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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 2 Hydrogen Chloride1 Acute Exposure Guideline Levels SUMMARY Hydrogen chloride (HCl) is a colorless gas with a pungent, suffocating odor. It is used in the manufacture of organic and inorganic chemicals, oil-well acidizing, steel pickling, food processing, and minerals and metals processing. A large amount of HCl is released from solid rocket fuel exhaust. It is an upper respiratory irritant at relatively low concentrations and may cause damage to the lower respiratory tract at higher concentrations. HCl is very soluble in water, and the aqueous solution is highly corrosive. 1 This document was prepared by the AEGL Development Team comprising Cheryl Bast (Oak Ridge National Laboratory) and National Advisory Committee (NAC) for Acute Exposure Guideline Levels for Hazardous Substances member John Hinz (Chemical Manager). The NAC reviewed and revised the document and the AEGL values as deemed necessary. Both the document and the values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concluded that the AEGLs developed in this document are scientifically valid conclusions on the basis of the data reviewed by the NRC and are consistent wit the NRC guidelines reports (NRC 1993, 2001).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 The lowest acute exposure guideline level (AEGL) values are based on a 45-minute (min) no-observed-adverse-effect level (NOAEL) of 1.8 parts per million (ppm) in exercising adult asthma patients (Stevens et al. 1992). No uncertainty factors (UFs) were applied for inter- or intraspecies variability because the study population consisted of sensitive humans. The same 1.8-ppm value was applied across the 10- and 30-min and 1-, 4-, and 8-hour (h) exposure times, because mild irritance generally does not vary greatly over time, and because it is not expected that prolonged exposure will result in an enhanced effect. The AEGL-2 for the 30-min and 1-, 4-, and 8-h time points was based on severe nasal or pulmonary histopathology in rats exposed at 1,300 ppm for 30 min (Stavert et al. 1991). A modifying factor (MF) of 3 was applied to account for the relatively sparse database describing effects defined by AEGL 2. The AEGL-2 values were further adjusted by a total UF of 10–3 for intraspecies variability, supported by the steep concentration- response curve, which implies little individual variability; and 3 for interspecies variability. Using the default value of 10 for interspecies variability would bring the total adjustment to 100 (total UF×MF) instead of 30. That would generate AEGL-2 values that are not supported by the total data set, including data on exercising asthmatic subjects, an especially sensitive subpopulation, because exercise increases HCl uptake and exacerbates irritation; no effects were noted in exercising young adult asthmatic subjects exposed to HCl at 1.8 ppm for 45 min (Stevens et al. 1992). A total UF of 10, accompanied by the MF of 3, is most consistent with the total database (see Section 6.3 for detailed support of uncertainty factors). Thus, the total factor is 30. Time-scaling for the 1-h AEGL exposure period was accomplished using the Cn×t=k relationship (C=concentration, t=time, and k is a constant), where n=1 based on regression analysis of combined rat and mouse LC50 data (concentrations lethal to 50% of subjects) (1 min to 100 min) as reported by ten Berge et al. (1986). The 4- and 8-h AEGL-2 values were derived by applying an MF of 2 to the 1-h AEGL-2 value, because time-scaling would yield a 4-h AEGL-2 of 5.4 ppm and an 8-h AEGL-2 of 2.7 ppm, close to the 1.8 ppm tolerated by exercising asthmatic subjects without adverse health effects. The 10-min AEGL 2 was derived by dividing the mouse RD50 (concentration expected to cause a 50% decrease in respiratory rate) of 309 ppm by a factor of 3 to obtain a concentration causing irritation (Barrow 1977). It has been determined that human response to sensory irritants can be predicted on the basis of the mouse RD50. For example, Schaper (1993) has validated the correlation of 0.03×RD50=
