Pub Date : 2025-10-24DOI: 10.1016/j.yrtph.2025.105971
Christopher J. Bowman , Ann Baker , Diann L. Blanset , Kimberly C. Brannen , Gary J. Chellman , Brian Enright , Wendy Halpern , Bethany R. Hannas , Kazushige Maki , Fumito Mikashima , Shermaine Mitchell-Ryan , Eve Mylchreest , Manjunatha K. Nanjappa , Helen Prior , Puck Roos , Dinesh Stanislaus , Angela R. Stermer , Jane Stewart , Katie Turner , Steven van Cruchten , Peter Theunissen
An assessment of potential developmental and reproductive toxicity (DART) is generally required to support clinical trials and marketing of pharmaceuticals. Although typically performed in rodents and rabbits, nonhuman primates (NHPs) are often used when they are the only pharmacologically relevant species. Regulatory guidances allow for weight of evidence (WoE) risk assessment for DART such that mature NHPs may not be needed to confirm expected or low risk of adverse pregnancy outcome. As such, there are numerous examples of WoE strategies to inform risk of adverse pregnancy outcome, but fewer to assess risk to male and/or female fertility, although emerging data indicate mature NHPs have limited impact on fertility risk assessment in product labels. Mature NHP data are most impactful to fill safety gaps when there are no relevant data from other species, limited information to establish WoE, and/or limited human data is available to characterize risk. In this review, we propose a detailed decision tree and examples to inform risk of adverse pregnancy outcome or male/female fertility impact by emphasizing and prioritizing WoE supplemented by experimental data where necessary, including use of NHPs as a last resort. Additional refinements to NHP use are also summarized.
{"title":"Minimizing use of nonhuman primates to inform risk to fertility and of adverse pregnancy outcomes with pharmaceuticals","authors":"Christopher J. Bowman , Ann Baker , Diann L. Blanset , Kimberly C. Brannen , Gary J. Chellman , Brian Enright , Wendy Halpern , Bethany R. Hannas , Kazushige Maki , Fumito Mikashima , Shermaine Mitchell-Ryan , Eve Mylchreest , Manjunatha K. Nanjappa , Helen Prior , Puck Roos , Dinesh Stanislaus , Angela R. Stermer , Jane Stewart , Katie Turner , Steven van Cruchten , Peter Theunissen","doi":"10.1016/j.yrtph.2025.105971","DOIUrl":"10.1016/j.yrtph.2025.105971","url":null,"abstract":"<div><div>An assessment of potential developmental and reproductive toxicity (DART) is generally required to support clinical trials and marketing of pharmaceuticals. Although typically performed in rodents and rabbits, nonhuman primates (NHPs) are often used when they are the only pharmacologically relevant species. Regulatory guidances allow for weight of evidence (WoE) risk assessment for DART such that mature NHPs may not be needed to confirm expected or low risk of adverse pregnancy outcome. As such, there are numerous examples of WoE strategies to inform risk of adverse pregnancy outcome, but fewer to assess risk to male and/or female fertility, although emerging data indicate mature NHPs have limited impact on fertility risk assessment in product labels. Mature NHP data are most impactful to fill safety gaps when there are no relevant data from other species, limited information to establish WoE, and/or limited human data is available to characterize risk. In this review, we propose a detailed decision tree and examples to inform risk of adverse pregnancy outcome or male/female fertility impact by emphasizing and prioritizing WoE supplemented by experimental data where necessary, including use of NHPs as a last resort. Additional refinements to NHP use are also summarized.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105971"},"PeriodicalIF":3.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474401","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 : 2025-10-23DOI: 10.1016/j.yrtph.2025.105970
David J. Snodin
In ICH Q3C five residual solvents are classified as “should be avoided” and are designated as Class 1 solvents. The solvents in question are: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane. Although multiple revisions to ICH Q3C have been made, PDE (permitted daily exposure) limits for Class 1 solvents remain unchanged from those originally proposed in 1997. Since that time, new toxicological data have become available, and additional expert assessments have been published. A detailed review of information currently available indicates that there is a case for a change to limits for all Class 1 solvents except benzene. Two of the solvents can be classified as mutagenic carcinogens making them eligible for determination of AI (acceptable intake) limits as described in ICH M7(R2). In addition, the concept of expressing limits as concentrations, based on the assumption of a daily drug-substance dose of 10 g, is challenged.
