SAFETY ASSESSMENT

Historically, most of the focus on safety of fragrance materials has been on effects on the skin. The Research Institute for Fragrance Materials is the organization of the self-regulatory system of the fragrance industry that is responsible for testing data for fragrance chemicals. Safety assessment included dermal toxicity, dermal irritation and sensitization, and if indicated, photoirritation and photosensitization. Since many of the same materials used to scent products have been used as flavors, some acute oral toxicity studies have been done as well. There are close to 3000 materials being used to scent products. Approximately 1300 of these materials have been assessed for safety by the RIFM and data has been published on around 1100 of these.

Considerable criticisms and concerns have been raised regarding materials that have not been evaluated, data that needs updating, selection process of materials to be reviewed, and lack of testing data for all routes of exposures and systemic effects. In addition, much of the data on which decisions are made are within the industry and not available publicly. Because of the sheer numbers or materials it is necessary to develop a practical and effective means of prioritizing the safety assessment

Because of the lack of available data on fragrance chemicals and their use, accurate assessment of use, exposure, etc outside the industry is difficult. As exposures and potential for health effects to specific materials becomes obvious due to clinical data, toxicological data, as well as presence in human tissue and the environment, assessment outside the industry is more likely to occur. 

INDUSTRY'S PLAN FOR ASSESSMENT

At present the industry is reviewing the procedure for evaluation of the safety of raw fragrance materials. The stated reasons for this review are related to the European Union's listing of fragrance materials lists substances that have not been evaluated by the RIFM, monographs previously published need to be revised and updated, and concerns raised regarding the selection process of chemicals for review.

The industry has proposed criteria for prioritizing.  Guidelines have been proposed for areas toxicological testing should be conducted and creation of a database of safety evaluations. The goal is to provide a scientific basis for decisions on fragrance material use. 

Criteria for Determining Order of Review

Volume of use, exposure, and structural aspects are to be used as guidelines to determine which materials should be tested first. A score is given in each area and added together to determine the priority.

Quantity of use is based on reported worldwide annual volume used in fragrance. Volumes of use may range from less than 1kg/year to over 1000 metric tons per year.  The higher the volume of chemicals used, the greater the potential for exposure and the higher the score.

*annual metric tons

The criterion for exposure is based on the level the material is used in a product. The RIFM surveyed the major international fragrance companies to find out at what concentrations specific fragrance ingredients were used in fragrance formulas. Assuming the formula made up 20% of the final product, the concentration in the final product was determined. A score was assigned according to the concentration in the final product.

Certain structural aspects are associated with specific toxic effects. Examining the structure of the chemicals helps pinpoint materials that may be more likely to be problematic. The chemicals are examined for structures that are associated with topical effects, acute/systemic effects, and carcinogenic effects and are assigned a score. There are 50 structure alerts including a default when the structure is not known. The scores for each type of structural alerts are added together for this category. For example a material that had an alert for topical effects, medium toxicity and carcinogenic effects would have a score of 12.

Scoring for structural alerts

Scores from each category are added to determine the priority for testing. A material with a volume of 500 metric tons, a use level of 1%, and had structural alerts for topical effects and medium toxicity would have a score of 20. The maximum score possible is 44. Materials with a higher score would be of higher priority for testing.

Criteria for Toxicological Data

In order to efficiently use resources and provide a realistic method of developing a toxicological database, the industry has developed an approach based on grouping similar materials together, utilizing existing data on closely related substances, and evaluation based on conditions of use.

There are a number of toxicological endpoints which may need to be assessed in order to provide data to determine safety. Not all endpoints may be necessary for every material. The following table summarizes some of the considerations for specific toxicological endpoints.

Rather than each individual chemical being assessed, it is planned to group similar materials into structure-activity groups. Then representative chemicals from that group would be assessed for safety rather than each individual material. There may be subgroups in which testing is necessary as well. The available data on groups of materials will be reviewed and it will be determined what additional testing would be needed to fill the gaps in information.

The first Fragrance Materials Reviews published using these concepts are those on linalool and related esters. Linalool was selected as the material for more extensive testing to provide data for the class as a whole as there is evidence the esters break down easily to the parent compound.

