Regulatory Toxicology and Pharmacology最新文献_第8页

Historical control data of rare events: Issues, chronological patterns and their relevance for toxicological evaluations 罕见事件的历史控制数据：问题、年代模式及其与毒理学评估的相关性。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-07-02 DOI: 10.1016/j.yrtph.2024.105673

Felix M. Kluxen

引用次数: 0

The need for guidance in antidepressant drug development: Revisiting the role of the forced swim test and tail suspension test 抗抑郁药物开发需要指导：重新审视强迫游泳试验和尾悬试验的作用。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-27 DOI: 10.1016/j.yrtph.2024.105666

Emily R. Trunnell , Julia Baines , Stephen Farghali , Tara Jackson , Kimberley Jayne , Rachel Smith , Tina Stibbe

{"title":"The need for guidance in antidepressant drug development: Revisiting the role of the forced swim test and tail suspension test","authors":"Emily R. Trunnell , Julia Baines , Stephen Farghali , Tara Jackson , Kimberley Jayne , Rachel Smith , Tina Stibbe","doi":"10.1016/j.yrtph.2024.105666","DOIUrl":"10.1016/j.yrtph.2024.105666","url":null,"abstract":"<div><p>Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable nonclinical efficacy tests. Two common tests used in nonclinical efficacy studies of antidepressants—the forced swim test (FST) and tail suspension test (TST)—have come under criticism in recent years for their inconsistency and lack of validity, yet they continue to be used in the pharmaceutical industry. In this review, we provide a rationale for why international pharmaceutical regulatory and guidance agencies should begin issuing direction on methods for non-clinical efficacy testing that traditionally use the FST and TST, particularly considering that some regulators, such as those in the U.S. and E.U., allow the authorization of clinical trials to proceed without requiring tests in animals. The area of antidepressant drug discovery represents an important opportunity for reducing the attrition of psychiatric drugs, harmonizing regulatory requirements, and reducing animal use. Specific recommendations for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have been provided.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105666"},"PeriodicalIF":3.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024001077/pdfft?md5=5a7a856b8fbe8513572985f4ed938e69&pid=1-s2.0-S0273230024001077-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retrospective application of ICH M7 to anti-hypertensive drugs in Brazil: Risk assessment of potentially mutagenic impurities ICH M7 在巴西抗高血压药物中的回顾性应用：潜在致突变杂质的风险评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-25 DOI: 10.1016/j.yrtph.2024.105669

Fernanda Waechter , Antonio Anax Falcao Oliveira , Ana Lucia Borges Shimada , Edson Bernes Junior , Elizabeth de Souza Nascimento

{"title":"Retrospective application of ICH M7 to anti-hypertensive drugs in Brazil: Risk assessment of potentially mutagenic impurities","authors":"Fernanda Waechter , Antonio Anax Falcao Oliveira , Ana Lucia Borges Shimada , Edson Bernes Junior , Elizabeth de Souza Nascimento","doi":"10.1016/j.yrtph.2024.105669","DOIUrl":"10.1016/j.yrtph.2024.105669","url":null,"abstract":"<div><p>Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105669"},"PeriodicalIF":3.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470455","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

Urinary MicroRNA biomarkers of nephrotoxicity in Macaca fascicularis 猕猴肾毒性的尿微RNA生物标志物

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-25 DOI: 10.1016/j.yrtph.2024.105668

Subham Dasgupta , Tatiana Sharapova , Prathap K. Mahalingaiah , Brian N. Chorley , Ahmed Shoieb , Takayuki Tsuji , Alef A.C. dos Santos , Rohit Chari , Ali Ebrahimi , Deidre A. Dalmas Wilk , Syril Pettit , Bhupinder Bawa , Erin Vaughan , Terry R. van Vleet , Constance A. Mitchell , Peter S.T. Yuen

