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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 1 Chlorine1 Acute Exposure Guideline Levels SUMMARY Chlorine is a greenish-yellow, highly reactive halogen gas that has a pungent, suffocating odor. The vapor is heavier than air and will form a cloud in the vicinity of a spill. Like other halogens, chlorine exists in the diatomic state in nature. Chlorine is extremely reactive and rapidly combines with both inorganic and organic substances. Chlorine is used in the manufacture of a wide variety of chemicals, as a bleaching agent in industry and household products, and as a biocide in water and waste treatment plants. 1   This document was prepared by the AEGL Development Team comprising Sylvia Talmage (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances, including Larry Gephart (Chemical Manager) and George Alexeeff and Kyle Blackman (Chemical Reviewers). 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) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid on the basis of the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Chlorine is an irritant to the eyes and respiratory tract; reaction with moist surfaces produces hydrochloric and hypochlorous acids. Its irritant properties have been studied in human volunteers, and its acute inhalation toxicity has been studied in several laboratory animal species. The data from the human and laboratory animal studies were sufficient for developing acute exposure guideline levels (AEGLs) for the five exposure durations (i.e., 10 and 30 minutes [min] and 1, 4, and 8 hours [h]). Regression analysis of human data on nuisance irritation responses (itching or burning of the eyes, nose, or throat) for durations of 30–120 min and during exposures to chlorine at 0–2 parts per million (ppm) determined that the relationship between concentration and time is approximately C2×t=k (where C= concentration, t=time, and k is a constant) (ten Berge and Vis van Heemst 1983). The AEGL-1 was based on a combination of studies that tested healthy human subjects as well as atopic individuals (Rotman et al. 1983; Shusterman et al. 1998) and asthmatic patients (D’Alessandro et al. 1996). Atopic and asthmatic individuals have been identified as susceptible populations for irritant gases. The highest no-observed-adverse-effect level (NOAEL) for notable irritation and significant changes in pulmonary function parameters was 0.5 ppm in two studies. Eight atopic subjects were exposed for 15 min in one study (Shusterman et al. 1998), and eight healthy exercising individuals and an exercising atopic individual were exposed for two consecutive 4-h periods in the other (Rotman et al. 1983). The subjects in the Shusterman et al. (1998) study experienced nasal congestion, but irritation was described as none to slight. The exercising atopic individual in the Rotman et al. (1983) study experienced nondisabling, transient, asymptomatic changes in pulmonary function parameters. The selection of 0.5 ppm is supported by the lack of symptoms and lack of changes in pulmonary air flow and airway resistance in five asthmatic subjects inhaling 0.4 ppm for 1 h (D’Alessandro et al. 1996). Because susceptible populations comprising atopic and asthmatic individuals were tested at similar concentrations, with incorporation of exercise into the protocol of one study, an intraspecies uncertainty factor (UF) of 1 was applied. The intraspecies UF of 1 is further supported by the fact that pediatric asthmatic subjects do not appear to be more responsive to irritants than adult asthmatic subjects (Avital et al. 1991). The AEGL-1 value was not time scaled for several reasons. First, the Rotman et al. (1983) study was for 8 h with a single 1-h break. Second, the response to chlorine appears to be concentration-dependent rather than time-dependent, as the pulmonary function parameters of individuals tested in this study, including

