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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 This page intentionally left blank.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 1 Chlorine Dioxide1 Acute Exposure Guideline Levels (AEGLs) PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/ AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 min to 8 h. Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain 1 This document was prepared by AEGL Development Team member Cheryl Bast of Oak Ridge National Laboratory along with Robert Benson (Chemical Manager), Bill Bress and Mark McClanahan (Chemical Reviewers) of the National Advisory Committee on Acute Exposure Guideline Levels for Hazardous Substances (NAC).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Chlorine dioxide (ClO2) is a yellow to reddish-yellow gas at room temperature. It has an unpleasant odor, similar to the odor of chlorine and reminiscent of nitric acid. It is a respiratory irritant. Pure chlorine dioxide is stable in the dark and unstable in light. Inhaled (airborne) chlorine dioxide acts primarily as a respiratory tract and ocular irritant. In air, chlorine dioxide readily dissociates both thermally and photochemically and may form chlorine, oxygen, hydrogen chloride, HClO3, HClO4.ClO, chlorine peroxide, and/or chlorine trioxide, dependent on temperature and humidity. Chlorine dioxide dissociates in water into chlorite and chloride, and to a lesser extent into chlorate (Budavari et al. 1996). The major use of chlorine dioxide is that of chemical pulp bleaching. Other uses include drinking water disinfection, the bleaching of textiles, flour, cellulose, leather, fats, oils, and beeswax; taste and odor control of water; as an oxidizing agent; and the in manufacture of chlorite salts (ACGIH

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 2001). In 2001, chlorine dioxide was used to decontaminate public buildings in the United States after the release of anthrax spores (ATSDR 2002). The acute inhalation database for chlorine dioxide is quite sparse for both human and animal exposures. The AEGL-1 was based on slight salivation, slight lacrimation, and slight chromodacryorrhea in rats exposed to 3 ppm chlorine dioxide for 6 h (DuPont 1955). A modifying factor of 2 was applied to account for the sparse data base. Interspecies and intraspecies uncertainty factors of 3 each were applied because chlorine dioxide is highly reactive and clinical signs are likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly between species or among individuals. Thus, the total uncertainty/modifying factor is 20. Using the default value of 10 for either intra- or interspecies variability would bring the total adjustment to 60 (total UF × MF) instead of 20. This would generate AEGL-1 values that are not supported by the total data set by yielding a value of 0.05 ppm, which is considered excessively low in light of the fact that no irritation was noted in rats exposed to 0.1 ppm chlorine dioxide 5 h/day for 10 weeks (Dalhamn 1957) and no irritation was noted in rats exposed at 5 ppm for 15 min, 2 or 4 times/day for 1 month (Paulet and Desbrousses 1974). The AEGL-1 value was held constant across all time points because minor irritation is not likely to be time dependent. The AEGL-2 was based on lacrimation, salivation, dyspnea, weakness, and pallor in rats exposed to 12 ppm chlorine dioxide for 6 h (DuPont 1955). Interspecies and intraspecies uncertainty factors of 3 each were applied because chlorine dioxide is highly reactive and clinical signs are likely caused by a direct chemical effect on the tissues; this type of port-of-entry effect is not expected to vary greatly between species or among individuals. A modifying factor of 2 was also applied to account for the sparse data base. Thus, the total uncertainty/modifying factor is 20. Using the default value of 10 for either intra- or interspecies variability would bring the total adjustment to 60 (total UF × MF) instead of 20. This would generate AEGL-2 values that are not supported by the total data set by yielding a 4-h