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 2–1 Summary of AEGLs Values for Hydrogen Chloride (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 (Nondisabling) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) NOAEL in exercising asthmatic subjects (Stevens et al. 1992) AEGL-2 (Disabling) 100 (156) 43 (65) 22 (33) 11 (17) 11 (17) Mouse RD50 (Barrow et al. 1977); histopathology in rats (Stavert et al. 1991) AEGL-3 (Lethal) 620 (937) 210 (313) 100 (155) 26 (39) 26 (39) Estimated NOEL for death from 1-h rat LC50 (Wohlslagel et al. 1976; Vernot et al. 1977) Abbreviations: LC50, concentration lethal to 50% of subjects; mg/m3, milligrams per cubic meter; NOAEL, no-observed-adverse-effect level; NOEL, no-observed-effect level; ppm, parts per million; RD50, concentration expected to cause a 50% decrease in respiratory rate. Threshold Limit Value (TLV) as a value that will prevent sensory irritation in humans. The multiplier 0.03 represents the half-way point between 0.1 and 0.01 on a logarithmic scale, and Alarie (1981) has shown that the RD50 multiplied by 0.1 corresponds to “some sensory irritation,” while the RD50 value itself is considered “intolerable to humans.” Thus, it is reasonable that one third of the RD50, a value half-way between 0.1 and 1 on a logarithmic scale, may cause significant irritation to humans. Furthermore, one-third of the mouse RD50 for HCl corresponds to an approximate decrease in respiratory rate of 30%, and decreases in the range of 20–50% correspond to moderate irritation (ASTM 1991). The AEGL-3 values were based on a 1-h rat LC50 study (Wohlslagel et al. 1976; Vernot et al. 1977). One-third of the 1-h LC50 of 3,124 ppm was
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 used to estimate a concentration causing no deaths. That estimate is inherently conservative (no deaths were observed in the same study at 1,813 ppm). A total UF of 10 will be applied—3 for intraspecies variation, because the steep concentration-response curve implies limited individual variability; and 3 to protect susceptible individuals. Using a full value of 10 for interspecies variability (total UF of 30) would yield AEGL-3 values that are inconsistent with the overall data set (see Section 7.3 for detailed support of UFs). Thus, the total UF is 10. The value was then time-scaled to the specified 10- and 30- min and 4-h AEGL exposure periods using the Cn×t=k relationship, where n=1 based on regression analysis of combined rat and mouse LC50 data (1 min to 100 min) as reported by ten Berge et al. (1986). The 4-h AEGL-3 value was also adopted as the 8-h AEGL-3 value because of the added uncertainty of time scaling to 8-h using a value of n derived for exposure durations up to 100 min. 1. INTRODUCTION HCl is a colorless gas with a pungent, suffocating odor. It is hygroscopic and produces whitish fumes in moist air. HCl is produced as a by-product of chemical syntheses of chlorinated compounds and is used in the manufacture of organic and inorganic chemicals, oil-well acidizing, steel pickling, food processing, and the processing of minerals and metals. A large amount of HCl is released from solid rocket fuel exhaust. It is very soluble in water, and the aqueous hydrochloric acid is quite corrosive (EPA 1994). The physicochemical data for hydrogen chloride are shown in Table 2–2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality 2.1.1. Case Reports No data concerning human lethality from HCl exposure were located in the available literature.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 2–2 Physicochemical Data for Hydrogen Chloride Parameter Value Reference Synonyms Muriatic acid, hydrochloric acid AIHA 1989 Chemical formula HCl AIHA 1989 Molecular weight 36.47 AIHA 1989 CAS registry no. 7647–01–0 AIHA 1989 Physical state Colorless, fuming gas AIHA 1989 Relative density 1.268 at 25°C AIHA 1989 Boiling/flash point −85°C/nonflammable AIHA 1989 Solubility in water Very soluble (82.3 g/100 ml) EPA 1994 Conversion factors in air 1 mg/m3=0.67 ppm 1 ppm=1.49 mg/m3 AIHA 1989 2.2. Nonlethal Toxicity 2.2.1. Experimental Studies Five male and five female adult asthmatic subjects (age 18 to 25 years [y]) were exposed to filtered air or HCl at 0.8 ppm or 1.8 ppm for 45 min (Stevens et al. 1992). Exposure levels were verified by an online filtering system during exposures and analyzed by ion exchange chromatography. Actual mean exposure concentrations were 0, 0.8±0.09, or 1.84±0.21 ppm. The subjects were healthy, except for having asthma, and wore half-face masks to allow for nasal and oral breathing and to control exposure of the eyes. The 45-min exposure sessions consisted of 15 min of exercise (treadmill walking at 2 miles per hour at an elevation grade of 10%) followed by 15 min of rest followed by another 15 min of exercise. Exposures to the test atmospheres were separated by at least 1 week (wk). Subjects rated severity of symptoms before, during, and after exposure on a scale of 1 to 5 (5 being most severe). Symptoms rated included upper respiratory (sore throat and nasal discharge), lower respiratory (cough, chest pain or burning, dyspnea, wheezing), and other (fatigue, headache, dizziness, unusual taste or smell). Pulmonary function measurements were performed while subjects were seated in a pressure-compensated volume-displacement body plethysmograph. The following parameters were measured: total respiratory resistance, thoracic gas volume at functional residual capacity,
