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No exposure-related deaths were observed in rats receiving chlorine dioxide in the drinking water for 90 days at concentrations that resulted in approximate doses as high as 11.5 mg/kg/day in males and

14.9 mg/kg/day in females (Daniel et al. 1990).

In a 14-day range-finding study of rats administered gavage doses of sodium chlorite in the range of 25– 200 mg/kg/day (equivalent to 18.6–149.2 mg chlorite/kg/day), one exposure-related death was observed in each sex (Harrington et al. 1995a). The deaths occurred in the 200 mg/kg/day group on treatment days 2 and 3. No treatment-related deaths occurred in the groups receiving chlorite doses ≤56 mg/kg/day. In the 13-week main study performed by these investigators, treatment-related mortality was noted between exposure weeks 10 and 13 in 4/30 rats (3 males and 1 female) receiving sodium chlorite by gavage at a level resulting in a chlorite dose of 80 mg/kg/day. No treatment-related mortality was observed at chlorite dose levels 18.6 mg/kg/day. Death was noted in all four female rats that were administered sodium chlorite by gavage at a dose level of 200 mg/kg/day (equivalent to 150 mg chlorite/kg/day) on gestation days 8–10 (Couri et al. 1982b).

Haag (1949) exposed groups of rats to chlorine dioxide in the drinking water for 2 years at concentrations that resulted in estimated doses of 0.07, 0.13, 0.7, 1.3, or 13 mg/kg/day. The results did not indicate any significant differences in mortality between controls and treated groups up to the highest exposure level tested. Survival was not significantly decreased in groups of rats exposed to chlorite (as sodium chlorite) in the drinking water for 2 years at concentrations that resulted in estimated chlorite doses as high as 81 mg/kg/day (Haag 1949). In another chronic study (Kurokawa et al. 1986), survival was not adversely affected in rats given sodium chlorite in the drinking water at concentrations that resulted in estimated chlorite doses as high as 32.1 mg/kg/day in males and 40.9 mg/kg/day in females. This study was terminated after 85 weeks of treatment, due to widespread Sendai viral infection in both treatment groups and controls. Exposure of mice to sodium chlorite for up to 85 weeks at concentrations resulting in estimated chlorite doses as high as 90 mg/kg/day did not appear to adversely affect survival. However, control males exhibited markedly reduced survival after 30 weeks of exposure, which was attributed to severe fighting (Kurokawa et al. 1986).

The only available LD50 value for chlorite is recorded in Table 3-2 and plotted in Figure 3-2.

3.2.2.2 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 3-2 and plotted in Figure 3-2.

No reports were located in which cardiovascular, musculoskeletal, dermal, ocular, or metabolic effects were associated with oral exposure of humans or animals to chlorine dioxide or chlorite.

Respiratory Effects. Extremely limited information is available regarding respiratory effects in humans following oral exposure to chlorine dioxide or chlorite. Respiratory distress was diagnosed in a patient who had ingested 10 g of sodium chlorite dissolved in 100 mL of water (Lin and Lim 1993). However, the respiratory distress was likely secondary to other effects such as severe methemoglobinemia. No adverse effects on respiration rate were seen in healthy adult males who ingested chlorine dioxide or chlorite every 3 days (for 16 days) at increasing doses of 0.1, 1, 5, 10, 18, and 24 mg/day or 0.01, 0.1, 0.5, 1.0, 1.8, and 2.4 mg/day, respectively (Lubbers et al. 1981). Assuming an average body weight of 70 kg, the individual doses were approximately 0.0014, 0.014, 0.070, 0.140, 0.26, and 0.34 mg/kg/day, respectively, for chlorine dioxide and a factor of 10 lower for respective chlorite doses. No adverse effects on respiration rate were observed in other healthy adult males who ingested chlorine dioxide or chlorite in daily amounts of 2.5 mg (0.04 mg/kg/day) for 12 weeks (Lubbers et al. 1981).

Information regarding respiratory effects in orally-exposed animals is limited to a report of a significantly increased incidence of nasal lesions (goblet cell hyperplasia and inflammation of nasal turbinates) following 90 days of exposure to chlorine dioxide in the drinking water at concentrations that resulted in estimated doses as low as 2 mg/kg/day in males and 8 mg/kg/day in females (Daniel et al. 1990). These nasal effects were likely caused by inhalation of chlorine dioxide vapors released from the water rather than a systemic respiratory effect following oral exposure.

Gastrointestinal Effects. Information in humans is limited to a single account of abdominal cramps, nausea, and vomiting within a few minutes after a 25-year-old Chinese male had consumed 10 g of sodium chlorite dissolved in 100 mL of water in an apparent suicide attempt (Lin and Lim 1993).

