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6
Hydrogen Cyanide

This chapter reviews physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on hydrogen cyanide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine from exposure to hydrogen cyanide and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 days). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to hydrogen cyanide.

BACKGROUND INFORMATION

Hydrogen cyanide is a colorless, poisonous liquid with a boiling point of 25.7°C (ATSDR 1997). Thus, at room temperature, hydrogen cyanide exists primarily as a gas. It has a faint odor of bitter almonds (ATSDR 1997), although not everyone is able to smell it (Hall and Rumack 1986). The chemical and physical properties of hydrogen cyanide are summarized in Table 6–1.

The major uses for hydrogen cyanide are in nylon and methyl methacrylate production (ATSDR 1997). It also is used in electroplating and mining and as an insecticide and rodenticide for fumigating enclosed spaces (e.g., ships and buildings) (ACGIH 1996; ATSDR 1997).



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Review of Submarine Escape Action Levels for Selected Chemicals 6 Hydrogen Cyanide This chapter reviews physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on hydrogen cyanide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine from exposure to hydrogen cyanide and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 days). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to hydrogen cyanide. BACKGROUND INFORMATION Hydrogen cyanide is a colorless, poisonous liquid with a boiling point of 25.7°C (ATSDR 1997). Thus, at room temperature, hydrogen cyanide exists primarily as a gas. It has a faint odor of bitter almonds (ATSDR 1997), although not everyone is able to smell it (Hall and Rumack 1986). The chemical and physical properties of hydrogen cyanide are summarized in Table 6–1. The major uses for hydrogen cyanide are in nylon and methyl methacrylate production (ATSDR 1997). It also is used in electroplating and mining and as an insecticide and rodenticide for fumigating enclosed spaces (e.g., ships and buildings) (ACGIH 1996; ATSDR 1997).

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 6–1 Summary of Physical and Chemical Properties for Hydrogen Cyanide Characteristic Value Molecular formula HCN Chemical structure H—C≡N Molecular weight 27.03 CAS number 74–90–8 Synonyms Formonitrile, hydrocyanic acid, prussic acid Physical state Gas or liquid Color Colorless gas or bluish-white liquid Odor Bitter almond odor Odor threshold 0.58 ppm Low threshold, 0.9 ppm High threshold, 5.0 ppm Melting point 13.4°C Boiling point 25.70°C Solubility in water Miscible Vapor pressure 630 mm Hg at 20°C 807 mm Hg at 27°C Vapor density (air=1) 0.941 Conversion factors 25°C, 1 atm 1 ppm=1.10 mg/m3 1 mg/m3=0.91 ppm Abbreviations: CAS, Chemical Abstract Service. Sources: Hartung 1994; Budavari et al. 1996; ATSDR 1997. In 1993, an estimated total of 2.23 million pounds of hydrogen cyanide (approximately 73.1% of the total environmental release) was released into the air from U.S. industrial facilities (EPA 1995). Hydrogen cyanide also is released into the air from natural biogenic processes of plants, bacteria, and fungi; however, an estimate of that amount is not available (Cicerone and Zellner 1983; Crutzen and Carmichael 1993; Fiksel et al. 1981; Knowles 1988). Biomass burning could represent a significant source (1.1–3.7 billion pounds annually) of atmospheric hydrogen cyanide (Crutzen and Carmichael 1993; Lobert and Warnatz 1993). Lowry et al. (1985) detected hydrogen cyanide in 12% of the fires they studied in Dallas, Texas. In 10% of the fires in which hydrogen cyanide was

