The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry

Developmental Effects. Neurodevelopmental effects, such as decreases in brain weight, brain cell number, exploratory behavior, and locomotor activity, have been observed in rat pups whose mothers were exposed to chlorine dioxide before mating and during gestation and lactation and other rat pups that were directly exposed via oral gavage only during postnatal development. Decreases in exploratory behavior and amplitude of auditory startle response have been reported in rat pups whose mothers were orally exposed to chlorite during gestation and lactation. Perinatal exposure to chlorine dioxide or chlorite has also resulted in altered serum thyroid hormone levels or activity. Although mechanisms of action responsible for mediating these chlorine dioxide- and chlorite-mediated thyroid hormone effects have not been identified, it is widely understood that the thyroid hormone, T3, is essential for normal development of the nervous system, and that T3 is synthesized from the deiodination of T4.

2.3 MINIMAL RISK LEVELS

Inhalation MRLs

An acute-duration inhalation MRL was not derived for chlorine dioxide because adequate human or animal data are not available.

No inhalation MRLs were derived for chlorite. The only available information regarding health effects following inhalation exposure to chlorite was limited to a single study of lethality in rats exposed to aerosols of sodium chlorite, an exposure scenario not likely to be encountered in environmental or occupational settings. Furthermore, lethality is a serious effect, and therefore cannot be used as the basis for deriving an MRL.

• An MRL of 0.001 ppm (0.003 mg/m³) has been derived for intermediate-duration inhalation exposure (15–365 days) to chlorine dioxide.

This MRL is based on a lowest-observed-adverse-effect-level (LOAEL) of 1 ppm for respiratory effects in rats. Paulet and Desbrousses (1970) exposed groups of 10 rats/sex (strain not specified) to chlorine dioxide vapors at concentrations of 0 or 2.5 ppm, 7 hours/day for 30 days. Chlorine dioxide-exposed rats exhibited respiratory effects that included lymphocytic infiltration of the alveolar spaces, alveolar vascular congestion, hemorrhagic alveoli, epithelial erosions, and inflammatory infiltrations of the bronchi. The study authors also reported slightly decreased body weight gain, decreased erythrocyte levels, and increased leukocyte levels, relative to controls. Recovery from the pulmonary lesions was apparent in rats examined after a 15-day recovery period. In a follow-up study designed to examine a lower exposure level (Paulet and Desbrousses 1972), eight Wistar rats (sex not reported) were exposed to chlorine dioxide vapors at a concentration of 1 ppm, 5 hours/day, 5 days/week for 2 months. The authors stated that weight gain and erythrocyte and leukocyte levels were not affected. Chlorine dioxide-induced respiratory effects included peribronchiolar edema and vascular congestion in the lungs. No alterations in epithelium or parenchyma were seen.

Collectively, these studies adequately identify a LOAEL for respiratory effects associated with intermediate-duration inhalation exposure to chlorine dioxide. The intermediate-duration inhalation MRL for chlorine dioxide was based on the LOAEL of 1 ppm identified in the Paulet and Desbrousses (1972) study, which was adjusted to 0.15 ppm (LOAELADJ) to compensate for intermittent exposure, converted to the human equivalent concentration (LOAELHEC) of 0.3 ppm, and then divided by an uncertainty factor of 300 (3 for interspecies extrapolation using dosimetric adjustments, 10 for the use of a LOAEL, and 10 to account for sensitive populations).

A chronic-duration inhalation MRL was not derived for chlorine dioxide because chronic inhalation exposure studies in humans or animals are not available. An approach using an uncertainty factor for extrapolating from intermediate- to chronic-duration exposure was not used because it is not known whether respiratory irritation, observed during intermediate-duration inhalation exposure to chlorine dioxide, might result in more persistent effects in cases of chronic-duration exposure. Furthermore, it is not likely that humans would be chronically exposed to significant concentrations of chlorine dioxide vapors in environmental or occupational settings.

Oral MRLs

Acute-duration oral MRLs were not derived for chlorine dioxide or chlorite because adequate human or animal data are not available.

• An MRL of 0.1 mg/kg/day has been derived for intermediate-duration oral exposure (15– 364 days) to chlorite.