{"title":"ICH Q3C revisited part I: Evaluation of class 1 residual solvents","authors":"David J. Snodin","doi":"10.1016/j.yrtph.2025.105970","DOIUrl":"10.1016/j.yrtph.2025.105970","url":null,"abstract":"<div><div>In ICH Q3C five residual solvents are classified as “should be avoided” and are designated as Class 1 solvents. The solvents in question are: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene and 1,1,1-trichloroethane. Although multiple revisions to ICH Q3C have been made, PDE (permitted daily exposure) limits for Class 1 solvents remain unchanged from those originally proposed in 1997. Since that time, new toxicological data have become available, and additional expert assessments have been published. A detailed review of information currently available indicates that there is a case for a change to limits for all Class 1 solvents except benzene. Two of the solvents can be classified as mutagenic carcinogens making them eligible for determination of AI (acceptable intake) limits as described in ICH M7(R2). In addition, the concept of expressing limits as concentrations, based on the assumption of a daily drug-substance dose of 10 g, is challenged.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"165 ","pages":"Article 105970"},"PeriodicalIF":3.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370380","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 : 2025-10-23DOI: 10.1016/j.yrtph.2025.105974
Osama Chahrour , Paul D. Cornwell , Penny Leavitt , Elizabeth A. Martin , Christina de Zafra , Susanne Glowienke , Angela White , Andrew Teasdale , Bruce Trela , Mayur S. Mitra , Wolfgang Muster , Jim Harvey
This position paper presents a science-based, holistic assessment of the toxicological risks posed by organic impurities in drug-linkers (D-L) used as intermediates in the production of Antibody-Drug Conjugates (ADCs) for oncology indications. The analysis outlined in this manuscript demonstrates that organic impurities present at levels at or below 1.0 % w/w in D-L intermediates are unlikely to result in adverse toxicological effects upon administration of the final ADC drug product. Due to the extremely low exposure (molar and weight) associated with 1.0 % w/w impurity level in the D-Ls, the authors propose to maintain the ICH Q3A criteria of not more than 1 mg/day limit however increase the qualification limit criteria for D-L related impurities from 0.15 % to 1.0 % w/w. Additionally, a methodology is introduced to assess the level of concern for non-conjugatable organic impurities, utilizing process-specific and ADC-specific factors to justify specifications for these impurities in D-L intermediates. Based on the minimal risk associated with D-L impurities at or below the discussed levels, the paper proposes a workflow for quality risk management of such impurities in D-Ls.
{"title":"Impurity qualification requirements for drug-linkers related impurities used to generate antibody-drug conjugates","authors":"Osama Chahrour , Paul D. Cornwell , Penny Leavitt , Elizabeth A. Martin , Christina de Zafra , Susanne Glowienke , Angela White , Andrew Teasdale , Bruce Trela , Mayur S. Mitra , Wolfgang Muster , Jim Harvey","doi":"10.1016/j.yrtph.2025.105974","DOIUrl":"10.1016/j.yrtph.2025.105974","url":null,"abstract":"<div><div>This position paper presents a science-based, holistic assessment of the toxicological risks posed by organic impurities in drug-linkers (D-L) used as intermediates in the production of Antibody-Drug Conjugates (ADCs) for oncology indications. The analysis outlined in this manuscript demonstrates that organic impurities present at levels at or below 1.0 % w/w in D-L intermediates are unlikely to result in adverse toxicological effects upon administration of the final ADC drug product. Due to the extremely low exposure (molar and weight) associated with 1.0 % w/w impurity level in the D-Ls, the authors propose to maintain the ICH Q3A criteria of not more than 1 mg/day limit however increase the qualification limit criteria for D-L related impurities from 0.15 % to 1.0 % w/w. Additionally, a methodology is introduced to assess the level of concern for non-conjugatable organic impurities, utilizing process-specific and ADC-specific factors to justify specifications for these impurities in D-L intermediates. Based on the minimal risk associated with D-L impurities at or below the discussed levels, the paper proposes a workflow for quality risk management of such impurities in D-Ls.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105974"},"PeriodicalIF":3.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370444","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 : 2025-10-23DOI: 10.1016/j.yrtph.2025.105967
Puck Roos , Diann L. Blanset , Peter JK. van Meer , Shermaine Mitchell-Ryan , Peter T. Theunissen , Katie J. Turner , Ronald L. Wange , Christopher J. Bowman
During development, potential adverse effects of pharmaceuticals on male and female fertility are evaluated. Although non-human primates (NHP) can be an appropriate model for some pharmaceuticals, there are scientific, ethical and practical limitations. We performed a retrospective analysis of the use of NHP for fertility assessment.
