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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 5 Hydrogen Cyanide1 Acute Exposure Guideline Levels SUMMARY Hydrogen cyanide (HCN) is a colorless, rapidly acting, highly poisonous gas or liquid that has an odor of bitter almonds. Most HCN is used as an intermediate at the site of production. Major uses include the manufacture of nylons, plastics, and fumigants. Exposures to HCN may occur in industrial situations as well as from cigarette smoke, combustion products, and naturally occurring cyanide compounds in foods. Sodium nitroprusside (Na2[Fe(CN)5 NO]·2H2O), which has been used as an antihypertensive in humans, breaks down into nonionized HCN. 1 This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member George Rodgers (Chemical Manager). The NAC reviewed and revised the document and the AEGL values as necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data and are consistent with the NRC guidelines reports (NRC 1993; NRC 2001).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 HCN is a systemic poison; toxicity is due to inhibition of cytochrome oxidase, which prevents cellular utilization of oxygen. Inhibition of the terminal step of electron transport in cells of the brain results in loss of consciousness, respiratory arrest, and ultimately, death. Stimulation of the chemoreceptors of the carotid and aortic bodies produces a brief period of hyperpnea; cardiac irregularities may also occur. The biochemical mechanisms of cyanide action are the same for all mammalian species. HCN is metabolized by the enzyme rhodanese which catalyzes the transfer of sulfur from thiosulfate to cyanide to yield the relatively nontoxic thiocyanate. Human exposures with measured concentrations were limited to occupational reports. Symptoms of exposed workers ranged from no adverse health effects to mild discomfort to frank central nervous system effects. Repeated or chronic exposures have resulted in hypothyroidism. Inhalation studies resulting in sublethal effects, such as incapacitation, and changes in respiratory and cardiac parameters were described for the monkey, dog, rat, and mouse; lethality studies were available for the rat, mouse, and rabbit. Exposure durations ranged from a few seconds to 24 hours (h). Regression analyses of the exposure duration-concentration relationships for both incapacitation and lethality for the monkey determined that the relationship is C2×t= k and that the relationship for lethality based on rat data is C2.6×t=k. The AEGL-1 is based on human monitoring studies in which the preponderance of data as a weight-of-evidence consideration indicates that an 8-h exposure to HCN at 1 parts per million (ppm) would be without adverse health effects for the general population. Although the exposures were of chronic duration (generally 8 h/day (d) for extended work periods) and the data are lacking in various aspects of specific exposure concentrations and well-documented exposure-related symptoms, it is human data which are most relevant in determining the AEGL-1 threshold of notable discomfort. Chronic exposures (5–15 years [y]) in three electroplating plants to mean concentrations of 6, 8, and 10 ppm produced exposure-related symptoms including headache, weakness, and objectionable changes in taste and smell (El Ghawabi et al. 1975), but the authors failed to relate symptoms to air concentrations. Over half of the workers presented with enlarged thyroids (characteristically observed in cases of chronic cyanide exposure), which may have been responsible for certain symptoms. In evaluating the El Ghawabi et al. (1975) study, a National Research Council (NRC) subcommittee concluded that a 1-h exposure at 8 ppm would cause no more than mild headache in healthy adults (NRC 2000). Mild headache meets the definition of the AEGL-1. Chronic exposures of 63 healthy adult cyanide-production workers to
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 geometric mean concentrations of ≤1 ppm of HCN (range, 0.01–3.3 ppm; measured with personal samplers), with potential exposures at 6 ppm (as measured with area samples), for part of a year resulted in no exposure-related adverse health effects (Leeser et al. 1990). Finally, although health effects were not specifically addressed, workers in five apricot kernel processing plants were exposed to air concentrations of HCN at <1 to 17 ppm (Grabois 1954). The fact that engineering controls were recommended “where required” at a time when the maximum allowable concentration was 10 ppm suggests that no untoward effects were occurring at the lower concentrations. The National Institute for Occupational Safety and Health (NIOSH) concluded from the Grabois (1954) data that 5 ppm was a no-effect concentration in an occupational setting (NIOSH 1976). Additional monitoring studies indicated that workers were routinely exposed to HCN at 4 to 6 ppm (Hardy et al. 1950; Maehly and Swensson 1970). Humans