Our findings show that PCL can be acutely toxic to early-developing zebrafish, potentially because of shed particles and oligomers, raising concerns about the widely recognized use of PCL in biomedical research and devices. First, the differences in toxic outcomes between our study and previous in vivo studies of PCL biomaterials likely stem from differences in local concentration, material properties, exposure route, matrix composition, and the model organism used and its developmental stage. Our study passively exposed early-developing fish embryos to a relatively high concentration of macroscopic unmodified PCL. In contrast, in vivo biomedical studies have implanted or injected engineered PCL biomaterials into developed (adult) mammals. Additionally, few studies have investigated the zebrafish response to PCL, and those that have primarily focused on small particles, not macroscopic items, as in our study. One study previously investigated the toxicity of finely ground PCL particles to developing zebrafish embryos and found no observable effect on mortality; however, this waterborne exposure was conducted at a concentration of 0.2 mg/mL, well below the concentration that acute toxicity was observed by us (150 times less than the LC50). Comparatively, in the same study, in vitro cytotoxicity at 10 mg/mL cell culture medium was observed. Recent work has suggested that PCL oligomers can improve the biocompatibility of PCL materials. However, these conclusions were based solely on two non-specific in vitro assays; thus, extrapolating these effects in vivo should be approached cautiously. Above all, the conditions used to test the biocompatibility of PCL medical devices are not analogous to those used in our study. So, the mechanisms of toxicity relevant to our study could have been missed or gone unrecognized previously.