AEGL-2 value of 0.23 ppm, yet rats repeatedly exposed to 3 ppm chlorine dioxide (Dupont 1955), 6 h/day for 10 days showed only minor irritation (slight salivation, slight lacrimation, and slight red ocular discharge on the first day of the study). This comparison shows that a combined uncertainty/modifying factor of 60 is excessively large. The concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 1986). To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n = 3 when extrapolating to shorter time points (30 min, 1 h, and 4 h) and n = 1 (8 h) when extrapolating to longer time points using the Cn × t = k equation. The 30-min AEGL-2 value was also adopted as the 10-min AEGL-2 value due to the added uncertainty of extrapolating from a 6-h time point to 10-min. The AEGL-3 was based on a study showing no deaths in rats exposed to 26 ppm chlorine dioxide for 6 h (DuPont 1955). Chlorine dioxide is highly reactive and causes serious adverse effects in the lung, including congestion and pulmonary edema. These effects are presumed to be the cause of death and are likely caused by a direct chemical effect on the tissue in the lung. As this effect is not expected to vary greatly among individuals or between species, intraspecies and interspecies uncertainty factors of 3 each were applied. A modifying factor of 2 was applied to account for the relatively sparse data base. Thus, the total uncertainty/ modifying factor is 20. Using the default value of 10 for either intra- or interspecies variability would bring the total adjustment to 60 (total UF × MF) instead of 20. This would generate AEGL-3 values that are not supported by the total data set by yielding a 4-h AEGL-3 value of 0.50 ppm. The value of 0.50 ppm is too low because it is below the 4-h AEGL-2 value of 0.69 ppm which was shown to be a reasonable lower limit of the disabling AEGL-2 value (see rationale above). The concentration-exposure time relationship for many irritant and systemically-acting vapors and gases may be described by Cn × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n = 3 when extrapolating to shorter time points (30 min, 1 h, and 4 h) and n = 1 (8 h) when extrapolating to longer time points using the Cn × t = k equation. The 30-min AEGL-3 value was also adopted as the 10-min AEGL-3 value due to the added uncertainty of extrapolating from a 6-h time point to 10 min. The proposed values appear in Table 1-1. I. INTRODUCTION Chlorine dioxide (ClO2) is a yellow to reddish-yellow gas at room temperature. It has an unpleasant odor, similar to the odor of chlorine and reminiscent of nitric acid. It is very reactive and a strong oxidizing agent. Pure chlorine dioxide is stable in the dark and unstable in light (Budavari

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 1-1 Summary Table of AEGL Values for Chlorine Dioxide (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 (Nondisabling) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) Slight salivation, slight lacrimation, and slight chromodacryorrhea in rats exposed to 3 ppm for 6 h (DuPont 1955) AEGL-2 (Disabling) 1.4 (3.9) 1.4 (3.9) 1.1 (3.0) 0.69 (1.9) 0.45 (1.2) Lacrimation, salivation, dyspnea, weakness, and pallor in rats exposed to 12 ppm for 6 h (DuPont 1955) AEGL-3 (Lethal) 3.0 (8.3) 3.0 (8.3) 2.4 (6.6) 1.5 (4.1) 0.98 (2.7) No lethality in rats exposed to 26 ppm for 6 h (DuPont 1955) et al. 1996). Inhaled (airborne) chlorine dioxide acts primarily as a respiratory tract and ocular irritant. In air chlorine dioxide gas readily decomposes both thermally and photochemically. Thermal decomposition is characterized by a slow induction period followed by a rapid autocatalytic phase that may be explosive if the initial concentration is above a partial pressure of 76 mm Hg. Unstable chlorine oxide may be formed as an intermediate, and the presence of water vapor is hypothesized to extend the duration of the induction period by reacting with the chlorine oxide intermediate. When water vapor concentrations are high, explosivity is minimized and all decomposition occurs in the induction phase; the water vapor inhibits