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 those for the atopic individual, did not increase between the 4- and 8-h measurements. The AEGL-2 values were based on two of the studies used to derive the AEGL-1. Both healthy and susceptible human subjects inhaled chlorine at 1.0 ppm for 1 h (D’Alessandro et al. 1996) or 4 h (Rotman et al. 1983). Both healthy and susceptible subjects experienced some sensory irritation and transient changes in pulmonary function measurements. Greater changes were observed in pulmonary parameters among the susceptible subjects compared with the normal groups. In the latter study (Rotman et al. 1983), an atopic individual experienced no respiratory symptoms other than some sensory irritation during the 4-h exposure, but his airway resistance nearly tripled. He experienced shortness of breath and wheezing during a second 4-h exposure. Five individuals with nonspecific airway hyper-reactivity or asthma also experienced a statistically significant fall in pulmonary air flow and an increase in airway resistance during a 1-h exposure at 1.0 ppm (D’Alessandro et al. (1996). There were no respiratory symptoms during the exposure. The susceptible individual in the Rotman et al. (1983) study remained in the exposure chamber for the full 4 h without respiratory symptoms. Therefore, when considering the definition of the AEGL-2, the first 4 h of exposure was a no-effect level in a susceptible individual. Because the subjects were susceptible individuals, one of the subjects was undergoing light exercise during the exposures (making him more vulnerable to sensory effects), and an exercising susceptible individual exhibited effects that did not impede escape for the 4-h exposure duration (consistent with the definition of the AEGL-2), an intraspecies UF of 1 was applied. Chlorine is a highly irritating and corrosive gas that reacts directly with the tissues of the respiratory tract with no pharmacokinetic component involved in toxicity; therefore, effects are not expected to vary greatly among other susceptible populations. Time-scaling was considered appropriate for the AEGL-2 because it is defined as the threshold for irreversible effects, which, in the case of irritants, generally involves tissue damage. Although the end point used in this case—a no-effect concentration for wheezing that was accompanied by a significant increase in airways resistance—has a different mechanism of action than that of direct tissue damage, it is assumed that some biomarkers of tissue irritation would be present in the airways and lungs. The 4-h 1-ppm concentration was scaled to the other time periods using the C2×t=k relationship. The scaling factor was based on regression analyses of concentrations and exposure durations that attained nuisance levels of irritation in human subjects (ten Berge and Vis

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 van Heemst 1983). The 10-min value was set equal to the 30-min value in order to not exceed the highest exposure of 4.0 ppm in controlled human studies. In the absence of human data, animal lethality data served as the basis for AEGL-3. The mouse was not chosen as an appropriate model for lethality because mice often showed delayed deaths, which several authors attributed to bronchopneumonia. Because the mouse was shown to be more sensitive to chlorine than the dog and rat, and because the mouse does not provide an appropriate basis for quantitatively predicting mortality in humans, a value below those resulting in no deaths in the rat (213 ppm and 322 ppm) and above that resulting in no deaths in the mouse (150 ppm) for a period of 1 h was chosen (MacEwen and Vernot 1972; Zwart and Woutersen 1988). The AEGL-3 values were derived from a 1-h concentration of 200 ppm. That value was calculated applying a total UF of 10–3 to extrapolate from rats to humans (interspecies values for the same end point differed by a factor of approximately 2 within each of several studies), and 3 to account for differences in human sensitivity. The susceptibility of asthmatic subjects relative to healthy subjects when considering lethality is unknown, but the data from two studies with human subjects showed that doubling a no-effect concentration for irritation and bronchial constriction resulted in potentially serious effects in asthmatic subjects but not in normal individuals. Time-scaling was considered appropriate for the AEGL-3, because tissue damage is involved. (Data in animal studies clearly indicate that time scaling is appropriate when lung damage is observed.) The AEGL-3 values for the other exposure times were calculated using the C2 ×t=k relationship, which was derived based on the end point of irritation from a study with humans. The calculated values are listed in Table 1–1. 1. INTRODUCTION Chlorine is the most abundant naturally occurring halogen. Halogens do not occur in the elemental state in nature. When formed experimentally, chlorine is a greenish-yellow, diatomic gas (Cl2) with a pungent, suffocating odor. Chlorine is used in the manufacture of a variety of nonagricultural chemicals, such as vinyl chloride and ethylene dichloride; as a bleaching agent in the paper industry (along with chlorine dioxide [ClO2]); as commercial and household bleaching agents (in the form of chlorates [ClO3−] and hypochlorites [OCl−]); and as a biocide in water purification and waste

