Paul S. Larson

Toxicologic studies on 2,4-dichlorophenyl-p-nitrophenyl ether☆

Abstract Studies on 2,4-dichlorophenyl- p -nitrophenyl ether (TOK ® , a new selective herbicide, were undertaken in several animal species to characterize its toxicity. In rats, the single po LD50 ± SD value for technical grade TOK (95%) was 2.63 ± 0.13 g/kg as compared to 3.58 ± 0.14 g/kg for 100% TOK. It did not produce skin irritation in rabbits or cutaneous sensitization in guinea pigs. Rats on dietary levels of 100 and 500 ppm for 13 wk, and on 10, 100, and 1000 ppm for 97 wk, showed no definite differences in growth, feed consumption, and mortality, as compared to respective controls. In the 13-wk study in rats, liver-to-body weight ratios at all dietary levels of TOK, except for males on 100 ppm, were significantly higher. Kidney ratios were elevated for female rats on 12,500 ppm and above and for male rats on 2,500 and 12,500 ppm. In the 97-wk study, organ-tobody weight ratios showed significant increases for kidneys and liver for male rats only on the 1000 ppm diet. No dose-related effects were noted on hemograms, urinary findings, and in microscopic examination of tissues in both the subchronic and chronic studies. In a 2-yr study in dogs given 20, 200, and 2000 ppm diets, no adverse trends were noted on growth, feed consumption, hematology, urinary findings, BSP, SGOT, SAP, BUN, and histopathologic findings. Significantly higher liver-to-body weight ratios appeared only in dogs on the 2000 ppm diet. Three-generation reproduction studies in rats throughout 2 mating cycles revealed no adverse trends in fertility, gestation, viability, and lactation indices for rats on 10 and 100 ppm diets; however, 1000 ppm diet affected the incidence of stillbirths and decreased pup survival, to a point where no pups were available for the F 1b generation, and 100 ppm caused some increase in stillbirths. Overall, in these studies, the highest no-effect level found was 10 ppm.

Acute, subchronic, and chronic toxicity of chlordecone

Oral LD50 values were 132 mg/kg for male rats, 126 mg/kg for female rats, 71 mg/kg for male rabbits, and approximately 250 mg/kg for dogs. The percutaneous LD50 for male rabbits was 410 mg/kg. Deaths were preceded by the development of severe tremors. Gross autopsy findings were essentially negative. Rats were fed chlordecone in concentrations of 1, 5, 10, 25, and 80 ppm for up to 2 years. All rats on 50 and 80 ppm died during the first 6 months. Depressed growth occurred at concentrations at low as 10 ppm for females and 25 ppm for males. Food consumption tended to increase as the dietary concentration of chlordecone became greater. This effect was associated with a measured increase in the metabolic rate. Concentrations of 5 ppm and higher accelerated and intensified the rate of development of proteinuria. Increased liver-to-body weight ratios were consistently observed. Elevated ratios for other organs measured (kidney, heart, spleen, and testes) were found at certain periods, but at higher chlordecone concentrations than required for liver. Principal histopathologic findings in rats were degenerative changes in liver cells (fatty changes, hyperplasia), kidney lesions (primarily glomerulosclerosis), and testicular atrophy. Hematocrit and hemoglobin values were reduced in rats receiving concentrations of 25 ppm and above. There was no evidence of a clotting defect, although some rats receiving 50 and 80 ppm showed a bleeding tendency. Beagle dogs fed chlordecone at concentrations of 1,5, and 25 ppm for periods up to 127 weeks exhibited few gross or histopathologic signs of toxicity.

Toxicologic and metabolic studies on pentachloronitrobenzene

In studies on technical grade pentachloronitrobenzene (PCNB), in a 3-generation reproduction study on rats, no adverse effects on any parameter appeared from diet levels through 500 ppm. Two-year feeding to beagle dogs established 30 ppm as the highest no-effect level tested; cholestatic hepatosis with secondary bile nephrosis was found in minimal degree on 180 ppm and in moderate degree on 1080 ppm, but was considered to be a reversible lesion. Storage of PCNB did not occur in tissues of the rat, dog, or cow (the latter fed at levels up to 1000 ppm). Traces of apparent PCNB were found in milk from treated cows, but this was also common to milk from control cows (analysis of the feed used showed apparent PCNB). Pentachloroaniline and methyl pentachlorophenyl sulfide, metabolites of PCNB, were found in tissues of treated animals of all 3 species, which together with absence of PCNB indicates rapid metabolism of the latter. In contrast, tissue storage of hexachlorobenzene and pentachlorobenzene, contaminants of technical PCNB, was found in all 3 species, in degrees paralleling their contents in the PCNB, indicative of a slower rate of metabolism of these compounds. Since PCNB is proposed for use as a soil fungicide in combination with 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (Terrazole®), the possibility of potentiation of toxicity was examined in acute oral tests on rats; no potentiation was found. In acute (24-hr) percutaneous toxicity tests in rabbits, no signs of intoxication resulted from application of 4 g/kg of PCNB as a 30% solution in corn oil.