the autocatalytic phase. The products of thermal decomposition of gaseous chlorine dioxide include chlorine, oxygen, hydrogen chloride, HClO3, and HClO4. The proportions of products formed depend on the ambient temperature and concentration of water vapor (Kaczur and Cawfield 1993). Photochemical decomposition of gaseous chlorine dioxide initially involves homolytic scission of the chlorine oxygen bond to form ClO and O. These products then generate secondary products including chlorine peroxide, chlorine, oxygen, and chlo-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 rine trioxide (Griese et al. 1992; Kaczur and Cawfield 1993). The chlorite ion does not persist in the atmosphere either in ionic form or as chlorite salt and is not likely to be inhaled. In aqueous media, chlorine dioxide is relatively unstable and dissociates in water into chlorite and chloride, and to a lesser extent into chlorate (Budavari et al. 1994. Chlorine dioxide is prepared from chlorine and sodium chlorite or potassium chlorate and sulfuric acid (Budavari et al. 1996). Chlorine dioxide is always made at the place where it is used because of the risk of rapid decomposition. The production volume of chlorine dioxide was estimated from the total sodium chlorate consumption for chemical pulp bleaching, as this use accounts for > 95% of all chlorine dioxide production. The annual production of chlorine dioxide in the United States was estimated to be 79, 81, 146, 226, and 361 kilotons for the years 1970, 1975, 1980, 1985, and 1990, respectively (ATSDR 2002). As stated above, the major use of chlorine dioxide is for chemical pulp bleaching. Other uses include drinking water disinfection and the bleaching of textiles, flour, cellulose, leather, fats, oils, and beeswax; taste and odor control of water; as an oxidizing agent; and in the manufacture of chlorite salts (ACGIH 2001). In 2001, chlorine dioxide was used to decontaminate public buildings in the United States after the release of anthrax spores (ATSDR 2002). Chemical and physical properties are listed in Table 1-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality A bleach tank worker died after exposure to 19 ppm chlorine dioxide for an undetermined duration; whereas, another worker exposed at the same time survived (Elkins 1959). No other details were reported. 2.2. Nonlethal Toxicity Elkins (1959) reported that 5 ppm chlorine dioxide was “definitely” irritating to humans. No other details were reported. Three odor thresholds have been reported for chlorine dioxide: 0.1 ppm (Ellenhorn and Barceloux 1988), 9.4 ppm (Amoore and Hautala 1983), and 15 ppm (Vincent et al. 1946). However, there are no reliable data to support these values.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 1-2 Chemical and Physical Data Parameter Value Reference Synonyms Chlorine peroxide: Chlorine oxide; Chlorine (IV) oxide IPCS, 1993 Molecular formula ClO2 Budavari et al. 1996 Molecular weight 67.45 Budavari et al. 1996 CAS Registry Number 10049-04-4 ACGIH, 2001 Physical state Gas Budavari et al. 1996 Color Yellow to reddish-yellow gas bluish-white liquid Budavari et al. 1996 Solubility in water 3.01 g/l at 25°C and 34 mmHg (decompose) Budavari et al. 1996 Vapor pressure 760 torr at 20°C ACGIH, 2001 Vapor density (air = 1) 2.3 ACGIH, 2001 Specific gravity 1.642 at 0°C (liquid) ACGIH, 2001 Melting point −59°C ACGIH, 2001 Boiling point 11°C ACGIH, 2001 Odor Unpleasant-similar to chlorine Budavari et al. 1996 Conversion factors 1 ppm = 2.76 mg/m3   Bronchitis and emphysema were reported in a 53-year-old chemist repeatedly exposed to low concentrations of chlorine dioxide over a period of several years and to higher concentrations in conjunction with three explosions (Petry 1954). Dyspnea of increasing severity and asthmatic bronchitis were reported apparently after cessation of the exposures. No exposure concentration was reported. A 49-year-old woman was exposed to an unknown concentration of chlorine dioxide accidentally generated while bleaching dried flowers (Exner-Friesfeld et al. 1986). She initially noticed a sharp, pungent