Chemical Reaction: A Deep Breath

For breath is life, and if you breathe well you will live long on earth.—Sanskrit Proverb

Fragrances are safe. Really safe. Work by the Research Institute for Fragrance Materials (RIFM) in the past decade has been extraordinary. The main challenge with the sophisticated methods that RIFM now employs is that, as the science gets deeper and deeper, it is harder for mere mortals to keep pace. Some key concepts important to understanding the current activities of RIFM center on risk assessment, environmental and aquatic safety, QRA (Quantitative Risk Assessment) for skin sensitization and respiratory effects. In addition, the International Fragrance Association (IFRA) issues yearly updates with captivating titles such as “43rd Amendment to the IFRA Code of Practice.”

There are more than 2,000 chemicals used in fragrances, and as more safety data is required, there must be a guide to allow the testing of the most critical ones first. RIFM has identified a simple numerical system to combine volume of use, concentration level in product and structural alerts to prioritize materials. The process was summarized in 20001. A molecule with a high priority is not necessarily bad, but it certainly moves to the top of the list for further evaluation.

Structural alerts, “structural moieties that elicit alerts for potential toxic effects,” are parts of molecules that have appeared in other suspect molecules. Structural alerts are divided into topical effects, acute/systemic effects and carcinogenic/mutagenic effects. The numbers weigh heavily toward potential carcinogenic/mutagenic effects. The values assigned for volume of use and concentration in finished products are shown in Figure 1. For the structural alert total, the value of each end point is added (2+4+6 would be the highest score for the structural alert part of the equation).

Getting to Know the Acronyms

The following paragraphs will contain quite a few acronyms. At first contact, it may seem to make the subject incomprehensible. Viewed another way, acronyms are an important portal into the subject. Learning what each acronym stands for is a valuable initial step in understanding, and popping them into Google is a great way to begin learning about the underlying science and technology.

Aquatic risk was addressed in 2002.2 The paper identified predicted environmental concentration (PEC) and predicted no-effect concentration (PNEC) for 2,141 materials in the RIFM database. Materials were deemed to have low environmental effect (PEC/PNEC<1) using ECOSAR (Ecological Structure Activity Relationship). Materials considered environmentally safe by the first rough cut comprised 92.3% of the database. The remaining materials are not implied to be problematic, merely that they merit closer examination. When all is said and done, fragrance material and its use does not add up to an environmental issue.

QRA for skin sensitization is intended to apply more sophisticated science to this area of fragrance safety. The old approach divided products into skin contact and non-skin contact, and further divided skin contact into leave-on and rinse off. The new approach led to 11 categories and 22 subcategories.

QRA requires materials to have an Acceptable Exposure Level (AEL) to be greater than the calculated consumer exposure level (CEL); AEL>CEL.

A key formula is:


Where WoE is Weight of Evidence, NESIL is No Expected Sensitization Induction Level, and SAF is the Sensitization Assessment Factor.

The potential for sensitization is derived from many areas—including the LLNA (Local Lymph Node Assay), which is a fully validated test for determining the potency of skin sensitizing chemicals. Dosage is a critical factor in evaluating safe use using QRA. The full scope of QRA looks very complicated to a nonspecialist, but these acronyms and mathematical relations are simply a glimpse at the machinery that generates the current categories and allowable use levels. They are the answer to the question “Where did those numbers come from?”

Down to Smell

The most important feature of fragrance is smell, and it is there that a strange situation arises. There is precious little information on what happens when we inhale fragrance. At the beginning of RIFM’s testing history, it was obvious that the most important route of exposure was through leave-on skin products—and, of course eye contact, should it happen. Breathing fragrances involves few molecules and is very transitory, so it was considered a minor issue.

A great change in fragrance use occurred in the 1990s, with a profusion of fragranced candles and plug-in air fresheners. All this fragrance in the air directed attention to the potential respiratory consequences, and we were made painfully aware of how little was known about this topic.

RIFM began a respiratory program several years ago. Since more than 2,000 chemicals are used in fragrance, it is impractical to start by testing them all. A surrogate formula was constructed (Figure 2) based on structural alerts, volume of use and likeliness to be used in an air freshener. Starting a program from scratch that will ultimately lead to publication in peer reviewed journals and then to be the basis of guidelines or standards is no small matter, and the RIFM respiratory program has a timelime currently stretching to 2011.

One of the early tests involved an aerosol spray of the surrogate fragrance. It was determined that a valid test result could be derived from a 30-minute exposure to an air freshener under residential use.3 A recent test studied the effect of fragrance on moderate asthmatics, and found no adverse effect caused by fragrance exposure. Since allergic responses in the lungs elicit similar responses to those on the skin, the IgE-6—an immunoglobulin that elicits an immune response—is one example of the markers for respiratory reactions in future clinical studies.4

The evolution in fragrance safety protocols has been RIFM’s response to changing demands, and it has far exceeded the pace of change in the past.

Fortunately, the situation should become more stable in the near future. There will always be updates and amendments, but the programs in place should provide a basic scaffolding for the foreseeable future. The fragrance industry has a long and honorable history of self regulation. When outside forces created new challenges, RIFM and the industry rose to the challenge. Yes, there are a lot of new acronyms and the science is demanding, but it is the symbol of progress and it will serve us well in the future.


  1. RA Ford, et al., Criteria for Development of a Database for Safety Evaluation of Fragrance Ingredients, Reg Tox Pharm 31 166–181 (2000)
  2. DT Salvito, et al., A framework for Prioritizing Fragrance Materials for Aquatic Risk Assessment, Env Tox Chem 21 (6) 1301–1308 (2002)
  3. RE Rogers, et al., Simulated Inhalation levels of Fragrance Materials in a Surrogate Air Freshener Formulation, Env Sci & Tech 39 (20) (2005)
  4. D Isola, et al., Chemical Respiratory Allergy and Occupational Asthma: What Are the Key Areas of Uncertainty?, J Appl Toxicol 28 249–253 (2008)

Steve Herman is the technical sales director for J&E Sozio. He has been an adjunct professor in the Fairleigh Dickinson University Masters in Cosmetic Science program since 1993, teaching Cosmetic Formulation Lab and Perfumery. His book, Fragrance Applications: A Survival Guide, was published by Allured Business Media, Carol Stream, IL, in 2001. He has served as chairman of the SCC’s New York chapter, and was elected to fellow status in 2002.

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