A database was created, consisting of pharmaceuticals submitted to the European Medicines Agency (2011–2022). Pharmaceuticals with repeat-dose toxicity studies or dedicated studies to evaluate surrogate fertility endpoints in NHP were included. Publicly available data on product characteristics, study design, observations on standard surrogate fertility endpoints (changes in reproductive organ weight and histopathology), additional surrogate fertility endpoints (changes in reproductive hormone levels, menstrual cycle, and sperm parameters), and labeling were collected.
In total, 263 pharmaceuticals were included. For 22 pharmaceuticals, adverse effects on surrogate fertility endpoints in NHP were reflected in the label. In all 22 cases, effects were predictable based on mechanism of action or rodent studies provided sufficient information on fertility. Hence, no clear scientific value of fertility assessment in sexually mature NHP was determined.
In conclusion, using NHP to evaluate effects on surrogate fertility endpoints of pharmaceuticals did not have a significant impact on fertility labeling.
{"title":"Retrospective evaluation of the use of non-human primates for fertility assessment of pharmaceuticals submitted for marketing approval in the EU","authors":"Puck Roos , Diann L. Blanset , Peter JK. van Meer , Shermaine Mitchell-Ryan , Peter T. Theunissen , Katie J. Turner , Ronald L. Wange , Christopher J. Bowman","doi":"10.1016/j.yrtph.2025.105967","DOIUrl":"10.1016/j.yrtph.2025.105967","url":null,"abstract":"<div><div>During development, potential adverse effects of pharmaceuticals on male and female fertility are evaluated. Although non-human primates (NHP) can be an appropriate model for some pharmaceuticals, there are scientific, ethical and practical limitations. We performed a retrospective analysis of the use of NHP for fertility assessment.</div><div>A database was created, consisting of pharmaceuticals submitted to the European Medicines Agency (2011–2022). Pharmaceuticals with repeat-dose toxicity studies or dedicated studies to evaluate surrogate fertility endpoints in NHP were included. Publicly available data on product characteristics, study design, observations on standard surrogate fertility endpoints (changes in reproductive organ weight and histopathology), additional surrogate fertility endpoints (changes in reproductive hormone levels, menstrual cycle, and sperm parameters), and labeling were collected.</div><div>In total, 263 pharmaceuticals were included. For 22 pharmaceuticals, adverse effects on surrogate fertility endpoints in NHP were reflected in the label. In all 22 cases, effects were predictable based on mechanism of action or rodent studies provided sufficient information on fertility. Hence, no clear scientific value of fertility assessment in sexually mature NHP was determined.</div><div>In conclusion, using NHP to evaluate effects on surrogate fertility endpoints of pharmaceuticals did not have a significant impact on fertility labeling.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105967"},"PeriodicalIF":3.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370430","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 : 2025-10-22DOI: 10.1016/j.yrtph.2025.105976
Mao-wen Weng, Xiaoling (Sharlene) Dai, Shaoping Wu, Jared Wilsey, Matt Lewis, Robert F. Shulfer, Marika Kamberi
Cohort of concern substances (CoCs) present challenges in medical device toxicological risk assessment. They are excluded from the lifetime threshold of toxicological concern (TTC) per ISO/TS 21726, because their toxic dose is < 1.5 μg/day and they may present a higher cancer risk. Relying solely on structural similarities with known toxicants is inadequate for assessing carcinogenic potency. This study selected chemicals from the Carcinogenic Potency Database (CPDB) to establish a framework for identifying potential CoCs. To do that, a threshold of Cancer Risk Specific Dose (CRSD) < 0.025 μg/kg/day was initially applied. Chemicals meeting this criterion are recognized as CoCs. However, the risk assessment could be impeded by particular uncertainties, such as the inability to determine the CRSD. In such cases, the identified CoCs were further categorized based on their mutagenicity determined by the Ames test results. A scatterplot reveals a significant correlation between the carcinogenic potency [ Log(0.5/TD50)+7] and acute systemic toxicity [Log(LD50)] in the CoCs-Ames (−) group (R2 = 0.72). For the CoCs-Ames (+) group (n = 124), 18 CoCs with available mutation slope data show cancer risk greater than the default risk of 1 in 100,000. This study provides a framework integrating scientific evidence and regulatory guidelines to identify potential CoCs.