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 1–1 Summary of AEGLs Values for Chlorine (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1a (Nondisabling) 0.5 (1.5) 0.5 (1.5) 0.5 (1.5) 0.5 (1.5) 0.5b (1.5) No to slight changes in pulmonary function parameters in humans (Rotman et al. 1983; D’Alessandro et al. 1996; Shusterman et al. 1998) AEGL-2 (Disabling) 2.8 (8.1) 2.8 (8.1) 2.0 (5.8) 1.0 (2.9) 0.7 (2.0) 1.0 ppm for 4 h was a NOAEL for an asthma-like attack in human subjects; the other values were time-scaled (Rotman et al. 1983; D’Alessandro et al. 1996) AEGL-3 (Lethal) 50 (145) 28 (81) 20 (58) 10 (29) 7.1 (21) Threshold for lethality in the rat (MacEwen and Vernot 1972; Zwart and Woutersen 1988) aThe distinctive, pungent odor of chlorine will be noticeable to most individuals at these concentrations. bBecause effects were not increased following an interrupted 8-h exposure of an atopic individual to 0.5 ppm, the 8-h AEGL-1 was set equal to 0.5 ppm. Abbreviations: mg/m3, milligrams per cubic meter; ppm, parts per million. treatment systems (Perry et al. 1994). Chlorine gas was used as a chemical warfare agent during World War I (Withers and Lees 1987). The vapor is heavier than air and will form a cloud in the vicinity of a spill. As of January 1999, world annual capacity for chlorine production was estimated at almost 50 million metric tons (CEH 2000). Chlorine is produced at chlor-alkali plants at over 650 sites worldwide, and North America accounts for 32% of capacity (operating rates are greater than 83% of capacity). In the early 1990s, chlorine was produced at 49 facilities, operated by 29 companies, in the United States (Perry et al. 1994). In 1993, U.S.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 production was reported at 24 billion pounds (C&EN 1994). The major global market for chlorine is ethylene dichloride production (about 33%) (CEH 2000). Chlorine is extremely reactive and enters into substitution or addition reactions with both inorganic and organic substances. Moist chlorine unites directly with most elements. Reaction with water produces hydrochloric (HCl) and hypochlorous acid (HClO) (Budavari et al. 1996; Perry et al. 1994). Other relevant chemical and physical properties are listed in Table 1–2. According to Amoore and Hautala (1983), the odor threshold is 0.31 ppm, and a range of 0.2–0.4 ppm was reported in other studies. There is considerable variation in detecting the odor among subjects; for many individuals, the ability to perceive the odor decreases over exposure time (NIOSH 1976). Chlorine is an eye and respiratory tract irritant and, at high doses, has direct toxic effects on the lungs. It reaches the lungs because it is only moderately soluble in water and it is not totally absorbed in the upper respiratory tract at high concentrations. The acute inhalation toxicity of chlorine has been studied in several laboratory animal species, and its irritant properties have been studied with human volunteers. 2. HUMAN TOXICITY DATA 2.1 Acute Lethality For humans, a 5-min lethal concentration in 10% of subjects (LC10) of 500 ppm (NTIS 1996) and a possible 30-min lethal exposure of 872 ppm have been reported (Perry et al. 1995). Both of those secondary sources cited data from Prentiss (1937) as well as data from other early sources. Although accidental releases have resulted in deaths (e.g., Jones et al. 1986), no studies were located in which acute lethal exposure concentrations were measured. Probit analysis of available information on the lethality of chlorine to animals and humans was used by Withers and Lees (1985b) to estimate a concentration lethal to 50% of the population (LC50). Their model incorporates the effects of physical activity, inhalation rate, the effectiveness of medical treatment, and the lethal toxic load function. The estimated 30-min LC50 at a standard