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4 Chemistry and Toxicity of Selected Disinfectants and By-Products Volume 3 of the Drinking Water and Health series examined the toxicity of several major disinfectants and many of the by-products formed during drinking water disinfection. This chapter updates that material by assessing current research data. Recommendations for future research are also provided. Risk quantification is an essential tool for rationalizing regulatory ac- tions. Where sufficient data are available, quantitative risk assessments are calculated for the substances reviewed in this chapter. Quantitative risk assessment includes four distinct components: hazard identification, exposure assessment, dose-response assessment, and characterization of human risk at projected levels and patterns of exposure. Following a thorough review of the toxicological data, compounds were classified according to whether they were or were not known (or suspected) carcinogens. For carcinogens, the multistage model was chosen for ex- trapolating from the high doses used in animal studies to the lower doses common in the environment of humans. This model appears to have a greater biological basis than most other models and in most cases is more conservative, usually producing higher estimates of risk at low doses. It incorporates the reasonable assumption of background additivity and is thus linear at low doses. For carcinogens, the risk to humans is expressed as the probability that persons weighing 70 kg would develop cancer sometime in their lives as a consequence of ingesting 1 liter of water containing 1 fig of the substance daily over a lifetime of 70 years. Although risks to a 10-kg child were not calculated, the disproportionately high intake of drinking water by children compared with that of adults would place them at greater risk. 80

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Selected Disinfectants and By-Products {31 For substances not identified as known or suspected carcinogens and for which there were adequate toxicity data from prolonged ingestion studies in humans or animals, the subcommittee calculated a suggested no-adverse- effect level (SNARL), using methods developed in earlier volumes of Drink- ing Water and Health and estimating dose-response relationships when data were sufficient. This conventional approach was taken by default in the absence of suitable low-dose extrapolation models and because a "safe" level has not been demonstrated for these noncarcinogenic effects. The SNARL was derived by estimating a no-observed-effect level (NOEL) for any given compound and then dividing it by an uncertainty or safety factor. Because of the pitfalls encountered in estimating NOELs, evidence supporting such a level in any given study was carefully weighed. Safety factors should be properly interpreted to indicate levels of confidence in the underlying studies. For some substances, the data base was adequate to permit an estimate of the magnitude of interspecies or intraspecies variability and to suggest a safety factor based on that estimation. Where such an estimate was not possible, safety factors devised in the first volume of Drinking Water and Health (1977, pp. 803-804) were used: 10 when satisfactory data from chronic epidemiological or clinical studies were used; 100 for well-conducted long-term animal studies; and 1,000 for short-term studies or studies with some potential inadequacies. Ingestion may not be the sole route of exposure to substances in drinking water that are examined in this review. Cooking, showers, bathing, swim- ming, and other activities could theoretically provide important toxic con- tributions. Given the absence of data on these noningestion routes, this report does not include specific estimates of their contribution to total exposure. Further, drinking water is not the only medium or source of exposure to many of the substances evaluated here. To allow for exposures through other routes, the subcommittee generally assumed that drinking water provides 20% of the total exposure to a given substance. CHLORINE CAS No. 7782-50-5 C12 Chlorine was previously reviewed in Volume 2 of Drinking Water and Health (NRC, 1980, pp. 18, 39, 144-1661. At room temperature, chlorine is a greenish-yellow gas. It has a melting point of-102C and a boiling point of-35C. Chlorine is widely used as a water supply disinfectant as well as an oxidizing or chlorinating agent in producing chlorinated organic compounds. When chlorine is added to water, the following reactions occur:

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82 DRINKING WATER AND HEALTH Cl2 + H2O ~ HOCl + H+ + C1 HOC1 ~ H + + OCl Very little chlorine is available in molecular form (C12) at pH values greater than pH 3.0. The hypochlorous acid (HOC1) that is formed may further ionize to produce hypochlorite ion (OC1- ~ and hydrogen ion (H + ). The dissociation of hypochlorous acid to hypochlorite and hydrogen ions is dependent on the pH of the solution. Before analytical methods were capable of distinguishing free chlorine (HOCl + OC1- ~ from combined chlorine (chloramines), it was recognized that chlorine residuals depended on chlorine dose in a complex manner. Low concentrations of added chlorine produce an equivalent amount of chlorine residual (oxidant), but subsequent addition of chlorine causes a reduction in the residual. After the loss of most of the residual chlorine, a point is reached beyond which additional chlorine produces a chlorine residual that is clearly more effective as a bactericide but less stable with time of contact. This point is known as the "breakpoint." Thus, chlori- nation of drinking water is practiced in two distinct ways, depending on the level of nitrogen present and the level of chlorine added. Marginal chlorination, or the use of the first residual produced, is really chlor- amination. Breakpoint chlorination, or addition of chlorine beyond the dip in the curve of residual produced versus chlorine added, is free residual chlorination (White, 19721. HEALTH ASPECTS Based on relatively early literature, the American Conference of Govern- mental Industrial Hygienists (ACGIH, 1986) recommends a threshold limit value (TLV' expressed as an 8-hour time-weighted average for workroom air of 1 ppm (approximately 3 mg/m3) for occupational exposures to protect against chronic lung changes, accelerated aging, and corrosion of teeth. Observations in Humans Occupational and domestic poisonings to chlorine gas have been re- ported (Philipp et al., 19851. No other recent studies were found. Observations in Other Species . . Potential mutagenicity to germ cells was studied by Meter et al. (1985~. Oral administration of chlorine (pH 8.5) to B6C3F1 mice at 4 and 8 ma/ kg of body weight (bw) per day for 5 weeks induced significant increases in sperm-head abnormalities. In another study by Chang and Barrow

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Selected Disinfectants and By-Products 83 (1984), sensory respiratory tolerance was shown to develop in F-344 male rats after repeated exposure up to 10 days to chlorine gas at 2.5 and 10 ppm. As indicated earlier in this report, the principal health concerns, other than exposure directly to chlorine gas, arise from the use of chlorine as a disinfectant in drinking water supplies, when various chlorinated by- products such as the trihalomethanes are formed. However, Vogt and coworkers (1979) showed in vivo production of chloroform after ingestion of sodium hypochlorite; several halogenated by-products produced in vivo were found in blood plasma and stomachs of rats 1 hour after NaOC1 injection; and various halogenated organics are known to be produced by chlorination of amino acids (Trehy and Bieber, 1981), nucleic acids (Oli- vieri et al., 1980), uracil (Dennis et al., 1978), and nucleotides (Hoyano etal.,1973~. Revis and co-workers (1986) studied the prevention, by calcium ion in drinking water, of atherosclerotic plaques and the effects on serum cho- lesterol concentrations induced in pigeons by lead and cadmium. Chlorine, chlorine dioxide, chlorite, and monochloramine were added individually to the drinking water of separate groups of pigeons at 2 and 15 mg/liter for 3 months. The chlorine was tested at two pH levels (6.5 and 8.5) to provide conditions under which essentially 99% HOCl and 99% OCl- were being administered. While methods were not specifically stated, apparently the investigators examined major blood vessels for lipid-con- taining material, counted the number of plaques, and measured their area on the vessel wall. Plaque formation was reduced but low-density- lipoprotein (LDL) cholesterol levels increased. The sample size in this study was too small with proportionately too few controls to produce statistically significant results. Marked effects were observed on serum thyroid T3 and T4 levels at very low doses of the disinfectants. The marked increases in serum T3 and T4 need to be further evaluated, as well as the relevance of the pigeon as an animal model. This study is also described in the section on chlorine dioxide. CHLORINE DIOXIDE CAS No. 10049-04-4 C1O2 Chlorine dioxide is a reddish-yellow gas that freezes at-59.5C, boils at 10C, and is explosive in air at concentrations of about 4% or more. It decomposes in water and dissolves in alkalies, forming a mixture of chlorite and chlorate. In addition to its utility in water treatment, it is used as a bleach for wood pulp, fats, and oils; a maturing agent for flour; a biocide; and an

