Threshold of Toxicological Concern (TTC) for Botanical Extracts (Botanical-TTC) derived from a meta-analysis of repeated-dose toxicity studies

Toxicol Lett. 2019 Nov:316:1-9. doi: 10.1016/j.toxlet.2019.08.006. Epub 2019 Aug 12.


Threshold of Toxicological Concern (TTC) is a promising approach for evaluating the human health risk for systemic toxicity when there is a lack of toxicological information. The threshold for systemic toxicity is reportedly 1800, 540, and 90 μg/day for Cramer I-III chemical structures, according to Munro's structural decision tree, and 0.15 μg/day for genotoxic compounds. However, the concept of TTC has been developed for single substances; therefore, the applicability of TTC for mixtures remains unclear. To expand application of probability approach for mixtures, a validation study using the point of departures (PoDs) derived from mixtures is required. In the present study, we investigated novel TTC of botanical extracts (Botanical-TTC) for cosmetics from a meta-analysis based on the PoDs derived from repeated dose toxicity testing in botanical extracts. Accordingly, 213 PoDs were determined by repeated-dose toxicity studies and divided using a default uncertainty factor of 100 combined with the extrapolation factor of study duration to calculate the derived-no-effect-level (DNEL) and derived-minimal-effect-level (DMEL). The minimum DNEL/DMEL was 1.6-fold higher than the Cramer III TTC. In addition, because human health risk below the 1 st percentile value (663 μg/day) was considered as extremely limited, the exposure level can be proposed as Botanical-TTC.

Keywords: Botanical extract; Botanical-TTC; Mixture; TTC; Threshold of Toxicological Concern.

Publication types

  • Meta-Analysis

MeSH terms

  • Animals
  • Consumer Product Safety
  • Cosmetics / toxicity*
  • Dose-Response Relationship, Drug
  • Humans
  • No-Observed-Adverse-Effect Level
  • Plant Extracts / toxicity*
  • Risk Assessment
  • Toxicity Tests*


  • Cosmetics
  • Plant Extracts