Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 5 (2007) / Chapter Skim
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Appendix 1 Chlorine Dioxide Acute Exposure Guideline Levels (AEGLs)
Appendix 1 Chlorine Dioxide Acute Exposure Guideline Levels (AEGLs)
Pages 11-52
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Appendixes
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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.
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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.
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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)
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. 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)
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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.
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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)
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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.
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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.
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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.
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Information on developmental/ reproductive effects was available only for the oral route of exposure from disinfected drinking water and these studies contain many confounding variables, making it impossible to definitively attribute the effects to chlorine dioxide. No genotoxicity or carcinogenicity data were located.
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TABLE 1-3 Summary of Acute Lethal Inhalation Data in Laboratory Animals Species Concentration (ppm) Exposure Time Effect Clinical Signs/Comment Reference Rat 54 1h Death during exposure Cyanosis, dyspnea, salivation, lacrimation, DuPont 1955 chromodacryorrhea Rat 38 4.5-6 h Death 4.5 h into exposure and 24-h post exposure Rat 26 6h No mortality Rat 260 4h Death 1 h into exposure Ocular discharge, epistaxis, pulmonary Dalhamn 1957 edema, circulatory engorgement Rat 10 4 h/day x 9 days (over 13 Death after 10-13 days Decreased body weight (2nd day)
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24 TABLE 1-3 Continued Species Concentration (ppm) Exposure Time Effect Clinical signs/ Comment Reference Mouse 70 30 min Death Animals died night following exposure Mouse 35 6h Death -- Mouse 20 2h No mortality No signs reported Mouse 10 1h No mortality No signs reported Guinea pig 150 44 min Death Death occurred during exposure Haller & Northgraves Guinea pig 150 5-15 min Death Death occurred 5-15 min post- exposure 1955 Guinea pig 1,000 3 min Death -- Guinea pig 150 45 min Death Taylor et al.
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Death was attributed to pulmonary congestion and edema observed at necropsy. No lethality was noted in a group of four rats exposed to 26 ppm chlorine dioxide for 6 h (DuPont 1955)
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reported that rats exposed to 35 ppm chlorine dioxide for 6 h died. No deaths were reported in rats exposed to 70 ppm for 30 min, 20 ppm for 2 h, or 10 ppm for 1 h.
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Clinical signs observed on the first day of the study included slight salivation, slight lacrimation, and slight chromodacryorrhea. These signs increased in severity with repeated exposures.
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to 0, 5, 10, or 15 ppm chlorine dioxide, 15 min, 2 or 4 times/day for 1 month. At 15 ppm, mortality was observed in 1/10 rats exposed 2 times/day and in 1/15 rats exposed 4 times/day.
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Taylor and Pfohl (1985) administered 0 or 100 ppm chlorine dioxide to female Sprague-Dawley rats in the drinking water 14 days prior to gestation and throughout gestation and lactation.
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In a dermal exposure study, the dorsal area of groups of five female SENCAR mice were shaved and the mice were placed in chambers containing 0, 1, 10, 100, 300, or 1000 ppm chlorine dioxide dissolved in water, 10 min/day for 4 days (Robinson et al.
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. The metabolic pathways of inhaled and ingested chlorine dioxide are likely different because chlorine dioxide dissociates in air to form chlorine, oxygen, hydrogen chloride, HClO3, HClO4.ClO, chlorine per
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and because chlorite does not persist in the atmosphere either in the ionic form or as the chlorite salt. Given the fact that gaseous chlorine dioxide readily decomposes, it is unlikely that chlorite would be formed from parent chlorine dioxide in the aqueous mucus of the upper respiratory tract; and if the chlorite were to form, it is unlikely that a sufficient amount would be absorbed to induce toxic effects similar to those noted after ingestion of chlorine dioxide in aqueous media.
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. Therefore, the use of information regarding exposure to chlorine dioxide in aqueous media is limited for the purposes of derivation of AEGL values for inhalation exposure.
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To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling will be performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation.
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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)
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Interspecies and intraspecies uncertainty factors of 3 each will be 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 will also be applied to account for the sparse data base.
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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.
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. 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)
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(2.7 mg/m3) TABLE 1-7 Summary of AEGL Values for Chlorine Dioxide (ppm [mg/m3]
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It is noted that subchronic animal data may support a higher value. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life-threatening health effects.
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1991. Reproductive effects on Long-Evans rats exposed to chlorine dioxide.
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1967. Prevalence of chronic respiratory diseases in a pulp mill and paper mill in the United States.
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1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm-head abnormalities in mice.
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1983. Effect of chlorine dioxide and its metabolites in drinking water on fetal development in rats.
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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, weak ness, and pallor in rats exposed to 12 ppm for 6 h.
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C3 × 0.5 h = 10,368 ppm·h 30 min AEGL-2 C3 = 20,736 ppm C = 27.5 ppm 30 min AEGL-2 = 27.5 ÷ 20 = 1.38 ppm C3 × 1 h = 10,368 ppm·h 1 h AEGL-2 C3 = 10,368 ppm C = 21.8 ppm 1 h AEGL-2 = 21.8 ÷ 20 = 1.09 ppm C3 × 4 h = 10,368 ppm·h 4 h AEGL-2 C3 = 2592 ppm C = 13.7 ppm 4 h AEGL-2 = 13.7 ÷ 20 = 0.69 ppm C1 × 8 h = 72 ppm·h 8 h AEGL-2 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. C3 × t = k (default for long- to short-time Scaling:
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Uncertainty factors: 3 for interspecies 3 for intraspecies Modifying factor: 2 for sparse database Total: 20 C3 × t = k (30 min, 1 h, 4 h) Scaling: (26 ppm)
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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)
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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)
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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.
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52 Chemical Toxicity - TSD All Data Chlorine Dioxide 1000 Human - No Effect Human - Discomfort Human - Disabling 100 Animal - No Effect Animal - Discomfort 10 ppm Animal - Disabling AEGL-3 Animal - Some Lethality 1 AEGL-2 Animal - Lethal AEGL-1 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Chemical toxicity -- TSD all data, chlorine dioxide.
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