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 forced expiratory volume, forced vital capacity, and maximal flow at 50% and 75% of expired vital capacity. Nasal work of breathing and oral ammonia levels were also measured. No adverse treatment-related effects were observed. There were no treatment-related increases in severity of upper respiratory, lower respiratory, or other symptoms reported by participants. No significant differences were reported between test and control exposures with regard to any of the pulmonary function tests. No treatment-related changes were observed in nasal work of breathing data. Oral ammonia levels showed a significant increase after exposure to both concentrations of HCl but not after exposure to air; the study authors conclude that this finding is counterintuitive and offer no explanation for the observation. 2.2.2. Case Reports Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that develops after a single exposure to high levels of a chemical irritant. Symptoms occur within minutes to hours after the initial exposure and may persist as nonspecific bronchial hyper-responsiveness for months to years (Bernstein 1993). It was given the name RADS by Brooks et al. (1985) in a retrospective analysis of 10 previously healthy people who had developed persistent airway hyper-reactivity after a single, high-level exposure to a chemical irritant. The acronym then gained acceptance in the medical community (Nemery 1996), because a name had finally been given to a clinical entity that physicians had encountered. Little or no published evidence had been previously available to verify the claim that asthma symptoms could be a consequence of a single inhalation exposure. This syndrome has been described after exposure to HCl. Promisloff et al. (1990) reported RADS in three male police officers (36–45 y old) who responded to a roadside chemical spill. The subjects were exposed to unquantified amounts of sodium hydroxide, silicon tetrachloride, and HCl as a by-product of trichlorosilane hydrolysis; due to the mixture if irritants involved in the release, it is likely that all compounds contributed to the RADS observed after this accident. In another report, Boulet (1988) described the case of a 41-y-old male nonsmoker who had a 6-y history of mild asthma. After cleaning a pool for 1 h with a solution containing hydrochloric acid, he developed a rapidly progressive and severe bronchospasm that was eventually diagnosed as RADS. No exposure concentration was reported. Turlo and Broder (1989) describe a retrospective review of occupational asthma records. A 57-y-old male, with a smoking history of
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 12 pack-years, had symptoms consistent with RADS after occupational exposure to hydrochloric acid and phosgene. No exposure concentrations were reported. Other data concerning acute inhalation exposure to HCl in humans are qualitative and dated, making accurate exposure assessment difficult. A summary of those data is presented in Table 2–3. 2.2.3. Epidemiologic Studies Epidemiologic studies regarding human exposure to HCl were not available. 2.3. Developmental and Reproductive Toxicity No human developmental or reproductive toxicity data concerning HCl were identified in the available literature. 2.4. Genetic Toxicology No data concerning the genotoxicity of HCl in humans were identified in the available literature. 2.5. Carcinogenicity Data concerning carcinogenicity from exposure to HCl are equivocal. A study of U.S. steel-pickling workers showed an excess risk for lung cancer in individuals exposed primarily to hydrochloric acid for at least 6 months (mo) (Beaumont et al. 1987, as cited in IARC 1992). However, no exposure concentrations were available and the subjects had also been exposed to mists of other acids. In a follow-up of the same cohort, Steenland et al. (1988) observed an excess incidence of laryngeal cancer. Again, the data are confounded by possible exposure to other acid gases, including sulfuric acid. In three case-control studies, no association was observed between occupational exposure to HCl and lung (Bond et al. 1986, as cited in IARC 1992), brain (Bond et al. 1983), or kidney (Bond et al. 1985) cancer. In another report, Bond et al. (1991) examined the records of 308 workers who