may differ in their sensitivity to the effects of HCN, but no data regarding specific differences among individuals were located in the available literature (occupational monitoring studies and the clinical use of nitroprusside solutions to treat chronic hypertension). The detoxifying enzyme rhodanese is present in large amounts in all individuals, including newborns. Because no specific susceptible populations were described following chronic exposures or during use of nitroprusside solutions to treat chronic hypertension, the potential differences in susceptibility among humans are not expected to exceed 3-fold. The 8-h AEGL-1 value was derived from a consideration of the dose-response data obtained from all of the monitoring studies cited and subsequently time-scaled to the shorter AEGL exposure durations. Although the exposures were of chronic duration in all studies, they represent the only viable human data available. Furthermore, because symptoms observed or reported at given concentrations for the multiple 8-h exposures of a typical work schedule should represent the greatest potential responses, the use of the data represents a conservative approach to AEGL derivation. All of the exposure durations reported exceed the AEGL exposure durations, so the longest, or 8-h, AEGL exposure duration was selected as the basis for AEGL development. Dividing the 8-h concentration of 5 ppm from the Grabois (1954), Hardy et al. (1950), or Maehly and Swensson (1970) studies by an intraspecies uncertainty factor (UF) of 3 or dividing the 1-h concentration of 8 ppm from the El Ghawabi et al. (1975) study by an intraspecies UF of 3 result in very similar AEGL-1 values. The resulting 8-h value of 1.7 ppm is also similar to the 8-h geometric mean value of 1 ppm in the Leeser et al. (1990) study that was derived without application of a UF. A UF should not be applied to the
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Leeser et al. (1990) study, because it was the lowest no-observed-adverseeffect level (NOAEL). Using the 8-h value of 1 ppm as the basis for time scaling to shorter durations, the conservative relationship of C3×t=k was chosen for the derivations. The 10-minute (min) AEGL-1 was set equal to the 30-min value so as not to exceed the highest personal exposure concentration of 3.3 ppm in the well-conducted Leeser et al. (1990) study. The AEGL-2 was based on an exposure of cynomolgus monkeys to a concentration of HCN at 60 ppm for 30 min, which resulted in a slight increase in the respiratory minute volume near the end of the exposure and a slight depressive effect on the central nervous system as evidenced by changes in electroencephalograms, also near the end of the exposure; there was no physiological response (Purser 1984). The mechanism of action of HCN is the same for all mammalian species, but the rapidity and intensity of the toxic effect is related to relative respiration rates as well as pharmacokinetic considerations. Based on relative respiration rates, the uptake of HCN by the monkey is more rapid than that of humans. The monkey is an appropriate model for extrapolation to humans because, compared with rodents, the respiratory systems of monkeys and humans are more similar in gross anatomy, the amount and distribution of types of respiratory epithelium, and airflow pattern. Because the monkey is an appropriate model for humans but is potentially more susceptible to the action of cyanide based on relative respiration rates, an interspecies UF of 2 was applied. Humans may differ in their sensitivity to HCN, but no data regarding specific differences among humans were located in the available literature. The detoxifying enzyme rhodanese is present in all individuals, including newborns. Therefore, an intraspecies UF of 3 was applied. The 30-min concentration of 60 ppm from the Purser (1984) study was divided by a combined interspecies and intraspecies UF of 6 and scaled across time for the AEGL-specified exposure periods using the relationship C2×t=k. The safety of the 30-min and 1-h values of 10 and 7.1 ppm, respectively, is supported by monitoring studies in which chronic exposures to average concentrations of 8 to 10 ppm may have produced primarily reversible central nervous system effects such as headaches in some workers (El Ghawabi et al. 1975). The rat provided the only data set for calculation of LC01 values for different time periods (E.I. du Pont de Nemours and Company 1981). The LC01 values were considered the threshold for lethality and were used as the basis for deriving AEGL-3 values. The mouse, rat, and rabbit were equally sensitive to the lethal effects of HCN, as determined by similar LC50 values for the same time periods (for example, 30-min LC50 values of 166, 177, and 189 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 for the mouse, rat, and rabbit, respectively). In an earlier study, times to death for several animal species showed that mice and rats may be slightly