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Since the sartans crisis in 2018, the detection of nitrosamines has highlighted systemic gaps in identifying contamination pathways across pharmaceutical supply chains. As impurities belonging to the “cohort of concern” following ICH M7 (R2) , nitrosamines present exceptionally high carcinogenic potency. Their mechanism of action relies on metabolic activation leading to the formation of adducts. If these lesions escape cellular repair systems, they can induce irreversible genetic mutations and carcinogenesis. With a TD50 typically below 1.5 mg/kg/day, this extreme toxicity prevents the application of the standard Threshold of Toxicological Concern (TTC) of 1,500 ng/day defined in ICH M7(R2). Acceptable Intake (AI) and carcinogenic potency assessment Patient safety is ensured through the establishment of an Acceptable Intake (AI), calculated for a theoretical excess cancer risk of 1 in 100,000 over a 70-year exposure. For compounds with sufficient data, the AI is derived through linear extrapolation from the most conservative TD50 values obtained in the most sensitive species. For NDSRIs (nitrosamines related to the active substance) lacking in vivo data, the CPCA (Carcinogenic Potency Categorisation Approach) recommended by the EMA is applied. This method classifies nitrosamines into five potency categories based on structural characteristics influencing metabolic activation. Alternatively, a negative Enhanced Ames Test (EAT) can justify the application of a limit of 1,500 ng/day. Sources and formation of nitrosamines   Control of these impurities requires a rigorous strategy. Nitrosamine formation generally results from the combination of amines with nitrosating agents under acidic conditions. Identified sources include: Contaminated or degraded solvents Nitrites present in excipients Risk management strategy Risk management follows three main steps: Proactive assessment Confirmatory testing Implementation of CAPA According to ICH M7, omission of specification may be considered if levels remain consistently ≤10% of the AI. Batch-by-batch control is required when levels are between 30% and 100% of the AI. When multiple nitrosamines are present, summation strategies must ensure that cumulative risk never exceeds the 1:100,000 threshold. Mitigation options Reformulation can be an effective mitigation strategy. The addition of nitrite scavengers or pH adjustment can slow nitrosation reactions. In some cases, these modifications may benefit from simplified procedures and avoid new bioequivalence studies. CEHTRA Expertise At CEHTRA, we mobilise our toxicology expertise and QSAR tools to support partners in the qualification of these impurities. This topic was presented during our latest webinar dedicated to nitrosamines and related regulatory expectations.Follow us to stay informed about upcoming webinars and publications.

Since 12 January 2026 , the European Union has reached a major milestone in the protection of public health and water resources. The transition period provided for under Directive (EU) 2020/2184 (recast Drinking Water Directive) has now ended. From now on, the systematic and harmonised monitoring of per- and polyfluoroalkyl substances (PFAS) is a legal obligation for all Member States.    1. A dual-threshold regulatory framework    The Directive now requires compliance with two distinct limit values, reflecting complementary monitoring objectives:  → “Sum of PFAS” (0.10 μg/L)   This parameter specifically targets 20 individual substances considered of concern. Listed in Annex III of the Directive, they include 10 perfluoroalkyl carboxylic acids (PFCAs) and 10 perfluoroalkyl sulfonic acids (PFSAs), with carbon chain lengths ranging from 4 to 13 atoms. The limit value is set at 100 ng/L for the sum of these compounds.  → “PFAS Total” (0.50 μg/L)   This parameter takes a much broader approach by covering all per- and polyfluoroalkyl substances . The limit value is set at 500 ng/L . The objective is to capture the total organofluorine load, including thousands of molecules not covered by the “Sum of PFAS”.  In accordance with Article 13(7) of the Directive, and following consultations with Member States, technical guidelines (C/2024/4910) have been published to define the analytical methods applicable to these two parameters.    2. Analytical control: requirements for the “Sum of PFAS”    The assessment of compounds under the “Sum of PFAS” relies on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The EN 17892:2024 standard, used as the reference analytical method, recommends two methodological approaches:  Part A (Direct injection): a rapid method in which unfiltered drinking water samples are injected directly into the LC-MS system.  Part B (SPE enrichment): this method involves solid-phase extraction (SPE) to concentrate the sample, providing higher sensitivity and lower quantification limits.    