smell and experienced coughing, pharyngeal irritation, and headache. Seven hours after exposure, she was hospitalized due to a worsening cough and dyspnea. Clinical findings included tachypnea, tachycardia, and rales on asculation. Clinical chemistry revealed marked leukocytosis. The chest x-ray was normal. The vital capacity and forced expiratory volume in 1 sec were decreased, to 73% and 70% of normal, respectively, and airway resistance was correspondingly increased. Blood gas examination revealed hypoxia despite alveolar hyperventilation. Symptoms resolved with corticosteroid treatment, and a follow-up examination two years post-exposure showed normal pulmonary function.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 In another case report, Meggs et al. (1995; 1996) evaluated 13 adults (12 females and 1 male) 5 years after an occupational exposure to chlorine dioxide associated with a leak in a water purification system pipe. No exposure concentration or duration data were presented. Observed long-term effects included sensitivity to respiratory irritants (13 people), disability accompanied by loss of employment (11 people), chronic fatigue (11 people), and nasal abnormalities, including talangectasia, paleness, edema, and thick mucous (13 people). Nasal biopsies from the exposed workers showed chronic inflammation with lymphocytes and plasma cells in 11 of the 13 people. This inflammation was described as mild in two persons, moderate in eight persons, and severe in one person. Nasal biopsies of three control subjects showed mild inflammation in one subject. The number of nerve fibers in biopsies from the exposed workers was greater than in biopsies from the control group. Gloemme and Lundgren (1957) studied 12 male employees who reported symptoms after they began work with chlorine dioxide at a sulfite-cellulose production factory. Spot samples of chlorine and chlorine dioxide during normal operations were generally <0.1 ppm. Occasional leaks from faulty vacuum lines would result in “high” levels of chlorine, chlorine dioxide, and/or sulfur dioxide. Chronic bronchitis was diagnosed in 7 of the 12 workers. The workers reported breathlessness, wheezing, irritant cough, and ocular discomfort associated with the leakages. Ferris et al. (1967) examined 147 men employed at a pulp mill; the length of employment was not reported. The workers were exposed to sulfur dioxide or chlorine and chlorine dioxide, with average chlorine dioxide concentrations ranging from 0 to 0.25 ppm and average chlorine concentrations ranging from 0 to 7.4 ppm. (Peak chlorine dioxide concentrations reached 2 ppm, and peak chlorine concentrations reached 64 ppm.) Shortness of breath, excess phlegm, and bronchitis were noted in the workers, with workers exposed to chlorine or chlorine dioxide exhibiting more severe symptoms than those exposed only to sulfur dioxide. Kennedy et al. (1991) compared health effects in 321 pulp mill workers exposed to chlorine dioxide and chlorine with 237 control workers at a rail yard. Personal time weighted average concentrations at the pulp mill were 5 to 14 ppm chlorine and <0.1 ppm chlorine dioxide. No air monitoring data from the rail yard were provided. Additionally, chlorine or chlorine dioxide “gassing” exposures from accidental releases were reported by 60% of the pulp mill workers. There were increased incidences of wheezing and breathlessness reported by pulp mill workers

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 compared to the rail yard workers; however, pulmonary function tests did not reveal any significant differences between the pulp mill workers and the rail yard controls. Airflow obstruction, as measured by FEV1, was increased (p < 0.05) in the pulp mill workers experiencing “gassing” incidents compared with those not experiencing “gassing” incidents. 