Urethan (ethyl carbamate) as a cosolvent of drugs commonly used parenterally in humans.

Urethan, a potent teratogenic and carcinogenic agent in experimental animals, has been used in Japan for the past 25 years as a cosolvent of water-insoluble analgesic and sedative drugs. Urethan is used also as a solubilizer and cosolvent for pesticides, fumigants, and cosmetics, because it is a good solvent for various organic materials (6). In the past, urethan was used clinically as an antineoplastic agent and a hypnotic (6). In experimental animals, urethan induces a high incidence of a variety of tumors (7, 13 15), malformations (8, 12), and chromosome aberrations (4). Carcinogenic effects of urethan via placenta (5, 9 11) and via mother 's milk (9) have also been reported. Furthermore, tumors and malformations were transmitted to the next generation of mice subsequent to urethan treatment (11). As shown in Chart 1, small amounts of urethan (10 ug /g body weight) induce lung tumors in mice. Sixty-three drugs, which are commonly used parenterally in Japan, and 72 cosmetics were analyzed chromatographically. A thin-layer chromatogram (Silica Gel 60 F254, 0.25 mm thick, 20 x 20 cm; E. Merck, Darmstadt, West Germany) was developed in: Solvent System A, acetone:petroleum ether (b.p. 30-60"; 3:7, v/v); Solvent System B, ethanol:benzene:aqueous 50% acetic acid (7:1:1, v/v/v); and Solvent System C, acetone:chloroform:ethyl ether:petroleum ether (1:2:2:5, v /v /v /v) . For the detection of carbamates as red spots on chromatograms, p-dimethylaminocinnamaldehyde (1 g in 50 ml of 6 s HCI and 50 ml of ethanol) was used (1). As authentic chemicals, methyl carbamate, ethyl carbamate (urethan) (Wako Pure Chemical Ind., Ltd., Osaka, Japan), isopropyl carbamate, n-butyl carbamate (Tokyo Chemical Ind., Co., Ltd., Tokyo, Japan), pyrabital (Grelan Pharmaceutical Co., Ltd., Tokyo, Japan), and aminopyrine (Sumitomo Chemical Ind., Co., Ltd., Osaka, Japan) were used. Four products for parenteral use showed positive results following these procedures and were chromatographically identical to urethan (Fig. 1). (a) Grelan Injection (pyrabitai, 200 rag; and aminopyrine, 100 mg, in 2 ml), (b) Nobion-A Injection (pyrabital, 200 mg; chlorpromazine hydrochloride, 12.5 mg; and diphenhydramine, 20 mg, in 2 ml), (c) NoblonB Injection (pyrabital, 300 mg; chlorpromazine hydrochloride, 25 mg; and diphenhydramine, 20 mg, in 2 ml), and (d) C-Noblon Injection (pyrabital, 200 mg; surpyrine, 100 mg; chlorpromazine hydrochloride, 15 mg; promethazine hydrochloride, I0 mg; and 8-chlortheophylline, 25 mg, in 2 ml) contain urethan as a cosolvent, because pyrabital is insoluble in water. These products have been manu-