3
Hydrogen Chloride

This chapter summarizes the relevant epidemiologic and toxicologic studies of hydrogen chloride. It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for hydrogen chloride. The committee’s recommendations for hydrogen chloride exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Hydrogen chloride is a colorless, corrosive, nonflammable gas with a pungent odor (Budavari et al. 1989). Leonardos et al. (1969) determined the odor threshold of hydrogen chloride to be 10 ppm by using a standardized procedure, a trained odor panel, and high-purity hydrogen chloride; the odor was described by the panel as “pungent.” A wide range of odor thresholds (HSDB 2008) have since been reported. On the basis of a literature review, Amoore and Hautala (1983) reported the odor threshold as 0.77 ppm. The irritating concentration has been reported as 33 ppm (Ruth 1986).

Hydrogen chloride is highly soluble in water and forms hydrochloric acid. Because hydrogen chloride is so hygroscopic, airborne hydrogen chloride is typically an aerosol of hydrochloric acid. Selected physical and chemical properties are shown in Table 3-1.



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3 Hydrogen Chloride This chapter summarizes the relevant epidemiologic and toxicologic stud- ies of hydrogen chloride. It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the Na- tional Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for hydrogen chloride. The committee’s recommendations for hydrogen chloride exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Hydrogen chloride is a colorless, corrosive, nonflammable gas with a pun- gent odor (Budavari et al. 1989). Leonardos et al. (1969) determined the odor threshold of hydrogen chloride to be 10 ppm by using a standardized procedure, a trained odor panel, and high-purity hydrogen chloride; the odor was described by the panel as “pungent.” A wide range of odor thresholds (HSDB 2008) have since been reported. On the basis of a literature review, Amoore and Hautala (1983) reported the odor threshold as 0.77 ppm. The irritating concentration has been reported as 33 ppm (Ruth 1986). Hydrogen chloride is highly soluble in water and forms hydrochloric acid. Because hydrogen chloride is so hygroscopic, airborne hydrogen chloride is typically an aerosol of hydrochloric acid. Selected physical and chemical prop- erties are shown in Table 3-1. 46

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47 Hydrogen Chloride TABLE 3-1 Physical and Chemical Properties of Hydrogen Chloride Synonyms Anhydrous hydrochloric acid CAS registry number 7647-01-0 Molecular formula HCl Molecular weight 36.47 Boiling point –85.05°C Melting point –114.22°C Flash point NA Explosive limits NA Specific gravity 1.268 at 25°C (air = 1.000) Vapor pressure 35,424 mmHg at 25°C Solubility 67.3 g/100 g of water at 30°C; soluble also in some polar organic solvents, such as methanol, ethanol, and ether 1 ppm = 1.49 mg/m3; 1 mg/m3 = 0.67 ppm Conversion factors Abbreviation: NA, not available or not applicable. Sources: Budavari et al. (1989), HSDB (2008). OCCURRENCE AND USE Hydrogen chloride is found naturally in the environment, is produced by the digestive system of most mammals, is a byproduct of many industrial proc- esses, and is used primarily to synthesize inorganic and organic chemicals, such as chlorine, ethylene dichloride, and methyl chloride (Hisham and Bommaraju 2005). Hydrogen chloride has been measured in the submarine atmosphere. Data collected on three nuclear-powered attack submarines indicate a range of 1-3 ppb (Hagar 2008). Whether the reported concentrations are representative of the submarine fleet is not known; few details were provided about the conditions on the submarines when the samples were taken. The committee located no other exposure data for the submarine environment. Hydrogen chloride emissions in the submarine are thought to arise from decomposition of halogenated hydrocar- bons and refrigerants (Hagar 2008). SUMMARY OF TOXICITY The toxicity of hydrogen chloride has been the subject of a number of re- views (NRC 1987; EPA 1995; Lam and Wong 2000; NRC 2002, 2004; ACGIH 2003). At high concentrations, hydrogen chloride is an irritant to the mucous membranes, eyes, and skin. Accidental exposure to gaseous products or mix-

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48 Exposure Guidance Levels for Selected Submarine Contaminants tures containing high concentrations of hydrogen chloride can result in a spec- trum of chronic effects, including recurrent acute respiratory illnesses and asthma. Prolonged hypoxemia is noted in case reports, but details of exposure duration are unknown. The maximum tolerable concentration in prolonged ex- posure of humans has been reported as 10 ppm, with a maximum tolerable con- centration for a few hours of 10-50 ppm (Henderson and Hagard 1943). Respira- tory tract effects in laboratory animals range from mild to moderate irritation at low concentrations (less than 100 ppm) to nasal lesions at moderate concentra- tions (100-500 ppm) and pulmonary damage at high concentrations (greater than 500 ppm). Death can result from severe pulmonary injury. Hydrogen chloride can cause functional and morphologic respiratory tract injuries, depending on exposure concentration and duration (Darmer et al. 1974; Hartzell et al. 1985; Burleigh-Flayer et al. 1985; Kaplan et al. 1988, 1993a, cited in NRC 2004; Stavert et al. 1991). Because of its high water solubility, most hydrogen chloride that is inhaled should be absorbed in the upper respiratory tract (Morris and Smith 1982), and this should result in low availability for systemic toxicity. However, hepatic, myocardial, and renal damage was observed in laboratory animals after repeated exposure at high concentrations (Machle et al. 1942). Those effects may be attributed to disturbances in acid-base metabolism or to reduction in blood oxygen concentrations resulting from pulmonary damage. Data on the genotoxicity, immunotoxicity, and male reproductive toxicity of hydrogen chloride exposure are either nonexistent or too sparse to support con- clusions. Neither epidemiologic studies nor lifetime animal cancer bioassays have yielded evidence of an association between hydrogen chloride exposure and cancer (Bond et al. 1991; IARC 1992; Sellakumar et al. 1985). Effects in Humans Accidental Exposures Accidental exposure can occur when hydrogen chloride is the sole agent or the dominant agent in a mixture, such as one produced by combustion of polyvinyl chloride. Published reports describe immediate skin, eye, and respira- tory tract irritation, particularly in the nose, pharynx, larynx, and tracheobron- chial tree. The reports described below do not include exposure concentrations, so they are of little use in setting exposure guidelines; they are provided as sec- ondary, supportive evidence of the outcomes observed in quantitative animal exposure studies. A 41-year-old nonsmoking nonatopic man with stable, mild asthma devel- oped rapidly progressive bronchospasm and acute respiratory failure requiring mechanical ventilation after cleaning a pool for 1 h with a product that contained hydrochloric acid. Severe asthma requiring oral corticosteroids and repeated hospitalizations persisted a year after the accident (Boulet 1988). A 57-year-old man with a 12-pack-year cigarette-smoking history developed irritant-induced