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Review of Submarine Escape Action Levels for Selected Chemicals detected, concentrations reached 15 ppm (parts per million). The maximum hydrogen cyanide concentration detected was 40 ppm. Humans normally are exposed to cyanide from ingesting cyanide- and amygdalin-containing foods or foods that contain fumigation residues and from inhaling cigarette smoke, automobile exhaust, and smoke from fires (HSDB 2001; NIOSH 1976). Each puff from an unfiltered cigarette contains 35 µg (micrograms) of hydrogen cyanide and the lung is exposed to a concentration of approximately 46 ppm (Carson et al. 1981). Trace amounts of cyanide are present normally in healthy people. The cyanide probably comes from the breakdown of cyanogenic food, from bacterial actions in the gastrointestinal tract, or from inhaled cigarette smoke (Ansell and Lewis 1970). TOXICOKINETIC CONSIDERATIONS This section provides information on absorption, distribution, metabolism, and excretion of hydrogen cyanide in humans and experimental animals exposed by inhalation or dermal contact. Absorption Inhalation Hydrogen cyanide is a weak acid with a dissociation constant of 4.93×10–10 and pKa of 9.31 (Weast et al. 1985). It is miscible in water and absorbed by moist respiratory tissues. Hydrogen cyanide is moderately lipid soluble and can diffuse across cellular membranes and is absorbed by the lung (Wolfsie and Shaffer 1959). Landahl and Herrmann (1950) measured retention of hydrogen cyanide in the nose and lung of human subjects. Two subjects inhaled 450 milliliters (mL) of hydrogen cyanide at 0.46–4.6 ppm in 1.5 s and held their breath for 2 s. The lung retained 58.5% of the inhaled hydrogen cyanide; when holding time was increased to 4 s, retention increased to 73%. Nasal absorption was estimated at 10–20% (Landhal and Herrmann 1950). The authors concluded that approximately 75% of hydrogen cyanide inhaled during normal breathing would be retained in the body. Hydrogen cyanide uptake in monkeys exposed by inhalation (face masks were used) was rapid, and the blood cyanide concentration reached steady state in 10–20 min (Purser et al. 1984). Dogs exposed by inhalation to an unknown concentration of hydrogen cyanide absorbed 16.0 milligrams

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Review of Submarine Escape Action Levels for Selected Chemicals (mg) (1.55 milligrams per kilogram (mg/kg)) and 10.1 mg (1.11 mg/kg). The dose was fatal, and the dogs died in 15 and 10 min, respectively. Dermal There is evidence that hydrogen cyanide gas can be absorbed through the skin. Three men protected by gas masks in an atmosphere containing 20,000 ppm hydrogen cyanide experienced marked dizziness, weakness, and throbbing pulse after 8–10 min (Drinker 1932). The symptoms lasted for several hours, but the men made a complete recovery. Walton and Witherspoon (1926) studied dermal absorption in guinea pigs and dogs exposed to hydrogen cyanide vapor. Exposing a small area of the shaved abdomen of guinea pigs for 30–60 min resulted in rapid respiration, twitching of muscles, convulsions, and death. Shaved and unshaved dogs were exposed whole-body, except for the head and neck, to hydrogen cyanide vapor (Walton and Witherspoon 1926). Toxicity was not observed in the dogs after exposure at 4,975 ppm for 180 min. Exposure at 13,400 ppm for 47 min resulted in death of the animals, thus, suggesting dermal absorption. Distribution Inhalation After absorption, hydrogen cyanide is rapidly distributed by the blood throughout the body (ATSDR 1997). A man who died after inhalation exposure to hydrogen cyanide had 0.75 mg hydrogen cyanide/100 g of tissue in the lung, 0.42 mg/kg in the heart, 0.41 mg/kg in the blood, 0.33 mg/kg in the kidney, and 0.32 mg/kg in the brain (ATSDR 1997). Finck (1969) reported that tissue cyanide concentrations in a man who died from inhalation of hydrogen cyanide were 0.5 mg/100 mL in blood, 0.11 mg/100 g in the kidney, 0.07 mg/100 g in the brain, 0.03 mg/100 g in the liver, 0.2 mg/100 mL urine, and 0.03 mg/100 g in the gastric contents. Blood concentrations of cyanide in unexposed healthy adults average 0–10.7 µg/100 mL (mean 4.8 µg/100 mL) (Feldstein and Klendshoj 1954). Tissue distribution of cyanide at autopsy and whole-blood cyanide levels in humans fatally poisoned vary widely depending on the duration of survival, which, in turn, varies according to the delays to initial resuscitation, the administration of antidotal therapy, and the intensive care supportive measures applied (Hall et al. 1987).

