AbstractThe embryotoxic and teratogenic potential of all‐transretinoic acid was assessed following exposure prior to and during early organogenesis in the cynomolgus monkey(Macaca fascicularis). Sixteen pregnant females were orally administered all‐transretinoic acid (Tretinoin, Hoffmann‐La Roche) once daily from GD 10–20 and twice daily from GD 21–24 at three different dosages, 5 (n=9), 10 (n=6) and 20 mg/kg (n=1). Adverse clinical signs resembling hypervitaminosis A were observed in one animal at 5 mg/kg, in three animals at 10 mg/kg, and in the animal treated with 20 mg/kg all‐transretinoic acid. Maternal weight loss was observed in the 10‐ and 20‐mg/kg groups. A dose‐dependent increase in embryolethality was observed, with 22% (2/9), 50% (3/6), and 100% (1/1) occurring at 5, 10, and 20 mg/kg, respectively. The majority of embryonic deaths occurred between GD 16 and 20; the incidence of these early losses was higher than in historical and concurrent controls. No malformations, but a single growth‐retarded fetus, was observed in the 5‐mg/kg group. Craniofacial malformations, consisting of external ear defects, mandibular hypoplasia, cleft palate, and temporal bone abnormalities, were seen in three viable fetuses in the 10‐mg/kg group. Skeletal variations were common to the majority (70%, 7/10) of viable fetuses in both dose groups and were increased relative to historical controls (32%, 25/77). Unlike previous studies with 13‐cis‐retinoic acid during the pre‐ and early organogenic stages of development (Hummler et al., Teratology 42:263‐272, 1990), no thymic hypo‐ or aplasia or heart anomalies were observed, which may be attributable to the slightly longer 13‐cisretinoic acid treatment period, i.e., GD 10–27. However, external ear and temporal bone defects were common to both all‐transand 13‐cisretinoic acid. The similarity observed in the malformation syndrome induced by both all‐transand 13‐cisretinoic acid in the cynomolgus monkey and 13‐cisretinoic acid embryopathy in humans supports this macaque species as a model for further developmental