Regulatory Toxicology and Pharmacology最新文献_第10页

The dangerous precedent of silencing government science 压制政府科学的危险先例。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-08 DOI: 10.1016/j.yrtph.2025.105927

Martin van den Berg Prof. Dr. ((Co)Editor-in-Chief)

引用次数: 0

Corrigendum to “Acute and 28-days repeated dose sub-acute toxicity study of gallic acid in albino mice” [Regulat. Toxicol. Pharmacol. RTP 101 (2019) 71–78] 《没食子酸对白化小鼠急性和28天重复给药亚急性毒性研究》的勘误表。Toxicol。杂志。RTP 101(2019) 71-78]。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-05 DOI: 10.1016/j.yrtph.2025.105917

Bhavesh C. Variya , Anita K. Bakrania , Prem Madan , Snehal S. Patel

引用次数: 0

Preliminary safety risk assessment of parabens in children's cosmetics sold in China 对羟基苯甲酸酯在中国销售的儿童化妆品中的初步安全风险评估

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-30 DOI: 10.1016/j.yrtph.2025.105935

Ren Wang, Cen Chen, Qiaoyuan Cheng, Yuanyang Wu, Linqi Yan, Zhen Xie, Zehua Li, Shanshan Liu, Yongjun Lou

Since adverse health outcomes of parabens added in children's cosmetics have been reported, it is important to investigate preliminary risk characteristic assessment of parabens preservatives in children's cosmetics. This study aimed to calculate exposure parameters using a combination experimental data and an exposure assessment tool to make safety assessment for parabens in children's cosmetics. The paraben concentration of different formulation types of 63 products of children's cosmetic products were measured by High Performance Liquid Chromatography. Based on product usage, paraben concentrations, exposure factors, behavioral patterns and exposure routes, the exposure parameters of parabens in children's cosmetics were calculated by mathematical mode from ConsExpo Web. A margin of safety (MoS) was calculated for safety evaluations. Results showed that 4-hydroxybenzoate methyl (MP) was the most commonly used paraben, which was used in 30.2 % of products, followed by propyl 4-hydroxybenzoate (PP) (12.7 %), ethyl 4-hydroxybenzoate (EP) and butyl 4-hydroxybenzoate (BP) both in 1.6 % of products. The concentrations of parabens in the cosmetic products were all within the safety limits required by the SCCS. The exposure to parabens decreased with increasing age in accordance with a published data. The MoS of parabens in children's cosmetics were all more than 100, indicating parabens to be of manageable risk and safe for use.

由于儿童化妆品中添加的对羟基苯甲酸酯对健康的不良影响已经有报道，因此对儿童化妆品中添加的对羟基苯甲酸酯防腐剂进行初步的风险特征评估是很重要的。本研究旨在结合实验数据和暴露评估工具计算暴露参数，对羟基苯甲酸酯在儿童化妆品中的安全性进行评估。采用高效液相色谱法测定了63种儿童化妆品中不同剂型对羟基苯甲酸酯的浓度。根据产品使用情况、对羟基苯甲酸酯浓度、暴露因素、行为模式和暴露途径，利用ConsExpo网站上的数学模型计算儿童化妆品中对羟基苯甲酸酯的暴露参数。计算安全边际（MoS）进行安全评价。结果表明，4-羟基苯甲酸甲酯（MP）是最常用的对羟基苯甲酸酯，占30.2%，其次是4-羟基苯甲酸丙酯（PP）（12.7%）， 4-羟基苯甲酸乙酯（EP）和4-羟基苯甲酸丁酯（BP），均占1.6%。化妆品中对羟基苯甲酸酯的浓度均在SCCS要求的安全范围内。根据公布的数据，对羟基苯甲酸酯的暴露随着年龄的增长而减少。对羟基苯甲酸酯在儿童化妆品中的最大含量都在100以上，表明对羟基苯甲酸酯具有可控的风险，可以安全使用。