Information regarding gastrointestinal effects in animals following oral exposure to chlorine dioxide or chlorite is also limited. Bercz et al. (1982) reported erythema and ulceration of the oral mucosa in adult African green monkeys exposed to chlorine dioxide in the drinking water for between 30 and 60 days at a concentration that resulted in a dose of approximately 9 mg/kg/day. Dose-related increased severity of salivation and histopathologic alterations in the stomach (including squamous epithelial hyperplasia, hyperkeratosis, ulceration, chronic inflammation, and edema) were observed in groups of rats administered sodium chlorite in gavage doses of 25 or 80 mg/kg/day (equivalent to 19 or 60 mg chlorite/kg/day, respectively) for 13 weeks; these effects were not seen at a dose level of 7.4 mg chlorite/kg/day (Harrington et al. 1995a).

Hematological Effects. Profound methemoglobinemia was diagnosed in a 25-year-old Chinese male after he had consumed 10 g of sodium chlorite dissolved in 100 mL of water in an apparent suicide attempt (Lin and Lim 1993). Other hematological effects, including ensuing intravascular coagulation, were likely secondary to the methemoglobinemia that persisted despite treatment with methylene blue. No indications of altered hematological parameters were seen in adult male subjects consuming chlorine dioxide in aqueous solution that resulted in a single dose of approximately 0.34 mg/kg of chlorine dioxide (Lubbers et al. 1981) or in other adult males consuming approximately 0.04 mg/kg/day for 12 weeks (Lubbers et al. 1981, 1984a). The same investigators tested chlorite for adverse effects in healthy adult males, and found no evidence of hematological effects after each subject consumed of a total of 1,000 mL of a solution containing 2.4 mg/L chlorite (approximately 0.068 mg/kg) in two doses (separated by 4 hours), or in other healthy normal or glucose-6-phosphate dehydrogenase (G6PD) deficient male subjects who consumed approximately 0.04 mg/kg/day for 12 weeks (Lubbers et al. 1981, 1984a, 1984b). No chlorine dioxide- or chlorite-induced hematological effects were seen among the inhabitants of a rural village who were exposed for 12 weeks via chlorine dioxide in the drinking water at weekly measured concentrations ranging from 0.25 to 1.11 mg/L (chlorine dioxide) or from 3.19 to 6.96 mg/L (chlorite) (Michael et al. 1981). In this epidemiological study, levels of chlorine dioxide in the drinking water before and after the treatment period were <0.05 mg/L. The chlorite level in the drinking water was 0.32 mg/L prior to chlorine dioxide treatment. At 1 and 2 weeks following cessation of treatment, chlorite levels dropped to 1.4 and 0.5 mg/L, respectively.

Some animal studies include reports of hematological effects following oral exposure to chlorine dioxide or chlorite. Abdel-Rahman and coworkers (Abdel-Rahman et al. 1984b; Couri and Abdel-Rahman 1980) exposed groups of male rats to chlorine dioxide in the drinking water, 20 hours/day for 11 or 12 months, at concentrations that resulted in estimated doses of 0.1, 1, 10, and 100 mg/kg/day. Abdel-Rahman et al. (1984b) noted that several hematological parameters were significantly altered in exposed rats, relative to controls, and included decreased osmotic fragility in the 10 and 100 mg/kg/day groups after 2, 4, 7, or 9 months of exposure, and in the 1 mg/kg/day group after 9 months of exposure; decreased erythrocyte counts in the 0.1 mg/kg/day and 100 mg/kg/day groups after 9 months of exposure, but not after 7 months; reduced hematocrit and hemoglobin levels in all groups at 9 months that did not exhibit clear dose-response patterns; increased hematocrit levels in the 10 and 100 mg/kg/day groups at 7 months; and increased mean corpuscular hemoglobin concentrations in the 10 and 100 mg/kg/day groups after 9 months. The study authors suggested that the decreased osmotic fragility may have been related to the disulfide bond between hemoglobin and the cell membrane as the result of oxidative stress. Couri and Abdel-Rahman (1980) found significant increases in blood glutathione reductase levels in rats of the 1, 10, and 100 mg/kg/day groups after 6 months of exposure. At 12 months of exposure, the blood glutathione reductase levels in all exposure groups were similar to those of controls, but the levels of blood glutathione peroxidase were significantly increased at 10 and 100 mg/kg/day. Blood catalase levels were increased in the 100 mg/kg/day group after 6 and 12 months of exposure and decreased in the 0.1 and 1 mg/kg/day groups after 6 months of exposure. The results of Couri and Abdel-Rahman (1980) generally indicate that chlorine dioxide and chlorite may induce increased blood glutathione oxidase activity and resulting decreased blood glutathione levels, which is consistent with the protective role of glutathione against oxidative cellular damage.