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Review of Submarine Escape Action Levels for Selected Chemicals Samples taken from rats exposed to fatal concentrations of hydrogen cyanide (356 or 1,180 ppm) showed that the pattern of tissue distribution of cyanide did not vary with the concentration used (Yamamoto et al. 1982). Data from the two dose groups were averaged. The tissue concentration of hydrogen cyanide was 4.4 µg/g wet weight in the lungs, 3.0 µg/g in the blood, 21.5 µg/g in the liver, 1.4 µg/g in the brain, and 0.68 µg/g in the spleen. Ballantyne (1983a) reported that rabbits exposed at 2,714 ppm for 5 minutes had cyanide concentrations of 170 µg/dL and 48 µg/dL in the blood and serum, 0 µg/100 g in the liver, 6 µg/100 g in the kidney, 50 µg/100 g in the brain, 62 µg/100 g in the heart, 54 µg/100 g in the lung, and 6 µg/100 g in the spleen. Hydrogen cyanide was identified in the lungs, blood, and heart of dogs exposed to unspecified fatal concentrations (Gettler and Baine 1938). Dermal No studies were found that examined distribution in humans after dermal exposure to hydrogen cyanide; there are limited data on the distribution in experimental animals after dermal exposure. Rabbits exposed by the dermal route to 33.75 mg CN–/kg as hydrogen cyanide had cyanide concentrations of 310 µg/dL in the blood, 144 µg/dL in the serum, 26 µg/100 g in the liver, 66 µg/100 g in the kidney, 97 µg/100 g in the brain, 10 µg/100 g in the heart, 120 µg/100 g in the lungs, and 21 µg/100 g in the spleen (Ballantyne 1983a). Metabolism Hydrogen cyanide is metabolized through several pathways. In the major metabolic pathway (60–80% of absorbed cyanide), cyanide is converted to thiocyanate in a reaction that is catalyzed by rhodanase or 3-mercaptopyruvate sulfur transferase (Baumann et al. 1934; Himwich and Saunders 1948; Wood and Cooley 1956; Singh et al. 1989). Minor pathways include the oxidation of hydrogen cyanide or thiocyanate to carbon dioxide, reaction with cystine to form 2-aminothiazoline-4-carboxylic acid and 2-imnothizolidine-4-carboxylic acid, reaction with hydroxocobalamine to form cyanocobalamin, and conversion of hydrogen cyanide to formic acid, which enters one-carbon metabolism in the body (Wood and Cooley 1956; Boxer and Rickards 1952; Ansell and Lewis 1970; Baumeister et al. 1975).

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Review of Submarine Escape Action Levels for Selected Chemicals Elimination No studies were found that examined elimination in humans or experimental animals exposed to hydrogen cyanide by inhalation or dermal contact. Studies in rats exposed to cyanide orally or by subcutaneous injection showed that cyanide is excreted primarily as thiocyanate in the urine but also is exhaled as a gas and excreted in feces (Ansell and Lewis 1970; Leuschner et al. 1991; Okoh 1983). HUMAN TOXICITY DATA Hydrogen cyanide is extremely toxic to humans regardless of the route of exposure. Exposure to high concentrations of hydrogen cyanide can lead quickly to incapacitation and death. Hydrogen cyanide primarily acts by directly inhibiting cellular respiration by binding to cytochrome oxidase, a terminal enzyme in the mitochondrial electron transport chain. As tissue oxygen concentrations rise, there is increased tissue oxygen tension and a decreased unloading for oxyhemoglobin. Oxygen utilization in situ is blocked, slowing oxidative metabolism and reducing the ability to meet substrate needs. Thus, the primary targets are the tissues that are most sensitive to hypoxia—the brain and the heart. Typical symptoms of hydrogen cyanide poisoning include headache, vertigo, lack of motor coordination, nausea, vomiting, tachypnea, weak pulse, cardiac arrhythmia, and convulsion (NRC 2000). Respiratory rate and depth are initially increased (hyperpnea), but this is followed by rapid respiratory collapse and arrest. The cyanide encephalopathy lesions in the brain are attributed primarily to a histotoxic anoxia. For a detailed review of the mechanism of toxicity of hydrogen cyanide, see ATSDR’s Toxicological Profile for Cyanide (ATSDR 1997). This section reviews human toxicity data on hydrogen cyanide from experimental studies, accidental exposure, and occupational studies. The data are summarized in Table 6–2. Experimental Studies Because of the small margin of safety, few controlled experimental studies of hydrogen cyanide toxicity have been conducted with human subjects. Barcroft (1931) exposed a man at a nominal concentration of 625 ppm for 1.5 min in an airtight chamber. Five minutes after the start of the experiment, the man developed a “momentary feeling of nausea”; at 10 min, he had difficulty concentrating in a conversation. No toxic effects were observed in several human volunteers (number not reported) exposed at 240 or 360 ppm for 1.5–2 min (Grubbs 1917).

