Pub Date : 2026-01-01Epub Date: 2025-11-06DOI: 10.1016/j.yrtph.2025.105983
Kim Z. Travis , Richard W. Lewis , Christine Barreau , Bastian Becker , Philippe F. Kennel
Fluoxapiprolin is a new fungicide developed for the control of oomycetes that damage crops such as tomato, potato, grapes and leafy vegetables. Human safety studies have shown no toxicity clearly attributable to fluoxapiprolin, highlighting its favourable toxicological profile compared to many other fungicides. It meets all human health risk assessment criteria without difficulty. However, fluoxapiprolin was tested up to a Kinetically-Derived Maximum Dose (KMD) rather than the conventional limit dose, making it necessary to justify this approach in the context of regulatory hazard assessment. Official guidance documents encourage the application of KMD approaches under specific conditions. In the case of fluoxapiprolin, oral absorption was shown to become saturated as doses increased, supporting the selection of the high dose in long-term studies based on a KMD rather than using a fixed limit dose. Even if a limit dose had been used, systemic exposure would have been only about twice as high as that observed at the KMD. Given the absence of treatment-related toxicity in any study and the relatively small difference in systemic exposure, the toxicological database is considered sufficient to identify relevant hazards and to support a robust human health risk assessment.
{"title":"Applicability of kinetically-based maximum dose studies for hazard and risk assessments of the fungicide fluoxapiprolin","authors":"Kim Z. Travis , Richard W. Lewis , Christine Barreau , Bastian Becker , Philippe F. Kennel","doi":"10.1016/j.yrtph.2025.105983","DOIUrl":"10.1016/j.yrtph.2025.105983","url":null,"abstract":"<div><div>Fluoxapiprolin is a new fungicide developed for the control of oomycetes that damage crops such as tomato, potato, grapes and leafy vegetables. Human safety studies have shown no toxicity clearly attributable to fluoxapiprolin, highlighting its favourable toxicological profile compared to many other fungicides. It meets all human health risk assessment criteria without difficulty. However, fluoxapiprolin was tested up to a Kinetically-Derived Maximum Dose (KMD) rather than the conventional limit dose, making it necessary to justify this approach in the context of regulatory hazard assessment. Official guidance documents encourage the application of KMD approaches under specific conditions. In the case of fluoxapiprolin, oral absorption was shown to become saturated as doses increased, supporting the selection of the high dose in long-term studies based on a KMD rather than using a fixed limit dose. Even if a limit dose had been used, systemic exposure would have been only about twice as high as that observed at the KMD. Given the absence of treatment-related toxicity in any study and the relatively small difference in systemic exposure, the toxicological database is considered sufficient to identify relevant hazards and to support a robust human health risk assessment.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105983"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477230","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}
Pub Date : 2026-01-01Epub Date: 2025-09-22DOI: 10.1016/j.yrtph.2025.105946
Rune Hjorth , Joop de Knecht , Eva B. Wedebye , Nikolai G. Nikolov , Damiën van Berlo , Henrik Tyle
For industrial substances registered under REACH at 1–10 tonnes per registrant/year, only the Ames test is required to address mutagenicity. When a substance tests positive in the Ames test, further testing is needed, but when the test result is negative, additional mutagenicity testing is only mandatory at a higher tonnage level. It is correspondingly known that some mutagens produced up to 10 tonnes per year/registrant are not identified. Based on battery (Q)SAR modelling, relying on agreement from both in vitro and in vivo models, advisory self-classifications (ASC) for mutagenicity are offered by the Danish EPA. In this present study, substances with ASC for mutagenicity are compared to the identified mutagens in low tonnage REACH registrations. We conclude that for only about a quarter of the low-tonnage substances with an Muta. 2 ASC, a positive experimental Ames result is available, leading to follow-up under REACH. We recommend improving the identification of mutagenic substances at the 1–10 tonnage band by including the in vitro micronucleus test to supplement the Ames test. Concerningly, the few low tonnage REACH dossiers that do provide in vivo data, mostly report negative micronucleus test results that are not conclusive due to missing information on bone marrow exposure.
