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22 DRINKING WATER AND HEALTH TABLE II-3 Carcinogenic Risk Estimates for Chlorobenzenea l Animal Sex Estimated Human Life- time Risk at a Daily Dose of 1 ~g/liter Upper 95% Confidence Estimate of Lifetime Cancer Risk per ~g/liter Fischer344 rat Male 3.71 X 10-8 2.13 X 10-7 . a Based on data from the National Toxicology Program, 1982a. Using the criteria for interpreting animal carcinogenicity data as out- lined in Chapter I, the committee based the above calculation on limited evidence. Teratogenicity No data were found by the committee. Conclusions and Recommendations A recent report indicates that chlorobenzene was weakly carcinogenic at a dose of 120 mg/kg in male rats. Therefore, a chronic SNARL will not be calculated because chlorobenzene is considered to be potentially carcino- · ~ genie ln humans. The basic conclusions and recommendations contained in the 1977 Dnnking Water and Health report remain valid, and mutagenicity and teratogenicity data are still needed. Bioassays for carcinogenesis fulfill the need for some data; however, well-designed studies of subchronic expo- sures should be conducted to identify species differences in potential hepa- totoxicity and to learn which effects should be used as a basis for establish- ing limits in drinking water. DICHLOROBENZENE I,2~ichiorobenzene, benzene I,2~ichIor~ CAS No. 95-501 ll o-Dichlorobenzene is used primarily as an intermediate in the synthesis of dyestuffs, herbicides, and degreasers. It is also used as a process solvent in the manufacture of toluene diisocyanate (Ware and West, 1977~. It has a
Toxicity of Selected Contaminants 23 melting point of17.6°C, a boiling point of 179°C, and a density of 1.3 g/ ml at 20°C (Weast and Selby, 19751. Its solubility in water at 25°C is 145,000 Igniter (Jacobs, 1957~. Most of the literature on o-dichlorobenzene does not distinguish this compound from other isomers or from dichlorobenzenes in general. Con- sequently, this review is limited to those data that clearly identify o-dichlo- robenzene as the chemical under study. METAB O LI S M Parke and Williams (1955) measured the excretion of o-dichlorobenzene by rabbits given a single oral dose of 500 mg/kg bw. Virtually all of the compound was excreted in 6 days, predominantly in urinary conjugates of glucuronide (ammo), ethereal sulfate (21%), and mercapturic acid (ado). The remainder was excreted as monophenols. HEALTH A SPE CTS Observations in Humans The commmttee found no info~,ation concerning the exposure of humans only to o-dichlorobenzene. Observations in Other Species Acute Effects The acute oral LDSo for guinea pigs was reported to range from 0.8 to 2.0 ~g/kg (Hollingsworth et al., 1958~. After 6-hour in- halation exposures the acute LCSo in mice was reported to be 1,236 ppm (6,825 mg/m3~; range, 1,201-1,279 ppm (Bonnet et al., 1979~. O-Dichlorobenzene produced increased urinary excretion of copropor- phyrin, porphobilinogen, and b-aminolevulinic acid, but the responses were less pronounced than those induced by the 1,4-isomer (Rimington and Ziegler, 1963~. Female Wistar rats dosed orally with o-dichloroben- zene at a level of 250 mg/kg for 3 days had an increase in liver weights and microsomal protein content and enhanced aminopyrine demethylase activ- ity in the liver (Ariyoshi et al., 1975~. O-Dichlorobenzene injected intraperitoneally into male Sprague-Dawley rats produced centrilobular necrosis that was enhanced by prior adminis- tration of phenobarbital (Reid et al., 1973), which was also found to en- hance the excretion of metabolites of o-dichlorobenzene. However, the lat- ter response was blocked by administration of SKF 525-A, confirming that
24 DRINKING WATER AND HEALTH the hepatotoxicity of o-dichlorobenzene is probably mediated through an activated metabolite. Ribonucleic acid (RNA) and protein synthesis was found to be strongly inhibited in HeLa cells exposed for 30 minutes to 350 ~g/ml concentra- tions of o-dichlorobenzene. A possible mechanism leading to such inhibi- tion is the uncoupling of oxidative phosphorylation (Myhr, 19731. Chronic Effects Repeated oral doses as high as 376 mg/kg given to female rats for 192 days produced a moderate increase in liver weights and a slight increase in kidney weights. After 7-hour inhalation exposures ad- ministered 5 days/week for 6 to 7 months at levels of 49 or 93 ppm (271 or 513 mg/m3), o-dichlorobenzene produced no adverse effects in rats, guinea pigs, rabbits, or monkeys (Hollingsworth et al., 19581. Because the number of animals used in this study was limited to 10 animals per dose level with up to 50~7O lethality, the data are of questionable value. Mutagenicity o-Dichlorobenzene was found to be nonmutagenic in eight histidine-requiring Salmonella strains and in a bacteriophage T4 mutation assay. However, the results remain inconclusive because no metabolic activation system was included in the assay procedures (Ander- sen et al., 1972~. Carcinogenicity o-Dichlorobenzene was tested for carcinogenicity in both sexes of the B6C3F~ mouse and the Fischer 344 rat (National Toxicol- ogy Program, 1982a). Dosages of 60 or 120 mg/kg bw were administered by garage to both sexes of the mice and the rat. o-Dichlorobenzene was administered in corn oil to groups of 50 rats and 50 mice of each sex 5 days/week for 2 years. There were also corresponding vehicle and un- treated control groups of SO rats and 50 mice of each sex. No compound-related carcinogenic effect was detected in either sex of the mice or rats; however, the maximum tolerated dose was probably not used in this study. No other effects were reported. Teratogenicity No data were found by the committee. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARLJ Chronic Exposure A tentative chronic SNARL is calculated below. Us- ing the lowest dose level from the carcinogenicity bioassay (60 mg/kg) and assuming that a 70-kg human consumes 2 liters of water dai'y, that 20~o of
Toxicity of Selected Contaminants 25 exposure is from water, an uncertainty factor of 1,000, and a factor of 5/, to correct from a 5- to 7-day weekly exposure, one may calculate the chronic SNARL as: 60 mg/kg X 70 kg X 0 2 X 5 = 0.3 mg/liter. 1,000 X 2 liters 7 The uncertainty factor of 1,000 is used because the bioassay from which this dose was selected has not been formally reviewed and published. This calculation must be reviewed when that occurs. Further studies of this chemical should be directed toward comparative pharmacokinetics, muta- genicity, and characterization of hepatotoxicity. DICHLOROBENZENE 1,4~ichlorobenzene; benzene, I,4~ichIorm CAS No. 106 4~7 Cl Cl p-Dichlorobenzene was renewed in the first volume of Dnnking Water and Health (National Research Council, 1977, pp. 681-686~. The following matenal, which became available after the 1977 report was prepared, up- dates and, in some instances, reevaluates the infonnation contained in the previous review. Also included are some references that were not assessed in the earlier report. The literature contains no important new information that would alter the basic conclusions drawn in 1977. METAB OLISM The metabolism of p-dichlorobenzene was extensively studied in rats fol- lowing repeated inhalation, oral, or subcutaneous doses (Hawkins et al., 1980~. After these exposures, residues detected by ]4C content were ob- senred in fat, kidneys, liver, and lungs, but they declined rapidly to levels below limits of detection within 5 days after exposure. From 91 No to 97~o of the dose was excreted in the urine. Biliary excretion ranged from 46~o to 63%, but the excreted material apparently was reabsorbed from the intes-