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 6–2 Human Toxicity Data, Exposure to Hydrogen Cyanide Subject Route Concentration (ppm) Duration Effect Reference EXPERIMENTAL STUDIES 1 man, 45 yr old, 70kg Inhalation 500–625 1.5 min Nausea and difficulty in concentrating Barcroft 1931 Several subjects Inhalation 240 2 min No symptoms Grubbs 1917   1.5 min No symptoms Grubbs 1917 Several subjects Inhalation 360     ACCIDENTAL EXPOSURES 12 men Inhalation NR NR Dizziness, dyspnea, shaky feeling, headaches, nausea, unconsciousness Peden et al. 1986 3 subjects Inhalation NR NR Semiconsciousness, headaches, nausea, sinus bradycardia, atrial fibrillation Nagler et al. 1978 2 subjects’ hands were exposed Dermal NR (liquid hydrogen cyanide) NR Breathing irregularities, coma, loss of deep reflexes, dilated pupils Potter 1950 OCCUPATIONAL STUDIES 36 workers, electroplating plant Inhalation 6.4±6.9 ppm 8.1±8.2 ppm 10.4±10.9 ppm 5–15yr Headaches, weakness, changes in taste and smell, nervous instability, throat irritation, lacrimation, vomiting, dyspnea, thyroid enlargement, increased rate of iodine accumulation in thyroid after 2 d of nonexposure. El Ghawabi et al. 1975

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Review of Submarine Escape Action Levels for Selected Chemicals Subject Route Concentration (ppm) Duration Effect Reference Workers in electroplating plant Inhalation ~5ppm NR Nasal irritation, ulceration of the nasal septum. Elkins 1959 23 male workers, electroplating plant Inhalation 0.2–0.7 (Concentration measurement probably not accurate.) NR Workers complained of typical symptoms of hydrogen cyanide poisoning (not specified), no health effects reported, higher concentrations of blood and urine cyanide and thiocyanate were measured compared with controls. Chandra et al. 1980 Workers, silver-reclaiming facility Inhalation 15 NR Loss of appetite, fatigue, dizziness, headaches, disturbed sleep, ringing in the ears, paresthesias of extremities, syncopes. Blanc et al. 1985 Abbreviations: NR, not reported; ppm, parts per million.

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Review of Submarine Escape Action Levels for Selected Chemicals Accidental Exposures Some information about cyanide toxicity in humans is available from research on accidental exposures—for example in industrial accidents—although the usefulness of these data is limited because exposure durations and concentrations are often not known or not reported, because small numbers of individuals were exposed, and because other details, such as possible exposure to other chemicals, also are often not reported. Scrutiny of blood cyanide concentrations in victims of cyanide poisoning could be misleading for the purposes of characterizing dose-response relationships, depending on the length of the delay before performing the assay (Chaturvedi et al. 1995). Fatalities have been reported after 30-min exposure to 135 ppm hydrogen cyanide and after 10 min exposure to 181 ppm (ATSDR 1997). Workers accidentally exposed to unknown concentrations of hydrogen cyanide experienced central nervous system (CNS), respiratory, and cardiovascular effects (Peden et al. 1986; Nagler et al. 1978). Peden et al. (1986) reported that 12 men who were exposed to hydrogen cyanide in industrial accidents experienced dizziness (n=8), dyspnea (n=8), a shaky feeling (n=6), headaches (n= 4), nausea (n=4), and unconsciousness (n=5). Within approximately 10 min, the unconscious men regained consciousness. The men who reported suffering from headaches stated that the headaches persisted for up to 8 h after hospital admission. Nagler et al. (1978) reported 3 cases of hydrogen cyanide poisoning after the accidental addition of cyanide salt to a sulfuric acid bath in an electroplating factory in Belgium. The workers experienced semiconsciousness, headaches, nausea, sinus bradycardia, and atrial fibrillation. Potter (1950) reported breathing irregularities, coma, loss of deep reflexes, and dilated pupils in 2 individuals whose hands were accidentally exposed to undetermined concentrations of hydrogen cyanide. Wurzburg (1996) reported complete recovery among 36 workers with inhalation exposure to hydrogen cyanide who were treated with pressure oxygen resuscitation and/or the administration of amyl nitrate by inhalation. One-third of the workers were unconscious and one was convulsing at the time treatment was initiated. Occupational Studies Occupational exposures to cyanide resulting from unsafe work practices and inadequate worker protection procedures typically involve longer term exposure to lower concentrations than those that are identified in association with industrial accidents. El Ghawabi et al. (1975) reported on the effects of hydrogen