{"title":"How many mutagens are missed under REACH due to limited low tonnage information requirements?","authors":"Rune Hjorth , Joop de Knecht , Eva B. Wedebye , Nikolai G. Nikolov , Damiën van Berlo , Henrik Tyle","doi":"10.1016/j.yrtph.2025.105946","DOIUrl":"10.1016/j.yrtph.2025.105946","url":null,"abstract":"<div><div>For industrial substances registered under REACH at 1–10 tonnes per registrant/year, only the Ames test is required to address mutagenicity. When a substance tests positive in the Ames test, further testing is needed, but when the test result is negative, additional mutagenicity testing is only mandatory at a higher tonnage level. It is correspondingly known that some mutagens produced up to 10 tonnes per year/registrant are not identified. Based on battery (Q)SAR modelling, relying on agreement from both <em>in vitro</em> and <em>in vivo</em> models, advisory self-classifications (ASC) for mutagenicity are offered by the Danish EPA. In this present study, substances with ASC for mutagenicity are compared to the identified mutagens in low tonnage REACH registrations. We conclude that for only about a quarter of the low-tonnage substances with an Muta. 2 ASC, a positive experimental Ames result is available, leading to follow-up under REACH. We recommend improving the identification of mutagenic substances at the 1–10 tonnage band by including the <em>in vitro</em> micronucleus test to supplement the Ames test. Concerningly, the few low tonnage REACH dossiers that do provide <em>in vivo</em> data, mostly report negative micronucleus test results that are not conclusive due to missing information on bone marrow exposure.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105946"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138608","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}
Pub Date : 2026-01-01Epub Date: 2025-10-25DOI: 10.1016/j.yrtph.2025.105973
Qian Guo , Meirong Shan , Yanhua Fu , Ni Li , Chu Wu , Wei Gao
This study utilized real-world data from the U.S. FDA Adverse Event Reporting System and the WHO VigiAccess database to identify and characterize safety signals associated with fruquintinib, providing insights for clinical practice and regulatory decision-making. Through a retrospective analysis of adverse event (AE) reports for fruquintinib from these two databases, disproportionality analysis methods such as the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) were employed to detect potential pharmacovigilance signals, with cross-database consistency evaluated. The analysis revealed 4641 and 3909 AEs associated with fruquintinib in the FAERS and VigiAccess databases, respectively. The study identified several AEs not currently documented in the drug label, including dysphonia and pain. In the FAERS database, significant signals were detected in systems not covered by the label, such as blood and lymphatic, psychiatric, immune, reproductive, and ear disorders. Other unreported signals included myelosuppression, headache, dizziness, and dyspnea. In conclusion, this study not only confirmed known adverse reactions to fruquintinib but also uncovered several potential new safety signals. These findings underscore the importance of ongoing post-marketing safety monitoring to optimize the drug's risk-benefit profile. The results provide critical safety information for clinicians managing refractory metastatic colorectal cancer with fruquintinib, supporting more vigilant patient management.
