3

Cyanogen
1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager Glenn Leach (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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3 Cyanogen1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager Glenn Leach (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agen- cy). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 160

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Cyanogen 161 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Cyanogen is a colorless gas with a pungent, penetrating, almond-like odor (ACGIH 2001). It is generally prepared by adding an aqueous solution of sodi- um or potassium cyanide to an aqueous solution of copper (II) sulfate or chlo- ride. It may also be prepared from hydrocyanic acid by using copper oxide or from hydrocyanic acid and nitrogen dioxide. It is used as a gas for welding and cutting heat-resistant metals, as a rocket and missile propellant, and as a fumi- gant (HSDB 2009). The hydrogen cyanide AEGL-1 values (NRC 2002) were adopted as the AEGL-1 values for cyanogen. That approach is supported by cyanogen irritation in humans (McNerney and Schrenk 1960). If AEGL-1 values were derived on the basis of the cyanogen data, the no-observed-effect level for irritation in hu- mans exposed to cyanogen for 6 min would be 8 ppm. Ocular and nasal irrita- tion was reported at the next highest concentration tested (16 ppm). An intraspe- cies uncertainty factor of 3 would be applied because contact irritation is a portal-of-entry effect and is not expected to vary widely between individuals. An interspecies uncertainty factor of 1 would be used because the study was con- ducted in humans. Thus, the threshold for irritation would be 2.7 ppm. Time scaling of this threshold would not be appropriate, because the critical effects (ocular and nasal irritation) are a function of direct contact with the cyanogen vapors and not likely to increase with duration of exposure (NRC 2001). How-

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162 Acute Exposure Guideline Levels ever, because human data on exposures of durations longer than 8 min are lack- ing and because of the potential for a systemic effect from the cyanide metabo- lite, the hydrogen cyanide AEGL-1 values were adopted as AEGL-1 values for cyanogen. The AEGL-1 values are all below the cyanogen irritation threshold of 2.7 ppm and are, thus, protective of both irritation and potential systemic cya- nide effects. In the absence of appropriate chemical-specific data to derive AEGL-2 values for cyanogen, the AEGL-3 values were divided by 3 to estimate the AEGL-2 values. That approach is justified by the steep concentration-response curve (0% mortality in rats exposed at 1,000 ppm for 15 min and 100% mortali- ty at 1,000 ppm for 30 min; 0% mortality in rats exposed at 500 ppm for 30 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 400 ppm for 45 min and 100% mortality at 500 ppm for 45 min; 0% mortality in rats exposed at 250 ppm for 60 min and 100% mortality at 400 ppm for 60 min) (McNerney and Schrenk 1960). Experimental concentrations causing no deaths in rats (McNerney and Schrenk 1960) were used as points-of-departure for the 10-min, 30-min, and 1-h AEGL-3 values. Specifically, the concentration associated with 0% mortality after 10 min of exposure was extrapolated from Figure 1 in the McNerney and Schrenk (1960) paper. That approach estimated that no deaths would occur fol- lowing a 10-min exposure at 1,530 ppm. The 30-min exposure at 500 ppm was used as the point-of-departure for the 30-min AEGL-3 value, and the 1-h expo- sure at 250 ppm was used as the point-of-departure for the 1-h AEGL-3 value. An intraspecies uncertainty factor of 3 was applied and was considered suffi- cient due to the steep concentration-response curve evidenced in the mortality data from McNerney and Schrenk (1960), which implies limited intraindividual variability. An interspecies uncertainty factor of 3 was also applied. Although a factor of 10 might normally be applied because there are insufficient data to define species sensitivity to cyanogen, application of a total uncertainty factor of 30 would yield AEGL-3 values inconsistent with the overall data base. (AEGL-3 values derived with a total uncertainty factor of 30 would be 50 ppm for 10 min, 17 ppm for 30 min, 8.3 ppm for 1 h, and 4.3 ppm for 4 and 8 h. Humans exposed to cyanogen at 8 ppm for 6 min experienced no irritation; those exposed at 16 ppm for 6 min experienced transient ocular and nasal irritation [McNerney and Schrenk 1960]. Rats and monkeys repeatedly exposed to cyanogen at 11 ppm for 6 h/day, 5 days/week for up to 6 months, experienced no treatment-related adverse effects. Rats repeatedly exposed to cyanogen at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects Lewis et al. [1984].) Therefore, the total uncertainty factor was 10. The 4- and 8-h AEGL-3 values were derived by applying a modifying fac- tor of 2 to the 1-h AEGL-3 value. That approach was used because time scaling using the equation Cn × t = k, with a default value of n = 1, and yielded possible 4- and 8-h AEGL-3 values of 6.3 and 3.2 ppm, respectively. Those values are inconsistent with the repeated-exposure data in both monkeys and rats (Lewis et