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84 DRINKING WATER AND HEALTH odor controller. The toxicity of chlorine dioxide was reviewed in Drinking Water and Health, Volume 4 (NRC, 1982, pp. 174-178~; the following material updates and reevaluates information on this disinfectant. METABOLISM Abdel-Rahman and coworkers (1980a, 1982) studied the absorption of 3 ml of a solution of 100 mg 36ClO2/liter of water given per os to male Wistar rats. The rate constant for absorption of the labeled C1 was 3.8/ hour. Within 72 hours, 31% of the label was excreted in the urine and 10% in the feces. The for in which Cl was excreted in feces was not identified; however, in buccal scrapings from monkeys, chlorine dioxide was reduced to a nonoxidizing substance rapidly (Bercz et al., 1982), suggesting that chlorine dioxide is rapidly altered after ingestion. Most of the labeled C1 found in the urine by Abdel-Rahman and associates was as chloride ion, with some chlorite and chlorate. Less than 5% of the administered dose of labeled Cl was found 72 hours after gavage in plasma, kidney, lung, stomach, duodenum, ileum, liver, spleen, and bone marrow. Moore and Calabrese (1980) administered 100 mg chlorine dioxide per liter of drinking water to A/J and C57L/J mice (18 mg/kg bw per day) for 30 days and studied possible effects on blood components, including glucose-6-phosphate dehydrogenase (G-6-PD), red blood cells, hemato- crit, mean corpuscular volume, mean corpuscular hemoglobin, mean cor- puscular hemoglobin concentration, reticulocyte count, and osmotic fragility. They found no significant effects on any of these parameters, though the G-6-PD activity in C57L/J mice was said to be reduced slightly. Bercz et al. (1986) summarized the conclusions from some of their studies of endocrine effects in Wistar and Sprague-Dawley rats and African Green monkeys, especially of chlorine dioxide on thyroid function. In both species ingestion of chlorine dioxide affects the mucosal surfaces of the alimentary tract and the chemical composition of nutrients and hor- mones within it, apparently by oxidation and covalent binding of bio- available iodide, which is ubiquitous in the digestive tract. Absorption of the iodinated molecules may be the mechanism for inhibition of activity by the thyroid and for an accelerated decrease in the concentration of thyroxin in the blood. HEALTH EFFECTS Observations in Humans Lubbers et al. (1981, 1982, 1983) exposed human volunteers to chlorine dioxide in a triphasic study; statistical analysis of the data was reported

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Selected Disinfectants and By-Products 85 by Lubbers and Bianchine (1984) and Lubbers et al. (19841. In phase I, the acute effects of increasing doses were investigated (Lubbers et al., 19811. Ten normal volunteers ingested two 500-ml portions of water containing chlorine dioxide 4 hours apart every fourth day for a total of 6 dosing days. Each portion was consumed within 15 minutes. The con- centration of chlorine dioxide was increased in steps on each of the 5 subsequent dosing days, from 0.1 mg/liter on the first day to 24 mg/liter on the final day. The maximum dose for a 70-kg person was 0.34 mg/kg bw. Hematic, blood chemical, urinary, and other values of the volunteers who ingested chlorine dioxide did not differ significantly from those of 10 volunteers who ingested plain water. Nevertheless, the investigators did not rule out the possibility that effects might become significant upon increased exposure. In phase II, 10 volunteers drank 500 ml of a solution containing chlorine dioxide concentrations of 5 mg/liter of water daily for 12 weeks. Weekly physical examinations and laboratory studies of blood and urine showed a statistically significant group-time interaction (p < 0.05) for group mean urea nitrogen values in the volunteers who ingested chlorine dioxide, but the investigators questioned the clinical significance of these changes. Phase III was concerned only with the effects of consumption of water containing sodium chlorite on G-6-PD-deficient subjects, which will be described in the section on that compound. Michael et al. (1981) conducted a prospective study of 197 inhabitants of a rural village using water disinfected with chlorine dioxide. They compared the hematological profiles of 87 males and 110 females (23 being less than 15 years of age) from this village with those of a group of 1 12 people (48 males and 64 females, 12 of whom were under 15 years of age) using unchlorinated water. The chlorinated water contained chlor- ine dioxide concentrations of 0.25-1.11 mg/liter and free-chlorine con- centrations of 0.45-0.91 mg/liter during the 12-week period of the study. The concentrations of chlorite and chlorate in the water were 3.2-7.0 ma/ liter and 0.87-1.8 mg/liter, respectively. The water treatment plant op- erated for only ~ hours a day, which was responsible, at least in part, for the variable concentrations measured. Neither the exposed group nor the comparison group of 118 persons showed any significant changes in he- matocrit, hemoglobin, erythrocyte count, white-cell count, reticulocyte count, mean corpuscular volume, methemoglobin level, serum creatinine, or serum total bilirubin from the preexposure levels to those measured after 115 days of exposure. Only blood urea nitrogen (BUN) was changed, the mean values of the test population at the end of the experiment being lower than at the beginning, with a slight but opposite trend in the com- parison group.