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49 Hydrogen Chloride asthma after exposure to a hydrochloric acid and phosgene mixture (Tarlo and Broder 1989). Finnegan and Hodson (1989) provided an overview of the 47 cases of hy- drogen chloride fume inhalation in the registry of the poison center of Guy’s Hospital, London. Exposure sources, durations, and circumstances were not specified. The dominant initial symptoms were nausea and vomiting, with bron- chospasm in those with a history of asthma and one report of laryngospasm. Symptoms typically resolved in a week. Rosenthal et al. (1978) reported persis- tent hypoxemia lasting for months in one of 11 workers exposed to a gaseous mixture of hydrogen chloride, phosphorus oxychloride, phosphorus pentachlo- ride, oxalyl chloride, and oxalic acid. Evidence of alveolar injury in the workers included reduction in diffusion capacity (three workers) and a finding of lung rales on physical examination (two workers). The following case is presented in detail because of the extensive clinical characterization of persistent hypoxemia, which indicated the ability of mixed hydrogen chloride vapor and mist to cause delayed-onset deep lung or paren- chymal injury. The case also illustrates a propensity for recurrent acute respira- tory illness after such an injury. A chemical factory released vapors that con- tained an unknown high concentration of hydrogen chloride, water, and trace amounts of phosphorous trichloride. The release resulted in a 15-min exposure of a 34-year-old woman who was working on her boat in an open marina 300 ft away. As reported by Finnegan and Hodson (1989), the strength of the mixture caused the paint on the boat to blister. The woman was hospitalized on the same day for symptoms of skin, eye, and respiratory tract irritation and for tachypnea, facial erythema, and hoarseness. She was discharged on the third day but read- mitted with dyspnea while talking and with hypoxemia without hypercapnea, corrected with 24-28% oxygen. Further evaluation to identify the cause of the hypoxemia showed a normal anatomic shunt of 3.2%, a normal ventilation- perfusion scan (which excluded pulmonary thromboembolism), and normal total lung capacity but reduced residual volume. Exercise challenge during this inter- val showed marked desaturation (from 94% to 82%). The hypoxemia persisted for a month despite treatment with prednisone, salbutamol, and beclomethasone. Hypoxemia recurred during two later viral infections that required hospitaliza- tion. A neighborhood exposure occurred when a container truck leaked 200 gal of hydrochloric acid while parked 150 ft from a mobile-home park; hydrogen chloride was later found in nearby ditches and a pond (Kilburn 1996). The acute illness among the investigating officer and residents included burning and tear- ing eyes, burning throat, headache, chest pain, shortness of breath, and influ- enza-like complaints. Follow-up assessment 20 months after the exposure com- pared findings between 45 adults and 24 children living in the zone of the cloud of fumes and 56 adults and 39 children living in a similar mobile-home court 1.4 miles from the site. The exposed group showed more respiratory symptoms, such as phlegm production and shortness of breath, than the reference group. After adjustment for sex, age, height, and cigarette-smoking, exposed adults