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Cyanogen 163 al. 1984). Rats exposed to cyanogen at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects. No effects were noted in ei- ther species similarly exposed at 11 ppm. AEGL values for cyanogen are presented in Table 3-1. 1. INTRODUCTION Cyanogen is a colorless gas with a pungent, penetrating, almond-like odor (ACGIH 2001). It is generally prepared by adding an aqueous solution of sodi- um or potassium cyanide to an aqueous solution of copper (II) sulfate or chlo- ride. It may also be prepared from hydrocyanic acid by using copper oxide or from hydrocyanic acid and nitrogen dioxide. It is used as a gas for welding and cutting heat-resistant metals, as a rocket and missile propellant, and as a fumi- gant (HSDB 2009). Selected chemical and physical properties of cyanogen are presented in Table 3-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Human lethality data on cyanogen were not found. 2.2. Nonlethal Toxicity An odor threshold of 235 ppm (500 mg/m3) and an irritating concentration of 15 ppm (32 mg/m3) for cyanogen were reported by Ruth (1986). TABLE 3-1 AEGL Values for Cyanogen Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm AEGL-1 values (nondisabling) (5.2 (5.2 (4.2 (2.7 (2.1 for cyanide were mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) adopted (NRC 2002). AEGL-2 50 ppm 17 ppm 8.3 ppm 4.3 ppm 4.3 ppm One-third the (disabling) (100 (36 (17 (9.0 (9.0 AEGL-3 values. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 150 ppm 50 ppm 25 ppm 13 ppm 13 ppm Concentrations (lethal) (320 (100 (53 (27 (27 causing no lethality mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in rats (McNerney and Schrenk 1960)

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164 Acute Exposure Guideline Levels TABLE 3-2 Chemical and Physical Data for Cyanogen Parameter Value Reference Synonyms Carbon nitride; cyanogene; dicyan; HSDB 2009 dicyanogen; ethanedinitrile; nitroloacetonitrile; oxalic acid dinitrile; oxalonitrile; oxalyl cyanide CAS registry no. 460-19-5 HSDB 2009 Chemical formula C2N2 HSDB 2009 Molecular weight 52.03 HSDB 2009 Physical state Colorless gas HSDB 2009 Melting point -27.83°C HSDB 2009 Boiling point -21.1°C HSDB 2009 Density/Specific gravity 0.9537 g/m3 at -21°C HSDB 2009 Solubility in water 450 cc/100 mL at 20°C HSDB 2009 Relative vapor density 1.8 (air = 1) HSDB 2009 Vapor pressure 4,300 mm Hg at 25°C HSDB 2009 Explosive limits Upper: 42.6%; lower: 6.6%, by IPCS 2012 volume in air Conversion factors in air 1 ppm = 2.1 mg/m3 NIOSH 2011 1 mg/m3 = 0.47 ppm Seven human subjects (four men and 3 women; ages 21-65 years) were exposed to cyanogen at 8 or 16 ppm in three separate tests (McNerney and Schrenk 1960). The tests were performed in a 1,185-ft3 sealed room. The cyano- gen gas contained less than 0.5% contaminants such as nitrogen, chlorine, and cyanogen chloride. Cyanogen concentrations were obtained by measuring the required volume of gas over mercury in a graduated, gas sampling tube and in- troducing it into the exposure space by displacement of the mercury. In the first test, four men and three women were exposed to cyanogen at 8 ppm for 6 min; none of the subjects detected an odor, and no ocular or nasal irritation was re- ported by the subjects. In the second test, three men and two women were ex- posed at 16 ppm for 6 min; none of the subjects detected an odor, all subjects reported ocular irritation, and four subjects reported nasal irritation (the subject who did not experiencing nasal irritation had mild cold symptoms). In the third test, four men and three women were exposed to cyanogen at 16 ppm for 8 min; none of the subjects detected an odor, and all subjects reported ocular and nasal irritation. During the 16-ppm tests, ocular irritation was noted immediately when the desired test concentration was attained. Ocular irritation was perceived sim- ultaneously with or slightly before the occurrence of nasal irritation. Both ocular and nasal irritation seemed to be transitory as signs persisted for several minutes following cessation of exposure. (There is a discrepancy in the description of the number of subjects for the first and second tests the report. The text suggests that the first test included five subjects and the second test included seven sub-

