CHEMICAL and PHYSICAL PROPERTIES

Benzyltrimethylammonium chloride is a quaternary ammonium compound with a structural resemblance to acetylcholine and other chemicals having cholinergic activity. It is an off-white to yellow powder (Figure 1) with a melting point of 236℃to 239℃.[1] It decomposes at 239℃, and the decomposition products include carbon monoxide, carbon dioxide, nitrogen oxides, hydrochloride gas, and ammonia. Benzyltrimethylammonium chloride is hygroscopic and soluble in water, ethanol, and butanol and slightly soluble in butyl phthalate and tributyl phosphate.[2-3]

PRODUCTION and USE

Benzyltrimethylammonium chloride is prepared by boiling benzyl chloride and trimethylamine in absolute ethanol. In addition, a reaction involving benzyl dimethylamine and methyl chloride, with or without solvent, may be used to manufacture this compound.[1] Benzyltrimethylammonium chloride is also prepared by dissolving phenylmethyl chloride in ether and adding 25% trimethylamine in methanol. The product is collected and recrystallized from alcohol and ether.[4]

Benzyltrimethylammonium chloride is used as a solvent for cellulose, a gelling inhibitor in polyester resins, a chemical intermediate , and a paint dispersant for the rubber industry. It is also used extensively as an acrylic dyeing agent in the textile industry . Benzyltrimethylammonium chloride is patented for use in plant growth regulator compositions and synthetic processes.

TOXICITY

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 enzyltrimethylammonium 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.[3]

Another study also had investigated the toxicokinetics of benzyltrimethylammonium chloride in the rodent strains that will be used in the bioassay, the F344 rat and the B6C3F1 mouse. The results are reported as follows:[5]

1. Benzyltrimethylammonium chloride -derived radioactivity was rapidly eliminated from the F344 rat and the B6C3F1 mouse following po. administration of 0.63-63 mg/kg of [ring-U-¹⁴C] benzyltrimethylammonium chloride. Greater than 90% of the radioactivity was excreted in urine and faeces within 24-h post-dosing.

2. Benzyltrimethylammonium chloride was poorly to moderately absorbed from the GI tract following po. administration. The percent of total dose absorbed did not exceed either 40% in the rat or 15% in the mouse.

3.Absorption was linear, but limited, over time following dermal administration of 63 mg/kg to the rat. Less than 10% of the total dose was absorbed from the skin within 24 h of benzyltrimethylammonium chloride application.

4. Metabolism of benzyltrimethylammonium chloride was minimal in both the rat and mouse. Toxicity (excessive cholinergic stimulation and mortality) appears to be attributable to the parent compound.

In conclusion, the limited absorption and rapid elimination of benzyltrimethylammonium chloride should result in little or no bioaccumulation in tissues following repeated exposure to low levels of this compound. The results suggest that greater human health risks may be associated with acute high level exposure rather than chronic low level exposure.

References

[1] Karsai, J., Sebestyén, E., Gaál, S., Gárdi, I., Siki, K., and Kíss, G. Plant growth regulating compositions and process for regulating plant growth. International Patent Application, 1986; Patent No. WO 86/07237.

[2] Sax, N.I., and Lewis, R.J., Sr. Dangerous Properties of Industrial Materials, 7th ed.,  Van Nostrand Reinhold, New York.1989; 426.

[3] NTP Toxicity Studies of Benzyltrimethylammonium Chloride (CAS No. 56-93-9) Administered by Gavage to F344/N Rats, Sprague-Dawley Rats, and B6C3F1 Mice. Toxic Rep Ser. 2000; 57: 1-F14.

[4] Hume, A.S., and Holland, W.C. Vasopressor and depressor activity of phenylalkyltrimethylammonium compounds. Arch. Int. Pharmacodyn. 1965;154,155-160.

[5]Sanders JM, Griffin RJ, Burka LT, Matthews HB. Toxicokinetics of the cholinomimetic compound benzyltrimethylammonium chloride in the male rat and mouse. Xenobiotica. 1995;25(3):303-313.