This MRL is based on a no-observed-adverse-effect-level (NOAEL) of 2.9 mg chlorite/kg/day and a LOAEL of 5.7 mg chlorite/kg/day for neurodevelopmental effects (lowered auditory startle amplitude) in rat pups that had been exposed throughout gestation and lactation via their mothers (Gill et al. 2000). Groups of 30 male and 30 female Sprague-Dawley rats (F0) received sodium chlorite in the drinking water at concentrations of 35, 70, or 300 mg/L (approximate chlorite doses of 3, 5.7, and 21 mg/kg/day for males and 3.9, 7.6, and 29 mg/kg/day for females) for 10 weeks prior to mating and during mating, after which exposure of females continued throughout gestation and lactation. Groups of F1 pups were continued on the same treatment regimen as their parents (chlorite doses of 2.9, 6, and 23 mg/kg/day and 3.9, 7.6, and 29 mg/kg/day for F1 males and females, respectively). Low-dose female pups exhibited slight, but statistically significant differences in some hematological parameters, relative to controls. No other effects were seen in pups of this exposure level, and the hematological effects were not considered to be adverse. A significant decrease in maximum response to an auditory startle stimulus was noted in mid-dose pups on postnatal day 24, but not on postnatal day 60. Mid-dose F1 pups also exhibited reduced liver weight. Significant effects at high dose included reduced absolute and relative liver weight in F1 males and females, reduced pup survival, reduced body weight at birth and throughout lactation in F1 and F2 rats, lower thymus and spleen weight in both generations, lowered incidence of pups exhibiting normal righting reflex and with eyes open on postnatal day 15, decreased in absolute brain weight for F1 males and F2 females, delayed sexual development in F1 and F2 males (preputial separation) and F1 and F2 females (vaginal opening), and lowered red blood cell parameters in F1 rats. The NOAEL of 2.9 mg/kg/day was divided by an uncertainty factor of 30 (10 for interspecies extrapolation and 3 to account for sensitive populations). An uncertainty factor of 3 rather than 10 was used for sensitive populations because the critical effect (neurodevelopmental delay) occurred in a sensitive population (perinatal rat pups).

Chlorine dioxide in drinking water rapidly degrades, predominately to chlorite (Michael et al. 1981). In laboratory animals, orally administered chlorine dioxide is rapidly converted to chlorite and chloride ion (Abdel-Rahman et al. 1980b). Being both a strong oxidizer and water soluble, chlorine dioxide is not likely absorbed in the gastrointestinal tract to any great extent. Chlorite is the most likely source of systemic toxicity resulting from oral exposure to either chlorine dioxide or chlorite. Therefore, the intermediate-duration oral MRL derived for chlorite should also be applicable to chlorine dioxide.

Chronic-duration oral MRLs were not derived for chlorine dioxide or chlorite. No human studies were available in which chronic oral exposure to chlorine dioxide or chlorite was evaluated, and available chronic-duration oral studies in animals identified LOAELs that were higher than those observed for developmental effects following exposures of significantly shorter duration.

 

3. HEALTH EFFECTS

3.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of chlorine dioxide and chlorite. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for chlorine dioxide and chlorite. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised.

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

3.2.1 Inhalation Exposure

Available human and animal data indicate that airborne chlorine dioxide (ClO2) primarily acts as a respiratory tract and ocular irritant. Chlorite (ClO2^-) does not persist in the atmosphere either in ionic form or as chlorite salt. Available information concerning health effects associated with inhalation exposure is limited to chlorine dioxide.

3.2.1.1 Death

Information regarding death in humans exposed to atmospheres of chlorine dioxide is limited to a single case in which a bleach tank worker died after being exposed for an unspecified amount of time (Elkins 1959). A chlorine dioxide vapor concentration of 19 ppm (52.4 mg/m³) was measured inside the tank.

Limited information is available regarding death in laboratory animals exposed to atmospheres of chlorine dioxide. Death resulted from the exposure of a single guinea pig for 44 minutes to an airborne chlorine dioxide concentration of 150 ppm (420 mg/m³); at the same concentration, exposure for 5 or 15 minutes was not lethal (Haller and Northgraves 1955).

Dalhamn (1957) exposed four rats to approximately 260 ppm (728 mg/m³) of chlorine dioxide for 2 hours. One of the rats died during exposure and the remaining three rats were sacrificed immediately following the 2-hour exposure period. Microscopic examination revealed pulmonary edema and circulatory engorgement. Dalhamn (1957) also reported death in three of five rats exposed to approximately 10 ppm (28 mg/m³) of chlorine dioxide, 4 hours/day for up to nine exposures in a 13-day period; clinical signs of toxicity included rhinorrhea and altered respiration.

In another study, rats were repeatedly exposed for 1 month (15 minutes/exposure, 2 or 4 times/day) to atmospheres containing 15 ppm (42 mg/m³) of chlorine dioxide (Paulet and Desbrousses 1974). Death was noted in 1/10 and 1/15 rats exposed 2 or 4 times/day, respectively. Histological examination of the exposed rats revealed nasal and ocular inflammation, bronchitis, and alveolar lesions. No deaths occurred in rats similarly exposed to 10 ppm (28 mg/m³) of chlorine dioxide.

3.2.1.2 Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for each systemic effect in each species and duration are recorded in Table 3-1 and plotted in Figure 3-1.

