The Research Institute for Fragrance Materials (RIFM) and Creme Global, in collaboration with fragrance and consumer products industries, have developed an aggregate exposure model for fragrance ingredients in cosmetics, personal care, and air care products. At the core of this model is product concentration data provided by manufacturers (fragrance suppliers and consumer product companies) and habits and practices survey data collected by Kantar Worldpanel. The model is dynamic and flexible, allowing for updates based on new data and evolving science, with several updates released since its inception. In the most recent phase of model development (Phase III), the 2007-2008 Kantar Worldpanel survey data have been updated, replacing them with habits and practices survey data collected in 2014 and 2015 for the same products acquired during the Phase I and Phase II updates to the model. In addition to replacing existing data, the new survey includes data on additional products, countries, and expanded age groups. The list of products in the model was also expanded to include several household care products. This manuscript summarizes the new data and presents comparisons between the exposure factor inputs for the new and old models.
Case studies for cosmetic ingredients propyl paraben, salicylic acid, methyl salicylate, D5 and methylisothiazolinone have been used to assess the functionality and performance of the online webtool PACEM (Probabilistic Aggregate Consumer Exposure Model), which is free and publicly available. PACEM can be used by a consumer safety assessor to estimate consumer aggregate exposures (from cosmetic and household care products) to a single ingredient present in multiple product types, used simultaneously by a consumer in any one day. In this evaluation, only cosmetic product exposure assessment has been reviewed. The tool uses probabilistic mathematical modelling approaches, incorporating survey data on the habits and practices of product use from different European populations. The model is used by an exposure assessor to generate either a) an external exposure dose metric (mg/kg/day), b) an internal systemic exposure dose (SED) metric (mg/kg/day) or c) a dermal load (μg/cm2). The case studies performed, indicate that PACEM is a useful tool for the cosmetics safety assessor, and generates credible outputs for regulatory dossier submissions.
Grouping of chemicals has been proposed as a strategy to speed up the screening and identification of potential substances of concern among the broad chemical universe under REACH. Such grouping is usually based on shared structural features and should only be used for the prioritization objectives. However, additional considerations (as well as structural similarity) are needed, e.g., mode of action, metabolic pathways, chemical reaction products and physicochemical properties, when regulatory management measures are considered (such as restriction, harmonized classification and labeling). Guidance documents from the European Chemicals Agency (ECHA) recommend considering toxicokinetic information to enhance the robustness of the grouping; however, examples of this approach are lacking. Therefore, this paper shares findings on chemical grouping based on ADME data generated for multiple esters of salicylic acid. These differ with respect to chain length and branching of the alcohol moiety of salicylic acid ester, resulting in a wide range of lipophilicity (LogP 0.21–10.88). Since LogP impacts skin absorption, as well as hydrolysis by carboxylesterases, the bioavailability and thus internal exposure to topically applied salicylate esters can vary considerably. Therefore, we collected skin absorption and metabolism data for 41 salicylates using in vitro testing and in silico models and combined the information to group them according to their potential systemic exposure to the major metabolite, salicylic acid. The results show that, despite a similar general chemical structure, their toxicokinetics vary considerably, indicating the need for better understanding of ADME properties to assess the internal exposure for sound risk assessment.
As part of the safety assessment of salicylate esters in cosmetics, we developed a metabolism factor based on in vitro to in vivo extrapolation (IVIVE) to provide a better estimation of the aggregate internal exposure to the common metabolite, salicylic acid. Optimal incubation conditions using human liver S9 were identified before measuring salicylic acid formation from 31 substances. Four control substances, not defined as salicylic esters but which could be mistaken as such due to their nomenclature, did not form salicylic acid. For the remaining substances, higher in vitro intrinsic clearance (CLint, in vitro) values generally correlated with lower LogP values. A “High-Throughput Pharmacokinetic” (HTPK) model was used to extrapolate CLint, in vitro values to human in vivo clearance and half-lives. The latter were used to calculate the percentage of substance metabolised to salicylic acid in 24 h in vivo following human exposure to the ester, i.e. the “metabolism factor”. The IVIVE model correctly reproduced the observed elimination rate of 3 substances using in silico or in vitro input parameters. For other substances, in silico only-based predictions generally resulted in lower metabolism factors than when in vitro values for plasma binding and liver S9 CLint, in vitro were used. Therefore, in vitro data input provides the more conservative metabolism factors compared to those derived using on in silico input. In conclusion, these results indicate that not all substances contribute equally (or at all) to the systemic exposure to salicylic acid. Therefore, we propose a realistic metabolism correction factor by which the potential contribution of salicylate esters to the aggregate consumer exposure to salicylic acid from cosmetic use can be estimated.