Abdel-Rahman and coworkers (Abdel-Rahman et al. 1984b; Couri and Abdel-Rahman 1980) also exposed male rats to sodium chlorite in the drinking water, 20 hours/day for up to 1 year, at concentrations that resulted in estimated doses of 1 or 10 mg/kg/day. Both dose levels resulted in increased mean corpuscular hemoglobin concentration (after 7, but not 9 months) and decreased osmotic fragility after 7–9 months). Erythrocyte glutathione levels were significantly decreased at dose levels 0.1 mg/kg/day by the end of the 1-year exposure period. No consistent treatment-related alterations in erythrocyte count, hematocrit, or hemoglobin levels were observed.

Harrington et al. (1995a) administered sodium chlorite to rats by gavage for 13 weeks, resulting in chlorite doses of 7.4, 19, or 60 mg/kg/day. Relative to controls, significant treatment-related hematological effects included decreased hematocrit and hemoglobin levels (high-dose males), increased methemoglobin and neutrophil levels (mid- and high-dose males), decreased lymphocyte count (mid-dose males), decreased mean erythrocyte count (high-dose males and females), morphological changes in erythrocytes (high-dose males and females), and increased spleen weights (high-dose males and mid- and high-dose females). An unexplained decrease in methemoglobin was observed in high-dose females.

No consistent alterations in hematological parameters (erythrocyte and total and differential leukocyte counts, hemoglobin levels, hematocrit, mean corpuscular volume) were observed in groups of male and female rats given chlorine dioxide in the drinking water for 90 days at concentrations that resulted in doses as high as 12 and 15 mg/kg/day for males and females, respectively (Daniel et al. 1990).

No significant alterations in hematological parameters were seen in adult African green monkeys given chlorine dioxide in the drinking water for up to 60 days at rising concentrations that resulted in estimated doses as high as 9 mg/kg/day (Bercz et al. 1982). Bercz and coworkers later exposed these same monkeys to sodium chlorite in the drinking water in rising concentrations that resulted in estimated chlorite doses as high as 58.4 mg/kg/day. Statistically significant dose-related hematological alterations in these monkeys included decreased erythrocyte levels and cell indices, decreased hemoglobin levels, and slight increases in reticulocyte and methemoglobin levels. However, the data were not presented in a manner that would allow identification of threshold doses for these effects.

Moore and Calabrese (1982) found no significant alterations in hematological parameters within groups of mice exposed to chlorine dioxide in the drinking water for 30 days, at a concentration that resulted in an estimated dose of 25 mg/kg/day. However, when similarly examining the hematotoxicity of chlorite, Moore and Calabrese (1982) found significant increases in mean corpuscular volume and osmotic fragility at a dose level of 19 mg/kg/day.

Heffernan et al. (1979b) observed significant methemoglobinemia within 1–2 hours in cats that had been administered chlorite in single doses of 20 or 64 mg/kg. These same investigators found no signs of methemoglobinemia in rats exposed to sodium chlorite in the drinking water for 30–90 days at concentrations that resulted in estimated chlorite doses as high as 50 mg/kg/day. Doses ≥10 mg/kg/day resulted in slight anemia at 30 days, but this condition appeared to improve at 60 and 90 days.

Hepatic Effects. No indications of adverse hepatic effects (assessed in tests of serum chemistry) were seen in adult male subjects consuming chlorine dioxide in aqueous solution that resulted in a dose of approximately 0.34 mg/kg (Lubbers et al. 1981) or in other adult males consuming approximately 0.04 mg/kg/day for 12 weeks (Lubbers et al. 1984a). The same investigators administered chlorite to healthy adult males, and found no evidence of adverse hepatic effects after each subject had consumed of a total of 1,000 mL of a solution containing 2.4 mg/L chlorite (approximately 0.068 mg/kg) in two doses (separated by 4 hours), or in other healthy normal or G6PD deficient male subjects who had consumed approximately 0.04 mg/kg/day for 12 weeks (Lubbers et al. 1984a, 1984b). No chlorine dioxide- or chlorite-induced signs of altered liver function were seen among the inhabitants of a rural village who were exposed for 12 weeks via chlorine dioxide in the drinking water at weekly measured concentrations ranging from 0.25 to 1.11 mg/L (chlorine dioxide) or from 3.19 to 6.96 mg/L (chlorite) (Michael et al. 1981). In this epidemiological study, levels of chlorine dioxide in the drinking water before and after the treatment period were <0.05 mg/L. The chlorite level in the drinking water was 0.32 mg/L prior to chlorine dioxide treatment. At 1 and 2 weeks following cessation of treatment, chlorite levels dropped to 1.4 and 0.5 mg/L, respectively.