3. The technical challenge of “PFAS Total”    The comprehensive measurement of PFAS represents a major scientific challenge, as no single method can quantify all compounds in this chemically diverse group. Three approximation methods are currently validated by the Commission:  TOP assay (Total Oxidizable Precursors)    This method uses chemical oxidation to convert PFAS precursors into measurable perfluorocarboxylic acids. However, it may lead to underestimation, as some compounds (notably perfluorinated ethers) are not fully oxidised.  EOF-CIC (Extractable Organic Fluorine)    This method measures extractable organic fluorine via combustion and ion chromatography. The result, expressed in ng/L of fluorine, is converted into PFOA-equivalent using a conversion factor of 1.45 (thus, 345 ng/L F corresponds to 500 ng/L PFAS Total).  LC-HRMS (High-resolution mass spectrometry)    This non-targeted approach enables the detection of a much broader range of compounds. However, it remains semi-quantitative and requires a high level of expertise to interpret signals and minimise false positives.    4. The critical case of trifluoroacetic acid (TFA)     TFA is an ultra-short-chain PFAS (2 carbon atoms), characterised by high mobility, persistence, and strong hydrophilicity. It enters the water cycle through the degradation of pesticides, refrigerants, or industrial discharges. In many Member States, concentrations measured in untreated water frequently exceed the 0.50 μg/L threshold, thereby surpassing the parametric value for “PFAS Total”.  To address this issue, the Commission requires a four-step reporting protocol:  Measure [PFAS Total] using an approximation method.  Measure [TFA] specifically using a targeted analytical method compliant with the Directive.  Report three values: [PFAS Total] , [TFA] , and the difference [PFAS Total] – [TFA] .  If the result is negative, the measurement is considered inconclusive.    5. Performance criteria  To ensure measurement reliability, the Directive establishes several analytical requirements at the point of compliance:  Limits of quantification (LOQ)    The overall LOQ must be ≤ 30% of the parametric value , i.e. 30 ng/L for Sum of PFAS. However, the Commission recommends an individual LOQ of ≤ 1.5 ng/L for each of the 20 substances. For “PFAS Total”, the LOQ must be ≤ 150 ng/L.  For the most toxic compounds identified by EFSA (PFHxS, PFOA, PFOS, PFNA), even lower target limits are recommended.  Measurement uncertainty    The Directive sets a maximum expanded uncertainty of 50% at the parametric value level. In practice, European laboratories generally achieve better performance, with uncertainties ranging from 18% to 39% depending on the method used.  Validation of measurements    At ultra-trace levels (ng/L), environmental and laboratory conditions become limiting factors. Member States must ensure that analytical methods used for monitoring and compliance demonstration are validated in accordance with EN ISO/IEC 17025 or an equivalent internationally recognised standard.  Current limitations    Unlike the “Sum of PFAS”, methods for measuring “PFAS Total” are not yet fully harmonised at the European level. Available data on measurement uncertainty and LOQ remain limited, making it difficult to fully assess compliance with regulatory performance criteria for this global parameter.    6. Immediate actions in case of exceedance    The entry into force of these requirements means that any non-compliance must trigger immediate corrective actions to protect public health.  Water managers, under the supervision of national authorities, must:  Inform the public transparently about risks and precautionary measures.  Shut down wells or abstraction points where PFAS levels are excessive.  Implement specific treatment processes (activated carbon, ion exchange resins, or reverse osmosis) to remove contaminants.  Restrict water use if necessary until compliance is restored.    Conclusion  The implementation of these provisions is part of the “Zero Pollution” Action Plan . The new reporting framework now requires systematic transmission of data on exceedances and incidents to the Commission.  Beyond tap-level compliance, a comprehensive approach is required, including risk assessment from the abstraction area onwards. Anticipating pollution sources, combined with mastering complex analytical protocols (particularly for PFAS Total and TFA), is essential for ensuring sustainable and secure water resource management.    Authors: Floriane DEMAILLY & Loris MISTRULLI References:   Directive (EU) 2020/2184: Directive (EU) 2020/2184 of the European Parliament and of the Council of 16 December 2020 on the quality of water intended for human consumption (recast), OJ L 435 , 23.12.2020, pp. 1–62 . Available on : http://data.europa.eu/eli/dir/2020/2184/oj  (accessed on 24/02/2026).  Commission Notice C/2024/4910: Technical guidelines regarding methods of analysis for monitoring of per- and polyfluoroalkyl substances (PFAS) in water intended for human consumption, OJ C, C/2024/4910. Available on : http://data.europa.eu/eli/C/2024/4910/oj (accessed on 24/02/2026).

