. Cyanides are moderately lipid-soluble and penetrate the epidermis readily.
In addition, some cyanides, such as potassium cyanide, have a corrosive effect on the skin that increases the rate of dermal absorption (NIOSH, 1976).
2.2 DISTRIBUTION
Following absorption, cyanide is rapidly distributed throughout the body by the blood.
Cyanide enters erythrocytes and is found at low concentrations in normal human blood and other
organs. Transplacental transfer of cyanide can occur. Higher plasma concentrations of
thiocyanate were found in the umbilical cord blood of infants born to smokers compared with those
born to nonsmokers (EPA, 1985). After nonlethal exposure, plasma cyanide levels tend to return
to normal levels within 4-8 hours. The estimated plasma half-life is 20 minutes to 1 hour
(Hartung, 1982). In cases of fatal oral poisoning, cyanide was detected in the brain, blood,
kidney, stomach wall, liver, and urine (Ansell and Lewis, 1970). Gettler and Baine (1938)
reported brain and liver cyanide levels of 0.06-1.37 mg/100 g and 0.22-0.91 mg/100 g tissue,
respectively, in four humans who ingested fatal doses of cyanide. Tissue levels in a human after
inhalation of hydrogen cyanide were 0.75, 0.42, 0.41, 0.33, and 0.32 mg hydrogen cyanide/100
g in the lung, heart, blood, kidney, and brain, respectively. Elevated levels of cyanide were seen
in erythrocytes and elevated levels of thiocyanate in the blood, liver, and kidneys of rats receiving
food fumigated with hydrogen cyanide (Howard and Hanzal, 1955). Results of a drinking water
study with rats indicate that subchronic cyanide administration (up to 160 mg/kg/day potassium
cyanide for 13 weeks) does not lead to saturation of cyanide detoxification pathways (Leuschner
et al., 1991).
2.3 METABOLISM
The principal pathway of cyanide metabolism is conversion to thiocyanate catalyzed by either
rhodanese (thiosulfate sulfurtransferase) or by 3-mercaptopyruvate sulfurtransferase. Both
enzymes are widely distributed in the body. Conversion of cyanide to the less toxic thiocyanate
by rhodanese is enhanced when cyanide poisoning is treated with the intravenous administration
of a sulfur donor such as sodium thiosulfate (ATSDR, 1989; Westley, 1980). The toxicity of
thiocyanate is significantly less than that of cyanide, but chronically elevated levels of blood
thiocyanate can inhibit the uptake of iodine by the thyroid gland, thereby reducing the formation
of thyroxine (Hartung, 1982). Other metabolic pathways include the conversion to 2-aminothiazoline-4-carboxylic acid; incorporation into a 1-carbon (formate) metabolic pool;
combination with hydroxycobalamine to form cyanocobalamine (B12); and combination with cystine
to form 2-aminothiazoline-4-carboxylic acid (ATSDR, 1989).
2.4 EXCRETION
In humans and animals, the major route of cyanide elimination from the body is via urinary
excretion of thiocyanate. Small amounts of thiocyanate are also eliminated via lung and feces
(EPA, 1985). Some free hydrogen cyanide is excreted unchanged in breath, saliva, sweat, and
urine (Hartung, 1982). An increased urinary excretion of thiocyanate was observed in case
hardeners exposed to 4-6 ppm cyanide vapor and cyanide salts over a period of several years
(NIOSH, 1976).
3. NONCARCINOGENIC HEALTH EFFECTS
3.1 ORAL EXPOSURES
3.1.1 Acute Toxicity
3.1.1.1 Human
Hydrogen cyanide and its simple soluble salts such as sodium and potassium cyanide are
among the most rapidly acting poisons with the central nervous system (CNS) as the target organ.
Ingestion of 50-100 mg sodium or potassium cyanide is followed by almost instantaneous collapse
and cessation of respiration. At much lower doses, the earliest symptoms are weakness, headache,
confusion, and occasionally nausea and vomiting. The respiratory rate and depth usually increase
at the beginning and at later stages become slow and gasping. If cyanosis is present, it usually
indicates that respiration has ceased or has been inadequate for some minutes. The most specific
symptom in acute cyanide poisoning is the bright red color of venous blood which is evidence of
the inability of the tissues to use oxygen (Hartung, 1982).
