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60 DRINKING WATER AND HEALTH Future research in animal models should be directed toward evaluating the physiological significance, if any, of the histopathological changes in- duced by methomyl in kidney tissue. PICLORAM 2-pyridinecarboxylic acid, 4-amin~3,5,6-trichloro- CAS No. 1918-02-1 NH2 Cl N COOH Picloram is a broad spectrum, persistent herbicide used on forage grasses. It is readily soluble in organic solvents (20,000 ppm in acetone) and water (430 ppm) (Johnson, 1971~; it is degraded by ultraviolet light (Wirthgen and Raffke, 1977~; and it is decomposed in water to negligible levels within 180 days (Johnson, 1971~. In the study by Johnson (1971), a standing pond was sprayed at a rate of 4 pounds/acre, which resulted in 2,400 ppb at time zero, 700 ppb at day 1, and 6 ppb at 180 days. METAB OLISM Picloram is rapidly absorbed from the gastrointestinal tract and is excreted virtually unchanged in the urine and feces of male Fischer 344 rats within 48 hours (Nolan et al., 1980~. Following a 10 mg/kg ~4C-picloram intra- venous dose, the isotope was cleared biphasically and excreted in the urine. The half-time for rapid and slow clearance from plasma was 6.3 and 128 minutes, respectively. Oral administration of the same dose resulted in comparable half-times of 29 minutes and 3.8 hours, respectively. At higher (1,400 mg/kg) oral doses, the plasma levels remained constant for 3 hours, then slowly declined. Balance studies in rats indicated that 98.4~o of the dose was recovered. Urinary excretion resulted in an 80~o to 84~o recovery, fecal excretion re- sulted in approximately 15~o recovery, less than 0.5~o was recovered in the bile, and virtually no radioactivity was recovered as trapped SCOT or as other volatile compounds (Nolan et al., 1980~.

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Toxicity of Selected Contaminants 61 HEALTH ASPECTS Observations in Humans The committee found no reports of adverse effects in humans. Observations in Other Species Acute Effects The acute oral LDso of picloram has been reported to be approximately 1.5 g/kg in mice, 4 to 8 g/kg in rats, and 2 to 3.5 g/kg in rabbits (Belov, 1971; Johnson, 1971; Nolan et al., 1980~. Single oral doses of 720 mg/kg in sheep and 540 mg/kg in cattle did not result in overt signs of toxicity. However, a toxic synergism between pi- cloram and (2,4-dichlorophenoxy~acetic acid (2,4-D) appears to exist in sheep. A 36 mg/kg dose of picloram plus 2,4-D at 134 mg/kg resulted in death of livestock (Jackson, 1966~. Chronic Effects Lifetime daily exposure of rats and dogs to diets con- taining 150 mg/kg bw doses of picloram resulted in no observable gross or microscopic signs of toxicity. In multigeneration studies conducted in rats at dietary concentrations up to 3,000 ppm, there was no evidence of ad- verse effects at the highest level tested (Johnson, 1971~. Inhalation exposure of rats to 150 mg/liter for 15 days resulted in no obvious signs of toxicity (Belov, 1971~. Mutagenicity In an in vivo cytogenetics study in male and female Sprague-Dawley rats, picloram administered orally at three dose levels (20, 200, and 2,000 mg/kg bw) produced no cytogenetic aberrations in bone marrow cells (Mensik et al., 1976~. The herbicide was found to be nonmutagenic in the Ames Salmonella assay (Andersen et al., 1972; Carere et al., 1978), but was mutagenic in Saccharomyces cerevisiae at 1 ppm (Guerzoni et al., 1976, abstract) and in the Streptomyces coelicolor for~vard mutation spot test (Carere et al., 1978~. No genetic effects were observed when picloram was tested for its ability to induce gene conver- sion, point mutations in the gene conferring resistance to 8-azaguanine, mitotic nondisjunction, and haploidization in Aspergillus nidulans (Bignami et al., 1977~. In summary, picloram was mutagenic in two out of four microbial test systems, but was nonmutagenic in an in vivo cytogenetics test with male and female rats.