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86 OR ~ N K' NG WATER AN D H EALTH The researchers believed that they had not ruled out the possibility of transient effects, such as a transient hemolytic anemia. They pointed out the lack of racial and ethnic diversity in their study population. Only one person exhibited a G-6-PD deficiency; his erythrocyte count, hemoglobin, and hematocrit declined by the end of the 3 months of exposure, but without a noteworthy change in methemoglobin or in any other effect studied. These variables had returned at least partly to normal by 90 days after the end of the exposure. Analysis of variance showed a small but significant association of met- hemoglobin with sex, of total bilirubin with age, of BUN with exposure (as mentioned earlier), of hemoglobin with age, and an exposure-sex-age association with erythrocyte count. The investigators thought that BUN changes might reflect a mild dehydration during the summer weather prevailing at the end of the study and pointed to a similar pattern in the BUN/creatinine ratio consistent with this interpretation. They recom- mended that further research on chlorine dioxide disinfection focus on high-risk persons who might be especially susceptible to oxidants. Tuthill et al. (1982) examined a population that had used water disin- fected with chlorine dioxide in the 1940s, comparing its morbidity and mortality with those of a neighboring community. The chlorine dioxide- exposed group had a significantly greater proportion of premature births, but this difference between the two communities disappeared when the effect of the age of the mother on premature parturition was taken into account. The only other significant difference after compensating for var- iations in feeding methods was a greater postnatal loss of weight by infants born into the exposed population. Three older studies deserve mention here: those by Gloemme and Lund- gren (1957), Elkins (1959, pp. 89-90), and Ferris et al. (19671. Gloemme and Lundgren studied 12 men who had experienced acute symptoms usu- ally related to the respiratory tract, and who worked in a Swedish sulfite pulping plant during the mid-1950s. They were exposed usually to less than 0.1 ppm chlorine dioxide and of Cl, with occasional exposures to low concentrations of sulfur dioxide or to comparatively large concentra- tions of chlorine dioxide. Slight chronic bronchitis was identified in seven of these men. In one case, a detected bronchitis disappeared, proving reversibility of the lesion. There were complaints among the 12 men also of irritation of eyes, respiratory tract, and G.I. tract. Elkins found that 5 ppm of chlorine dioxide in air was definitely an irritant to the respiratory and the G.I. tracts. A concentration of 19 ppm of chlorine dioxide in the air within a bleach tank was reported by Elkins to have caused the death of a man assigned to work within the tank. Ferris et al. compared two populations of workers: one of 124 individuals working in a plant making Kraft paper and the other of 147 people working in a sulfite pulp mill and

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Selected Disinfectants and By-Products {37 with an average duration of possible exposure to chlorine dioxide, chlorine, and sulfur dioxide of 6 times that of the workers in the paper mill. Ferris and coworkers found no significant differences in ventilatory function or respiratory symptoms between the two populations. Observations in Other Species Acute Effects No studies of acute effects were found. Subchronic Elects Bercz et al. (1982) studied possible hematological effects in African Green monkeys given water that contained 100 mg chlorine dioxide/liter to yield a daily dose of 9.5 mg/kg bw during a 6- week period. This dose was without effects on measured components, but the monkeys were said not to have tolerated higher doses. Monkeys given chlorine dioxide at this dose level, but not those given 3.5 mg/kg bw per day, had decreased serum levels of thyroxine. The effect on secretions of thyroxine appears not to have been due to formation of chlorite or chlorate, as daily doses of 43 or 44 mg/kg bw of these compounds did not alter the concentration of thyroxine in the serum. Abdel-Rahman et al. (1980b) and