more sensitive to HCN than monkeys (and presumably humans). The differences in sensitivity were attributed, at least partially, to the more rapid respiratory rate of the rodent compared to body weight. Because LC50 values for several species were within a factor of 1.5 of each other and the respiration rate of rodents is higher than that of humans, resulting in more rapid uptake of HCN, an interspecies UF of 2 was applied. Humans may differ in their sensitivity to HCN, but no data regarding specific differences among humans were located in the available literature. The detoxifying enzyme rhodanese is present in all individuals, including newborns. Therefore, an intraspecies UF of 3 was applied to protect sensitive individuals. The 15- and 30-min and 1-h LC01 values (138, 127 and 88 ppm, respectively) were divided by a total UF of 6. The 15-min LC01 value was time scaled to 10 min to derive the 10-min AEGL-3; the 30-min LC01 was used for the 30-min AEGL-3 value; and the 60-min LC01 was used to calculate the 1-, 4-, and 8-h AEGL-3 concentrations. For the AEGL-3 values, scaling across time utilized empirical data (i.e., the lethal concentration-exposure duration relationship for the rat in the key study, C2.6 ×t=k). The safety of the 4- and 8-h AEGL-3 values of 8.6 and 6.6 ppm is supported by the lack of severe adverse effects in healthy workers chronically exposed to similar values during monitoring studies (Grabois 1954; El Ghawabi et al. 1975). The values appear in Table 5–1. I. INTRODUCTION Hydrogen cyanide (HCN) is a colorless, highly poisonous gas or liquid (below 26.7 °C) having an odor of bitter almonds (Hartung 1994; Pesce 1994). It is a weak acid. Exposures may occur in industrial situations as well as from cigarette smoke and combustion products and from naturally occurring cyanide compounds in foods. There is a potential for exposure when any acid is mixed with a cyanide salt. Intravenously administered sodium nitroprusside (Na2[Fe(CN)5NO]·2H2O) has been used clinically to lower blood pressure (Schulz et al. 1982). Chemical and physical properties are listed in Table 5–2. HCN is produced commercially by the reaction of ammonia, methane, and air over a platinum catalyst or from the reaction of ammonia and methane. HCN is also obtained as a by-product in the manufacture of acrylonitrile and may be generated during many other manufacturing processes (Pesce 1994). In 1999, there were 34 companies operating 47 HCN production facilities in
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 5–1 Summary Table of AEGL Values for Hydrogen Cyanide (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a 2.5 2.5 2.0 1.3 1.0 No adverse health effects—humans (Hardy et al. 1950; Grabois 1954; Maehly and Swensson 1970; Leeser et al. 1990); mild central nervous system effects— humans (El Ghawabi et al. 1975) (Nondisabling) (2.8) (2.8) (2.2) (1.4) (1.1) AEGL-2 17 10 7.1 3.5 2.5 Slight central nervous system depression— monkey (Purser 1984) (Disabling) (19) (11) (7.8) (3.9) (2.8) AEGL-3b 27 21 15 8.6 6.6 Lethality (LC01)—rat (E.I. du Pont de Nemours 1981) (Lethal) (30) (23) (17) (9.7) (7.3) aThe bitter almond odor of HCN may be noticeable to some individuals at the AEGL-1. bValues for different time points were based on separate experimental values closest to the time point of interest. the United States, Western Europe, and Japan (CEH 2000). The estimated production capacity was 3.5 billion pounds. The demand for HCN is expected to increase by 2.8% per year through 2004. Most HCN is used at the production site (CEH 2000). HCN is widely used; according to Hartung (1994), the major uses are in the fumigation of ships, buildings, orchards, and various foods; the production of various resin monomers such as acrylates, methacrylates, and hexamethylenediamine; and the production of nitriles. HCN may also be generated during the use of cyanide salts in electroplating operations and mining. Pesce (1994) estimated the following usage percentages: adiponitrile for nylon, 41%; acetone cyanohydrin for acrylic plastics, 28%; sodium cyanide for gold recovery, 13%; cyanuric chloride for pesticides and other agricultural products, 9%; chelating agents such as EDTA, 4%; and methionine for animal feed, 2%. CEH (2000) lists the following three dominant products: acetone cyanohydrin (for methyl methacrylate), adiponitrile (for hexamethylenediamine), and sodium cyanide (used as a reagent). The U.S. Department of Transportation subjects HCN to rigid packaging, labeling, and shipping regulations. HCN can be purchased in cylinders rang-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 ing from 300 mL to 75 kg. Tank car sizes are 24 and 46 tons. Since 1950, there have been no accidents during the bulk transportation of HCN (Pesce 1994). HCN is usually shipped as a water solution containing a stabilizer of 0.05% phosphoric acid (HSDB 2000). 