level of activity (inhalation rate of 12 liters [L]/min) for the regular, vulnerable, and average (regular plus vulnerable) populations, as described by the authors, were 250,100, and 210 ppm,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 1–2 Chemical and Physical Properties of Chlorine Parameter Value Reference Synonyms Bertholite; hypochlorite; hypochlorous acid Budavari et al. 1996 Molecular formula Cl2 Budavari et al. 1996 Molecular weight 70.9 Budavari et al. 1996 CAS registry no. 7782–50–5 Budavari et al. 1996 Physical state Gas Budavari et al. 1996 Color Greenish-yellow Budavari et al. 1996 Solubility in water 0.092 moles/L Budavari et al. 1996 Vapor pressure 5,025 mm Hg at 20°C Matheson Gas Co. 1980 Vapor density 1.4085 at 20°C AIHA 1988 Density (water=1) 1.56 at boiling point Perry et al. 1994 Melting point −101°C Budavari et al. 1996 Boiling point −34.05°C Budavari et al. 1996 Flammability Nonflammable Matheson Gas Co. 1980 Conversion factors in air 1 ppm=2.9 mg/m3 1 mg/m3=0.34 ppm ACGIH 2001 respectively. The LC10 for the three populations were 125, 50, and 80 ppm, respectively. 2.2. Nonlethal Toxicity Exposures at 30 ppm and 40–60 ppm have been reported to cause intense coughing and serious damage, respectively (ILO 1998), but no documentation of those values was given. 2.2.1. Experimental Studies Five well-conducted and well-documented studies using human volunteers were located. Those studies are summarized in Table 1–3.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 1–3 Summary of Irritant Effects in Humansa Concentration (ppm) Exposure Timeb Effect References 0.4 1 h No pulmonary function changes in subjects with airway hyperreactivity/asthma D’Alessandro et al. 1996 0.5 15 min Change in nasal air resistance in rhinitic subjects (no change in nonrhinitic subjects); no effect on pulmonary peak flow, rhinorrhea, postnasal drip, or headache in either type of subject Shusterman et al. 1998 0.5 8 h Perception of odor, no discomfort, no effects, no changes in pulmonary function measurements for healthy individuals; some changes for atopic individual Anglen 1981; Rotman et al. 1983 1.0 1 h Statistically significant but modest changes in FEV1 and Raw for normal and asthmatic subjects D’Alessandro et al. 1996 1.0 2 h No noticeable effects Joosting and Verberk 1974 1.0 4 h Irritation for some sensations; no changes in pulmonary function measurements Anglen 1981 1.0 4 h Transient changes in pulmonary function measurements (airway resistance) Rotman et al. 1983 1.0 8 h Irritation (itchy eyes, runny nose, mild burning in throat); transient changes in pulmonary function measurements; atopic subject could not complete full 8-h exposure because of wheezing and shortness of breath Anglen 1981; Rotman et al. 1983

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 2.0 15 min Perception of odor; no significant irritation effects Anglen 1981 2.0 30 min Not significantly different from control group for irritant effects, irritancy indices Anglen 1981 2.0 1 h Itching or burning of throat, urge to cough at nuisance level Anglen 1981 2.0 2 h Very slight irritation of eyes, nose, and throat; no changes in pulmonary function Joosting and Verberk 1974 2.0 2 h No significant changes in pulmonary function Anglen 1981 2.0 4 h 50% response of subjects to sensations characterized as nuisance: itching or burning of nose or throat, urge to cough, runny nose, general discomfort; transient changes in pulmonary function Anglen 1981 2.0 8 h Not immediately irritating, objectionable after several hours; increased mucous; transient changes in pulmonary function Anglen 1981 4.0 2 h Nuisance level of throat irritation, perceptible to nuisance level of nose irritation and cough Joosting and Verberk 1974 aThe Anglen (1981) and Joosting and Verberk (1974) studies were performed with healthy adults. Atopic individuals were included in the Shusterman et al. (1998) and Rotman et al. (1983) studies, and healthy subjects as well as asthmatic subjects were included in the D’Alessandro (1996) study. b8-h studies were composed of two segments with a 30-min or 1-h break after 4 h.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 O’Neil, C.E. 1991. Immune responsiveness in chlorine exposed rats. PB92–124478. National Institute for Occupational Safety and Health, Cincinnati, OH. OSHA (Occupational Safety and Health Administration). 1989. 