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Review of Submarine Escape Action Levels for Selected Chemicals cyanide exposure in 36 chronically exposed (5–15 yr) workers in 3 electroplating factories in Egypt. The workers were all nonsmokers. Twelve 15-min breathing-zone air samples were collected in each factory. The average (standard deviation (SD), range) hydrogen cyanide concentrations in the three factories were reported to be 6.4 ppm (6.9, 4.2–8.8), 8.1 ppm (8.3, 5.9–9.6), and 10.3 ppm (10.9, 8.2–12.4), although the fact that the SDs are greater than the range of observed values makes these numbers of suspect validity. Compared with 20 unexposed control subjects of comparable age and social status, the workers reported significantly higher incidences of headache (81% of exposed individuals versus 30% of unexposed individuals), weakness (78% versus 20%), changes in taste and smell (78% versus 0%), giddiness (56% versus 15%), throat irritation (44% versus 5%), vomiting (44% versus 5%), effort dyspnea (44% versus 10%), lacrimation (25% versus 0%), and precordial pain (19% versus 5%). Fifty-six percent of workers had mild or moderate thyroid enlargement, although none showed evidence of clinical thyroid disease, and the likelihood of thyroid enlargement was not related to duration of employment at the plant. Uptake of 131I by the thyroid was increased at 4 and 24 h, whereas 131PBI concentrations at 72 h were within normal limits. This increased uptake was unexpected and could reflect an effect of acute cyanide withdrawal or the effect of a cyanide-induced iodine deficiency leading to an increased secretion of thyrotropic hormone. Compared with controls, workers had higher hemoglobin and lymphocyte counts, as well as a higher frequency of punctate basophilia (a sign associated with intoxication by chemicals other than cyanide). Urinary thiocyanate concentrations were correlated with the air sample concentrations. Thirty-six workers in a silver-reclaiming facility were evaluated after one worker died from cyanide poisoning (Blanc et al. 1985). The mean duration of employment at the plant was 11 mo (SD 10 mo), and the workers were examined an average of 10 mo after their last employment at the plant. The day after the plant was closed, the time-weighted (24-h) average air concentration of cyanide was 15 ppm Retrospective reporting of symptoms experienced during the workers’ period of employment revealed that 78% of them experienced headache, 72% dizziness, 68% nausea, 58% eye irritation, 58% loss of appetite, 47% epistaxis, 47% easy fatigue, 39% dyspnea, 31% chest pain, 25% hemoptysis, 14% paresthesias of extremities, and 14% syncope. The prevalence of these symptoms in the month preceding the interview ranged from 11% (nausea and chest pain) to 50% (eye irritation). Severity of symptoms was associated in a dose-response manner with an exposure index based on work history. Two other studies examining workers in electroplating plants also reported respiratory symptoms and other unspecified “typical symptoms of hydrogen cyanide poisoning” (Chandra et al. 1980; Elkins 1959). In general, the usefulness of the occupational studies in setting exposure limits is limited by methodology. In one study (Blanc et al. 1985), for instance,

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Review of Submarine Escape Action Levels for Selected Chemicals a selection bias could have resulted from the fact that the subjects were identified by investigating officers of the state attorney general’s office rather than through a complete ascertainment of all potentially exposed workers. In most studies, symptom prevalence was based on self-reports, and reports often were elicited by an interviewer who was not blinded to a worker’s job history. Coexposure to other chemicals could have produced some of the nonspecific symptoms attributed to cyanide exposure. A high degree of uncertainty is associated with the concentrations of cyanide to which workers were exposed, and past exposures might have been higher than those measured by air sampling conducted after the identification of cyanide exposure as a problem in a plant. Exposure might have been oral or dermal, as well as by inhalation, resulting in overestimation of the toxicity of the measured air concentration. Furthermore, it might not be possible to generalize data from a setting that involves chronic, low-level hydrogen cyanide exposure to one of acute exposure to comparable air concentrations. Finally, the increased prevalence of symptoms in workers was detected only when investigators sought the data. The studies were not initiated in response to workers’ complaints about poor health or about their inability to work well because of their symptoms. EXPERIMENTAL ANIMAL TOXICITY DATA There are numerous experimental animal studies examining hydrogen cyanide toxicity after acute exposure. The studies are summarized below, experimental details are presented in Table 6–3. Acute Exposure Several laboratories examined lethality due to inhalation exposure to hydrogen cyanide. The concentrations that cause death in 50% of test animals (LC50) are similar across species. Rat LC50 values range from 196 to 503 ppm for exposures that last 5–15 minutes (Ballantyne 1983a; Barcroft 1931; Higgins et al. 1972; Vernot et al. 1977), from 110 to 200 ppm for 30-min exposures (Ballantyne 1983a; Kimmerle 1974; Levin et al. 1987), and from 120 to 144 ppm for 1 h exposures (Ballantyne 1983a; Kimmerle 1974). Mouse LC50 values ranged from 166 to 323 ppm for exposures up to 30 min (Higgins et al. 1972; Vernot et al. 1977; Matijak-Schaper and Alarie 1982). All Swiss-Webster mice exposed at 150 ppm for 4 h died, but only 1 of 10 mice exposed at 100 ppm for 4 h died (Pryor et al. 1975). Rabbit LC50 values range from 140 to 372 ppm for exposures up to 1 h (Ballantyne 1983a; Barcroft 1931). Etteldorf (1939) exposed dogs at 36 ppm for 10 min and 1 of the three animals died. One of 2 dogs died when exposed

