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LINDANE BACKGROUND INFOR - T ION Lindane is the gas- isomer of hexachlorocyclohexane and is commonly referred to by the misnomer hexachlorobenzene. Technical-grade 1 indane contains 99 percent ga~-hexachlorocyclohexane, but also contains 1 percent of other isomers. Lindane in Stable in the presence of 1 ight, heat, air, carbon dioxide, and strong acids; however, it is dehalogenated in the presence of alkali. Physical and chemical properties of 1 indane are shown in Table 1. About 1 mil 1 ion pounds of 1 indane are used yearly in the United States. It is used primarily for seed treatment and to control various wood-inhabiting beetles. Very little lindane is used for termite control; for this purpose, application is primarily to soil as a surface spray, rather than by injection or trenching. Lindane is also used in the treatment of scabies and 1 ice infestation. Lindane was the subject of an EPA rebuttable presumption against registration proceedings. Booker Chemical Corporation terminated production as a resul t of the proceedings, and there has been no reported production in the United States ~ ince 1976. SUMMARY OF TOXICITY INFO~T ION , Several comprehensive reviews of 1 indane are available (NRC, 1977b; IARC, 1974, 1979; EPA, 197 9d) . EFFECTS IN HUMANS l Several reports have 1 inked exposure to 1 indane with development of aplas tic anemia, ant these nave been reviewed elsewhere (NRC, 197 7b; IARC, 1979; Morgan et al., 1980) . However, this result has not been replicated in a seeiefactory denial model, and no fir causal relationabip has been established between lindane exposure and anemia. Nantel et al . ( 1977) investigated the health effects in 50 people who ate foot contaminated with lindane. Within hours, all experienced one or more of the following: nausea, vomiting, diarrhea, headache, dizziness, and paresthesia. Twenty suffered grand mat seizures and were hospitalized for 1 d. A series of reports (Brassow et al., 1981; Baumann et al., 1980, 1981; To~zal' et at., 1981) described the health status of 60 men (mean age, 40 yr) involved in lindane production for 1-30 yr (mean, 7.2 ye); 20 cleave ant 20 fairy workers were used as controls. The authors found no increase in mortality, no impairment of the central nervous syeeemor peripheral motor nerves, and co effects onECGe, liver enzymes, red and white blood cells, platelet counts, or hemoglobin. Neurologic effects were measured through electromyograms, e 1 ec troencephal ograme, ma tor~nerve c onduc tion ve ~ oc i ty, f oref inger tremors, and dexterity tracking tests. The authors noted an increas e — 29 —
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in polymorponuclear leukocytes and prothrombin time. In 54 of the workers and in controls, blood concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were measured. There was no difference in FSIl, and testosterone concentrations were slightly, but not significantly, lower than those in controls. Lindane workers had significantly higher LIl concentrations. Further research is needed to determine whether these changes represent an adverse health risk. EFFECTS IN ANIMALS Ac ute Exposure The oral LDsos of lindane for mice, rats, guinea pigs, ant rabbits are 86, 125-230, 100-127, ant 60-200 mg/kg of body weight, respectively (Gaines, 1969). The dermal LDs`' in rats is 1,000 mg/kg f o r mal e ~ and 90 0 mg/kg f or f emal e ~ . S igns o f intoxicat ion inc lude diarrhea, hypothermia, hyperirritability, incoordination, and consul ~ ions . Chronic Exposure and Care Erogenic ity Lindane was administered daily by stomach tube to male and female rats for 6 ma at 32 mg/~g or for 17 ma at 10 mg/kg (Klimmer, 1955~. Observed effects in rats given 32 mg/kg included fatty degeneration of the liver and renal tubular epithelium, vacuolization of cerebral cells, and an increase in mortality. Effects were not observed at the lower dosage. Rats were also given lindane in the diet at 2, 3. 