{"title":"Real-world safety of fruquininib in refractory metastatic colorectal cancer: A cross-database study","authors":"Qian Guo , Meirong Shan , Yanhua Fu , Ni Li , Chu Wu , Wei Gao","doi":"10.1016/j.yrtph.2025.105973","DOIUrl":"10.1016/j.yrtph.2025.105973","url":null,"abstract":"<div><div>This study utilized real-world data from the U.S. FDA Adverse Event Reporting System and the WHO VigiAccess database to identify and characterize safety signals associated with fruquintinib, providing insights for clinical practice and regulatory decision-making. Through a retrospective analysis of adverse event (AE) reports for fruquintinib from these two databases, disproportionality analysis methods such as the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) were employed to detect potential pharmacovigilance signals, with cross-database consistency evaluated. The analysis revealed 4641 and 3909 AEs associated with fruquintinib in the FAERS and VigiAccess databases, respectively. The study identified several AEs not currently documented in the drug label, including dysphonia and pain. In the FAERS database, significant signals were detected in systems not covered by the label, such as blood and lymphatic, psychiatric, immune, reproductive, and ear disorders. Other unreported signals included myelosuppression, headache, dizziness, and dyspnea. In conclusion, this study not only confirmed known adverse reactions to fruquintinib but also uncovered several potential new safety signals. These findings underscore the importance of ongoing post-marketing safety monitoring to optimize the drug's risk-benefit profile. The results provide critical safety information for clinicians managing refractory metastatic colorectal cancer with fruquintinib, supporting more vigilant patient management.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105973"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424549","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}
Pub Date : 2026-01-01Epub Date: 2025-11-11DOI: 10.1016/j.yrtph.2025.105988
Yanzhe Xu, Yun Zhu, Jianyang Lin, Jürgen Borlak
Serial blood collection is a key requirement for pharmacological and toxicological studies in rodents, but existing approaches such as tail vein, retro-orbital, or catheter-based sampling are constrained by limited sample volume, variability, and welfare concerns. We developed a percutaneous technique for serial blood sampling from the external jugular vein in male Wistar rats under isoflurane anaesthesia. The method was evaluated over 14 days by monitoring body weight, behaviour, haematological and clinical chemistry parameters in a preclinical safety study at a No-Observable-Adverse-Effect-Level dose setting. Rats tolerated repeated sampling without distress, skin lesions, or behavioural abnormalities. Isoflurane induction was rapid and uneventful, and blood samples (0.5–1 ml) were consistently obtained within 2 min. Body weight changes were minimal across sessions (1.2 % after the first to 0.2 % after the sixth), indicating procedural adaptation. Haematological values remained within reference ranges, with only a significant reduction in RDW-CV, while biochemical parameters including AST, CK, and lipids showed no significant alterations; minor, non-adverse trends included reduced ALT (p < 0.041) and non-significant cholesterol and minimal non-significant increases in plasma creatinine. This study establishes repeated percutaneous jugular vein puncture as a minimally invasive, welfare-compliant, and reliable method for longitudinal blood sampling in anaesthetised rats without catheterisation, supporting robust preclinical research.
{"title":"Serial blood collection in anaesthetised rats: Enhancing animal welfare without the need for jugular vein catheterisation","authors":"Yanzhe Xu, Yun Zhu, Jianyang Lin, Jürgen Borlak","doi":"10.1016/j.yrtph.2025.105988","DOIUrl":"10.1016/j.yrtph.2025.105988","url":null,"abstract":"<div><div>Serial blood collection is a key requirement for pharmacological and toxicological studies in rodents, but existing approaches such as tail vein, retro-orbital, or catheter-based sampling are constrained by limited sample volume, variability, and welfare concerns. We developed a percutaneous technique for serial blood sampling from the external jugular vein in male Wistar rats under isoflurane anaesthesia. The method was evaluated over 14 days by monitoring body weight, behaviour, haematological and clinical chemistry parameters in a preclinical safety study at a No-Observable-Adverse-Effect-Level dose setting. Rats tolerated repeated sampling without distress, skin lesions, or behavioural abnormalities. Isoflurane induction was rapid and uneventful, and blood samples (0.5–1 ml) were consistently obtained within 2 min. Body weight changes were minimal across sessions (1.2 % after the first to 0.2 % after the sixth), indicating procedural adaptation. Haematological values remained within reference ranges, with only a significant reduction in RDW-CV, while biochemical parameters including AST, CK, and lipids showed no significant alterations; minor, non-adverse trends included reduced ALT (p < 0.041) and non-significant cholesterol and minimal non-significant increases in plasma creatinine. This study establishes repeated percutaneous jugular vein puncture as a minimally invasive, welfare-compliant, and reliable method for longitudinal blood sampling in anaesthetised rats without catheterisation, supporting robust preclinical research.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105988"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513679","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}
Pub Date : 2026-01-01Epub Date: 2025-11-08DOI: 10.1016/j.yrtph.2025.105985
Carole L. Yauk , Anthony M. Lynch , Vasily N. Dobrovolsky , Maik Schuler , Stephanie L. Smith-Roe , Devon Fitzgerald , Jake Higgins , Naveed Honarvar , Frank Le Curieux , Shoji Matsumura , Sheroy Minocherhomji , Leslie Recio , Jesse J. Salk , Kei-ichi Sugiyama , Takayoshi Suzuki , John W. Wills , Francesco Marchetti
Error-corrected sequencing (ECS) is a transformative method for in vivo mutagenicity assessment, enabling direct, highly sensitive measurement of mutation frequency and spectrum. ECS addresses key limitations of the transgenic rodent (TGR) assay, including lack of integration into standard toxicity studies, restricted model availability, and limited alignment with the 3R principles. To support regulatory acceptance, an expert workgroup of the International Workshops on Genotoxicity Testing (IWGT) reviewed ECS technologies and developed consensus recommendations for its inclusion into Organisation for Economic Co-operation and Development (OECD) test guidelines. The working group agreed that ECS: produces results that are concordant with validated TGR assays; can be incorporated into standard ≥28-day repeat-dose toxicity studies; and, data interpretation should be based on overall mutation frequency compared with concurrent vehicle controls. The working group emphasized harmonized data reporting aligned with OECD principles and endorsed study designs that enable quantitative risk assessment. Overall, the working group agreed that ECS offers a significant advancement over current mutagenicity assays by enabling the use of diverse models beyond conventional TGR systems described in OECD test guideline 488. The working group fully supports the application of ECS to generate in vivo mutagenicity data for regulatory submissions and recommends its inclusion in future OECD test guidelines.
{"title":"Application of error-corrected sequencing technologies for in vivo regulatory mutagenicity assessment","authors":"Carole L. Yauk , Anthony M. Lynch , Vasily N. Dobrovolsky , Maik Schuler , Stephanie L. Smith-Roe , Devon Fitzgerald , Jake Higgins , Naveed Honarvar , Frank Le Curieux , Shoji Matsumura , Sheroy Minocherhomji , Leslie Recio , Jesse J. Salk , Kei-ichi Sugiyama , Takayoshi Suzuki , John W. Wills , Francesco Marchetti","doi":"10.1016/j.yrtph.2025.105985","DOIUrl":"10.1016/j.yrtph.2025.105985","url":null,"abstract":"<div><div>Error-corrected sequencing (ECS) is a transformative method for <em>in vivo</em> mutagenicity assessment, enabling direct, highly sensitive measurement of mutation frequency and spectrum. ECS addresses key limitations of the transgenic rodent (TGR) assay, including lack of integration into standard toxicity studies, restricted model availability, and limited alignment with the 3R principles. To support regulatory acceptance, an expert workgroup of the International Workshops on Genotoxicity Testing (IWGT) reviewed ECS technologies and developed consensus recommendations for its inclusion into Organisation for Economic Co-operation and Development (OECD) test guidelines. The working group agreed that ECS: produces results that are concordant with validated TGR assays; can be incorporated into standard ≥28-day repeat-dose toxicity studies; and, data interpretation should be based on overall mutation frequency compared with concurrent vehicle controls. The working group emphasized harmonized data reporting aligned with OECD principles and endorsed study designs that enable quantitative risk assessment. Overall, the working group agreed that ECS offers a significant advancement over current mutagenicity assays by enabling the use of diverse models beyond conventional TGR systems described in OECD test guideline 488. The working group fully supports the application of ECS to generate <em>in vivo</em> mutagenicity data for regulatory submissions and recommends its inclusion in future OECD test guidelines.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105985"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490177","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}
Pub Date : 2026-01-01Epub Date: 2025-10-10DOI: 10.1016/j.yrtph.2025.105960
Hiwa Mohammad Qadr , Najeba Farhad Salih , Alla Ahmed Muhamad Amin
Water quality assessment represents a fundamental component of public health surveillance programs. Radon concentrations in potable water constitute a significant contributor to environmental contamination and radiological exposure pathways. Consequently, this investigation quantified radon concentrations in tap water samples collected from the Ranya region of Iraqi Kurdistan, utilizing passive detection methodology employing CR-39 solid-state nuclear track detectors. Radiological safety and physicochemical properties of the tap water were evaluated. Measured radon concentrations exhibited a range of 0.068–0.194 Bq L−1, with a mean of 0.107 Bq L−1. All concentrations remained substantially below established regulatory thresholds of 11.1 Bq L−1 for USEPA and 100 Bq L−1 for WHO guidelines. In addition, the maximum annual effective doses from 222Rn ingestion were 4.143, 4.888, and 8.167 μSv y−1 for adults, children, and infants, respectively. Children and adults received lower annual effective doses than infants, though all age groups remained well below the WHO safety threshold of 100 μSv y−1. Cancer risk estimates for all age groups also remained below global reference levels. A strong positive correlation was not found between 222Rn levels and tap water parameters. It appears that the results dispel local fears of significant radioactive risks by showing that radon concentrations are within the limits set by international organizations.