Couri and Abdel-Rahman (1980) gave male Swiss Webster mice and Sprague-Dawley rats 1, 10, 100, or 1,000 mg chlorine dioxide per liter of drinking water. If the rats drank 0.1 ml/ kg bw per day and the mice 0.18 ml/kg bw per day, the first three concentrations would yield daily doses of 0.1, 1, and 10 mg/kg bw for rats and 0.18, 1.8, and 18 mg/kg bw for mice. (Because the highest concentration was expected to induce a decrease in water consumption, a dose corresponding to that concentration was not estimated.) At 2, 4, 6, and 12 months of exposure, the following were assayed: glutathione reductase, glutathione peroxidase, catalase, glutathione, and methemo- globin. There were various statistically significant changes, as judged by use of multiple t-tests, but there was no consistency with respect to dose or to period of exposure, except for an increase in both species in catalase activity at 1,000 mg/liter and at 10 and 100 mg/liter in mice. At no time nor at any dose was there an increased methemoglobinemia in either species. In another experiment from the same laboratory (Abdel-Rahman et al., 1984), osmotic fragility was studied in rats given drinking water containing 10 to 1,000 mg chlorine dioxide/liter (about 1 to 100 mg/kg bw per day). There was a dose-related increase in resistance of erythrocytes to hemolysis in hypotonic media (i.e., decreased fragility) in animals given water con- taining 10 to 100 mg/liter. When the concentration was increased from 100 to 1,000 mg/liter, the increase in resistance was not proportional to

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88 DRINKING WATER AND HEALTH the earlier ones, perhaps because of the markedly decreased water con- sumption mentioned above. Mutagenicity Meter et al. (1985) observed no increase in sperm-head or chromosomal aberrations or in micronuclei formation in CD-1 mice administered aqueous chlorine dioxide by Savage (3.2, 8, or 16 mg/kg bw per day) for 5 days. The sperm heads were examined at 1, 3, and 5 weeks after the last dose, to detect effects at all stages of spermatogenesis. No evidence that Clot induces mutational change was found. Carcinogenicity No investigation of possible carcinogenicity of C1O2 was found. Reproductive Toxicity Abdel-Rahman et al. (1984) found a dose-re- lated decrease in testicular uptake of 3H-thymidine in male rats given 10 or 100 mg of chlorine dioxide/liter or 10 mg/kg bw per day) in their drinking water (65% and 38% of control levels, respectively). This sug- gests a reduction in cell division in the testes but does not indicate what effect, if any, there was on spermatogenesis or on hormone production. Teratogenicity Orme et al. (1985) gave female rats drinking water containing chlorine dioxide concentrations of 2, 20, or 100 mg/liter starting 2 weeks prior to mating and continuing through lactation, 21 days after parturition. At the highest concentration, 100 mg/liter (14 mg/kg bw per day), there was a significant depression of the concentration of thyroxine in serum in the pups, but not in the dams, at the time of weaning. No significant thyroid effects were seen in pups from the group ingesting 20 mg of chlorine dioxide/liter. There was a decrease (p = 0.08) in ex- ploratory and locomotor activity in pups born to dams given 100 mg/liter but not in pups from dams given 20 mg/liter (3 mg/kg bw per day). In a second experiment, pups born to dams drinking plain water were admin- istered chlorine dioxide at concentrations of 14 mg/kg bw by stomach tube per day between days 5 and 20 after birth. There was a larger depression in serum thyroxine and a greater and more consistent delay in development of exploratory and locomotor activity (p < 0.05) than in the first exper- iment. Taylor and Pfohl ( 1985) observed a significant reduction in cell number, as judged by total DNA content, in the cerebella of rat pups born to dams given water containing chlorine dioxide concentrations of 100 mg/liter through gestation and lactation. Pups given 14 mg/kg bw per day by stomach tube had reduced numbers of cells in both cerebellum and fore- brain at 11 days postpartum and exercised less than normal on a voluntary running wheel at 50-60 days postpartum (though administration of chlor- ine dioxide had ended at 20 days of age).