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Cyanogen 165 jects; however, the data table indicates that the first test had seven subjects and the second test had five subjects. It was assumed that the data table correctly lists the number of subjects in each test. In either case, the study results are unaf- fected.] Results are summarized in Table 3-3. In an additional test (McNerney and Schrenk 1960), three men and one woman attempted to detect the odor of cyanogen drawn from a sampling tube connected to a chamber where concentrations of 50, 100, and 250 ppm were produced; none of the subjects detected any odor. 2.3. Case Reports No case reports on cyanogen were found. 2.4. Developmental and Reproductive Effects Data on the developmental and reproductive toxicity of cyanogen in hu- mans were not available. 2.5. Genotoxicity No information regarding the genotoxicity of cyanogen in humans was available. 2.6. Carcinogenicity No information regarding the carcinogenicity of cyanogen in humans was available. 2.7. Summary Cyanogen inhalation data in humans are sparse. Cyanogen causes immedi- ate ocular and nasal irritation at 16 ppm, but no irritation was noted at 8 ppm. No developmental toxicity, reproductive toxicity, genotoxicity, or carcinogenici- ty data were available. TABLE 3-3 Effects of Acute Cyanogen Exposure in Humansa Number per Group Experiencing Effects Concentration Duration Odor Ocular Irritation Nasal Irritation 8 ppm 6 min 0/7 0/7 0/7 16 ppm 6 min 0/5 5/5 4/5b 16 ppm 8 min 0/7 7/7 7/7 a Adapted from McNerney and Schrenk 1960. b The subject without irritation had mild cold symptoms.

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166 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Groups of six male albino rats were exposed to a total of six different con- centrations of cyanogen for six different durations (McNerney and Schrenk, 1960). The tests were performed in a 2-ft3 galvanized metal exposure chamber. A plexiglass door, bolted to the chamber, sealed the unit and allowed for obser- vation of the rats during exposure. The cyanogen gas used contained less than 0.5% contaminants such as nitrogen, chlorine, and cyanogen chloride. Cyanogen concentrations were obtained by measuring the required volume of gas over mercury in a graduated, gas sampling tube and introducing it into the exposure space by displacement of the mercury. Experimental parameters and mortality incidence are summarized in Table 3-4. Observations during exposure included (in chronologic order) blinking, rubbing of forepaws over eyes and nose, hud- dling together with inactivity, slow gasping, tearing, yellow fluid from the nose and mouth, restlessness and “panic-type” movements, accentuated and poorly coordinated movements, bright pink coloration of the skin, labored breathing, deep and frequent gasping, tremors, sluggishness, prostration, shallow breathing, and death. All deaths occurred during or shortly after exposure except in the group exposed at 250 ppm for 120 min; two rats died during exposure, one died 7 h after exposure and exhibited signs of central nervous system damage starting at cessation of exposure through death, and one died 7 days after exposure and did not show any clinical signs. None of the rats showed any treatment-related gross lesions at necropsy. TABLE 3-4 Mortality in Male Albino Rats after Acute Exposure to Cyanogena Concentration (ppm) Duration (min) Mortality Incidence 4,000 7.5 3/6 4,000 15 6/6 2,000 7.5 0/6 2,000 15 6/6 1,000 15 0/6 1,000 30 6/6 500 30 0/6 500 45 6/6 400 45 0/6 400 60 6/6 250 60 0/6 250 120 4/6 a Adapted from McNerney and Schrenk 1960.

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Cyanogen 167 3.1.2. Mice Lethality was reported in mice exposed to cyanogen at 2,600 ppm for 12 min or 15,000 ppm for 1 min. However, lethality data were not provided and no additional details were available (Flury and Zernik 1931, as cited in Kopras 2012). 3.1.3. Cats Lethality was reported in cats exposed to cyanogen at 100 ppm for 2-3 h, at 200 ppm for 0.5 h, or 2,000 ppm for 13 min. However, lethality data were not provided and no additional details were available (Flury and Zernik 1931, as cited in Kopras 2012). 3.1.4. Rabbits Lethality was reported in rabbits exposed to cyanogen at 300 ppm for 3.5 h or 400 ppm for 1.8 h. However, lethality data were not provided and no addi- tional details were available (Flury and Zernik 1931, as cited in Kopras 2012). 3.1.5. Summary of Animal Lethality Data Well-described animal lethality data are restricted to studies in rats. On the basis of signs of toxicity, cyanogen is similar to other cyanides. Signs of irrita- tion are followed by central nervous system effects and eventually death. 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of 30 male Charles River albino rats were exposed to cyanogen at 0, 11, or 25 ppm for 6 h/day, 5 days/week for up to 6 months, in 4.8-m3 stainless steel and glass chambers (Lewis et al. 1984). Chambers had pyramidal top and bottom sections to obtain uniform dispersion of the test atmosphere. Cyanogen (99% pure) was introduced into the chamber from a compressed gas cylinder through a pressure regulator, metering valve, and flow meter. Breathing zone samples were taken two to six times per exposure period and analyzed by gas chromatography. Six rats per exposure group were killed after 2 days, 5 days, 1 month, 3 months, or 6 months of exposure. Serum T3 and T4, hematocrit values, and hemoglobin concentrations were measured. Gross necropsies were per- formed, and lung tissue samples were collected for analysis of moisture content. Mean exposure concentrations of cyanogen over the 6-month period were 11.2 ppm (± 1.5 ppm) and 25.3 ppm (± 3.3 ppm). At the end of the 6-month exposure