29 CFR Part 1910, Air Contaminants: Final Rule. Fed. Regist. 54(12):2455–2456 (Thursday, January 19, 1989). Patil, L.R.S., R.G Smith, A.J.Vorwald, and T.F.Mooney. 1970. The health of diaphragm cell workers exposed to chlorine. Am. Ind. Hyg. Assoc. J. 31:678–686. Perry, W.G., F.A.Smith, and M.B.Kent. 1994. The halogens. Pp. 4482–4505 in Patty’s Industrial Hygiene and Toxicology, Vol. 2, Part F, G.F.Clayton and F.E.Clayton, eds. New York, NY: John Wiley & Sons, Inc. Prentiss, A.M. 1937. Chemicals in War; a Treatise on Chemical Warfare. New York: McGraw-Hill Book Company. Rafferty, P. 1980. Voluntary chlorine inhalation: A new form of self-abuse? Br. Med. J. 281:1178–1179. Rothery, S.P. 1991. Hazards of chlorine to asthmatic patients. Br. J. Gen. Pract. 41:39. Rotman, H.H., M.J.Fliegelman, T.Moore, R.G.Smith, D.M.Anglen, C.J. Kowalski, and J.G.Weg. 1983. Effects of low concentration of chlorine on pulmonary function in humans. J. Appl. Physiol. 54:1120–1124. Rupp, H., and D.Henschler. 1967. Effects of low chlorine and bromine concentrations on man. Int. Arch. Gewerbepathol. 23:79–90. Schlagbauer, M., and D.Henschler. 1967. Toxicity of chlorine and bromine with single and repeated inhalation. Int. Arch. Gewerbepath. Gewerbehyg. 23:91. Shroff, C.P., M.V.Khade, and M.Srinivasan. 1988. Respiratory cytopathology in chlorine gas toxicity: A study in 28 subjects. Diagn. Cytopathol. 4:28–32. Shusterman, D.J., M.A.Murphy, and J.R.Balmes. 1998. Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas. J. Allergy Clin. Immunol. 101:732–740. Silver, S.D., F.P.McGrath, and R.L.Ferguson. 1942. Chlorine median lethal concentration data for mice. DATR 373. Edgewood Arsenal, MD. ten Berge, W.F., and M.Vis van Heemst. 1983. Validity and accuracy of a commonly used toxicity-assessment model in risk analysis. IChemE Symposium Series No. 80:I1–I12. ten Berge, W.F., A.Zwart, and L.M.Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapors and gases. J. Hazard. Mater. 13:301–310. Underhill, F.P. 1920. The lethal War Gases: Physiology and Experimental Treatment. New Haven, CT: Yale University Press. Pp. 20. 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.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Weedon, F.R, A.Hartzell, and C.Setterstrom. 1940. Toxicity of ammonia, chlorine, hydrogen cyanide, hydrogen sulfide and sulfur dioxide gases. V. Animals. Contrib. Boyce Thompson Inst. 11:365–385. Weill, H., R.George, M.Schwarz, and M.Ziskind. 1969. Late evaluation of pulmonary function after acute exposure to chlorine gas. Amer. Rev. Resp. Dis. 99:374–379. Withers, R.M.J., and F.P.Lees. 1985a. The assessment of major hazards: The lethal toxicity of chlorine, Part 1: Review of information on toxicity. J. Hazard. Mater. 12:231–282. Withers, R.M.J., and F.P.Lees. 1985b. The assessment of major hazards: The lethal toxicity of chlorine., Part 2: model of toxicity to man. J. Hazard. Mater. 12:283–302. Withers, R.M.J., and F.P.Lees. 1987. The assessment of major hazards: The lethal toxicity of chlorine, Part 3: Crosschecks from gas warfare. J. Hazard. Mater. 15:301–342. Witschi, H.R., and J.A.Last. 1996. Toxic responses of the respiratory system. In Casarett and Doull’s Toxicology: The Basic Science of Poisons. New York, NY: McGraw-Hill. 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. 3:61–69. Wolf, D.C., K.T.Morgan, E.A.Gross, C.Barrow, O.R.Moss, R.A.James, and J.A. Popp. 1995. Two-year inhalation exposure of female and male B6C3F1 mice and F344 rats to chlorine gas induces lesions confined to the nose. Fundam. Appl. Toxicol. 24:111–131. Wood, B.R., J.L.Colombo, and B.E.Benson. 1987. Chlorine inhalation toxicity from vapors generated by swimming pool chlorinator tablets. Pediatrics 79:427–430. Zwart, A., and R.A.Woutersen. 1988. Acute inhalation toxicity of chlorine in rats and mice: Time-concentration-mortality relationships and effects on respiration. J. Hazard. Mater. 19:195–208.