How is the safety of ingredients used in skincare products evaluated?

While the regulation regarding cosmetic ingredients varies across different regions of the world, there are several standards in place everywhere to ensure their safety and that of their ingredients. In Europe, Regulation (EC) No 1223/2009 mandates a strict safety assessment of ingredients before they are put on the market. This regulation includes annexes listing authorised, prohibited, or restricted substances. This is particularly the case for preservatives, UV filters and colourants. In all instances, the safety of ingredients is based on rigorous toxicological studies and the demonstration of their harmlessness under the intended conditions of use. The main tests used to evaluate the safety of ingredients are as follows.

• Evaluation of the degree of purity.

  The first criterion considered when assessing the safety of a cosmetic ingredient is its purity level. To ensure consumer safety, it is indeed necessary to verify that the ingredient contains neither impurities nor contaminants. This step is particularly important for plant extracts, which may contain residues of pesticides or heavy metals. The purity of ingredients is evaluated using various analytical techniques such as liquid chromatography or mass spectrometry. The degree of purity is then compared to the quality standards set by the pharmacopoeia to ensure that the ingredient meets the defined safety thresholds.

• Evaluation of acute toxicity.

  The assessment of acute toxicity aims to determine whether an ingredient can have harmful effects after a single or short-term exposure. It allows for the determination of the median lethal dose LD50, that is, the dose causing the death of 50% of the test subjects. In cosmetics, the main route of toxicity observed is the percutaneous route, although the oral route is also tested for products likely to be ingested. This type of testing is primarily carried out ex vitro on human skin models. They measure the cell viability after application of the ingredient at various concentrations. The results obtained allow for the definition of safe concentration limits for use in cosmetic formulations.

• Evaluation of genotoxic potential.

  The genotoxic potential of a cosmetic ingredient refers to its ability to alter the DNA of cells, which could potentially lead to genetic mutations, or even cancers. According to the amended Directive 76/768/EEC, the use in cosmetic products of substances classified as carcinogenic, mutagenic or toxic for reproduction CMR of category 1, 2 and 3 is prohibited, with the exception of certain substances, deemed safe by the SCCS or European Scientific Committee for Consumer Safety.

  The assessment of genotoxicity in cosmetic ingredients is therefore crucial. Among the tests commonly performed is the Ames test. This evaluates the ability of an ingredient to induce mutations in bacterial strains. This test is typically supplemented by trials on human cells. If an ingredient presents a potential genotoxic risk, additional studies in vitro and/or in vivo are conducted by the safety assessor.

• Evaluation of local tolerance.

  The local tolerance of an ingredient is assessed to ensure that it does not irritate the skin, eyes, or mucous membranes when applied topically. Models in vitro, such as human epidermis reconstructions, are frequently used to evaluate skin irritation. These tests are typically complemented by skin sensitisation tests, such as the Direct Peptide Reactivity Assay (DPRA) and the Human Cell Line Activation Test (h-CLAT), which simulate an ingredient's ability to induce an allergic reaction by analysing its reactivity with proteins and its ability to activate immune cells. The aim of these various experiments is once again to adjust the concentration of ingredients in formulation in order to create cosmetics that are safe to use.

• Evaluation of the anticipated systemic exposure.

  The assessment of anticipated systemic exposure aims to determine the quantity of an ingredient that could reach the bloodstream after being applied topically. For this, skin diffusion tests in vitro are carried out on human skin models or artificial membranes to measure the rate of penetration and the amount of ingredient that crosses the skin barrier. These data are then combined with pharmacokinetic models to estimate the risks of systemic exposure and to define concentration thresholds ensuring that the active ingredient remains on the skin surface.

• Determination of the No Observed Adverse Effect Level (NOAEL).

  The NOAEL represents the highest dose at which an ingredient does not cause any adverse effects. It is observable during in vitro or in vivo tests carried out over an extended period. Once the NOAEL is established, the assessor can calculate the safety margin, taking into account the hazard presented by an ingredient and the degree of consumer exposure to this ingredient. The higher the ratio, the more the consumer is protected against potential systemic effects. A safety margin greater than 100 is required, in accordance with the guidelines of the European Scientific Committee for Consumer Safety.

• Regulation (EC) No 1272/2008 of the European Parliament and of the Council concerning the classification, labelling and packaging of chemical substances and mixtures (CLP).

• Regulation (EC) No 1223/2009 of the European Parliament and the Council.

• SCHNEIDER S. Global Cosmetic Regulations? A Long Way To Go. Global Regulatory Issues for the Cosmetics Industry (2009).

• ANSM. Recommendations to manufacturers or those responsible for marketing regarding the evaluation of safety for human health of an ingredient or a combination of ingredients for cosmetic use (2021).