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

3.2.2.6 Developmental Effects

Information regarding developmental effects in humans following oral exposure to chlorine dioxide or chlorite is limited.

Tuthill et al. (1982) retrospectively compared infant morbidity and mortality data for a community that had utilized chlorine dioxide as a drinking water disinfectant in the 1940s with data of a neighboring community that used conventional drinking water chlorination practices. Exposure to chlorine dioxide-treated water did not adversely affect fetal or perinatal mortality, or birth weight, maximum weight loss, weight loss at 6 days, sex ratio, or birth condition. The authors reported a significantly greater proportion of premature births in the community using chlorine dioxide, as judged by physician assessment. However, other measures of premature birth, such as birth weight and gestational age, did not support the results based on physician assessment. Infants from the community using chlorine dioxide exhibited statistically significantly greater maximum weight loss after birth and smaller weight gain in 6 days, although these effects appeared to be partially linked to the mode of feeding practiced by the mother.

Kanitz et al. (1996) followed 548 births at Galliera Hospital, Genoa, Italy, and 128 births at Chiavari Hospital, Chiavari, Italy, during 1988–1989. Data on infant birth weight, body length, cranial circumference, and neonatal jaundice and on maternal age, smoking, alcohol consumption, education, and preterm delivery were collected from hospital records. Women in Genoa were exposed to filtered water disinfected with chlorine dioxide, sodium hypochlorite, or both; trihalomethane levels varied from 8 to 16 ppb in sodium hypochlorite-treated water and from 1 to 3 ppb in chlorine dioxide-disinfected water. Levels of chlorine dioxide in the water immediately after treatment were <0.3 mg/L, while chlorine residue was <0.4 mg/L. Women residing in Chiavari used water pumped from wells, without any disinfection treatment, and served as the comparison group (controls). Odds ratios (ORs) were determined for the somatic parameters by comparison of groups exposed to chlorine dioxide, sodium hypochlorite, or both with controls and adjusted for maternal education level, income, maternal age, alcohol consumption, and smoking, as well as for sex of the child. Neonatal jaundice occurred more frequently (OR=1.7; 95% confidence interval [CI]=1.1–3.1) in infants whose mothers resided in the area where surface water was disinfected with chlorine dioxide, when compared with infants with mothers using nondisinfected well water. Infants born to mothers residing in areas where surface water was disinfected had smaller cranial circumference (≤35 cm) (OR=2.2, 95% CI=1.4–3.9 for chlorine dioxide; OR=3.5, 95% CI=2.1–8.5 for sodium hypochlorite vs. untreated well water; OR=2.4, 95% CI=1.6–5.3 for both vs. untreated well water). In addition, these infants had a smaller body length (≤49.5 cm) (OR=2.0, 95% CI=1.2–3.3 for chlorine dioxide vs. untreated well water; OR=2.3, 95% CI=1.3–4.2 for sodium hypochlorite vs. untreated well water). Risks for low birth weight (≤2,500 g) were reported to be increased among mothers residing in areas using water disinfected with chlorine dioxide, but these associations were not statistically significant. For preterm delivery (≤37 weeks), small but not statistically significant increased risks were found among mothers residing in the area using chlorine dioxide. The study authors concluded that infants of women who consumed drinking water treated with chlorine compounds during pregnancy were at higher risk for neonatal jaundice, cranial circumference ≤35 cm, and body length ≤49.5 cm.

Interpretability of the results of Kanitz et al. (1996) is limited by lack of consideration of exposure and potential confounding variables such as lack of quantitative exposure information, exposure to other chemicals in the water, and nutritional habits of the women. In addition, baseline values for the infant sex ratio and percentage of low-weight births for the comparison group deviate from values presented by the World Health Organization for Italy. For example, the sex ratio (male/female live births x100) used in the study for the comparison group was 86, but most recent data (1996; as cited in WHO 2002) for Italy indicate a sex ratio value of 106. Although the percentage of low-weight births in the control group for the Kanitz et al. (1996) study was 0.8%, the percentage of low-weight births (<2,500 g) in Italy for 1994 was 6%. The quality of the untreated well water is not known (i.e., whether it contained any chemical or biological contaminants).

Källén and Robert (2000) found no adverse effects on congenital malformations, childhood cancer, infant mortality, low Apgar score, neonatal jaundice, or neonatal hypothyroidism among infants and children who lived in areas where drinking water was disinfected with chlorine dioxide, compared to controls living in areas where chlorination of drinking water was not practiced. This study is limited because levels of chlorination products and byproducts in the drinking water were not monitored.