{"title":"Exploration of a framework to identify cohort of concern substances in medical device risk assessment","authors":"Mao-wen Weng, Xiaoling (Sharlene) Dai, Shaoping Wu, Jared Wilsey, Matt Lewis, Robert F. Shulfer, Marika Kamberi","doi":"10.1016/j.yrtph.2025.105976","DOIUrl":"10.1016/j.yrtph.2025.105976","url":null,"abstract":"<div><div>Cohort of concern substances (CoCs) present challenges in medical device toxicological risk assessment. They are excluded from the lifetime threshold of toxicological concern (TTC) per ISO/TS 21726, because their toxic dose is < 1.5 μg/day and they may present a higher cancer risk. Relying solely on structural similarities with known toxicants is inadequate for assessing carcinogenic potency. This study selected chemicals from the Carcinogenic Potency Database (CPDB) to establish a framework for identifying potential CoCs. To do that, a threshold of Cancer Risk Specific Dose (CRSD) < 0.025 μg/kg/day was initially applied. Chemicals meeting this criterion are recognized as CoCs. However, the risk assessment could be impeded by particular uncertainties, such as the inability to determine the CRSD. In such cases, the identified CoCs were further categorized based on their mutagenicity determined by the Ames test results. A scatterplot reveals a significant correlation between the carcinogenic potency [ Log(0.5/TD<sub>50</sub>)+7] and acute systemic toxicity [Log(LD<sub>50</sub>)] in the CoCs-Ames (−) group (R<sup>2</sup> = 0.72). For the CoCs-Ames (+) group (n = 124), 18 CoCs with available mutation slope data show cancer risk greater than the default risk of 1 in 100,000. This study provides a framework integrating scientific evidence and regulatory guidelines to identify potential CoCs.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105976"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368588","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 : 2025-10-22DOI: 10.1016/j.yrtph.2025.105977
Ashley Roberts , Hiroaki Sato , Masahiko lino , Toshimitsu Kuribayashi
The safety of heat-killed Lactiplantibacillus plantarum strain L-137 (HK L-137) was evaluated in a 28-day dose range finding study and a 90-day study in Crl:CD (SD) rats administered a formulation containing 20 % HK L-137 and 80 % dextrin (LP20) at dose levels of 0, 1,000, 2000 and 3000 mg/kg bw/day by gavage. No death or moribundity occurred in any animal in any group and no effects were reported in terms of bodyweight gain or food consumption at each of the dose levels. In the 90-day study, no treatment-related adverse effects were recorded in each dose group for the functional observation battery, spontaneous activity movement or ophthalmological measurements, hematology, clinical chemistry, thyroid stimulating hormone, triiodothyronine, urinalysis, vaginal smears, gross pathology, organ weights or histopathology. While several statistically significant changes were identified including male thyroxine levels, these were shown not to be dose-dependent, were of low magnitude, with the majority of changes found to be within historical control values. As there were no histological correlates, these changes were considered incidental without toxicologic significance and not attributable to HK L-137. The NOEL for LP20 in the 90-day toxicity study was therefore considered 3000 mg/kg bw/day or 600 mg/kg bw/day for HK L-137 in both males and females for food use.
用含20% HK L-137和80%糊精（LP20）的配方，分别以0、1000、2000和3000 mg/kg bw/d灌胃，对热致死植物乳杆菌L-137菌株（HK L-137）的安全性进行了28天的剂量范围研究和90天的研究。在任何一组的任何动物中均未发生死亡或死亡，并且在每种剂量水平下均未报告对体重增加或食物消耗的影响。在90天的研究中，各剂量组的功能观察电池、自发活动运动或眼科测量、血液学、临床化学、促甲状腺激素、三碘甲状腺原氨酸、尿液分析、阴道涂片、肉眼病理、器官重量或组织病理学均未记录到与治疗相关的不良反应。虽然确定了包括男性甲状腺素水平在内的一些统计上显着的变化，但这些变化显示不具有剂量依赖性，幅度较小，大多数变化被发现在历史控制值范围内。由于没有组织学上的相关性，这些变化被认为是偶然的，没有毒理学意义，不能归因于HK L-137。因此，在为期90天的毒性研究中，LP20的NOEL被认为是3,000毫克/公斤体重/天，HK L-137的NOEL被认为是600毫克/公斤体重/天，供雄性和雌性食用。
{"title":"Safety and regulatory assessment of heat-killed Lactiplantibacillus plantarum strain L-137 (HK L-137) as a food ingredient","authors":"Ashley Roberts , Hiroaki Sato , Masahiko lino , Toshimitsu Kuribayashi","doi":"10.1016/j.yrtph.2025.105977","DOIUrl":"10.1016/j.yrtph.2025.105977","url":null,"abstract":"<div><div>The safety of heat-killed <em>Lactiplantibacillus plantarum</em> strain L-137 (HK L-137) was evaluated in a 28-day dose range finding study and a 90-day study in Crl:CD (SD) rats administered a formulation containing 20 % HK L-137 and 80 % dextrin (LP20) at dose levels of 0, 1,000, 2000 and 3000 mg/kg bw/day by gavage. No death or moribundity occurred in any animal in any group and no effects were reported in terms of bodyweight gain or food consumption at each of the dose levels. In the 90-day study, no treatment-related adverse effects were recorded in each dose group for the functional observation battery, spontaneous activity movement or ophthalmological measurements, hematology, clinical chemistry, thyroid stimulating hormone, triiodothyronine, urinalysis, vaginal smears, gross pathology, organ weights or histopathology. While several statistically significant changes were identified including male thyroxine levels, these were shown not to be dose-dependent, were of low magnitude, with the majority of changes found to be within historical control values. As there were no histological correlates, these changes were considered incidental without toxicologic significance and not attributable to HK L-137. The NOEL for LP20 in the 90-day toxicity study was therefore considered 3000 mg/kg bw/day or 600 mg/kg bw/day for HK L-137 in both males and females for food use.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105977"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368621","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 : 2025-10-22DOI: 10.1016/j.yrtph.2025.105969
Catherine Willett , Giorgia Pallocca , Annamaria Carusi , Nathalie Alépée , Patience Browne , Marie Darracq-Ghitalla-Ciock , Fabian A. Grimm , Jay Ingram , Laura Holden , Kamel Mansouri , Hans Raabe , Clive Roper , Katherine Santizo , Barbara G. Schmitt , Li Xiang , Thomas A. Ward , Bryan Zhou
The Animal-Free Safety Assessment (AFSA) Collaboration invited a select group of international experts, representing regulatory bodies, industry, method developers, and academia, to a workshop to develop a regulatory strategy implementing non-animal approaches to assess acute toxicity endpoints. The workshop, held in Loch Lomond, Scotland, from 28 April to 1 May, 2025, aimed to develop a decision tree (DT) approach that could support the implementation of non-animal methods and the phased-out use of animal testing for systemic acute and local toxicity.
This DT approach provides a transparent decision-making workflow that assists users in applying appropriate opportunities for waiving testing, non-animal testing methods (NAMs), and other adaptations consistently across chemical regulations. DTs also serve to increase awareness of the application of non-animal approaches and ensure compliance with the last resort requirement for animal studies. This workshop aimed to review the suitability of the proposed framework, formulate overarching recommendations for its implementation and provide specific feedback and timelines to finalise endpoint-specific DTs for acute oral toxicity, eye irritation and corrosion, skin irritation and corrosion, and skin sensitisation. This report summarises the overarching discussions and findings tackled during the meeting. The individual endpoint-specific DTs will be described in follow-up scientific publications.
