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NTP technical report on the toxicity studies of p-tert-butylcatechol ( CAS No. 98-29-3) administered in feed to F344/N rats and B6C3F1 mice.

[molecular structure: see text] p-tert-Butylcatechol is used as an antioxidant, stabilizer, and polymerization inhibitor for styrene, butadiene, neoprene, and other olefins and reactive monomers. p-tert-Butylcatechol was nominated by the National Cancer Institute and the U.S. Food and Drug Administration for testing based on reports of its increasing levels of production and use and to compare the toxicity of p-tert-butylcatechol with that of similar antioxidants, butylated hydroxyanisole and butylated hydroxytoluene, which are added to food. Male and female F344/N rats and B6C3F1 mice were exposed to p-tert-butylcatechol (greater than 99% pure) in feed for 15 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 290 to 2,470 mg p-tert-butylcatechol/kg body weight to rats and 590 to 8,200 mg/kg to mice). All animals in the 50,000 ppm groups were killed moribund on day 8 (rats) or by day 7 (mice). Mean body weights of all groups of rats exposed to 6,250 ppm or greater were significantly less than those of the controls. Mean body weights of male mice exposed to 12,500 or 25,000 ppm and of 25,000 ppm female mice were significantly less than those of the controls. Female rats, male and female mice in the 25,000 ppm groups, and 12,500 ppm male mice lost weight during the studies. Feed consumption by exposed rats generally decreased with increasing exposure concentration; feed consumption by exposed mice was similar to that by the controls. Thymus weights of 25,000 ppm rats and mice were significantly less than those of the controls. Gross findings noted at necropsy included thin carcasses for three male and all female rats in the 12,500 ppm groups and all male and female rats and mice in the 25,000 and 50,000 ppm groups. No exposure-related lesions were observed microscopically. In the 14-week studies, groups of 10 male and 10 female rats and mice were fed diets containing 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm p-tert-butylcatechol (equivalent to average daily doses of approximately 70 to 1,030 mg/kg to rats and 135 to 2,815 mg/kg to mice). All animals survived to the end of the studies. Mean body weights of male rats exposed to 1,562 ppm or greater, female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm were significantly less than those of the controls. Feed consumption by male and female rats in the 6,250 and 12,500 ppm groups at week 1 and the 12,500 ppm groups at week 14 was less than that by the controls; feed consumption by exposed and control mice was similar. An erythrocytosis, indicated by increased hematocrit values, hemoglobin concentrations, and erythrocyte counts, was observed in 6,250 and 12,500 ppm rats on day 4 and in 12,500 ppm rats on day 22. At these time points, a transient hepatic effect was demonstrated by increases in alanine aminotransferase activities and bile salt concentrations in exposed rats. In 12,500 ppm male rats, absolute left cauda epididymis, epididymis, and testis weights were decreased by 15%, 10%, and 9%, respectively, compared to the controls. The number of spermatid heads per testis and epididymal sperm motility of male rats in the 12,500 ppm group were significantly less than those of the controls. The numbers of cycling female rats and females with regular estrous cycles were decreased in the 6,250 and 12,500 ppm groups. Exposed groups of females had significantly fewer estrous cycles than did the controls. Estrous cycle length increased with increasing exposure concentration; female rats in the 6,250 and 12,500 ppm groups had significantly longer cycles and spent more time in diestrus and less time in proestrus, estrus, and metestrus than did the controls. Female mice in the 12,500 ppm group had a significantly longer estrous cycle than did the controls. The incidences of hyperkeratosis of the forestomach epithelium were significantly increased in male and female rats in all exposed groups and in 12,500 ppm female mice. The incidences of hyperplasia of the forestomach epithelium were significantly increased in male and female rats exposed to 3,125 ppm or greater, male mice exposed to 12,500 ppm, and female mice exposed to 6,250 or 12,500 ppm. The severities of the forestomach lesions were minimal to moderate in male rats and minimal to mild in female rats and in mice. All male rats exposed to 6,250 or 12,500 ppm had minimal cytoplasmic alteration in the liver. The absorption, distribution, metabolism, and excretion of p-tert-butylcatechol following intravenous injection, gavage dosing, or dermal application were determined in male F344/N rats and B6C3F1 mice. The absorption of [(14)C]-p-tert-butylcatechol following gavage dosing or dermal application was high. The percent absorption following dermal application increased with increasing dose. Peak concentrations of [(14)C]-p-tert-butylcatechol equivalents in plasma were reached 1 hour after gavage dosing (200 mg/kg) and 2 hours after dermal application (60 mg/kg); no parent compound was detected in the plasma extracts. Regardless of route of administration, p-tert-butylcatechol derived radioactivity was readily excreted in the urine and was markedly nonpersistent in the tissues. p-tert- Butylcatechol was excreted as p-tert-butylcatechol sulfate and other polar metabolites that included predominately sulfate conjugates; it was not excreted as the parent compound. One metabolite was determined to be an O-methyl- ON-sulfate of p-tert-butylcatechol. p-tert-Butylcatechol (10 to 1,000 microg/plate) was not mutagenic in any of several strains of S. typhimurium with or without rat or hamster liver S9. Bone marrow micronucleus tests in which 125 to 500 mg/kg p-tert-butylcatechol was administered three times by intraperitoneal injection to male rats gave negative results. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in the peripheral blood of male or female mice administered p-tert-butylcatechol in feed for 14 weeks. No significant alteration in the percentage of polychromatic erythrocytes in mouse bone marrow was observed. In summary, the primary toxicity of p-tert-butylcatechol was to the forestomach of rats and mice. In the 14-week study in rats, forestomach toxicity was observed at all exposure concentrations, and the no-observed-adverse-effect level (NOAEL) was not reached for this effect. In the 14-week study in mice, the NOAEL for forestomach toxicity was 1,562 ppm.[1]

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