Endocrine Disruptors in Cosmetics: The Regulatory Debate Intensifies

Introduction

The identification and regulation of endocrine-disrupting chemicals (EDCs) in cosmetic products emerged as one of the most contentious and scientifically complex challenges facing EU regulators during 2022 [1]. Endocrine disruptors are substances that alter the function of the endocrine system and consequently cause adverse health effects in an intact organism, its progeny, or (sub)populations, according to the World Health Organization definition [2]. Concerns regarding EDCs in cosmetics center on ingredients such as parabens, triclosan, certain UV filters (e.g., benzophenone-3, octinoxate), and phthalates, which have demonstrated endocrine activity in in vitro assays and, in some cases, wildlife studies [3]. However, translating these findings into human health risk assessment and regulatory action requires navigating complex scientific uncertainties regarding low-dose effects, mixture toxicity, and the distinction between hazard identification and risk characterization [4].

The EU regulatory framework for EDCs evolved significantly following adoption of Commission Regulation (EU) 2018/605, which established scientific criteria for determination of endocrine-disrupting properties under the Biocidal Products Regulation and Plant Protection Products Regulation [5]. These criteria, based on WHO definitions, require demonstration of three elements: (1) an adverse effect in an intact organism or its progeny; (2) an endocrine mode of action; and (3) a biologically plausible causal link between the two [6]. Application of these criteria to cosmetic ingredients under Regulation (EC) No 1223/2009 remained subject to debate, as the cosmetic regulation does not explicitly reference endocrine disruption as a standalone hazard category, instead relying on the general safety requirement in Article 3 and the CMR (carcinogenic, mutagenic, or toxic to reproduction) restrictions in Article 15 and Annex II [7].

Regulatory Framework and Legal Analysis

Regulation (EC) No 1223/2009 does not contain a specific provision addressing endocrine disruptors as a distinct hazard class [8]. Instead, the regulatory framework relies on several interconnected provisions. Article 3 establishes the general safety requirement, stating that “a cosmetic product made available on the market shall be safe for human health when used under normal or reasonably foreseeable conditions of use” [9]. Article 10 requires a safety assessment addressing all relevant toxicological endpoints, and Article 15 prohibits the use of CMR substances classified under Regulation (EC) No 1272/2008 (CLP Regulation) as category 1A, 1B, or 2, except under specific derogations [10].

The intersection between endocrine disruption and CMR classification is significant, as many EDCs exert their adverse effects through disruption of hormonal pathways critical to reproduction and development [11]. Substances that cause reproductive toxicity through endocrine mechanisms may be classified as toxic to reproduction (category 1A, 1B, or 2) under CLP criteria, thereby triggering the Article 15 prohibition [12]. However, the CLP classification system requires demonstration of adverse effects at the organism level, and substances showing endocrine activity in vitro without confirmed adverse outcomes in vivo may not meet CMR classification criteria [13].

Commission Regulation (EU) 2018/605 established scientific criteria for EDC identification that have influenced the broader regulatory discourse [14]. These criteria require: (1) evidence of an adverse effect in an intact organism or its progeny, or evidence of an adverse effect in (sub)populations; (2) evidence of an endocrine mode of action, i.e., an interaction with the endocrine system; and (3) the adverse effect is a consequence of the endocrine mode of action [15]. The criteria explicitly adopt a hazard-based approach, meaning that substances meeting the criteria are identified as EDCs regardless of potency or exposure level [16]. This contrasts with the risk-based approach traditionally applied in cosmetic safety assessment, where the margin of safety calculation integrates both hazard (NOAEL) and exposure (SED) [17].

The SCCS has addressed endocrine disruption in several opinions and guidance documents, emphasizing that safety assessment must consider all relevant toxicological endpoints, including endocrine-mediated effects [18]. The SCCS Notes of Guidance (10th Revision, SCCS/1602/18) state that “the safety assessor should consider whether the substance has endocrine disrupting properties and whether this could lead to adverse effects under the conditions of use” [19]. However, the Notes of Guidance do not prescribe specific testing protocols for endocrine disruption, instead recommending that assessors consider available data from standardized toxicity studies (e.g., repeated-dose toxicity, reproductive toxicity, developmental toxicity) that may reveal endocrine-mediated effects [20].