Estimating Exposures

In order to evaluate the safety of fragrance materials, it is necessary to have some idea of exposures. Routes of exposure, the level of exposure, the duration, and other factors play important roles in evaluating the safety of materials. At present the industry continues to focus on skin as the primary route of exposure and cosmetics as the primary source of exposure.*

The amount of fragrance is not the same in all products. Typically perfumes have the highest concentration of fragrance. The amount of fragrance in the product does not necessarily correlate with the intensity or persistence of the odor.

Typical percentage of fragrance in finished products

Concentration of fragrance in the product is only one consideration of exposure to the skin. A product with a higher concentration of fragrance may yield a lower exposure if it is applied to only a small area than one with a lower concentration applied to a larger area. To evaluate dermal exposures both the concentration and the area applied must be considered. Further both exposures of single products and multiple products must be considered.

The plan for collecting data is to utilize the International Fragrance Association (IFRA) to survey industry to determine maximum topical exposure concentrations, distributions of concentrations likely to be encountered in a range of cosmetic products, and annual volume of use of fragrance materials. The full procedure and how it is to be implemented has been outlined by Cadby et al (2002).

Discussion

A sound scientific process is needed to evaluate the safety of fragrance materials. The industry's plan for assessment is a good start and long overdue. However, there are several major aspects that are not addressed. These areas need to be a part of the formal assessment process.

Exposures other than cosmetics

Only about 25% of fragrance materials are used in cosmetics. Around 60% are used in soaps, detergents, fabric softeners, and cleaners. Assessment of exposure to non-cosmetic use has not been done.

Fragrance in laundry products are of especial concern in regards to skin contact. Factors that increase skin absorption include heat, moisture, and occlusion. Clothing is in constant contact with skin and covers large areas of the body. Body heat and moisture potentially increases absorption.

Further laundry products are often highly scented. The scent is designed to last a long time, often for weeks. Part of this is made possible by selection of enduring fragrance materials and part is possible because of delivery systems. Cyclodextrins, hollow specialized starch materials are often used to allow a time released system that is activated by moisture. Surprisingly these molecules are of respirable size and are hygroscopic. There is potential for release of fragrance materials onto moist airways.

Assessment of mixtures

While health and safety data is needed on individual substances, fragrance formulations are complex mixtures. Materials may have synergistic, antagonistic, or additive effects. Multiple scented products are used on a daily basis. So not only do mixtures in individual products need to be considered, but also the exposure to multiple mixtures.

Some common fragrance materials are dermal enhancers and may increase the absorption of materials that would not normally penetrate the skin. Dermal absorption of materials in mixtures may be very different than absorption of singular materials.

The use of multiple known sensitizers in products is a major concern. It is well known that when similar materials are patch tested together, there is a higher incidence of positive reactions than when the materials are tested individually. This strongly suggests that the use of multiple sensitizers in a product increases the likely hood of an allergic reaction.

Companies could be surveyed to find out which materials are commonly used together in fragrance formulations. While it would be impossible to assess every possible formulation, such a survey would provide valuable clues which would provide a starting point for studies on mixtures. Data collected on volume, level of use, and frequency of use of fragrance materials would also provide clues of which materials would most likely be in mixtures.

Inhalation  

The primary functions of scented products are to impart an odor to a product or mask the odor of other materials in the product. By design, fragrance materials volatilize into the air where they are then inhaled.  There is exposure not only to the user of the product, but also to those that breathe the air. Further there is not exposure to one product, but to multiple products.

Dermal assessment includes both exposures to single products and multiple products. Respiratory exposure to multiple products needs to include sources of exposure from the environment. For example a person may use a dozen scented products in a day, but they encounter many more. A little of each scented product each person uses ends up in the air.

Inhalation as a route of systemic exposure and impact on the airways and lungs has not been assessed.

The industry has been aware for over 25 years the respiratory system was a potential route of systemic exposure and that fragrance chemicals were irritating to both upper and lower airways. No assessment of fragrance safety is complete without considering respiratory effects.

Olfactory and other intranasal pathways provide direct connections to the brain. Studies have shown inhalation of fragrance chemicals have direct effects on the Central Nervous System. Acute neurological effects need to be considered in addition to the proposed subchronic toxicity testing. In order for industry assessment to be complete, these and other deficits must be addressed.