Cyanide exerts its toxic effect by forming a complex with ferric ion (Fe+3) of mitochondrial
cytochrome oxidase, the enzyme that catalyzes the terminal step in the electron transport chain,
thereby preventing use of oxygen by cells. Since cytochrome oxidase occupies a central role in
the use of oxygen in all cells, its inhibition leads to the disruption of cellular respiration producing
cytotoxic hypoxia. In addition to binding to cytochrome oxidase, cyanide combines with approximately 2% of methemoglobin normally present (ATSDR, 1989; U.S. EPA, 1985; Hardy and
Boylen, 1983).
Numerous reports describe suicides or suicide attempts through ingestion of cyanide
compounds (NIOSH, 1976). However, these studies generally do not report dose levels. Wolnik
et al. (1984) reported an incident in which seven persons died after ingestion of capsules of a pain
medication contaminated with 500-800 mg potassium cyanide. Recoveries from ingestion of 3-5 g
potassium cyanide without therapy and up to 6 g potassium cyanide with therapy have been
documented. However, results of oral intoxication with cyanide must be interpreted with caution
because the presence of food in the digestive tract may retard absorption (U.S. Air Force, 1989).
A recent case report described cyanide poisoning in a 2-year-old child who had ingested
acetonitrile in a cosmetic nail glue remover. When ingested, acetonitrile is slowly metabolized to
cyanide, and symptoms of cyanide toxicity develop over a latency period of several hours (Losek
et al., 1991).
3.1.1.2 Animal
Oral LD50s in rats are 8.5 mg/kg for hydrogen cyanide (U.S. Air Force, 1989), 6.4 mg/kg for
sodium cyanide, 10 mg/kg for potassium cyanide, 39 mg/kg for calcium cyanide, 21 mg/kg for
potassium silver cyanide, and 123 mg/kg for silver cyanide (ATSDR, 1989). Gettler and Baine
(1938) reported that dogs treated orally with 20, 50, or 100 mg/kg potassium cyanide died 155,
21, or 8 minutes, respectively, after dosing.
3.1.2 Subchronic Toxicity
3.1.2.1 Human
Information on the subchronic oral toxicity of cyanide to humans was unavailable.
3.1.2.2 Animal
Adult rats exposed to 200 mg potassium cyanide/L drinking water for 21 days had significantly
higher liver weights compared with controls, but no effect on liver weight occurred when
potassium cyanide was administered in the diet at a dose of 200 mg/kg diet (Palmer and Olson,
1979).
No adverse effects were seen in dogs exposed to sodium cyanide at dietary doses of 3 mg
cyanide/kg body weight/day for 30-32 days (EPA, 1985). However, Hertting et al. (1960)
observed degenerative changes (necrosis, reduced RNA content, and inflammation) in ganglion
cells of the CNS of dogs administered sodium cyanide in capsules containing 3 mg cyanide/kg/day
for 15 months.
3.1.3 Chronic Toxicity
3.1.3.1 Human
In tropical regions of Africa, a high incidence of ataxic neuropathy, goiter, amblyopia, and
other disorders has been associated with chronic ingestion of cassava, one of the dietary staples
containing cyanogenic glycosides that release hydrogen cyanide when metabolized in vivo
(EPA, 1984; Westley, 1980). Nutritional deficiencies such as diets low in vitamin B12, riboflavin,
and protein exacerbate the neurotoxic effects of cyanides (Westley, 1980).
3.1.3.2 Animal
Howard and Hanzal (1955) exposed male and female rats to a diet fumigated with hydrogen
cyanide at levels of 0, 76, or 190 mg HCN/kg food for 104 weeks. No treatment-related effects
on growth rate, no gross signs of toxicity, and no histologic lesions in tissues examined were
observed.