{"title":"Urinary MicroRNA biomarkers of nephrotoxicity in Macaca fascicularis","authors":"Subham Dasgupta , Tatiana Sharapova , Prathap K. Mahalingaiah , Brian N. Chorley , Ahmed Shoieb , Takayuki Tsuji , Alef A.C. dos Santos , Rohit Chari , Ali Ebrahimi , Deidre A. Dalmas Wilk , Syril Pettit , Bhupinder Bawa , Erin Vaughan , Terry R. van Vleet , Constance A. Mitchell , Peter S.T. Yuen","doi":"10.1016/j.yrtph.2024.105668","DOIUrl":"10.1016/j.yrtph.2024.105668","url":null,"abstract":"<div><p>Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105668"},"PeriodicalIF":3.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024001090/pdfft?md5=6baa7d7a0f5da3c6c450cf9c300bbd9b&pid=1-s2.0-S0273230024001090-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A sustainable and innovative method to determine parabens in body creams for exposure and risk assessment 一种可持续的创新方法，用于测定身体乳霜中的对羟基苯甲酸酯，以进行暴露和风险评估。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-25 DOI: 10.1016/j.yrtph.2024.105667

Thalita da Silva Ramos, Karina Borba Gonçalves, Luiz Paulo de Aguiar Marciano, Mariana Azevedo Rosa, Isarita Martins

{"title":"A sustainable and innovative method to determine parabens in body creams for exposure and risk assessment","authors":"Thalita da Silva Ramos, Karina Borba Gonçalves, Luiz Paulo de Aguiar Marciano, Mariana Azevedo Rosa, Isarita Martins","doi":"10.1016/j.yrtph.2024.105667","DOIUrl":"10.1016/j.yrtph.2024.105667","url":null,"abstract":"<div><p>Methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) are among the most widely used preservatives in cosmetics, drugs, and foods. These compounds have been associated with toxic effects due to the overuse of products with parabens in their formulation. The toxicity of parabens may be correlated to endocrine disruption, owing to their ability to mimic the actions of estradiol. In this paper, a simple, sustainable, robust, and innovative dispersive liquid-liquid microextraction (DLLME) technique was developed and employed to extract these xenobiotics from body cream samples, aiming to calculate the margin of safety (MoS) to assess the risk of exposure. The validated method presented suitable linearity (r > 0.99), lower limits of detection (ranging from 0.01 to 0.04 % w/w), and satisfactory precision and accuracy (ranging from 4.33 to 10.47, and from −14.25 to 13.85, respectively). Seven of the ten analysed samples presented paraben contents within the acceptable concentration according to European legislation. The MoS value obtained for PrP (37.58) suggested its reduced safety, indicating that PrP may significantly contribute to systemic exposure resulting from the use of personal care products.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105667"},"PeriodicalIF":3.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458988","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

Lanthanum nitrate demonstrated no genotoxicity in the conducted tests 在已进行的测试中，硝酸镧未显示出遗传毒性。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-25 DOI: 10.1016/j.yrtph.2024.105670

Li Juntao , Li Wenxue , Yang Guangyu , Li Xudong , Zhuang Runxuan , Zhang Bo , Zhu Wei

{"title":"Lanthanum nitrate demonstrated no genotoxicity in the conducted tests","authors":"Li Juntao , Li Wenxue , Yang Guangyu , Li Xudong , Zhuang Runxuan , Zhang Bo , Zhu Wei","doi":"10.1016/j.yrtph.2024.105670","DOIUrl":"10.1016/j.yrtph.2024.105670","url":null,"abstract":"<div><p>Given the widespread applications in industrial and agricultural production, the health effects of rare earth elements (REEs) have garnered public attention, and the genotoxicity of REEs remains unclear. In this study, we evaluated the genetic effects of lanthanum nitrate, a typical representative of REEs, with guideline-compliant in vivo and in vitro methods. Genotoxicity assays, including the Ames test, comet assay, mice bone marrow erythrocyte micronucleus test, spermatogonial chromosomal aberration test, and sperm malformation assay were conducted to assess mutagenicity, chromosomal damage, DNA damage, and sperm malformation. In the Ames test, no statistically significant increase in bacterial reverse mutation frequencies was found as compared with the negative control. Mice exposed to lanthanum nitrate did not exhibit a statistically significant increase in bone marrow erythrocyte micronucleus frequencies, spermatogonial chromosomal aberration frequencies, or sperm malformation frequencies compared to the negative control (P > 0.05). Additionally, after a 24-h treatment with lanthanum nitrate at concentrations of 1.25, 5, and 20 μg/ml, no cytotoxicity was observed in CHL cells. Furthermore, the comet assay results indicate no significant DNA damage was observed even after exposure to high doses of lanthanum nitrate (20 μg/ml). In conclusion, our findings suggest that lanthanum nitrate does not exhibit genotoxicity.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105670"},"PeriodicalIF":3.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470453","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