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX A Derivation of Chlorine AEGLs Derivation of AEGL-1 Key studies: Rotman et al. 1983; D’Alessandro et al. 1996; Shusterman et al. 1998 Toxicity end point: Transient pulmonary function changes in atopic individual exposed at 0.5 ppm for an interrupted 8 h; non-significant changes in pulmonary peak air flow in eight atopic individuals exposed at 0.5 ppm for 15 min; no statistically significant pulmonary parameter changes in asthmatic subjects exposed at 0.4 ppm for 1 h Time-scaling: No time scaling; because there is adaptation to the slight irritation that defines the AEGL-1 end point, the same value (0.5 ppm) was used across all time points Uncertainty factors: 1, because susceptible individuals were tested and one of the susceptible individuals was exercising, making him more susceptible to sensory irritation (no-effect level in healthy exercising individuals of both genders) Calculations: Because the 0.5 ppm concentration was indicative of a NOAEL for more serious pulmonary changes, the 0.5 ppm concentration was used for all exposure durations. The susceptible individual underwent an interrupted 8-h exposure at 0.5 ppm without increased symptoms, so that concentration was also used for the 8-h AEGL-1

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Derivation of AEGL-2 Key studies: Rotman et al. 1983; D’Alessandro et al. 1996 Toxicity end point: No-effect concentration for serious health effect (asthma-like attack) in a sensitive, exercising individual exposed at 1 ppm for 4 h and in individuals with airway hyper-reactivity (including 3 asthmatic individuals) exposed at 1 ppm for 1 h Time-scaling: C2×t=k (ten Berge and Vis van Heemst 1983) (1 ppm)2×240 min=240 ppm2·min Uncertainty factors: 1. The value was based on effects consistent with the AEGL-2 definition in a susceptible, exercising individual and in asthmatics subjects 30-min AEGL-2: C2×30 min=240 ppm2·min C=2.8 ppm 1-h AEGL-2: C2×60 minutes=240 ppm2·min C=2 ppm 4-h AEGL-2: 1 ppm for 4 h; basis for derivation of other exposure durations 8-h AEGL-2: C2×480 min=240 ppm2·min C=0.71 ppm The 10-min AEGL-2 was set equal to the 30-min AEGL-2 so that the highest human test concentration of 4.0 ppm was not exceeded. Derivation of AEGL-3 Key studies: Zwart and Woutersen 1988; MacEwen and Vernot 1972

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Toxicity end point: 1-h lethality value; an end point below the highest concentration resulting in no deaths in the rat and above the highest concentration resulting in no deaths in the mouse was chosen because the mouse was shown to be more sensitive than other mammals to irritant gases, including chlorine, and does not provide an appropriate basis for quantitatively predicting mortality in humans Time-scaling: C2×t=k (ten Berge and Vis van Heemst 1983) (200 ppm/10)2×60 min=24,000 ppm2·min Uncertainty factors: Combined uncertainty factor of 10   3 for interspecies variability (interspecies values for the same end point differed by a factor of approximately 2 in several studies)   3 for differences in human sensitivity (the toxic effect is the result of a chemical reaction with biologic tissue of the respiratory tract, which is unlikely to differ among individuals) 10-min AEGL-3: C2×10 min=24,000 ppm2·min C=50 ppm 30-min AEGL-3: C2×30 min=24,000 ppm2·min C=28.3 ppm 1-h AEGL-3: 200 ppm/10=20 ppm 4-h AEGL-3: C2×240 min=24,000 ppm2·min C=10 ppm 8-h AEGL-3: C2×480 min=24,000 ppm2·min C=7.1 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLORINE (CAS No. 7782–50–5) DERIVATION SUMMARY AEGL-1 10 min 30 min 1 h 4 h 8 h 0.5 ppm 0.5 ppm 0.5 ppm 0.50 ppm 0.50 ppm Key references: (1) Rotman, H.H., M.J.Fliegelman, T.Moore, R.G.Smith, D.M.Anglen, C.J.Kowalski, and J.G.Weg. 1983. Effects of low concentrations of chlorine on pulmonary function in humans. J. Appl. Physiol. 54:1 120–1124. (2) Shusterman, D.J., M.A.Murphy, and J.R.Balmes. 1998. Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas. J. Allergy Clin. Immunol. 101:732–740. (3) D’Alessandro, A., W.Kuschner, H.Wong, H.A. Boushey, and P.D.Blanc. 1996. Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity. Chest 109:331–337. Test species/strain/number: Eight male subjects, one atopic subject (Rotman et al. 1983); eight atopic subjects and eight nonatopic subjects (Shusterman et al. 1998); five asthmatic subjects and five nonasthmatic subjects (D’Alessandro et al. 1996). Exposure route/concentrations/durations: Inhalation; 0.0, 0.5, 1.0 ppm for 8 h; break at 4 h for an unreported period of time to undergo pulmonary function tests followed by chamber reentry; subjects exercised for 15 min of every hour during exposures; sham exposures were included (Rotman et al. 1983) Inhalation; 0.0 ppm or 0.5 ppm for 15 min (Shusterman et al. 1998) Inhalation; 0.4 ppm or 1.0 ppm for 1 h (D’Alessandro et al. 1996) Effects: 0.5 ppm for 4 h—no effects in eight of nine subjects; transient changes in pulmonary functions in one of nine subjects. 