The ability of both natural and synthetic chemicals to mimic the effects of hormones in humans and animals is recognized for decades. Since the publication of Rachel Carson's book—Silent Spring, in 1962, new projects have been proposed every year to develop cutting-edge scientific approaches that reflect the growing understanding of endocrine toxicology and the effects of endocrine disruptors (EDCs) (EC, 2024, Endocrine disruptors; EPA, 2024, Endocrine disruptors; OECD, 2018, Evised Guidance Document). Water disinfection by-products (DBPs) are also contaminants of emerging concern. Haloacetic acids (HAAs) are the most common and abundant class of chemicals in chlorinated water, along with trihalomethanes, and have been classified as cytotoxic, genotoxic, teratogenic, mutagenic and carcinogenic compounds in various bioassays (Perez-Albaladejo et al., 2023, Science of the Total Environment). However, despite the global information on the toxicity of HAAs, little is known about the potential adverse impact of these DBPs to the aquatic life. In order to evaluate the ecological risk of three selected HAAs commonly detected in water, laboratory in vivo acute toxicity tests were performed using the water flea Daphnia magna. As in natural conditions pollutants coexist, this study also considered situations of simultaneous exposure to HAAs and other common EDCs, such as atrazine, bisphenol A, arsenic and nitrate. An increase in the toxicity of the HAAs was observed when the compounds were combined in a ternary mixture (54.9% ± 10.3%; EC50 = 183.7), as well as in the presence of nitrate, with a significant decrease of the EC50 value (EC50 = 148.6). On the other hand, the quaternary mixtures of atrazine and arsenic did not show significant differences of toxicity when compared to the ternary mixture, and there was even an increase of the EC50 value in the presence of BPA (EC50 = 218.0). This suggests that the presence of these pollutants in water, within the legal limits, does not potentiate the acute toxic effects of the haloacetic acids, contrary to what was expected, given the toxicity of the single compounds. Environmental mixtures are often highly complex, thus developing robust models to predict their behavior and toxicity is critical. A predictive assessment of mixtures’ toxicity of similar and dissimilar-acting toxicants was performed from the concentration–response analyses of individual compounds by the models concentration addition (CA) and independent action (IA). The agreement between the experimental and predicted effective concentration was then observed and confirmed via the application of the model deviation ratio (MDR).