{"title":"Preliminary safety risk assessment of parabens in children's cosmetics sold in China","authors":"Ren Wang, Cen Chen, Qiaoyuan Cheng, Yuanyang Wu, Linqi Yan, Zhen Xie, Zehua Li, Shanshan Liu, Yongjun Lou","doi":"10.1016/j.yrtph.2025.105935","DOIUrl":"10.1016/j.yrtph.2025.105935","url":null,"abstract":"<div><div>Since adverse health outcomes of parabens added in children's cosmetics have been reported, it is important to investigate preliminary risk characteristic assessment of parabens preservatives in children's cosmetics. This study aimed to calculate exposure parameters using a combination experimental data and an exposure assessment tool to make safety assessment for parabens in children's cosmetics. The paraben concentration of different formulation types of 63 products of children's cosmetic products were measured by High Performance Liquid Chromatography. Based on product usage, paraben concentrations, exposure factors, behavioral patterns and exposure routes, the exposure parameters of parabens in children's cosmetics were calculated by mathematical mode from ConsExpo Web. A margin of safety (MoS) was calculated for safety evaluations. Results showed that 4-hydroxybenzoate methyl (MP) was the most commonly used paraben, which was used in 30.2 % of products, followed by propyl 4-hydroxybenzoate (PP) (12.7 %), ethyl 4-hydroxybenzoate (EP) and butyl 4-hydroxybenzoate (BP) both in 1.6 % of products. The concentrations of parabens in the cosmetic products were all within the safety limits required by the SCCS. The exposure to parabens decreased with increasing age in accordance with a published data. The MoS of parabens in children's cosmetics were all more than 100, indicating parabens to be of manageable risk and safe for use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105935"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144921531","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}

引用次数: 0

The association between cadmium exposure and the risk of early liver disease: A systematic review and meta-analysis 镉暴露与早期肝病风险之间的关系：一项系统综述和荟萃分析。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-09-15 DOI: 10.1016/j.yrtph.2025.105942

Hualing Zhang , Yue Jing , Lan Guan , Jianlan Luo , Ming Zeng

Currently, liver diseases are considered to be one of the most prevalent diseases that jeopardize people's health. Existing studies have found that heavy metal cadmium (Cadmium, Cd) exposure is associated with liver disease, but the results of studies on the risk of cadmium on liver disease are inconsistent. In order to further investigate the relationship between cadmium exposure and the risk of early liver disease in the population, this study was conducted by searching PubMed, Cochrane Library, Web of Science, CNKI and Wanfang databases and performing meta-analysis of the relevant literature, so as to systematically evaluate the effect of cadmium exposure on the risk of liver disease. A total of 5201 relevant articles were retrieved. Based on inclusion and exclusion criteria, 25 articles were included in the meta-analysis. Review Manager 5.4 was used for quality assessment, with most studies rated as low risk of bias. Heterogeneity testing showed significant results (P < 0.05). Meta-analysis showed that cadmium exposure increased the risk of elevated liver enzymes (OR = 1.38, 95 % CI: 1.27–1.50), MAFLD (OR = 1.14, 95 % CI: 1.07–1.22) and liver fibrosis (OR = 1.39, 95 % CI: 1.14–1.70). Sensitivity analysis and publication bias detection indicated that the results were reliable. Therefore, the conclusion of this study is that environmental cadmium exposure increases the risk of liver disease, and the extent and dose of cadmium exposure in the population should be further controlled.

目前，肝脏疾病被认为是危害人类健康的最普遍的疾病之一。已有研究发现重金属镉（cadmium, Cd）暴露与肝脏疾病有关，但有关镉对肝脏疾病风险的研究结果并不一致。为了进一步探讨镉暴露与人群早期肝病风险的关系，本研究通过检索PubMed、Cochrane Library、Web of Science、CNKI和万方等数据库，并对相关文献进行meta分析，系统评价镉暴露对人群早期肝病风险的影响。共检索到5201篇相关文章。根据纳入和排除标准，25篇文章被纳入meta分析。使用Review Manager 5.4进行质量评估，大多数研究被评为低偏倚风险。异质性检验结果有显著性差异（P < 0.05）。荟萃分析显示，镉暴露增加了肝酶升高（OR=1.38, 95% CI: 1.27-1.50）、MAFLD （OR=1.14, 95% CI: 1.07-1.22）和肝纤维化（OR=1.39, 95% CI: 1.14-1.70）的风险。敏感性分析和发表偏倚检测表明结果是可靠的。因此，本研究的结论是环境镉暴露会增加肝脏疾病的风险，人群中镉暴露的程度和剂量应进一步控制。

