Application of a next generation risk assessment framework, integrated testing strategy defined approaches and read-across for evaluating the skin sensitization potency: Case studies with 5-hydroxymethylfurfural and 5,5'-oxydimethylenebis (2-furfural).

The regression based defined approach for skin sensitization potency assessment based on NAM data from OECD accepted tests.

The transparency and explainability of uncertainties related to read-across predictions are critical for filling toxicological data gaps. As frameworks for evaluating read-across have become standardised, so has the identification and characterisation of the various types of uncertainty, particularly those related to chemical similarity. However, it has proven more challenging to assess overall uncertainty, particularly in defining what constitutes "tolerable" uncertainty. In this study, seven areas of uncertainty related to read-across were identified and their impact on read-across for two endpoints assessed; six related to aspects of chemical structure and properties, and a further one to uncertainty within the biological data used for read-across. The impact of uncertainty associated with these seven factors was related to ordinal categories. Examples of uncertainty assessment in read-across data gap filling, where different source analogues and the same target substances were evaluated, are provided for skin sensitisation and sub-chronic systemic toxicity. The resulting scheme, a generic tabular matrix, offers a flexible and adaptable approach for assessing uncertainties related to read-across predictions, particularly those from a single-source analogue and includes an overall uncertainty level for the read-across. Analysis of existing read-across predictions provides a means to define the level of tolerable uncertainty.

The transition toward non-animal safety assessment has driven the development of in vitro models for skin sensitization, particularly those targeting key event 2 (KE2) within the adverse outcome pathway (AOP). While conventional KE2 assays often rely on randomly integrated reporter systems, the EndoSens model utilizes CRISPR/Cas9-mediated knock-in to precisely insert a luciferase reporter into the endogenous HMOX1 locus in HaCaT keratinocytes, providing a genomically anchored and physiologically relevant system. To enable reproducible adoption across laboratories, we established a standardized protocol with defined quality control (QC) criteria, incorporating cinnamyl alcohol as a quantitative positive control and a cytotoxicity pre-screen to identify non-cytotoxic test concentrations. Evaluation using ten OECD TG 442D reference chemicals and ten additional compounds demonstrated the assay's robust performance in discriminating skin sensitizers with high inter-laboratory consistency, supporting its integration as a reliable in vitro component within defined approaches (DA) for animal-free skin sensitization assessment.

RIFM fragrance ingredient safety assessment, ethyl palmitate, CAS Registry Number 628-97-7.

RIFM fragrance ingredient safety assessment, ethyl octadecanoate, CAS Registry Number 111-61-5.

Derivation of a Point of Departure using NAMs for application in Quantitative Risk Assessment of fragrance materials.

Cucurbita maxima (pumpkin) leaves have been traditionally used in folk medicine for the treatment of inflammation, fever, and oxidative stress-related disorders. However, scientific validation of these claims remains limited. This study aimed to evaluate the anti-inflammatory, antioxidant, and protective effects of C. maxima leaf aqueous extract and to elucidate its phytochemical composition and molecular mechanisms of action. The phytochemical profile of the aqueous extract was determined using UPLC-ESI-MS/MS analysis. In vivo anti-inflammatory activity was assessed in a benzylthiouracil-induced inflammation model by measuring white blood cell (WBC) counts, C-reactive protein (CRP) levels, and histopathological changes in liver and kidney tissues. In vitro anti-inflammatory potential was evaluated through the protein denaturation inhibition assay, using diclofenac as a reference. Pharmacokinetic and toxicity properties of major compounds were predicted using ADMET tools, while molecular docking studies were performed to evaluate interactions with COX-1 and COX-2 enzymes. UPLC-ESI-MS/MS analysis revealed a complex mixture of polyphenols, with caffeic acid (56.04%), rutin (9.25%), ferulic acid (8.79%), and myricetin-3-rhamnose (8.62%) as the main constituents. The extract significantly reduced inflammation by normalizing WBC counts (from 7.2 to 4.5×109/L), lowering CRP levels (from 630 to 220mg/L), and protecting liver and kidney tissues. The extract also inhibited protein denaturation in vitro (IC50=2.976mg/mL) compared to diclofenac (IC50=0.718mg/mL). Molecular docking revealed that major flavonoids exhibited strong binding affinities toward COX-1 and COX-2, often surpassing diclofenac, supported by stable hydrogen bonding and hydrophobic interactions. ADMET and toxicity predictions indicated good intestinal absorption for several major compounds, absence of predicted hepatotoxicity or skin sensitization, and generally low acute toxicity, with high predicted LD50 values and no mutagenic risk for most constituents. These findings support the traditional use of C. maxima leaves in folk medicine for the management of inflammation-related conditions, fever, and associated oxidative stress. Further isolation of the key active constituents and clinical evaluation are recommended to confirm their therapeutic efficacy.