1.0 ppm for 4 h—some irritation, transient changes in pulmonary functions in nine subjects including an atopic individual; asthma-like episode in one of nine subjects when exposure duration extended to more than 4 h (Rotman et al. 1983).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 0.5 ppm for 15 min—nasal congestion; nonsignificant changes in pulmonary peak flow (Shusterman et al. 1998). 0.4 ppm for 1 h—no statistically significant pulmonary function effect in asthmatic individuals (D’Alessandro et al. 1996). End point/concentration/rationale: 0.5 ppm forr 4 h resulted in no effects in healthy human subjects and transient changes in pulmonary functions for a susceptible individual who had obstructive airways disease prior to the exposure. The 0.5-ppm concentration was chosen as the basis for the AEGL-1 because the next highest concentration produced effects consistent with an AEGL-2 (coughing, wheezing, and a considerable increase in airways resistance) in a susceptible individual. Supported by studies of Shusterman et al. (1998) and D’Alessandro et al. (1996). Uncertainty factors/rationale: Total uncertainty factor: 1 Interspecies: Not applicable; human subjects tested. Intraspecies: 1. An atopic individual who had obstructive airways disease prior to the exposure and was considered characteristic of the “susceptible” population was tested. This individual was did not exhibit adverse effects. The choice of an intraspecies uncertainty factor of 1 is supported by another study in which a concentration of 0.4 ppm for 1 h was a no-effect concentration for changes in pulmonary function parameters in individuals with airway hyper-reactivity/asthma and by a study in asthmatic subjects exposed at 0.4 ppm Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable; human data used Time-scaling: Not applied; because 0.5 ppm appeared to be the threshold for more severe changes in pulmonary parameters in the atopic individual regardless of exposure duration, the 0.5 ppm was used for all AEGL-1 exposure durations. Data adequacy: The Angelen (1981) study was well conducted and documented and reinforces a study conducted earlier at the same facilities in which 31 male and female subjects were tested for sensory irritation. The Rotman et al. (1983) study went into greater detail than the earlier study, measuring 15 pulmonary function parameters before, during, and after exposures. Subjects were exercising during exposures and this study included a susceptible individual. The choice of intraspecies uncertainty factor was supported by a study of shorter duration with asthmatics.

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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 2.8 ppm 2.8 ppm 2.0 ppm 1.0 ppm 0.71 ppm Key references: (1) Rotman, H.H., M.J.Fliegelman, T.Moore, R.G. Smith, D.M.Anglen, C.J.Kowalski, and J.G.Weg. 1983. Effects of low concentrations of chlorine on pulmonary function in humans. J. Appl. Physiol. 54:1120–1124. (2) D’Alessandro, A., W.Kuschner, H.Wong, H.A. Boushey, and P.D.Blanc. 1996. Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity. Chest 109:331–337. Test species/strain/gender/number: Nine human male subjects, including atopic individual (Rotman et al. 1983); 10 human subjects of which five had airway reactivity/asthma (D’Alessandro et al. 1996) Exposure route/concentration/duration: Inhalation; 0.0, 0.5, 1.0 ppm for 8 h; break at 4 h for an unreported time period to undergo pulmonary function tests followed by chamber reentry; subjects exercised for 15 min of every hour during exposures; sham exposures were included (Rotman et al. 1983) Inhalation; 0.4 or 1.0 ppm for 1 h (D’Alessandro et al. 1996) Effects: 0.5 ppm for 4 h—no effects in eight healthy subjects; transient changes in pulmonary functions in one of nine subjects. 1.0 ppm for 4 h—some irritation, transient changes in pulmonary functions nine subjects including an atopic individual; asthma-like episode in one of nine subjects when exposure duration extended beyond 4 h. 1.0 ppm for 1 h—increased airway resistance in asthmatic individuals (D’Alessandro et al. 1996). End point/concentration/rationale: 1 ppm for 4 h was a no-effect exposure for serious health symptoms in an atopic exercising individual, and 1 ppm for 1 h was a symptomless effect on airway resistance in asthmatic individuals. However, the increase in airways resistance was considered the NOAEL for an AEGL-2 effect. Uncertainty factors/rationale: Total uncertainty factor: 1 Interspecies: Not applicable; human subjects tested. Intraspecies: 1. A susceptible exercising individual who had obstructive airways disease prior to the exposure and was considered characteristic of the “susceptible” population was tested. The application of an intraspecies uncertainty factor of 1 is supported by another study in which individuals with airway hyperreactivity/asthma

