Threshold of Toxicological Concern (TTC)

Threshold of toxicological concern (TTC)

Risk assessment for most human health effects is based on the threshold of a critical toxicological effect, usually derived from animal experiments. The Threshold of Toxicological Concern (TTC) is a concept that aims to establish a generic exposure level for all chemicals below which there would be no appreciable risk to human health. The threshold is based on a statistical analysis of the toxicological data from a broad range of chemicals and on the extrapolation of the underlying animal data to a no-effect dose considered to represent a negligible risk to human health.
The TTC approach has been incorporated into some risk assessment processes in regulatory schemes. Examples include chemicals in food and feed.


Cramer Classification Scheme

The Cramer classification scheme (tree) is probably the best known approach for structuring chemicals in order to make a TTC estimation. The tree relies primarily on chemical structures and estimates of total human intake to establish priorities for testing. The procedure uses recognized pathways for metabolic deactivation and activation, toxicity data and the presence of a substance as a component of traditional foods or as an endogenous metabolite.

Substances are classified into one of three classes:
Class I contains substances of simple chemical structure with known metabolic pathways and innocuous end products which suggest a low order of oral toxicity.
Class II contains substances that are intermediate. They possess structures that are less innocuous than those in Class 1 but they do not contain structural features that are suggestive of toxicity like those in Class 3.
Class III contains substances with chemical structures that permit no strong initial impression of safety and may even suggest a significant toxicity.
For more information on the Cramer Classification Scheme you can read the original scientific publication here:
Cramer GM, Ford RA & Hall RL (1978). Estimation of Toxic Hazard - A Decision Tree Approach. Food and Cosmetics Toxicology 16, 255-276.

TTC datasets

Datasets that have been used to develop and refine the TTC approach (Munro, COSMOS) can be downloaded from the publicly accessible COSMOS database.


The JRC commissioned the development of a computer program, Toxtree, to implement various rule-based estimation approaches, including the Cramer classification scheme.
Toxtree is standalone software application that can be run on the Microsoft Windows operating system as well as on different platforms with Java. The latest version of this software can be downloaded (free of charge) from here