Updating exposure assessment for skin sensitization quantitative risk assessment for fragrance materials.

In 2008, a proposal for assessing the risk of induction of skin sensitization to fragrance materials Quantitative Risk Assessment 1 (QRA1) was published. This was implemented for setting maximum limits for fragrance materials in consumer products. However, there was no formal validation or empirical verification after implementation. Additionally, concerns remained that QRA1 did not incorporate aggregate exposure from multiple product use and included assumptions, e.g. safety assessment factors (SAFs), that had not been critically reviewed. Accordingly, a review was undertaken, including detailed re-evaluation of each SAF together with development of an approach for estimating aggregate exposure of the skin to a potential fragrance allergen. This revision of 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. The use of alternative non-animal methods is not within the scope of this paper. Ultimately, only longitudinal clinical studies can verify the utility of QRA2 as a tool for the prevention of contact allergy to fragrance materials.

Application of the Margin of Exposure (MoE) approach to substances in food that are genotoxic and carcinogenic: example: benzene, CAS: 71-43-2.

The role of genotoxic events in the aetiology of benzene induced tumours cannot be ruled out. Dose response modelling of the data for benzene gave a BMDL10 for female Zymbal gland carcinoma of 17.6 mg/kg-bw/d following adjustment to daily average doses. The MOEs ranged from 2 x 10(6) to 0.4 x 10(6) depending on the assumptions used in the exposure estimation.

Application of the margin of exposure (MoE) approach to substances in food that are genotoxic and carcinogenic: example: methyleugenol, CASRN: 93-15-2.

The weight of evidence points to weak genotoxic activity of methyleugenol, the putative genotoxic carcinogen being 1'-sulphate ester metabolite. Dose response modelling of the data for methyleugenol gave a BMDL10 for male rat liver adenoma or carcinoma (combined) of 7.9 mg/kg-bw/d following adjustment to daily average doses. The MoEs ranged from 100 to 800 depending on the assumptions used in the exposure estimation.

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.

Reproducible prediction of contact allergenic potency using the local lymph node assay.

A considerable body of data has been accumulated which demonstrates that the local lymph node assay (LLNA) can provide a valuable estimation of the contact allergenic potency of a substance. This estimate is obtained via interpolation of the LLNA dose-response curve and is expressed as the concentration of the chemical required to evince a 3-fold stimulation of proliferation in lymph nodes draining the site of application compared to the vehicle-treated controls (EC3). It has also been shown that the EC3 estimates are reproducible and are stable over time. In the present work, we have extended this information by a demonstration of the inherent biological variability surrounding EC3 estimation, using data derived (from a single laboratory) from the testing of isoeugenol as a positive control. Isoeugenol gave EC3 values ranging from 0.5 to 2.6% (n = 29), with a mean and standard deviation of 1.2 +/- 0.6%. Given that EC3 values for a variety of contact allergens range over several orders of magnitude, these results further endorse the utility of EC3 values as a reliable indicator of human contact allergenic potency.

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).