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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-
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26 DRINKING WATER AND HEALTH final tract since subsequent fecal excretion was negligible. The major uri- nary excretion products were the sulfate and glucuronide conjugates of 2,5-dichlorophenol. Two minor urinary components were identified as di- hydroxydichlorobenzene and a mercapturic acid conjugate of p-dichloro- benzene. In contrast to their findings for o-dichlorobenzene, Reid et al. (1973) found that the metabolism (and excretion) of p-dichlorobenzene was not enhanced by pretreatment with phenobarbital, and p-dichloro- benzene was not hepatotoxic, even to the pretreated animals. HEALTH EFFECTS Observations ir' Humans A single case of aplastic anemia allegedly occurred following occupational exposure to p-dichlorobenzene and naphthalene (Harden and Baetjer, 1978). Observations in Other Species Acute Effects The single dose LDso in Wistar rats was reported to be 2.5 + 0.01 g/kg (Zupko and Edwards, 1949~. In another study, p-dichlo- robenzene administered to rats in a single oral dose decreased hexobarbi- tal-induced sleeping time (Carlson and Tardiff, 1976~. In short-term stud- ies with male rats given oral doses of p-dichlorobenzene generally ranging from 250 to 770 mg/kg/day, urinary excretion of coproporphyrin was in- creased severalfold, uroporphyrin and porphobilinogen slightly increased, and b-aminolevulinic acid moderately increased (Rimington and Ziegler, 1963~. In male Holtzman Sprague-Dawley rats, p-dichlorobenzene did not increase bile duct-pancreatic fluid flow following intraperitoneal injection at a dose of 1.4 mM bw (Yang et al., 1979~. Chronic Effects When p-dichlorobenzene was administered to male rats for 90 days at doses of 0, 10, 20, and 40 mg/kg bw, it significantly increased ethylp-nitrophenyl phenylphosphonothionate (EPN) detoxifica- tion, benzo~a~pyrene hydroxylase, and azoreductase (Carlson and Tardiff. 1976~; however, the chemical was not hepatotoxic. These results indicated that the chemical enhanced metabolism of foreign compounds. Oral doses of p-dichlorobenzene given to female rats at doses of S0, 100, or 200 mg/kg daily for as long as 120 days produced significant dose-dependent in- creases in liver weight and liver porphyrin content, but they did not affect urinary excretion of porphyrins (Carlson, 1977~. Rimington and Ziegler
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Toxicity of Selected Contaminants 27 (1963) gave p-dichlorobenzene to male albino rats by gastric intubation for as long as 41 days. Urinary coproporphyrin, uroporphyrin, porphobilino- gen, and b-aminolevulic acid were all significantly increased over controls after only 5 days at a dose of 770 mg/kg. There was no change in hepatic glutathione content. Mutagenicity No mutagenicity data were found by the committee. Carcinogenicity No additional data on the carcinogenicity of this com- pound have become available since its last review in Drinking Water and Health (National Research Council, 1977~. In June 1980, the National Cancer Institute/National Toxicology Program (1982a) initiated a carcino- genesis bioassay of p-dichlorobenzene in B6C3~ mice and Fischer 344 rats. Dosages of 200 or 600 mg/kg be were administered by gavage to both sexes of the mice and to the female rats. Male rats were given 150 or 300 mg/kg. The p-dichlorobenzene was administered in corn oil to groups of 50 rats and SO mice of each sex 5 days/week for 2 years. There were also corresponding vehicle and untreated control groups of 50 rats and 50 mice of each sex. Histopathologic findings of the study were not available at the time of this review. Teratogenicity No data were found by the committee. CONCLUSIONS AND RECOMMENDATIONS In the 1977 review of this chemical, the Safe Drinking Water Committee calculated an acceptable daily intake (ADI) of 0.0134 mg/kg/day, based on the data available at that time. This resulted in the calculation of a suggested no-adverse-response level of 0.094 mg/liter. This value con- tinues to be the recommended SNARL for chronic exposure. However, be- cause this chemical is being tested as a possible carcinogen, the SNARL should be reviewed when the bioassay is complete. The other basic conclu- sions and recommendations contained in the earlier volume are still valid for this chemical. Because large quantities of this chemical are used, studies should be conducted to determine its reproductive effects, teratogenicity, and muta- genicity, especially from oral exposures. Acute and subchronic toxicity tests emphasizing potential hepatic toxic responses would also be desir- able. Any need for further chronic tests should be assessed after the results of the carcinogenesis assay have been published.