[Updated] China Unveils Guidelines for Threshold of Toxicological Concern (TTC) Method and Read-across Method in Cosmetic Safety Assessment

Editor’s Note: This article was originally published on March 25, 2024, and was updated on May 11, 2024, as per the latest developments.

On April 30, 2024, China's National Institutes for Food and Drug Control (NIFDC) released the finalized version of the Technical Guidelines for Application of Threshold of Toxicological Concern (TTC) Method and the Technical Guidelines for Application of Read-across Method.

The following are the key highlights of the draft Technical Guidelines for Application of Threshold of Toxicological Concern (TTC) Method and the draft Technical Guidelines for Application of Read-across Method.

In a move to advance cosmetic safety assessment practices, China National Institutes for Food and Drug Control (NIFDC) published the draft version of the Technical Guidelines for Application of Threshold of Toxicological Concern (TTC) Method (the TTC Technical Guidelines) and the Technical Guidelines for Application of Read-across (the Read-across Technical Guidelines) for cosmetic safety assessment respectively on March 20, 2024.

Both guidelines are open for public comments until April 7, 2024. Interested stakeholders are encouraged to provide feedback to [email protected] before the deadline.

Draft TTC Technical Guidelines

The draft TTC Technical Guidelines consists of six sections and three appendices, stipulating the application scope, terminology and definition, substances classification, evaluation procedures, etc. pertinent to the TTC method. Key highlights include:

1. Offering further clarity on TTC method’s application scope, on the basis of the Technical Guidelines for Cosmetic Safety Assessment 2021.

Applicable Situations

The TTC method is applicable to the assessment of both cosmetic ingredients and risk substances, with clear chemical structures, without severely mutagenic alert structures, low content and lack of systematic toxicology research data.

Inapplicable Situations

1. Metal or metal compounds

2. Strong carcinogens (such as aflatoxins, nitroso compounds, benzidines, etc.)

3. Proteins

4. Steroids

5. Substances with high molecular weight

6. Substances with strong bioaccumulation, radioactive chemical substances

7. Ingredients with preservative, sunscreen, coloring, hair dyeing, freckle removing and whitening, anti-hair loss, anti-acne, anti-wrinkle (except physical anti-wrinkle), anti-dandruff, deodorant functions, and those with higher biological activity; (In the finalized version, this item is changed to "Ingredients with preservative, sunscreen, coloring, hair dyeing, freckle removing and whitening functions")

8. Nanomaterials, inorganics, ingredients with inhalation risk

2. Clarifying the classification of substances in TTC assessment and their corresponding TTC thresholds.

Substances Classification		TTC (µg/kg/day)
Potential DNA-Reactive Mutagens/Carcinogens		0.0025
Non-potential DNA-Reactive Mutagens/Carcinogens	Cramer Class I: Substances with simple structure, easy metabolism, and low oral toxicity.	46
	Cramer Class II: Substances that are intermediate	2.3
	Cramer Class III: substances that may suggest significant toxicity.	2.3

3. Extending the applicable scope of the TTC method to mixtures. The TTC Technical Guidelines stipulates that “The content of the identified ingredients in the mixture should not be less than 80% (In the finalized version, this number is changed to 50%). For known ingredients, appropriate assessment methods should be used for safety assessment to ensure safe use. In case of ingredients with similar structures, dose superposition assessment should be carried out. For unknown ingredients, if the Cramer Class cannot be determined, the overall Cramer Class will be considered as the class with the lowest TTC, that is, Cramer III.”

Industry experts point out that this opens doors for many plant extracts lacking safety data to undergo assessment, offering hope to stakeholders regarding the inclusion of these plant extracts raw materials in formulas.

Draft Read-across Technical Guidelines

With five sections and two appendices, the draft Read-across Technical Guidelines outline the application scope, basic principles, and evaluation procedures of Read Across, along with a flowchart and an example of its application in cosmetic safety assessments.

Compared to the Technical Guidelines for Cosmetic Safety Assessment 2021, the draft Read-across Technical Guidelines introduce applicable and inapplicable situations. Specifically, the read-across assessment is applicable to non-functional ingredients and risk substances, but does not apply to ingredients with preservative, sunscreen, coloring, hair dyeing, freckle removing and whitening, anti-hair loss, anti-acne, anti-wrinkle (except physical anti-wrinkle), anti-dandruff, deodorant functions, or those with higher biological activity. (In the finalized version, the scope of inapplicability is narrowed to "ingredients with preservative, sunscreen, coloring, hair dyeing, freckle removing and whitening functions.")