Fetal malformations produced in rats by N‐isopropyl‐α‐(2‐methylhydrazino)‐p‐toluamide hydrochloride (procarbazine)

Abstract

Single intraperitoneal injections of N‐isopropyl‐α‐(2‐methylhydrazino)‐p‐toluamide hydrochloride (procarbazine) at doses ranging from 5–550 mg/kg were given to pregnant rats on the fifth to twelfth, fourteenth, and seventeenth days of gestation. Malformations were seen in twenty‐first‐day fetuses exposed to doses that were slightly higher than one‐half (250 mg/kg on 17th day) to one forty‐fifth (12 mg/kg on 12th day) the single dose that was lethal to females (550 mg/kg) when they were treated once on the fifth, sixth, ninth to twelfth, fourteenth, or seventeenth day of gestation. Tail and appendicular defects were observed after treatment on all eight days, injury to the brain only after that on the ninth day, facial clefts on the ninth or tenth day, and cleft palate and shortened jaws on the sixth, ninth, twelfth, fourteenth, and seventeenth days. Malformations were not seen with any of the doses used on the seventh or eighth day of gestation. Attempts to protect the twelfth‐day fetus against the teratogenic effects of 100 mg/kg of procarbazine by administration of various amounts of L‐methionine were only partially successful.

Teratogenic assessment of three methylated hydrazine derivatives in the rat

“…Chaube and Murphy (1969) produced tail and appendicular defects, cleft palates, shortened jaws, and brain malformations in Wistar rat pups when dams were injected intraperitoneally with /V-isopropyl-a-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine). Terata were seen at doses that produced no deleterious maternal effects.…”

“…This confusion seems to have arisen from the Chaube and Murphy (1969) report that procarbazine [/V-isopropyl-a-(2-methylhydrazino)-p-toluamide hydrochloride] was teratogenic in the rat and the Mercier-Parot and Tuchmann-Duplessis (1969) report that the chlorhydrate of 1-methyl-2-p-(isopropylcarbamyl)benzylhydrazine was teratogenic in the rabbit and mouse. These two reports apparently resulted in the misreference to the teratogenic effects of MMH (NIOSH, 1977(NIOSH, , 1978.…”