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168 Acute Exposure Guideline Levels period, the mean body weights of rats in the control, 11 ppm, and 25 ppm groups were 543 g, 589 g, and 470 g, respectively. The decrease in the 25-ppm group compared with controls was statistically significant (p < 0.05). Mean values for serum T3 and T4, hematocrit values, and hemoglobin concentrations were unaf- fected by treatment. There were no treatment-related effects noted at necropsy. 3.2.2. Mice It was reported that mice exposed to cyanogen at 235 ppm for 15 min “re- covered”. No additional details were available (Flury and Zernik, 1931, as cited in Kopras 2012). 3.2.3. Rabbits It was reported that rabbits exposed to cyanogen at 100 ppm for 4 h had “practically no effect” and rabbits exposed at 200 ppm for 4 h had “slight symp- toms”. No additional details were available (Flury and Zernik, 1931, as cited in Kopras 2012). 3.2.4. Cats It was reported that cats exposed to cyanogen at 50 ppm for 4 h had “se- vere symptoms but recovered”. No additional details were available (Flury and Zernik, 1931, as cited in Kopras 2012). 3.2.5. Monkeys Groups of five male rhesus monkeys were exposed to cyanogen at 0, 11, or 25 ppm for 6 h/day, 5 days/week for up to 6 months in 4.8-m3 stainless steel and glass chambers (Lewis et al. 1984). Chambers had pyramidal top and bot- tom sections to help attain uniform dispersion of the test atmosphere. Cyanogen (99% pure) was introduced into the chamber from a compressed gas cylinder through a pressure regulator, metering valve, and flow meter. Breathing zone samples were taken two to six times per exposure period and analyzed by gas chromatography. Behavioral tests involving lever pressing activity on a variable interval schedule of reinforcement were conducted daily after exposure and for 4 weeks following the end of the exposure period. Electrocardiograms were per- formed prior to exposure and immediately following the last exposure. Serum T3 and T4, hematocrit values, and hemoglobin concentrations were measured throughout the course of exposure. Gross necropsies were performed, and lung tissue samples were collected for analysis of moisture content. Mean exposure concentrations over the 6-month period were 11.2 ppm (± 1.5 ppm) and 25.3 ppm (± 3.3 ppm).

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Cyanogen 169 Behavioral testing suggested an increase in response rate in all three groups during the exposure period compared with the baseline measurements. Mean increases were 20%, 14%, and 145% (p = 0.06) for the control, 11 ppm, and 25 ppm groups, respectively. The increase in the 25-ppm group was consid- ered “marginal” and transitory, as the response rate returned to normal before the end of the study (Data were presented in averaged intervals such that no as- sessment of behavioral effects after a day of exposure was possible.) There were no treatment-related effects on electrocardiograms. Mean values for serum T3 and T4, hematocrit values, and hemoglobin concentrations were unaffected by treatment. Total lung moisture content was lower in both the 11-ppm and 25- ppm groups compared with controls; however, because the effect was not signif- icant (p > 0.3) and was not noted in the rats (see Section 3.2.1), the investigators found the effect to be of questionable toxicologic significance. There were no other treatment-related effects noted at necropsy. 3.2.6. Summary of Nonlethal Toxicity in Animals Nonlethal acute inhalation toxicity data are sparse. Repeated-exposure ex- periments in both rats and monkeys suggest that exposure to cyanogen at 11 ppm for up to 6 months yielded no adverse treatment-related effects. Decreased body weight was noted in rats and marginal-transitory behavioral effects were noted in monkeys exposed to cyanogen at 25 ppm for up to 6 months. 3.3. Developmental and Reproductive Effects No developmental or reproductive toxicity data in animals were found. 3.4. Genotoxicity No genotoxicity data on cyanogen were found. 3.5. Carcinogenicity No carcinogenicity data on cyanogen were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition Definitive metabolism and disposition data for cyanogen in humans or an- imals were not available. Cyanogen is reportedly converted in the body partly to hydrogen cyanide and partly to cyanic acid (Flury and Zernik, 1931, as cited in Kopras 2012). It reportedly hydrolyzes to yield one mole of hydrogen cyanide