Numerous animal studies are available in which developmental end points have been evaluated following oral exposure to chlorine dioxide or chlorite. Some studies cited effects such as decreases in brain weight, brain cell number, exploratory behavior, locomotor activity, and serum thyroxine levels 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. Effects such as decreases in serum thyroxine levels, body weight and growth, exploratory behavior, and amplitude of auditory startle response were reported in rat pups whose mothers were exposed to chlorite before mating and during gestation and lactation.

Chlorine Dioxide. Mobley et al. (1990) administered chlorine dioxide in the drinking water of female rats for 10 days prior to mating with unexposed males, and during gestation and lactation (until postconception days 35–42) at a concentration that resulted in an estimated dose of 13 mg/kg/day. No treatment-related effects were seen in litter size at birth, pup weight gain, or day of eye opening. Litter weight at birth was significantly lower (5%) than controls. At ages 36 through 39 days postconception, exploratory activity was significantly depressed, relative to controls, but not on day 40. On postconception days 37 and 38, no significant treatment-related effects were seen in serum T3 or T4 levels in male pups (serum thyroid hormone levels were not tested in female pups), but T3 uptake was significantly decreased. By postconception day 42, T3 uptake in the exposed male pups was no longer significantly different from controls. The authors suggested that reduced T3 uptake may be the source of delay in exploratory activity.

Orme et al. (1985) exposed rat dams to chlorine dioxide in the drinking water for 2 weeks prior to mating and throughout gestation and lactation at concentrations resulting in estimated doses of 0.26, 2.6, or 13 mg/kg/day. Maternal body weights were not significantly affected by treatment. No significant treatment-related effects were seen in pup body weights or age at eye opening. Consistent, but not significantly lower activity levels were observed in 13 mg/kg/day pups, relative to controls, on postpartum days 15–20. At 13 mg/kg/day, pups also exhibited significantly depressed serum T4 and elevated T3 levels, relative to controls, when tested on postpartum day 21. A significant correlation was noted between T4 levels and locomotor activity. In the same report, pups of unexposed rat dams were administered chlorine dioxide in a gavage dose of 14 mg/kg/day on postnatal days 5–20. Relative to controls, treated pups exhibited lower body weights at 14 and 21 days (17 and 33% lower, respectively), lower activity levels at days 18 and 19 (but not days 15–17 and 20), and lower serum T4 levels on postpartum day 21. Age at eye opening and serum T3 levels were not significantly different from controls. A significant correlation was noted between T4 levels and locomotor activity.

Taylor and Pfohl (1985) found no significant treatment-related effects on body weights of male rat pups whose mothers had been exposed to chlorine dioxide in the drinking water for 14 days prior to mating and throughout gestation and lactation at a concentration that resulted in an estimated dose of 13 mg/kg/day. Female rat pups were not assessed in this study. Compared with controls, the treated pups exhibited consistently (but not significantly) lower activity levels (assessed at 10–20 days of age), significantly decreased whole brain weight (primarily because of a decrease in cerebellar weight) and cerebellar total DNA content (due to a decrease in total cell number) in 21-day-old pups, and decreased exploratory activity at 60 days of age. Other pups were exposed to chlorine dioxide only during postnatal days 5–20 at a daily gavage dose of 14 mg/kg. At 21 days of age, these pups exhibited significant decreases in body weight, absolute and relative whole brain and forebrain weights, and forebrain DNA content and total cell number, compared with controls. Decreased DNA content and total cell number were seen in the cerebellum and forebrain when tested at 11 days of age.

Toth et al. (1990) administered chlorine dioxide to male and female rat pups at a daily gavage dose of 14 mg/kg on postnatal days 1–20. Examinations were performed on selected pups at ages 11, 21, and 35 days, and results were compared to control pups. Significantly lower (5–7% lower) body weights and decreased ratio of forebrain content to cerebellum weight were noted at all three examination times. Significantly lower forebrain weights were seen on days 21 and 35, along with accompanying reductions in protein content (days 21 and 35) and reduced DNA content (day 35). Serum T3 and T4 levels were not affected by chlorine dioxide treatment. A slight, but statistically significant decrease in free T4 was reported at day 21, but the toxicological significance is not clear.

