Ask a RIFM Scientist: What is TTC, and how does it help avoid animal testing?



The Threshold of Toxicological Concern, or TTC, was first conceived in 1990 in a review of the United States Food and Drug Administration’s (FDA) regulatory policy on food additives, referred to then as the Threshold of Regulation, or ToR.

The TTC approach has been developed and refined over three decades. It plays a strategic role in the Research Institute for Fragrance Materials’ (RIFM’s) commitment to ensuring the safe use of fragrance ingredients without using animals.

Kaushal Joshi, PhD, leads RIFM’s Reproductive Toxicology testing program. Dr. Joshi co-authored a recently published paper detailing an expansion of the dataset supporting the use of TTC.

Q: What is TTC, and how does it work?

A: Simply put, TTC is a level of exposure to a substance, beneath which there are no concerns for adverse effects.

To define a fragrance ingredient’s TTC, we must first identify its potency based on chemical structure and reactivity: low, medium, or high. Then, we take the aggregate exposure—how much of the ingredient consumers come in contact with from all products used—and compare that exposure to what we know to be a safe-use level of similarly potent ingredients.

If a consumer’s total aggregate exposure to an ingredient is below the TTC, we know there is no appreciable risk of toxic effects associated with the ingredient.

Q: What makes TTC so useful?

A: TTC is used explicitly for chemicals that have limited or no toxicity data available because scientists have not tested them on animals.

In 2013, the European Union implemented a ban on animal testing for both finished cosmetics products and the ingredients used in cosmetics products, including fragrance ingredients.

RIFM began using the TTC approach as part of its safety assessment program before this ban. As a result of its pioneering use of TTC, RIFM has saved more than 265,000 animals.

Q: Your specific area of study is the reproductive system and human development process. Can scientists that are focused on other aspects of human health use TTC?

A: Yes. RIFM scientists may also use the TTC to assess an ingredient’s potential for other endpoints. There are different TTC thresholds for other endpoints:


‚ÄčRepeated dose toxicity, which refers to regular exposure over an extended time

Local respiratory toxicity

Skin sensitization, or the induction of an allergic reaction after repeated skin contact.

Scientists evaluating skin sensitization potential call it the DST, for Dermal Sensitization Threshold.

Q: Does each ingredient have a single TTC for all aspects of human health?

A: No. The TTC or DST is dependent in part upon which aspect of human health the scientist is assessing. For instance, inhalation TTCs are different than TTCs for reproductive toxicity.

(RIFM outlined the differences in TTC between areas of human health in the peer-reviewed RIFM Criteria Document.)

Q: How reliable is TTC?

A: The European Scientific Committees on Consumer Safety (SCCS), Health and Environmental Risks (SCHER), and Emerging and Newly Identified Health Risks (SCENIHR) published a joint opinion paper in 2012 on TTC.

In their report, the Committees verified the TTC approach as scientifically valid for human health risk assessment of systemic toxic effects caused by chemicals present at minimal levels.

It is important to note that scientists can only use the TTC approach with ingredients that have robust exposure data.

That is why, in 2010, RIFM partnered with data analytics software leaders Creme Global to develop and maintain an aggregate exposure model and database—a person’s total exposure to an ingredient through all products used—based on actual usage data. Further, RIFM understands the importance of monitoring the exposure to fragrance ingredients and now has a policy to conduct concentration surveys at least every five years on every fragrance ingredient.

(Watch this space to register for a November 18, 2020 webinar on the Creme RIFM Aggregate Exposure Model. This event will be open to all and free of charge.)

Q: What does your recently published paper add to the understanding of TTC?

A: RIFM partnered with scientists at Proctor and Gamble (P&G) to validate the current TTC exposure limit values and to bolster support for the use of TTC as a tool to conduct safety assessments for fragrance ingredients.

RIFM and P&G scientists first curated materials from the RIFM Database—the most extensive collection of fragrance ingredient data in the world—based on their available data and chemical structures.

We then combined the curated ingredients with a dataset from another recent publication. Notably, many new medium potency ingredients were added, which has historically contained the lowest number of ingredients, and thus the least amount of data.
The resulting estimates for TTC limits support the current values and bolster the data in the medium potency class, thereby strengthening the use of TTC as a tool to conduct safety assessments for fragrance ingredients.