{"title":"The association between cadmium exposure and the risk of early liver disease: A systematic review and meta-analysis","authors":"Hualing Zhang , Yue Jing , Lan Guan , Jianlan Luo , Ming Zeng","doi":"10.1016/j.yrtph.2025.105942","DOIUrl":"10.1016/j.yrtph.2025.105942","url":null,"abstract":"<div><div>Currently, liver diseases are considered to be one of the most prevalent diseases that jeopardize people's health. Existing studies have found that heavy metal cadmium (Cadmium, Cd) exposure is associated with liver disease, but the results of studies on the risk of cadmium on liver disease are inconsistent. In order to further investigate the relationship between cadmium exposure and the risk of early liver disease in the population, this study was conducted by searching PubMed, Cochrane Library, Web of Science, CNKI and Wanfang databases and performing meta-analysis of the relevant literature, so as to systematically evaluate the effect of cadmium exposure on the risk of liver disease. A total of 5201 relevant articles were retrieved. Based on inclusion and exclusion criteria, 25 articles were included in the meta-analysis. Review Manager 5.4 was used for quality assessment, with most studies rated as low risk of bias. Heterogeneity testing showed significant results (<em>P</em> < 0.05). Meta-analysis showed that cadmium exposure increased the risk of elevated liver enzymes (OR = 1.38, 95 % CI: 1.27–1.50), MAFLD (OR = 1.14, 95 % CI: 1.07–1.22) and liver fibrosis (OR = 1.39, 95 % CI: 1.14–1.70). Sensitivity analysis and publication bias detection indicated that the results were reliable. Therefore, the conclusion of this study is that environmental cadmium exposure increases the risk of liver disease, and the extent and dose of cadmium exposure in the population should be further controlled.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105942"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081476","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}

引用次数: 0

Permeation studies of chlorpyrifos through skin and synthetic membranes to improve the in vitro dermal absorption assay of lipophilic compounds with ethanolic receptors 毒死蜱通过皮肤和合成膜的渗透研究，以改善具有乙醇受体的亲脂化合物的体外皮肤吸收测定

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-23 DOI: 10.1016/j.yrtph.2025.105931

Dorinda Marques-da-Silva , Margarida Franco , Cristiana Violante , Ricardo Lagoa

The in vitro percutaneous absorption assay is standardized, but the common use of 50 % ethanol in the receptor compartment for lipophilic compounds is questioned. In parallel, the demand for animal-free methodologies is driving the application of synthetic membranes without standardization guidelines. To address these issues, this study investigated the permeation of the lipophilic compound chlorpyrifos using different ethanol-containing receptor fluids with human and pig skin ex vivo, and silicone and STRAT-M® membranes. The results considered several factors, particularly chlorpyrifos solubility and the contact angles between skin models and receptor fluids. Original experimental approaches demonstrated that ethanol from the receptor rapidly crosses to the donor compartment increasing chlorpyrifos diffusivity. Compared to the described in vivo dermal absorption, human skin and STRAT-M® yielded the best predictive permeation parameters. However, high percentage of ethanol in the receptor fluid can lead to an overestimation of percutaneous absorption. Summing up, it is important to carefully determine the concentration of ethanol to be used in the receptor fluid of lipophilic compounds’ assays while further research with synthetic membranes is needed prior to their wider adoption.

体外经皮吸收测定是标准化的，但在亲脂化合物的受体室中普遍使用50%乙醇是有疑问的。与此同时，对无动物方法的需求正在推动没有标准化指导方针的合成膜的应用。为了解决这些问题，本研究使用不同的含乙醇受体液体研究了亲脂化合物毒死蜱在人、猪离体皮肤、硅胶和STRAT-M®膜上的渗透。结果考虑了几个因素，特别是毒死蜱的溶解度和皮肤模型与受体液体之间的接触角。最初的实验方法表明，乙醇从受体迅速穿越到供体室增加毒死蜱的扩散。与所描述的体内皮肤吸收相比，人体皮肤和STRAT-M®产生了最好的预测渗透参数。然而，受体液中乙醇的高百分比可导致对经皮吸收的高估。综上所述，在亲脂化合物的受体液中仔细确定乙醇的浓度是很重要的，而在合成膜的广泛应用之前，需要对其进行进一步的研究。