No reports were located in which gastrointestinal, musculoskeletal, endocrine, dermal, or metabolic effects were associated with inhalation exposure of humans or animals to chlorine dioxide or chlorite.

Respiratory Effects. Limited human data indicate that airborne chlorine dioxide is a primary respiratory tract irritant. In a case of accidental inhalation exposure to chlorine dioxide in the paper industry, exposure to 5 ppm (14 mg/m³) for an unspecified amount of time was reported to be irritating (Elkins 1959). In another case report, a woman experienced coughing, pharyngeal irritation, and headache while mixing a bleach solution that was then used to bleach dried flowers (Exner-Freisfeld et al. 1986). The mixing process resulted in the release of chlorine dioxide. Increasing cough caused the woman to abandon the bleaching process. Seven hours later, the woman began experiencing intensified coughing and dyspnea that resulted in hospitalization (16 hours after the exposure) with clinical findings of cough, dyspnea, tachypnea, and rales. Pulmonary function tests revealed reduced VC (vital capacity) and FEV1 (forced expiratory volume in 1 second) values and increased resistance. Blood gas analysis and blood chemistry revealed hypoxemia and leukocytosis, respectively. Corticosteroid treatment resulted in the alleviation of clinical signs and improved lung function, which was in the normal range at the 2-year follow-up examination.

Nasal abnormalities (including injection, telangectasia, paleness, cobblestoning, edema, and thick mucus) were observed in 13 individuals (1 man and 12 women) who had been accidentally exposed to chlorine dioxide from a leak in a water purification system pipe 5 years earlier (Meggs et al. 1996). These individuals also exhibited sensitivity to respiratory irritants. Nasal biopsies revealed chronic inflammation in the lamina propria of 11/13 chlorine dioxide-exposed individuals, compared with 1/3 control individuals. The severity of inflammation was significantly increased in the chlorine dioxide exposed group, compared to controls.

Several investigators examined the respiratory health of workers who had been occasionally exposed to increased levels of chlorine dioxide resulting from equipment failure (Ferris et al. 1967, 1979; Gloemme and Lundgren 1957; Kennedy et al. 1991). Since the results of these studies are confounded by concurrent exposure to chlorine gas and/or sulfur dioxide, the reported respiratory effects (such as coughing, wheezing, shortness of breath, and excess phlegm) could not be specifically attributed to chlorine dioxide.

Animal studies also indicate that the respiratory system is a major target of toxicity following inhalation exposure to chlorine dioxide. Dalhamn (1957) reported the results of several inhalation studies in laboratory animals. In one study, a single 2-hour inhalation exposure of four rats to a chlorine dioxide concentration of 260 ppm (728 mg/m³) resulted in pulmonary edema and nasal bleeding. Respiratory distress was reported in three other rats subjected to 3 weekly 3-minute exposures to decreasing concentrations of airborne chlorine dioxide from 3,400 to 800 ppm (from 9,520 to 2,240 mg/m³); bronchopneumonia was observed in two of these rats. In a third rat study, repeated exposure to approximately 10 ppm (28 mg/m³) of chlorine dioxide (4 hours/day for 9 days in a 13-day period) resulted in rhinorrhea, altered respiration, and respiratory infection. No indications of adverse effects were seen in rats exposed to approximately 0.1 ppm (0.28 mg/m³) of chlorine dioxide 5 hours/day for 10 weeks.

Paulet and Desbrousses (1970, 1972, 1974) conducted a series of studies in which laboratory animals were exposed to atmospheres of chlorine dioxide. Nasal discharge and localized bronchopneumonia (with desquamation of alveolar epithelium) were noted in rats exposed to an airborne concentration of 10 ppm (28 mg/m³), 2 hours/day for 30 days. Similar, but less severe, respiratory tract effects were observed in another group of rats exposed to a concentration of 5 ppm (14 mg/m³), 2 hours/day for 10 days. Bronchial inflammation and alveolar congestion and hemorrhage were observed in rats exposed to 2.5 ppm (7 mg/m³), 7 hours/day for 30 days. Alveolar congestion and hemorrhage were also seen in rabbits following inhalation exposure to 2.5 ppm (7 mg/m³), 4 hours/day for 45 days. In a group of rats and rabbits sacrificed 15 days after exposure termination, recovery from the pulmonary lesions was apparent (Paulet and Desbrousses 1970). Vascular congestion and peribronchiolar edema were noted in the lungs of rats exposed to a concentration of 1 ppm (2.8 mg/m³), 5 hours/day, 5 days/week for 2 months (Paulet and Desbrousses 1972). The LOAEL of 1 ppm for respiratory effects, identified in this study, served as the basis for the derivation of an intermediate-duration inhalation MRL for chlorine dioxide (see Section 2.3). In another rat study, exposure to concentrations of 10 or 15 ppm (28 or 42 mg/m³) for periods as short as 15 minutes (2 or 4 times/day for 1 month) resulted in nasal, bronchial, and alveolar inflammation. These effects had subsided in a 15 ppm (42 mg/m³) group of rats sacrificed 15 days following exposure termination. This study identified a NOAEL of 5 ppm (14 mg/m³) for respiratory effects (Paulet and Desbrousses 1974).

