Fragrance Materials Safety Assessment
DATABASE

Yax Thakkar, T. Kobets, Anne Marie Api, J. D. Duan, G. M. Williams

This study evaluated the Chicken Egg Genotoxicity Assay (CEGA) as a biologically relevant new approach methodology (NAM) by confirming target tissue exposure and metabolic activation in embryo-fetal chicken livers. Using imaging, LC/MS, and RNA sequencing, the results demonstrated that benzo(a)pyrene reached the liver, was bioactivated into genotoxic metabolites, and induced DNA damage, supporting CEGA’s utility as a robust alternative to traditional in vivo genotoxicity testing.

Nikaeta Sadekar, Holger Peter Behrsing, et al

This study introduces a novel approach for assessing the safety of inhalation exposure to respiratory irritants by integrating in vitro and in silico methods. By simulating airway surface depositions and comparing them to in vitro effect concentrations, the researchers calculated a margin of exposure greater than 100-fold, demonstrating the potential of non-animal testing strategies in inhalation safety evaluations.

Julia Scheel, Nora L. Krutz, et al

A critical examination of the limitations of current clinical methods in diagnosing respiratory sensitization caused by low molecular weight chemicals (LMWCs), highlighting challenges in proving their sensitization potential. It offers recommendations to enhance these approaches, aiming to improve the regulatory process for the identification and classification of respiratory sensitizers. 

Siti Amelia Juraimi, Cesar Scrochi, et al

This study provides critical data on the habits and practices of cosmetics and personal care product use in Singapore, filling a gap in exposure data for the Asia-Pacific region. By integrating this data into the global Creme-RIFM Aggregate Exposure model, the research enhances safety assessments of product ingredients, ensuring more accurate safety evaluations worldwide.

Kristine L. Witt, Jan van Benthem, et al

This study introduces an innovative screening strategy for assessing the genetic safety of botanicals, combining in silico modeling, in vitro assays, and case studies to reduce reliance on animal testing. The research, led by the Health and Environmental Sciences Institute’s Botanical Safety Consortium, provides a more reliable and ethical framework for evaluating botanical ingredients used in consumer products, enhancing safety assessments, and aligning with global efforts to refine toxicological evaluation methods.

Kaushal Joshi, Darren M. Green, et al

This study demonstrates that using in vitro human skin absorption data provides a more realistic assessment of consumer exposure to fragrance ingredients, leading to more accurate risk evaluations. By examining three commonly used salicylates in real-world topical formulations, the research highlights how chemical structure, application vehicle, and occlusion levels significantly impact skin absorption rates.

Lapczynski A, Belanger S E, et al

Octahydro‐tetramethyl‐naphthalenyl‐ethanone (OTNE) is a high-production volume fragrance material with widespread usage in various down-the-drain consumer products. Owing to OTNE’s high production volume and the conservative nature of the RIFM framework, RIFM identified the need to utilize a species sensitivity distribution (SSD) approach to reduce the PNEC uncertainty for OTNE. The researchers found that the aquatic invertebrate Daphnia magna was the most sensitive taxon to OTNE, whereas Desmodesmus subspicatus, a species of algae, was the least sensitive. This paper makes OTNE, already one of the most well-studied fragrance materials, the first to have an aquatic SSD developed.

Lee I, Scrochi C, et al

RIFM collaborated with scientific modeling, data analytics, and computing company Creme Global, to compare the fragrance exposure of the highest product users (95^th percentile) to the Threshold of Toxicological Concern (TTC) and Dermal Sensitization Threshold (DST) to determine a realistic understanding of consumer exposure to fragrance. The results showed that even the most loyal fragranced product users were exposed to fragrance at levels well below the TTC and DST.

Moustakas H, Date M, et al

Integrating computational chemistry and toxicology can improve the read-across analog approach to fill data gaps in chemical safety assessment. Read-across is a structure−activity analysis encompassing various techniques and approaches to solve gaps in toxicity prediction. The concept of chemical similarity is central to the read-across method. The scientists found that applying endpoint-specificity in read-across analog selection scientifically expands potential read-across options and helps to avoid performing in vivo testing.

Na M, O’Brien D, Gerberick G. Frank, et al

RIFM collaborated with Procter & Gamble (P&G) on a report on using the animal-alternative SENS-IS assay to determine the sensitization potential for fragrance ingredients. The results showed that SENS-IS provides a useful approximation of skin potency to help identify ingredients for further testing.