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Review of Submarine Escape Action Levels for Selected Chemicals Goat Inhalation 300 15 min 1 of 4 died Barcroft 1931 Goat Inhalation 400 10 min 3 of 4 died Barcroft 1931 ACUTE EXPOSUE (NONLETHAL TOXICITY) Rat Inhalation 50 3 min 1 paralyzed at 2.5 min; the other not paralyzed. Moss et al. 1951 Rat Inhalation 55 30 min Changes in lung dynamics, lung phospholipids. Bhattacharya et al. 1994 Mouse Inhalation 23 30 min Respiratory depression of 20% Matijak-Schaper and Alarie 1982 Mouse Inhalation 30 24 h Lung congestion Pryor et al. 1975 Mouse Inhalation 41.7 30 min Incapacitation Sakurai 1989 Mouse Inhalation 63 30 min Respiratory depression of 50% Matijak-Schaper and Alarie 1982 Mouse Inhalation 120 30 min Respiratory depression of 80% Matijak-Schaper and Alarie 1982 Rabbit Ocular 0.9 mg CN–/kg as hydrogen cyanide 1 application Keratitis, rapid breathing, weak and ataxic movements, convulsions, coma. Ballantyne 1983b Rabbit Dermal 1.92 mg CN–/kg as hydrogen cyanide 1 application Tremors, retrocolic spasms, convulsions Ballantyne 1994

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Review of Submarine Escape Action Levels for Selected Chemicals Species Route Concentration (ppm) Duration Effect Reference Monkey Inhalation 100–156 8–19min Incapacitation Purser et al. 1984 Monkey Inhalation 60 30 min Slight central nervous system effects Purser et al. 1984 REPEATED EXPOSURE Rat Inhalation 200 12.5 min every 4 d for a total of 5 exposures Possible changes in blood enzymes attributed to cardiac effects. O’Flaherty and Thomas 1982 Abbreviations: LC50, median lethal concentration; LD50, median lethal dose; ppm, parts per million.

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Review of Submarine Escape Action Levels for Selected Chemicals at 100 ppm for 15 min and 1 of 3 dogs died when exposed at 200 ppm for 10 min (Barcroft 1931). No deaths occurred in dogs exposed at 60, 70, 100, or 200 ppm for 1 h, 30 min, 30 min, or 5 min, respectively (Barcroft 1931). Deaths occurred in goats exposed at 200–400 ppm for 10–60 min, but did not occur in goats exposed at 140 ppm for 60 min (Barcroft 1931). Monkeys exposed at 100 ppm for 1 h did not die (Barcroft 1931). One of 3 monkeys died when exposed at 140 ppm for 30 min; the same results were observed when monkeys were exposed at 200 ppm for 30 min (Barcroft 1931). All monkeys (3 in each group) died when exposed at 170 ppm for 60 min or 400 ppm for 3 min (Barcroft 1931). The CNS, respiratory system, and possibly, the cardiovascular system of experimental animals are affected by exposure to hydrogen cyanide. Four cynomolgus monkeys exposed at 60 ppm for 30 min experienced a slight depressive effect on the CNS as shown by changes in brain wave activity and reduced auditory cortical evoked potential (Purser et al. 1984). Purser et al. (1984) found a roughly linear relationship between air concentration and time to incapacitation for 30-min exposures of 80–180 ppm (e.g., the regression suggested that increasing the concentration from 100 to 200 ppm reduced the time to incapacitation from 25 min to 2 min). Observed effects included hyperventilation (within 30 s), loss of consciousness, bradycardia with arrhythmias, and T-wave abnormalities. The animals recovered rapidly after exposure. Bhattacharya et al. (1994) exposed Wistar rats at 55 ppm for 30 min and found changes in the rats’ lung parameters, including increases in air flow, transthoracic pressure, and tidal volume, as well as decreases in respiratory rate (60–70%) and minute volume. There was also a significant decrease in phospholipids in the lungs. Matijak-Schaper and Alarie (1982) reported that exposure of Swiss-Webster mice at 63 ppm for 30 min resulted in a 50% decrease in respiration rate. The incapacitation time for Jcl ICR mice exposed at 41.7 ppm was 30 min (Sakurai 1989). Some studies suggest a synergistic lethality of cyanide and carbon monoxide, although data from other studies are more consistent with additivity. In white rats, Moss et al. (1951) reported that the LC50 was considerably reduced if exposure to hydrogen cyanide occurred in the presence of 2,000 ppm carbon monoxide (although hydrogen cyanide concentrations were calculated rather than measured directly in the exposure chamber). Similarly, Norris et al. (1986) found that the LC50 for potassium cyanide, administered intraperitoneally (4–9 mg/kg) was significantly lower in mice administered carbon monoxide (0.63–0.66%) than it was in mice pretreated with air. The data suggested a synergistic rather than an additive effect, although the mechanism was unclear insofar as carbon monoxide pretreatment did not alter blood cyanide concentrations. Chaturvedi et al. (1995) also found that co-exposure to carbon monoxide and hydrogen cyandide did not appreciably affect hydrogen cyanide uptake. In a set of experiments with Fischer-