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50 Exposure Guidance Levels for Selected Submarine Contaminants showed lower mean forced vital capacity (FVC; 70% vs 79%) and lower forced expiratory volume at 1 s (FEV1; 61% vs 72%). Self-reports of mood state showed greater tension, depression, anger, extreme fatigue, and confusion and lower vigor in the exposed group. Dyer and Esch (1976) performed a clinical study of 170 firefighters who were exposed one to four times to polyvinyl chloride thermal degradation prod- ucts. Acute symptoms included pain in the throat, neck, and anterior part of the chest; dyspnea; severe headache; dizziness; and irregular pulse. Electrocardi- ography showed that 20% had extrasystoles. Twelve firefighters required hospi- talization and treatment with oxygen, bronchodilators, antihistamines, and de- congestants. None had to retire because of permanent airway disorders. Markowitz et al. (1989) conducted a retrospective cohort study of 80 fire- fighters exposed in 1985 to burning polyvinyl chloride; they used 15 unexposed firefighters as control subjects. Air analysis during a recreation of the polyvinyl chloride combustion showed the primary decomposition products to be hydro- gen chloride (6,800 ppm), carbon monoxide (9,300 ppm), carbon dioxide (26,000 ppm), and methane (1,760 ppm). Smaller quantities of benzene (146 ppm) and other organic compounds, primarily acetylene (420 ppm), were de- tected. The concentrations of nitric oxide, nitrogen dioxide, methyl pyrrole, and an unidentified chlorinated agent were 3-6 ppm. Phosgene, vinyl chloride, dioc- tylphthalate, and polychlorinated biphenyls were not detected. One hour after the fire began, firefighters reported rashes and eye irritation. Five to 6 weeks after the incident, symptoms with a higher relative risk in exposed firefighters included eye irritation, skin irritation, rash or itching, sore throat, headache, rest- lessness, dizziness, blurred vision, stomach pain, tingling or numbness, dry mouth, chest pain, wheezing, coughing, shortness of breath, increased thirst, muscle or joint pain, tiredness, and daytime drowsiness. Promisloff et al. (1990) reported the development of reactive-airways dys- function syndrome (RADS) in three Philadelphia police officers after exposure to toxic fumes from a roadside truck accident. The accident resulted in a large chemical spill and fire on a major highway. Exposures were to sodium hydrox- ide and hydrochloric acid generated by hydrolysis of silicon tetrachloride and trichlorosilane. Exposure concentrations were not discussed. In summary, the officers developed persistent coughing and headache within hours of exposure and exertional dyspnea and wheezing later. Inhalation challenge showed airway hyperreactivity to methacholine; exercise challenge showed no oxyhemoglobin desaturation. Initial spirometry was normal, but an accelerated decline in func- tion (decreases in FEV1 and FEV1/FVC%) occurred over the following year. Experimental Studies Human exposure studies performed in laboratories in the late 1800s and first half of the 1900s remain an important source of hydrogen chloride expo- sure-response information (Table 3-2). A limitation of the data is that the meth-

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51 Hydrogen Chloride ods and results are reported in less detail than current practice dictates. Elkins (1959) recommended a maximum allowable concentration of 5 ppm on the basis of immediate symptoms of nose and throat irritation. Lower concentrations might have promoted tooth decay but were not considered to be harmful. All concentrations above 10 ppm were reported as highly irritating, although some workers adapted over time. Workplace exposure measurements included 16 ppm in waste carbonizing, 11 ppm in acid dipping, and 23 ppm in tanning processes. Henderson and Hagard (1943) reported that hydrogen chloride at 35 ppm caused irritation of the throat on short exposure, and 10 ppm was the maximum concentration tolerable for prolonged exposure. The maximum concentration tolerable for a few hours was 10-50 ppm, the maximum concentration tolerable for 1 h was 50-100 ppm, and concentrations of 1,000-2,000 ppm were reported as dangerous for even short exposure. Heyroth (1963) cited an 1889 dissertation that reported that work is im- possible when one inhales hydrogen chloride at 50-100 ppm, difficult but possi- ble at 10-50 ppm, and undisturbed at 10 ppm. Stevens et al. (1992) exposed 10 18- to 25-year-old asthmatics to low con- centrations of hydrogen chloride (0.8 and 1.8 ppm) in a controlled human expo- sure study. The subjects were exposed three times: once to filtered air, once to hydrogen chloride at 0.8 ppm, and once to hydrogen chloride at 1.8 ppm. Expo- sures were separated by at least a week. The 45-min exposure was evenly di- vided into two periods of exercise separated by a period of rest. The exercise consisted of walking on a treadmill at 2 mph with an inclination of 10%. The subjects reported no increases in respiratory symptoms and had insignificant changes in pulmonary function between pre-exposure and postexposure meas- urements. There was a significant rise in oral ammonia concentrations—a find- ing that was counterintuitive in that the authors had expected a slight decrease because of neutralization caused by the inhaled acid gas. The authors concluded that people who had mild asthma had no adverse respiratory effects of exposure to hydrogen chloride at low concentrations. Occupational and Epidemiologic Studies Kremer et al. (1995) conducted a cross-sectional study to evaluate the rela- tionship between occupational exposure to low concentrations of airway irritants and airway responsiveness to histamine, a marker of airway hyperreactivity. Of a cohort of 688 male workers, 119 were potentially exposed to acid mists con- taining sulfur dioxide and hydrogen chloride vapors and aerosols of sulfate and hydrogen chloride. Company policies prevented employment of workers who might be exposed to the acid mists if they had a suspected history of asthma-like symptoms during the 5-year period before the study. Time-weighted average (7- h, TWA) concentrations were determined by personal sampling and indicated maximum concentrations of 0.3 mg/m3 for sulfur dioxide vapor, of 2.1 mg/m3

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52 TABLE 3-2 Hydrogen Chloride: Human Exposure Studies Concentration (ppm) Duration Effect Reference 0.77 Unspecified Geometric mean of odor Amoore and Hautala 1983 thresholds 1-5 Unspecified Odor threshold Heyroth 1963 10 Unspecified Odor threshold Leonardos et al. 1969 <5 Unspecified Apparently not harmful, may promote tooth Elkins 1959 decay ≥5 Unspecified Immediately irritating Elkins 1959 > 10 Occupational Highly irritating, but workers developed Elkins 1959 some tolerance 10 Prolonged Maximum tolerable Henderson and Hagard 1943 10-50 A few hours Maximum tolerable Henderson and Hagard 1943; Jacobs 1967 35 Short Throat irritation Henderson and Hagard 1943 50-100 1h Maximum tolerable Henderson and Hagard 1943; Jacobs 1967 1,000-2,000 Short (less than 1 h) Dangerous Henderson and Hagard 1943; Jacobs 1967

