Impact of study design and database parameters on NOAEL distributions used for toxicological concern (TTC) values

- In the past, influence of study design and database parameters on TTC values was scarcely investigated.
- The present work investigates impact of study design and database parameters on lowest NOAEL distributions.
- Lowest NOAEL distributions are mildly sensitive for study design and database parameters.
- Current TTC values therefore are influenced only to minor degree by the parameters investigated here.

TTC values for chemicals with unknown toxicity but known structure are derived from 5th percentiles of NOAEL distributions from compounds with known toxicity. The impact of chemical structures on TTC values was repeatedly investigated but not the impact of parameters such as study numbers per compound and differences in study design. Recently, study design parameters such as application route with related dose-decrements, dose-spacing and number of animals per group but not exposure duration were found to affect NOAEL distributions. Here, the impact of study design parameters on lowest NOAEL distributions and consequently on TTC values was analyzed in a database on 423 Cramer class III pesticides. Using NOAELs related to lowest LOAELs instead of lowest NOAELs, excluding studies with a dose spacing >8, and standardizing NOAELs to the initial dose animals received shifted the 5th percentile of NOAEL distributions from 0.22 to 0.5 mg/kg body weight per day. In contrast, weighting of NOAELs for the study numbers per compound shifts 5th percentiles downwards to lower values by 10-20%. The results show that database and study design parameters influence NOAEL distributions to a minor degree and derived TTC values therefore can be considered reliable in that perspective.