{"title":"Comprehensive study of radon levels, health risks, and physiochemical properties in tap water consumed in Iraqi Kurdistan using solid-state nuclear track detectors","authors":"Hiwa Mohammad Qadr , Najeba Farhad Salih , Alla Ahmed Muhamad Amin","doi":"10.1016/j.yrtph.2025.105960","DOIUrl":"10.1016/j.yrtph.2025.105960","url":null,"abstract":"<div><div>Water quality assessment represents a fundamental component of public health surveillance programs. Radon concentrations in potable water constitute a significant contributor to environmental contamination and radiological exposure pathways. Consequently, this investigation quantified radon concentrations in tap water samples collected from the Ranya region of Iraqi Kurdistan, utilizing passive detection methodology employing CR-39 solid-state nuclear track detectors. Radiological safety and physicochemical properties of the tap water were evaluated. Measured radon concentrations exhibited a range of 0.068–0.194 Bq L<sup>−1</sup>, with a mean of 0.107 Bq L<sup>−1</sup>. All concentrations remained substantially below established regulatory thresholds of 11.1 Bq L<sup>−1</sup> for USEPA and 100 Bq L<sup>−1</sup> for WHO guidelines. In addition, the maximum annual effective doses from <sup>222</sup>Rn ingestion were 4.143, 4.888, and 8.167 μSv y<sup>−1</sup> for adults, children, and infants, respectively. Children and adults received lower annual effective doses than infants, though all age groups remained well below the WHO safety threshold of 100 μSv y<sup>−1</sup>. Cancer risk estimates for all age groups also remained below global reference levels. A strong positive correlation was not found between <sup>222</sup>Rn levels and tap water parameters. It appears that the results dispel local fears of significant radioactive risks by showing that radon concentrations are within the limits set by international organizations.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105960"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280764","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}
Zirconium(IV) butoxide (ZB; CAS 1071-76-7) is widely used in industrial applications as a catalyst, stabilizer, and precursor for ceramic materials utilized in medical devices such as artificial bones and teeth. Metal alkoxide compounds, including ZB, are easily hydrolyzed, polymerized, and precipitated in aqueous environments. Although a no-observed-adverse-effect level (NOAEL) for ZB has been estimated by extrapolating its hydrolysis product, 1-butanol, ZB toxicological profile remains unclear, leaving data gaps for risk evaluation. In this study, we developed a method for ZB preparation and administration using corn oil as vehicle, in which ZB was retained its polymerizable form. A 13-week repeated-dose oral toxicity study was conducted in 6-week-old Crl:CD(SD) rats. Groups of ten males and females were orally administered ZB at doses of 0 (vehicle: corn oil), 100, 300, and 1000 mg/kg body weight (bw)/day, or 1-butanol at 116 mg/kg bw/day, which was equivalent to its level after dosing ZB at 1000 mg/kg bw/day. No toxicologically significant effects were observed after ZB administration. The NOAEL for ZB was estimated to be 1000 mg/kg bw/day in both sexes. These results provide essential toxicological data for safety assessment and regulatory evaluation of ZB.