4, 5, or 10 ppm for 12 ma, and no adverse effects were obeer~red (Melis, 1 9 55) . In a 2-yr feeding study (WHO/FAD, 1967), lindane was given to rats in the diet at 25, 50, or 100 ppm. At 50 and 100 ppm, there was hypertrophy of the liver, and at 100 ppm also fatty degenerative changes. No effects were observed at 25 ppm. Several authors have investigated the care ~nogenic potential of lindane. These studies have been thoroughly reviewed (NRC, 1977b; Reuber, 1979; IARC, 1979~. Nagasaki et al. (1972a) fed male mice lintane in the diet at 100, 250, or 500 ppm for 24 ok; no rumors were observed at any dose. Thorpe and Walker (1973) administered lindane to CF1 mice in the diet at 400 ppm; both sexes had increase. in liver t''~rs, compared with controls. In an NCI (1977c) bioassay, groups of 50 B6C3F} mice of each sex were given lindens in the tier at 80 or 160 ppe for 80 wk. Me incidence of hepatocellular carcinoma was significantly greater in the low~dose group, but not the high-dose group, compared with controls. The investigatore concluded that lindens was not carcinogenic under the condition. of the test. Groups of 50 mice of each sex were given lindane in the diet at 12.5, 25, or 50 ppm for 80 wk (Weisee and Herbet, 1977~; there was no significant increase in tumors, compared wi th c ontro 1~. The carcinogenicity of lindane has also been investigated in rate. Nagasaki et al . ( 1972b) administered 1 indane to groups of seven - 30
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Wistar rats in the diet at 250, 5()0, ant 1,000 ppm. At 48 Wk. one rat at the highest dose had a hepatoma and three others had hypertrophic nodules without signs of malignant tumors. In another study (NCI, 1977c), groups of 50 Osborne~ende} rats of each sex were given lindane in the diet--at 236 or 472 ppm for males and 135 or 270 ppm for females--for 80 wk. There was no statistically significant increase in tumors in any of the test groups. Teratogenicity and Reproductive Effects No effects on reproductive function were observed and there was no increase in malformations in a three-generation rat study in which 1 indane was given in the diet at 25, SO, or 100 ppm (Palmer et al ., 1978b). Teratogenic effects were not observed when lindane was given orally at 5, 10, or 15 mg/kg of body weight to rabbits on days 6-18 of gestation and to rats on days 6-16 of gestation (Palmer et al., 1978a) When 1 indane was given orally for 4 ma at ().5 mg/kg to female rats, disturbances in the estrus cycle and diminished reproductive capacity were observed (Nai~htein and Leibovich, 1911~. There was an increase in the incidence of stillborn pups when beagles were given lindane at 7.5 or 15 mg/kg from day 5 through the end of gestation. Khera _ al . ( 1979) administered Benesan (50 percent lindane) to rats oral ly at 0 ~ 6.25, 12.5 ~ or 25 mg/kg on days 6-15 or pregnancy There were no observed effects on fetal body weight or survival and no increase in Intrauterine deaths or anomal ies in the groups exposed to 1 indane. Mu tagenic i ey In a dominant-lethal assay, no mutations or reproductive effects were observed (NRC, 1977b). Lintane was not mutagenic in the host~ediated assay with Salmonella typhimurium or Serratia marcescens. Toxicokinet ic ~ In animals, 1 indane is biotransfonned to chlorophenole ~ trichlorophenol , tetrachlorophenol , and pentachlorophenol), which are excreted free or as sulfuric acid or glucuronic acid conjugates (Engat et al., 1976; Freal and Chadwick, 1973~. Chadwick et al. (1975) reported that 1 indane is f irat converted to a hexachlorocyclohexane intermediate and then to two tetrachlorophenol ~ and three trichlorophenol a. Lindane accumulates primarily in body fat ~ Davidow and Frawley, 1951; Oshibe, 1972~. In rats given lindane in the diet at 800 mg/kg of diet for 20 month, adipose tissue was the primary store (l)avidow and Frawley, 1951~. Concentration. in other tissues were lower by at reset 80 percent. Lindane was eliminated from tissue within 3 wk af ter exposure ended . Concentrations of 1 indane in the general populations of many countries have ranged from 0.02 to 1.43 ppm in adipose tissue and from 0.0031 to 0.0042 ppm in blood (Durham, 1969~. — 31 —
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EXISTING GUIDELINES AND STANDARDS The EPA (1979d) nas estimated that exposure of lindane in the drinking water at a concentration of 5.4 ag/L would result in a lifetime cancer rise of 10~6. The ACGIH (1981) has recommended a TEV-TWA of 0.5 mg/m3 and a TLV-STEL of 1.5 mg/m3. The OSHA (1981) permissible workplace exposure ~ imit is 0. S mg/m3. Both agencies noted that 1 Mundane is absorbed through the skin and that dermal exposure should therefore be avoided. — 32 —
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