Ask a RIFM Scientist: What is repeated dose toxicity, and why does RIFM study it?


RIFM’s scientists dedicate their careers to ensuring that consumers can safely enjoy their favorite fragranced products. Soaps, shampoos, deodorants, and other personal care products are not for one-time use, and that’s why RIFM’s Fragrance Ingredient Safety Assessment Program studies the use of odor-producing materials over extended periods.

Dan Selechnik, PhD, leads RIFM’s Repeated Dose Toxicity efforts.

Q: What is repeated dose toxicity, and why is it part of RIFM’s Safety Assessment process?

Often, our body’s response to a single exposure or only a few exposures to an ingredient (what we call acute exposure) does not provide a full picture of how the ingredient may affect us. The repeated dose perspective examines the effects of frequent and regular ingredient exposures over a prolonged period. We use fragrance products daily for most of our lives (what we call chronic exposure), so repeated dose studies provide a better simulation of real-life conditions.  

Q: How does studying an ingredient’s potential for repeated dose toxicity differ from studying how it might affect the skin?

That’s a great question. Simply put, there are two broad aspects of human health-related studies:

Systemic refers to an ingredient’s general effects on the body, such as changes to multiple organs.

Local refers to the effects an ingredient might have on one particular organ or site, such as the skin or the lungs.

When we study repeated dose toxicity, we are looking at the potential systemic effects.

Q: What sorts of things do you measure when studying the systemic effects of an ingredient over time?

The acronym ADME captures a good portion of it. ADME stands for Absorption, Distribution, Metabolism, and Excretion.

Absorption refers to an ingredient’s potential to enter the body.

Distribution refers to where in the body an ingredient might travel.

Metabolism is a more complicated process, wherein the body breaks down a substance to use and eliminate it. The substance may change its molecular structure during this process, and scientists refer to each of these new, temporary structures as metabolites.

Excretion refers specifically to the elimination of the ingredient.

The liver and kidneys are two of the most metabolically active organs, and we commonly see these organs exhibit effects in response to fragrance ingredient exposures. Depending on their nature and severity, these effects may be adverse, meaning “of concern,” or adaptive, meaning not necessarily a cause for concern.

Evaluating an ingredient’s ADME profile requires a lot of data interpretation. Advancements in research and technology have refined our conclusions over time, and will continue to do so, requiring refinement in the future. We also must consider that some effects may result from a chemical’s metabolites rather than from the chemical itself.

Q: What does the future hold for RIFM’s repeated dose toxicity program?

We are currently researching new approach methodologies, or NAMs, that serve as alternatives to animal testing.

One such approach is IVIVE, which stands for in vitro (in a test tube or Petri dish) to in vivo (in a living organism) extrapolation. Using this approach, we can use the data that we gather from studying how an ingredient affects cells or tissues in a Petri dish to make predictions about how it may affect animals or humans.

Also, we are refining the concept of TTC, or the Threshold of Toxicological Concern. The TTC is a level of exposure to a substance, beneath which there are no concerns for adverse effects.

The TTC defines a safety threshold for a consumer’s external exposure to a fragrance ingredient—how much the person comes in contact with the substance.

We are focusing research on the internal TTC, or iTTC. The iTTC defines a safety threshold for a consumer’s real-world internal exposure to a fragrance ingredient.

Ultimately, through our research, RIFM strives for more ethical and accurate methods of risk assessment.