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170 Acute Exposure Guideline Levels and one mole of cyanate (McNerney and Schrenk 1960). Clinical signs noted in cyanogen-exposed animals are similar to those noted in hydrogen cyanide- exposed animals. 4.2. Mechanism of Toxicity The mechanism of toxicity of cyanogen is reportedly similar to that of hy- drogen cyanide (Kopras 2012). Hydrogen cyanide is a systemic poison that acts on the central nervous system. It interrupts cellular respiration by inhibiting cy- tochrome oxidase, thus blocking electron transfer to oxygen (Rieders 1971). Tissue oxygen concentrations rise, resulting in increased tissue oxygen tension and a decreased unloading for oxyhemoglobin. As a consequence, oxidative metabolism may slow to a point where it cannot meet metabolic demands. That is particularly critical in the brainstem nuclei where lack of an energy source results in central respiratory arrest and death. Cyanide can inhibit many other enzymes, particularly those that contain iron or copper, but cytochrome oxidase appears to be the most sensitive enzyme (Rieders 1971). Cyanide also stimulates the chemoreceptors of the carotid and aortic bodies to produce a brief period of hyperpnea. Cardiac irregularities may occur, but death is due to respiratory ar- rest. Brain lesions have been associated with exposure of animals to hydrogen cyanide at high concentrations (NRC 2002). 4.3. Structure-Activity Relationships Cyanogen is structurally similar to cyanide and other nitriles. At relatively low concentrations, cyanogen appears to be much more irritating than hydrogen cyanide. In human subjects exposed to cyanogen at 16 ppm for 6 or 8 min, ocu- lar irritation was noted immediately. The ocular irritation was perceived simul- taneously with or slightly before the occurrence of nasal irritation (McNerney and Schrenk 1960). In contrast, although signs of systemic cyanide poisoning (headache, vertigo, weakness, and numbness) were noted in humans occupation- ally exposed to hydrogen cyanide at concentrations of 5-75 ppm, no irritation was reported (NRC 2002). Qualitatively, clinical signs in animals exposed to cyanogen are consistent with clinical signs associated with cyanide exposure. However, rat data suggest that cyanogen is less acutely toxic than hydrogen cyanide by a factor of 10 (McNerney and Schrenk 1960; ACGIH 2001). Analysis of available rat data suggests that this assumption may be true for very short exposure durations (up to approximately 15 min), but not for longer durations (30 min to 1 h). The 5- min rat LC50 values for hydrogen cyanide range from approximately 400-500 ppm (NRC 2002), and three of six rats died when exposed to cyanogen at 4,000 ppm for 7.5 min (McNerney and Schrenk 1960). A 15-min rat LC50 value for

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Cyanogen 179 APPENDIX A DERIVATION OF AEGL VALUES FOR CYANOGEN Derivation of AEGL-1 Values The AEGL-1 values for hydrogen cyanide were adopted as AEGL-1 values for cyanogen. That approach is supported by cyanogen irritation in humans (McNerney and Schrenk 1960). The no-observed effect level for irritation in humans was 8 ppm for 6 min. Ocular and nasal irritation was noted at the next highest concentration tested (16 ppm). If that study were used as the basis for deriving AEGL-1 values for cyanogen, the point-of-departure would be 8 ppm. An intraspecies uncertainty factor of 3 would be applied because contact irritation is a portal-of-entry effect and is not expected to vary widely between individuals. An interspecies uncertainty factor of 1 would be applied because the study was conducted in humans. Thus, the threshold for irritation would be 2.7 ppm. Time scaling of that concentration would not be appropriate, because the critical effect (ocular and nasal irritation) is a function of direct contact with the cyanogen vapors and not likely to increase with duration of exposure (NRC 2001). However, because human data on exposures to cyanogen for durations longer than 8 min are lacking and because of the potential for a systemic effect from the cyanide metabolite, the hydrogen cyanide AEGL-1 values (NRC 2002) were adopted as AEGL-1 values for cyanogen. The AEGL-1 values are all below the cyanogen irritation threshold of 2.7 ppm and are, thus, protective for both irritation and potential systemic cyanide effects. 10-min AEGL-1: 2.5 ppm 30-min AEGL-1: 2.5 ppm 1-h AEGL-1: 2.0 ppm 4-h AEGL-1: 1.3 ppm 8-h AEGL-1: 1.0 ppm Derivation of AEGL-2 Values AEGL-2 values for cyanogen were derived by taking one-third of the respec- tive AEGL-3 values (see below), because there were no data on cyanogen consistent with an AEGL-2 end point. That approach is justified by the steep concentration- response relationship (0% mortality in rats exposed at 1,000 ppm for 15 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 500 ppm for 30 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats ex- posed at 400 ppm for 45 min and 100% mortality at 500 ppm for 45 min; 0% mortal- ity in rats exposed at 250 ppm for 60 min and 100% mortality at 400 ppm for 60 min [McNerney and Schrenk 1960]).

