Many plant protection products (PPPs) that are authorized in the European Union for agricultural and private use consist of more than one active substance. Combination products with several active ingredients are frequently used with other PPPs in tank mixtures in a spraying sequence of field applications. Therefore, the assessment of mixture toxicity effects under realistic treatment regimes presents an essential part for the environmental risk assessment of PPPs. Many studies have addressed effects of toxicant mixtures on various organisms and endpoints. The model of concentration addition (CA) seems in many cases able to predict the joint effect of toxicant mixtures, both for aquatic and terrestrial organisms. Nevertheless, there is still a lack of understanding regarding the predictability of mixture toxicity for chronic effects and effects at higher levels of biological organization in different environmental compartments. For this, we evaluated in the present COMBITOX project existing literature and available data. We also critically reviewed available models and approaches (i.e. HAIR 2014, SYNOPS-WEB, PRIME-beta etc.) regarding their usefulness for predicting the combined risk of treatment regimes for terrestrial and aquatic ecosystems. Furthermore, we analyzed an unique and large data set of actual PPP spray series from twelve different agricultural crops in Germany to determine crop specific treatment regimes. Four spray series were selected to quantify the additional environmental risk of treatment regimes compared to single applications of active substances. The additional risk was determined using the concept of the maximum cumulative ratio (ratio of the toxicity-exposure ratio, TER, of the most toxic substance in a mixture to the cumulative TER of all components in a mixture). Our analyses show that CA can predict chronic mixture toxicity at the individual level in many cases when toxicity data are based on chronic ECx values than less precise NOEC-values. In contrast, existing scientific literature and studies from regulatory databases hamper a clear statement on the applicability of concepts such as CA or independent action for the prediction of mixture effects on community endpoints. We further identified crop specific patterns especially in terms of applied PPP classes and treatment frequency. The risk assessment of the four spray series revealed an additional risk of treatment regimes with a median factor of 2.18 (50th percentile) to 5.26 (90th percentile) considering all investigated risk indicators and spray series. Finally, we developed a new approach, MITAS, to assess the time-dependent mixture exposure and toxicity in a treatment regime. We conclude that the additional risk of PPP applications in treatment regimes is ecotoxicologically relevant and must be considered for a protective risk assessment of PPPs. However, uncertainties remain regarding the influence of synergistic effects, indirect effects, seed coating, repeated exposure or environmental stressors on the impact of PPP treatment regimes.