Philbrick et al. (1979) treated male rats with 0 or 1500 mg potassium cyanide/kg diet for
11.5 months. Decreased weight gain and primary myelin degeneration of the spinal cord were
seen at the end of the treatment period. Decreased plasma thyroxin levels occurred at 4 months
with recovery by 11 months. Rats maintained on a methionine- or vitamin B12-deficient diet
appeared to be affected more severely.
3.1.4 Developmental and Reproductive Toxicity
3.1.4.1 Human
Congenital hypothyroidism is present in 15% of newborns in certain areas of Zayre where
cassava is a staple food. This incidence is approximately 500 times that observed in industrial
countries (Ermans, 1980).
3.1.4.2 Animal
No adverse effects were observed on reproductive performance or lactation of rats fed 500 mg
cyanide/kg diet throughout gestation and lactation. Litter size, weight of pups at birth, and food
consumption and growth rate of pups were not significantly different from controls (Tewe and
Maner, 1981a). However, fetuses of sows fed 277 or 521 mg cyanide/kg diet throughout gestation
and lactation exhibited decreased organ to body weight ratios for thyroid, heart, and spleen when
compared with those born to sows fed 31 mg cyanide/kg diet for the same time period.
Hyperplasia of the kidney glomeruli and morphological changes in thyroid cells were seen in sows
at all three exposure levels (Tewe and Maner, 1981b).
Frakes et al. (1986) exposed female golden hamsters to cyanogenic glycosides in diets
containing cassava meal on days 3-14 of gestation. The low cyanide cassava contained
approximately 0.6 mmol/kg (46 ppm), and the high cyanide cassava 7.9 mmol/kg (600 ppm)
cyanide. Cassava-fed dams gained less weight than the controls, and the offspring showed reduced
fetal weight and reduced ossification. In another study, hamsters treated orally with 200-275
mg/kg D,L-amygdalin (a cyanogenic glycoside and most common constituent of laetrile) on gestation day 8 exhibited maternal toxicity at doses of 250 mg/kg and greater (Willhite, 1982). Dams
treated simultaneously with thiosulfate were protected from toxicity. Fetuses of amygdalin-treated
dams revealed a dose-related increase in abnormalities such as exencephaly (brain outside skull),
encephalocele (hernia of brain), and rib anomalies, whereas simultaneous treatment with thiosulfate
induced a low incidence of such abnormalities. The teratogenic effects after oral amygdalin
exposure were attributed to cyanide released by bacterial action in the gastrointestinal tract.
3.1.5 Reference Dose
3.1.5.1 Subchronic
ORAL RfDs:
0.02 mg/kg/day (cyanide, free)
0.04 mg/kg/day (sodium cyanide)
0.04 mg/kg/day (calcium cyanide)
0.04 mg/kg/day (cyanogen)
0.05 mg/kg/day (potassium cyanide)
0.05 mg/kg/day (chlorine cyanide)
0.05 mg/kg/day (zinc cyanide)
0.1 mg/kg/day (silver cyanide)
0.2 mg/kg/day (potassium silver cyanide)
(EPA, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 5
PRINCIPAL STUDY: Howard and Hanzal, 1955; derivation reported in EPA, 1990a-e;
1991b-e).
COMMENT: The same study and comments apply to the subchronic and chronic RfD.
The study is described in Subsect. 3.1.3.2.