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53 Hydrogen Chloride for hydrogen chloride aerosol, and of 0.5 mg/m3 for sulfate aerosol. For some work operations, peak hydrogen chloride vapor exposures of up to 40 mg/m3 (27 ppm) occurred (averaging a few minutes). There was a trend toward a reduced prevalence of histamine reactivity in the acid-mist group; however, the mixed exposure and pre-employment selection bias limit the usefulness of this study in the present analysis. Possible carcinogenic effects of hydrogen chloride were evaluated with a nested case-control study of 308 lung-cancer cases and 616 comparison workers among a cohort of 19,608 chemical-manufacturing employees (Bond et al. 1991). Exposure reconstruction was performed by an industrial hygienist famil- iar with plant operations. The duration of hydrogen chloride exposure was calcu- lated by summing the time spent on jobs with a TWA greater than zero. Cumu- lative exposure was derived by multiplying the time spent on each job by the midpoint of the TWA range for that job and summing across all jobs. Workers were then classified into four exposure groups: 0, 0.1-3.9, 4-12.4, and at least 12.5 ppm-years. There was no association between hydrogen chloride exposure and lung cancer whether analyzed by duration of exposure, cumulative expo- sure, highest average exposure, or latency. Coggon et al. (1996) assessed the risk of cancer from inhalation of min- eral-acid mists with a cohort study and a nested case-control study of 15 men with upper aerodigestive tumors in a 93% follow-up sample of 4,401 men em- ployed since 1950 at two battery plants and two steel works in Britain. The 15 upper aerodigestive cancers included four of the lip, three of the larynx, two of the tongue, one of the nasal sinus, two of the gum or retromolar area, two of the pharynx or nasopharynx, and one of the tonsil. The odds ratio (OR) was doubled for cumulative acid exposure, measured according to whether a person had worked for over 5 years in jobs with exposures in excess of 1 mg/m3 (OR, 2.0; 95% confidence interval [CI], 0.4-10). There was no dose-response relationship for risk related to maximum exposure to acid mists. There was no information on smoking and alcohol consumption in the cohort, but the authors stated that lung cancer in men with definite exposure to acid mists was close to expectation (standardized mortality ratio, 0.98; 95% CI, 0.78-1.22). Effects in Animals Acute Toxicity Acute exposures of laboratory animals to hydrogen chloride were summa- rized in reviews by NRC (1987, 2002, 2004), Lam and Wong (2000), and ACGIH (2003). A number of LC50 values have been calculated for exposure times ranging from 5 to 60 min in rats and mice (Higgins et al. 1972, cited in NRC 2004; MacEwen and Vernot 1972, cited in NRC 1987; Darmer et al. 1974; Wohlslagel et al. 1976, cited in NRC 2004; Vernot et al. 1977; Anderson and Alarie 1980, cited in NRC 2004). Mice appear to be more sensitive than rats to

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54 Exposure Guidance Levels for Selected Submarine Contaminants the lethal effects of hydrogen chloride. For a 60-min exposure, the LC50 values in mice were 1,108 ppm (Wohlslagel et al. 1976, cited in NRC 2004) and 1,322 ppm (MacEwan and Vernot 1972, cited in NRC 2004). NRC (2004) combined rat and mouse LC50 data for exposures of 1-100 min and, on the basis of regres- sion analysis, determined that n = 1 was appropriate for application of the rela- tionship Cn × t = k, where C = concentration, t = time, and k = constant, defined by ten Berge et al. (1986) for time-scaling. Nonhuman primates, guinea pigs, rabbits, rats, and mice have been used in a number of nonlethal single-exposure investigations of hydrogen chloride. Ba- boons (n = 1, 2, or 3) were exposed to a range of hydrogen chloride concentra- tions for 5-15 min to assess respiratory effects and the potential of hydrogen chloride to impair escape behavior (Kaplan 1987; Kaplan et al. 1985, cited in NRC 1987, 2004; Kaplan et al. 1986, cited in NRC 2002; Kaplan et al. 1988). Concentrations of 16,570 and 17,290 ppm (5 min) caused severe dyspnea and resulted in delayed death due to pneumonia and pulmonary edema (Kaplan et al. 1985, cited in NRC 1987, 2004). At 500, 5,000, or 10,000 ppm (15 min), respi- ratory rate and minute volume were increased, arterial oxygen decreased (5,000 and 10,000 ppm), but lung function was normal when measured 3 days and 3 months after exposure (Kaplan et al. 1988). Irritant effects ranged from cough- ing and frothing at the mouth at lower concentrations (810-940 ppm) to profuse salivation, blinking, and head-shaking at higher concentrations (16,570-17,290 ppm), but there was no loss of escape capability at 11,400 or 17,290 ppm. No sign of irritation was observed in a baboon exposed to hydrogen chloride at 190 ppm for 5 min (Kaplan et al. 1985, cited in NRC 1987, 2004). It should be noted that individual baboons may have been used for more than one exposure (NRC 2004). Four groups of investigators have studied the effects of acute (15-30 min) hydrogen chloride exposure in guinea pigs (Kaplan et al. 1993b, cited in NRC 2004; Malek and Alarie 1989; Burleigh-Flayer et al. 1985; Machle et al. 1942). Results were not always consistent among studies, perhaps because of the dif- ferent study designs and end points monitored. Hydrogen chloride was shown to be a sensory and pulmonary irritant at exposure concentrations of 320-1,380 ppm (Burleigh-Flayer et al. 1985). Kaplan et al. (1993b, cited in NRC 2004) observed a decrease in respiratory rate at 520 or 3,940 ppm but little effect on blood gases and a decrease in arterial pH in animals exposed only at 3,940 ppm. Malek and Alarie (1989) focused on time to incapacitation by using a chamber exercise-wheel apparatus. Guinea pigs exercised on the wheel for 10 min before the start of hydrogen chloride exposure. The authors observed gasp- ing and death in guinea pigs exposed at 586 ppm. Hydrogen chloride concentra- tions of 140 and 162 ppm caused coughing, gasping, and incapacitation; time to incapacitation was 16.5 and 1.3 min, respectively. Guinea pigs exposed at 107 ppm showed only mild irritation (details were not provided) and were not inca- pacitated during the 30 min of exposure. Machle et al. (1942) exposed groups of three guinea pigs and three rabbits to hydrogen chloride at various concentrations (about 34-14,000 ppm) and for

