V.K. Rowe

Study of the teratogenicity of 2,3,7,8-tetrachiorodibenzo-p-dioxin in the rat

Abstract 2,3,7,8-Tetrachlorodibenzo-p-dioxin was given orally to pregnant rats on days 6–15 of gestation, at levels of 0 (control), 0·03, 0·125, 0·5, 2·0 and 8·0 μg/kg/day. No adverse effect on the foetuses was noted at the 0·03-μg/kg level, but in the groups given doses of 0·125–2·0 μg/kg, foetal mortality, early and late resorptions and foetal intestinal haemorrhage were observed, with the incidence increasing as the dose increased. There was no evidence of maternal toxicity at 0·03 and 0·125 μg/kg/day, but at 0·5 and 2·0 μg/kg/day there was a decrease in maternal weight gain. Severe maternal toxicity and embryotoxicity were evident at the 8·0-μg/kg/day dose, maternal weight loss and early resorptions occurring in all cases. The results suggest that teratogenic effects attributed earlier to 2,4,5-trichlorophenoxyacetic acid may have been due to 2,3,7,8-tetrachlorodibenzo-p-dioxin, which was present as a contaminant at a level of about 30 ppm in the sample of the herbicide tested.

TOXICOLOGY OF ACRYLAMIDE.

Abstract This laboratory became interested in acrylamide early in 1954, when it became apparent that the material had great potential as a monomer and comonomer to make resins with unique flocculating action, and later as a dry strength improver in the manufacture of paper and paperboard. At that time, there were no published data on the toxicity of acrylamide. Later, it was learned that American Cyanamid Com- pany was sponsoring work on the material, portions of which have been reported by Hamblin (1956) and Kuperman (1958) . It soon became quite apparent that the rather high and unusual toxicity of the monomer would require extensive toxicologic study in order that recommendations for safe industrial handling could be ascertained, and to evaluate the safety in commercial use of polymers or copolymers which might contain small amounts of residual acrylamide.

The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals.

Abstract Groups of laboratory animals were exposed repeatedly for up to six months to either 500, 200, 100 or 50 ppm vinyl chloride in air. Detectable changes occurred at all but the lowest concentration. The results are discussed and handling precautions suggested.

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to man

Abstract Five human male volunteers ingested a single dose of 5 mg/kg without incurring detectable clinical effects. Concentrations of 2,4,5-T in plasma and its excretion were measured at intervals after ingestion. The clearances of 2,4,5-T from the plasma as well as its excretion from the body occurred via apparent first-order rate processes with half-lives of 23.10 and 23.06 hr, respectively. Essentially all of the 2,4,5-T was absorbed into the body and excreted unchanged in the urine. In the body, 65% of the 2,4,5-T resided in the plasma where 98.7% was bound reversibly to protein. The volume of distribution was 0.079 liters/kg. Utilizing the kinetic constants from the single dose experiment, the expected concentrations of 2,4,5-T in the plasma of individuals receiving repeated daily doses of 2,4,5-T were calculated. From these calculations, it was determined that the plasma concentrations would essentially reach a plateau after 3 days. If the daily dose ingested in mg/kg is A 0 , the concentration in the plasma after attaining plateau would range from 12.7 A 0 to 22.5 A 0 μg/ml. This range would converge to approximately 17 A 0 μg/ml as the daily dose A 0 is distributed throughout the day.

Toxicologic investigations of polyacrylamides

Abstract Polyacrylamide resins (Separan NP10 and AP30 flocculants) are high molecular weight polymers with low single oral toxicity to rats. Long-term feeding studies of these resins have involved three two-year studies in rats, one one-year study in dogs, and one two-year study in dogs. These poly-acrylamides are quite low in repeated oral toxicity. The laboratory animals tolerated 5–10% in their total diet without effects other than those believed to be attributable indirectly to the large, hydrophilic, nonnutritive bulkiness of the materials. The unequivocal “no ill-effect” levels were 1% in the diet of rats and 5–6% in the diet of dogs. Studies with carbon-14 tagged resin indicate that negligible amounts of polymer, if any, pass through the walls of the gastrointestinal tract of the rat. Fish were maintained in water containing 1000 ppm of these resins for 5 days and 100 ppm for 90 days without apparent adverse effect. Environmental health and medical surveys of industrial personnel confirm the low degree of hazard associated with these materials. Adequate bases exist for establishing the safety of these products from the public health aspect for many applications wherein small amounts may possibly occur in the food or drink of animals or human subjects.

