title: NTP Toxicity Studies of Benzyltrimethylammonium Chloride (CAS No. 56-93-9) Administered by Gavage to F344/N Rats, Sprague-Dawley Rats, and B6C3F1 Mice.
abstract: Benzyltrimethylammonium chloride is widely used as a solvent for cellulose, a gelling inhibitor in polyester resins, a chemical intermediate, a paint dispersant, and an acrylic dyeing agent. It is also used in plant growth regulator compositions and synthetic processes. The National Institute of Environmental Health Sciences nominated benzyltrimethylammonium chloride for study due to its high production volume and the potential for occupational exposure, as well as the limited information on toxicity of this chemical. Male and female F344/N rats and B6C3F1 mice received benzyltrimethylammonium chloride by gavage for 16 days or 13 weeks. Animals were evaluated for hematology, clinical chemistry, histopathology, neurotoxicity, and reproductive toxicity. Genetic toxicology studies were conducted in Salmonella typhimurium and in mouse peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 0, 16, 32, 63, 125, or 250 mg benzyltrimethylammonium chloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. Groups of five male and five female mice received 0, 63, 125, 250, 500, or 1,000 mg/kg benzyltrimethylammonium chloride in deionized water by gavage, 5 days per week for 16 days. All rats in the 125 and 250 mg/kg groups, all mice in the 250, 500, and 1,000 mg/kg groups, and one 125 mg/kg female mouse died on day 1 of the studies. Clinical findings observed in 125 mg/kg male and female rats included abnormal breathing, ataxia, lethargy (males only), nasal and eye discharge, and tremors. Salivation was slightly increased in male and female rats in the 63 mg/kg groups. Female mice in the 125 mg/kg group had a significantly greater absolute liver weight than that of the vehicle controls. No gross or microscopic changes observed in rats or mice were considered related to chemical administration. In the 13-week studies, groups of 10 male and 10 female rats and mice received benzyltrimethylammonium chloride in deionized water by gavage at doses of 0, 12.5, 25, 50, or 100 mg/kg, 5 days per week for 13 weeks. Benzyltrimethylammonium chloride generally had little effect on the body weights of rats or mice. Final mean body weights of dosed animals were within 8% (rats) or 3% (mice) of the control group body weights. The deaths of two female rats and one male and one female mouse administered 100 mg/kg were the result of pharmacologic effects on the cardiovascular system. Some cholinergic effects including chromodacryorrhea, lacrimation, salivation, pupillary constriction, altered gait, and mild tremors were observed at nonlethal doses in rats; these effects were accompanied by alterations in body position. No significant target organ toxicity was observed in dosed rats or mice. Benzyltrimethylammonium chloride was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation enzymes. However, significant increases in the frequency of micronucleated normochromatic erythrocytes were found in the peripheral blood of male and female mice administered benzyltrimethylammonium chloride by gavage for 13 weeks. Based on the mortality observed in the 16-day and 13-week studies, rats and mice appeared to be equally sensitive to benzyltrimethylammonium chloride. The minimally toxic dose for rats and mice was estimated to be 50 mg/kg.