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.