The toxicity of chloroform as determined by single and repeated exposure of laboratory animals

The acute and chronic toxicity of chloroform has been studied in laboratory animals. An acute oral LD50 of 2.0 (1.0-3.8) g/kg was determined for male rats. When applied to the skin of rabbits, chloroform produced slight to moderate irritation and delayed healing of abraded sking. Absorption of chloroform through the skin of rabbits was apparent but absorption is not expected to present a practical acute hazard. Liquid chloroform produced slight injury to the eyes of rabbits which took over a week to heal. Repeated 1-hour exposures five days per week for six months to either 85.50 or 25 ppm of the vapor of chloroform resulted in adverse effects in all or some species studied: rats, rabbits, guinea pigs and dogs. The effects at 25 ppm were slight and reversible. Rats exposed to 25 ppm for 4.2 or 1 hour/day for 6 months were not adversely affected. Based on experimental data and published reports on human experience as well as industrial experience with carbon tetrachloride, the authors suggest that when workers exposures can be expected to be repeated and prolonged, the exposure concentrations be maintained below 25 ppm vapor and that the time weighted average not exceed 10 ppm.

Study of the effects of high levels of 2,4,5-trichlorophenoxyacetic acid on foetal development in the rat

Abstract Commercial-grade 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), containing 0·5 ppm 2,3,7,8-tetrachlorodibenzo- p -dioxin, did not produce a teratogenic response when administered orally to rats on days 6–15 of gestation at a dosage level of 50 mg/kg/day. In the foetuses, minimal effects in the form of a slightly higher incidence of delayed ossification of the skull bones were observed. 2,4,5-T given on days 6–10 of gestation at a level of 100 mg/kg/day was toxic to the dams and caused a high incidence of maternal deaths. Four of 25 pregnant rats survived. Of these, three had complete early resorptions and one had a litter of 13 viable foetuses which showed toxic effects but no terata.

Toxicity of a Solvent Mixture of 1,1,1-TrichIoroethane and Tetrachloroethylene as Determined by Experiments on Laboratory Animals and Human Subjects

Abstract The toxicological properties of a solvent mixture (Dowclenef EC cleaner) consisting by weight of 75% inhibited 1,1,1-trichloroethane (Chlorothene NU solvent) and 25% tetrachloroethylene were studied on rats, mice, guinea pigs, rabbits, dogs and human subjects. The material was low in oral toxicity, not appreciably irritating to the eyes or skin, not absorbed through the skin to an appreciable extent, and was low in toxicity when inhaled. The animals given seven-hour exposures five days a week for six months to a vapor concentration of 1,000 ppm of the mixture suffered slight changes of a reversible character in the liver and kidney. Rats exposed four hours a day for six months to 1,000 ppm and the animals (4 species) exposed seven hours a day for six months to 500 ppm exhibited no evidence of adverse effects. Human subjects were exposed seven hours a day for up to five days to 500 ppm and subjected to intensive medical study. No adverse effects were detected. The rate of excretion of the solvent ...

Ethylenimine: Studies of the distribution and metabolism in the rat using carbon-14

The metabolic fate of ethylenimine has been studied in the rat. About half of the dose administered intraperitoneally was excreted in the urine. A small amount of ethylenimine was excreted, as such, in the urine, but the major portion of the excreted radioactivity was found in a number of unidentified products. Three to five percent of the dose was expired as CO2, and 1–3% was expired as a volatile, basic material, probably ethylenimine. Radioactivity was widely distributed with some accumulation found in the liver, intestines, cecum, spleen, and kidneys. Fat depots were not highly labeled. Kinetic data indicate that the activity retained in the tissues of the rat after 24 hours was essentially unavailable for further metabolism.

The Toxicity of Boron Trifluoride when inhaled by Laboratory Animals.

Abstract Rats, rabbits, and guinea pigs were exposed seven hours per day, five days per week for periods up to six months duration to atmospheres containing boron trifluoride in concentrations calculated to be 12.8, 7.7, or 3.0 ppm. Analysis showed concentrations to be about one-half of these levels. The major effect of repeated inhalation was respiratory irritation causing injury ranging from death to a slight increase in pneumonitis. On basis of the study, a value of 0.3 ppm is tentatively suggested as a threshold limit value for boron trifluoride.