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 showed similar pulmonary function changes and some clinical symptoms but no asthma-like attack following exposure at 1.0 ppm for 1 h. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable; human data used Time-scaling: Cn×t=k where n=2. This value describes the concentration-exposure duration relationship for the end point of nuisance irritation (ten Berge and Vis van Heemst 1983, IChemE Symposium Series No. 80:17–21). Data adequacy: The Angelen (1981) study was well conducted and documented and reinforces a study conducted earlier at the same facilities in which 31 male and female subjects were tested for sensory irritation. The Rotman et al. (1983) study went into greater detail than the earlier study, measuring 15 pulmonary function parameters before, during, and after exposures. Subjects were exercising during exposures, and a susceptible individual was included. The choice of intraspecies uncertainty factor was supported by a study of shorter duration with asthmatic subjects (D’Alessandro et al. 1996).

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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 50 ppm 28 ppm 20 ppm 10 ppm 7.1 ppm Key references: (1) MacEwen, J.D. and E.H.Vernot. 1972, Toxic Hazards Research Unit Annual Technical Report. 1972. Wright-Patterson Air Force Base, Dayton, OH; (2) Zwart, A. and Woutersen. 1988. Acute inhalation toxicity of chlorine in rats and mice: time-concentration mortality relationships and effects on respiration. J. Hazard. Mater. 19:195–208; (3) O’Neil, C.E. 1991. Immune responsiveness in chlorine exposed mice. PB92-124478, Prepared for NIOSH, Cincinnati, OH. Test species/strain/gender/number: (1) Sprague-Dawley rats, 10/exposure group; (2) Wistar-derived rats, 10/exposure group; (3) BALB/c mice, 10/exposure group Exposure route/concentrations/durations: Inhalation; (1) 213–427 ppm for 1 h, (2) 322–595 ppm for 1 h, (3) 50–250 ppm for 1 h Effects: (1) no deaths at 213 ppm for 1 h (Sprague-Dawley rat); (2) no deaths at 322 ppm for 1 h (Wistar-derived rat); (3) no deaths at 150 ppm for 1 h (BALB/c mouse) End point/concentration/rationale: 200 ppm for 1 h (the estimated mean of highest experimental nonlethal values for the rat and mouse) was chosen as the basis for the 1-h AEGL-3. Mice appeared to be unusually sensitive to chlorine, and in some studies, delayed deaths were attributed to bronchopneumonia rather than direct effects of chlorine. Uncertainty factors/rationale: Total uncertainty factor: 10 Interspecies: 3. The mouse and rat LC50 values did not differ by more than a factor of 2 to 3, and the mouse was consistently more sensitive. In some mouse studies delayed deaths were attributed to bronchopneumonia rather than direct effects of chlorine exposure. Intraspecies: 3. Chlorine is a highly reactive, irritating, and corrosive gas whose effect on respiratory tissues is not expected to differ greatly among individuals. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applied Time-scaling: Cn×t=k where n=2. This value describes the concentration-exposure duration relationship for the end point of nuisance irritation (ten Berge and Vis van Heemst 1983, IChemE Symposium Series

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 No. 80:17–21). The irritation mechanism of action leads to pulmonary edema and potential lethality. An n of 2 is also relevant to animal lethality studies. Data adequacy: The database for chlorine is extensive with multiple studies of lethality conducted at several exposure durations and involving several species. Studies with multiple dosing regimens showed a clear dose-response relationship. Longer-term studies that support the safety of the values were also available. Tissue and organ pathology indicated that the toxic mechanism was the same across species.