Several cosmetic ingredients have been subject to SCCS review specifically addressing endocrine concerns. Parabens (methyl-, ethyl-, propyl-, butyl-, and isobutylparaben) were reviewed in SCCS/1514/13, which concluded that methyl- and ethylparaben are safe at maximum concentrations of 0.4% (as acid) for individual esters and 0.8% for mixtures, but expressed concerns regarding propyl- and butylparaben due to weak estrogenic activity and potential cumulative exposure [21]. The SCCS recommended that propyl- and butylparaben concentrations be limited to 0.14% (as acid) for leave-on products, reflecting a precautionary approach to endocrine-active substances [22]. Triclosan, an antimicrobial agent with demonstrated endocrine activity, was restricted to 0.3% in toothpaste, hand soap, and certain other products, and prohibited in other cosmetic categories due to concerns regarding thyroid disruption and antimicrobial resistance [23].

UV filters have been particularly controversial, as several commonly used sunscreen ingredients exhibit estrogenic or anti-androgenic activity in vitro [24]. Benzophenone-3 (oxybenzone) was reviewed by the SCCS in SCCS/1546/14, which concluded that it is safe at concentrations up to 6% in sunscreen products, despite in vitro estrogenic activity, based on low systemic exposure and absence of adverse effects in repeated-dose and reproductive toxicity studies [25]. However, subsequent studies demonstrating high dermal absorption and systemic bioavailability of benzophenone-3, coupled with detection in human urine and breast milk, have renewed concerns and prompted calls for re-evaluation [26].

Toxicological and Safety Science Considerations

The toxicological assessment of endocrine disruptors requires integration of mechanistic data (demonstrating interaction with endocrine pathways) and apical endpoints (demonstrating adverse effects in intact organisms) [27]. In vitro assays such as estrogen receptor (ER) binding assays, androgen receptor (AR) binding assays, and steroidogenesis assays can identify substances with endocrine activity, but positive results do not necessarily predict adverse effects in vivo due to factors such as metabolism, bioavailability, and compensatory homeostatic mechanisms [28]. The OECD has developed a conceptual framework for testing and assessment of endocrine disruptors, organizing assays into five levels ranging from in vitro mechanistic assays (Level 2) to extended one-generation reproductive toxicity studies (Level 5) [29].

For cosmetic ingredients, the SCCS emphasizes that safety assessment must consider the weight of evidence from all available studies, including in vitro mechanistic data, in vivo toxicity studies, toxicokinetic data, and human exposure information [30]. The margin of safety calculation remains the primary tool for risk characterization, with the NOAEL derived from the most sensitive relevant endpoint in the most appropriate study [31]. If endocrine-mediated effects are observed in repeated-dose or reproductive toxicity studies, the NOAEL for those effects is used to calculate MoS, and an MoS ≥100 is generally considered acceptable [32].

However, endocrine disruptors present several challenges to conventional MoS-based risk assessment. First, some EDCs exhibit non-monotonic dose-response relationships, where effects at low doses differ from effects at high doses, potentially due to receptor saturation, feedback mechanisms, or activation of different signaling pathways [33]. Non-monotonic dose-response curves complicate NOAEL determination and may result in underestimation of risk if low-dose effects are not adequately characterized [34]. Second, EDCs may exert effects during critical windows of development (e.g., fetal development, puberty) that are not captured in standard repeated-dose toxicity studies using adult animals [35]. Developmental and reproductive toxicity studies are better suited to detect these effects, but are not always available for cosmetic ingredients [36].

Third, mixture effects are particularly relevant for EDCs, as multiple ingredients in a cosmetic formulation, or multiple products used concurrently, may act on the same endocrine pathway, potentially resulting in additive or synergistic effects [37]. The SCCS Notes of Guidance acknowledge that “the safety assessor should consider the possibility of combined effects from multiple ingredients” but provide limited methodological guidance for mixture assessment [38]. Concentration addition and independent action models have been proposed for EDC mixture assessment, but their application to cosmetic formulations remains challenging due to data limitations and uncertainty regarding interaction mechanisms [39].