2.3. Developmental/Reproductive Effects No data concerning developmental or reproductive effects of chlorine dioxide inhalation in humans were identified in the available literature; however, epidemiological studies of populations consuming chlorine dioxide- treated drinking water were located. A retrospective study was conducted using 1940s birth records from Chicopee, Massachusetts; this community utilized “relatively high” levels of chlorine dioxide for water disinfection (Tuthill et al. 1982). The morbidity and mortality experience of infants born in Chicopee was compared to that of infants born in Holyoke, Massachusetts, a geographically contiguous community that utilized traditional chlorination practices. There was no difference in fetal, neonatal, or infant mortality; or in birthweight, sex ratio or birth condition between infants born in the two communities. There was an apparent increase (p < 0.05) in the number of infants judged as premature by physician assessment in the chlorine-dioxide-exposed population (7.8%) compared with the control community (5.8%). However, there was no increase in prematurity when data were evaluated controlling for the age of the mother. In another study, Kanitz et al. (1996) conducted an epidemiological study comparing 548 infants born to mothers (Genoa, Italy) who had consumed water disinfected with chlorine dioxide (<0.3 mg/mL) and/or sodium hypochlorite with 128 infants born to mothers (Chiavari, Italy) who had consumed primarily untreated well water. There was a higher frequency of infants with small (≤49.5 cm) body length in mothers exposed to chlorinated water (chlorine dioxide adjusted odds ratio [OR] = 2.0 [95% CI = 1.2-3.3]; sodium hypochlorite OR = 2.3 [95% CI = 1.3-4.2]) compared with those exposed to well water. There was also a higher frequency of infants with small (≤35 cm) cranial circumference in mothers exposed to chlorinated water (chlorine dioxide adjusted OR = 2.2 [95% CI = 1.4-3.9]; sodium hypochlorite OR = 3.5 [95% CI = 2.1-8.5]) compared with those exposed to well water. There was also an approximate doubling of cases of neonatal jaundice in infants of mothers who consumed the disinfected water. The conclusions that can be drawn

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Elkins, H.B. 1959. The Chemistry of Industrial Toxicology. 2nd Edition. John Wiley & Sons, New York. Pp. 89-90. Ellenhorn, M.J. and Barceloux, D.G. (Eds). 1988. Medical Toxicology, diagnosis and treatment. Elsevier. New York. Exner-Freisfeld, H., Hronenberger, H., Meier-Sydow, J., and Nerger, K.H. 1986. Bleaching agent poisoning with sodium chlorite. The toxicology and clinical course. Dtsch. Med. Wochenschr. 111: 1927-1930. Ferris, B.G., Burgess, W.A., and Worcester, J. 1967. Prevalence of chronic respiratory diseases in a pulp mill and paper mill in the United States. Br. J. Ind. Med. 24: 26-37. Gloemme, J., and Lundgren, K.D. 1957. Health hazards from chlorine dioxide. Arch. Ind. Health. 16: 169-176. Griese, M.H., Kaczur, J.J, and Gordon, G. 1992. Combining methods for the reduction of oxychlorine residuals in drinking water. J. Amer. Water Works Asoc. 84:69-77. Haller, J.F. and Northgraves, W.W. 1955. Chlorine dioxide and safety. TAPPI. 38: 199-202. Hayashi, M., Kishi, M., Sofuni, T, Ishidate, M. 1988. Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. Food Chem. Toxicol. 26: 487-500. Hecht, A. 1950. Chlordioxyd- ein Gefahrliches Reizgas. Arch. Gewerbepath. U. Gewerbehyg. 13: 363-369. Farbwerke Bayer, Leverkusen. IPCS (International Programme on Chemical Safety). 1993. International Chemical Safety Card. Chlorine Dioxide. Ishidate, M., T. Sofani, K. Yoshikawa, M. Hayashi, T. Nohmi, M. Sawada and A. Matsuoka. 1984. Primary mutagenicity screening of food additives currently used in Japan. Food Chem. Toxicol. 22: 633-636. Kaczur, J.J., and Cawfield, D.W. 1993. Chlorine oxygen acids and salts (ClO2, HClO2). In: Kroschwitz, J.I., ed. Kirk-Othmer encyclopedia of chemical technology. Vol. 5. New York, NY: John Wiley & Sons, Inc. pp. 969-971. Kanitz, S., Franco, Y., Patrone, V., Caltabellotta, M., Raffo, E., Riggi, C., Timitilli, D, and Ravera, G. 1996. Association between drinking water disinfection and somatic parameters at birth. Environ. Health Perspect. 