The recent amendment to the European Cosmetic Regulation significantly expands the list of fragrance allergens that must be declared on the INCI label (Regulation (EU) No 2023/1545 updating certain entries of Annex III of the EU Cosmetic Regulation).  In the original version of Regulation (EC) No 1223/2009, 26 allergens were subject to mandatory labelling. Two of them ,Lyral and Lilial, have since been prohibited. The new regulation adds 57 additional substances , bringing the total number of l abelled allergens to 81 . These include individual molecules as well as botanical extracts and essential oils that may induce skin allergy. Products already on the market containing these substances must be reviewed more closely, both to ensure correct labelling and to clarify potential risks.  The intrinsic risk of skin sensitisation of a product does not automatically change. However, if a substance was not previously identified, it may now need to be considered, particularly if the product claims to be “hypoallergenic” or suitable for “sensitive skin.”  Among the newly concerned substances are widely used cosmetic ingredients such as:  Vanillin   Benzaldehyde   Lavandin oil and extracts (Lavandula Hybrida Oil)   Peppermint oil (Mentha Piperita Oil)   Labelling is required when concentrations exceed:  0.001% in leave-on products   0.01% in rinse-off products   The regulatory deadlines are clearly defined:  Products placed on the market must comply by July 31, 2026   Products already on the market must comply by July 31, 2028   This regulatory development requires companies to conduct a systematic review of fragrance compositions, supplier data, and safety documentation.  However, labelling is only one part of the regulatory obligation.  Beyond Labelling: Annex I Requires a Complete Safety Assessment   Article 10 and Annex I: Mandatory Update of the Cosmetic Product Safety Report (CPSR) Article 10 of Regulation (EC) No 1223/2009 and Annex I require a complete safety assessment based on documented toxicological profiles and the calculation of the Margin of Safety (MOS) for each ingredient. Article 10(1)(c) specifies that the Safety Report (CPSR) must be updated whenever new relevant information becomes available.  A compliant cosmetic safety assessment requires :  The use of documented toxicological profiles   Evaluation of local effects (sensitisation, irritation, phototoxicity) and systemic effects, including identification of relevant concerns (critical warnings)  Calculation of the Systemic Exposure Dose (SED)   Determination of the Margin of Safety (MOS)   Integration of conclusions into the Cosmetic Product Safety Report (CPSR)  Margin of Safety (MOS): The Central Indicator in Cosmetic Risk Assessment The Margin of Safety (MOS) is the core regulatory indicator used to demonstrate ingredient safety within the CPSR framework.  It quantitatively expresses the relationship between hazard (NOAEL or relevant point of departure POD) and actual consumer exposure.  A product may comply with labelling thresholds while still requiring an in-depth evaluation. It is important to note that the 2012 SCCS opinion focused on skin sensitisation and did not address other potential toxicological endpoints.  Regulatory compliance therefore relies on a structured demonstration of the hazard × exposure assessment , not solely on verification of labelling thresholds.  Allergens requiring labeling (underscored) are identified based on their final concentration and the type of product. A margin of safety or margin of exposure is calculated each time it is possible.   Operational Impact: Recalculation of Margins of Safety and Update of the PIF   The transition from 24 to 81 labelled allergens significantly increases operational complexity:  Verification of fragrance compositions and botanical extracts  Recalculation of cumulative concentrations  Verification of the need to add allergens to the ingredient list  Confirmation of exposure scenarios  Reassessment of risks and recalculation of Margins of Safety  Update of the safety assessment through the CPSR and the Product Information File (PIF)   Any modification in concentration or formulation may directly impact the SED and consequently the MOS.  Traceability and reproducibility of calculations therefore become essential.  Toxicological Database and Digital Cosmetic Risk Assessment Tool In this context, the use of a structured toxicological database combined with a digital cosmetic risk assessment tool facilitates:  Harmonised access to toxicological profiles  Consistent calculation of SED and Margin of Safety  Generation of documentation compliant with Annex I  Consideration of the SCCS assessment methods and other international frameworks.  