2. HUMAN TOXICITY DATA HCN is among the most rapidly acting of all known poisons. Absorption occurs by all routes; the mechanism of action is inhibition of cellular respiration. The respiratory, central nervous, and cardiovascular systems are the primary targets of an acute exposure. Information on human exposures was limited to exposures to high concentrations for short time intervals, poorly documented accidental exposures, and chronic occupational exposures. TABLE 5–2 Chemical and Physical Data Parameter Value Reference Synonyms Formonitrile, hydrocyanic acid, prussic acid ACGIH 1996 Molecular formula HCN Budavari et al. 1996 Structure H−C≡N ATSDR 1997 Molecular weight 27.03 Budavari et al. 1996 CAS registry number 74–90–8 ACGIH 1996 Physical state Gas or liquid Budavari et al. 1996 Color Colorless gas, bluish-white liquid Budavari et al. 1996 Solubility in water Miscible Budavari et al. 1996 Vapor pressure 807 mm Hg at 27°C Hartung 1994 Vapor density (air=1) 0.941 Budavari et al. 1996 Liquid density (water=1) 0.687 Budavari et al. 1996 Melting point −13.4°C Budavari et al. 1996 Boiling point 25.6°C Budavari et al. 1996 Odor Bitter almond Ruth 1986 Conversion factors 1 ppm=1.10 mg/m3 1 mg/m3=0.91 ppm ACGIH 1996
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 According to Hartung (1994), a few breaths at “high concentrations” may be followed by rapid collapse and cessation of respiration. If the exposure continues, unconsciousness is followed by death. At much lower concentrations, the earliest symptoms may be numbness, weakness, vertigo, some nausea, and rapid pulse. The respiratory rate increases initially and at later stages becomes slow and gasping. Chronic exposures have been related to thyroid enlargement. Cardiac effects include electrocardiogram changes (HSDB 2000). HCN is not considered a lacrimator (Weedon et al. 1940). Should individuals survive the acute phase of HCN intoxication, recovery can be uneventful and without permanent sequelae. In addition to occupational exposures, humans are exposed to cyanide in their diets (from cyanide- and amygdalin-containing foods and fumigation residues) and through cigarette smoke, automobile exhaust, and fires (NIOSH 1976; HSDB 2000). Exposure from smoking is not trivial; each puff from an unfiltered cigarette, which contains 35 μg of HCN, momentarily exposes the lung to a concentration of approximately 46 ppm (Carson et al. 1981). Yamanaka et al. (1991) reported that mainstream cigarette smoke contains HCN at 40–70 ppm, and side-stream smoke contains less than 5 ppm. The odor of HCN has been described as that of bitter almond. The ability to detect the odor varies widely and about 20% of the population is genetically unable to discern this characteristic odor (Snodgrass 1996). A review of literature on odor thresholds revealed that the odor threshold for HCN can range from 0.58 to 5 ppm (Amoore and Hautala 1983; Ruth 1986). An irritating concentration was not reported. 2.1. Acute Lethality Although a great many deaths have occurred from accidental, intentional, or occupational exposures to HCN, in only a few cases are specific exposure concentrations known. In a review of human fatalities (ATSDR 1997), it was stated that exposure to airborne concentrations of HCN at 180 to 270 ppm were fatal, usually within several minutes, and a concentration of 135 ppm was fatal after 30 min. The average fatal concentration for humans was estimated at 546 ppm for 10 min. The latter data point is based on the work of McNamara (1976), who considered the resistance of man to HCN to be similar to that of the goat and monkey and four times that of the mouse. Fatal levels of HCN cause a brief period of central nervous system stimulation followed by depression, convulsions, coma with abolished deep reflexes and dilated pupils, and death. Several review sources, such as Dudley et al. (1942),
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Hartung (1994), and ATSDR (1997), report human toxicity data that appear to be based largely on pre-1920 animal data. 2.2. Nonlethal Toxicity Several studies of occupational exposures and one study with a human subject were located. In the occupational exposures (summarized in Table 5– 3), neurological symptoms consistent with cyanide intoxication were demonstrated, but the likelihood of concomitant exposure to other chemicals could not be ruled out. For example, cleaners and cutting oils, as well as sodium and copper cyanide, may be present in electroplating operations (ATSDR 1997). The experimental human study involved the exposure of a single subject and a dog to a high concentration for a short exposure period. Adverse health consequences on systems other than the central nervous and respiratory systems have been documented during occupational and/or accidental exposures. Generally, these effects occurred following chronic exposures, but the cardiovascular and dermal effects could occur following acute exposures. For example, cardiovascular effects (palpitations, hypotension, and chest pain) (El Ghawabi et al. 