Repeated administration of pharmaceutical-grade medium chain triglycerides, a common pharmacologic excipient, confers dose-dependent toxicity by the intraperitoneal but not oral route in mice*

ABSTRACT Pharmaceutical-grade medium chain triglycerides (MCTs) are common excipients for in vivo pharmacological studies in laboratory animals, and as an experimental therapeutic in certain metabolic and neurological disorders. In this study, we examined the tolerability of repeated administration of a pharmaceutical-grade formulation of three MCTs—caprylic, capric, and lauric acid - in mice via the oral (PO) and intraperitoneal (IP) routes. We administered either 8 or 4 µL of 100% MCTs or saline/gram of body weight twice daily for seven days. During administration and for seven days after, we monitored weight change and clinical presentation. On day 14, or upon meeting euthanasia criteria, animals were sacrificed for gross necropsy, histology, and complete blood count. We observed significant weight loss, clinical decline and 100% mortality in animals receiving 8 µL/g of MCTs via the IP route of administration. Gross necropsy revealed serosanguinous fluid in the thoracic cavity, dark red mottled lungs, and adhesions in the abdominal cavity. Histology confirmed inflammation of the lungs, mediastinum, and peritoneum. Mild gross lesions and initial weight loss (through day 3) were also present in mice receiving 4 µL/g of MCTs IP. However, these animals regained weight by day seven and exhibited no clinical decline or mortality. None of these adverse effects were seen in animals receiving either 8 µL/g of MCTs PO or 8 µL/g of saline IP. These findings suggest repeated IP administration of MCTs may cause dose-dependent toxicity, and mortality at high doses, but confers no adverse effects when administered via the PO route. SIGNIFICANCE STATEMENT Medium chain triglycerides (MCTs) are commonly used as an excipient in pharmacological studies involving laboratory animals. Our work provides much needed safety information regarding adverse effects of repeated MCTs administration via the intraperitoneal, but not the oral, route in mice.