Lee I, Na M, O’Brien D, et al

In a collaborative paper, RIFM, along with L’Oréal and Charles River Laboratories, report on the results of using the U-SENS assay.Fragrance ingredients were tested using the U-SENS™ assay and results compared to weight of evidence from historical data. RIFM anticipates that the U-SENS assay will be added to the OECD Guideline as one of the “me too” assays.

Thakkar Y, Moustakas H, Api AM, et al

In order to evaluate the genotoxic potential of mintlactone, in vitro and in vivo genotoxicity tests were conducted. Results from bacterial mutagenicity tests varied across different batches of differing purity with positive results observed in TA98 only. In the absence of dependable scientific information on the purity and/or storage stability of mintlactone, its safety for use as a fragrance ingredient could not be substantiated.

Na M, O’Brien D, Lavelle M, et al

This study aimed to define skin sensitization potency of fragrance materials via weight of evidence approach, incorporating all available 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 useful resource in evaluation of nonanimal methods, as well as in risk assessment.

Ritacco G, Hilberer A, Lavelle M, et al

An improved methodology to the safety assessment of fragrance materials for photoirritation is described in detail.  The tiered approach, which relies on animal-alternative methods, is shown to minimize the likelihood of photoirritation from fragrance materials. 

Sadekar N, Boisleve F, Dekant W, et al

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.

Lee I, Na M, Lavelle M, et al

This 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 in turn inform the International Fragrance Association (IFRA) Standards.

Thakkar Y, Moustakas H, Aardema M, et al

An evaluation of the utility of the 3D reconstructed skin micronucleus assay (3DRSMN) to assess clastogenic/aneugenic potential of the fragrance chemicals. Results from evaluations of 22 fragrance materials in the 3DRSMN assay compared with those from an in vivo micronucleus assay were shown to be in 100% agreement.

Api AM, Belsito D, Botelho D, et al

RIFM has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

Date MS, O’Brien D, Botelho DJ, et al

A valuable approach to chemical safety assessment is the use of read-across chemicals to provide safety data to support the assessment of structurally similar chemicals.

Patel A, Joshi K, Rose J, et al

The use of threshold of toxicological concern (TTC) supports the safety assessment of exposure to low levels of chemicals when toxicity data are limited. A major goal for the RIFM safety assessment program is to invest in alternative methods to animal testing for use in assessment of fragrance materials.

Nishijo T, Api AM, Gerberick GF, et al

Skin sensitization evaluation is a key part of the safety assessment of ingredients in consumer products, which may have skin sensitizing potential.

Api AM, Basketter D, Bridges J, et al

This revision of the Quantitative Risk Assessment 1 (QRA1), termed QRA2, provides an improved method for establishing safe levels for sensitizing fragrance materials in multiple products to limit the risk of induction of contact allergy.

Fragrance Skin Sensitization Evaluation and Human Testing: 30-Year Experience

The human repeated insult patch test (HRIPT) has a history of use in the fragrance industry as a component of safety evaluation, exclusively to confirm the absence of skin sensitization at a defined dose. The aim of the study was to document the accumulated experience from more than 30 years of conducting HRIPTs.

Api AM, Basketter DA, Cadby PA, et al

Based on chemical, cellular, and molecular understanding of dermal sensitization, an exposure-based quantitative risk assessment (QRA) can be conducted to determine safe use levels of fragrance ingredients in different consumer product types.

Politano VT, Api AM

With implementation of the dermal sensitization QRA approach for fragrance ingredients, IFRA/RIFM are recommending use of the RIFM standard human repeated insult patch test (HRIPT) protocol for generation of confirmatory human data for the induction of dermal sensitization in a normal human population.

Comiskey D, Api AM, Barrett C, et al

In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products.

Safford B, Api AM, Barratt C, et al

Ensuring the toxicological safety of fragrance ingredients used in personal care and cosmetic products is essential in product development and design, as well as in the regulatory compliance of the products.

Safford RJ, Api AM, Roberts DW, Lalko JF

The evaluation of chemicals for their skin sensitising potential is an essential step in ensuring the safety of ingredients in consumer products.

Api AM, Vey M

Significant developments have recently been incorporated in the way dermal sensitization risk assessments are conducted for fragrance ingredients.

Roberts DW, Api AM, Safford RJ, Lalko JF

An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential.

Comiskey D, Api AM, Barratt C, et al

Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey.

Safford B, Api AM, Barrett C, et al

As part of a joint project between the Research Institute for Fragrance Materials (RIFM) and Crème Global, a Monte Carlo model (here named the Creme RIFM model) has been developed to estimate consumer exposure to ingredients in personal care products.