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180 Acute Exposure Guideline Levels 10-min AEGL-2: 150 ppm ÷ 3 = 50 ppm 30-min AEGL-2: 50 ppm ÷ 3 = 17 ppm 1-h AEGL-2: 25 ppm ÷ 3 = 8.3 ppm 4-h AEGL-2: 13 ppm ÷ 3 = 4.3 ppm 8-h AEGL-2: 13 ppm ÷ 3 = 4.3 ppm Derivation of AEGL-3 Values Key study: McNerney, J.M., and H.H. Schrenk. 1960. The acute toxicity of cyanogen. Am. Ind. Hyg. Assoc. J. 2(21):121-124. Toxicity end point: Concentrations of cyanogen causing no deaths in rats is 1,530 ppm for 10 min (extrapolated from Figure 1 of paper by McNerney and Schrenk [1960]); 500 ppm for 30 min; and 250 ppm for 1 h. Time scaling: None Uncertainty factors: 3 for interspecies differences; a factor of 10 might normally be applied because there are insufficient data to define species sensitivity to cyanogen. However, application of a total uncertainty factor of 30 would yield AEGL-3 values inconsistent with the overall data base. (AEGL-3 values derived with a total uncertainty factor of 30 would be 50 ppm for 10 min, 17 ppm for 30 min, 8.3 ppm for 1 h, 4.3 ppm for 4 h, and 4.3 ppm for 8 h. Humans exposed at 8 ppm for 6 min experienced no irritation; those exposed at 16 ppm for 6 min experienced transient ocular and nasal irritation [McNerney and Schrenk 1960]. Rats and monkeys repeatedly exposed to cyanogen at 11 ppm for 6 h/day, 5 days/week for up to 6 months, experienced no treatment-related adverse effects. Rats repeatedly exposed at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects [Lewis et al. 1984].) 3 for intraspecies variability; considered sufficient due to the steep concentration-response curve (0% mortality in rats exposed at 1,000 ppm for 15 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats

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Cyanogen 181 exposed at 500 ppm for 30 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 400 ppm for 45 min and 100% mortality at 500 ppm for 45 min; 0% mortality in rats exposed at 250 ppm for 60 min and 100% mortality at 400 ppm for 60 min [McNerney and Schrenk 1960]), which implies limited intraindividual variability. Modifying factor: 2; applied to the 1-h AEGL-3 value to derive the 4- and 8-h AEGL-3 values. That approach was used because time scaling using the equation Cn × t = k, with n = 1, would yield 4- and 8-h AEGL-3 values of 6.3 and 3.2 ppm, respectively. Those values are inconsistent with the repeated-exposure data in both monkeys and rats (Lewis et al. 1984). Rats repeatedly exposed to cyanogen at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects. No effects were noted in either species similarly exposed at 11 ppm. Calculations: 10-min AEGL-3: 1,530 ppm ÷ 10 = 150 ppm 30-min AEGL-3: 500 ppm ÷ 10 = 50 ppm 1-h AEGL-3: 250 ppm ÷ 10 = 25 ppm 4-h AEGL-3: 25 ppm ÷ 2 = 13 ppm 8-h AEGL-3: 25 ppm ÷ 2 = 13 ppm

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182 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CYANOGEN Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm (5.2 mg/m3) (5.2 mg/m3) (4.2 mg/m3) (2.7 mg/m3) (2.1 mg/m3) Data adequacy: The AEGL-1 values for hydrogen cyanide (NRC 2002) were adopted as the AEGL-1 values for cyanogen. That approach is supported by cyanogen irritation in humans (McNerney and Schrenk 1960). If AEGL-1 values were derived from the cyanogen data, the no-observed effect level for irritation in humans would be 8 ppm for 6 min. Ocular and nasal irritation was noted at the next highest concentration tested (16 ppm). An intraspecies uncertainty factor of 3 would be applied because contact irritation is a portal-of-entry effect and is not expected to vary widely between individuals. An interspecies uncertainty factor of 1 would be applied because the study was conducted in humans. Thus, the threshold for irritation would have been 2.7 ppm. Time scaling of that concentration would not be appropriate, because the critical effects (ocular and nasal irritation) are a function of direct contact with the cyanogen vapors and not likely to increase with duration of exposure (NRC 2001). However, because human data on exposures to cyanogen for durations longer than 8 min are lacking and because of the potential for a systemic effect from the cyanide metabolite, the hydrogen cyanide AEGL-1 values (NRC 2002) were adopted as AEGL-1 values for cyanogen. The AEGL-1 values are all below the cyanogen irritation threshold of 2.7 ppm and are, thus, protective for both irritation and potential systemic cyanide effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 50 ppm 17 ppm 8.3 ppm 4.3 ppm 4.3 ppm (100 mg/m3) (36 mg/m3) (17 mg/m3) (9.0 mg/m3) (9.0 mg/m3) Data adequacy: The data on cyanogen were inadequate for deriving AEGL-2 values, so the values were estimated by taking one-third of the AEGL-3 values. That approach is supported by steep concentration-response curve (0% mortality in rats exposed at 1,000 ppm for 15 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 500 ppm for 30 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 400 ppm for 45 min and 100% mortality at 500 ppm for 45 min; 0% mortality in rats exposed at 250 ppm for 60 min and 100% mortality at 400 ppm for 60 min (McNerney and Schrenk1960).