104: 516-520. Kennedy, S.M., Enarson, D.A., Janssen, R.G., and Chan-Yeung, M. 1991. Lung health consequences of reported accidental chlorine gas exposures among pulpmill workers. Am. Rev. Respir. Dis. 143: 74-79. Meggs, W.J., Elksheikh, T., Metzger, W.J., and Albernaz, M.S. 1995.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Nasal pathology of persistent rhinitis after chlorine dioxide exposure. J. Allergy & Clinical Immunology. 95:260. Meggs, W.J., Elksheikh, T., Metzger, W.J., Albernaz, M.S., and Bloch, R.M. 1996. Nasal pathology and ultrastructure in patients with chronic airway inflammation (RADS and RUDS) following an irritant exposure. J. Clinical Toxicology. 34: 383-396. Meier, J.R., Bull, R.J., Stober, J.A., and Cimino, M.A. 1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm-head abnormalities in mice. Environ. Mutagen. 7: 210-212. Miller, R.G., Kopler, F.C., and Condie, L.W. et al. 1986. Results of toxicological testing of Jefferson Parish pilot plant samples. Environ. Health Perspect. 69: 129-139. Mobley, S.A., Taylor, D.H., Laurie, R.D., et al. 1990. Chlorine dioxide depresses T3 uptake and delays development of locomotor activity in young rats. In: Jolley, R.L., et al., eds. Water chlorination: chemistry, environmental impact, and health effects, vol 6. Chelsea, MI: Lewis Publications, pp. 347-358. Moore, G.S., E.J. Calabrese, S.R. DiNardi and R.W. Tuthill. 1978. Potential health effects of chlorine dioxide as a disinfectant in potable water supplies. Med. Hypotheses 4: 481-496. NIOSH (National Institute for Occupational Safety and Health). 1997. NIOSH Pocket Guide to Chemical Hazards. Publication 94-116, U.S. Department of Health and Human Services; U.S. Government Printing Office, Washington, DC. Paulet, G. and Desbrousses, S. 1972. On the action of chlorine dioxide at low concentrations on laboratory animals. Arch. Mal. Med. Trav. Secur. Soc. 31: 97-106. Paulet, G. and Desbrousses, S. 1970. On the toxicology of chlorine dioxide. Arch. Mal. Med. Trav. Secur. Soc. 33: 59-61. Paulet, G. and Desbrousses, S. 1974. Action of discontinuous exposure to chlorine dioxide on the rat. Arch. Mal. Med. Trav. Secur. Soc. 35: 797-803. Petry, H. 1954. Chlordioxyd- ein Gefahrliches Reizgas. Arch. Gewerbepath. U. Gewerbehyg. 13: 363-369. Robinson, M., Bull, R.J., Schmaer, M., and Long, R.F. 1986. Epidermal hyperplasia in the mouse skin following treatment with alternate drinking water disinfectants. Environ. Health Perspect. 69: 293-300. 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.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 SDU Uitgevers 2000. Nationale MAC List (under the auspices of the Ministry of Social Affairs and Employment), The Hague, The Netherlands. Smith, R.P. and Wilhite, C.C. 1990. Chlorine dioxide and hemodialysis. Regul. Toxicol. Pharmacol. 11: 42-62. Suh, D.H., Abdel-Rahman, M.S., and Bull, R.J. 1983. Effect of chlorine dioxide and its metabolites in drinking water on fetal development in rats. J. Appl. Toxicol. 3: 75-79. Taylor, D.H. and Pfohl, R.J. 1985. Effects of chlorine dioxide on the neurobehavioral development of rats. In: Jolley, R.L., et al., eds. Water chlorination: chemistry, environmental impact, and health effects, vol 6. Chelsea, MI: Lewis Publications, pp. 355-364. Taylor, M.C., White, J.F., Vincent, G.P., and Cunningham, G.L. 1940. Sodium chlorite (Properties and reactions). Indust. Engin. Chem. 32: 899-903. 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. Toth, G.P., Long, R.E., Mills, T.S., and Smith, M.K. 1990. Effects of chlorine dioxide on the developing rat brain. J. Toxicol. Environ. Health. 31: 29-44. Tuthill, R.W., Giusti, R.A., Moore, G.S., et al. 1982. Health effects among newborns after prenatal exposure to Chlorine dioxide-disinfected water. Environ. Health Perspect. 46: 39-45. U.S. EPA (U.S. Environmental Protection Agency). 2000. Toxicological Review of Chlorine Dioxide and Chlorite. In Support of Summary Information on the Integrated Risk Information System (IRIS). September, 2000. EPA/635/R-00/007. Vincent, G.P., MacMahin, J.J., Synan, J.F. 1946. The use of chlorine dioxide in water treatment. Am. J. Public Health. 36: 1035-1037.