The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 7 saccharides/saccharide derivatives as used in cosmetic products; all of these ingredients are reported to function as skin-conditioning agents-humectant in cosmetics. The Panel reviewed data relevant to the safety of these ingredients in cosmetic formulations and concluded that Anhydrogalactose, Anhydroglucitol, Anhydroxylitol, Arabinose, Psicose, Saccharide Hydrolysate, and Saccharide Isomerate are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Tetrasodium Glutamate Diacetate and Beta-Alanine Diacetic Acid, which are reported to function as chelating agents in cosmetic products. The Panel reviewed the available data to determine the safety of these ingredients. The Panel concluded that Tetrasodium Glutamate Diacetate is safe in cosmetics in the practices of use and concentration described in this safety assessment, and that the available data are insufficient to make a determination that Beta-Alanine Diacetic Acid is safe under the intended conditions of use in cosmetic formulations.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of Salicylic Acid and 17 salicylates; 15 of these ingredients were previously reviewed by the Panel, and 3 are reviewed herein for the first time. Some of the reported functions in cosmetics for ingredients in this group are hair and skin conditioning agents, and, less frequently, preservatives and fragrance ingredients. Upon review of relevant new data, including frequency and concentration of use, and consideration of data from the previous CIR report, the Panel concluded that these ingredients are safe in cosmetics in the present practices of use and concentration described in the safety assessment when formulated to be non-irritating and non-sensitizing, which may be based on a quantitative risk assessment (QRA).

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 4 (sugarcane)-derived ingredients. These ingredients are mostly reported to function in cosmetics as skin-conditioning agents. Industry should use good manufacturing practices to minimize impurities that could be present in botanical ingredients. The Panel considered the available data and concluded that Saccharum Officinarum (Sugarcane) Bagasse Powder, Saccharum Officinarum (Sugarcane) Extract, Saccharum Officinarum (Sugarcane) Juice Extract, Saccharum Officinarum (Sugarcane) Wax are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 24 silicate ingredients that are solid inorganic oxides, comprising, in part, silicon dioxide, which can be derived from naturally occurring minerals or can be produced synthetically. Reported functions in cosmetics include abrasives, absorbents, bulking agents, and deodorant agents. The Panel reviewed all relevant data and concluded that the silicate ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-irritating, with the exception that the available data are insufficient to make a determination of safety for the use of naturally sourced (i.e., mined) silicate ingredients in products that may be incidentally inhaled.

The international cosmeceutical sector has experienced unprecedented expansion, compelling regulatory bodies to enhance and update systems to tackle consumer protection, product effectiveness, and ethical issues. This review critically evaluates and contrasts regulatory settings in key markets, such as the European Union, United States, Canada, Japan, China, India, and Brazil. The examination is concentrated on key features including product definitions, pre-market approval procedures, and ingredient regulation, labeling requirements, post-market surveillance, and integrating ethical and environmental considerations. The outcome shows significant advances in regulatory harmonization, especially in the area of ingredient safety and adverse event reporting; however, there are still considerable challenges. Pioneering among these are the lack of a standard definition for "cosmeceuticals," highly variable ingredient limitations, and uneven application practice across jurisdictions. The speedy growth of e-commerce and cross-border sales additionally complicates regulatory control, adding to the possibility of non-compliant or counterfeited products reaching consumers. The review also identifies a shortage of empirical evidence to document the actual impact of recent regulatory reforms in the real world, as well as on innovation and market access. The present study recommends the promotion of international harmonization of standards, enhancement of post-market surveillance, convergence of ethical and sustainability dimensions, and targeted support for small- and medium-sized enterprises. Henceforth, while important progress has been achieved, the future of the industry rests on creating nimble, science-informed, and internationally harmonized regulatory systems that can keep pace with changing technologies and consumers' and public health priorities, ensuring both consumer safety and industry innovation.

BackgroundPlastics have been widely used for several decades, but their persistence in the environment has resulted in the widespread presence of microplastics (MPs) in the air, water, and soil. With particle sizes smaller than 5 mm, MPs are now recognized as emerging contaminants of concern owing to their potential impact on human health.ObjectiveThis study aimed to conduct a critical narrative umbrella review of published reviews and primary studies on microplastic exposure and human health. Specifically, the objective was to synthesize evidence across the major exposure pathways (ingestion, inhalation, and dermal), summarize the associated health outcomes, and critically appraise common themes, inconsistencies, and knowledge gaps. This review provides guidance for future research and policy directions by aligning findings with methodological strengths and limitations.ResultsMPs are consistently detected in food, water, air, human stool, blood, placenta, and breast milk. Reported outcomes include gastrointestinal inflammation, gut microbiota disruption, respiratory diseases, endocrine and reproductive dysfunction, and possible neurotoxicity. Inhalation is increasingly recognized as significant, and ingestion remains the most studied, whereas dermal exposure is underexplored.ConclusionMicroplastics represent a pervasive and complex public health challenge. This umbrella review underscores the need for harmonized methodologies, epidemiological investigations, and mechanistic studies that reflect real-world exposure. Strengthening this evidence base is essential for risk assessment, regulation, and public awareness of the health impacts of microplastics.

Bisphenol A (BPA) is a prevalent environmental endocrine disruptor with potential impacts to the neurological system in humans. This study used an integrated method combining network toxicology, molecular docking, and molecular dynamics simulations to explore the molecular mechanisms underlying BPA-induced neurotoxicity. We identified 255 potential neurotoxicity-related targets through the integration and comprehensive analysis of multiple data sources, including the Comparative Toxicogenomics Database (CTD), ChEMBL, STITCH, GeneCards, and the Online Mendelian Inheritance in Man (OMIM) database. Analysis of the protein-protein interaction (PPI) network unveiled 52 core targets, among which TNF, TP53, INS, ESR1, and PTGS2 emerged as pivotal hubs in the toxicity network. Functional enrichment analysis indicated that the core targets of BPA's influence on neurotoxicity are predominantly enriched in vital signaling cascades, including inflammatory responses, pathways of neurodegeneration, MAPK signaling pathway, serotonergic synapse pathway, and pathways in cancer. Molecular docking results demonstrated that BPA exhibited stable binding interactions with core targets. Furthermore, molecular dynamics simulations provided insights into the interactions between BPA and key targets (ESR1, TNF, and TP53), supporting the potential conformational stability of these complexes. Collectively, these computational findings contribute to understanding the potential molecular mechanisms of BPA-induced neurotoxicity and are informative for generating hypotheses related to its pathogenesis.

Chronic ozone exposure in urban environments compromises lung function, predisposing individuals to severe sepsis outcomes from common infections. Pyroptosis, a type of programmed cell death, is implicated in sepsis and lung injury, and its regulation is crucial for understanding disease severity. We focused on pyroptosis due to its role in inflammation, tissue damage, and organ dysfunction in septic patients, as well as its link to ozone exposure through inflammasome activation. To elucidate the underlying molecular mechanisms, we integrated bioinformatics and experimental approaches. We analyzed public genomic data repositories to identify pyroptosis-related genes and those linked to sepsis and ozone-induced lung injury. Three pyroptosis-related genes (caspase-1, interleukin-1β, and gasdersmin D) were upregulated, while adenosine deaminase acting on RNA 1 (ADAR1) was downregulated. To validate these findings, mice were exposed to ozone followed by lipopolysaccharide-induced sepsis. After 12 hours, lung tissue damage, inflammation, and pyroptosis were assessed. Two-way ANOVA revealed significant LPS × ozone interactions, with one-way ANOVA showing dose-dependent ozone effects on inflammation and pyroptosis. Results confirmed the bioinformatics predictions, showing ADAR1 levels initially increased in septic mice but declined with ozone exposure. Concurrently, ozone exacerbated caspase-1-mediated pyroptosis in lung tissue. Our findings demonstrate that ozone preexposure worsens septic lung injury by modulating ADAR1 and pyroptosis. By elucidating the ADAR1-pyroptosis interplay, this study highlights a novel mechanism contributing to the pathogenesis of ozone-induced lung injury in sepsis, revealing ADAR1 as a key regulatory molecule.

Exposure to diesel exhaust air pollutants is a key environmental threat for pulmonary and cardiovascular diseases. Oxidative stress and Transient Receptor Potential Vanilloid-1 (TRPV1) receptors exhibit pivotal contributions in mediating lung injury induced by environmental pollutants. This study investigates the histological changes in lung tissue induced by short-term particulate-free filtered diesel exhaust (FDE) exposure, with a focus on TRPV1 receptor expression and oxidative stress pathways. Male rats were allocated to four groups randomly: Non-exposed (NE), clean air exposed (CAE), FDE-exposed, and NAC pre-treated FDE-exposed groups. FDE exposure lasted 5 hours per day for five days, with histological examination and TRPV1 expression analysis conducted on day six. The NAC pre-treated group received NAC (200 mg/kg) for five days prior to each exposure. Lung tissue samples were analyzed using hematoxylin and eosin staining, and immunofluorescence for TRPV1 expression. FDE exposure caused significant histological alterations, including alveolar septal thickening, interstitial inflammation, capillary congestion, perivascular inflammation, bronchial epithelial necrosis, endothelial discontinuity, and interstitial fibrosis, as classified by a semi-quantitative INHAND (International Harmonization of Nomenclature and Diagnostic) scoring criteria for rats, visualized on a heat map. TRPV1 expression was upregulated in FDE-exposed lung tissues, particularly around congested vessels and thickened septa. NAC pre-treatment significantly reduced both histological damage and TRPV1 expression. Our study highlights a potential mechanistic relationship between TRPV1 receptor expression and oxidative stress pathways in the lung damage induced by FDE exposure, underscoring the therapeutic potential of NAC in countering these effects.

The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement with regulators to optimize NAM utility in supporting the safety and efficacy of new drugs. Previously, we published an FDA/CDER perspective on nonclinical testing strategies, discussed the opportunities and challenges of using NAMs to replace, reduce, and refine animal testing in drug development, and reported gaps and challenges underserved by existing nonclinical testing approaches that CDER Pharmacology/Toxicology reviewers face. Here, we demonstrate how FDA/CDER has historically incorporated NAMs into standard nonclinical assessments, describing how specific tests became validated and internationally accepted alternatives to animal testing for regulatory decision-making. We also provide a CDER/OND Pharmacology/Toxicology reviewer perspective on NAMs submitted to support new drug development, in an effort to provide insight into our experience with NAMs submitted for CDER-regulated products. Furthermore, we provide a CDER/OND Pharmacology/Toxicology reviewer perspective on the future of NAM incorporation into nonclinical development programs for new drugs as scientific technology continues to evolve. Ultimately, we hope that by sharing the FDA/CDER/OND experience with NAMs thus far and providing considerations for refining NAM submissions, we will (1) illustrate our scientific approach to evaluating NAM submissions, (2) reiterate FDA/CDER's steadfast commitment to the 3Rs, and (3) foster confidence in our continued efforts to encourage nonclinical test NAM submissions for regulatory decision-making, while maintaining our mission to protect public health and patients from unintended harm.

Drug discovery and development is a complex, lengthy, and expensive process that takes on average 10-15 years and approximately $1-2 billion USD for approval of a new drug. While the studies needed to support clinical development are generally outlined in guidance documents, there is much less guidance on how to translate the nonclinical data into clinical designs. Nonclinical studies are performed to conduct the First-in-Human clinical trial, which is the first major milestone to advance new promising drug candidates, and are conducted primarily to determine the safe dose range for clinical development. Resolving how to move forward, and even when to move forward, requires significant cross-functional collaboration with pathologists, ADME scientists, biologists, and clinical staff. There are many reasons why drug candidates may fail; these could be as simple as insufficient understanding of the nature of the translational process, failure to effectively integrate the data from different pharmacologically relevant species, or erosion of the margin of safety during chronic toxicology studies. The case studies described here were designed to help participants in the 2024 American College of Toxicology (ACT) Continuing Education course "Translational Challenges from Nonclinical to Clinical Program: Case Study Examples" to improve their skills in managing translational challenges from nonclinical to clinical program encountered during drug development.

The device development process encompasses an intersection of biological, physical, and engineering sciences principles culminating in translation of data from nonclinical animal studies to predict potential tissue responses in human patients. Evaluation of tissue reactions to the implanted device relies heavily on the core discipline of toxicologic pathology. Historically and currently, a disconnect between physical and biological scientists is highlighted by the frequent miscommunications due to differences in scientific language and divergent approaches to animal study design and/or data generation and interpretation. To facilitate communication among biologists, engineers, and materials scientists in the medical device community, this article provides fundamental principles and key resources necessary for rational pathology evaluation of tissue responses to implanted devices from the expert perspective of experienced toxicologic pathologists. The unique contributions of toxicologic pathologists to developing and marketing medical devices will be discussed, emphasizing the role of expert pathologists in balancing scientific issues with respect to evaluating biological responses and regulatory considerations. Additionally, discrepancies will be addressed that may arise if regulatory guidance is applied rigidly rather than adjusted as warranted by the context-specific evidence to best answer particular safety-related questions.

Per- and polyfluoroalkylated substances (PFAS) are persistent anthropogenic chemicals widely distributed in the environment that are known to have toxic effects in animals and humans following exposure. Some PFAS have been shown to activate peroxisome proliferator-activated receptor α (PPARα), a transcription factor involved in lipid metabolism, leading to dyslipidemia or liver toxicity. PFAS comprise a wide range of compounds, and variations in their structural characteristics could reveal important details regarding the level of PPARα activation. In this work, using a Chemically Activated LUciferase eXpression (CALUX) assay, we experimentally tested the PPARα activation efficiency of several PFAS compounds of varying chain lengths and functional groups. Activation and potency were compared across and within PFAS class based on chemical differences. When compounds with the same number of carbons or perfluorinated carbons were compared across class, the rank from high to low activator class remained the same. Perfluorocarboxylated ether was found to be the strongest class, while polyfluorotelomer was the weakest, suggesting the importance of structural features in PPARa activation. Perfluorocarboxylates were consistently better PPARα activators than perfluorosulfonates. Comparing within these 2 classes, the number of perfluorinated carbon atoms better predicted activation than the number of carbon atoms. In the perfluorocarboxylated ether, perfluorocarboxylate, and perfluorosulfonate classes, a direct correlation existed between potency and the percentage of PPARα activation (R = 0.702), a novel observation. These findings provide new insights regarding distinct chemical characteristics of PFAS compounds which may be predictive of PPARα activation level.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of five -derived ingredients as used in cosmetic products; all of these ingredients are reported to function as skin-conditioning agents in cosmetics. Industry should use current good manufacturing practices to minimize impurities that could be present in these botanical ingredients. The Panel reviewed data relevant to the safety of these ingredients in cosmetic formulations, and concluded that the five -derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Sukré™, a highly purified l-arabinose produced from hydrolyzed acacia, has potential uses as a natural sweetener. To evaluate the safety of l-arabinose, a battery of GLP-compliant in vitro and in vivo studies were conducted with Sukré™ (Compound Solutions, Inc, USA). No mortality, morbidity, or adverse effects were observed in a 28-day subchronic toxicity study conducted in rats administered doses up to 7200 mg/kg bw/day Sukré™ by gavage. Thus, the 28-day oral subchronic NOAEL for Sukré™ in male and female Wistar rats was 7200 mg/kg bw/day, the highest dose tested. Furthermore, results of in vitro studies (a bacterial reverse mutation assay, a mammalian chromosomal aberration study, and a mammalian micronucleus study) demonstrate that Sukré™ was non-mutagenic and non-clastogenic. Collectively, these observations indicate that oral consumption of Sukré™ is not of toxicological concern and provide supportive evidence for the safe oral consumption of Sukré™ as an ingredient in foods.

HFO-1234ze(E) is being developed as a next-generation propellant (excipient), with near zero global warming potential, for use in pressurized metered dose inhalers. In accordance with regulatory guidance, an assessment of the carcinogenic potential of HFO-1234ze(E) was required to gain regulatory approval as a new excipient. HFO-1234ze(E) was therefore evaluated in two-year carcinogenicity studies in mice and rats by the inhalation route of administration. Study assessments included in-life observations, organ weights, histopathology, and hematology. Group mean (sex combined) inhaled doses were 2132, 6218, and 21,193 mg/kg/day in mice and 379, 120,8 and 3918 mg/kg/day in rats; in both studies, control animals were exposed to air alone under the same conditions as HFO-1234ze(E)-exposed animals. HFO-1234ze(E) was well tolerated at all doses. There were no HFO-1234ze(E)-related in-life effects and no neoplastic or non-neoplastic findings or effects on hematology in either study. In summary, HFO-1234ze(E) was not carcinogenic in mice or rats. These data support the use of HFO-1234ze(E) as a medical propellant.

Byakangelicol, a furanocoumarin derived from , possesses anti-inflammatory and antitumor activities. Since cytochrome P450 2A6 (CYP2A6) is the major enzyme responsible for coumarin metabolism, it is important to evaluate the effect of byakangelicol on CYP enzyme activity. The purpose was to explore the effects of byakangelicol on CYPs and to provide a reference for its drug development and clinical application. The present study investigated the impact of byakangelicol on CYPs in human liver microsomes (HLMs). Byakangelicol demonstrated the capacity to suppress the activities of CYP1A2, 2A6, and 3A4 in HLMs, with IC values of 19.42, 10.11, and 12.80 μM, respectively. Byakangelicol exhibited competitive inhibition of CYP1A2 and 2A6 with values of 9.86 μM and 5.23 μM, whereas the inhibitory effect on CYP3A4 was noncompetitive with a value of 6.55 μM. In addition, the inhibitory effect of byakangelicol on CYP3A4 was found to be time-dependent ( = 0.041 min and = 6.67 μM). This study revealed the inhibitory properties of byakangelicol on CYP1A2, 2A6, and 3A4 activity in HLMs. It suggests the potential for drug-drug interactions when byakangelicol is co-administered with drugs metabolized by these CYPs. These findings offer a foundation for investigating the interaction of byakangelicol with other drugs, which may assist in clinical prescription and drug development.

