Thresholds of Toxicological Concern for Cosmetics

COSMOS Webinar on TTC

The COSMOS webinar "Threshold of Toxicological Concern – an approach for safety assessment and its applicability to cosmetics-related chemicals" was held on 24 July 2014, hosted by the American Society for Cellular and Computational Toxicology (ASCCT).

The webinar slides can be downloaded here.

A recording of the webinar is available here.

  • Establishment of thresholds of toxicological concern (TTC) to ensure safety of chemicals for endpoints relating to human repeated dose toxicity.

The Threshold of Toxicological Concern (TTC) is a widely applied risk assessment approach that establishes a human exposure threshold value for chemicals, below which there is a low probability of an appreciable risk to human health.

COSMOS assesses the extension of the current TTC approach for application to cosmetic ingredients and extrapolation from the oral to dermal route exposure, which is particularly relevant for cosmetics.

To assist TTC development, a dataset containing repeated dose toxicity data for cosmetic ingredients is being derived by matching cosmetic ingredients in the COSMOS Cosmetics Inventory with publicly available oral repeated dose toxicity data. The identification of NOELs will include a full quality control procedure. This COSMOS TTC dataset of reliable No Observed Effect Level (NOEL) values extends that originally provided in the Munro TTC dataset (Munro et al 1996). For example, the COSMOS database includes many classes of compounds which are not present in the Munro dataset. This will provide greater relevance to the determination of TTC for materials used in cosmetics. An extensive database of dermal penetration data is also being curated and quality assured for the analysis of oral to dermal extension of the TTC approach.

The Cramer scheme (proposed by Cramer et al 1978) is the most commonly used scheme to classify chemicals for TTC for non-cancer endpoints. It categorises chemical substances into three classes (I, II and III) depending on their expected level of oral systemic toxicity (low, medium, and high). COSMOS will update the use of the traditional Cramer classes with a scheme that is not only more relevant to cosmetic ingredients but also based around modes of action, building on the mechanistic knowledge. The initial outcome of some of these analyses has already been published by Worth et al (2012).

Thresholds of Toxicological Concern for Cosmetics.

ILSI-EU TTC Expert Groups

COSMOS partner ILSI Europe TTC Task Force has set up two expert groups with the aim to deliver opinions and recommendations to guide COSMOS in the effort to expand the current TTC approach so that it will have a broader applicability and regulatory acceptance for cosmetic ingredients.

Expert Group 1: Development of criteria to be applied in the extension of the current TTC approach to cosmetics ingredients

This expert group advises on the structure and creation of the database for cosmetics by recommending inclusion criteria for chemicals and toxicological studies (quality and selection) and supports the evaluation of the data collection. Using this new database, the expert group is investigating the application of TTC to cosmetics by evaluating the chemical space of cosmetic ingredients as it compares to the existing Munro database, and whether the existing Cramer Classes are appropriate, or whether additional TTC tiers and thresholds need to be established.

Expert Group 2: Evaluation of oral-to-dermal extrapolation

The current TTC approach was developed from an oral toxicity database and questions have been raised about its applicability to dermal exposure. This expert group focuses on the technical issues associated with oral-to-dermal extrapolation, identifying data needs and assessing the feasibility of extrapolation. Additionally, the group is investigating possible methods, building on the work of Kroes et al. (2007), to improve extrapolation and the appropriateness of the use of modelled data.

More information can be found on the ILSI Europe website.


Kroes R, Renwick AG, Feron V, Galli CL, Gibney M, Greim H, Guy RH, Lhuguenot JC, van de Sandt JJM (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45: 2533-2562

Munro IC, Ford RA, Kennepohl E, Sprenger JG (1996) Correlation of structural class with No-Observed-Effect Levels: A proposal for establishing a Threshold of Concern. Food Chem. Toxicol. 34: 829-867

Worth A, Cronin M, Enoch S, Fioravanzo E, Fuart-Gatnik M, Pavan M, Yang C, Applicability of the Threshold of Toxicological Concern (TTC) approach to cosmetics – preliminary analysis. JRC report EUR 25162 EN. Publications Office of the European Union, Luxembourg, 2012, available at: repository/


This is European Comission Project. Seventh Framework Programme. Cosmetics Europe, The Personal Care Association. COLIPA, The European trade association for the cosmetic, toiletry and perfumery industry.