Perinatal death and respiratory apparatus dysgenesis due to a bis (dichloroacetyl) diamine.
N, N1-bis (dichloroacetyl) diamine 1, 8-octomethylenediamine (WIN 18,446) is an experimental drug which was first investigated as a male contraceptive. It is soluble in lipid solvents but not in water. The administration of 1,200 to 1,600 mg/kg to pregnant rats on the tenth day of gestation produced multiorgan fetal malformations. Smaller doses, 400 to 800 mg/kg, especially if divided over 2 or 3 days, caused perinatal death. Thus, 60 to 100% of offspring of rats given WIN 18,446 on the tenth and 11th days of gestation died at birth or within 4 days (Taleporos et al., 78). The present study investigated such deaths. At doses of 200 mg/kg on day 10 or 50 mg/kg on days 10 and 11, 67% of offspring had defective or absent diaphragms, 48% had tracheobronchiomegaly with cystic lungs, and 67% had pleural hemorrhage. At doses of 100 mg/kg given on 1 day or 25 mg/kg each day for 2 days, 50% had tracheobronchiomegaly with cystic lungs and rudimentary acini. At lower doses (18.8 mg/kg X 2 or 12.4 mg/kg X 3), a majority of fetal lungs had rudimentary acini, thick septa, few capillaries, and wide cuffs of perivascular connective tissue. Thus, a chemical given during organogenesis produced dysgenesis of the respiratory apparatus. Varying the dose produced malformed lungs with persistently deficient acini which model such human lung faults as tracheobronchiomegaly (Mournier-Kuhn Syndrome; Mounier-Kuhn, '32), bronchiolar dysplasia (Wilson-Mikity Syndrome), and perinatal death with acinar failure resembling neonatal hyaline membrane disease.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D003959:Diamines / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D008168:Lung / Q000002:abnormalities; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D015619:Respiratory System Abnormalities; D013092:Spermatogenesis-Blocking Agents / Q000009:adverse effects*
D003959:Diamines; D013092:Spermatogenesis-Blocking Agents; C002491:N,N'-bis(dichloroacetyl)-1,8-octamethylenediamine