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 level of exposure for all chemicals below which there would be no appreciable risk to human health. Application of the TTC concept is sometimes used as a means of waiving testing based on knowledge of exposure limits. The threshold is based on a statistical analysis of the toxicological data from a broad range of different and/or structurally related 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 concept has been incorporated into some risk assessment processes in regulatory schemes. Examples include food additives and food contact materials. Two main approaches exist: a General Threshold of Toxicological Concern; this is what is applied by the FDA (the so-called Threshold of Regulation for Food contact materials). The second approach is a TTC in relation to structural information and/or toxicological data of chemicals.

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.

  1. Class I contains substances of simple chemical structure with known metabolic pathways and innocuous end products which suggest a low order of oral toxicity.
  2. 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.
  3. Class III contains substances with a chemical structures that permit no strong initial impression of safety and may even suggest a significant toxicity.


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. 2 Runtime Environment, Standard Edition 1.5 (or newer) installed. This software can be downloaded (free of charge) from this website.
Visit the download area of Toxtree


Cramer GM, Ford RA & Hall RL (1978). Estimation of Toxic Hazard - A Decision Tree Approach. Food and Cosmetics Toxicology 16, 255-276.