Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for deve lopmental toxicity. Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and wa ter consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and similar t o 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugeno l exposure included dose-related evidence of sedation and aversion to treat ment (rooting behavior) in all isoeugenol groups, as well as an increased i ncidence of piloerection at greater than or equal to 500 mg/kg/day. Materna l body weight, weight gain, and gestational weight gain (corrected for grav id uterine weight) were reduced at all doses in a dose-related manner. Grav id uterine weight was significantly decreased at the mid and high doses, wh ereas maternal relative liver weight was increased at all three dose levels . During treatment (gd 6 to 20), maternal relative food consumption was sig nificantly decreased at the high dose, and maternal relative water consumpt ion was elevated in the mid- and high-dose groups. Prenatal mortality (reso rption or late fetal death) was unaffected. At 1000 mg/kg/day, average feta l body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups , except for an increase in the incidence of unossified sternebra(e), a ske letal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uter ine weight), and the maternal toxicity no observed adverse effect level (NO AEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.