Candidate low-toxicity working fluids are evaluated for active internal thermal control systems in various NASA applications, such as human exploration missions and low-earth orbit spacecraft. The principal goal is to attain a lower freezing point than pure water (currently popular), for added protection against system blockage or bursting in either expected low temperature environments or in the event of failure. Fluids considered for moderate-temperature freeze protection include aqueous solutions of ethylene glycol, propylene glycol, denatured ethyl alcohol, glycerin, and potassium acetate. For very low-temperature freeze protection, the liquids Fluorinert 72, Hydrofluoroether 7100, D-Limonene, R-116, and R-134a are considered. Fluid performance with regard to pump power and heat exchange is evaluated based on comparison with water for fixed hardware and operating conditions. Estimates are developed for the influence of relevant fluid properties on the flow in lines, valves, cold plates, and heat exchangers, based on Shuttle water loop hardware specifications. Safety issues involving toxicity and flammability in the event of fluid leakage are also assessed.Regarding performance, ethanol/water solutions are most effective in reaching freeze points as low as -50 °C (particularly in minimizing pump power), followed by ethylene glycol and propylene glycol. The performance penalty for modest freeze protection is substantial for systems originally designed for pure water. For instance, a freeze point of -7 °C involves: (i) pump power increases of 30%, 40%, and 60% for ethanol, ethylene glycol, and propylene glycol solutions respectively, and (ii) significant decreases in heat exchanger (8-10%) and cold plate (14-19%) heat transfer coefficients. These results suggest that even modest freeze protection will require redesign of water-based systems, to accommodate higher system pressure drop, larger heat exchangers and cold plates, and larger tubing and heat exchanger passages.Despite the performance advantage of ethanol, even dilute solutions pose a flammability risk (e.g. 36 °C flash point for 20% ethanol) and thus are not feasible. Unlike ethylene glycol, which is mildly toxic through both ingestion and inhalation, propylene glycol is suitable for direct food contact and appears completely safe for ITCS applications. Considering both performance and safety, we recommend use of (appropriately inhibited) propylene glycol/water solutions for ITCS freeze protection down to -50 °C, provided that the ITCS is designed (or redesigned) for the appropriate solution properties, rather than those of pure water. Among fluids providing extreme freeze protection (below -50 °C), Fluorinert 72 appears to be totally safe and is generally recommended. Despite better performance, R-116, R-134a, and HFE 7100 pose toxicity concerns, and D-Limonene is a potential flammability risk due to its flash point of 46 °C.