Two-year carcinogenicity study of a novel plasticizer, bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), by oral diet in Han Wistar rats 对汉代 Wistar 大鼠口服新型增塑剂双（2-乙基己基）环己烷-1,4-二甲酸酯（Eco-DEHCH）进行为期两年的致癌性研究

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-17 DOI: 10.1016/j.yrtph.2024.105664

Da Som Jeong , Ji-Young Lee , Hyo-Jeong Han , Soo Min Ko , Dong Hyun Lee , Yerin Lee , Woo-Chan Son

{"title":"Two-year carcinogenicity study of a novel plasticizer, bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), by oral diet in Han Wistar rats","authors":"Da Som Jeong , Ji-Young Lee , Hyo-Jeong Han , Soo Min Ko , Dong Hyun Lee , Yerin Lee , Woo-Chan Son","doi":"10.1016/j.yrtph.2024.105664","DOIUrl":"https://doi.org/10.1016/j.yrtph.2024.105664","url":null,"abstract":"<div><p>Plasticizers are necessary for the usability of various products, including food contact materials. Exposure to plasticizers is most commonly made through the oral route. Several plasticizers have been reported to have adverse effects on humans and the environment. Thus, the present study aimed to determine the long-term toxicity and carcinogenicity of a novel plasticizer called bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), which is an ecofriendly and biologically less harmful replacer. Groups of 50 male and 50 female Han Wistar rats were fed Eco-DEHCH at daily doses of 1,600, 5,000, or 16,000 ppm in their diet for at least 104 weeks. The rats were regularly monitored for mortality, clinical signs, body weight, food consumption, food efficiency, and perceivable mass. All animals were subjected to complete necropsy and histopathological examination. The results indicate that the rats well tolerated chronic exposure to Eco-DEHCH at highest daily doses of 16,000 ppm, with was equivalent to 805.1 mg/kg/day in males and 1060.6 mg/kg/day in females and did not show signs of toxicity or carcinogenicity. In conclusion, Eco-DEHCH could be a safe and promising alternative plasticizer.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105664"},"PeriodicalIF":3.4,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141424451","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

Review of dose setting for the extended one-generation reproductive toxicity studies (OECD TG 443): Considerations on ECHA's dose level selection recommendations 审查延长一代生殖毒性研究（OECD TG 443）的剂量设定：对欧洲化学品管理局剂量水平选择建议的考虑。

IF 3 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-15 DOI: 10.1016/j.yrtph.2024.105665

Manon Beekhuijzen , Emily Richmond , Jason Manton , Pragati S. Coder , Katy Goyak , Rashin Ghaffari , Susan L. Makris , Steven Van Cruchten , Leah Zorrilla , Shermaine Mitchell-Ryan

{"title":"Review of dose setting for the extended one-generation reproductive toxicity studies (OECD TG 443): Considerations on ECHA's dose level selection recommendations","authors":"Manon Beekhuijzen , Emily Richmond , Jason Manton , Pragati S. Coder , Katy Goyak , Rashin Ghaffari , Susan L. Makris , Steven Van Cruchten , Leah Zorrilla , Shermaine Mitchell-Ryan","doi":"10.1016/j.yrtph.2024.105665","DOIUrl":"10.1016/j.yrtph.2024.105665","url":null,"abstract":"<div><p>During 2020, The European Chemicals Agency (ECHA) began evaluating the OECD Test Guideline 443: Extended One Generation Reproductive Toxicity Study (EOGRTS) to analyze specific aspects related to study design, conduct and toxicological findings. A significant outcome of this ECHA evaluation focused on adequate dose level selection. Subsequently, ECHA published recommendations for DART studies, however, these recommendations seemingly do not align with the principles of the 3Rs, animal welfare or human safety goals, specifically, regarding three aspects. First, the requirement to segregate testing for sexual function and fertility from the ability to produce normally developing offspring increases the risk of inadequate identification of postnatal hazards for development and sexual function and fertility, therefore failing human health protection goals. Second, the current ECHA high-dose level setting recommendations for EOGRTS exceed the MTD (Maximum Tolerated Dose), and therefore compromise the interpretation of the biological response relative to the intrinsic effect of the chemical under evaluation. Third, the combination of these aspects will result in an increase in the number of animals tested, increasing animal welfare concerns.</p><p>This paper reflects the consensus of subject matter experts, professional, and scientific societies who have authored and signed on to this statement. The signatories encourage ECHA to adopt a revised science-driven approach to the dose selection criteria that strikes a balance between regulatory vigilance and scientific pragmatism.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105665"},"PeriodicalIF":3.0,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141401335","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 database makes the poison: How the selection of datasets in QSAR models impacts toxicant prediction of higher tier endpoints 数据库造就毒药：QSAR 模型中数据集的选择如何影响对更高级别终点的毒物预测。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-12 DOI: 10.1016/j.yrtph.2024.105663