{"title":"Permeation studies of chlorpyrifos through skin and synthetic membranes to improve the in vitro dermal absorption assay of lipophilic compounds with ethanolic receptors","authors":"Dorinda Marques-da-Silva , Margarida Franco , Cristiana Violante , Ricardo Lagoa","doi":"10.1016/j.yrtph.2025.105931","DOIUrl":"10.1016/j.yrtph.2025.105931","url":null,"abstract":"<div><div>The <em>in vitro</em> percutaneous absorption assay is standardized, but the common use of 50 % ethanol in the receptor compartment for lipophilic compounds is questioned. In parallel, the demand for animal-free methodologies is driving the application of synthetic membranes without standardization guidelines. To address these issues, this study investigated the permeation of the lipophilic compound chlorpyrifos using different ethanol-containing receptor fluids with human and pig skin <em>ex vivo</em>, and silicone and STRAT-M® membranes. The results considered several factors, particularly chlorpyrifos solubility and the contact angles between skin models and receptor fluids. Original experimental approaches demonstrated that ethanol from the receptor rapidly crosses to the donor compartment increasing chlorpyrifos diffusivity. Compared to the described <em>in vivo</em> dermal absorption, human skin and STRAT-M® yielded the best predictive permeation parameters. However, high percentage of ethanol in the receptor fluid can lead to an overestimation of percutaneous absorption. Summing up, it is important to carefully determine the concentration of ethanol to be used in the receptor fluid of lipophilic compounds’ assays while further research with synthetic membranes is needed prior to their wider adoption.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105931"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919993","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}

引用次数: 0

Challenges and opportunities of read-across for the tumor promotion effects of microcystins 微囊藻毒素促肿瘤作用的解读挑战与机遇。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-09-11 DOI: 10.1016/j.yrtph.2025.105938

Cynthia B. Pestana , Daniela Morais Leme , Enzo Zini Moreira Silva , Sahra Kiessig , James W. Firman , Carsten Kneuer , Philip Marx-Stoelting , Mark T.D. Cronin

The microcystins (MCs) are a family of cyclic oligopeptides toxins expressed in at least 30 cyanobacterial species and are liable to pose significant hazard to human health due to hepatotoxicity. Microcystin-leucine arginine (MC-LR) is the most extensively studied and toxic congener and classified as possibly carcinogenic to humans based on tumor promotion activity in the liver. Given the substantial toxicity data gaps for the MCs, read-across was assessed to evaluate the tumor promotion effects of a series of data-poor MC congeners based on in vivo information for MC-LR as the source molecule. Lines of evidence from in silico estimates of structural similarity, physico-chemical properties, hepatotoxicity, genotoxic and carcinogenicity were compiled to support the filling of data gaps. Uncertainties were evaluated according to scenario 4 of the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF). The read-across process followed a previously proposed harmonized framework to apply the common principles together with information from new approach methodologies (NAMs). Lines of evidence were consistent across the MC congeners and the uncertainties were found to be acceptable for data gap filling. Read-across strategies, with known caveats and restrictions, were shown to be applicable for large, complex molecules such as the MCs.

微囊藻毒素（MCs）是一种环状寡肽毒素家族，在至少30种蓝藻物种中表达，由于肝毒性可能对人类健康造成重大危害。微胱氨酸-亮氨酸精氨酸（MC-LR）是研究最广泛的毒性同源物，根据其在肝脏中的肿瘤促进活性，被归类为可能对人类致癌。鉴于MCs的毒性数据存在大量空白，我们基于MC- lr作为源分子的体内信息，评估了一系列缺乏数据的MC同系物的肿瘤促进作用。从结构相似性、物理化学性质、肝毒性、遗传毒性和致癌性的计算机估计中收集证据，以支持填补数据空白。根据欧洲化学品管理局（ECHA）解读评估框架（RAAF）的情景4评估不确定性。跨读过程遵循先前提出的统一框架，将共同原则与新方法方法学（NAM）信息一起应用。证据线显示了MC同系物之间的一致性，并且发现不确定性可以接受数据空白填充。具有已知警告和限制的读取策略被证明适用于像mc这样的大型复杂分子。