1975; Blanc et al. 1985; Peden et al. 1986), hematological effects (increased or decreased hemoglobin) (El Ghawabi et al. 1975; Kumar et al. 1992), hepatic effects (increased serum alkaline phosphatase activity but not serum bilirubin) (Kumar et al. 1992), gastrointestinal effects (nausea and vomiting) (El Ghawabi et al. 1975), endocrine effects (thyroid enlargement) (Hardy et al. 1950; El Ghawabi et al. 1975; Blanc et al. 1985), and dermal effects (burns and rashes) (Blanc et al. 1985; Singh et al. 1989) have been observed. Authors of several studies, including Hardy et al. (1950), observed that some of the symptoms of chronic cyanide exposure are a result of thiocyanate-induced goiter. These authors noted that goiter has also been reported following thiocyanate therapy for hypertension. El Ghawabi et al. (1975) compared the symptoms of 36 workers exposed to HCN in three electroplating factories in Egypt with a referent group; employment ranged between 5 and 15 y. None of the workers in either the exposed or control groups were smokers. Cyanide exposure resulted from a plating bath that contained copper cyanide, sodium cyanide, and sodium carbonate. Concentrations of cyanide in the breathing zone of the workers ranged from 4.2 to 12.4 ppm (means in the three factories: 6, 8, and 10 ppm). Fifteen-minute air samples were collected in NaOH and analyzed colorimetrically. Symptoms reported most frequently by exposed workers compared with the
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 TABLE 5–3 Occupational Exposures to Hydrogen Cyanide Concentration (ppm) Effect Reference Breathing zone: 0.7 Work area: 0.2 Undefined symptoms of HCN poisoning Chandra et al. 1980 Geometric mean values of personal samples: 0.03–0.96 (range: 0.01–3.3) Area samples: up to 6 No clear exposure related symptoms or adverse health effects; employment for 1–40 y Leeser et al. 1990 2–8 (average 5) Monitoring study; no symptoms reported Maehly and Swensson 1970 4–6 Monitoring study; no symptoms reported Hardy et al. 1950 5–13 Headache, fatigue, weakness, tremor, pain, nausea; symptoms increased with years of employment of 0–15 y Radojocic 1973 <1–17 in different work areas; <1–6.4, general workroom air Health effects not reported; NIOSH (1976) considered 5 ppm a no-effect concentration Grabois 1954 6, 8, 10 (mean concentrations) range, 4.2–12.4 Most frequent symptoms: headache, weakness, and changes in taste and smell; employment 5–15 y El Ghawabi et al. 1975 Unknown; NRC (2000) suggests these exposures were >15 Headache, dizziness, nausea or vomiting, almond or bitter taste, eye irritation, loss of appetite Blanc et al. 1985 25–75 for approximately 1 h Numbness, weakness, vertigo, nausea, rapid pulse, and flushing of the face Parmenter 1926 referent control group were, in descending order of frequency: headache, weakness, and changes in taste and smell. Lachrimation, vomiting, abdominal colic, precordial pain, salivation, and nervous instability were less common. The authors made no attempt to correlate the incidences of these symptoms
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 with concentrations. Although there were no clinical manifestations of hypoor hyperthyroidism, 20 of the workers had thyroid enlargement to a mild or moderate degree; this conditions was accompanied by higher 131I uptake compared with the referent controls. Exposed workers also had significantly higher blood hemoglobin, lymphocyte cell counts, cyanmethemhemoglobin, and urinary thiocyanate levels than controls. Urinary thiocyanate levels were correlated with cyanide concentration in workplace air. Two workers in the factory with a mean exposure of 10 ppm suffered psychotic episodes; recovery occurred within 36 to 48 h. Although the sample size was small, the study used well-matched controls and included a biological index of exposure (urinary thiocyanate). The NRC Subcommittee on Spacecraft Maximum Allowable Concentrations, in evaluating the El Ghawabi et al. (1975) data, concluded that “8 ppm would likely produce no more than mild CNS effects (e.g., mild headache) which would be acceptable for 1-hour exposures” of healthy adults (NRC 2000). ATSDR (1997) noted that exposure to cleaners and cutting oils may have contributed to the effects observed in this study. Grabois (1954) surveyed HCN levels in five plants that processed apricot kernels in order to determine possible health hazards. The survey was performed by the Division of Industrial Hygiene of the New York State Department of Labor. Work area concentrations in the plants ranged from <1 to 17 ppm, and two areas in one of the plants had levels of 17.0 ppm (comminuting area) and 13.9 ppm (cooking area). The general workroom atmosphere in this plant averaged a 6.4 ppm concentration of HCN. Medical questionnaires were not given and the health status of the employees was not reported. However, recommendations were made for controlling HCN exposures “where required,” presumably where