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55 Hydrogen Chloride various times (5 min to 6 h). Animals that survived 2 months or longer were killed. Detailed results were not provided, but no animals survived exposure to hydrogen chloride at 679 ppm for 6 h. At lower concentrations, mild inflamma- tory reactions with some peribronchial fibrosis and lymph node hyperplasia were observed in the guinea pigs. Lobular pneumonia and pulmonary abscesses were observed in rabbits exposed at lower concentrations. However, no patho- logic changes (presumably in lungs, liver, kidneys, and heart) were observed in animals exposed at the lowest concentration studied (34 ppm 6 h/day, 5 days/week for 4 weeks). Several scientists reported acute hydrogen chloride exposure studies in rats that resulted in nonlethal effects. Exposures to hydrogen chloride at 11,800 ppm and higher for 5 min produced extreme irritation of the mucous mem- branes, eyes, and respiratory tract (Darmer et al. 1974; Kaplan et al. 1986, cited in NRC 2002). Rats did not lose their ability to escape via a signal-avoidance task unless the exposure concentration of hydrogen chloride were high enough to induce death (87,600 ppm) (Kaplan 1987, cited in ACGIH 2003; Kaplan et al. 1988, cited in ACGIH 2003). Irritation of the eyes, mucous membranes, and respiratory tract and erythema occurred when animals were exposed at 1,800- 4,500 ppm for 1 h, and 20% or higher mortality occurred when rats were ex- posed at 2,600 ppm or higher for 1 h (Wohlslagel et al. 1976, cited in NRC 2002). Concentration-related decreases in respiratory rate and minute volume were observed after 30-min exposures at 200 ppm and higher (Hartzell et al. 1985). The RD50 (the concentration that produces a 50% decrease in respiratory frequency) was determined to be 560 ppm. Stavert et al. (1991) showed dramatic differences in response to hydrogen chloride exposure between nose-breathing rats and mouth-breathing rats. The mouth-breathing rats were fitted with a mouthpiece attached to an endotracheal tube. At 1,300 ppm for 30 min, 46% of the mouth-breathing rats and 6% of the nose-breathing rats died. Survivors were killed 24 h after exposure, and their nasal cavities, tracheas, and lungs were ex- amined microscopically. Epithelial-cell necrosis and severe inflammation were observed in the tracheas of mouth-breathing rats, but the findings were limited to the nasal cavities of nose-breathing rats. Similarly, lung weights were in- creased in the mouth-breathing rats compared with control animals, but not in the nose-breathing rats. In summary, functional respiratory effects were ob- served in rats after 30-min exposure to hydrogen chloride at 200 ppm or higher, and lethality was observed in mouth-breathing rats exposed at 1,300 ppm for the same duration. Mice appear to be more sensitive to acute hydrogen chloride exposures than rats (Higgins et al. 1972, cited in NRC 2004). In general, mice die at hy- drogen chloride concentrations that are about one-third of the concentrations that kill rats. Studies in mice by Doub (1933, cited in NRC 2002), Darmer et al. (1974), Wohlslagel et al. (1976, cited in NRC 2002, 2004), Lucia et al. (1977), Barrow et al. (1977, 1979), and Kaplan et al. (1993b) yielded the following ob- servations:

