Bolstering the existing database supporting the non-cancer Threshold of Toxicological Concern values with toxicity data on fragrance-related materials

Regul Toxicol Pharmacol. 2020 Oct:116:104718. doi: 10.1016/j.yrtph.2020.104718. Epub 2020 Jun 27.


The use of threshold of toxicological concern (TTC) supports the safety assessment of exposure to low levels of chemicals when toxicity data are limited. The Research Institute for Fragrance Materials (RIFM) delivers safety assessments for fragrance materials that result in safe products for consumer use. A major goal for the RIFM safety assessment program is to invest in alternative methods to animal testing for use in assessment of fragrance materials. This includes use of TTC, which provides a pragmatic approach for safety evaluation of fragrance materials in the absence of chemical-specific toxicity data and reduces the need to generate new animal data. To bolster the TTC approach for support of fragrance materials and specifically to strengthen the Cramer class II threshold, the RIFM database was reviewed with a goal of identifying fragrance materials with data that can be added to the existing TTC databases. The RIFM database identified a total of 476 chemicals that were added to the existing TTC databases. The chemicals were then individually assigned a Cramer class and 238, 76 and 162 chemicals in Cramer class I, II and III respectively were identified. The RIFM-TTC dataset was then combined with the COSMOS-Federated TTC dataset for a total of 421, 111 and 795 chemicals in Cramer class I, II and III respectively. The combined dataset further expands the chemical space thereby providing more robust 5th percentile thresholds. Moreover, the combined dataset bolsters the threshold for Cramer class II to include a total of 111 chemicals which is an improvement over the original (Munro) TTC dataset which only included 28 chemicals in Cramer Class II and the COSMOS Federated dataset which had 40 chemicals. This allows for a more reliable and robust 5th percentile NOAEL value for Cramer class II chemicals of 1.27 mg/kg bw/day. The 5th percentile NOAELs for Cramer class I, II and III from the combined dataset are 4.91, 1.27 and 0.29 mg/kg bw/day, which supports the threshold values derived from the original Munro dataset. This work confirms the adequacy of the existing TTC values and provides further support for the use of TTC as a tool to conduct safety assessments for fragrance materials. It further opens the future possibility of updating the existing values with more robust TTC values for fragrance and cosmetic materials.

Keywords: Cramer classification; Research institute of fragrance materials; Threshold of toxicological concern.

MeSH terms

  • Animals
  • Databases, Factual*
  • Humans
  • No-Observed-Adverse-Effect Level
  • Odorants*
  • Perfume / toxicity*
  • Risk Assessment


  • Perfume