3.1.5.2 Chronic
ORAL RfDs:
0.02 mg/kg/day (cyanide, free)
0.04 mg/kg/day (sodium cyanide)
0.04 mg/kg/day (calcium cyanide)
0.04 mg/kg/day (cyanogen)
0.05 mg/kg/day (potassium cyanide)
0.05 mg/kg/day (chlorine cyanide)
0.05 mg/kg/day (zinc cyanide)
0.1 mg/kg/day (silver cyanide)
0.2 mg/kg/day (potassium silver cyanide)
(EPA, 1990a-e; 1991b-e)
NOAELs:
10.8 mg/kg/day (cyanide, free)
20.4 mg/kg/day (sodium cyanide)
19.1 mg/kg/day (calcium cyanide)
21.6 mg/kg/day (cyanogen)
27.0 mg/kg/day (potassium cyanide)
25.3 mg/kg/day (chlorine cyanide)
24.3 mg/kg/day (zinc cyanide)
55.7 mg/kg/day (silver cyanide)
82.7 mg/kg/day (potassium silver cyanide)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 5
CONFIDENCE:
Study Medium
Data Base Medium
RfD Medium
VERIFICATION DATES: 08/05/85 (all compounds)
PRINCIPAL STUDY: Howard and Hanzal, 1955; derivation reported in EPA, 1990a-e;
1991b-e)
COMMENTS: All RfD calculations are based on data from one study in which no effects
were observed in rats fed hydrogen cyanide in the diet for 2 years at a level that provided
females a dose of 10.8 mg/kg/day cyanide (NOAEL). The corresponding NOAEL for
each cyanide compound was based on molecular weights. An uncertainty factor (UF) of
100 was used to account for species extrapolation (10) and sensitive populations (10). A
modifying factor (MF) of 5 was used to account for the apparent tolerance to cyanide
when it is ingested with food rather than when it is administered by gavage or in drinking
water.
3.2 INHALATION EXPOSURES
3.2.1 Acute Toxicity
3.2.1.1 Human
Numerous cases of acute cyanide intoxication via inhalation have been cited in the literature.
Of the different routes of exposure and different cyanide compounds, inhalation of hydrogen
cyanide results in the most rapid onset of poisoning, producing almost immediate collapse,
respiratory arrest, and death within minutes (EPA, 1985). Inhalation of 270 ppm is immediately
fatal; exposure to 110-135 ppm is fatal after 1/2-1 hour or longer. The estimated LC50 after 10
minutes is 546 ppm (Hartung, 1982).
3.2.1.2 Animal
Inhalation of cyanide by animals also leads to rapid acute toxicity and death. Higgins et al.
(1972) reported LC50s of 323 ppm for mice and 503 ppm for rats exposed to hydrogen cyanide for
5 minutes. The estimated LC50s for 30-min exposures to hydrogen cyanide are 142 ppm for rats
(U.S. Air Force, 1989), 182 ppm for cats, and 410 ppm for goats (ten Berge et al., 1986). Dogs
exposed to 1.1 or 1.6 mg/kg hydrogen cyanide died following a 10- to 15-min exposure (Gettler
and Baine, 1938). Loss of consciousness, hyperventilation, bradycardia, arrhythmias, and T-wave
abnormalities were observed in monkeys exposed to 87-196 ppm hydrogen cyanide for 30 minutes
(Purser et al., 1984).
3.2.2 Subchronic Toxicity
3.2.2.1 Human
An individual who had been exposed sporadically to cyanide vapor for 6 years exhibited loss
of appetite, nervousness, vertigo, headache, nausea, and vomiting (Wuthrich, 1954). Sandberg
(1967) described symptoms of cyanide toxicity in a goldsmith apprentice who polished gold
5-10 times/day for 4 years and was exposed to cyanide by both inhalation and dermal contact. The
polishing solution used was prepared by adding potassium cyanide to water, heating to boiling, and
then adding hydrogen peroxide; this process liberated hydrogen cyanide gas and splattered the
skin. Symptoms included headache, listlessness, numbness, and partial paralysis of the left arm
and leg, partial loss of vision in the left eye, and an altered EKG. All symptoms disappeared
within 4 months.
3.2.2.2 Animal
No effects on the myocardial ultrastructure were seen in rabbits exposed continuously to
0.55 mg/m3 hydrogen cyanide for 28 days (Hugod, 1981).
3.2.3 Chronic Toxicity
3.2.3.1 Human
El Ghawabi et al. (1975) reported mild to moderate thyroid enlargement and increased uptake
of iodine by the thyroid in 20/36 male electroplating workers exposed to an average of
6.4-10.4 ppm cyanide for 5-15 years. Other symptoms included breathing difficulties, headache,
weakness, changes in smell and taste, giddiness, throat irritation, vomiting, and precordial pain.
Also reported were significantly increased hemoglobin levels and lymphocyte counts. Nonexposed
workers had much lower incidences of these symptoms. Hardy and Boylen (1983) reported
dermatitis, itching, scarlet rash, papules, and severe irritation of the nose leading to obstruction,
bleeding, and in some cases perforation of the septum in electroplaters chronically exposed to
cyanide.