concentrations were above the then maximum recommended concentration of 10 ppm. NIOSH (1976), in interpreting the Grabois (1954) data, stated that 5 ppm was a no-effect level, and higher concentrations were only rarely present. Chandra et al. (1980) studied the effects of HCN exposure on 23 male workers engaged in electroplating and case hardening. The workers avoided cyanogenic foods such as cabbage and almonds for 48 h prior to blood and urine sampling. In spite of the low exposure levels—0.8 mg/m3 (0.7 ppm) in the breathing zone and 0.2 mg/m3 (0.2 ppm) in the general work area—the workers complained of typical symptoms of HCN poisoning (symptoms not stated); however, no objective measures of adverse health effects were reported. Higher blood and urine cyanide and thiocyanate were measured in exposed workers compared with a control group. Higher levels of blood and urine cyanide and thiocyanate were present in smokers than in nonsmokers in both the exposed and control groups.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX A TIME-SCALING CALCULATIONS FOR HYDROGEN CYANIDE FIGURE A-1 Regression line for incapacitation in monkeys (data of Purser et al. ) Data: Time (min) Concentration (ppm) Log time Log concentration 19 100 1.2788 2.0000 16 102 1.2041 2.0086 15 123 1.1761 2.0899 8 147 0.9031 2.1673 8 156 0.9031 2.1931 Regression Output: Intercept 2.6131 Slope −0.4769 R Squared 0.9142 Correlation −0.9561 Degrees of Freedom 3 Observations 5 n=2.1 k=301326
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 FIGURE A-2 Regression Line for LC50 values in rats (dta of E.I du Pont de Nemours ) Data: Time (min) Concentration (ppm) Log time Log concentration 5 369 0.6990 2.5670 15 196 1.1761 2.2923 30 173 1.4771 2.2380 60 139 1.7782 2.1430 Regression Output: Intercept 2.8044 Slope −0.3854 R Squared 0.9490 Correlation −0.9742 Degrees of Freedom 2 Observations 4 n=2.59 k=1.9E+07
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX B DERIVATION OF AEGL VALUES Derivation of AEGL-1 Key study: Leeser et al. 1990 Supporting studies: El Ghawabi et al. 1975; Hardy et al. 1950; Grabois 1954; Maehlyand Swensson 1970; Toxicity end point: No adverse effect in healthy adult humans occupationally exposed at geometric mean concentration of ≤1 (range 0.01–3.3 ppm, personal samplers [up to 6 ppm, area samples]) or 5 ppm; mild headache in adult humans occupationally exposed at 8 ppm. The exposure duration was considered to be 8 h. Uncertainty factor: An uncertainty factor was not applied to the Leeser et al. (1990) 1-ppm concentration because it is the lowest NOAEL. A factor of 3 for intraspecies differences was applied to the supporting studies because no susceptible populations were identified. The uncertainty factor was applied to the 8-h 5 ppm and 8 ppm concentrations, which resulted in concentrations close to the 8-h 1-ppm concentration in the Leeser et al. (1990) study. Scaling: C3×t=k (conservative time-scaling relationship, because the relationship between concentration and exposure duration for the headache effect is unknown). An 8-h 1 ppm concentration was used as the starting point for time scaling. Calculations: (C3/uncertainty factors)×t=k (1 ppm)3×480 min=480 ppm3·min
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 10-min AEGL-1: (480 ppm3·min/10 min)1/3=3.6 ppm Because 3.6 ppm is above the highest exposure concentration in the Leeser et al. (1990) study, as measured by personal monitors, the 10-min value was set equal to the 30-min value. 30-min AEGL-1: (480 ppm3·min/30 min)1/3=2.5 ppm 1-h AEGL-1: (480 ppm3·min/60 min)1/3=2.0 ppm 4-hour AEGL-1: (480 ppm3·min/240 min)1/3=1.3 ppm 8-hour AEGL-1: 1.0 ppm Derivation of AEGL-2 Key study: Purser 1984 Toxicity end point: Slight central nervous system depression in monkeys inhaling 60 ppm for 30 min. Scaling: C2×t=k (this document; based on regression analysis of incapacitation and lethality data for the monkey) Uncertainty factors: 2 for interspecies 3 for intraspecies combined uncertainty factor of 6 Calculations: (C2/uncertainty factors)×t=k (60 ppm/6)2×30 min=3,000 ppm2·min 10-min AEGL-2: (3,000 ppm2·min/10 min)1/2=17 ppm 30-min AEGL-2: 60 ppm/6=10 ppm 1-hour AEGL-2: (3,000 ppm2·min/60 min)1/2=7.1 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 4-hour AEGL-2: (3,000 ppm2·min/240 min)1/2=3.5 ppm 8-hour AEGL-2: (3,000 ppm2·min/480 min)1/2=2.5 ppm Derivation of AEGL-3 Key study: E.I. du Pont de Nemours 1981 Toxicity end point: 15-min LC01 of 138 ppm in the rat 30-min LC01 of 127 ppm in the rat 1-h LC01 of 88 ppm in the rat LC01 derived by probit analysis Scaling: C2.6×t=k (this document; based on the E.I. du Pont de Nemours  rat data set) Uncertainty factors: 2 for interspecies 3 for intraspecies combined uncertainty factor of 6 Calculations: (C2.6/uncertainty factors)×t=k (138 ppm/6)2.6×15 min=52,069.5 ppm2.6·min (127 ppm/6)2.6×30 min=83,911 ppm2.6·min (88 ppm/6)2.6×60 min=64,656.6 ppm2.6·min 10-min AEGL-3: (52,069.5 ppm2.6·min/10 min)1/2.6=27 ppm 30-min AEGL-1: 127 ppm/6=21 ppm 1-h AEGL-1: 88 ppm/6=15 ppm 4-h AEGL-1: (64,656.6 ppm2.6·min/240 min)1/2.6=8.6 ppm 8-h AEGL-1: (64,656.6 ppm2.6·min/480 min)1/2.6=6.6 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR HYDROGEN CYANIDE (CAS No. 74–90–8) AEGL-1 10 min 30 min 1 h 4 h 8 h 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm Key reference: Leeser, J.E., J.A.Tomenson, and D.D.Bryson. 