July 2026: A Regulatory Trigger for Systematic Risk Reassessment Therefore, Regulation (EU) No 2023/1545 updates the list of labelled allergens under Annex III of the EU Cosmetic Regulation and requires an update of the regulatory dossier.  The July 2026 deadline should be considered a regulatory trigger to:  To re-examine fragrance compositions and botanical extracts with regard to labelling requirements  To verify the Margins of Safety and confirm warnings or the absence of risk, and to update the CPSR accordingly The expansion of allergen labelling aims to enhance transparency.  However, consumer protection ultimately depends on the robustness of the cosmetic risk assessment and the scientific justification of safety through the Margin of Safety .  In regulatory practice, compliance does not merely consist of updating the INCI list.  It requires a continuously documented, traceable and scientifically substantiated assessment framework. These updates are therefore not simply an administrative revision of the ingredient list; they require regulatory and scientific expertise which, at least for Part B of the CPSR — covering the safety assessment — must be validated by a qualified safety assessor (toxicologist, pharmacist, etc.), as defined in Article 10 of the EU Cosmetic Regulation.  Would you like to ensure the safe assessment of allergens in your cosmetic formulas? Our experts can assist you in identifying allergens, conducting toxicological assessments, and ensuring your products comply with European and international requirements. To learn more about COSMETICK and our approach to cosmetic risk assessment, please contact: Clarisse Bavoux : Toxicologist, Deputy Chief Executive Officer in charge of digital solutions Florian Gautier : Cosmetics Market Leader References : Commission Regulation (EU) 2023/1545 of 26 July 2023 amending Regulation (EC) No 1223/2009 of the European Parliament and of the Council as regards labelling of fragrance allergens in cosmetic products  https://eur-lex.europa.eu/eli/reg/2023/1545/oj/eng   Regulation (EU) (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products https://eur-lex.europa.eu/eli/reg/2009/1223/oj/eng   Scientific Committee on Consumer Safety SCCS, Opinion on Fragrance allergens in cosmetic products. SCCS/1459/11. 27 June 2012 https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_102.pdf    To comment on LinkedIn : https://www.linkedin.com/feed/update/urn:li:activity:7427743381092544512/

CEHTRA provides regulatory, toxicology and risk assessment expertise for the chemical, biocides, PPP, cosmetics, pharma, food industries, ... Your partner in regulatory compliance and product safety Simplify your regulatory compliance with our expertise and innovative tools. Our sectors Contact us Nos programmes Recognized expertise in Regulatory Affairs and Risk Assessment For over 25 years, CEHTRA has been supporting chemical industry players across key strategic sectors. We assist manufacturers, formulators, distributors, and importers in areas including industrial chemicals (REACH), biocides (BPR), plant protection products (PPP), cosmetics, pharmaceuticals, and food products, including novel foods & supplements, as well as packaging, and other sectors related to health, environmental protection, and product safety. Thanks to our multidisciplinary expertise in toxicology, ecotoxicology, risk assessment and international regulations, we offer tailor-made solutions adapted to the specific requirements of each market, both within and outside Europe. Contact an Expert Our Areas of Expertise biocides Explore chemicals Explore cosmetics Explore food Explore packaging Explore pharmaceuticals Explore plant protection Explore all Explore Digital Solutions for Regulatory Affairs & Toxicology Your performance, our smart solutions. Nitrosamines: understanding carcinogenic risk and control strategies Since the sartans crisis in 2018, the detection of nitrosamines has highlighted systemic gaps in identifying contamination pathways across pharmaceutical supply chains. As impurities belonging to the “cohort of concern” following ICH M7 (R2), nitrosamines present exceptionally high carcinogenic potency. PHARMACEUTICAL PFAS in Drinking Water: Technical Analysis of a New Regulatory Era for Water Utilities Since 12 January 2026, the European Union has reached a major milestone in the protection of public health and water resources. The transition period provided for under Directive (EU) 2020/2184 (recast Drinking Water Directive) has now ended. TOXICOLOGY New Fragrance Allergens: July 2026 Deadline and CPSR Updates for Cosmetic Products The recent amendment to the European Cosmetic Regulation significantly expands the list of fragrance allergens that must be declared on the INCI label (Regulation (EU) No 2023/1545 updating certain entries of Annex III of the EU Cosmetic Regulation). In the original version of Regulation (EC) No 1223/2009, 26 allergens were subject to mandatory labelling. DIGITAL SOLUTIONS 1 2 3 4 5 Need guidance? Speak with our specialists Select a sector:* First name:* Last name:* Company or Organization:* Email:* How can we help you? Submit