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Cyanogen 183 AEGL-3 VALUES 10 min 30 min 1h 4h 8h 150 ppm 50 ppm 25 ppm 13 ppm 13 ppm (320 mg/m3) 100 mg/m3) (53 mg/m3) (27 mg/m3) (27 mg/m3) Reference: McNerney, J.M. and H.H. Schrenk. 1960. The acute toxicity of cyanogen. Am. Ind. Hyg. Assoc. J. 2(21):121-124. Test species/Strain/Sex/Number: Rat; albino; male; 6/group Exposure route/Concentrations/Durations: Inhalation, 250-4,000 ppm for 7.5-120 min. Effects: Lethality Concentration (ppm) Duration (min) Mortality 4,000 7.5 3/6 4,000 15 6/6 2,000 7.5 0/6 2,000 15 6/6 1,000 15 0/6 1,000 30 6/6 500 30 0/6 500 45 6/6 400 45 0/6 400 60 6/6 250 60 0/6 250 120 4/6 End point/Concentration/Rationale: Experimental concentrations causing no deaths in rats used as points-of-departure for the 10-min, 30-min, and 1-h AEGL-3 values. The 10-min point-of-departure of 1,530 ppm was extrapolated from Figure 1 in the McNerney and Schrenk (1960) paper, the 30-min exposure at 500 ppm was the point-of- departure for the 30-min AEGL-3 value, and the 1-h exposure at 250 ppm was the point- of-departure for the 1-h AEGL-3 value. Uncertainty factors/Rationale: Total uncertainty factor was 10. Interspecies: 3, a factor of 10 might normally be applied because there are insufficient data to define species sensitivity to cyanogen. However, application of a total uncertainty factor of 30 would yield AEGL-3 values inconsistent with the overall data base. (AEGL- 3 values derived with a total uncertainty factor of 30 would be 50 ppm for 10 min, 17 ppm for 30 min, 8.3 ppm for 1 h, 4.3 ppm for 4 h, and 4.3 ppm for 8 h. Humans exposed to cyanogen at 8 ppm for 6 min experienced no irritation; those exposed at 16 ppm for 6 min experienced transient ocular and nasal irritation [McNerney and Schrenk 1960]. Rats and monkeys repeatedly exposed at 11 ppm for 6 h/day, 5 days/week for up to 6 months, experienced no treatment-related adverse effects. Rats repeatedly exposed at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects [Lewis et al. 1984]). Intraspecies: 3, considered sufficient due to the steep concentration-response curve (0% mortality in rats exposed at 1,000 ppm for 15 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 500 ppm for 30 min and 100% mortality at 1,000 ppm for 30 min; 0% mortality in rats exposed at 400 ppm for 45 min and 100% mortality at 500 ppm for 45 min; 0% mortality in rats exposed at 250 ppm for 60 min and 100% mortality at 400 ppm for 60 min [McNerney and Schrenk 1960]), which implies limited intraindividual variability.

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184 Acute Exposure Guideline Levels Modifying factor: 2, applied to the 1-h AEGL-3 value to derive the 4- and 8-h AEGL-3 values. That approach was used because time scaling using the equation Cn × t = k, with n = 1, would yield 4- and 8-h AEGL-3 values of 6.3 and 3.2 ppm, respectively. Those values are inconsistent with the repeated-exposure data in both monkeys and rats (Lewis et al. 1984). Rats repeatedly exposed to cyanogen at 25 ppm for 6 h/day, 5 days/week for up to 6 months, experienced only decreased body weight, and monkeys similarly exposed showed only marginal behavioral effects. No effects were noted in either species similarly exposed at 11 ppm. Animal-to-human dosimetric adjustment: Not applicable Time scaling: Performed to determine the 10-min point-of-departure from a 7.5-min exposure at 2,000 ppm. Time scaling was performed using the equation Cn × t = k equation, with n = 1 (default value when extrapolating to longer durations) to derive a value protective of human health (NRC 2001). Data adequacy: Sparse data set. Support from repeated-exposure studies.