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 2–3 Inhalation Exposure of Humans to Hydrogen Chloride Approximate Concentration Exposure Time Effect Reference 0.77 ppm; 1–5 ppm; 10 ppm Unspecified Geometric mean of odor thresholds; odor threshold; odor threshold Amoore and Hautala 1983; Heyroth 1963; Leonard et al. 1969 0.8 ppm and 1.8 ppm 45 min No effects in exercising asthmatic subjects Stevens et al. 1992 ≥5 ppm Unspecified Immediately irritating Elkins 1959 >10ppm Occupational Highly irritating, although workers develop some tolerance Elkins 1959 10 ppm Prolonged Maximum tolerable Henderson and Hagard 1943 10–50 ppm A few hours Maximum tolerable Henderson and Hagard 1943 35 ppm Short Throat irritation Henderson and Hagard 1943 50–100 ppm 1 h Maximum tolerable Henderson and Hagard 1943 1,000–2,000 ppm Short Dangerous Henderson and Hagard 1943 died of lung, bronchus, or trachea cancer. The workers were divided into groups for exposure duration as follows: <1 y, 1–4.9 y, or >5 y. Exposure concentrations were 0, 0.25, 1.5, or 3.75 ppm. No association was found between HCl exposure and cancer incidence. In a Canadian population-based case-control study, an increased risk for oat cell carcinoma was suggested in workers exposed to hydrochloric acid; however, no excess risk was observed for all types of lung cancer combined or for other histological types of lung cancer individually (Siemiatycki 1991, as cited in IARC 1992). 2.6. Summary No treatment-related effects were observed in exercising, young adult asthmatic subjects exposed to HCl at 0.8 ppm or 1.8 ppm for 45 min. Reac-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 tive airway dysfunction syndrome (RADS) has been described in people exposed to undetermined concentrations of HCl. Data concerning carcinogenicity from exposure to HCl are equivocal and are confounded by occupational exposure to other chemicals. No data concerning genetic toxicology or developmental or reproductive toxicity in humans from HCl exposure were located in the available literature. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Guinea Pigs Malek and Alarie (1989) observed 100% mortality in exercising guinea pigs exposed to HCl at 586 ppm for approximately 3 min, although no deaths were observed in guinea pigs exposed at 162 ppm for 30 min. Burleigh- Flayer et al. (1985) exposed guinea pigs to HCl at 320, 680, 1,040, or 1,380 ppm for 30 min. Mortality was as follows: 2/8 during exposure at 1,380 ppm; 1/8 following exposure at 1,380 ppm; and 2/8 following exposure at 1,040 ppm. These studies describe both lethal and nonlethal effects and are described in detail in Section 3.2.2. No mortality was observed in guinea pigs (unspecified strain) exposed to HCl at 3,667 ppm for 5 min; however, at 4,333 ppm for 30 min or 667 ppm for 2 to 6 h, 100% mortality was observed (Machle et al. 1942). 3.1.2. Rats and Mice Darmer et al. (1974) examined the acute toxicity of HCl vapor or aerosol in groups of 10 male Sprague-Dawley rats exposed to HCl at 410–30,000 ppm and groups of 10 male ICR mice exposed to HCl at 2,100–57,000 ppm for 5 or 30 min. HCl concentrations were monitored continuously during exposures, and chloride ion specific electrode analysis was utilized to determine actual concentrations. Particle size distribution was analyzed for aerosol generation. Animals were observed for 7 d post-exposure. Examination of animals dying during exposure revealed moderate to severe gross changes in the lungs and upper respiratory tract. Badly damaged nasal and tracheal epithelium, moderate to severe alveolar emphysema, atelectasis, and spotting of the lung were noted at necropsy. Survivors at the higher concentrations exhibited a clicking breathing noise, difficulty
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 2–4 LC50 Values for Hydrogen Chloride Vapor and Aerosol in Rats and Mice (ppm) Species 10-min LC50 Values 30-min LC50 Values Vapor Aerosol Vapor Aerosol Rat 41,000 31,000 4,700 5,600 Mouse 13,700 11,200 2,600 2,100 Source: Darmer et al. 1974. breathing, and bloody discharge from the nares. The authors conclude that there is no differential toxicity between the vapor and aerosol. Mice appear to be more sensitive than rats to the acute inhalation toxicity of HCl. LC50 values are presented in Table 2–4 (above). Wohlslagel et al. (1976) also examined the acute toxicity of HCl in rats and mice (data are also reported in Vernot et al. 1977). Groups of 10 male CFE (Sprague-Dawley derived) rats and groups of 10 female CF-1 (ICR derived) mice were exposed to HCl vapor for 60 min. HCl concentrations were continuously monitored during exposures by specific ion analysis. Toxic signs observed during exposure included increased grooming and irritation of the eyes, mucous membranes, and