Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.

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. The key steps are: (1) determination of benchmarks (no expected sensitization induction level (NESIL)); (2) application of sensitization assessment factors (SAF); and (3) consumer exposure (CEL) calculation through product use. Using these parameters, an acceptable exposure level (AEL) can be calculated and compared with the CEL. The ratio of AEL to CEL must be favorable to support safe use of the potential skin sensitizer. This ratio must be calculated for the fragrance ingredient in each product type. Based on the Research Institute for Fragrance Materials, Inc. (RIFM) Expert Panel's recommendation, RIFM and the International Fragrance Association (IFRA) have adopted the dermal sensitization QRA approach described in this review for fragrance ingredients identified as potential dermal sensitizers. This now forms the fragrance industry's core strategy for primary prevention of dermal sensitization to these materials in consumer products. This methodology is used to determine global fragrance industry product management practices (IFRA Standards) for fragrance ingredients that are potential dermal sensitizers. This paper describes the principles of the recommended approach, provides detailed review of all the information used in the dermal sensitization QRA approach for fragrance ingredients and presents key conclusions for its use now and refinement in the future.

Consumer exposure to fragrance ingredients: providing estimates for safety evaluation.

To fully apply already published procedures for the safety evaluation of fragrance ingredients, it is necessary to estimate exposure through different routes and leading to different potential endpoints. Worst-case scenario calculations indicate that deposition on the surface of the skin following use of cosmetics represents the major route of exposure to fragrance ingredients when conservative estimates for evaporation, rinsing, and other forms of product removal are employed. Hydroalcoholic perfumes and colognes deliver the highest dose after single product use. Surveys of formulas used in this type of product allow the calculation of average maximum or upper 97.5th percentile concentration of the ingredient in formulas. With this type of exaggeration, the use of estimates of "typical" cosmetic use can be maximized to take account of excessive consumption patterns for both short-term and long-term exposure estimates. In the latter case, multiple product use must be considered. Short-term exposure (single product doses) of an ingredient found at an average maximum use level of P% in fragrances is taken to be 0.2 x P% or 3P microg/cm(2). Using upper 97.5th percentile concentrations (P(97.5)) of individual ingredients in fragrances, the long-term exposure is taken to be P(97.5) x 2,547 microg/kg body wt/day. The estimates of long-term exposure incorporate a number of highly conservative assumptions (e.g., over a long period, every product used will contain a fragrance with this ingredient at this high (P(97.5)) level).