{"title":"Challenges and opportunities of read-across for the tumor promotion effects of microcystins","authors":"Cynthia B. Pestana , Daniela Morais Leme , Enzo Zini Moreira Silva , Sahra Kiessig , James W. Firman , Carsten Kneuer , Philip Marx-Stoelting , Mark T.D. Cronin","doi":"10.1016/j.yrtph.2025.105938","DOIUrl":"10.1016/j.yrtph.2025.105938","url":null,"abstract":"<div><div>The microcystins (MCs) are a family of cyclic oligopeptides toxins expressed in at least 30 cyanobacterial species and are liable to pose significant hazard to human health due to hepatotoxicity. Microcystin-leucine arginine (MC-LR) is the most extensively studied and toxic congener and classified as possibly carcinogenic to humans based on tumor promotion activity in the liver. Given the substantial toxicity data gaps for the MCs, read-across was assessed to evaluate the tumor promotion effects of a series of data-poor MC congeners based on <em>in vivo</em> information for MC-LR as the source molecule. Lines of evidence from <em>in silico</em> estimates of structural similarity, physico-chemical properties, hepatotoxicity, genotoxic and carcinogenicity were compiled to support the filling of data gaps. Uncertainties were evaluated according to scenario 4 of the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF). The read-across process followed a previously proposed harmonized framework to apply the common principles together with information from new approach methodologies (NAMs). Lines of evidence were consistent across the MC congeners and the uncertainties were found to be acceptable for data gap filling. Read-across strategies, with known caveats and restrictions, were shown to be applicable for large, complex molecules such as the MCs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105938"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058456","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}

引用次数: 0

Preclinical safety, tolerability and pharmacokinetics of a novel cyclobenzaprine hydrochloride nasal spray 新型盐酸环苯扎林鼻喷雾剂的临床前安全性、耐受性和药代动力学

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-25 DOI: 10.1016/j.yrtph.2025.105930

Chitrang R. Shah , Sudhir R. Patel , Laxit K. Bhatt , Viral I. Rajwadi , Urvit P. Patel , Hitesh Kadu , Jitendra H. Patel , Harilal Patel , Ramchandra K. Ranvir , Rajesh Sundar , Ritu N. Laddha , Mukul R. Jain

These studies examined the effects of repeated intranasal administration of Cyclobenzaprine hydrochloride in rats and dogs. In rats, doses up to 1.05 mg/animal/day over 28 days showed no mortality or toxicity. Body weight, feed intake, ophthalmological and neurobehavioral assessments, and clinical pathology evaluations remained unaffected. Microscopic examinations revealed minimal non-adverse hyperplasia at the administration site in the nasal cavity. No histopathological changes were observed in other organs or tissues, establishing the NOAEL at 1.05 mg/animal/day. In dogs, doses up to 10.5 mg/animal/day over 14 days were well-tolerated, with only mild local irritation observed as nasal itching, which resolved quickly post-dosing. Body weights, food consumption, and comprehensive neurobehavioral assessments, including ECG examinations and reflex tests, showed no adverse effects. Hematological, clinical chemistry, and urinalysis variations were minimal and non-dose-dependent. Microscopic evaluations of the nasal cavity and other anatomical structures showed mild non-adverse changes, with no significant histopathological findings in the olfactory epithelium, olfactory bulb, or brain. These findings indicate that Cyclobenzaprine Hydrochloride Nasal Spray is well-tolerated with a NOAEL of 1.05 mg/animal/day in rats and ≥10.5 mg/animal/day in dogs, suggesting potential for safe intranasal administration in clinical use.

这些研究检查了大鼠和狗反复鼻内给予盐酸环苯扎林的影响。在大鼠中，剂量高达1.05毫克/只动物/天，持续28天，没有死亡或毒性。体重、采食量、眼科和神经行为评估以及临床病理评估均未受影响。显微镜检查显示鼻腔给药部位有少量非不良增生。其他器官和组织未见组织病理学改变，NOAEL为1.05 mg/只/d。在狗中，在14天内，高达10.5 mg/只/天的剂量耐受性良好，仅观察到轻微的局部刺激，如鼻痒，给药后迅速消退。体重、食物消耗和综合神经行为评估，包括心电图检查和反射测试，均未显示不良反应。血液学、临床化学和尿液分析的变化很小且不依赖剂量。鼻腔和其他解剖结构的显微镜检查显示轻微的非不良变化，嗅觉上皮、嗅球或大脑没有明显的组织病理学发现。这些结果表明，盐酸环苯扎林鼻喷雾剂耐受性良好，大鼠的NOAEL为1.05 mg/动物/天，狗的NOAEL为≥10.5 mg/动物/天，提示临床应用时鼻内给药是安全的。

{"title":"Preclinical safety, tolerability and pharmacokinetics of a novel cyclobenzaprine hydrochloride nasal spray","authors":"Chitrang R. Shah , Sudhir R. Patel , Laxit K. Bhatt , Viral I. Rajwadi , Urvit P. Patel , Hitesh Kadu , Jitendra H. Patel , Harilal Patel , Ramchandra K. Ranvir , Rajesh Sundar , Ritu N. Laddha , Mukul R. Jain","doi":"10.1016/j.yrtph.2025.105930","DOIUrl":"10.1016/j.yrtph.2025.105930","url":null,"abstract":"<div><div>These studies examined the effects of repeated intranasal administration of Cyclobenzaprine hydrochloride in rats and dogs. In rats, doses up to 1.05 mg/animal/day over 28 days showed no mortality or toxicity. Body weight, feed intake, ophthalmological and neurobehavioral assessments, and clinical pathology evaluations remained unaffected. Microscopic examinations revealed minimal non-adverse hyperplasia at the administration site in the nasal cavity. No histopathological changes were observed in other organs or tissues, establishing the NOAEL at 1.05 mg/animal/day. In dogs, doses up to 10.5 mg/animal/day over 14 days were well-tolerated, with only mild local irritation observed as nasal itching, which resolved quickly post-dosing. Body weights, food consumption, and comprehensive neurobehavioral assessments, including ECG examinations and reflex tests, showed no adverse effects. Hematological, clinical chemistry, and urinalysis variations were minimal and non-dose-dependent. Microscopic evaluations of the nasal cavity and other anatomical structures showed mild non-adverse changes, with no significant histopathological findings in the olfactory epithelium, olfactory bulb, or brain. These findings indicate that Cyclobenzaprine Hydrochloride Nasal Spray is well-tolerated with a NOAEL of 1.05 mg/animal/day in rats and ≥10.5 mg/animal/day in dogs, suggesting potential for safe intranasal administration in clinical use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105930"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916770","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}

引用次数: 0

A new method of consistency evaluation of brain drugs: a case study of edaravone 脑药物一致性评价新方法——以依达拉奉为例。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-08-30 DOI: 10.1016/j.yrtph.2025.105933

Liqiang Gu , Yanping Hu , Yinfang Lai , Sheng Zhang , Haoran Wang , Xiaozhen Xu , Lingfang Chen , Yuhua Shi , Jiechao Chen , Xiaochun Sun , Yuan Zhang , Lingzhi Hu

Bioequivalence test is typically conducted by determining the drug concentration in plasma. However, this is not suitable for brain drugs (like Edaravone) that have targets in CNS. The amount of a drug in target site in the CNS is responsible for its activity in the brain, while the concentration of a drug in the blood has a weak impact on the CNS. In this paper, a new consistency evaluation method for brain drugs was established. 16 rats were divided into two groups. One group was administered the test preparation, and the other group was administered the control preparation. Then, cerebrospinal fluid (CSF) samples were collected. All of the CSF samples were examined by LC-MS. The 90 % confidence interval of the geometric mean ratio of AUC_0-t was 90.30–150.59 %, and 91.79–211.06 % for C_max. In addition, the result indicated that the two preparations were not bioequivalent in the CNS, although the concentration-time profile and pharmacokinetic parameters were quite similar. The results revealed the particularity and complexity of the bioequivalence test for brain drugs that have targets in the CNS. The feasibility of the test was confirmed, and our results provide useful information for the consistency evaluation of brain drugs.

生物等效性试验通常是通过测定血浆中药物浓度来进行的。然而，这不适用于以中枢神经系统为靶点的脑药物（如依达拉奉）。药物在中枢神经系统中靶部位的含量决定其在大脑中的活性，而药物在血液中的浓度对中枢神经系统的影响较弱。本文建立了一种新的脑药物一致性评价方法。将16只大鼠分为两组。一组给予试验制剂，另一组给予对照制剂。然后采集脑脊液（CSF）样本。所有脑脊液样本均采用LC-MS检测。AUC0-t几何平均比值的90%置信区间为90.30 ~ 150.59%，Cmax的90%置信区间为91.79 ~ 211.06%。此外，结果表明，虽然两种制剂的浓度-时间谱和药代动力学参数非常相似，但在中枢神经系统中不具有生物等效性。结果揭示了以中枢神经系统为靶点的脑药物生物等效性试验的特殊性和复杂性。验证了实验的可行性，为脑药物的一致性评价提供了有用的信息。

{"title":"A new method of consistency evaluation of brain drugs: a case study of edaravone","authors":"Liqiang Gu , Yanping Hu , Yinfang Lai , Sheng Zhang , Haoran Wang , Xiaozhen Xu , Lingfang Chen , Yuhua Shi , Jiechao Chen , Xiaochun Sun , Yuan Zhang , Lingzhi Hu","doi":"10.1016/j.yrtph.2025.105933","DOIUrl":"10.1016/j.yrtph.2025.105933","url":null,"abstract":"<div><div>Bioequivalence test is typically conducted by determining the drug concentration in plasma. However, this is not suitable for brain drugs (like Edaravone) that have targets in CNS. The amount of a drug in target site in the CNS is responsible for its activity in the brain, while the concentration of a drug in the blood has a weak impact on the CNS. In this paper, a new consistency evaluation method for brain drugs was established. 16 rats were divided into two groups. One group was administered the test preparation, and the other group was administered the control preparation. Then, cerebrospinal fluid (CSF) samples were collected. All of the CSF samples were examined by LC-MS. The 90 % confidence interval of the geometric mean ratio of AUC<sub>0-t</sub> was 90.30–150.59 %, and 91.79–211.06 % for C<sub>max</sub>. In addition, the result indicated that the two preparations were not bioequivalent in the CNS, although the concentration-time profile and pharmacokinetic parameters were quite similar. The results revealed the particularity and complexity of the bioequivalence test for brain drugs that have targets in the CNS. The feasibility of the test was confirmed, and our results provide useful information for the consistency evaluation of brain drugs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105933"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966519","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}

引用次数: 0

An extended Reference Chemical Potency List (RCPL) for characterising the performance of New Approach Methodologies (NAMs) in measuring the skin sensitisation potency of fragrance chemicals 一种扩展的参考化学效价表（RCPL），用于表征新方法方法（NAMs）在测量芳香化学品的皮肤致敏效价方面的性能。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-09-13 DOI: 10.1016/j.yrtph.2025.105944

Amaia Irizar , Hans Bender , James W. Bridges , Peter Griem , Andreas Natsch , Matthias Vey , Ian Kimber

The development of a Reference Chemical Potency List (RCPL), and its purpose, has been described previously. That original RCPL comprised 33 chemicals, of varying skin sensitising activity, for each of which a discrete Potency Value (PV) was derived, based upon the best available human and/or animal (local lymph node assay) data. The purpose of the RCPL was to provide a reliable tool that would facilitate evaluation of the ability of New Approach Methodologies (NAMs) to measure skin sensitising potency. We here report the construction of an extended RCPL with 77 additional chemicals by applying the weight of evidence framework used previously. This extended RCPL adheres to the salient features of the original database. These comprise a focus largely on fragrance chemicals, provision of a wide range of chemical structures and of skin sensitising potency, the inclusion of both direct and indirect (pre- and pro-) haptens, the exclusion of NAMs data for the derivation of PVs, and avoidance of the use of potency categories for the classification of chemicals. It is anticipated that this extended RCPL will provide a more powerful database with which to assess the strengths and weakness of recently developed NAMs in the measurement of skin sensitising potency.

参考化学效价表（RCPL）的制定及其目的已在前面描述过。最初的RCPL包含33种化学物质，具有不同的皮肤致敏活性，每种化学物质的独立效价（PV）是基于最佳可用的人类和/或动物（局部淋巴结测定）数据得出的。RCPL的目的是提供一个可靠的工具，以促进评估新方法方法（NAMs）测量皮肤致敏效力的能力。我们在这里报告了一个扩展的RCPL的建设与77个额外的化学品应用权重的证据框架以前使用。这个扩展的RCPL遵循原始数据库的显著特性。这些包括主要关注芳香化学品，提供广泛的化学结构和皮肤致敏效力，包括直接和间接（前半抗原和前半抗原）半抗原，排除衍生pv的NAMs数据，以及避免使用效力类别对化学品进行分类。预计这种扩展的RCPL将提供一个更强大的数据库，用于评估最近开发的NAMs在测量皮肤致敏效力方面的优势和劣势。

{"title":"An extended Reference Chemical Potency List (RCPL) for characterising the performance of New Approach Methodologies (NAMs) in measuring the skin sensitisation potency of fragrance chemicals","authors":"Amaia Irizar , Hans Bender , James W. Bridges , Peter Griem , Andreas Natsch , Matthias Vey , Ian Kimber","doi":"10.1016/j.yrtph.2025.105944","DOIUrl":"10.1016/j.yrtph.2025.105944","url":null,"abstract":"<div><div>The development of a Reference Chemical Potency List (RCPL), and its purpose, has been described previously. That original RCPL comprised 33 chemicals, of varying skin sensitising activity, for each of which a discrete Potency Value (PV) was derived, based upon the best available human and/or animal (local lymph node assay) data. The purpose of the RCPL was to provide a reliable tool that would facilitate evaluation of the ability of New Approach Methodologies (NAMs) to measure skin sensitising potency. We here report the construction of an extended RCPL with 77 additional chemicals by applying the weight of evidence framework used previously. This extended RCPL adheres to the salient features of the original database. These comprise a focus largely on fragrance chemicals, provision of a wide range of chemical structures and of skin sensitising potency, the inclusion of both direct and indirect (pre- and pro-) haptens, the exclusion of NAMs data for the derivation of PVs, and avoidance of the use of potency categories for the classification of chemicals. It is anticipated that this extended RCPL will provide a more powerful database with which to assess the strengths and weakness of recently developed NAMs in the measurement of skin sensitising potency.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"163 ","pages":"Article 105944"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070352","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}

引用次数: 0

A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans. 基于生理的药代动力学（PBPK）模型来校准大鼠和人异丁基代谢系列的剂量测定。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-01 Epub Date: 2025-07-26 DOI: 10.1016/j.yrtph.2025.105914

Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber

We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.

我们针对异丁基代谢系列（包括醋酸异丁酯、异丁醇、异丁醛和异丁酸）在大鼠和人体内建立了基于生理学的药代动力学（PBPK）模型。考虑到化学相似性，我们使用先前开发的丙基代谢系列PBPK模型作为框架来创建异丁基PBPK模型。为了支持模型的建立，我们测量了大鼠和人血液和肝脏S9组分中乙酸异丁酯的体外代谢。我们的研究结果表明，与大鼠相比，人类肝脏S9组分中乙酸异丁酯的水解速度更快，而血液中的水解速率在两种物种之间相似。在封闭的室内实验中，将大鼠暴露于醋酸异丁酯或异丁醇中，结果显示，与其他异丁基化合物相比，血液中异丁醇的浓度更高。利用这些数据参数化模型，PBPK模型准确地模拟了大鼠和人血液中异丁基化合物的可用时间过程浓度。异丁基PBPK模型能够比较各种异丁基化合物暴露和种类之间的内部剂量度量，并允许计算产生相同剂量度量的等效外部暴露。监管机构可以使用该PBPK模型来预测和调整异丁基化合物的内部剂量指标，以进行风险评估。

{"title":"A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans.","authors":"Jordan N Smith, Kimberly J Tyrrell, Karl K Weitz, Willem Faber","doi":"10.1016/j.yrtph.2025.105914","DOIUrl":"10.1016/j.yrtph.2025.105914","url":null,"abstract":"<p><p>We developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series, which includes isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Given chemical similarities, we used a previously developed PBPK model for the propyl metabolic series as a framework to create the isobutyl PBPK model. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Our findings indicated that humans exhibited faster isobutyl acetate hydrolysis in liver S9 fractions compared to rats, while hydrolysis rates in blood were similar between the two species. Experiments involving closed chamber exposures of rats to isobutyl acetate or isobutanol revealed higher isobutanol concentrations in blood compared to other isobutyl compounds. Using these data to parameterize the model, the PBPK model accurately simulated available time-course concentrations of isobutyl compounds in blood of rats and humans. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105914"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732945","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}

引用次数: 0