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Review of Submarine Escape Action Levels for Selected Chemicals 344 male rats, however, Levin et al. (1987) reported that carbon monoxide and hydrogen cyanide acted additively rather than synergistically, which failed to support the conclusions of Moss et al. (1951). In fact, the results indicated that hydrogen cyanide exerts a depressive effect on carbon monoxide uptake. Other experiments in mice by Sakurai (1989) also failed to demonstrate a synergism between hydrogen cyanide and carbon monoxide exposures. Levin et al. (1987) did report, however, that the LC50 of hydrogen cyanide was reduced in the presence of 5% carbon dioxide. Dermal Dermal and ocular toxicity has been assessed in rabbits (Ballantyne 1983a,b). The LD50 (dose that is lethal to 50% of test animals) for dermal toxicity is 6.7 mg CN–/kg as hydrogen cyanide; the LD50 for ocular toxicity is 1.0 mg CN–/kg as hydrogen cyanide (Ballantyne 1983a,b). The effects observed when rabbits were exposed dermally at 1.92 mg CN–/kg as hydrogen cyanide include tremors, retrocolic spasms, and convulsions. Rabbits that were administered 0.9 mg CN–/ kg as hydrogen cyanide in their conjunctival sacs were reported to have keratitis, rapid breathing, weak and ataxic movements, convulsions, and coma (Ballantyne 1983a,b). Repeated Exposure O’Flaherty and Thomas (1982) subjected rats to 5 repeated exposures at 200 ppm for 12.5 min every 4 d. The animals showed increased cardiac-specific creatine phosphokinase in the blood and ectopic heartbeat during the first 2 min after injection of norepinephrine (after the fifth exposure). Cardiac lesions were not induced. NAVY’S RECOMMENDED SEALS The Navy proposes to set a SEAL 1 of 1 ppm and a SEAL 2 of 4.5 ppm for exposure to hydrogen cyanide. The Navy based the SEALs on NIOSH (1994) recommended daily limit of 4.7 ppm and on the American Conference of Governmental Industrial Hygienists Threshold Limit Value (TLV) (ACGIH 1998) of 4.5 ppm.