Carmelo (1955) examined a group of 17 cyanide fumigators, 13 of which had experienced
acute symptoms of cyanide poisoning with loss of consciousness. The men had worked with
cyanide for 1-27 years. A high incidence of nervous disorders, including vertigo, equilibrium
disturbances, and nystagmus, was reported. Also noted were precordial pain, EKG abnormalities,
and hypertrophic gastritis.
Exposure to cyanide in tobacco smoke has been associated with amblyopia, Leber's hereditary
optic atrophy, retrolobular neuritis, and optic nerve atrophy, disorders involving defective cyanide
metabolism and vitamin B12 deficiency (EPA, 1984).
According to NIOSH (1976), chronic cyanide toxicity bears a striking similarity to thiocyanate
intoxication, and it has been suggested that the symptoms ascribed to chronic cyanide poisoning
may, in fact, be due to the toxicity of its metabolic product, thiocyanate. Heavy smoking and
eating of cabbage-type vegetables can exacerbate the symptoms of cyanide exposure due to
additional formation of thiocyanate.
3.2.3.2 Animal
Information on the chronic inhalation toxicity of cyanide in animals was unavailable.
3.2.4 Developmental and Reproductive Toxicity
3.2.4.1 Human
Pregnant women who smoke may increase the susceptibility of their infants to the toxic effects
of cyanide. Smoking during pregnancy has been associated with a higher risk of giving birth to
low body weight infants and of perinatal death (EPA, 1985).
3.2.4.2 Animals
Information on the developmental and reproductive inhalation toxicity of cyanide in animals
was unavailable.
3.2.5 Reference Concentration/Dose
Data are presently insufficient to calculate an RfC.
3.3 OTHER ROUTES OF EXPOSURE
3.3.1 Acute Toxicity
3.3.1.1 Human
Rieders (1971) reported that fatalities occurred following dermal exposure to 5% aqueous
hydrogen cyanide and 10% aqueous potassium cyanide.
3.3.1.2 Animals
Neurotoxic effects including convulsions and coma preceded death in guinea pigs dermally
exposed to hydrogen cyanide (Walton and Witherspoon, 1926). LD50 values reported for rabbits,
administered aqueous solutions of cyanides by instillation into the conjunctival sac of the eye, are
1.09 mg/kg, 7.87 mg/kg, and 5.05 mg/kg for hydrogen cyanide, potassium cyanide, and sodium
cyanide, respectively. For all compounds, signs of toxicity and death occurred 3-12 minutes after
the eyes were treated (Ballantyne, 1983).
3.3.2 Subchronic Toxicity
3.3.2.1 Human
In an early study, Collins and Martland (1908) reported permanent disability resulting from
dermal exposure to cyanide in a hotel worker who polished silver for 2 years by dropping silver
into a potassium cyanide solution and wiping it off without gloves. Symptoms included itching,
diarrhea, headache, pain and stiffness in the back, weakness of arms and legs, urine retention, and
dark discoloration of arms, legs, and nails. Eventually, clinical manifestations resembling acute
anterior poliomyelitis developed.
3.3.2.2 Animal
Rats treated by subcutaneous injection with sodium cyanide at doses of 0.61, 1.31, or
1.72 mg/kg/day (as cyanide), 3 days/week for 3 months developed necrotic lesions of the corpus
callosum and optic nerve. High mortality was observed at all dose levels (Lessell, 1971).
3.3.3 Chronic Toxicity
Information on the chronic toxicity of cyanide in humans and animals by other routes of
exposure was unavailable.
3.3.4 Developmental and Reproductive Toxicity
3.3.4.1 Human
Information on the developmental and reproductive toxicity of cyanide in humans by other
routes of exposure was unavailable.