1990. A cross-sectional study of the health of cyanide salt production workers. Report No. OHS/R/2, ICI Central Toxicology Laboratory, Alderley Park, Maccles field, Cheshire, U.K. Supporting references: (1) El Ghawabi, S.H., M.A.Gaafar, A.A.El-Saharti, S.H. Ahmed, K.K.Malash and R.Fares. 1975. Chronic cyanide exposure: A clinical, radioisotope, and laboratory study. Brit. J. Ind. Med. 32:215–219. (2) Grabois, B. 1954. Monthly Review 33:33; Publication of the Division of Industrial Hygiene, New York Department of Labor, September 1954. (3) Maehly, A.C. and A.Swensson. 1970. Cyanide and thiocyanate levels in blood and urine of workers with low-grade exposure to cyanide. Int. Arch. Arbeitsmed. 27:195–209. (4) Hardy, H.L., W.M.Jeffries, M.M.Wasserman, and W.R. Waddell. 1950. Thiocyanate effect following industrial cyanide exposure—report of two cases. New Engl. J. Med. 242:968–972. Test Species/Strain/Number: Occupational exposures/63 employees, mean age 44.7 (Leeser et al. 1990) Occupational exposures/36 workers (El Ghawabi et al. 1975) Occupational exposures/five factories (Grabois 1954) Occupational exposures/94 workers (Maehly and Swensson 1970) Occupational exposures/factories (Hardy et al. 1950) Exposure Route/Concentrations/Durations: Inhalation/geometric mean exposure of ≤1 ppm (range, 0.01–3.3 ppm; personal samplers), up to 6 ppm (area samples)/mean service years, 16.5 (Leeser et al. 1990); Inhalation/average exposure 8 ppm/5–15 y (El Ghawabi et al. 1975); Inhalation/5 ppm/unknown/(Grabois 1954; Maehly and Swensson 1970; Hardy et al. 1950).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Effects: No exposure related adverse symptoms or health effects (surveys and medical examinations taken in spring and fall of year) (Leeser et al. 1990); mild headache, other symptoms (El Ghawabi et al. 1975); no effects reported (Grabois 1954; Maehly and Swensson 1970; Hardy et al. 1950). End point/Concentration/Rationale: 1 ppm from the Leeser (1990) study; 8 ppm from the El Ghawabi et al. (1975) study; or 5 ppm from the Hardy et al. (1950), Grabois (1954), and Maehly and Swensson (1970) studies were considered no-adverse-effect to mild effect concentrations for an 8-h work day. The NRC adjusted the chronic 8 ppm value of El Ghawabi et al. (1975) to a 1-h exposure for healthy adults. Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: Not applicable Intraspecies: An uncertainty factor was not applied to the Leeser et al. (1990) 1 ppm concentration, as it is the lowest NOAEL. A factor of 3 was applied to the supporting studies as no specific susceptible populations were identified in monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals including newborns. Application of the uncertainty factor to the El Ghawabi et al. (1975; as adjusted by the NRC) and Grabois (1954) data results in a value close to the 8-h 1 ppm concentration in the Leeser et al. (1990) study. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time scaling: Because of the long-term exposure duration of the key studies, the conservative time-scaling value of n=3 (k=480 ppm3·min) was applied when scaling to shorter exposure durations. The starting point for time scaling was an 8-h concentration at 1 ppm. Data adequacy: The preponderance of data from the key studies support an 8-h no-effect concentration of 1 ppm. The Leeser et al. (1990) study encompassed subjective symptoms as well as extensive medical examinations. The occupational monitoring study of El Ghawabi et al. (1975), in which it is believed that workers inhaling a mean concentration of 8 ppm may suffer mild headaches, supports the safety of the derived values. The values are also supported by a NIOSH (1976) report in which 5 ppm was identified as a no-effect concentration in the Grabois et al. (1954) occupational study. Additional monitoring studies support the values.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-2 10 min 30 min 1 h 4 h 8 h 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm Key references: (1) Purser, D.A. 1984. A bioassay model for testing the incapacitating effects of exposure to combustion product atmospheres using cynomolgus monkeys. J. Fire Sciences 2:20–36. (2) Purser, D.A., P.Grimshaw and K.R.Berrill. 