Dermal absorption is a critical determinant of systemic exposure and risk for cosmetic ingredients with endocrine activity [40]. Many EDCs are lipophilic and may achieve significant dermal penetration, particularly from leave-on products applied to large body surface areas [41]. For example, benzophenone-3 demonstrates dermal absorption of approximately 1-2% in in vitro studies, but in vivo biomonitoring studies have detected the compound in urine of >95% of the US population, suggesting that actual exposure may be higher than predicted from in vitro data [42]. The SCCS has emphasized that dermal absorption data should be generated using validated methods and, where possible, confirmed through biomonitoring studies [43].

Systemic exposure dosage (SED) calculation for EDCs must account for aggregate exposure from multiple cosmetic products and, where relevant, other sources such as food, drinking water, and environmental contamination [44]. For parabens, the SCCS considered aggregate exposure from cosmetics, food, and pharmaceuticals when establishing safe use concentrations [45]. For UV filters, exposure from sunscreen products is typically the dominant source, but concurrent use of multiple products (e.g., sunscreen, moisturizer, foundation) containing the same UV filter must be considered [46].

Practical Compliance Guidance

For Responsible Persons, managing endocrine disruption concerns requires a proactive, science-based approach that integrates hazard identification, exposure assessment, and risk characterization. First, ingredient selection should prioritize substances with robust safety data, including reproductive and developmental toxicity studies that can detect endocrine-mediated effects [47]. Suppliers should be required to provide comprehensive toxicological dossiers, including information on endocrine activity from in vitro assays and in vivo studies [48].

Second, safety assessment under Article 10 must explicitly address endocrine disruption potential. Part A of the CPSR should summarize available data on endocrine activity, including results from ER/AR binding assays, steroidogenesis assays, and any in vivo studies demonstrating endocrine-mediated effects [49]. Part B should evaluate whether endocrine activity could result in adverse effects under the conditions of use, considering dermal absorption, SED, and MoS [50]. If the MoS is below 100, or if data gaps preclude confident risk characterization, reformulation or additional testing should be considered [51].

Third, claims substantiation under Article 20 and Commission Regulation (EU) No 655/2013 must be carefully managed for products marketed with “hormone-free,” “endocrine-safe,” or similar claims [52]. Such claims imply that the product does not contain EDCs, but given the scientific complexity and ongoing debate regarding EDC identification criteria, substantiating these claims requires comprehensive ingredient screening and documentation [53]. The Technical Document on Cosmetic Claims emphasizes that claims must be supported by adequate and verifiable evidence, and unsubstantiated claims may constitute misleading advertising [54].

Fourth, Responsible Persons should monitor regulatory developments, including SCCS opinions on specific ingredients, Commission proposals for Annex amendments, and evolving EDC identification criteria [55]. The EU Chemicals Strategy for Sustainability, published in October 2020, commits to minimizing exposure to EDCs and proposes a “one substance, one assessment” approach that would harmonize EDC identification across regulatory frameworks [56]. Implementation of this strategy may result in additional restrictions on cosmetic ingredients identified as EDCs under the criteria established in Regulation (EU) 2018/605 [57].

Fifth, transparency and communication with consumers are increasingly important as public awareness of EDCs grows. Article 21 grants consumers the right to request information from the Responsible Person regarding the safety of specific ingredients, and Responsible Persons should be prepared to provide clear, science-based explanations of how endocrine disruption concerns have been addressed in the safety assessment [58]. Proactive communication, such as publication of ingredient safety summaries on company websites, can build consumer trust and reduce reputational risk [59].

Conclusion

The intensifying regulatory debate surrounding endocrine disruptors in cosmetics during 2022 reflected the inherent tension between hazard-based identification criteria and risk-based safety assessment. While Regulation (EC) No 1223/2009 does not explicitly address endocrine disruption as a standalone hazard category, the general safety requirement in Article 3 and the CMR restrictions in Article 15 provide a framework for managing EDC risks. The SCCS’s emphasis on weight-of-evidence evaluation, margin of safety calculation, and consideration of aggregate exposure offers a scientifically robust approach to EDC risk assessment, but data gaps and methodological uncertainties remain. Responsible Persons must navigate this complex landscape through rigorous ingredient screening, comprehensive safety assessment, proactive monitoring of regulatory developments, and transparent communication with consumers and authorities. As the EU Chemicals Strategy for Sustainability advances and EDC identification criteria are harmonized across regulatory frameworks, the cosmetic industry should anticipate additional restrictions and prepare for reformulation of products containing ingredients identified as EDCs.

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