Abstract 1. 1. The advantages of the thermodynamic scale for measuring toxic potency are discussed and three methods for preparing solutions of known thermodynamic activity are shown to give similar results for threshold narcosis. 2. 2. The thermodynamic activities of physically toxic substances required to produce threshold narcosis in barnacle larvae lie in the range 0.01–1.0. 3. 3. Substitution of polar groups into the paraffin structure results in an increase in narcotic potency while the addition of methylene groups decreases toxicity; ultimately the higher members of an homologous series become non-toxic. 4. 4. Increase in molecular volume causes a decrease in the narcotic potency while an increase in molecular symmetry increases the narcotic potency. 5. 5. A thermodynamic analysis of the solution of non-polar substances in a three-dimensional biophase predicts an increase in threshold narcotic activity with molar volume which is in accordance with observations. 6. 6. The results support the space-occupying theory of narcotic action.