Although Bisphenol A (BPA) is still used in consumer products, concerns about its toxicity led to the adoption of structurally related replacement products such as Bisphenol F (BPF) and Bisphenol S (BPS). Unfortunately, comparing the biological responses to BPA and BPA substitutes can be challenging, as the available information is often derived from different studies using various animal strains and experimental protocols. To address this issue, we directly compared the impacts of BPA, BPF, and BPS in the same exposure study. Briefly, 8-week-old male Fischer rats were exposed to BPA, BPF, or BPS (at five different doses) and to 17α-ethinylestradiol (positive control for estrogenicity) by gavage for 28 consecutive days. Rat health, dietary intakes, and weight gains were monitored, 24-hour urine samples were collected, and blood and tissues were harvested at the terminal necropsy. The impacts of BPA, BPF, and BPS on rat weight gains, organ weights and histology, liver enzymatic activities, hematology, clinical chemistry, and serum hormone levels were relatively modest and mostly limited to the highest doses administered. However, bisphenol cross-contamination observed in urine samples from the vehicle control group may have interfered with the evaluation of their effects at lower doses. Although BPA, BPF, and BPS exposures all shared similarities with the 17α-ethinylestradiol positive control group, their impacts on serum hormone levels and endocrine-responsive tissues also presented noticeable differences. This suggests that BPA, BPF, and BPS may interfere with endocrine functions through slightly different molecular mechanisms.

The rasH2 mouse model has become the primary alternative to a 2-year mouse carcinogenicity study in safety testing of human pharmaceuticals. In this publication, we present the neoplastic incidence for 2291 control males, 2191 control females, 575 MNU-treated males, 559 MNU-treated females, and 210 urethane-treated males and females in rasH2 carcinogenicity studies conducted from 2012 to 2024 as well as survival, body weights, and selected non-neoplastic microscopic findings for control and positive control mice. Inclusion of a positive control group is recommended to ensure regulatory acceptance. Survival of controls at the end of 26 weeks was approximately 96% with similar percentages of survivors in the 13-week urethane-treated positive controls in contrast to a survival percentage of approximately 17% in MNU-treated positive controls. Malignant neoplasms accounted for most early deaths in control and positive control mice. Major neoplasms in control mice included Harderian gland adenomas, bronchioloalveolar adenomas and carcinomas, and splenic hemangiosarcomas, while the predominant neoplasms in MNU-treated mice included squamous cell papillomas and carcinomas of the nonglandular stomach and malignant lymphomas. The percentage of urethane-treated mice developing bronchioloalveolar neoplasms was over 98% in both sexes. When compared to control mice, MNU-treated mice had lower mean body weights while urethane-treated mice had higher mean body weights. Major non-neoplastic findings in control mice were subcapsular cell hyperplasia (51.78% to 89.41%) and skeletal muscle myopathy (77.17% to 80.71%). Other non-neoplastic findings included retinal degeneration in MNU-treated mice (∼87% in both sexes) and bronchioloalveolar hyperplasia in urethane-treated mice (≥53% in both sexes).

The Tg.rasH2 mouse is a validated bioassay system for evaluation of carcinogenic potential, and it is confirmed to be sensitive to both genotoxic and nongenotoxic carcinogens. This is also one of the models specified in ICH S1B Guidance, enabling 6-month carcinogenicity studies as an alternative to traditional 2-year bioassays. We conducted a 26-week carcinogenicity study at our test facility on Tg.rasH2 mice sourced from CLEA Japan Inc., in a process to generate historical control database. Although historical control data have been published for these mice sourced from Taconic Biosciences Inc., USA, there is a dearth of published literature citing spontaneous incidence of neoplastic findings in Tg.rasH2 mice sourced from CLEA Japan. We have therefore presented the spontaneous tumor incidence in our study and compared it with the previously published tumor incidence for Tg.rasH2 mice sourced from Taconic, USA. The comparison reveals a similarity of tumor incidence between the mice from these two sources.