Substances from packaging systems that are leached into packaged medical products may have a safety impact on patients to whom such medical products are administered. The potential safety impact depends on the identity and concentration of the leached substances. The concentration above which a leachable must be identified in order to assess its safety impact is frequently estimated using an internal standard to "calibrate" the analytical response of a chromatographic system. Such an estimate is accurate to the extent that the responses of the internal standard and leachables are similar. To establish the accuracy of the internal standard approach, a database of gas chromatography-flame ionization detection (GC-FID) and gas chromatography-mass spectrometry (GC-MS) responses was generated for thirty-eight leachables and eight internal standard candidates. Although the FID and MS responses of many of the leachables and internal standards fell within a narrow band, acidic and basic compounds produced responses that were discernibly different from those of neutral analytes. While most of the internal standards were suited for concentration estimation, three of the candidates, dimethylphthalate, triphenylphosphate and 4,4-dibromobiphenyl, produced the smallest mean error in estimated concentration for the analytes examined. As the FID and MS responses were linear, internal standards could be used to estimate leachables concentrations even when the difference in leachable versus internal standard concentrations was as great as a factor of 25. A multiplier may be appropriate to adjust an estimated concentration to its greatest possible value, and it is this value that is used to convert an estimated Analytical Evaluation Threshold (AET) into a working or final AET.