Suh et al. (1983) administered chlorine dioxide in the drinking water of female rats for 2.5 months prior to mating with unexposed males, and during gestation days 1–20 at levels that resulted in estimated doses of 0.13, 1.3, or 13 mg/kg/day. The only reported maternal effect was a slight (but not significantly) decreased maternal body weight gain in 1.3 and 13 mg/kg/day dams, relative to controls. Fetal effects included a significant dose-response trend for decreasing number of implants per litter and number of live fetuses per dam, and significantly increased total fetal weights and male fetal weights in the 13 mg/kg/day group, compared with controls. No significant effects were seen in crown-rump length or skeletal anomalies.

Carlton et al. (1991) administered chlorine dioxide to rats in gavage doses of 2.5, 5, or 10 mg/kg for 56 days prior to mating and during 10 days of mating (males) and 14 days prior to mating and throughout mating, gestation, and lactation (females). Relative to controls, pups in the exposure groups exhibited no significant differences in death before weaning, mean litter size, or mean body weight. Significantly lower absolute vaginal weight and vagina-to-body weight ratio were seen in F1 females of the 10 mg/kg/day exposure group; no significant changes in reproductive organ weights were observed in F1 males.

Chlorite. Gill et al. (2000; results previously published in CMA 1996) conducted a 2-generation study to examine reproductive, developmental, neurological, and hematological end points in rats exposed to sodium chlorite. Male and female rats (F0) received sodium chlorite in the drinking water at concentrations that resulted in estimated chlorite doses of 3, 5.7, or 21 mg/kg/day for males and 3.9, 7.6, and 29 mg/kg/day for females. The treatment period lasted for 10 weeks prior to mating and during mating, after which males were sacrificed; exposure of females continued throughout gestation and lactation. Sodium chlorite concentrations were adjusted during lactation to maintain a constant intake during a period of increased water intake. F1 generation pups were continued on the same treatment regimen as their parents (chlorite doses of 2.9, 6, or 23 mg/kg/day and 3.9, 8, or 29 mg/kg/day for F1 males and females, respectively). Mating commenced at approximately 14 weeks of age to produce F2a rats that were maintained through weaning on postnatal day 21. Due to a reduced number of litters in the mid-dose F1-F2a generation, the F1 animals were remated following weaning of the F2a rats to produce an F2b generation. Significant alterations related to treatment at high-dose included reduced absolute and relative liver weight in F1 males and females, reduced pup survival (increase in number of pups found dead and/or killed prematurely during lactation) and reduced body weight at birth and throughout lactation in F1 and F2 rats, lower thymus and spleen weight in both generations, decreased absolute brain weight for F1 males and F2 females, delayed sexual development in F1 and F2 males (preputial separation) and females (vaginal opening), and lowered red blood cell parameters and white blood cell counts in F1 rats. In the mid-dose groups, reduced absolute and relative liver weight in F1 males was observed. In addition, a significant decrease in maximum response to an auditory startle stimulus was noted in mid- and high-dose groups on postnatal day 24, but not on postnatal day 60. The NOAEL of 2.9 mg/kg/day, identified in this study, served as the basis for the derivation of an intermediate-duration oral MRL for chlorite. A LOAEL was 5.7 mg/kg/day for lowered auditory startle response amplitude and hematotoxicity on postnatal day 24.

Mobley et al. (1990) exposed female rats to chlorite in the drinking water for 10 days prior to mating with unexposed males and during gestation and lactation until postnatal days 42–53 at concentrations that resulted in estimated chlorite doses of 2.6 or 5.2 mg/kg/day. Chlorite exposure did not adversely affect litter size or pup weight gain. Significant, consistent decreases in exploratory activity were observed in the 5.2 mg/kg/day group on postnatal days 36–39, but not on days 39–41. In the 2.6 mg/kg/day group, there were significant decreases in activity on days 36 and 37, but not on days 38–40. No significant alterations in serum T3 or T4 levels or free T4 levels were observed in male pups (female pups were not assessed for thyroid hormone levels). The day of eye opening in the treatment groups was similar to that of controls.

Carlton et al. (1987) exposed groups of 12 male rats to sodium chlorite in the drinking water for 56 days prior to mating and throughout a 10-day mating period. Groups of 24 female rats were also exposed to sodium chlorite for 14 days prior to mating, during the mating period, and throughout gestation and lactation. Estimated chlorite doses were 0.09, 0.9, or 9 mg/kg/day for males and 0.1, 1, or 10 mg/kg/day for females. No significant alterations in litter survival rates, median day of eye opening, or median day of observed vaginal patency were observed. Significant decreases in serum T3 and T4 levels were consistently observed in high-dose groups of F1 males and females at postnatal days 21 and 40.