丁二氧化锆（ZB; CAS 1071-76-7）作为催化剂、稳定剂和前驱体广泛应用于医疗器械（如人造骨和牙齿）的陶瓷材料。金属醇氧化合物，包括ZB，在水环境中很容易水解、聚合和沉淀。虽然通过外推其水解产物- 1-丁醇估计了ZB的无观察到的不良反应水平（NOAEL），但ZB的毒理学特征仍不清楚，为风险评估留下了数据空白。在本研究中，我们开发了一种以玉米油为载体的ZB制备和给药方法，该方法保留了ZB的可聚合形式。对6周龄大鼠进行了为期13周的重复给药口服毒性研究。每组10只雄性和雌性分别口服剂量为0、100、300和1,000 mg/kg体重(bw)/天的ZB（对照剂：玉米油），或剂量为116 mg/kg体重/天的1-丁醇，其剂量与ZB剂量为1,000 mg/kg体重/天后的水平相当。ZB给药后未见明显毒理学效应。两性对ZB的NOAEL估计为1,000 mg/kg bw/day。这些结果为ZB的安全性评价和监管评价提供了必要的毒理学数据。
{"title":"Evaluation of 13-week repeated-dose oral toxicity of zirconium(IV) butoxide in Crl:CD(SD) rats","authors":"Yasumasa Murata , Jun-ichi Akagi , Yuko Doi , Takako Iso , Takaaki Umano , Kenichi Masumura , Mariko Matsumoto , Takeshi Toyoda , Kumiko Ogawa","doi":"10.1016/j.yrtph.2025.105968","DOIUrl":"10.1016/j.yrtph.2025.105968","url":null,"abstract":"<div><div>Zirconium(IV) butoxide (ZB; CAS 1071-76-7) is widely used in industrial applications as a catalyst, stabilizer, and precursor for ceramic materials utilized in medical devices such as artificial bones and teeth. Metal alkoxide compounds, including ZB, are easily hydrolyzed, polymerized, and precipitated in aqueous environments. Although a no-observed-adverse-effect level (NOAEL) for ZB has been estimated by extrapolating its hydrolysis product, 1-butanol, ZB toxicological profile remains unclear, leaving data gaps for risk evaluation. In this study, we developed a method for ZB preparation and administration using corn oil as vehicle, in which ZB was retained its polymerizable form. A 13-week repeated-dose oral toxicity study was conducted in 6-week-old Crl:CD(SD) rats. Groups of ten males and females were orally administered ZB at doses of 0 (vehicle: corn oil), 100, 300, and 1000 mg/kg body weight (bw)/day, or 1-butanol at 116 mg/kg bw/day, which was equivalent to its level after dosing ZB at 1000 mg/kg bw/day. No toxicologically significant effects were observed after ZB administration. The NOAEL for ZB was estimated to be 1000 mg/kg bw/day in both sexes. These results provide essential toxicological data for safety assessment and regulatory evaluation of ZB.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105968"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355834","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}
Pub Date : 2026-01-01Epub Date: 2025-10-13DOI: 10.1016/j.yrtph.2025.105965
Hanna KL. Johansson, Anna Kjerstine Rosenmai, Julie Boberg, Monica K. Draskau, Marie Louise Holmer, Terje Svingen, Marta Axelstad
{"title":"Using read-across to identify isobutylparaben as an endocrine disruptor","authors":"Hanna KL. Johansson, Anna Kjerstine Rosenmai, Julie Boberg, Monica K. Draskau, Marie Louise Holmer, Terje Svingen, Marta Axelstad","doi":"10.1016/j.yrtph.2025.105965","DOIUrl":"10.1016/j.yrtph.2025.105965","url":null,"abstract":"","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105965"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302929","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}
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