Human environmental and dietary exposure to trans-capsaicin--the pungent ingredient in chili peppers--is ubiquitous. Moreover, based on the highly selective agonism of trans-capsaicin for TRPV1 receptors, drug products containing high concentrations of trans-capsaicin are under development as analgesics. For instance, a high-concentration (8% w/w) pure trans-capsaicin dermal patch (designated NGX-4010) is in advanced clinical evaluation for the management of neuropathic pain of peripheral origin. Our objective was to investigate effects of trans-capsaicin on embryo/fetal development, consequent to maternal exposure, from implantation to closure of the hard palate. trans-Capsaicin was delivered systemically by means of either a patch [NGX-4010 (25, 37.5, or 50 cm(2))] to pregnant Sprague-Dawley rats on days of presumed gestation (DGs) 7 through 17, or via a 10% w/v capsaicin liquid formulation (CLF), at dosages of 3, 6.5 or 13 mul/cm(2) applied to a 200-cm(2) area on the back on DGs 7 though 19 to timed-mated New Zealand white rabbits. In rats, the maternal no-observable-effect level (NOEL) was less than 25 cm(2) but no cesarean-sectioning or litter parameters were affected by application of NGX-4010 at patch sizes as high as 50 cm(2). The only test article-related observations were delays in skeletal ossification, evident as significant reductions in the average number of metatarsals and ossified hindlimb and forelimb phalanges that occurred in the 50 cm(2) NGX-4010 dose group. Although the values for ossified metatarsals were outside the historical control range, ossified hindlimb and forelimb phalanges were within historical control ranges. No other gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were caused by application of the NGX-4010. In rabbits, the maternal NOEL was less than 3 mul/cm(2) CLF (or 0.3 mg/cm(2)trans-capsaicin) per 200 cm(2), but no cesarean-sectioning or litter parameters were affected. No fetal alterations (malformations or variations) were caused by dosages of CLF as high as 13 mul/cm(2) (or 1.3 mg/cm(2)trans-capsaicin). Taken together, these data suggest that tran s-capsaicin should not be considered a developmental toxicant.