Toxicologic studies on 3′,4′-dichloropropionanilide

Studies on 3′,4′-dichloropropionanilide (DCPA), a selective herbicide, are presented. For rats and dogs the single estimated po LD50 ± SD values are 1384 ± 99 mg/kg and 1217 ± 8 mg/kg, respectively. In subchronic (13 wk) studies in rats on 0, 100, 330, 1000, 3300, 10,000 and 50,000 ppm diets, survival of rats on the 50,000 ppm diet was affected, and at 10,000 and 3300 ppm, growth and feed consumption were depressed. Polychromatophilia was observed in rats on the 1000 and 330 ppm diets; the effect was marked in rats on the 10,000 and 3300 ppm diets. Significant decreases in hemoglobin values were found between controls and the 3 highest diet levels for 13 wk. In a chronic (2 yr) study in rats on 0, 100, 400 and 1600 ppm diets, significant decrease in growth and increase in organ-to-body weights ratio for spleen, liver of females, and testes of rats on the 1600 ppm diet were noted. No dose-related effects were noted on hemograms, except for significant decreases in hemoglobin values for females on the 1600 ppm diet, urinary findings and histopathology. In a 2 yr study in dogs on 0, 100, 600 and 4000 ppm diets, no adverse trends were noted on survival, hematology, urinary findings, liver function tests, organ-to-body weight ratios (with the exception of the heart of dogs on the 4000 ppm diet) and histopathology. However, body weight of dogs on 4000 ppm diets was significantly depressed. In multigeneration studies in rats on 0, 100, 300 and 1000 ppm diets, no apparent deleterious effects or adverse trends were noted. Histopathologic studies on F3b weanlings revealed no lesions. In summary, this study establishes 400 ppm as the overall apparent no-effect level.

Acute and subchronic toxicity of mirex in the rat, dog, and rabbit.

Abstract The acute and subchronic (13 weeks) toxicity of orally administered mirex was studied in mongrel dogs, beagle dogs, and rats. Percutaneous toxicity was evaluated in rabbits. The acute oral LD50 in male mongrel dogs was found to be > 1000 mg/kg. Beagles of both sexes fed 4 and 20 ppm of mirex for 13 weeks exhibited no toxic effects. Two animals receiving 100 ppm died during the test period. Also observed at this dosage level were a reduced rate of weight gain, abnormal blood chemistry values, increased liver/body weight ratios, and decreased spleen/body weight ratios. No histopathologic changes were attributed to mirex. Male and female rats received diets containing 0, 5, 20, 80, 320, and 1280 ppm. No significant adverse effects were observed at levels of 5, 20, and 80 ppm. The following were observed at 320 and 1280 ppm; depressed growth, decreased hemoglobin concentrations, elevated white cell counts, enlarged livers showing histopathological changes, and deaths in the 1280-ppm groups. Rabbits exposed percutaneously to 3.33 or 6.67 g of mirex bait/kg, 6–7 hr each day, 5 days a week, for 9 weeks, exhibited no evidence of mirex intoxication.

A toxicologic evaluation of 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (ETMT)☆☆☆

Abstract The following studies were conducted on 3-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (ETMT, Terrazole), a soil fungicide: acute oral toxicity in rats, rabbits, and dogs; acute and subchronic percutaneous toxicity in rabbits; subchronic feeding to rats and dogs; 2-year feeding to rats and dogs; and a three-generation reproduction study in rats. CD rats, albino rabbits, and mongrel and beagle dogs were employed. The acute oral toxicity values (LD50 ± SD) were: rats, 1077 ± 78 mg/kg; rabbits, 779 ± 532 mg/kg; dogs > 5000 mg/kg (premedicated with morphine). The test material was added to the diet of rats at levels of 0, 78, 156, 312, 625, and 1250 ppm (subchronic study) and 0, 10, 80, and 640 ppm (chronic study and reproductive study); and to the diet of dogs at levels of 0, 100, 400, and 1600 ppm (subchronic study); and 0, 10, 100, and 1000 ppm (chronic study). Three-month feeding in rats resulted only in growth inhibition at 1250 ppm and elevated liver to body weight ratios at 625 and 1250 ppm. Dogs fed 3 months showed a decrease in spleen-to-body weight ratios at all feeding levels and a higher liver-to-body weight ratio at 1600 ppm. No consistent adverse dose-related effects were apparent in the 2-year rat feeding study. The following findings were noted only in dogs that received the 1000-ppm diet: a lesser body weight gain, increases in SAP, SGOT, serum cholinesterase, BSP retention, liver weights; cholestatic hepatosis with secondary bile nephrosis. No adverse effects were apparent at 10 or 100 ppm. In the three-generation reproduction study, no adverse effects were apparent on fertility, gestation, viability, lactation, number of stillborn, and mean number of pups born and weaned per litter. Adverse effects occurred only on the 640-ppm diet and these consisted of lower weaning weights of offspring and depressed body weight gains of parent rats.