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Key study: DuPont 1955 Toxicity end point: Slight lacrimation, slight salivation, and slight chromodacryorrhea in rats exposed to 3 ppm for 6 h. Scaling: None. Value was held constant across time points since minor irritation is unlikely to be time dependent. Uncertainty factors: 3 for interspecies   3 for intraspecies Modifying factor: 2 for sparse data base Total uncertainty/ modifying factor: 20   10 min, 30 min, 1 h, 4 h, 8 h: 3 ppm ÷ 20 = 0.15 ppm Derivation of AEGL-2 Key study: DuPont 1955 Toxicity end point: Lacrimation, salivation, dyspnea, weakness, and pallor in rats exposed to 12 ppm for 6 h. Scaling: C3 × t = k (default for long- to short-time extrapolation)   C1 × t = k (default for short- to long-time extrapolation)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Uncertainty factors: 3 for interspecies   3 for intraspecies Modifying factor: 2 for sparse database Total: 20 Scaling: C3 × t = k (30 min, 1 h, 4 h) (12 ppm)3 × 6 h = 10,368 ppm·h   C1 × t = k (8 h) (12 ppm)1 × 6 h = 72 ppm·h 10 min AEGL-2 1.38 ppm (The 30-min AEGL-2 is adopted as the 10-min value) 30 min AEGL-2 C3 × 0.5 h = 10,368 ppm·h   C3 = 20,736 ppm   C = 27.5 ppm   30 min AEGL-2 = 27.5 ÷ 20 = 1.38 ppm 1 h AEGL-2 C3 × 1 h = 10,368 ppm·h   C3 = 10,368 ppm   C = 21.8 ppm   1 h AEGL-2 = 21.8 ÷ 20 = 1.09 ppm 4 h AEGL-2 C3 × 4 h = 10,368 ppm·h   C3 = 2592 ppm   C = 13.7 ppm   4 h AEGL-2 = 13.7 ÷ 20 = 0.69 ppm 8 h AEGL-2 C1 × 8 h = 72 ppm·h   C1 = 9 ppm   8 h AEGL-2 = 9 ÷ 20 = 0.45 ppm Derivation of AEGL-3 Key study: DuPont 1955 Toxicity end point: No mortality in rats exposed to 26 ppm for 6 h. Scaling: C3 × t = k (default for long- to short-time

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5   extrapolation)   C1 × t = k (default for short- to long-timeextrapolation) Uncertainty factors: 3 for interspecies 3 for intraspecies Modifying factor: 2 for sparse database Total: 20 Scaling: C3 × t = k (30 min, 1 h, 4 h) (26 ppm)3 × 6 h = 105,456 ppm·h   C1 × t = k (8 h) (26 ppm)1 × 6 h = 156 ppm·h 10 min AEGL-3 2.98 ppm (The 30 min AEGL-3 is adopted as the 10-min value) 30 min AEGL-3 C3 × 0.5 h = 105,456 ppm·h C3 = 210912 ppm C = 59.5 ppm 30 min AEGL-3 = 59.5 ÷ 20 = 2.98 ppm 1 h AEGL-3 C3 × 1 h = 105,456 ppm·h C3 = 105,456 ppm C = 47.2 ppm 1 h AEGL-3 = 47.2 ÷ 20 = 2.36 ppm 4 h AEGL-3 C3 × 4 h = 105,456 ppm·h C3 = 26,364 ppm C = 29.8 ppm 4 h AEGL-3 = 29.8 ÷ 20 = 1.49 ppm 8 h AEGL-3 C1 × 8 h = 156 ppm·h C = 19.5 ppm 8 h AEGL-3 = 19.5 ÷ 20 = 0.975 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLORINE DIOXIDE (CAS No. 10049-04-4) DERIVATION SUMMARY AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h 0.15 ppm 0.15 ppm 0.15 ppm 0.15 ppm 0.15 ppm Key Reference: DuPont (1955). Summary of Toxicological Evaluations of Chlorine Dioxide. Haskell Laboratory for Toxicology and Industrial Medicine, Haskell Lab Report No. 80-55 E.I. du Pont de Nemours and Company, Inc., Wilmington, DE. Test Species/Strain/Number: Rat/Sprague-Dawley/male/4. Exposure Route/Concentrations/Durations: Inhalation/ 3 ppm/ 6 h. Effects: Slight lacrimation, slight salivation, slight chromodacryorrhea. End point/Concentration/Rationale: Slight lacrimation, slight salivation, slight chromodacryorrhea in rats exposed to 3 ppm for 6 h. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 Chlorine dioxide is highly reactive and clinical signs are likely caused by a direct chemical effect on the tissues. This type of port-of-entry effect not expected to vary greatly between species or among individuals. Using the default value of 10 for either intra- or interspecies variability would generate AEGL-1 values that are not supported by the total data set by yielding a value of 0.05 ppm, which is considered excessively low in light of the fact that no irritation was noted in rats exposed to 0.1 ppm chlorine dioxide 5 h/day for 10 weeks (Dalhamn 1957) and no irritation was noted in rats exposed at 5 ppm for 15 min, 2 or 4 times/day for 1 month (Paulet and Desbrousses 1974). Modifying Factor: 2—sparse database. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: AEGL-1 values were held constant across time points since minor irritation is unlikely to vary with time.