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Review of Submarine Escape Action Levels for Selected Chemicals ADDITIONAL RECOMMENDATIONS FROM THE NRC AND OTHER ORGANIZATIONS Recommended exposure guidance levels for hydrogen cyanide from the NRC and other organizations are summarized in Table 6–4. SUBCOMMITTEE ANALYSIS AND RECOMMENDATIONS Submarine Escape Action Level 1 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 1 of 1 ppm for hydrogen cyanide is too conservative. The subcommittee recommends a SEAL 1 of 10 ppm. This value is based on a study in which workers in an electroplating plant chemically exposed at 10 ppm for 5–15 years reported headaches, weakness, changes in taste and smell, nervous instability, throat irritation, lacrimation, vomiting, dyspnea, and thyroid enlargement (El Ghawabi et al. 1975). The subcommittee’s recommended SEAL 1 is supported by an additional occupational study in which workers at a silver-reclaiming facility chemically exposed to hydrogen cyanide at a concentration of 15 ppm reported loss of appetite, fatigue, dizziness, headaches, disturbed sleep, ringing in the ears, paresthesia of extremities, and syncope. The subcommittee concludes that irritant effects associated with exposure to hydrogen cyanide at less than 10 ppm should be tolerable for up to 10 d. Submarine Escape Action Level 2 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 4.5 ppm for hydrogen cyanide is too conservative. The subcommittee recommends a SEAL 2 of 15 ppm. The recommended SEAL 2 is also based on the El Ghawabi et al. (1975) study, which is discussed under the derivation of SEAL 1. It is supported by studies in monkeys that show some central nervous system effects (e.g., changes in brain wave activity and reduced auditory cortical evoked potential) occur after a 30-min exposure at a concentration of 60 ppm (Purser et al. 1984). The subcommittee concludes that exposures of submariners to hydrogen cyanide at a concentration of 15 ppm for only 1 d is not likely to produce any irreversible health effects.

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 6–4 Recommendations from Other Organizations for Hydrogen Cyanide Organization Type of Exposure Level Recommended Exposure Level Reference ACGIH TLV-C 4.7 ppm (as cyanide) ACGIH 1998 AIHA ERPG1 ERPG2 ERPG3 NR 10 ppm 25 ppm AIHA 2001 DFG MAK (8 h/d during 40-h workweek) 10 ppm DFG 1997   Peak Limit (30 min maximum duration, 4 times per shift) 20 ppm   NAC Proposed AEGL-1 Proposed AEGL-2 Proposed AEGL-3 1.0 ppm 2.5 ppm 6.6 ppm Federal Register, March 15, 2000, 65(51):14185– 14197. NASA SMAC:   NRC 2000   1 h 24 h 7 d 30 d 180 d 8 ppm 4 ppm 1 ppm 1 ppm 1 ppm   NIOSH Ceiling Concentration 4.7 ppm NIOSH 1994 NIOSH IDLH 50 ppm NIOSH 1994; Ludwig et al. 1994 OSHA PEL 10 ppm NIOSH 1994 Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; AIHA, American Industrial Health Association; DFG, Deutsche Forschungsgemeinschaft; ERPG, emergency response planning guideline; IDLH, immediately dangerous to life and health; MAK, maximum concentration values in the workplace; NAC, National Advisory Committee; NASA, National Air and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NR, not recommended; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure level; ppm, parts per million; SMAC, spacecraft maximum allowable concentrations; TLV-C, Threshold Limit Value-ceiling.

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Review of Submarine Escape Action Levels for Selected Chemicals DATA GAPS AND RESEARCH NEEDS As noted by NRC (2000), the major impediment to setting exposure limits for hydrogen cyanide is the absence of strong dose-response inhalation data for humans and animals, especially for lower exposure concentrations (less than 15 ppm) sustained over a period of days. Therefore, the subcommittee recommends that research be done to obtain dose-response data at concentrations of 5–15 ppm for exposures lasting up to 1 d. Additional data are also needed on the effects of combined exposure to hydrogen cyanide and other combustion gases. Determining whether the combined effects of exposure to carbon monoxide and hydrogen cyanide are additive or synergistic is an issue of particular importance, and therefore, research should be done to obtain that data. The impacts of other environmental parameters (e.g., humidity, temperature, pressure) of the disabled submarine environment on hydrogen cyanide toxicity also require additional study. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1996. Hydrogen cyanide and cyanide salts. Supplements to the Sixth Edition Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 1998. Hydrogen Cyanide. Supplements to the Sixth Edition Documentation of the Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 2001. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook Fairfax, VA: American Industrial Hygiene Association. Ansell, M., and F.A.S.Lewis. 1970. A review of cyanide concentrations found in human organs. A survey of literature concerning cyanide metabolism, normal, non-fatal, and fatal body cyanide levels. J. Forensic Med. 17(4):148–155. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Cyanide (Update). U.S. Department for Health and Human Services. Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. Ballantyne, B. 1983a. The influence of exposure route and species on the acute lethal toxicity and tissue concentrations of cyanide. Pp. 583–586 in Developments in the Science and Practice of Toxicology, A.W.Hayes, R.C.Schnell, and T.S.Miya, eds. New York, NY: Elsevier. Ballantyne, B. 1983b. Acute systemic toxicity of cyanides by topical application to the eye. J. Toxicol. Cutan. Ocul. Toxicol. 2:119–129.

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