Limited information is available regarding hepatic effects in animals following oral exposure to chlorine dioxide or chlorite. Daniel et al. (1990) exposed male and female rats to chlorine dioxide in the drinking water for 90 days at concentrations that resulted in estimated doses of 1.9, 3.6, 6.2, or 11.5 mg/kg/day for males and 2.4, 4.6, 8.2, or 14.9 mg/kg/day for females. Significantly depressed mean absolute liver weights were observed in males at doses ≥3.6 mg/kg/day and females of the 8.2 mg/kg/day dose group. However, these groups also exhibited decreased water consumption. Moore and Calabrese (1982) found significant increases in G6PD activity in mice receiving sodium chlorite in the drinking water for 30 days at a concentration that resulted in a chlorite dose of 19 mg/kg/day.

Renal Effects. No chlorine dioxide- or chlorite-induced signs of altered renal function were seen among the inhabitants of a rural village who were exposed for 12 weeks via chlorine dioxide in the drinking water at weekly measured concentrations ranging from 0.25 to 1.11 mg/L (chlorine dioxide) or from 3.19 to 6.96 mg/L (chlorite) (Michael et al. 1981). In this epidemiological study, levels of chlorine dioxide in the drinking water before and after the treatment period were <0.05 mg/L. The chlorite level in the drinking water was 0.32 mg/L prior to chlorine dioxide treatment. At 1 and 2 weeks following cessation of treatment, chlorite levels dropped to 1.4 and 0.5 mg/L, respectively. Acute renal failure developed in a 25-year-old Chinese male some days after he had consumed 10 g of sodium chlorite dissolved in 100 mL of water in an apparent suicide attempt (Lin and Lim 1993), but this effect followed earlier signs of profound methemoglobinemia and respiratory distress.

Information regarding renal effects in animals is limited. Moore and Calabrese (1982) found no evidence of renal effects in mice exposed to sodium chlorite in the drinking water for up to 180 days at a concentration that resulted in an estimated chlorite dose of 25 mg/kg/day. Haag (1949) reported treatment-related pathological effects (distension of the glomerular capsule and appearance of a pale pinkish staining material in the renal tubules) in the kidneys of rats exposed to chlorite in the drinking water for 2 years at concentrations that resulted in estimated doses of 7 or 13 mg/kg/day. Increased relative kidney weights, in the absence histopathological renal effects, were observed in rats administered sodium chlorite in gavage doses of 80 mg/kg/day (equivalent to 60 mg chlorite/kg/day) for 13 weeks (Harrington et al. 1995a).

Endocrine Effects. No reports were located in which endocrine effects could be associated with oral exposure to chlorine dioxide or chlorite in humans.

Information from animal studies is limited to accounts of significantly reduced serum levels of the T4 thyroid hormone in African green monkeys consuming approximately 9 mg chlorine dioxide/kg/day from the drinking water for 6 weeks or approximately 58.4 mg chlorite/kg/day for 8 weeks (Bercz et al. 1982), and a single report of significantly increased adrenal weight in female rats administered sodium chlorite gavage doses ≥25 mg/kg/day (≥19 mg chlorite/kg/day) for 13 weeks (Harrington et al. 1995a). Refer to Section 3.2.2.6 for information regarding altered serum hormone levels in laboratory animals that had been exposed via their mothers during prenatal and postnatal development.

Body Weight Effects. No reports were located in which body weight effects could be associated with oral exposure to chlorine dioxide or chlorite in humans.

Abdel-Rahman et al. (1984b) reported significantly reduced body weight gain (up to 18% lower than controls) in male rats exposed to chlorine dioxide in the drinking water for 11 months at concentrations resulting in estimated doses ranging from 0.12 to 120 mg/kg/day. The same authors reported similar, but less pronounced, reduced body weight gain in rats exposed to sodium chlorite at concentrations that resulted in chlorite doses of approximately 1.2 and 12 mg/kg/day. Although this effect appeared earlier at the highest concentration, mean terminal body weight after 11 months of exposure was lower in low-dose rats than in high-dose rats. Furthermore, the authors did not provide information regarding water and food consumption. Kurokawa et al. (1986) reported slightly decreased body weight gain (<10% lower than controls) in male and female rats exposed to sodium chlorite in the drinking water for up to 85 weeks at concentrations that resulted in estimated chlorite doses of 13.5 and 24 mg/kg/day in males and 21 and 31 mg/kg/day in females. The results of Kurokawa et al. (1986) are of questionable toxicological significance because water intake among sodium chloride treatment groups was lower than that of controls and the study had to be terminated early due to a Sendai virus infestation within all study groups.

