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HEPTACHLO R BACKGROUND INFOR^T ION Heptachlor, a chlorinated cyclodiene, i8 a white to 1 ight tan, waxy solid, which is available as a tust, dust concentrate, emulsifiable concentrate, wettable powder, and o it solution. Technical-grate heptachlor is approximately 73 percent heptachlor and 28 percent trans-culordane and related compounte. It is a broad-spectrum insecticide that in the past was registered for use on 22 crops. After cancellation hearings held by the EPA in 197B, heptachlor's user were restricted to corn cutworms, some seed treatments, some crops, and termite control. It za expected that by 1983 subterranean termite control will be the only use of heptachlor (Dover et al., 1981~. Approximately 1-2 mil 1 ion pounds 0 f heptach 1 or are produced annual ly . Whereas about 25 percent of that produced was for termite control in 1974, nearly 90 percent was for termite control in 1980. The physical and chemical properties of hepLachlor are shown in Table 1. SUGARY OF TOXICITY INFOR~A'r ION Several comprehensive reviews of heptachlor are available (NRC, 1977a,b; IARC, 1974, 1979; EPA, 1979b). EFFECTS IN HUMANS There are very few reports on effects of human exposure to heptachior. Symptoms of poisoning with heptachlor would be expected to be similar to those with other cyclodienes and to include headache, dizziness, incoordination, tremors, and seizures. These effects could occur from oral, dental, or respiratory exposure. Reports of occupational exposure to chlordane (Wang and MacMahon, 1979; Shintell and Associates, 1980) included exposure to heptachlor. These are described in the section of this report on chlordane. EFFECTS IN ANIMALS Acute and Short-e Exposure The oral LDso values of heptacalor have been reported to se 100 and 162 mg/kg for male and female rats, respectively (Gaines, 1969~. The dermal LDso. are 195 and 250 mgJkg for male and female rats, respectively. Truhaut et al . ( 15~74) reported that the oral Loses of heptachlor were 105 mg/kg for rats and 100 mg/kg for hamsters. He peach 1 or i ~ c overt et za vivo by me cro somal oxidat ion e o heptach 1 or epoxide, a more toxic compound. The oral LDso of heptachlor epoxide for rats is 62 mg/kg (Sperling and Ewinike, 1969~. 19 ~
Heptachlor was administered daily to sheep, pigs, and rats at 2 and 5 mg/~g of body weight for 78-86 d (Kacew et al., 1973). The authors reported hepatic necrosis in all three species, with rats the most selective. Ch ronic Exposure ant Care inozenic icy The carcinogenicity data on heptachlor have been extensively reviewed elsewhere (Epstein, 1976; NRC, 1977a,b; IARC, 1979~. Unpublished studies of Kettering Laboratories have been reported by Epstein (1976~. Heptachlor of unspecified purity was given to CF rats at 1.5 3, 5, 7, and 10 mg/kg of diet for 100 wk. Tumore were observed in both controls and test groups. Statistical analysis by Epstein (1976) showed a significant increase in multiple-site tumors in females at 5, 7, and 10 mg/kg. NCI (1977b) has reported the results of a bioassay of technical-grade heptachlor (72 percent heptachlor, 18 percent trane-chlordane, 2 percent c~-chlordane, and 2 percent nonachlor) in Osborne-Mendel rats. Groups of 50 ret o of each sex were given heptachlor in the diet for do wk (38.9 and 77.9 ppm for males and 25.7 ant 51.3 ppm for females). No hepatic tumors were observed. Epstein (1976) also reviewed unpublished studies on the carcinogenicity of heptachlor in mice. In one study, C3H mice were given heptachlor at 10 mg/kg of diet for 2 yr. The original report concluded that heptachlor increased the incidence of benign hepatomas, but not malignant tumors, compared with controls. After histologic reevaluation (Epstein, 1976), it was concluded that there was a significant increase in hepatic carcinomas, compared with controls. In a second study reviewed by Epstein (1976), CD-1 mice were fed a mixture of 75 percent heptachlor epoxide and 25 percent heptachlor at 1, 5, and 10 mg/kg of diet for 18 mot 'there was a significant increase in hepatic carcinomas in males and females at 10 mg/kg and in males at 5 mg/kg. NCI (1977b) investigated the carcinogenic potential of technical-grate heptachlor in B6C3?1 mice. Groups of 50 mice of each sex were given heptachlor in the diet for 80 wk (6.1 and 13.8 ppm for males and 9 and 18 ppm for females). There was a highly significant dose-related increase in hepatocellular carcinoma. Teratogenicity and Reproductive Ef feces Heptachlor given to rats in the diet at 6 mg/kg body weight on an unspecified schedule caused a decrease in litter size in a multigcceration study (llestitzova, 1967~. Cataracts were obeervet in the parents and offspring~-in the latter group, soon after they opened their eyce. Rcaults of liver- and kidney-function tests were norm in al 1 test groups. Mutagenic ity Heptachlor was not mutagenic when tested in several strains of Salmonella typimurium with or without a rat-liver microsomal activation system (Marshall et al., 1976) . In a dominant-lethal tent, 20
rats were fed a diet containing neptachlor at 1 or 5 mg/kg for 3 generations (Cerey et al., 1973~. There were significant increases in the numbers of resorbed fetuses and increases in the numbers of abnormal mitoses in the second and third generations. A dominant-leehal test was also conducted in mice (Arnold et al., 197 7~. Male mice were given single doses of a mixture of 25 percent heptachlor and 75 percent heptachlor epoxide orally or intraperitoneally at 7.5 or 15 mg/kg of body weight and mated with untreated females. There was no effect on pregnancy rates, early deaths, or n''mber of live implants per female. To xicokinet ice In animals, heptachlor is rapidly oxidized by microsomal enzymes to 2, 3-heptachlor epaxide ~ Davidow and Radomaki, 195 3) . This reaction also occurs in soils and plants (Gannon and Bigger, 1958; Cannon and Decker, 1958a). Heptachlor epoxide is more toxic than heptachlor in animals. Heptachlor is also hydrolyzed to 1-hydroxy-4,5,6, 7,8,8- hexachloro-3a,4, 7, 7a-tetrahydro-4,5-methanoindene, which is then converted to the epoxide (Lu et al., 1975) . Heptachlor accumulates in body fat as the epaxide. Radomaki and Davidow ( 1953) found that, when rats were given heptachlor at 30 mg/kg of diet, the maximal concentration of heptachlor epoxide in fat was reached in 2-4 wk. The concentration fell to zero 12 wk af ter exposure ended. Heptachlor epoxide was found in the adipose tissue in the general population of several countries (Abooet et al., 1972; Curley et al., 1973~. EXIST ING GUIDELINES AND STANDARDS The EPA ( 1979b) has estimated that exposure to heptachlor in drinking water at 0.023 ng/L would be associated with a carcinogenic risk of lo-6 . The ACGIH (1981) has recommended a TLV-TWA of 0.5 mg/m3 and a ILV-STEL of 2.0 mg/~3. The OSaK (1981) permissible workplace exposure 1 imit is ().5 mg/~3. Both agencies noted that heptachlor is absorbed through the skin and that dermal exposure aboult therefore be avo ided . 21