Decamethylcyclopentasiloxane (D₅) is a low-molecular-weight cyclic siloxane used primarily as an intermediate in the production of several widely-used industrial and consumer products and intentionally added to consumer products, personal products and some dry cleaning solvents. The global use requires consideration of consumer use information and risk assessment requirements from various sources and authoritative bodies. A global “harmonized” risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA’s Integrated Risk Information System (IRIS), Health Canada and various independent scientific committees of the European Commission, as well as provide guidance for chemical safety assessments under REACH in Europe, and other relevant authoritative bodies. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure, utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model to estimate internal dose metrics, benchmark modeling to determine a point of departure (POD), and a margin of safety (MOS) evaluation to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D₅ including high lipophilicity, high volatility with low blood-to-air partition coefficients and extensive metabolic clearance that regulate tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D₅ using a MOS approach based on an internal dose metric removes the subjective application of uncertainty factors that may be applied across various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects.