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In 2022, the Research Institute for Fragrance Materials (RIFM) advanced its science significantly with an unprecedented 12 research papers published in peer-reviewed scientific journals.

These publications provide insights and methodologies to expand understanding and further avoid animal and human testing.

An NCS Criteria Document

Natural Complex Substances (NCS) are fragrance ingredients extracted from plants that are complex mixtures of many components. The safety assessment of NCS is similar to and just as robust as the stepwise process RIFM uses to assess discrete fragrance ingredients. In addition, the same endpoints are evaluated via the latest science and animal-testing alternatives.

Co-authored with members of the Expert Panel for Fragrance Safety, The RIFM approach to evaluating Natural Complex Substances (NCS) was published in Food and Chemical Toxicology.

A Criteria Document for Photoirritation

Photoirritation is a skin reaction that occurs when an exogenous (not something your body made) substance is applied to the skin and exposed to ultraviolet (UV) rays. In photoirritation, the affected area of the skin may resemble an exaggerated sunburn. These one-time effects go away over time and occur in anyone given enough of the substance combined with UV light.

For a substance to be photoirritating, it must absorb UV rays. However, of the more than 1800 ingredients with no photoirritation data, some 94% do not absorb UV rays, meaning they pose no concern for photoirritation. This paper, which provides an update for photoirritation to the original Criteria Document, looks at case studies of 108 ingredients that do absorb, outlining RIFM’s tiered approach to assessing their safe use with no reliance on animal testing.

Use of alternative test methods in a tiered testing approach to address photoirritation potential of fragrance materials, written in collaboration with the Institute for In Vitro Sciences (IIVS), was published in Regulatory Toxicology and Pharmacology.

Determining sensitization potency using weight-of-evidence

This study aimed to define the skin sensitization potency of fragrance materials via the weight-of-evidence approach, incorporating all available historical human, animal, in vitro, in chemico, and in silico data. All available data on 106 fragrance materials were considered to assign each material into 1 of the 6 defined potency categories (extreme, strong, moderate, weak, very weak, and nonsensitizer). These results may serve as a helpful resource in the evaluation of nonanimal methods, as well as in risk assessment.

Weight of Evidence Approach for Skin Sensitization Potency Categorization of Fragrance Ingredients was published in Dermatitis.

A weight-of-evidence approach to preventing skin sensitization

RIFM’s Skin Team published an update for skin sensitization to the Criteria Document. The paper details how RIFM derives the NESIL, short for “no expected sensitization induction level,” using all available data. The NESIL is used to help identify maximum acceptable concentrations of an ingredient in fragranced products, which inform the International Fragrance Association (IFRA) Standards.

Derivation of the no expected sensitization induction level for dermal quantitative risk assessment of fragrance ingredients using a weight of evidence approach was published in Food and Chemical Toxicology.

Evidence for adding an assay to an OECD Guideline

RIFM’s innovative, science-based animal alternative methods anticipated the new OECD Guideline 497: Defined Approaches on Skin Sensitization.

In collaboration with L’Oréal and Charles River Laboratories, RIFM tested fragrance ingredients in the U-SENS™ assay and compared the results to the weight of evidence from historical data. As a result, RIFM anticipates that the U-SENS assay will be added to the OECD Guideline as one of the “me too” assays.

Assessment of the skin sensitization potential of fragrance ingredients using the U-SENS™ assay was published in Toxicology In Vitro.

A novel assay to predict skin potency

SENS-IS is an animal-alternative model that uses the reconstructed human skin to determine the hazard and potency of potential skin sensitizers. This study showed that SENS-IS provides a useful approximation of skin potency to help identify fragrance ingredients for further testing.

Benchmarking performance of SENS-IS assay against the weight of evidence skin sensitization potency categories, written in collaboration with Procter & Gamble, was published in Regulatory Toxicology and Pharmacology.

Verifying a 3D skin model to assess genotoxicity

When in vitro (in Petri dish or test-tube) studies show results for DNA mutations or chromosome breaks and alterations, an animal follow-up study was once necessary to confirm these results. RIFM’s Genotoxicity Team and colleagues published a paper verifying the use of the EpiDerm 3D Skin assay as an animal-alternative method to assess the clastogenic/aneugenic potential of fragrance ingredients.

Use of the EpiDerm^TM 3D reconstructed skin micronucleus assay for fragrance materials was published in Oxford Academic’s Mutagenesis.

Evaluating a genotoxicity screening tool

The Genotoxicity Team also published a paper evaluating the effectiveness of the BlueScreen HC, a mammalian cell-based assay for measuring genotoxicity. RIFM uses the assay as a screening tool to prioritize fragrance ingredients for higher-tier testing. This report compared the BlueScreen results of 371 ingredients with in vitro and historical in vivo (animal) data and found that the BlueScreen tool did not produce false-negative results.

The BlueScreen HC assay to predict the genotoxic potential of fragrance materials was published in Mutagenesis.

Developing a list of respiratory sensitizers

In this collaboration with numerous academic institutions and industry leaders, a list of 97 reported respiratory sensitizers was generated and less than 10 chemicals were confirmed with compelling evidence for induction of respiratory sensitization in humans from occupational exposures. This reference list will help for developing novel research on respiratory sensitization.

Identifying a reference list of respiratory sensitizers for the evaluation of novel approaches to study respiratory sensitization was published in Critical Reviews in Toxicology.

An endpoint-specific framework for read-across

Read-across is a safety assessment approach in which study data on one chemical can be used as a proxy to support the safe use of a structurally similar chemical lacking study data.

Dr. Moustakas discussed the importance and impact of the newly published paper in a recent Ask a RIFM Scientist posting. “Endpoint specificity in read-across analog selection makes read-across a more scientific process,” he explained. “In addition, it expands the potential read-across options RIFM scientists have, which allows them to ensure the safety of more fragrance ingredients while avoiding extra testing and saving animal lives.”

An Endpoint-Specific Framework for Read-Across Analog Selection for Human Health Effects was published in Chemical Research in Toxicology.

When read-across may not be appropriate

When grouping chemicals, it is critical to define the applicability domain because minor differences in chemical structure can lead to significant differences in toxicity. In collaboration with Procter & Gamble, RIFM  looked at the example of isoeugenol and methyl eugenol, which are scheduled for review by IARC in June 2023, to illustrate that structural similarity alone may not be sufficient to group chemicals for hazard classification.

A Cautionary tale for using read-across for cancer hazard classification: Case study of isoeugenol and methyl eugenol was published in Regulatory Toxicology and Pharmacology.

When safe use can’t be confirmed

In rare cases where existing methods cannot verify a material’s genetic safety, RIFM publishes its findings in the peer-reviewed literature. That material will then be banned for use as a fragrance ingredient. For example, this was recently the case with mintlactone; the findings were published in Assessment of the genotoxic potential of mintlactone in Food and Chemical Toxicology.

RIFM’s peer-reviewed and published safety assessments and research papers are made free to the public via the open-access Fragrance Material Safety Resource Center.