Couri et al. (1982b) exposed pregnant rats to sodium chlorite in the drinking water during gestational days 8–15 at concentrations that resulted in estimated chlorite doses of 70, 440, or 610 mg/kg/day. The litters were either delivered at term or by cesarean section on gestational day 22. Significant decreases in crown-rump length were observed at all doses in term-delivered litters and in the 70 mg/kg/day group that was cesarean-delivered. Fetal weights were not adversely affected. An increase in the number of resorbed and dead fetuses was observed in cesarean-delivered litters of all exposure levels; two litters out of five were totally resorbed in the high-dose group. Postnatal growth and the incidences of soft tissue and skeletal malformations were not adversely affected.

Suh et al. (1983) administered chlorite in the drinking water of female rats for 2.5 months prior to mating with unexposed males and during gestational days 0–20 at chlorite concentrations that resulted in estimated doses of 0.13 or 1.3 mg/kg/day; the dams were killed on gestational day 20. No treatment-related effects were seen regarding resorptions, dead fetuses, or fetal body weights. Crown-rump length was significantly higher in the high-dose group compared with controls, but the difference was very small and is probably not biologically significant. Chlorite exposure did not significantly alter incidence of skeletal anomalies.

Moore and coworkers (Moore and Calabrese 1982; Moore et al. 1980b) exposed pregnant mice to sodium chlorite in the drinking water throughout gestation and lactation at a concentration that resulted in an estimated chlorite dose of 23 mg/kg/day. A decrease in the conception rate (number of females positive for vaginal plug/number of females producing litters; 39 vs. 56% in controls) was observed; the statistical significance was not reported. No significant alterations in gestation length, litter size, number of pups dead at birth, or number of pups alive at weaning were observed. Pup growth was adversely affected, as shown by significant decreases in average pup weaning weight and birth-to-weaning growth rate.

Harrington et al. (1995b) treated rabbits with sodium chlorite via their drinking water on gestation days 7–20 at levels that resulted in estimated chlorite doses of 10, 26, or 40 mg/kg/day. Dams were sacrificed on gestation day 28. Although the number and mean percentage of major external and visceral and skeletal abnormalities were increased in the 26 and 40 mg/kg/day groups (external/visceral: 6.6 and 2.9%, respectively, vs. 1.5% in controls; skeletal: 5.4 and 0%, respectively, vs. 0% in controls), the authors did not consider these to be treatment-related adverse effects. Mean fetal weights in the 26 and 40 mg/kg/day groups were slightly decreased (<9%, relative to controls). In the 26 and 40 mg/kg/day groups, the incidence of minor skeletal abnormalities (13.9 and 14.2% for the 26 and 40 mg/kg/day groups, respectively, vs. 7.7% in controls) and skeletal variants related to incomplete fetal bone ossification was higher than for controls. The authors state in their discussion that these alterations in fetal body weight and delayed ossification indicate embryonic growth retardation. Decreases in maternal food and water consumption and body weight gain may be responsible, at least in part, for some of the fetal effects.

Skowronski et al. (1985) administered Alcide (a liquid sterilizer consisting of sodium chlorite and lactic acid that form chlorine dioxide) to mice and rats in gavage doses of 1 and 0.1 mL, respectively, on gestation days 6–15. No signs of maternal toxicity were observed, and there were no statistically significant adverse fetal effects.

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

3.2.2.7 Cancer

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

Kurokawa et al. (1986) performed a cancer bioassay on rats and mice that were exposed to sodium chlorite in the drinking water. Rats were exposed to concentrations that resulted in estimated chlorite doses of 13.5 or 24 mg/kg/day in males and 21 or 31 mg/kg/day in females. All groups of rats became infected with the Sendai virus, causing a premature termination of the study after 85 weeks of exposure. Mice were exposed for 80 weeks to concentrations that resulted in estimated doses of 45 or 90 mg/kg/day. Mice received distilled water only for an additional 5 weeks following the 80-week treatment period. Yokose et al. (1987) also published a report of the mouse data presented in Kurokawa et al. (1986). The two accounts vary slightly in exposure duration information and in reported numbers of tumor-bearing mice at study end. Yokose et al. (1987) indicated that exposure of mice was terminated at 80 weeks according to a guideline for carcinogenicity studies from the Ministry of Health and Welfare of Japan.