Cardiovascular Effects. Information regarding cardiovascular effects in humans following inhalation exposure to chlorine dioxide is limited to a single account of tachycardia that developed in a woman several hours after having been exposed to an unknown concentration of chlorine dioxide that had triggered respiratory effects severe enough to force her to leave the area where she had been bleaching dried flowers (Exner-Freisfeld et al. 1986). The tachycardia was likely secondary to the primary respiratory effects.

Circulatory engorgement was observed in rats that had been exposed to atmospheres containing a chlorine dioxide concentration of approximately 260 ppm (728 mg/m³) for 2 hours (Dalhamn 1957). This effect was likely secondary to respiratory distress.

Hematological Effects. Information regarding hematological effects in humans following inhalation exposure to chlorine dioxide is limited to a single account of marked leukocytosis diagnosed in a woman several hours after she had been exposed to an unknown concentration of chlorine dioxide that triggered respiratory effects severe enough to force her to leave the area where she had been bleaching dried flowers (Exner-Freisfeld et al. 1986).

Significantly increased blood erythrocyte and leukocyte levels were reported in rats exposed to atmospheres containing a chlorine dioxide level of approximately 10 ppm (28 mg/m³), 2 hours/day for 30 days (Paulet and Desbrousses 1970). These effects were not seen in a group of rats exposed to 5 ppm (14 mg/m³), 2 hours/day for 10 days.

Hepatic Effects. No information was located regarding hepatic effects in humans following inhalation exposure to chlorine dioxide.

Paulet and Desbrousses (1974) found no signs of liver effects in rats exposed to atmospheres containing chlorine dioxide levels as high as 10 ppm (28 mg/m³), 2 hours/day for 30 days. On the other hand, Dalhamn (1957) reported acute liver congestion in rats that had been exposed to atmospheres of approximately 10 ppm of chlorine dioxide for 4 hours/day over 9 days in a 13-day period. However, the liver congestion may have been secondary to primary respiratory effects.

Renal Effects. No information was located regarding renal effects in humans following inhalation exposure to chlorine dioxide.

Evidence of renal effects in animals is limited to a single report of renal hyperemia in two of three rats subjected to 3 weekly 3-minute exposures to decreasing concentrations of airborne chlorine dioxide from 3,400 to 800 ppm (from 9,520 to 2,240 mg/m³); however, two of three control rats similarly exhibited renal hyperemia (Dalhamn 1957).

Ocular Effects. Workers employed at a sulfite-cellulose production facility reported ocular discomfort that was associated with periods when equipment failure resulted in relatively high air concentrations of chlorine dioxide (Gloemme and Lundgren 1957). However, this finding was confounded by concurrent exposure to chlorine gas and sulfur dioxide.

Animal studies indicate that exposure to chlorine dioxide at airborne concentrations ≥10 ppm (28 mg/m³) may result in ocular irritation (Dalhamn 1957; Paulet and Desbrousses 1970, 1974).

Body Weight Effects. No information was located regarding body weight effects in humans following inhalation exposure to chlorine dioxide.

Limited animal data indicate that repeated inhalation exposure to chlorine dioxide concentrations ≥10 ppm (28 mg/m³) may result in depressed body weight gain (Dalhamn 1957; Paulet and Desbrousses 1970); however, this effect may be secondary to primary respiratory effects.

No reports were located in which the following health effects in humans or animals could be associated with inhalation exposure to chlorine dioxide:

3.2.1.3 Immunological and Lymphoreticular Effects

3.2.1.4 Neurological Effects

3.2.1.5 Reproductive Effects

3.2.1.6 Developmental Effects

3.2.1.7 Cancer

3.2.2 Oral Exposure

3.2.2.1 Death

No information was located regarding death in humans following oral exposure to chlorine dioxide or chlorite.

Shi and Xie (1999) indicated that an acute oral LD50 value (a dose expected to result in death of 50% of the dosed animals) for stable chlorine dioxide was >10,000 mg/kg in mice. In rats, acute oral LD50 values for sodium chlorite (NaClO2) ranged from 105 to 177 mg/kg (equivalent to 79–133 mg chlorite/kg) (Musil et al. 1964; Seta et al. 1991; Sperling 1959).