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56 Exposure Guidance Levels for Selected Submarine Contaminants • 5-min exposures. Hydrogen chloride produced severe irritation of the mucous membranes and eyes and some irritation of exposed skin at concentra- tions of 3,200 ppm or higher. • 10-min exposures. Hydrogen chloride is a sensory irritant with an RD50 of 309 ppm. A decrease in respiratory rate was observed above 40 ppm, and small superficial ulcerations were observed in respiratory epithelium of the nasal cavity near its junction with squamous epithelium at a concentration as low as 17 ppm. As the concentration of hydrogen chloride increased, the muco- sal ulcerations increased in severity and extent, gradually extending up the sides and septum of the nasal cavity. • 15-min exposures. Hydrogen chloride produced a decrease in respira- tory rate at 475 ppm or higher followed by 50% or greater mortality after expo- sure. The time between exposure and death was inversely related to exposure concentration. No abnormal histopathologic findings were observed in the respi- ratory tract (nares to lungs) of the 475-ppm exposure group, but causes of death were not stated. • 30-min exposures. Hydrogen chloride produced severe irritation of the mucous membranes and some irritation of exposed skin at concentrations of 410 ppm or higher. • 60-min exposures. Hydrogen chloride produced irritation of the mu- cous membranes and eyes, respiratory distress, corneal opacity, and erythema at concentrations of 560 ppm or higher. Twenty percent mortality was observed at 560 ppm. In summary, minimal microscopic lesions were observed in the nasal cavi- ties of mice exposed to hydrogen chloride at 17 ppm for 10 min, but this infor- mation was not consistent with results of other studies, which showed no lesions at 475 ppm for 15 min. However, mortality was observed in mice exposed to hydrogen chloride at 475 ppm for 15 min or at 560 ppm for 1 h. A slight de- crease in respiratory rate occurs at 40 ppm, and the RD50 was 309 ppm. Repeated Exposures and Subchronic Toxicity A few inhalation studies of hydrogen chloride that used more than a single exposure have been performed in laboratory animals. Buckley et al. (1984) in- vestigated the induction of respiratory tract lesions in mice after exposure to chemical sensory irritants. Histopathologic lesions were observed in the nasal cavity after exposure to hydrogen chloride at 310 ppm 6 h/day for 3 days. Le- sions included exfoliation, erosion, ulceration, and necrosis of the nasal respira- tory epithelium. However, nasal cavity lesions were minimal in the olfactory epithelium, and no effects were observed in the lungs of mice exposed to hydro- gen chloride. In a 4-week study by Machle et al. (1942), no histopathologic le- sions (presumably in the lungs, liver, kidneys, and heart) were observed in three rabbits, three guinea pigs or one monkey exposed to hydrogen chloride at 34

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59 Hydrogen Chloride sign and results is provided in the section “Chronic Toxicity.” The authors counted tumors observed in the respiratory tract and total number of tumors in organs outside the respiratory tract. There was no evidence of excess tumor for- mation in animals exposed only to hydrogen chloride compared with the control group. The combination of hydrogen chloride and formaldehyde did not affect the incidence of nasal cavity carcinogenesis compared with the incidence of nasal tumors observed in the formaldehyde-only exposure group. The conclu- sion was that hydrogen chloride did not promote the carcinogenicity of formal- dehyde. TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS Toxicokinetic studies of hydrogen chloride were not found in the litera- ture. The high water solubility of hydrogen chloride indicates rapid adsorption of hydrogen chloride on mucous membranes after inhalation. Morris and Smith (1982) predicted that more than 99% of inhaled hydrogen fluoride would be absorbed by the upper respiratory tract in rats. Because hydrogen chloride, like hydrogen fluoride, has high water solubility and reactivity, it should also be highly absorbed in the upper respiratory tract of rats. Inhalation studies of hy- drogen chloride in laboratory animals have shown tissue injury in the most ante- rior regions of the nasal cavity with much less or even negligible injury in the posterior areas of the nasal cavity or downstream in the trachea and lungs (Buckley et al. 1984; Stavert et al. 1991). The high water solubility and rapid dissolution of hydrogen chloride partly explain the low systemic toxicity ob- served after hydrogen chloride exposure (Machle et al. 1942; Toxicogenics 1984; Sellakumar et al. 1985). However, high concentrations of hydrogen chlo- ride (for example, greater than 500 ppm) appear to saturate the absorption or buffering capacities of the nasal mucosa, and pulmonary damage—such as con- gestion, mild hemorrhage, and multifocal acute alveolitis—is observed more frequently (Burleigh-Flayer et al. 1985; Kaplan et al. 1993b). Tracheal injury was also observed in mouth-breathing rats exposed to hydrogen chloride at 1,300 ppm for 30 min, but no lower respiratory effects were observed in nose- breathing rats under the same exposure conditions (Stavert et al. 1991). Thus, humans may be more susceptible to lung effects when breathing through their mouths than when breathing through their noses under identical exposure condi- tions. Once absorbed into the mucous layers and membranes, hydrogen chloride is not metabolized but dissociates into hydrogen ions and chloride ions (pK, -7 in aqueous medium). The hydrogen ions react with water to produce hydronium ions, which, as proton donors, react readily with organic molecules. That reac- tion is presumably responsible for cellular injury and, if severe enough, cell death. Fluid accumulates at the site of injury and explains why pulmonary edema and such other factors as vascular changes and interference in gaseous transfer (of oxygen in particular) are associated with the cause of animal death

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60 Exposure Guidance Levels for Selected Submarine Contaminants (Machle et al. 1942; Darmer et al. 1974). The chloride ions derived from disso- ciation of hydrogen chloride are likely to be distributed throughout the body because they are normal electrolytes. In general, it is presumed that chloride ions generated from hydrogen chloride inhalation—even brief exposures at high con- centrations—are not sufficient to perturb the body’s electrolyte balance. INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed acceptable expo- sure limits or guidelines for inhaled hydrogen chloride. Selected values are summarized in Table 3-3. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for hy- drogen chloride are summarized in Table 3-4. The current U.S. Navy values are provided for comparison. 1-Hour EEGL Biologic end points that were considered the most relevant for derivation of the 1-h EEGL were mild irritation of the eyes and mucosal surfaces and al- terations in respiratory frequency at hydrogen chloride concentrations that pro- duced reversible effects. Alteration in respiratory rate is a sensitive indicator of sensory and pulmonary irritation (ASTM International 2004). Chemicals that decrease respiratory frequency by 20-50% are considered moderate irritants (ASTM International 2004). An approximate 10% decrease in respiratory rate was observed in mice exposed to hydrogen chloride at 40 ppm for 10 min (Bar- row et al. 1977). The RD50 values in mice and rats were 309 ppm (Barrow et al. 1977) and 560 ppm (Hartzell et al. 1985), respectively. Fifteen-minute expo- sures of baboons at 500 ppm (Kaplan et al. 1988) and 30-min exposures of rats at 200 ppm (Hartzell et al. 1985), of sedentary guinea pigs at 320 ppm (Bur- leigh-Flayer et al. 1985), and of exercising guinea pigs at 107 ppm (Malek and Alarie 1989) produced alterations in respiratory rate or mild irritation, which returned to normal after exposure. However, exercising guinea pigs exposed at 140 ppm or higher exhibited respiratory distress and incapacitation (Malek and Alarie 1989). The small superficial ulcerations in nasal respiratory epithelium of mice that Lucia et al. (1977) found after a 10-min exposure at 17 ppm were con- sidered reversible lesions of insufficient concern for setting a 1-h EEGL.