3.3.4.2 Animal
Cyanide was administered to golden hamsters by continuous infusion at a rate of 0, 0.126,
0.1275, or 0.1295 mmol/kg/hr on gestational days 6 through 9 (Doherty et al., 1982). The total
dose administered was equivalent to 30-40 times the subcutaneous LD50. A high incidence of
malformations and resorptions was observed in all offspring of all treatment groups. Neural tube
defects, the most common malformation, consisted of exencephaly and encephalocele. Also
observed were hydropericardium, crooked tail, and decreased fetal crown to rump length.
Administration of both cyanide and thiocyanate simultaneously protected against the toxic and
teratogenic effects of sodium cyanide.
3.4 TARGET ORGANS/CRITICAL EFFECTS
3.4.1 Oral Exposures
3.4.1.1 Primary Target Organs
1. Central nervous system: In humans, chronic ingestion of cassava, a food rich in
cyanogenic glycosides, caused various neuropathies and amblyopia. Chronic exposure of
rats and subchronic exposure of dogs to cyanide produced degenerative changes of spinal
cord and ganglion cells of the CNS, respectively. Although the CNS is a primary target
organ, the toxic effects of cyanide are due to blockage of electron transport by cytochrome
oxidase, thereby causing cytotoxic hypoxia in all tissues.
2. Thyroid: Thyroid abnormalities have been reported in humans chronically exposed
to cyanogens in cassava. In rats, increased thyroid weights and decreased levels of plasma
thyroxin, indicative of depressed thyroid function, were reported. Histopathologic thyroid
changes have been observed in sows exposed to cyanide during gestation and lactation.
3. Reproduction and Development: Congenital hypothyroidism was reported in human
newborns in areas were cassava is staple food. Offspring of hamsters fed diets containing
cassava showed decreased fetal weight and ossification. Teratogenic effects (exencephaly,
encephalocele, and rib abnormalities) occurred in hamsters fed diets containing amygdalin.
3.4.1.2 Other Target Organs
Kidney: Hyperplasia of kidney glomeruli was seen in sows exposed to cyanide during
gestation and lactation.
3.4.2 Inhalation Exposures
3.4.2.1 Primary Target Organs
1. Central nervous system: Subchronic and chronic effects of cyanide in humans include
vertigo, equilibrium disturbances, nystagmus, nervousness, headache, weakness, loss of
appetite, and changes in smell and taste. Exposure to cyanide in tobacco smoke has been
associated with effects on the optic nerve.
2. Cardiovascular and/or respiratory system: Precordial pain, EKG abnormalities, and
breathing difficulties were recorded in humans occupationally exposed to cyanides. These
effects may be related to CNS toxicity rather than direct effects.
3. Gastrointestinal tract: After exposure to cyanide, workers developed nausea, vomiting,
and gastritis. However, these effects may also be related to CNS effects.
4. Thyroid: Enlarged thyroids were reported in electroplaters exposed to cyanides.
5. Reproduction and Development: Smoking during pregnancy has been associated with
a higher risk of giving birth to low body weight infants and of perinatal death. However,
other agents than cyanide present in tobacco smoke could be responsible for this effect.
3.4.2.2 Other Target Organs
Skin: Dermatitis, itching, scarlet rash, papules, and severe irritation of the nose have
been reported in workers chronically exposed to cyanide.
4. CARCINOGENICITY
4.1 ORAL EXPOSURES
Information on the carcinogenicity of cyanide in humans or animals for oral exposure was
unavailable.
4.2 INHALATION EXPOSURES
Information on the carcinogenicity of cyanide in humans or animals for inhalation was
unavailable.
4.3 OTHER ROUTES OF EXPOSURE
Information on the carcinogenicity of cyanide in humans or animals for other routes of
exposure was unavailable.
4.4 EPA WEIGHT-OF-EVIDENCE
Classification D--Not classifiable as to human carcinogenicity (EPA, 1991b)
Basis--Pertinent data regarding the carcinogenicity of cyanide have not been located in the
available literature.
4.5 CARCINOGENICITY SLOPE FACTORS
No carcinogenicity slope factors were calculated.
5. REFERENCES
Ansell, M. and F.A.S. Lewis. 1970. "A review of cyanide concentrations found in human
organs--A survey of literature concerning metabolism, "normal," nonfatal, and fatal body
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