{"title":"The Decision Tree approach as a strategy for the global phase out of animal testing for acute and local toxicity for chemicals: recommendations from an expert workshop","authors":"Catherine Willett , Giorgia Pallocca , Annamaria Carusi , Nathalie Alépée , Patience Browne , Marie Darracq-Ghitalla-Ciock , Fabian A. Grimm , Jay Ingram , Laura Holden , Kamel Mansouri , Hans Raabe , Clive Roper , Katherine Santizo , Barbara G. Schmitt , Li Xiang , Thomas A. Ward , Bryan Zhou","doi":"10.1016/j.yrtph.2025.105969","DOIUrl":"10.1016/j.yrtph.2025.105969","url":null,"abstract":"<div><div>The Animal-Free Safety Assessment (AFSA) Collaboration invited a select group of international experts, representing regulatory bodies, industry, method developers, and academia, to a workshop to develop a regulatory strategy implementing non-animal approaches to assess acute toxicity endpoints. The workshop, held in Loch Lomond, Scotland, from 28 April to 1 May, 2025, aimed to develop a decision tree (DT) approach that could support the implementation of non-animal methods and the phased-out use of animal testing for systemic acute and local toxicity.</div><div>This DT approach provides a transparent decision-making workflow that assists users in applying appropriate opportunities for waiving testing, non-animal testing methods (NAMs), and other adaptations consistently across chemical regulations. DTs also serve to increase awareness of the application of non-animal approaches and ensure compliance with the last resort requirement for animal studies. This workshop aimed to review the suitability of the proposed framework, formulate overarching recommendations for its implementation and provide specific feedback and timelines to finalise endpoint-specific DTs for acute oral toxicity, eye irritation and corrosion, skin irritation and corrosion, and skin sensitisation. This report summarises the overarching discussions and findings tackled during the meeting. The individual endpoint-specific DTs will be described in follow-up scientific publications.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105969"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368575","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}
Non-animal methods for skin sensitization assessment have been developed and adopted as OECD test guidelines. However, no single new approach methodology (NAM) can fully replace animal-based methods, leading to the development of defined approaches like OECD GL497. This study advances quantitative risk assessment (QRA) for skin sensitization using Artificial Neural Network (ANN) models to predict LLNA EC3 values. As a case study, six substances were evaluated using ANN models based on the Direct Peptide Reactivity Assay (DPRA) and the Amino acid Derivative Reactivity Assay (ADRA). These substances included four with known structures (Metol, Dibenzyl Ether, Safranal, and Lyral) and two with unknown structures (Verbena Oil and Oakmoss Extract). Most predicted EC3 values were within a 10-fold range of observed values, demonstrating model reliability. Incorporating ADRA molar and gravimetric method data, ANN models successfully predicted EC3 values for both substances with known and unknown structure, showing their applicability to natural complex substances like botanical extracts. A new skin sensitization risk assessment flow incorporating ANN models is proposed, contributing to the 3Rs by providing a reliable, non-animal method for determining Points of Departure (PoD) and advancing Next Generation Risk Assessment (NGRA) for cosmetic ingredients.
{"title":"Case studies on skin sensitization risk assessment: estimating the PoD using artificial neural network-based models for substances with known and unknown structure","authors":"Kosuke Imai , Yuri Hatakeyama , Tomomi Atobe, Toshiyuki Ohtake, Shiho Oeda, Morihiko Hirota","doi":"10.1016/j.yrtph.2025.105978","DOIUrl":"10.1016/j.yrtph.2025.105978","url":null,"abstract":"<div><div>Non-animal methods for skin sensitization assessment have been developed and adopted as OECD test guidelines. However, no single new approach methodology (NAM) can fully replace animal-based methods, leading to the development of defined approaches like OECD GL497. This study advances quantitative risk assessment (QRA) for skin sensitization using Artificial Neural Network (ANN) models to predict LLNA EC3 values. As a case study, six substances were evaluated using ANN models based on the Direct Peptide Reactivity Assay (DPRA) and the Amino acid Derivative Reactivity Assay (ADRA). These substances included four with known structures (Metol, Dibenzyl Ether, Safranal, and Lyral) and two with unknown structures (Verbena Oil and Oakmoss Extract). Most predicted EC3 values were within a 10-fold range of observed values, demonstrating model reliability. Incorporating ADRA molar and gravimetric method data, ANN models successfully predicted EC3 values for both substances with known and unknown structure, showing their applicability to natural complex substances like botanical extracts. A new skin sensitization risk assessment flow incorporating ANN models is proposed, contributing to the 3Rs by providing a reliable, non-animal method for determining Points of Departure (PoD) and advancing Next Generation Risk Assessment (NGRA) for cosmetic ingredients.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105978"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368602","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 : 2025-10-22DOI: 10.1016/j.yrtph.2025.105979