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TABLE 3-3 Selected Inhalation Exposure Levels for Hydrogen Chloride from the National Research Council and Other Agenciesa Organization Type of Level Exposure Level (ppm) Reference Occupational ACGIH TLV-ceiling 2 ACGIH 2003 NIOSH REL-ceiling 5 NIOSH 2005 OSHA PEL-ceiling 5 29 CFR 1910.1000 Spacecraft NASA SMAC Lam and Wong 2000 1-h 5 24-h 2.5 30-day 1 180-day 1 Submarine NRC EEGL NRC 1987 1-h 20 24-h 20 CEGL NRC 1987 90-day 0.5 SEAL 1 (10-day) 20 NRC 2002 SEAL 2 (24-h) 35 (Continued) 61

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62 TABLE 3-3 Continued Organization Type of Level Exposure Level (ppm) Reference General Public NAC/NRC AEGL-1 (1-h) 1.8 NRC 2004 AEGL-2 (1-h) 22 AEGL-1 (8-h) 1.8 AEGL-2 (8-h) 11 a Comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regulatory Standards or Guidance Levels”). Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; CEGL, continu- ous exposure guidance level; EEGL, emergency exposure guidance level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupa- tional Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SEAL, submarine escape action level; SMAC, spacecraft maximum allowable concentration; TLV, Threshold Limit Value.

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Hydrogen Chloride 63 TABLE 3-4 Emergency and Continuous Exposure Guidance Levels for Hydrogen Chloride Current U.S. Navy Values Committee Recommended Values Exposure Level (ppm) (ppm) EEGL 1-h 5 9 24-h 2 3 CEGL 90-day 1 1 Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level. To derive a 1-h EEGL, the extensive data sets of respiratory-rate altera- tions and RD50 determinations in laboratory animals exposed to hydrogen chlo- ride were used as predictive measures of hydrogen chloride irritancy in humans. Alarie (1981) has used the mouse RD50 value to derive 8-h Threshold Limit Values (TLVs) of dozens of chemical irritants empirically. Schaper (1993) de- veloped an extensive database on 295 airborne materials with RD50 values and demonstrated a high correlation of TLVs with 0.03 times the RD50 (there were TLVs for 89 chemicals). For hydrogen chloride, the proposed TLV would be 9.3 ppm (0.03 times 309 ppm). Because the TLV is defined as a level of exposure that a typical worker can experience without an unreasonable risk of disease or injury, the committee recommends 9 ppm as the 1-h EEGL. Experimental stud- ies in humans support that recommendation. Elkins (1959) concluded that expo- sures to hydrogen chloride at 5 ppm or higher were immediately irritating and exposures at over 10 ppm highly irritating, although some workers developed some tolerance. Henderson and Hagard (1943) reported that 50-100 ppm for 1 h was the maximum tolerable concentration and that 10 ppm for prolonged expo- sure was the maximum tolerable concentration. 24-Hour EEGL There is no firm database for establishing a 24-h EEGL. To derive the 24- h EEGL, the committee considered two approaches: one based on sensory irrita- tion and the other on histopathology of the nasal cavity. The first approach uses the empirically derived 8-h TLV of 9.3 ppm—a value that is considered to be preventive of sensory irritation in humans (described above)—and applies an uncertainty factor of 3 to account for extrapolation of 8-h responses to continu- ous 24-h exposures (9.3/3 = about 3 ppm). It is unclear whether the concentra- tion-time relationship defined by ten Berge et al. (1986) applies for sensory irri- tation from hydrogen chloride, but in this case, the use of an uncertainty factor