exposed skin. By the end of the exposure period, rapid, shallow breathing and yellow-green fur discoloration were observed. Necropsy of animals that died during or after exposure revealed pulmonary congestion and intestinal hemorrhage in both species. Rats also showed thymic hemorrhages. Calculated LC50 values were 3,124 ppm for rats and 1,108 ppm for mice. As was also reported in the Darmer (1974) study, mice appear to be more sensitive than rats to the acute inhalation toxicity of HCl. Data are summarized in Table 2–5. Higgins et al. (1972) also compared HCl toxicity in rats and mice. Groups of 10 Wistar rats and 15 ICR mice were exposed to various concentrations of HCl vapors for 5 min. HCl concentrations were monitored continuously during exposures via specific ion electrode analysis. Again, data suggest that mice are more sensitive to the lethal effects of HCl than are rats. Data are summarized in Table 2–6. Buckley et al. (1984) exposed groups of 16–24 male Swiss-Webster mice (25–30 g) to HCl at 309 ppm (RD50) 6 h/day (d) for 3 d. HCl concentrations were analyzed at least once per hour during exposures using infrared spectrometry. All mice were moribund or had died after the three exposures. Exfoliation, erosion, ulceration, and necrosis of the respiratory epithelium were observed.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 2–5 Mortality in Rats and Mice Exposed to Hydrogen Chloride for 60 Min Rats Mice Concentration (ppm) Mortality Concentration (ppm) Mortality 1,813 0/10 557 2/10 2,585 2/10 985 3/10 3,274 6/10 1,387 6/10 3,941 8/10 1,902 8/10 4,455 10/10 2,476 10/10 LC50 (95% CI)=3,124 ppm (2,829–3,450) LC50 (95% CI)=1,108 ppm (874–1,404) Abbreviation: CI, confidence interval. Sources: Wohlslagel et al. 1976; Vernot et al. 1977. In another study, Anderson and Alarie (1980) reported a 30-min LC50 value of 10,137 ppm for normal mice and a value of 1,095 ppm for trachea-cannulated mice. 3.1.3. Rabbits No mortality was observed in rabbits (unspecified strain) exposed to HCl at 3,667 ppm for 5 min; however, at 4,333 ppm for 30 min or 667 ppm for 2 to 6 h, 100% mortality was observed (Machle et al. 1942). 3.2. Nonlethal Toxicity 3.2.1. Nonhuman Primates Kaplan (1985) exposed juvenile male baboons (1 per concentration) to HCl at 190, 810, 2,780, 11,400, 16,570, or 17,290 ppm for 5 min. HCl exposure concentrations were continuously monitored using a “modified French standard test method.” This method is based on continuous titration of the chloride ion with silver nitrate. The animals had been trained to perform an escape test. Escape was observed at 11,400 ppm and 17,290 ppm, and avoidance was observed at all other concentrations. The author
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Kaplan, H.L., W.G.Switzer, R.K.Hinderer, and A.Anzeuto. 1993b. Studies of the effects of hydrogen chloride and polyvinyl chloride (PVE) smoke in rodents. J. Fire Sci. 11:512–552. Kusewitt, D.F., D.M.Stavert, G.Ripple, T.Mundie, and B.E.Lehnert. 1989. Relative acute toxicities in the respiratory tract of inhaled hydrogen fluoride, hydrogen bromide, and hydrogen chloride. Toxicologist 9:36. Leonardos, G., Kendall, and N.J.Barnard. 1969. Odor threshold determinations of 53 odorant chemicals. J. Air Pollut. Control Assoc. 19:91–95. Lucia, H.L., C.S.Barrow, M.F.Stock, and Y.Alarie. 1977. A semi-quantitative method for assessing anatomic damage sustained by the upper respiratory tract of the laboratory mouse, Mus musculis. J. Combust. Toxicol. 4:472–486. Machle, W., K.V.Kitzmiller, E.W.Scott, and J.F.Treon. 1942. The effect of inhalation of hydrogen chloride. J. Ind. Hyg. Toxicol. 22:222–225. Malek, D.E., and Y.Alarie. 1989. Ergometer within a whole-body plethysmograph to evaluate performance of guinea pigs under toxic atmospheres. Toxicol. Appl. Pharmacol. 101:340–355. Nemery, B. 1996. Late consequences of accidental exposure to inhaled irritants: RADS and the Bhopal disaster. Eur. Respir. J. 9:1973–1976. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs). U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Cincinnati, OH. NRC (National Research Council). 1987. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 7. Washington DC: National Academy Press. NRC (National Research Council). 1991. Permissible Exposure Levels and Emergency Exposure Guidance Levels for Selected Airborne Contaminants. Washington, DC: National Academy Press. Pp. 37–52. NRC (National Research Council). 2000. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 4. Washington DC: National Academy Press. NTIS (National Technical Information Service). 