1984. Intoxication by cyanide in fires: A study in monkeys using polyacrylonitrile. Arch. Environ. Health 39:393–400. Test species/Strain/Sex/Number: Cynomolgus monkeys, 4 per exposure group (gender not stated) Exposure route/Concentrations/Durations: Inhalation, 60, 100, 102, 123, 147, or 156 ppm for 30 min Effects: (30-min exposures) 60 ppm increased respiratory minute volume and slight changes in EEGs near end of exposure 100 ppm incapacitation (semi-conscious state) in 19 min 102 ppm incapacitation in 16 min 123 ppm incapacitation in 15 min 147 ppm incapacitation in 8 min 156 ppm incapacitation in 8 min End point/Concentration/Rationale: The 30-min exposure to 60 ppm, a NOAEL, was chosen because the next higher tested concentration, 100 ppm, resulted in incapacitation within the 30-min exposure period. Uncertainty factors/Rationale: Total uncertainty factor: 6 Interspecies: 2—The monkey is an appropriate model for humans, the small size and higher respiratory rate of the monkey may result in more rapid uptake and greater sensitivity than in humans. Intraspecies: 3—No specific susceptible populations were identified during monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals, including newborns. Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Time scaling: Cn×t=k, where n=2 and k=3,000 ppm2·min on the basis of regression analysis of time-concentration relationships for both incapacitation times of 8 to 19 min and lethality data (3–60 min) for the monkey. Data Adequacy: Although human data are limited to primarily occupational monitoring studies, the data base on animal studies is good. The test atmosphere in the key study was supplied via a face mask to the restrained test subjects; restrained animals have been shown to be more sensitive than unrestrained animals to inhaled toxicants. Relative species sensitivity to inhaled HCN may be related to breathing rate. Compared to rodents, the slower breathing rate of humans and monkeys may make them less sensitive to the effects of HCN. The following two supporting studies were located: 1. A 30-min exposure of rats at 55 ppm resulted in changes in lung phospholipids and lung dynamics. Use of an uncertainty factor of 6 results in a 30-min AEGL-2 of 9.2 ppm, which is similar to the AEGL value. 2. Humans inhaling mean concentrations at 10 or 15 ppm in electroplating or silver-reclaiming factories for up to 15 y reported symptoms including headache, fatigue, effort dyspnea, and syncopes. There was no evidence that these symptoms occurred on the first day of employment.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 AEGL-3 10 min 30 min 1 h 4 h 8 h 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm Key reference: E.I. du Pont de Nemours and Company 1981. Inhalation toxicity of common combustion gases. Haskell Laboratory Report No. 238–81. Haskell Laboratory, Newark, DE Test species/Strain/Sex/Number: Crl:CD male rats, 10/exposure group Exposure route/Concentrations/Durations: Inhalation 273, 328, 340, 353, 441, 493, or 508 ppm for 5 min 110, 175, 188, 204, 230, 251, 283, or 403 ppm for 15 min 128, 149, 160, 183, 222, or 306 ppm for 30 min 76, 107, 154, 183, or 222 ppm for 60 min Effects (LC01 values were calculated by Haskell Laboratory using probit analysis): 5-min LC01: 283 ppm 15-min LC01: 138 ppm 30-min LC01: 127 ppm 60-min LC01: 88 ppm End point/Concentration/Rationale: The LC01, the threshold for lethality, was used as the basis for the derivation of the AEGL-3. The 15-min LC01 was used to calculate the 10-min value; the 30-min LC01 was used for the 30-min value; and the 60-min LC01 was used to derive the 1-, 4-, and 8-h AEGL-3 values. Uncertainty factors/Rationale: Total uncertainty factor: 6 Interspecies: 2—LC50 values for the same exposure durations for several species (rat, mouse, and rabbit) were within a factor of approximately 1.5 of each other. Based on relative respiration rates, humans are expected to be less sensitive than rodents. The mechanism is the same for all species. Intraspecies: 3—No specific susceptible populations were identified during monitoring studies or during the clinical use of nitroprusside solutions to control hypertension. The detoxifying enzyme rhodanese is present in all individuals, including newborns. Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 2 Time scaling: Cn×t=k where n=2.6 was derived from empirical data and used in a regression analysis of time-concentration relationships for rat LC50 values conducted at time periods of 5, 15, 30, and 60 min in the key study. However, the 15-, 30-, and 60-min values were calculated directly from the empirical (LC01) data. The k value of 52,069.5 ppm2.6·min, based on the 15-min LC01, was used for the 10-min value and the k value of 64,656.6 ppm2.6·min, based on the 1-h LC01, was used for the 4- and 8-h AEGL-3 values. Data adequacy: The study was well conducted. The HCN concentrations were continuously monitored using infrared spectrophotometry and validated by gas chromatography. One supporting study was located: exposure of rats to 30 ppm for 24 hours resulted in lung congestion but no deaths. Use of a total uncertainty factor of 6 and extrapolation across time to 30 minutes results in a 30-minute AEGL-3 of 22 ppm which is similar to the derived value of 21 ppm.
Representative terms from entire chapter: