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In vitro and in silico methods that can reduce the need for animal testing are being used with increasing frequency to assess chemical risks to human health and the environment. The rate of hepatic biotransformation is an important species-specific parameter for determining bioaccumulation potential and extrapolating in vitro bioactivity to in vivo effects. One approach to estimating hepatic biotransformation is to employ in vitro systems derived from liver tissue to measure chemical (substrate) depletion over time which can then be translated to a rate of intrinsic clearance (CL int ). In the present study, cryopreserved hepatocytes from humans, rats, and rainbow trout were used to measure CL int values for 54 industrial and pesticidal chemicals at starting test concentrations of 0.1 and 1 μM. A data evaluation framework that emphasizes the behavior of Heat-Treated Controls (HTC) was developed to identify datasets suitable for rate reporting. Measured or estimated ("greater than" or "less than") CL int values were determined for 124 of 226 (55 %) species-chemical-substrate concentration datasets with acceptable analytical chemistry. A large percentage of tested chemicals exhibited low HTC recovery values, indicating a substantial abiotic loss of test chemical over time. An evaluation of K OW values for individual chemicals suggested that in vitro test performance declined with increasing chemical hydrophobicity, although differences in testing devices for mammals and fish also likely played a role. The current findings emphasize the value of negative controls as part of a rigorous approach to data quality assessment for in vitro substrate depletion studies. Changes in current testing protocols can be expected to result in the collection of higher quality data. However, poorly soluble chemicals are likely to remain a challenge for CL int determination., (Published by Elsevier B.V.)