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64 Exposure Guidance Levels for Selected Submarine Contaminants of 3 gives the same result as applying that relationship (9 ppm for 8 h = 3 ppm for 24 h), assuming n = 1. The second approach uses the LOAEL from the 90- day inhalation toxicity study in rats and mice (Toxigenics 1984) and applies an uncertainty factor of 3 to account for interspecies differences (10/3 = about 3 ppm). Additional uncertainty factors for extrapolating a LOAEL to no-observed- adverse-effect level (NOAEL) or a 6-h exposure to a 24-h exposure were not applied because the lesions observed in the 90-day study (minimal to mild rhini- tis in rats and minimal to mild intracytoplasmic eosinophilic globules in nasal epithelium in mice) were considered tolerable and reversible for a single 24-h exposure. Thus, the same value was derived with the two approaches, and 3 ppm is recommended as a 24-h EEGL. 90-Day CEGL Biologic end points that were considered the most relevant for derivation of the 90-day CEGL were histopathologic changes in tissues of the respiratory tract after repeated hydrogen chloride exposure. Two long-term inhalation toxic- ity studies, a 90-day study in rats and mice (Toxigenics 1984) and a lifetime (128-week) study in rats (Sellakumar et al. 1985), concluded that minimal to mild alterations in the upper respiratory tract (nasal cavity) and middle respira- tory tract (larynx to trachea) resulted from exposure to hydrogen chloride at 10 ppm. The lesions (such as rhinitis and tracheal hyperplasia) were considered neither tumorigenic nor life-threatening. With 10 ppm as a minimal-effect LOAEL, a 90-day CEGL of 1 ppm was derived as follows. An uncertainty fac- tor of 3 was applied to obtain a NOAEL from the LOAEL. The lesions observed at 10 ppm were due to superficial irritation and were minimal in severity, so an uncertainty factor of 3 was used rather than the standard default of 10. An addi- tional uncertainty factor of 3 was applied for interspecies extrapolation. The lesions observed in the 90-day study were consistent between species and strains of laboratory animals, so the default factor of 10 for interspecies extrapolation was reduced. As discussed in Chapter 1, the use of two uncertainty factors of 3 is rounded to 10, so the resulting 90-day CEGL value is 1 ppm (10/10). An addi- tional adjustment for extrapolating from intermittent exposure (6 h/day 5 days/week) to continuous exposure (24 h/day 7 days/week) was not applied be- cause the rhinitis observed in the 90-day study did not increase in severity given the findings in the 128-day study. Both studies appear to have performed thor- ough histopathologic evaluations of the animals’ respiratory tract, so the dura- tion of exposure to hydrogen chloride at low concentrations does not appear to be a critical factor in producing effects. Support that the committee’s CEGL value is protective is the epidemiologic study by Kremer et al. (1995), in which workers exposed to hydrogen chloride aerosols at 2.1 mg/m3, sulfur dioxide va- por at 0.3 mg/m3, and sulfate aerosols at 0.5 mg/m3 for several years, including peak exposure to hydrogen chloride vapor at up to 40 mg/m3 (27 ppm) for some work operations, did not show airway hyperreactivity.

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Hydrogen Chloride 65 DATA ADEQUACY AND RESEARCH NEEDS Information in the scientific literature suggests that concentration, not ex- posure duration, is responsible for irritant effects of chemical irritants. Well- designed inhalation toxicity studies are needed to demonstrate that that observa- tion applies to hydrogen chloride. Little is known about the acid-base buffering capacity of mucous membranes and tissues of the respiratory tract. Because hy- drogen chloride dissociates rapidly to hydronium ions on contact with tissue surfaces, studies designed to quantitate the acid-buffering capacity of mucosal surfaces and tissues of the nasal cavity may be of value for studying dosimetry and threshold effects of hydrogen chloride. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2003. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs) for 2003. American Conference of Governmental Hy- gienists, Cincinnati, OH. Alarie, Y. 1981. Dose-response analysis in animal studies: Prediction of human re- sponses. Environ. Health Perspect. 42:9-13. Albert, R.E., A.R. Sellakumar, S. Laskin, M. Kuschner, N. Nelson, and C.A. Snyder. 1982. Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. J. Natl. Cancer Inst. 68(4):597-603. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with Threshold Limit Values and volatilities for 214 industrial chemi- cals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. Anderson, R.C., and Y. Alarie. 1980. Acute lethal effects of polyvinylchloride thermal decomposition products in normal and cannulated mice. P. A3 [Abstract 9] in Ab- stract of Papers Society of Toxicology Nineteenth Annual Meeting, March 9-11, 1980, Washington, DC. ASTM (American Society for Testing and Materials) International. 2004. Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals. ASTM E981-04. West Conshohocken, PA: ASTM International. 11pp. Barrow, C.S., Y. Alarie, M. Warrick, and M.F. Stock. 1977. Comparison of the sensory irritation response in mice to chlorine and hydrogen chloride. Arch. Environ. Health 32(2):68-76. Barrow, C.S., H. Lucia, and Y.C. Alarie. 1979. A comparison of the acute inhalation toxicity of hydrogen chloride versus the thermal decomposition products of poly- vinyl chloride. J. Combust. Toxicol. 6:3-12. Bond, G.G., G.H. Flores, B.A. Stafford, and G.W. Olsen. 1991. Lung cancer and hydro- gen chloride exposure: Results from a nested case-control study of chemical work- ers. J. Occup. Med. 33(9):958-961. Boulet, L.P. 1988. Increases in airway responsiveness following acute exposure to respi- ratory irritants: Reactive airway dysfunction syndrome or occupational asthma? Chest 94(3):476-481.

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Hydrogen Chloride 69 Stevens, B., J.Q. Koenig, V. Rebolledo, Q.S. Hanley, and D.S. Covert. 1992. Respiratory effects from the inhalation of hydrogen chloride in young adult asthmatics. JOM 34(9):923-929. Tarlo, S.M., and I. Broder. 1989. Irritant-induced occupational asthma. Chest 96(2):297- 300. ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. Toxigenics, Inc. 1984. 90-Day Inhalation Toxicity Study of Hydrogen Chloride Gas in B6C3F1 Mice, Sprague-Dawley Rats, and Fischer-344 Rats, Revised. Toxigenics Study 420-1087. Decauter, IL: Toxigenics, Inc. 68 pp. Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solu- tions. Toxicol. Appl. Pharmacol. 42(2):417-423. Wohlslagel, J., L.C. DiPasquale, and E.H. Vernot. 1976. Toxicity of solid rocket motor exhaust: Effects of HCl, HF, and alumina on rodents. J. Combust. Toxicol. 3:61- 70.