*2.5. Estimated Daily Intake (EDI) and MOE Calculation*

The EDIs of PAs resulting from the consumption of (herbal) teas was calculated as described before [20], as shown in Equation (1). The interim REP factors for each individual PA, which derived from the data of in vitro cytotoxicity and genotoxicity in *Drosophila* and acute toxicity in rodents (LD50) [12], were used to correct the PA concentrations.

$$\text{EDI} = \frac{\text{Sum of concentration of each PA by or no REP correction} \times \text{daily intake of (herbal) tea}}{\text{Body weight}} \tag{1}$$

where the daily intake of (herbal) tea was estimated to be 2 g, which roughly corresponds to one cup of tea; REP factors were 1.0 for cyclic diesters and heliotridine-type (7S) open diesters, 0.3 for heliotridine-type (7S) monoesters, 0.1 for retronecine-type (7R) open diesters and 0.01 for retronecine-type (7R) monoesters (e.g., indicine, intermedine and lycopsamine) (supporting data S1, Table S2). A default adult body weight of 70 kg was used as suggested [23].

The MOE values for the chronic lifetime exposure to (herbal) teas were calculated as follows:

$$\text{MOE} = \frac{\text{BMDL}^{10} \text{of } \text{riddedlliine}}{\text{EDI}} \tag{2}$$

where the BMDL10 of riddelliine is 237 μg/kg bw/day; the MOE values for the short-term exposure were calculated based on Haber's rule and a lifetime expectancy of 75 years, as described previously [21]. The MOE value being below 10,000 suggests a potential health risk related to the exposure that cannot be excluded and high priority might be given for risk management [3].

The maximum number of weeks that could result in an MOE of 10,000 based on the daily consumption of one cup of tea was calculated as Equation (3), according to the previous studies [3,14,15].

$$\text{The maximum number of weeks} = \frac{\text{BMDL10 of rideldlinine} \ast \text{75 years} \ast \text{52 weeks}}{\text{EDI} \ast \text{MOE}} \tag{3}$$

All calculations above were based on an assumption that the concentrations reported are representative for the specific tea and that the exposure to PAs is exclusively due to that tea.