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Selected Disinfectants and By-Products 89 Sub et al. (1983) examined the effects of chlorine dioxide and its metabolites on fetal development in the rat. Female rats were administered chlorine dioxide at 0, 1, 10, or 100 mg/liter of drinking water for 2.5 months prior to and throughout gestation. The small number of dams bred (six to nine per test group), an unusually high percentage of abnormal control fetuses (Gino), and uncertainty as to the unit of statistical com- parison (fetus or litter) preclude statistical significance of observed skeletal variations and decreased number of implants per dam. A statistically significant increase in fetal body weight at the 100-mg/liter dose level may be a consequence of the reduced litter size observed at this dose. Sub et al. (1983) gave groups of six to eight female Sprague-Dawley rats drinking water containing chlorine dioxide concentrations of 0, 1, 10, or 100 mg/liter (O. 0.1, 1, or 10 mg/kg bw per day) for 2.5 months, before they were bred with untreated males. Exposure was continued throughout gestation. At the highest dose, there were reductions in mean number of implants and mean number of live fetuses per dam. The small number of litters and the unusually high percentage of abnormal fetuses among the control litters (approximately 31%) preclude statistical significance of skeletal variations observed and invite questions as to the validity of the study. Other Effects Revis et al. (1986) investigated the effects of drinking water containing chlorine dioxide at 2 or 15 ppm on thyroid function and on plasma cholesterol in rabbits and pigeons. In pigeons supplied drinking water containing 15 ppm chlorine dioxide for 3 months, concentrations of T4 in the plasma were reported to be significantly reduced whether they were on a normal or a high-cholesterol diet, as compared with those of controls. In most of the groups, T4 levels were reported to be significantly lower after imbibing water containing a 2-ppm concentration of chlorine dioxide. Increases in plasma cholesterol were seen frequently in groups with the lower T4 levels, especially in those given the high-cholesterol diet and the water at 15 ppm chlorine dioxide. Revis et al. suggest that these effects are mediated by-products formed by the reaction of chlorine dioxide, hypochlorite, and monochloramine with organic matter in the upper gastrointestinal tract. The significance of this study for humans is unknown because little information exists on pigeon thyroid function. Further, the statistical and hormone measurement methods used in this study appear inappropriate to the experimental design. CONCLUSIONS AND RECOMMENDATIONS Chlorine dioxide produces hematological effects in both humans and laboratory animals. The mechanism of these effects is not known; how- ever, it is believed to be related to the oxidant properties of chlorine

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90 DRINKING WATER AND HEALTH dioxide and its aqueous reaction products, chlorite and chlorate. In ad- dition, thyroid and developmental neurological effects have been observed in laboratory animals. The thyroid effects of chlorite are thought to be caused by its oxidation of dietary iodide in the gastrointestinal tract. The oxidized iodide then binds to either food or tissue and is unavailable for absorption. The mechanisms of the neurological anomalies are unknown. Orme et al. (1985) found that levels of 14 mg/kg bw per day produced drops in T4 levels and abnormal neurological development in rat pups born to dams exposed during gestation and lactation. The investigators were able to show a no-observed-effect level (NOEL) of 3 mg/kg bw per day. In addition, Bercz et al. (1982) were able to show a NOEL of 3.5 mg/kg bw per day for thyroid effects in monkeys, supporting the more recent results by Orme et al. (19851. The committee selected the NOEL of 3.0 mg/kg bw per day and an uncertainty factor of 100 to estimate a chronic suggested no-adverse-effect level (SNARL) assuming that a 70-kg human consumes 2 liters of water daily, which contributes 20% of total intake: 3 mg/kg low/day x 70 kg x 0.2 0.21 mg/liter, or = 100 x 2 liters 210 ~g/liter. A SNARL may also be estimated for a 10-kg child consuming 1 liter of water daily, which contributes 20% of total intake: 3 mg/kg low/day x 10 kg x 0.2 100 x 1 liter CHLORAMINES Monochioramine CAS No. 10599-90-3 NH2C _ 0.06 mg/liter, or 60 ~g/liter. Pure monochloramine is a colorless, unstable, and pungent liquid with a freezing point of-66C. It decomposes above-50C and forms ni- trogen, chlorine, and nitrogen bichloride (Cotton and Jones, 1955; Ko- vacic et al., 19701. Monochloramine is used as an intermediate in the Raschig process for the industrial production of hydrazine. However, aqueous solutions of monochloramine formed by the chlorination of natural waters containing ammonia hold the primary environmental significance of the compound.