Darshan Mehta, Kiara Fairman, Miao Li , Jeffrey Fisher , Frederick A. Beland, Gonçalo Gamboa da Costa, Annie Lumen
Oseltamivir phosphate is a lipophilic prodrug that is metabolized to the active form, oseltamivir carboxylate, by carboxylesterase 1 enzymes in the liver in humans and in the liver and gut in rhesus macaques. Oseltamivir carboxylate is hydrophilic and distributes extensively in extracellular fluids, including plasma, and is eliminated primarily by the kidneys through glomerular filtration and tubular secretion. Pregnant women have lower systemic exposure to oseltamivir carboxylate due to an increase in plasma volume and total body water, leading to an increased apparent volume of distribution and increased renal excretion. To evaluate the differences in oseltamivir pharmacokinetics during pregnancy, a study was conducted previously using rhesus monkeys that were administered oseltamivir phosphate via intravenous and nasogastric routes at doses of 2.5 mg/kg body weight during the three trimesters of pregnancy. In the current study, we present a physiologically based pharmacokinetic (PBPK) model to help characterize the pharmacokinetic data that were collected in the previous study and demonstrate how the model can be used to predict the pharmacokinetics of oseltamivir and oseltamivir carboxylate in pregnant women. As it can be challenging to obtain rich clinical data in pregnant women, evaluating drug pharmacokinetics in preclinical species using tools such as PBPK models can provide reliable estimates of drug disposition across species during sensitive life stages such as pregnancy. Using the PBPK modeling approach, we were able to successfully characterize a reduction in oseltamivir carboxylate exposure during pregnancy in rhesus macaques (20–25 % decrease in AUC) and satisfactorily extend the model predictions to humans by accounting for physiological changes that occur throughout the different stages of pregnancy. The rhesus macaque can thus be considered a promising animal model for extrapolating pharmacokinetic predictions during pregnancy, especially for drugs or chemicals that are metabolized by hydrolysis reactions and primarily eliminated by renal excretion.
{"title":"Physiologically based pharmacokinetic modeling of oseltamivir in pregnant rhesus macaques to inform clinical dosing across trimesters","authors":"Darshan Mehta, Kiara Fairman, Miao Li , Jeffrey Fisher , Frederick A. Beland, Gonçalo Gamboa da Costa, Annie Lumen","doi":"10.1016/j.yrtph.2025.105979","DOIUrl":"10.1016/j.yrtph.2025.105979","url":null,"abstract":"<div><div>Oseltamivir phosphate is a lipophilic prodrug that is metabolized to the active form, oseltamivir carboxylate, by carboxylesterase 1 enzymes in the liver in humans and in the liver and gut in rhesus macaques. Oseltamivir carboxylate is hydrophilic and distributes extensively in extracellular fluids, including plasma, and is eliminated primarily by the kidneys through glomerular filtration and tubular secretion. Pregnant women have lower systemic exposure to oseltamivir carboxylate due to an increase in plasma volume and total body water, leading to an increased apparent volume of distribution and increased renal excretion. To evaluate the differences in oseltamivir pharmacokinetics during pregnancy, a study was conducted previously using rhesus monkeys that were administered oseltamivir phosphate via intravenous and nasogastric routes at doses of 2.5 mg/kg body weight during the three trimesters of pregnancy. In the current study, we present a physiologically based pharmacokinetic (PBPK) model to help characterize the pharmacokinetic data that were collected in the previous study and demonstrate how the model can be used to predict the pharmacokinetics of oseltamivir and oseltamivir carboxylate in pregnant women. As it can be challenging to obtain rich clinical data in pregnant women, evaluating drug pharmacokinetics in preclinical species using tools such as PBPK models can provide reliable estimates of drug disposition across species during sensitive life stages such as pregnancy. Using the PBPK modeling approach, we were able to successfully characterize a reduction in oseltamivir carboxylate exposure during pregnancy in rhesus macaques (20–25 % decrease in AUC) and satisfactorily extend the model predictions to humans by accounting for physiological changes that occur throughout the different stages of pregnancy. The rhesus macaque can thus be considered a promising animal model for extrapolating pharmacokinetic predictions during pregnancy, especially for drugs or chemicals that are metabolized by hydrolysis reactions and primarily eliminated by renal excretion.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"164 ","pages":"Article 105979"},"PeriodicalIF":3.5,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368577","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":"2025-10-21","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号