Plants hold significant promise for dermatological applications. However, the potential for phytochemicals, particularly essential oils, to cause skin irritation or sensitization necessitates rigorous safety evaluation for products derived from medicinal plants. This Phase I study was therefore designed to investigate the safety profile of three novel herbal ointment formulations prepared from essential oils on the healthy human skin of volunteers. An open-label, randomized controlled Phase I trial was conducted with 30 healthy volunteers in Ethiopia. Participants were randomly assigned (10 each) to one of the three investigational herbal ointments in a 1:1:1 ratio. For each participant, placebo (vehicle), 2%, and 5% concentrations of the allocated investigational product were applied concurrently using an occlusive patch test, followed by a photo-patch test and a repeated open application test (ROAT). Participants were followed for 14 days to monitor for skin reactions and adverse events. The primary endpoint was the occurrence of serious adverse reactions (SAR) associated with investigational products. All 30 enrolled participants completed the study with full adherence to the required procedures as per the protocol. No serious adverse reaction related to the investigational herbal products (IHPs) were observed throughout the trial. A total of six non-serious adverse events were recorded among five study participants, none of which was assessed as related to the IHPs. Baseline and end-of-study laboratory parameters and vital signs remained stable, with no clinically significant abnormalities detected. All three investigational herbal ointment formulations demonstrated a favorable safety profile when applied to healthy human skin. These findings support further clinical development of the products and warrant subsequent studies to evaluate the long-term safety and efficacy for the intended dermatological application. Trial Registration: The trial was registered under the number PACTR202311887239866.

In vitro assessment of respiratory sensitization potential and allergic asthma: A miRNA-based approach.

Textile chemicals may constitute a hazardous exposure and lead to skin sensitization or other health problems. Children, due to their thinner, less developed skin, are more susceptible to this exposure. To investigate the occurrence and levels of 50 textile chemicals in children´s skin-close clothing. Further, to investigate the washout effect of these textile chemicals and their tendencies to migrate from the textile fibres into artificial sweat. Screening of 60 children's clothes purchased on the Swedish retail market was performed using coupled automated thermal desorption-gas chromatography/mass spectrometry (ATD-GC/MS). Among the most frequently occurring chemicals were non-regulated quinolines, halogenated arylamines, phthalates, and nitrobenzenes. The highest concentrations were found for benzyl benzoate, 1400 μg/g, and 2-bromo-4,6-dinitroaniline, 300μg/g. The highest number and levels of chemicals were detected in garments made of 100% polyester, while the fewest and lowest levels were determined in light-coloured cotton. Laundry experiments revealed that cotton garments had the greatest washout effect, whereas most of the chemical content remained in 100% polyester garments even after 10 laundry cycles. Results indicate a lower exposure from the investigated cotton garments, especially after laundry. On the other hand, cotton exhibited threefold greater chemical migration into artificial sweat than polyester. The strong dependence on fibre material is important to consider when estimating the bioaccessible chemical exposure from garments and related health risks.

Bisphenol A is a high production volume chemical used extensively in the manufacture of polycarbonate plastics, epoxy resins, and thermal printer paper with a high potential for occupational and post-production dermal exposure. Bisphenol A-containing plastics were commonly used in food packaging resulting in significant public exposure through leaching into foodstuff. The public is also at risk of dermal exposure due to environmental contamination. Due to public health concerns regarding the potential for endocrine disrupting effects, efforts have been applied to replace bisphenol A with safer alternatives. Bisphenol A has been shown to cause skin sensitization in humans; however, there is a paucity of information available on the sensitizing potential of structural analogues which are increasingly being employed as substitutes. We utilized new approach methodologies (NAMs) addressing key events 1-3 of the adverse outcome pathway for skin sensitization to address the potential of bisphenol A substitutes to induce dermal sensitization. Defined approaches (DA) were applied to further classify and categorize potency according to OECD TG 497. The NAMs and DAs confirmed that bisphenol A was a skin sensitizer in potency category UN GHS 1B. Bisphenol B, AP, and E were also classified as UN GHS 1B sensitizers, and bisphenol AF as UN GHS 1A/1B depending on DA, while 2,4-bisphenol S and F were borderline sensitizers, and bisphenol S was classified as a non-sensitizer. These data provide evidence of skin sensitization hazard for the bisphenol structural analogues tested, except for bisphenol S, suggesting that they present risks for dermal allergy.

Epoxy polymers, widely used in industries such as wind turbine production, are common causes of allergic contact dermatitis (ACD). However, gaps remain mostly regarding the type of occupational exposure (specific tasks) and protective strategies. To evaluate epoxy resin sensitisation in a wind turbine blade plant and assess its associations with tasks, medical history, clinical patterns, and personal protective equipment (PPE) use. A cross-sectional study was performed in a large wind turbine blade facility. A group of volunteer workers completed a questionnaire on occupational/medical history, PPE use, and symptoms. Onsite patch testing included the European Baseline-, epoxy-, and isocyanate series. Data were analysed using SPSS and R (p < 0.05). Among 131 workers tested (7.4% of the workforce), seven (5.3%), all from high-exposure tasks, showed positive reactions to epoxy compounds: Bisphenol F resin (5), Bisphenol A resin (4), and hardeners/additives (5). Hand dermatitis was the predominant ACD pattern, with a median time to onset of 8 months after employment. No associations were found between sensitisation and previous medical history or PPE compliance. The ACD to epoxy resin is a significant concern in wind turbine blade manufacturing. Accurate diagnosis requires patch testing with epoxy-specific series, beyond the European Baseline series. Prevention should extend beyond PPE, addressing airborne exposure and cross-contamination.