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Data Adequacy: Data are extremely sparse. The AEGL-1 value is considered protective because no irritation was noted in rats exposed to 0.1 ppm chlorine dioxide 5 h/day for 10 weeks (Dalhamn, 1957) and no irritation was noted in rats exposed at 5 ppm for 15 min, 2 or 4 times/day for 1 month (Paulet and Desbrousses, 1974). AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 1.4 ppm 1.4 ppm 1.1 ppm 0.69 ppm 0.45 ppm Key Reference: DuPont (1955). Summary of Toxicological Evaluations of Chlorine Dioxide. Haskell Laboratory for Toxicology and Industrial Medicine, Haskell Lab Report No. 80-55 E.I. du Pont de Nemours and Company, Inc., Wilmington, DE. Test Species/Strain/Sex/Number: rat/Sprague-Dawley/male/4. Exposure Route/Concentrations/Durations: Inhalation, 12 ppm for 6 h. Effects: Lacrimation, salivation, dyspnea, weakness, and pallor. End point/Concentration/Rationale: Lacrimation, salivation, dyspnea, weakness, and pallor in rats exposed to 12 ppm for 6 h. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 Chlorine dioxide is highly reactive and clinical signs are likely caused by a direct chemical effect on the tissues. This type of port-of-entry effect is not expected to vary greatly between species or among individuals. Using the default value of 10 for either intra- or interspecies variability would generate AEGL-2 values that are not supported by the total data set by yielding a 4-h AEGL-2 value of 0.23 ppm, yet rats repeatedly exposed to 3 ppm chlorine dioxide (Dupont, 1955), 6 h/day for 10 days showed only minor irritation (slight salivation, slight lacrimation, and slight red ocular discharge on the first day of the study). Modifying Factor: 2—sparse database. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: Cn × t = k, where the exponent, n, is the conservative default of 1 and k is 72 ppm·h (8 h) or 3 and k is 10,368 ppm·h (30 min, 1 h, 4 h). The 30-min AEGL-2 value was adopted as the 10-min value. Data Adequacy: Both human and animal data are extremely sparse.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 3.0 ppm 3.0 ppm 2.4 ppm 1.5 ppm 0.98 ppm Key Reference: DuPont (1955). Summary of Toxicological Evaluations of Chlorine Dioxide. Haskell Laboratory for Toxicology and Industrial Medicine, Haskell Lab Report No. 80-55 E.I. du Pont de Nemours and Company, Inc., Wilmington, DE. Test Species/Strain/Sex/Number: rat/Sprague-Dawley/male/2 or 4 Exposure Route/Concentrations/Durations: Inhalation, 54 ppm for 1 h, 38ppm for 4.5-6 h, 26 ppm for 6 h. Effects: 54 ppm, 1 h: death of 2/2 rats 38 ppm, 4.5-6 h: death of 2/2 rats 26 ppm, 6 h: No deaths of 4/4 rats End point/Concentration/Rationale: No mortality/26 ppm for 6 h. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 Chlorine dioxide is highly reactive and causes serious adverse effects in the lung, including congestion and pulmonary edema. These effects are presumed to be the cause of death and are likely caused by a direct chemical effect on the tissue in the lung. This effect is not expected to vary greatly between species or among individuals. Using the default value of 10 for either intra- or interspecies variability would generate AEGL-3 values that are not supported by the total data set by yielding a 4-h AEGL-3 value of 0.50 ppm. The value of 0.50 ppm is too low because it is below the 4-h AEGL-2 value of 0.69 ppm which was shown to be a reasonable lower limit for the disabling AEGL-2 value. Modifying Factor: 2—sparse database. Animal to Human Dosimetric Adjustment: Insufficient data. Time Scaling: Cn × t = k, where the exponent, n, is the conservative default of 1 and k is 156 ppm·h (8 h) or 3 and k is 105,456 ppm·h (30 min, 1 h, 4 h). The 30 min AEGL-3 value was adopted as the 10-min value. Data Adequacy: Both human and animal data are extremely sparse.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX C CATEGORY PLOT FOR CHLORINE DIOXIDE

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 FIGURE C-1 Chemical toxicity—TSD all data, chlorine dioxide.