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Toxicokinetic–toxicodynamic (TKTD) modeling has received increasing attention in terms of the regulatory environmental risk assessment of chemicals. This type of mechanistic model can integrate all available data from individual‐level bioassays into a single framework and enable refined risk assessments by extrapolating from laboratory results to time‐variable exposure scenarios, based, for instance, on surface water exposure modeling (e.g., FOCUS). Dynamic energy budget (DEB) models coupled with TKTD modules (DEB–TKTD) constitute the leading approach to assess and predict sublethal effects of chemicals on individual organisms. However, thorough case studies are rare. We provide a state‐of‐the‐art example with the standard aquatic test species Ceriodaphnia dubia and the fungicide azoxystrobin, including all steps, from bespoke laboratory toxicity tests to model calibration and validation, through to environmental risk assessment. Following the framework proposed in the European Food Safety Authority Scientific Opinion from 2018, we designed bespoke good laboratory practice–compliant laboratory toxicity studies based on test guideline 211 of the Organisation for Economic Co‐operation and Development and then identified robust parameter values from those data for all relevant model parameters through model calibration. The DEB–TKTD model, DEBtox2019, then informed the design of the validation experiment. Once validated, the model was used to perform predictions for a time‐variable exposure scenario generated by FOCUS. A moving time‐window approach was used to perform the environmental risk assessment. This assessment method reduces uncertainty in the risk assessment while maintaining consistency with the traditional measures of risk. Environ Toxicol Chem 2024;43:2409–2421. © 2024 Syngenta Crop Protection AG. ibacon GmbH and The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]