Congenital malformations induced by niclosamide ethanolamine in correspondence to the LD50

ABSTRACT

The acute oral and intraperitoneal LD50 of niclosamide ethanolamine [NE] were determined in female albino rats as 6.81 g/kg and 346.74 mg/kg, respectively. In teratology study, the pregnant rats orally administered NE in dosage levels based on the oral LD50 as 50, 100, 200 or 400 mg/kg on gestational days 9, 11 or 8 - 15. Maternal body weight gains were lower than controls. No maternal death occurred. Fetuses were removed on day 21 of pregnancy by caeserian section and examined by routine teratological methods. The resorption rate significantly increased while number of implants/litter, number of live fetuses, fetal weights and crown-rump lengths were reduced at all dose levels and treatment intervals except for fetuses from dams given 50 mg/kg on day 11 of gestation. The sex ratio of live fetuses obtained from NE treated dams on gestational period 8 - 15 indicated lethal potential towards females. A variety of gross malformations occurred, i.e. cranial meningocele, encophalocele, scoliosis, absence of external genitalia, imporforate anus, crooked tail, adactyly and club foot. In addition, NE in the higher doses [200, 400 mg/kg] on gestational days 9 or 8 - 15, exerted amelia and micraomelia. The skeletal anomalies observed included cranioschisis. non-ossification of occipital bone, delayed ossification, missing of sacral and caudal vertebrae, fusion of cervical vertebrae, misshapen, bipartite and surplus sternebrae, fused, rudimentary and missing ribs, absence of phalanges and digits. The most observed internal soft tissue malformations were dilated ventricles, cranial hemorrhage, internal hydrocephaly, microcephaly, meningoencephalocele, anophthalmia and/or microphthalmia, hepatomegaly, parietal liver hernia, increased renal pelvis cavitation, renal agenesis and/or hypoplasia, absence of ureters, enlarged adrenals, agenesis of testis, agenesis or hypoplasia of uterus. Commonly recorded anomalies included the urogenital syndrome of malformations. The occurrence of these defects was dose and period dependent. This study provided substantial evidence of the teratogenic, embryotoxic and fetotoxic potential of NE