Harrington et al. (1995a) found no significant adverse body weight effects in rats administered up to 60 mg chlorite/kg/day (via gavage) for 13 weeks. No treatment-related effects on body weight were seen in male rats that were administered chlorine dioxide in gavage doses of 2.5, 5, or 10 mg/kg/day for 56 days prior to mating and 10 more days during mating, or in female rats administered the same doses for 14 days prior to mating and throughout mating, gestation, and lactation (Carlton et al. 1991). No significant adverse body weight effects were seen in mice given sodium chlorite in the drinking water for up to 180 days at concentrations resulting in estimated chlorite doses as high as 25 mg/kg/day (Moore and Calabrese 1982) or in other mice exposed to sodium chlorite for 80 weeks at a concentration that resulted in an estimated chlorite dose of 90 mg/kg/day (Kurokawa et al. 1986).

3.2.2.3 Immunological and Lymphoreticular Effects

No reports were located in which immunological or lymphoreticular effects could be associated with oral exposure to chlorine dioxide or chlorite in humans.

Animal data are restricted to limited accounts of treatment-related altered thymus and spleen weights. Daniel et al. (1990) observed reduced spleen weights in female, but not male, rats exposed to chlorine dioxide in the drinking water for 90 days at concentrations that resulted in estimated doses ranging from 2 to 15 mg/kg/day, but the basis for this effect was not discussed. Harrington et al. (1995a) found significantly increased spleen weights in male rats administered sodium chlorite by gavage at a dose level of 80 mg/kg/day (60 mg chlorite/kg/day) for 13 weeks and in female rats similarly treated with 10 or 60 mg chlorite/kg/day. In this study, increased spleen weights were attributed to morphological changes in erythrocytes. Significantly lower spleen and thymus weights were seen in F1 and F2 rats that had been exposed to sodium chlorite via their mothers during gestation and lactation and via the drinking water after weaning (Gill et al. 2000).

3.2.2.4 Neurological Effects

No reports were located in which neurological effects could be associated with oral exposure to chlorine dioxide or chlorite in humans or animals. Refer to Section 3.2.2.6 for information regarding neurodevelopmental effects.

3.2.2.5 Reproductive Effects

No reports were located in which reproductive effects could be associated with oral exposure to chlorine dioxide or chlorite in humans.

A paucity of evidence exists for reproductive effects in animals following oral exposure to chlorine dioxide or chlorite. Slight, but significantly altered sperm morphology and motility were observed in male rats exposed to sodium chlorite in the drinking water for 66–76 days at concentrations that resulted in estimated chlorite doses of 9 and 37 mg/kg/day. No dose-related alterations in fertility rates or reproductive tissues (both gross and histopathological examination) were seen and no adverse effects were observed at a chlorite dose level of 0.9 mg/kg/day (Carlton and Smith 1985; Carlton et al. 1987).

Significantly decreased testicular deoxyribonucleic acid (DNA) synthesis was noted in male rats given chlorine dioxide or chlorite (as sodium salt) in the drinking water for 3 months at concentrations that resulted in estimated chlorine dioxide and chlorite doses ≥1.3 and 0.13 mg/kg/day, respectively (Abdel-Rahman et al. 1984b), and other male rats exposed for 3 weeks to a concentration that resulted in a chlorine dioxide dose of 13 mg/kg/day or a chlorite dose of 1.3 mg/kg/day (Suh et al. 1983). A treatment-related decreased number of implants was noted in untreated females that had been mated with chlorine dioxide-treated males of the 13 mg/kg/day level (Suh et al. 1983). No significant increases in abnormal sperm-head morphology were seen in mice given chlorine dioxide or chlorite in gavage doses as high as 16 and 40 mg/kg/day, respectively, for 5 days followed by 3 weeks without treatment prior to testing (Meier et al. 1985). Carlton et al. (1991) found no significant treatment-related effects on fertility rates or sperm parameters in rats following the administration of chlorine dioxide in gavage doses as high as 10 mg/kg/day for 56 days prior to mating and throughout a 10-day mating period (males) and 14 days prior to mating and throughout mating, gestation, and lactation (females).

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in each species and duration are recorded in Table 3-2 and plotted in Figure 3-2.