No chlorite-related increased tumor incidences were observed in rats. Significant increases in liver and lung tumors were observed in the male mice. Incidence of hyperplastic nodules in the liver was significantly increased in the low- and high-dose groups relative to controls (3/35 [reported as 6/35 in Yokose et al. 1987], 14/47, and 11/43, in the control, low-, and high-dose groups, respectively) and combined incidence of liver hyperplastic nodules and hepatocellular carcinoma was increased in the low-dose group (7/35, 22/47, and 17/43, respectively). Incidence of lung adenoma (0/35, 2/47, and 5/43, respectively) and combined incidence for lung adenoma and adenocarcinoma (0/35, 3/47, and 7/43, respectively) were significantly increased in the high-dose group compared with controls. The study authors noted that incidences of liver hyperplastic nodules and lung adenomas in the treated animals were within the range of historical controls in their laboratory and in the National Toxicology Program laboratories. In addition, high mortality in the control males because of fighting reduced the sample size, making statistical comparisons between controls and treated animals difficult to interpret. In the female mice, the only significant alteration in tumor incidence was a significantly lower incidence of malignant lymphoma/leukemia in the high-dose group (7/47, 5/50, and 1/50, respectively). The exposure durations of both rat and mouse studies were considerably less-than-lifetime exposure guidelines for adequate carcinogenicity studies.

Using three short-term assays, Miller et al. (1986) found no evidence of carcinogenic potential of drinking water disinfected with chlorine dioxide. In an initiation-promotion assay, water was disinfected with chlorine dioxide, after which water samples containing chlorine dioxide residue were concentrated and administered orally to mice 3 times/week for 2 weeks. The mice were then exposed to 12-tetradecanylphorbal-13-acetate (a known cancer promoter) in acetone by dermal applications 3 times/week for 20 weeks. No significant increases in the number of skin tumors or the number of tumors per animal were observed, compared with vehicle controls. In a lung adenoma assay, groups of female Strain A mice received 0.25 mL gavage doses of the concentrated water samples 3 times/week for 8 weeks, followed by a 16-week observation period. The number of animals with lung adenomas and the number of adenomas per animal were not significantly altered compared with vehicle controls. In the third assay, partially hepatectomized rats were exposed to a single oral dose of the concentrated water samples followed 1 week later by administration of 500 mg/L sodium phenobarbital (a known cancer promoter) in drinking

water for 56 days. Examination of livers in the treated rats did not reveal significant treatment-induced increases in gamma glutamyl transpeptidase-positive foci (an indicator of preneoplastic liver changes).

3.2.3 Dermal Exposure

The database for health effects related to dermal exposure to chlorine dioxide or chlorite is extremely limited. No reports were located regarding adverse effects in humans following dermal exposure to chlorine dioxide or chlorite. Available information in animals is restricted to a report that a solution containing chlorine dioxide concentrations of approximately 9.7–11.4 mg/L was nonirritating to the skin of mice in a 48-hour test. Dermal exposure to high concentrations would be expected to result in irritation, due to the oxidizing properties of chlorine dioxide and chlorite. Sodium chlorite was not carcinogenic in mice treated dermally for 51 weeks. Nor did sodium chlorite appear to be a cancer promoter in mice initiated with a single dermal dose of dimethylbenzanthracene followed by 51 weeks of dermal exposure to sodium chlorite.

The toxicity of Alcide, an antimicrobial compound consisting of solutions of sodium chlorite and lactic acid that produce chlorine dioxide when mixed, was assessed in laboratory animals following repeated exposure and in fetuses of pregnant animals following in utero exposure during critical periods of organogenesis (Abdel-Rahman et al. 1987a, 1987b; Gerges et al. 1985). However, levels of exposure to sodium chlorite and chlorine dioxide were not known and uncertainty exists regarding the potential for the formation of other reactive substances that could trigger toxic responses.

3.2.3.1 Death

No reports were located regarding death in humans or animals following dermal exposure to chlorine dioxide or chlorite.

3.2.3.2 Systemic Effects

No reports were located in which respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, endocrine, ocular, or body weight effects could be associated with dermal exposure to chlorine dioxide or chlorite in humans or animals.