2000. Hydrogen Chloride. Registry of Toxic Effects of Chemical Substances (RTECS) [Online]. Available: http://www.ntis.gov/search/product.asp?ABBR=SUB5363&starDB=GRAHIST [October 1, 2000]. OSHA (Occupational Safety and Health Administration). 1999. CFR 29 Part 1910. Occupational Safety and Health Standards. Air Contaminants. U.S. Department of Labor, Washington, DC. Pavlova, T.E. 1976. Disturbance of development of the progeny of rats exposed to hydrogen chloride. Bull. Exp. Biol. Med. 82:1078–1081. Promisloff, R.A., G.S.Lenchner, and A.V.Cichelli. 1990. Reactive airway dysfunction syndrome in three police officers following a roadside chemical spill. Chest 98:928–929. Sakurai, T. 1989. Toxic gas tests with several pure and mixed gases using mice. J. Fire. Sci. 7:22–77.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Schaper, M. 1993. Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am. Ind. Hyg. Assoc. J. 54:488–544. Ministry of Social Affairs and Employment (SDU Uitgevers). 2000. National MAC (Maximum Allowable Concentration) List, 2000. Ministry of Social Affairs and Employment, The Hague, The Netherlands. Sellakumar, A.R., C.A.Snyder, J.J.Solomon, and R.E.Albert. 1985. Carcinogenicity of formaldehyde and hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81:401–406. Siemiatycki, J., ed. 1991. Risk Factors for Cancer in the Workplace. Boca Raton, FL: CRC Press. Stavert, D.M., D.C.Archuleta, M.J.Behr, and B.E.Lehnert. 1991. Relative acute toxicities of hydrogen fluoride, hydrogen chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing rats. Fundam. Appl. Toxicol. 16:636–655. Steenland, K., T.Schnorr, J.Beaumont, W.Halperin, and T.Bloom. 1988. Incidence of laryngeal cancer and exposure to acid mists. Br. J. Ind. Med. 45:766–776. 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 34:923–929. 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. Hazard. Mater. 13:301–309. Toxigenics, Inc. 1984. 90-day Inhalation Toxicity Study of Hydrogen Chloride Gas in B6C3F1 Mice, Sprague-Dawley Rats, and Fischer-344 Rats, Revised. Decatur, IL: Toxigenics, Inc. Pp. 66. Turlo, S.M., and I.Broder. 1989. Irritant-induced occupational asthma. Chest 96:297–300. 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 solutions. Toxicol. Appl. Pharmacol. 42:417–423. 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.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX A Time-Scaling Calculations for Hydrogen Chloride Derivation of AEGL-1 Key study: Stevens et al. 1992 Toxicity end point: No-observed-adverse-effect level in exercising asthmatic subjects. Time-scaling: C1×t=k (ten Berge 1986); (1.8 ppm)1×0.75 h=1.35 ppm·h Uncertainty factor: None 10-min, 30-min, 1-h, 4-h, and 8-h AEGL-1: 1.8 ppm Derivation of AEGL-2 10-min AEGL-2 Key study: Barrow et al. 1977 Toxicity end point: Mouse RD50 of 309 ppm to obtain a concentration causing irritation. 10-min AEGL-2: 309 ppm÷3=100 ppm 30-min, 1-, 4-, and 8-h AEGL-2 Key Study: Stavert et al. 1991
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Toxicity end point: Severe nasal (nose-breathers) or pulmonary (mouth-breathers) effects in rats exposed at 1,300 ppm for 30 min. Time-scaling: C1×t=k (ten Berge 1986); (1,300 ppm)1×0.5 h=650 ppm·h Uncertainty factors: 3 for intraspecies variability 3 for interspecies variability Modifying factor: 3 for sparse database 30-min AEGL-2: C1×0.5 h=650 ppm·h C=1,300 ppm 30 min AEGL-2=1,300 ppm÷30=43 ppm 1-h AEGL-2: C1×1 h=650 ppm·h C=650 ppm 1-h AEGL-2=650 ppm÷30=21.6 ppm 4-h AEGL-2: 1-h AEGL-2÷2=1 ppm 8-h AEGL-2: 1-h AEGL-2÷2=11 ppm Derivation of AEGL-3 Key Study: Wholslagel et al. 1976; Vernot et al. 1977 Toxicity end point: One-third of the rat 1-h LC50 as an estimate of a no-effect level for death (3,124 ppm÷3=1,041 ppm) Time-scaling: C1×t=k (ten Berge 1986) (1,041 ppm)1×1 h=1,041 ppm·h
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Uncertainty factors: 3 for intraspecies variability 3 for interspecies variability 10-min AEGL-3: C1×0.167 h=1,041 ppm·h C=6,234 ppm 10-min AEGL-3=6,234 ppm÷10=623.4 ppm 30-min AEGL-3: C1×0.5 h=1,041 ppm·h C=2,082 ppm 30-min AEGL-3=2,082 ppm÷10=208 ppm 1-h AEGL-3: C1×1 h=1,041 ppm·h C=1,041 ppm 1-h AEGL-3=1,041 ppm÷10=104.1 ppm 4-h AEGL-3: C1×4 h=1,041 ppm·h C=260.25 ppm 4-h AEGL-3=260.25 ppm÷10=26 ppm 8-h AEGL-3: 8-h AEGL-3=4-h AEGL-3=26 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR HYDROGEN CHLORIDE (CAS Reg. No. 7647–01–0) DERIVATION SUMMARY AEGL-1 10 min 30 min 1 h 4 h 8 h 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm Key reference: Stevens, B. et al. 1992. Respiratory effects from the inhalation if hydrogen chloride in young adult asthmatics. JOM. 34:923–929. Test species/strain/number: human/adult asthmatic subjects/10 Exposure route/concentrations/durations: inhalation at 0, 