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Selected Disinfectants and By-Products 179 Heffernan, W. P., C. Guion, and R. J. Bull. 1979b. Oxidative damage to the erythrocyte induced by sodium chlorite, in vivo. J. Environ. Pathol. Toxicol. 2:1487-1499. Helliwell, M., and J. Nunn. 1979. Mortality in sodium chlorate poisoning. Br. Med. J. 1:1119. Kurokowa, Y., N. Takamura, Y. Matsushima, T. Imazawa, and Y. Hayashi. 1984. Studies on the promoting and complete carcinogenic activities of some oxidizing chemicals in skin carcinogenesis. Cancer Lett. 24:299-304. Lubbers, J. R., and J. R. Bianchine. 1984. Effects of the acute rising dose administration of chlorine dioxide, chlorate and chlorite to normal healthy adult male volunteers. J. Environ. Pathol. Toxicol. Oncol. 5(4/5):215-228. Lubbers, J. R., S. Chauhan, and J. R. Bianchine. 1981. Controlled clinical evaluations of chlorine dioxide, chlorite and chlorate in man. Fund. Appl. Toxicol. 1:334-338. Lubbers, J. R., S. Chauan, and J. R. Bianchine. 1982. Controlled clinical evaluations of chlorine dioxide, chlorite and chlorate in man. Environ. Health Perspect. 46:57-62. Lubbers, J. R., J. R. Bianchine, and R. J. Bull. 1983. Safety of oral chlorine dioxide, chlorite, and chlorate ingestion in man. Pp. 1335-1341 in R. L. Jolley, W. A. Brungs, J. A. Cctruvo, R. B. Cumming, J. S. Mattice, and V. A. Jacobs, eds. Water Chlorination: Environmental Impact and Health Effects, Vol. 4. Book 2: Environment, Health, and Risk. Ann Arbor Science, Ann Arbor, Mich. Lubbers, J. R. S. Chauhan, J. K. Miller, and J. R. Bianchine. 1984. The effects of chronic administration of chlorine dioxide, chlorite and chlorate to normal healthy adult male volunteers. J. Environ. Pathol. Toxicol. Oncol. 5(4/5):229-238. Meter, J. R., R. J. Bull, J. A. Stober, and M. C. Cimino. 1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm- head abnormalities in mice. Environ. Mutagen. 7:201-21 1 . Moore, G. S., and E. J. Calabrese. 1980. The effects of chlorine dioxide and sodium chlorite onerythrocytesofA/J and C56L/J mice. J. Environ. Pathol. Toxicol. 4(2,3):513- 524. Moore, G. S., and E. J. Calabrese. 1982. Toxicological effects of chlorite in the mouse. Environ. Health Perspect. 46:31-37. NRC (National Research Council). 1980. Drinking Water and Health, Vol. 3. National Academy Press, Washington, D.C. 415 pp. NRC (National Research Council). 1982. Drinking Water and Health, Vol. 4. National Academy Press, Washington, D.C. 299 pp. Stavrou, A., R. Butcher, and A. Sakula. 1978. Accidental self-poisoning by sodium chlorate weed-killer. The Practitioner 221:397-399. Steffen, C., and R. Seitz. 1981. Severe chlorate poisoning: Report of a case. Arch. Toxicol. 48:281-288. Sub, D. H., M. S. Abdel-Rahman, and R. J. Bull. 1983. Effect of chlorine dioxide and its metabolites in drinking water on fetal development in rats. J. Appl. Toxicol. 3:75- 79. Sub, D. H., M. S. Abdel-Rahman, and R. J. Bull. 1984. Biochemical interactions of chlorine dioxide and its metabolites in rats. Arch. Environ. Contam. Toxicol. 13:163- 169. Chloroform and DibromochIoromethane Ahmadizadeh, M., C.-H. Kuo, and J. B. Hook. 1981. Nephrotox~city and hepatotoxicity of chloroform in mice: Effect of deuterium substitution. J. Toxicol. Environ. Health 8:105-111.