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Cyanogen 185 APPENDIX C CATEGORY PLOT FOR CYANOGEN Chemical Toxicity - TSD All Data Cyanogen 100000 Human - No Effect Human - Discomfort 10000 Human - Disabling Animal - No Effect 1000 ppm Animal - Discomfort 100 Animal - Disabling AEGL-3 Animal - Partially Lethal 10 AEGL-2 Animal - Lethal AEGL-1 AEGL 1 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of toxicity data and AEGL values for cyanogen.

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186 TABLE C-1 Data Used in the Category Plot for Cyanogen Source Species Sex No. Exposures ppm Minutes Category Comments AEGL-1 2.5 10 AEGL AEGL-1 2.5 30 AEGL AEGL-1 2.0 60 AEGL AEGL-1 1.3 240 AEGL AEGL-1 1.0 480 AEGL AEGL-2 50 10 AEGL AEGL-2 17 30 AEGL AEGL-2 8.3 60 AEGL AEGL-2 4.3 240 AEGL AEGL-2 4.3 480 AEGL AEGL-3 150 10 AEGL AEGL-3 50 30 AEGL AEGL-3 25 60 AEGL AEGL-3 13 240 AEGL AEGL-3 13 480 AEGL Rat 1 4,000 7.5 PL Rat 1 4,000 15 3 Rat 1 2,000 7.5 2 Rat 1 2,000 15 3 Rat 1 1,000 15 2

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Rat 1 1,000 30 3 Rat 1 500 30 2 Rat 1 500 45 2 Rat 1 400 45 2 Rat 1 400 60 3 Rat 1 250 120 PL Mouse 1 2,600 12 3 Assumes all dead/worst case scenario. Mouse 1 15,000 108 3 Assumes all dead/worst case scenario. Cat 1 300 210 3 Assumes all dead/worst case scenario. Cat 1 400 30 3 Assumes all dead/worst case scenario. Rabbit 1 100 120 3 Assumes all dead/worst case scenario. Rabbit 1 200 30 3 Assumes all dead/worst case scenario. Rabbit 1 2,000 13 3 Assumes all dead/worst case scenario. Rabbit 1 100 240 0 Questionable data point. Rabbit 1 200 240 1 Questionable data point. Cat 1 50 240 2 Questionable data point. Human 1 8 6 0 Human 1 16 6 1 Human 1 16 8 1 Categories: 0 = no effect, 1 = discomfort, 2 = disabling, PL = partial lethality, 3 = lethal. 187

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188 Acute Exposure Guideline Levels APPENDIX D DERIVATION OF HYDROGEN CYANIDE AEGL-1 VALUES AND COMPARISON OF HYDROGEN CYANIDE AND CYANOGEN AEGL VALUES HYDROGEN CYANIDE AEGL-1 VALUES (NRC 2002) 10 min 30 min 1h 4h 8h 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, 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. Br. J. Ind. Med. 32(3):215-219. (2) Grabois, B. 1954. Exposure to hydrogen cyanide in processing of apricot kernels. Monthly Review NY Department of Labor 33:33-36. (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(3):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 years (El Ghawabi et al. 1975); Inhalation/5 ppm/unknown (Hardy et al. 1950; Grabois 1954; Maehly and Swensson 1970). 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 (Hardy et al. 1950; Grabois 1954; Maehly and Swensson 1970). End point/Concentration/Rationale: 8 ppm from the El Ghawabi et al. (1975) study; 5 ppm from the Hardy et al. (1950), Grabois (1954), and Maehly and Swensson (1970) studies; or 1 ppm from the Leeser (1990) study, 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.

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Cyanogen 189 Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: Not applicable Intraspecies: 3, 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. The uncertainty factor was not applied to the Leeser et al. (1990) 1 ppm concentration as it is the lowest no-observed-adverse-effect level. 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 of 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 support 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. COMPARISON OF AEGL VALUES FOR CYANOGEN AND HYDROGEN CYANIDE Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 Cyanogen 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm Hydrogen cyanide 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 1.0 ppm AEGL-2 Cyanogen 50 ppm 17 ppm 8.3 ppm 4.3 ppm 4.3 ppm Hydrogen cyanide 17 ppm 10 ppm 7.1 ppm 3.5 ppm 2.5 ppm AEGL-3 Cyanogen 150 ppm 50 ppm 25 ppm 13 ppm 13 ppm Hydrogen cyanide 27 ppm 21 ppm 15 ppm 8.6 ppm 6.6 ppm