Lyle D. Burgoon , Felix M. Kluxen , Anja Hüser , Markus Frericks

{"title":"The database makes the poison: How the selection of datasets in QSAR models impacts toxicant prediction of higher tier endpoints","authors":"Lyle D. Burgoon , Felix M. Kluxen , Anja Hüser , Markus Frericks","doi":"10.1016/j.yrtph.2024.105663","DOIUrl":"10.1016/j.yrtph.2024.105663","url":null,"abstract":"<div><p>As the United States and the European Union continue their steady march towards the acceptance of new approach methodologies (NAMs), we need to ensure that the available tools are fit for purpose. Critics will be well-positioned to caution against NAMs acceptance and adoption if the tools turn out to be inadequate. In this paper, we focus on Quantitative Structure Activity-Relationship (QSAR) models and highlight how the training database affects quality and performance of these models. Our analysis goes to the point of asking, “are the endpoints extracted from the experimental studies in the database trustworthy, or are they false negatives/positives themselves?” We also discuss the impacts of chemistry on QSAR models, including issues with 2-D structure analyses when dealing with isomers, metabolism, and toxicokinetics. We close our analysis with a discussion of challenges associated with translational toxicology, specifically the lack of adverse outcome pathways/adverse outcome pathway networks (AOPs/AOPNs) for many higher tier endpoints. We recognize that it takes a collaborate effort to build better and higher quality QSAR models especially for higher tier toxicological endpoints. Hence, it is critical to bring toxicologists, statisticians, and machine learning specialists together to discuss and solve these challenges to get relevant predictions.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105663"},"PeriodicalIF":3.4,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0273230024001041/pdfft?md5=e00f77e13812a68ab0ced4960d4e80ae&pid=1-s2.0-S0273230024001041-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Grouping of short alkyl-chain branched carboxylic acids for developmental toxicity 对短烷基链支链羧酸的发育毒性进行分组。

IF 3.4 4区医学

Regulatory Toxicology and Pharmacology Pub Date : 2024-06-11 DOI: 10.1016/j.yrtph.2024.105662

Thomas Colnot , Wolfgang Dekant

{"title":"Grouping of short alkyl-chain branched carboxylic acids for developmental toxicity","authors":"Thomas Colnot , Wolfgang Dekant","doi":"10.1016/j.yrtph.2024.105662","DOIUrl":"10.1016/j.yrtph.2024.105662","url":null,"abstract":"<div><p>Read-across (RAx) and grouping of chemicals into categories are well-known concepts in toxicology. Recently, ECHA proposed a grouping approach for branched-chain carboxylic acids (BCAs) including more than 60 branched-chain saturated carboxylic acids for hazard identification. Grouping was based only on structural considerations. Due to developmental effects of two members, ECHA postulated that “all short carbon chain acids … are likely reproductive and developmental toxicants”. This work analyzes available data for BCAs. The number of compounds in the group can be significantly reduced by eliminating metal and organic salts of BCAs, compounds of unknown or variable composition, and complex reaction products or biological materials (UVCB compounds). For the resulting reduced number of compounds, grouping is supported by similar physicochemical data and expected similar biotransformation. However, analysis of adverse effects for compounds in the group and mechanistic information show that BCAs, as a class, do not cause developmental effects in rats. Rather, developmental toxicity is limited to selected BCAs with specific structures that share a common mode of action (histone deacetylase inhibition). Thus, the proposed grouping is unreasonably wide and the more detailed analyses show that structural similarity alone is not sufficient for grouping branched-chain carboxylic acids for developmental toxicity.</p></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"151 ","pages":"Article 105662"},"PeriodicalIF":3.4,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311476","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