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182 DRINKING WATER AND HEALTH Page, T., R. H. Harris, and S. S. Epstein. 1976. Drinking water and cancer mortality in Louisiana. Science 193:55-57. Palmer, A. K., A. E. Street, F. J. C. Roe, A. N. Worden, and N. J. Van Abbe. 1979. Safety evaluation of toothpaste containing chloroform. II. Long term studies in rats. J. Environ. Pathol. Toxicol. 2(3):821-833. Pereira, M. A., G. L. Knutsen, and S. L. Herren-Freund. 1985. Effect of subsequent treatment of chloroform or phenobarbital on the incidence of liver and lung tumors initiated by ethylnitrosourea in 15 day old mice. Carcinogenesis 6:203-207. Pohl, L. R., and G. Krishna. 1978. Deuterium isotope effect in bioactivation and hepa- totoxicity of chloroform. Life Sci. 23: 1067- 1072. Pohl, L. R., B. Bhooshan, N. F. Whittaker, and G. Krishna. 1977. Phosgene: A metabolite of chloroform. Biochem. Biophys. Res. Commun. 79:684-691. Rapson, W. H., M. A. Nazar, and V. V. Butsky. 1980. Mutagenicity produced by aqueous chlorination of organic compounds. Bull. Environ. Contam. Toxicol. 24:590-596. Roe, F. J. C., A. K. Palmer, A. N. Worden, and N. J. Van Abbe. 1979. Safety evaluation of toothpaste containing chloroform. I. Long-term studies in mice. J. Environ. Pathol. Toxicol. 2(3):799-819. Ruch, R. J., J. E. Klaunig, N. E. Schultz, A. B. Askari, D. A. Lacher, M. A. Pereira, and P. Goldblatt. 1986. Mechanisms of chloroform and carbon tetrachloride toxicity in primary cultured mouse hepatocytes. Environ. Health Perspect. 69:301-305. Smith, J. H., and J. B. Hook. 1984. Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol. Appl. Pharmacol. 73:511-524. Stevens, J. L., and M. W. Anders. 1981. Effect of cysteine, diethyl maleate, and pheno- barbital treatments on the hepatotoxicity of [iH]- and [2H]chloroform. Chem.-Biol. Interact. 37:207-217. Withey, J. R., B. T. Collins, and P. G. Collins. 1983. Effect of vehicle on the pharma- cokinetics and uptake of four halogenated hydrocarbons from the gastrointestinal tract of the rat. J. Appl. Toxicol. 3:249-253. Young, T. B., D. A. Wolf, and M. S. Kanarek. In press. Case-control study of colon cancer and drinking water trihalomethanes in Wisconsin. Int. J. Epidemiol. Haloacids Blackshear, P. J., P. A. H. Holloway, and K. G. M. M. Alberti. 1974. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem. J. 142:279-286. Crabb, D. W., E. A. Yount, and R. A. Harris. 1981. The metabolic effects of dichlo- roacetate. Metab. Clin. Exp. 30:1024-1039. Davis, M. E. 1986. Effect of chloroacetic acids on the kidneys. Environ. Health Perspect. 69:209-214. Demaugre, F., C. Cepanec, and J.-P. Leroux. 1978. Characterization of oxalate as a catabolite of dichloroacetate responsible for the inhibition of gluconeogenesis and py- ruvate carboxylation in rat liver cells. Biochem. Biophys. Res. Commun. 85:1180-1185. Dierickx, P. J. 1984. In vitro binding of acetic acid and its chlorinated derivatives by the soluble glutathione S-transferases from rat liver. Res. Commun. Chem. Pathol. Phar- macol. 44:327-330. Evans, O. B. 1982. Dichloroacetate tissue concentrat~ons and its relationship to hypolac- tatemia and pyruvate dehydrogenase activation. Biochem. Pharmacol. 31:3124-3126.

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