Understand the EU Packaging and Packaging Waste Regulation (PPWR) and prepare your business for compliance. CEHTRA supports companies with regulatory expertise, impact assessment and guidance on packaging compliance and sustainability requirements. PPWR - Packaging and Packaging Waste Regulation Supporting companies in understanding and complying with the EU Packaging and Packaging Waste Regulation (PPWR). Contact our PPWR experts What is the PPWR Regulation? The Packaging and Packaging Waste Regulation (PPWR) is a major regulatory initiative introduced by the European Union to reduce packaging waste and strengthen circular economy objectives. The regulation will introduce new obligations related to packaging design, recyclability, labelling, and waste reduction targets, affecting companies placing packaged products on the EU market. As the regulatory framework evolves, companies must anticipate these requirements to ensure compliance and adapt their packaging strategies accordingly. Contact our experts Why the PPWR Matters for Your Business The PPWR regulation will impact a wide range of industries placing packaged products on the European market. Companies may need to review: Packaging design and material choices Labelling and information requirements Responsibilities of economic operators Compliance timelines and regulatory obligations Waste reduction and recyclability targets Understanding these regulatory developments early is essential to anticipatepotential operational and compliance challenges. Who is concerned by the PPWR? The PPWR regulation applies to all companies placing packaged products on the EU market, including manufacturers, importers, distributors and brand owners across sectors such as cosmetics, food, pharmaceuticals and consumer goods. How CEHTRA Supports Your PPWR Compliance CEHTRA works alongside companies to translate regulatory requirements into practical compliance strategies. Our approach focuses on helping businesses: understand the regulatory framework anticipate operational impacts identify potential compliance gaps implement appropriate regulatory strategies By combining regulatory expertise and industry experience, CEHTRA helps companies prepare for upcoming packaging regulations and navigate complex compliance requirements. Discover all our packaging services Prochains webinaires Afin d’aider les entreprises à mieux comprendre les évolutions réglementaires liées au PPWR, CEHTRA organise régulièrement des webinaires dédiés aux réglementations sur les emballages et aux enjeux de conformité. Ces sessions permettent d’explorer les principaux sujets réglementaires et d’échanger directement avec nos experts. PPWR Regulation – Key Requirements and Regulatory Timeline Speaker: Baptiste Reverdy Date: 15 April 2026 French Date: 27 May 2026 English Register to the webinar Register to the webinar Preparing for the PPWR Regulation? The upcoming Packaging and Packaging Waste Regulation (PPWR) will introduce new requirements affecting packaging design, labelling, and compliance responsibilities. CEHTRA experts can help you assess potential impacts and anticipate regulatory obligations. Contact us to discuss how we can support your PPWR compliance strategy. Request support

Explore CEHTRA’s regulatory expertise across biocides, cosmetics, pharma, REACH, crop protection, and more. Our sectors Explore CEHTRA’s regulatory expertise across biocides, cosmetics, pharma, chemicals, environment, and more sectors. Explore Regulatory support across markets CEHTRA supports companies across a wide range of regulated sectors. From product design to market launch, our multidisciplinary experts offer tailor-made regulatory solutions that combine scientific excellence with strategic vision. biocides Explore chemicals Explore cosmetics Explore food Explore medical devices Explore packaging Explore pharmaceuticals Explore plant protection Explore Need guidance? Speak with our specialists Select a sector:* First name:* Last name:* Company or Organization:* Email:* How can we help you? Submit