Current acne management relies largely on topical and systemic pharmacotherapy, but these treatments frequently cause cutaneous adverse reactions. Such side effects are of particular concern in patients with initial skin sensitivity, highlighting the need for personalized approaches. This 12-week prospective observational study included 308 Korean acne patients to compare the clinical efficacy of a specific dermo-cosmetic (DC) formulation used as monotherapy versus combination therapy in acne patients, and to evaluate a sensitivity-based approach to improve quality of life. Patients were classified into DC monotherapy (n = 151) or combination therapy (n = 157), and to sensitive (n = 144) or non-sensitive (n = 164) subgroups. Primary outcomes were Global Evaluation of Acne (GEA), total lesion count, and sebum secretion levels. Secondary outcomes included skin sensitization score, tolerance assessment, quality of life, and adverse events. The DC monotherapy group showed significantly greater improvement in GEA scores, fewer sensitivity symptoms, improved quality of life, and greater tolerability than the combination therapy group (all p < 0.0001). In the sensitive patient subgroup, DC monotherapy was also significantly superior to combination therapy in terms of GEA, tolerability, sensitivity symptoms, and quality of life (all p < 0.0001). In patients without initial sensitivity, improvement in GEA (p = 0.0079), total lesion count (p < 0.0001), and sebum secretion (p < 0.0001) was significantly greater in the combination therapy than in the DC monotherapy. These findings suggest that baseline skin sensitivity may represent an important determinant of treatment selection and support a sensitivity-guided personalized treatment approach in acne management.

SkinCast: an AI-driven mechanistically interpretable model for predicting skin sensitization of environmentally released consumer product ingredients.

Update to RIFM fragrance ingredient safety assessment, γ-hexalactone, CAS Registry Number 695-06-7.

Update to RIFM fragrance ingredient safety assessment, myristic acid, CAS Registry Number 544-63-8.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of coated granulated calcium iodate anhydrous as nutritional feed additive for all animal species. The additive is already authorised for use with all animal species. The applicant has provided evidence that the additive under assessment complies with the conditions of the authorisation. In addition, a modification in the manufacturing process (i.e. addition of 0.2% sepiolite) is proposed. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP Panel) confirms that the calcium iodate component of the additive remains safe for the target species under the approved conditions. However, due to the absence of adequate data on some of the coating agents used in the manufacture of the additive, the Panel cannot conclude on the safety of coated granulated calcium iodate anhydrous for the target species and the environment. Due to the lack of adequate iodine deposition data and information on the safety of some of the coating agents listed by the applicant, the FEEDAP Panel cannot conclude on the safety for the consumer. With regard to the safety for the users, the additive is not considered irritant to skin or eyes; however, it should be considered as a skin and respiratory sensitiser. Exposure of users by any route is considered a risk and should be minimised. The FEEDAP Panel concludes that the additive is an efficacious source of iodine in feed for all animal species.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of a proanthocyanidin-rich dry extract obtained from the fruit of Vaccinium macrocarpon Aiton (cranberry extract) when used as a sensory feed additive for dogs and cats. The additive is not currently authorised for use in feed. The FEEDAP Panel concluded that cranberry extract is safe for dogs at 610 mg/kg complete feed and for cats at 155 mg/kg complete feed. Regarding user safety, the additive is not irritant to skin or eyes but is a potential skin and respiratory sensitiser. Exposure of users by inhalation and dermal routes is considered a risk. The Panel concluded that the additive has the potential to be efficacious as a sensory additive (flavouring agent, palatability enhancer) in dogs and cats when added to feed at 122 and 155 mg/kg complete feed, respectively.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of FlorEquilibre® Chat when used as a zootechnical additive (functional groups: gut flora stabilisers) for cats. The product under assessment is based on viable cells of Bifidobacterium animalis subsp. lactis CNCM I-3993, Lactobacillus acidophilus CNCM I-3231, Ligilactobacillus salivarius CNCM I-3233, Bifidobacterium longum CNCM I-3227 and Lacticaseibacillus paracasei CNCM I-4901. All five strains were suitable for the qualified presumption of safety (QPS) approach to safety assessment. The identity of the strains was established, and no acquired antimicrobial resistance genes were detected, except in B. animalis subsp. lactis CNCM I-3993. Therefore, the FEEDAP Panel concluded that the use of the strains, except for CNCM I-3993, is presumed safe for the target species and the environment. The Panel also concluded that the use of B. animalis subsp. lactis CNCM I-3993 represents a safety concern for the target species, the users and the environment because the strain harbours an acquired antimicrobial resistance gene (tet(W)). Therefore, FlorEquilibre® Chat is considered not safe for the target species, users and the environment. Regarding user safety, FlorEquilibre® Chat is an eye and skin irritant, and a skin and respiratory sensitiser and exposure via any route is considered a risk. Based on the data provided, the Panel cannot conclude on the efficacy of the additive for cats.