Regulatory Toxicology and Pharmacology最新文献

{"title":"Protective Effects of Rosa canina Fruit Extract against Kidney Damage Induced by CCl4.","authors":"Hanaa S S Gazwi, Amany E Ragab, Osama I A Soltan, Mohamed A Abdein, Bushra Shakoor, Nusrat Shafiq, Inas Hussein Refaat, Salim S Al-Rejaie, Sinisa Djurasevic, Mohamed Mohany, Asmaa H Zaki","doi":"10.1016/j.yrtph.2025.105913","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105913","url":null,"abstract":"<p><p>The study explored the nephroprotective potential of Rosa canina (dog rose) ethanolic fruit extract against carbon tetrachloride (CCl4)-induced nephrotoxicity in rats, while also analyzing its phytochemical composition using UPLC-ESI-MS/MS. Male Wistar rats were allocated into five groups: control, R. canina extract alone, CCl4-induced nephrotoxicity, CCl4 with R. canina extract and CCl4 with silymarin. UPLC-ESI-MS/MS revealed 15 compounds in R. canina extract, predominantly anthocyanins, flavonoids, and lycopene. Treatment with R. canina extract significantly ameliorated CCl4-induced kidney dysfunction, abating oxidative stress and inflammation. Enhanced expression of HO-1 (heme oxygenase-1) and Nrf2 (nuclear factor erythroid 2-related factor 2) mRNA in the kidney suggested their involvement in protective mechanisms. Inhibition of HO-1 attenuated R. canina's protective effect against CCl4-induced kidney injury, underscoring the significance of the Nrf2/HO-1 pathway. For further validation, high throughput molecular docking analysis were performed. The docking analysis revealed the interaction between HO-1 and Nrf2 against Pelarginidin, Malvidin and Petunidin. Among all the three compounds, pelargonidin showed the highest binding score of -9.3kcal/mol and -7.7kcal/mol against Nrf2 and HO-1 respectively. In conclusion, R. canina extract, rich in phenolics, exhibited nephroprotective effects via inflammation and oxidative stress attenuation, potentially mediated through Nrf2/HO-1 pathway modulation against CCl4-induced nephrotoxicity.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105913"},"PeriodicalIF":3.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies to reduce the use of non-human primates in the development of oncology therapeutics: CD3-bispecifics.","authors":"Smitha Ps Pillai, Kaushik Datta, Petra Lutterbuese, Smita Salian-Mehta, Weimin Chen, Richard Stebbings, Binu Philip, Caren M Villano","doi":"10.1016/j.yrtph.2025.105910","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105910","url":null,"abstract":"<p><p>Pharmaceutical companies, which are IQ DruSafe/3R-TPS members, explored novel ways to reduce reliance on non-human primate (NHP) use in nonclinical drug development. These companies conducted a survey on NHP use in toxicology studies during discovery and development of CD3-bispecific antibodies (BsAbs) for the treatment of cancer. The objectives of the survey were to collect data on and case study examples of both first-in-human (FIH)-enabling (≤1-month) and Phase II/III-enabling (3-month) NHP studies conducted with CD3-BsAbs. The survey addressed study design elements, e.g. number of dose groups, number of animals/dose group, recovery arms, etc. when a study is deemed warranted. Survey questions also focused on whether data from Phase II/III-enabling studies addressed patient risk that was not identified in FIH-enabling studies, and whether Phase II/III-enabling studies impacted regulatory decisions pertaining to clinical development. The survey findings enabled the development of a Weight of Evidence (WoE) approach to assess the utility of Phase II/III-enabling toxicity studies in understanding potential safety risks with CD3 BsAbs and informing later-stage molecule development. Both study design optimization and WoE approaches offer a path for reduced NHP use without compromising nonclinical safety assessment of CD3-BsAbs for oncology indications, as illustrated by several case examples.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105910"},"PeriodicalIF":3.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into sanguinarine toxicity in Rats: Integrating toxicokinetics, oxidative stress, and gut microbial alterations","authors":"Yufeng Xu ,&nbsp;Zhiqin Liu ,&nbsp;Wenqing Sun ,&nbsp;Lin Wang ,&nbsp;Zihui Yang ,&nbsp;Zhen Dong ,&nbsp;Jianguo Zeng","doi":"10.1016/j.yrtph.2025.105911","DOIUrl":"10.1016/j.yrtph.2025.105911","url":null,"abstract":"<div><div>Sanguinarine (SAN), a bioactive benzophenanthridine alkaloid derived from <em>Macleaya cordata</em>, has gained attention as a plant-based pesticide and veterinary therapeutic. However, its toxicity mechanisms, particularly concerning toxicokinetics (TK) and gut microbiota interactions, remain poorly understood. This research assessed the acute and subacute toxicity, toxicokinetics, oxidative stress reactions, and changes in gut microbiota associated with SAN in Sprague-Dawley rats. A single oral dose by gavage resulted in a LD₅₀ of 1000 mg/kg·bw (male) and 926 mg/kg·bw (female), classifying SAN under GHS Category 4. Subacute exposure (14 days at 1/10, 1/50, and 1/100 LD₅₀) induced multi-organ damage, including pulmonary haemorrhage, hepatic steatosis, and renal tubular necrosis, with females exhibiting relatively higher sensitivity. Surviving rats recovered from toxic damage during the 14-day recovery period. Toxicokinetic analysis demonstrated dose-dependent plasma concentration curves, nonlinear elimination kinetics, and tissue accumulation in the liver and kidneys. Assays measuring oxidative stress showed unexpected rises in overall antioxidant capacity alongside marked inhibition of glutathione peroxidase, indicating targeted redox disruption. Gut microbiota sequencing identified dose-dependent dysbiosis: high-dose SAN reduced Firmicutes/Bacteroidetes ratios, depleted Lactobacillus, and enriched opportunistic pathogens (Klebsiella, Streptococcus), alongside altered short-chain fatty acid (SCFA) profiles. These findings underscore SAN's potential to induce systemic toxicity through oxidative stress, metabolic disruption, and gut microbiome-mediated inflammation. The LOEAL observed in this study for subacute exposure (14 days) to SAN was 10 mg/kg and the safe use of SAN should be emphasized.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105911"},"PeriodicalIF":3.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platform-based opportunities to streamline animal use in support of the 3Rs – recommendations from an antibody-drug conjugate analysis","authors":"Christina L. Zuch de Zafra ,&nbsp;Christopher M. Carosino","doi":"10.1016/j.yrtph.2025.105912","DOIUrl":"10.1016/j.yrtph.2025.105912","url":null,"abstract":"<div><div>The field of antibody drug conjugates (ADCs) continues to be an active area of development which has greatly evolved over the past 25 years since the first approved ADC in 2000 (Mylotarg). Simultaneously, increasing attention is being given to the use of animals, particularly large animal species, in biopharmaceutical drug development in the wake of the global COVID-19 pandemic and legislation implemented/pending in the US Congress (the FDA Modernization Act). A recent publication summarizing data from an analysis of 14 antibody-drug conjugates (ADCs) provides a springboard for the recommendation of best practices to streamline nonclinical toxicology evaluation for these molecules. Additionally, key principles from the ADC molecule class may be applied to other biologic platforms, such as CD3 bispecific antibodies and possibly cell and gene therapy. Widespread adoption of modernized program strategies should lead both to a reduction in the use of animals in nonclinical toxicology evaluation and to more rapid delivery of new medicines to patients with unmet medical needs.</div><div>The primary goal of nonclinical toxicology evaluation in the pharmaceutical industry is the identification of hazards and characterization of their monitorability, manageability, and reversibility in support of clinical trials and the eventual marketing of new drugs. An additional key deliverable of a toxicology program is the determination of appropriate dose levels to be evaluated in clinical trials. To accomplish these goals, nonclinical toxicology studies have traditionally utilized animal models in keeping with recommendations of global health authorities (e.g., ICH M3 for small molecule drugs and ICH S6 for biologic drugs). Although the 3Rs of ethical animal use (reduce, refine, replace) have been recognized since the late 1950s (Russell and Burch, 1959), increasing attention is being given to the use of animals in pharmaceutical research. The COVID-19 pandemic and accompanying ban on the export of non-human primates (NHPs) from China highlighted the dependence of nonclinical safety evaluation on NHPs, particularly for biologics and other modalities that have limited cross-reactivity. This realization contributed to the passage of the FDA Modernization Act 2.0 and the drafting of additional legislation (FDA Modernization Act 3.0) and the recent ‘Roadmap to Reducing Animal Testing in Preclinical Safety Studies’ which codify support in the US for the refinement of nonclinical toxicology programs and signal an opportunity for decreased reliance on animal models for safety evaluation. Similarly, the European Federation of Pharmaceutical Industries and Associations (EFPIA) recently released ‘EFPIA Recommendations on Phasing Out Animal Testing for Chemical Safety Assessments’ with comparable assessments and recommendations aimed at the evolution of pharmaceutical toxicity testing away from animal studies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105912"},"PeriodicalIF":3.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radon activity levels in beverages and drinking water in Jazan, Saudi Arabia: a health risk assessment","authors":"Entesar H. EL-Araby","doi":"10.1016/j.yrtph.2025.105909","DOIUrl":"10.1016/j.yrtph.2025.105909","url":null,"abstract":"<div><div>This study investigated radon concentrations in water and soft drinks from the Jazan region of Saudi Arabia using a CR39 detector. Sample analysis revealed radon concentrations ranging from 1.65 to 5.70 Bq/L in drinking water and 1.60–3.78 Bq/L in soft drinks, likely influenced by industrial processing. All measured values were below international safety thresholds, including USEPA limit 11.1 Bq/L and WHO guideline 100 Bq/L. Annual effective doses (AEDs) were calculated for ingestion and inhalation. Ingestion posed the greatest risk: 24.08 μSv/yr (water) and 20.32 μSv/yr (soft drinks). Inhalation doses were lower: 8.31 μSv/yr and 7.01 μSv/yr, respectively, and remained within the WHO and ICRP limits (100 μSv/yr). Ingestion doses slightly exceeded the reference value of the Scientific Committee on the Effects of Atomic Radiation (10 μSv/yr). The results highlight that ingestion is the main route of exposure and underscore the need for continuous monitoring and quality control. This is the first comprehensive assessment of radon in beverages from Jazan and provides vital baseline data for health policy and risk assessment in Saudi Arabia.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105909"},"PeriodicalIF":3.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Considerations for use of humanized IgG1/4 Göttingen minipigs in safety assessment of antibody-based therapeutics\" [Regul. Toxicol. Pharmacol., (161) (2025) 105855].","authors":"Anna Engstrom, Tine Dahlbaek Hannibal, Jerome Egli, Beatrice Gauthier, Mikkel Lykke Krarup, Daniela Gallo, Andres Eskjær Jensen, Steven Van Cruchten, Steven Bulera, Miranda Cornet, Sabine Elisabeth Hammer, David Henry, Bjoern Jacobsen, John Kendrick, Lars Siim Madsen, Sofiene Mhedhbi, Steven Oag, Henrik Duelund Pedersen, Manuela Teti, Pramila Singh","doi":"10.1016/j.yrtph.2025.105908","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105908","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105908"},"PeriodicalIF":3.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the lifetime cumulative dose as a basis for carcinogenic potency of nitrosamines – a key tenet underpinning less-than-lifetime approaches for establishing acceptable intake limits","authors":"Susan P. Felter ,&nbsp;Ashley M. Mudd ,&nbsp;David J. Ponting ,&nbsp;Rob Thomas ,&nbsp;Alisa Vespa ,&nbsp;Timothy J. McGovern ,&nbsp;Andreas Zeller ,&nbsp;Roland Froetschl ,&nbsp;Bodo Haas ,&nbsp;Yi Yang ,&nbsp;Anthony Lynch ,&nbsp;Angela White ,&nbsp;Matthew Schmitz ,&nbsp;Raechel Puglisi ,&nbsp;Joel P. Bercu","doi":"10.1016/j.yrtph.2025.105903","DOIUrl":"10.1016/j.yrtph.2025.105903","url":null,"abstract":"<div><div>Potential health risks associated with <em>N</em>-nitrosamine (NAs) impurities in pharmaceuticals have received significant attention. Regulatory guidance recommends methods to establish Acceptable Intake limits (AIs) that are protective for daily lifetime exposure. However, questions remain whether the same limit should apply to NA impurities in drug products used for less than lifetime (LTL). The ICH M7(R2) guidance addresses this for mutagenic impurities by establishing higher AIs for LTL exposures; however, this has not been adopted in current regulatory guidance for NA impurities which fall under the Cohort of Concern (potentially high potency carcinogens). The research described herein addresses one key knowledge gap: that carcinogenic potency of NAs is a function of total exposure rather than dose rate, a fundamental principle underlying the ICH M7(R2) approach for LTL. Data were evaluated from rodent carcinogenicity bioassays for eight NAs and aflatoxin B1 (another high potency carcinogen) involving exposure durations from 21 to 120 weeks. For all case studies, carcinogenic potency was found to be a function of total cumulative dose rather than daily dose, aligning with the ICH M7(R2) guidance, which posits that higher AI limits can be justified for LTL durations. Remaining knowledge gaps will be addressed in a subsequent publication.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105903"},"PeriodicalIF":3.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity evaluation of ten nitrosamine drug substance-related impurities using 2D and 3D HepaRG cell models","authors":"Ji-Eun Seo ,&nbsp;Hannah Xu ,&nbsp;Xilin Li ,&nbsp;Aisar H. Atrakchi ,&nbsp;Timothy McGovern ,&nbsp;Karen L. Davis Bruno ,&nbsp;David A. Keire ,&nbsp;Nan Mei ,&nbsp;Robert H. Heflich ,&nbsp;Xiaoqing Guo","doi":"10.1016/j.yrtph.2025.105906","DOIUrl":"10.1016/j.yrtph.2025.105906","url":null,"abstract":"<div><div>The evaluation of nitrosamine drug substance-related impurities (NDSRIs) has become a regulatory priority due to potential carcinogenicity. Previously, we evaluated mutagenicity and genotoxicity of NDSRIs using the enhanced Ames Test (EAT) and human TK6 cells. In this study, we investigated the genotoxicity of ten of these NDSRIs using metabolically competent human HepaRG cells. DNA damage and micronucleus (MN) formation were evaluated in both 2D and 3D models using the CometChip and flow-cytometry-based MN assays, respectively. After 24-h exposure, five EAT-positive NDSRIs, <em>N</em>-nitroso-duloxetine, <em>N</em>-nitroso-fluoxetine, <em>N</em>-nitroso-lorcaserin, <em>N</em>-nitroso-nortriptyline, and <em>N</em>-nitroso-varenicline, significantly induced DNA damage in both 2D and 3D models and increased MN and γH2A.X formation in 3D spheroids. Only three EAT-positive NDSRIs, <em>N</em>-nitroso-duloxetine, <em>N</em>-nitroso-fluoxetine, and <em>N</em>-nitroso-nortriptyline, increased MN frequency in 2D cultures. The five EAT-negative NDSRIs, <em>N</em>-nitroso-diclofenac, <em>N</em>-nitroso-folic acid, <em>N</em>-nitroso-paroxetine, <em>N</em>-nitroso-desvaleryl-valsartan, and <em>N</em>-nitroso-desvaleryl-valsartan methyl ester, showed no DNA damage or MN formation in either model. Quantitative comparisons showed that <em>N</em>-nitroso-nortriptyline was the most potent genotoxicant in HepaRG cells. Overall, the ten NDSRIs exhibited the same positive/negative genotoxicity outcomes in both the EAT and 3D HepaRG spheroids. These findings support the use of 3D HepaRG spheroids as an alternative <em>in vitro</em> model for detecting NDSRI-induced genotoxicity and confirming NDSRI responses in the EAT.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105906"},"PeriodicalIF":3.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mixture risk assessment approaches to evaluate oral exposure to PFAS: Outputs and recommendations of an expert workshop","authors":"Wieneke Bil,&nbsp;Julia Hartmann,&nbsp;Martine Bakker,&nbsp;Bas Bokkers","doi":"10.1016/j.yrtph.2025.105907","DOIUrl":"10.1016/j.yrtph.2025.105907","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) often co-occur as contaminants in drinking water and food. Various mixture risk assessment (MRA) approaches have been published to address the associated human health risks.</div><div>The Dutch National Institute for Public Health and the Environment (RIVM) organized an online workshop to discuss PFAS MRA approaches. Over 50 experts participated, representing research institutes, universities and government organizations internationally. A discussion document with scientific literature and considerations on PFAS MRA approaches was shared with participants ahead of the workshop.</div><div>The workshop yielded overall agreement among participants in support of evidence pointing towards no interaction and dose-additivity of PFAS mixtures. Participants broadly supported the need for a flexible, component-based MRA approach to accommodate the variability in PFAS mixtures and the integration of new PFAS. Overall, the workshop underscored the need to ensure that risk assessments are both scientifically robust and practically feasible, and showed that the global mixture risk assessment community is largely in agreement regarding evaluation of PFAS.</div><div>The input received as well as the outcomes of this workshop were used by RIVM in a recommendation to the World Health Organisation (WHO) on suitable approaches for assessment of PFAS in food and drinking water.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105907"},"PeriodicalIF":3.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of NAMs in a weight of evidence approach to evaluate the safety via the inhalation route of acetylated vetiver oil, in spray products","authors":"Fanny Boisleve ,&nbsp;Hind Assaf Vandecasteele ,&nbsp;James Baily ,&nbsp;Kamil Czuchrowski ,&nbsp;Malik Diop ,&nbsp;Catherine Gadras ,&nbsp;David Herbst ,&nbsp;Christina Hickey ,&nbsp;Amaia Irizar ,&nbsp;Boris P. Müller ,&nbsp;Nikaeta Sadekar ,&nbsp;Paul Sterchele ,&nbsp;Matthias Vey ,&nbsp;Nicola J. Hewitt","doi":"10.1016/j.yrtph.2025.105905","DOIUrl":"10.1016/j.yrtph.2025.105905","url":null,"abstract":"<div><div>Acetylated Vetiver Oil (AVO) is a fragrance ingredient. We evaluated the systemic and local toxicity of AVO via inhalation from use of cosmetic spray products.</div><div>Systemic exposure after inhalation was calculated using a deterministic 2-Box model. The “local inhalation toxicological threshold of concern” (TTC_inh) was used in a weight of evidence (WoE) for the potential of AVO to cause local respiratory toxicity and the <em>in vitro</em> model, MucilAir™ was used to evaluate respiratory irritation.</div><div>AVO exposure by inhalation of sprayed cosmetic products does not add significant exposure compared to dermal exposure. The Margin of Safety (NOAEL compared to total systemic AVO exposure) is &gt; 400, indicating no concern for systemic toxicity. Regarding local toxicity, total aggregate exposure to AVO in sprayable cosmetic products is significantly lower than the TTC_inh. There were no injurious effects to MucilAir™ tissues by 0.2 % and 1 % AVO. When the NOAEL from the MucilAir™ assay (1 %) and the aggregated exposure were compared, the Margin of Exposure was 137.</div><div>In conclusion, based on a WoE approach, the concentrations of AVO used in cosmetic products are not expected to carry a risk of local irritation effects on the respiratory tract or add significantly to aggregate systemic exposure.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"162 ","pages":"Article 105905"},"PeriodicalIF":3.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}