0.8, or 1.8 ppm for 45 min while exercising (1.8 ppm was determinant for AEGL-1) Effects: No treatment-related effects were observed in any of the individuals tested End point/concentration/rationale: The highest concentration tested was a no-effect level for irritation in a sensitive human population (10 asthmatic individuals tested) and was selected as the basis for AEGL-1. Effects assessed included sore throat, nasal discharge, cough, chest pain or burning, dyspnea, wheezing, fatigue, headache, unusual taste or smell, total respiratory resistance, thoracic gas volume at functional residual capacity, forced expiratory volume, and forced vital capacity. All subjects continued the requisite exercise routine for the duration of the test period. Uncertainty factors/rationale: Interspecies: 1, test subjects were human Intraspecies: 1, test subjects were sensitive population (exercising asthmatic subjects) Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data Time-scaling: The AEGL-1 values for a sensory irritant were held constant across time because it is a threshold effect and prolonged exposure will not result in an enhanced effect. In fact one may become desensitized to the respiratory tract irritant over time. Also, this approach was considered valid since the end point (no treatment-related effects at the highest concentration tested in exercising asthmatics) is inherently conservative
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Data quality and research needs: The key study was well conducted in a sensitive human population and is based on no treatment-related effects. In addition, the direct-acting irritation response is not expected to vary greatly among individuals. Therefore, confidence in the AEGL values derived is high.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 AEGL-2 10 min 30 min 1 h 4 h 8 h 100 ppm 43 ppm 22 ppm 11 ppm 11 ppm Key references: Stavert et al. 1991. Relative acute toxicities of hydrogen chloride, hydrogen fluoride, and hydrogen bromide in nose-and pseudo-mouth-breathing rats. Fundam. Appl. Toxicol. 16:636–655. (30-min, 1-, 4-, and 8-h) Barrow, C.S., Alarie, Y., Warrick, M., and Stock, M.F. 1977. Comparison of the sensory irritation response in mice to chlorine and hydrogen chloride. Arch. Environ. Health. 32:68–76. (10-min) Test species/strain/number: F-344 rats, 8 males/concentration (30-min, 1-, 4-, and 8-h); Male Swiss Webster mice (10-min) Exposure route/concentrations/durations: inhalation at 0 or 1,300 ppm for 30 min (1,300 ppm was determinant for 30-min, 1-, 4-, and 8-h AEGL-2) Effects (30-min, 1-, 4-, and 8-h): 0 ppm, no effects; 1,300 ppm, severe necrotizing rhinitis, turbinate necrosis, thrombosis of nasal submucosa vessels in nose-breathers; 1,300 ppm, severe ulcerative tracheitis accompanied by necrosis and luminal ulceration in mouth-breathers (determinant for AEGL-2); RD50=309 ppm (determinant for 10-min AEGL-2) End point/concentration/rationale: 1,300 ppm for 30 min, severe lung effects (ulcerative tracheitis accompanied by necrosis and luminal ulceration) or nasal effects (necrotizing rhinitis, turbinate necrosis, thrombosis of nasal submucosa vessels histopathology) in pseudo-mouth-breathing male F-344 rats (30-min, 1-, 4-, and 8-hr); RD50 of 309 ppm÷3 to estimate irritation (10-min) Uncertainty Factors/Rationale (30-min, 1-, 4-, and 8-hr): Total uncertainty factor: 10 Intraspecies: 3, steep concentration-response curve implies limited individual variability Interspecies: 3, the use of an intraspecies uncertainty factor of 10 would bring the total uncertainty/modifying factor to 100 instead of 30. That would generate AEGL-2 values that are not supported by data on exercising asthmatic subjects, an especially sensitive subpopulation because exercise increases hydrogen chloride uptake and exacerbates irritation. No effects were noted in exercising young adult asthmatic subjects exposed to HCl at 1.8 ppm for 45 min (Stevens et al. 1992). Using a total UF of 30 would yield 4- and 8-h values of 3.6 ppm (instead of 11 ppm). It is not supportable to predict that humans would be disabled by exposure at 3.6 ppm for 4- or 8-h when exercising asthmatic subjects exposed to one-half that level for 45 min had no effects. The