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62 DRINKING WATER AND HEALTH Carci~zogenicity In a National Cancer Institute (1978) carcinogenicity bioassay of picloram, the test material was administered for 80 weeks to both sexes of Osborne Mendel rats at dietary levels of approximately 7,435 or 14,875 ppm. In addition, male and female B6C3F~ mice were fed pi- cloram at levels of approximately 2,500 or S,000 ppm in their diet. The histopathological findings indicated that there were no excess tumors in the male or female mice or in the male rats receiving the test material in their diets. However, the incidence of neoplastic nodules in the livers of female rats was significantly associated with picloram administration and there was an increase in the incidence of C-cell adenomas of the thyroid, which did not show an association with picloram administration. No other tumor at any other site was considered to be related to the exposure. The report concluded that "the findings are suggestive of the ability of the com- pound to induce benign tumors in the livers of female Osborne Mendel rats." Although these data have been reviewed by another scientist (Rueber, 1981), who viewed the results differently, the first analysis done by the Na- tional Cancer Institute appears to be the most objective and is supported by a review of the data by Robens (1978, abstract). These differences in interpretation, based on different diagnoses of identical slides, must be resolved to arrive at a more definitive assessment of the potential carcinogenicity of picloram. Teratogenicity Multigeneration studies, in which rats were exposed to picloram from gestation through reproductive cycles to levels as high as 3,000 ppm diet, produced no evidence of effects on fertility, gestation, via- bility of pups, lactation, or skeletal development. Pregnant rats receiving doses of 1,000 mg/kg/day during organogenesis were normal, but there was a slight increase in embryo resorption. A dose of 2,000 mg/kg/day was toxic to the mothers, but did not induce malformations in the pups. The dose of 750 mg/kg/day was not toxic to the mothers or the fetuses (John- son, 1971~. Thompson et al. (1972) found no teratogenic action when this com- pound was fed to rats in concentrations as high as 1,000 mg/kg bw on gestational days 6 through IS. No neonatal adverse affects were noted. From these limited data, it can only be concluded that picloram is not teratogenic in the rat. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARLJ Chronic Exposure The report by Johnson (1971) indicated that a 150 mg/kg dose of picloram can be regarded as a no-obsenred-effect dose.

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Toxicity of Selected Contaminants 63 Using this dose for a 70-kg human drinking 2 liters of water daily and an uncertainty factor of 1,000, and assuming that 205'o of exposure is pro- vided by water, one can calculate the chronic SNARL as: 150 mg/kg X 70 kg X 0 2 = 1 ns m~/liter- 1,000 X 2 liters The uncertainty factor of 1,000 was used because the issue of carcinogenic- ity has not yet been resolved and also because the Johnson (1971) study does not provide enough information for a complete judgment of its ade- quacy. Picloram is relatively nontoxic in rats fed concentrations as high as 3,000 ppm in the diet through three generations. It is not teratogenic in the rat or mutagenic in two out of four bacterial tester strains with or without micro- somal activation. The results of carcinogenicity testing in rats and mice are equivocal. At levels of 14,875 ppm, benign hepatomas were observed in female rats. Pi- cloram-related tumors were not reported in male rats or mice of both sexes. ROTENONE [l]benzopyrano[3,4-bifuro [2,3-h][llbenzopyran-6(6H) one, 1,2,12,12a-tetrahydr~8,9~imethoxy-2-(1-methylethenylY, [2R12CY, 6aa,2aaF CAS No. 83-794 OCH3 CH3O ~r~ CH2 H , Car H CH3 In the form of ground derris root, rotenone has been used as a nonpersis- tent insecticide to control pests on plants and animals and as a fish poison to manage or to eliminate undesirable species in reservoirs, lakes, and streams (Fukami et al., 1967~. First isolated in 1895, world consumption is