Teratogenesis and reproductive safety evaluation of the retinoid etretin (Ro 10-1670)

Abstract

Reproduction and teratology studies were performed with etretin, the free acid analog of the retinoid etretinate. The lowest teratogenic dose of etretin in mice, rats and rabbits was 3, 15 and 0.6 mg/kg, respectively. In all three species, the lowest dose which was embryolethal, fetolethal or reduced the survivability of the pups during lactation was 2-3 times higher than the above doses. In rats, the lowest effective dose of etretin was 3 mg/kg in both the study for fertility and general reproductive performance and the peri- and postnatal study. The main adverse effect in these two experiments was a reduced survival of the F1-generation.

Gene-Teratogen Interactions in Chemically Induced Congenital Malformations

“…Similar malformations to those described above were observed in fetuses of many animal species including monkeys, rats, mice, rabbits and hamster after excessive retinoid administration in pregnancy [18][19][20][21]. Administration of RA to mouse embryos also results in limb and axial skeleton malformations [22][23][24].…”

Structure-activity relationships of retinoids in developmental toxicology

“…One mg / kg etretin failed to induce malformations (Kistler and Hummler, 1985). The arotinoid Ro 13-6298 induced malformations in NMRI mice at doses as low as 0.0 I 0 mg/ kg/d i.p.…”

“…Two, 4, or 8 mg / kg etretinate or 15 or 30 mg / kg etretin administered orally on days 7-16 induced a variety of dysmorphia similar to those described for the hamster. Additionally, etretinate, etretin, all-trans-RA , and 13-cis-RA are teratogenic in the rabbit (Kamm, 1982;Kistler and Hummler, 1985;Hummler and Schupback, 1981). animals dosed, 10 fetuses were malformed; 4 were normal; and I was resorbed.…”

“…The N-ethyl amide (Ro 11-1430, motretinid) of etretin, which is the major teratogenic metabolite of etretinate (Kistler and Hummler, 1985), was inactive as a teratogen at a dose of 177 mg/ kg, however an extremely large dose (350 mg / kg) was teratogenic. This same paradigm was observed for other retinamides including the N-ethyl and N-(2-hydroxyethyl) amides of all-J.!…”

Is There a Reproductive Safety Risk in Male Patients Treated with Acitretin (Neotigason^®/Soriatane^®)?

“…This means that even if theoretically all the seminal fluid (10 ml) of a patient treated with acitretin remains in the vagina of his partner and is totally absorbed following sexual intercourse, the so-called vaginal dose would be 400,000 times lower than the oral therapeutic dose of 50 mg/day. Of note, this dose is also approximately 100,000 times lower than the highest non-teratogenic dose (0.2 mg/kg/day) observed in rabbits – the animal species most sensitive to the teratogenic effects of acitretin [6]. …”