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 shorter time points would yield values 4–7 times above 1.8 ppm; however, the confidence in the time scaling for hydrogen chloride is good for times up to 100-min because the n value was derived from a regression analysis of rat and mouse mortality data with exposure durations ranging from 1 min to 100 minutes. The 30-min value of 43 ppm derived with the total UF of 10 is reasonable in light of the fact that baboons exposed to 500 ppm for 15 min experienced only a slightly increased respiratory rate Modifying factor: 30-min, 1-, 4-, and 8-h: 3, based on sparse database for AEGL-2 effects and the fact that the effects observed at the concentration used as the basis for AEGL-2 were somewhat severe 10-min: the 10-min AEGL-2 was derived by dividing the mouse RD50 of 309 ppm by a factor of 3 to obtain a concentration causing irritation (Barrow et al. 1977). One-third of the mouse RD50 for hydrogen chloride corresponds to an approximate decrease in respiratory rate of 30%, and decreases in the range of 20–50% correspond to moderate irritation (ASTM 1991). Animal to human dosimetric adjustment: Insufficient data Time-scaling: Cn×t=k where n=1, based on regression analysis of combined rat and mouse LC50 data (1 min to 100 min) reported by ten Berge et al. (1986). Data point used to derive AEGL-2 was 30 min. AEGL-2 values for 1-h exposure period was based on extrapolation from the 30-min value. The 4- and 8-h AEGL-2 values were derived by applying a modifying factor of 2 to the 1-h AEGL-2 value because time scaling would yield a 4-h AEGL-2 value of 5.4 ppm and an 8-h AEGL-2 of 2.7 ppm, close to the 1.8 ppm tolerated by exercising asthmatic subjects without adverse health effects. Data quality and research needs: Confidence is moderate since the species used is more sensitive than primates to the effects of hydrogen chloride, the chemical is a direct-acting irritant, and a modifying factor was included to account for the relative severity of effects and sparse database.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 AEGL-3 10 min 30 min 1 h 4 h 8 h 620 ppm 210 ppm 100 ppm 26 ppm 26 ppm Key references: Vernot, E.H., MacEwen, J.D., Haun, C.C., Kinkead, E.R. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42:417–423. Wohlslagel, J., DiPasquale, L..C., Vernot, E.H. 1976. Toxicity of solid rocket motor exhaust: Effects of HCl, HF, and alumina on rodents. J. Combustion Toxicol. 3:61–70. Test species/strain/gender/number: Sprague-Dawley rats, 10 males/concentration Exposure route/concentrations/durations: inhalation at 0, 1,813, 2,585, 3,274, 3,941, or 4,455 ppm for 1 h Effects: Concentration Mortality 0 ppm 0/10 1,813 ppm 0/10 2,585 ppm 2/10 3,274 ppm 6/10 3,941 ppm 8/10 4,455 ppm 10/10 LC50 reported as 3,124 ppm (determinant for AEGL-3) End point/concentration/rationale: one-third of the 1-h LC50 (1,041 ppm) was the estimated concentration causing no deaths. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Intraspecies: 3, steep concentration-response curve implies limited individual variability Interspecies: 3, because (1) the steep concentration-response curve for lethality observed in the Wohlslagel et al. (1976) study in which 1,041 ppm (one-third of the LC50 of 3124 ppm) was lower than the LC0 of 1,813 ppm. This is a conservative selection of the LC0 and the steep concentration-response curve argues for little interindividual variability; (2) AEGL-3 values generated from a total uncertainty factor of 30 would be close to the AEGL-2 values (within a factor of 2) generated above which are reasonable when compared with data on exercising asthmatics; (3) Sellakumar et al. (1985) exposed rats to HCl at 10 ppm for 6 h/d, 5 d/wk for life and only observed increased trachael and laryngeal hyperplasia. The estimated 6-h AEGL-3 using an intraspecies uncertainty factor of 3 is 17 ppm, close to the level used in the lifetime
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 study in which only mild effects were induced; (4) rats exposed at 50 ppm for 6 h/d, 5 d/wk for 90 d (Toxigenics 1984) exhibited mild rhinitis. This level is already 2 times that of the AEGL-3 value for death. Thus, the total uncertainty factor is 10. Modifying factor: Not applicable Animal to human dosimetric adjustment: Insufficient data Time scaling: Cn×t=k where n=1, based on regression analysis of rat and mouse mortality data (1 min to 100 min) reported by ten Berge et al. (1986). Reported 1-h data point was used to derive AEGL-3 values. AEGL-3 values for 10-min, 30-min, and 4-h were based on extrapolation from the 1-h value. The 4-h value was adopted as the 8-h value. Data quality and research needs: Study is considered appropriate for AEGL-3 derivation because exposures are over a wide range of HCl concentrations and utilize a sufficient number of animals. Data were insufficient to derive a no-effect level for death. One-third of the LC50 has been utilized previously for chemicals with steep concentration-response curves. Also, in the key study, no deaths were observed in rats exposed at 1,813 ppm.
Representative terms from entire chapter: