Regulatory Toxicology and Pharmacology最新文献_第3页

Risk assessment and pharmacokinetic modeling of incidental ingestion of ethanol from mouthwash 漱口水中偶然摄入乙醇的风险评估和药代动力学模型。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.yrtph.2025.106018

Daniel G. Kougias , Michael Kovochich , Sadaff Ejaz , Abdulkarim Najjar , Smruti Nair , Boris Michelin , Christopher Chu , Michael D. Southall

Mouthwashes containing ethanol for antiseptic properties have a long history of use and well-established oral hygiene benefits by significantly enhancing the control of dental biofilm and reducing gingival inflammation. Despite the substantial health benefits from ethanol-containing mouthwashes, there has been ongoing scrutiny by regulatory and health authorities of products containing ethanol resulting from the classification of consumption of alcohol-containing beverages as a potential carcinogen. Unlike alcohol-containing beverages, mouthwash products are not intended to be ingested, and the potential ethanol exposure is substantially lower for mouthwash products. Therefore, we conducted a risk assessment that benchmarked estimated and modeled incidental exposure to ethanol in mouthwash products against endogenous blood levels, dietary exposure, and health-based guidance values for ethanol. All mouthwash-use scenarios, including average, 90th-percentile, and maximum-label use, resulted in relatively low estimated ethanol exposures that were below various reference and health-based guidance values (HBGVs), including the HBGV of 1 g/day for ethanol (16.7 mg/kg/day in a 60-kg human), a conservative value that is considered to be protective against all chronic health endpoints, including cancer. The findings suggest that ethanol from mouthwash does not significantly contribute to systemic levels of ethanol, falls within dietary intake levels, and remains below HBGVs. Taken together, this assessment concludes that incidental oral exposure of ethanol-containing mouthwashes represents a de minimis health risk.

含乙醇的漱口水具有悠久的使用历史和良好的口腔卫生效益，可显著增强对牙生物膜的控制和减少牙龈炎症。尽管含乙醇漱口水对健康有实质性的好处，但由于将含酒精饮料归类为潜在致癌物，监管机构和卫生当局一直在对含乙醇产品进行审查。与含酒精饮料不同的是，漱口水产品不能被摄入，而且漱口水产品中潜在的乙醇含量要低得多。因此，我们进行了一项风险评估，根据内源性血液水平、饮食暴露和基于健康的乙醇指导值，对漱口水产品中乙醇的意外暴露进行了基准评估和建模。所有漱口水使用情景，包括平均、90百分位和最大标签使用，导致相对较低的估计乙醇暴露量，低于各种参考值和基于健康的指导值（HBGV），包括乙醇的HBGV为1 g/天（60公斤体重的人为16.7 mg/kg/天），这是一个保守值，被认为对所有慢性健康终点都有保护作用，包括癌症。研究结果表明，漱口水中的乙醇对全身乙醇水平没有显著影响，在饮食摄入水平范围内，并保持在hbgv以下。综上所述，本次评估得出的结论是，偶然口腔接触含乙醇漱口水的健康风险极小。

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引用次数: 0

Confidence in new approach methods (NAMs): Ensuring reproducibility, operationalising context-of-use and alignment with decision-making needs 对新方法（NAMs）的信心：确保可重复性，操作使用环境和与决策需求的一致性。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-20 DOI: 10.1016/j.yrtph.2025.106016

Miriam N. Jacobs , Heli M. Hollnagel , Karma Fussel , Giel Hendriks , Ioanna Katsiadaki , Susanne N. Kolle , Morné E. van der Mescht , Andreas Natsch , Hans Raabe , Amanda Ulrey , Robert Landsiedel

引用次数: 0

Establishing best practice for N-nitrosamine read-across and surrogate selection 建立n -亚硝胺读取和替代选择的最佳实践。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-20 DOI: 10.1016/j.yrtph.2025.106009

David J. Ponting , Gabriela de Oliveira Silveira , Philip Rowell , Crina I. Heghes , Adrian Fowkes , Christopher G. Barber

Read-across is, ultimately, achieving a confident decision on the activity of a compound based on an analogue compound with robust toxicity data. The use of read-across assessments for the determination of acceptable intakes for N-nitrosamine compounds is recommended in regulatory guidance for this critical impurity class and is given an equal weight to the tier-0 screening approach, the Carcinogenic Potency Categorization Approach (CPCA), as well as in vitro and in vivo toxicological studies. However, read-across assessment is a multifaceted, manual process which requires the expert assessment of many factors. The complexities of performing read-across have been acknowledged as a driving force for the introduction of the CPCA. Prior to this there was a significant backlog of compounds needing a read-across assessment for a compound-specific acceptable intake (AI) as control to the class-specific threshold of toxicological concern (TTC) was unachievable. It was however clear from subjective assessment that control to the class-specific limit was unwarranted from a safety perspective. In this article the authors propose factors that should be considered in both the manual read-across and the new generation of semi-automated in silico tools for read-across assessment, in order to ensure that a robust assessment is performed, and a confident conclusion can be both reached and documented. Key case studies are presented for several NDSRIs, showing the applicability of this approach.

最终，读取是基于具有可靠毒性数据的类似化合物，对化合物的活性做出自信的决定。在这一关键杂质类别的监管指南中，推荐使用跨读评估来确定n -亚硝胺化合物的可接受摄入量，并与0级筛选方法、致癌效力分类方法（CPCA）以及体外和体内毒理学研究同等重要。然而，通读评估是一个多方面的人工过程，需要专家对许多因素进行评估。执行读取的复杂性已被认为是引入CPCA的推动力。在此之前，有大量积压的化合物需要对化合物特异性可接受摄入量（AI）进行解读评估，因为无法实现对类别特异性毒理学关注阈值（TTC）的控制。然而，从主观评估中可以清楚地看出，从安全的角度来看，控制到特定类别的限制是没有根据的。在这篇文章中，作者提出了在手动读取和新一代的半自动计算机读取评估工具中应该考虑的因素，以确保执行稳健的评估，并且可以达成并记录一个自信的结论。提出了几个NDSRIs的关键案例研究，显示了该方法的适用性。

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引用次数: 0

Dietary administration of α-terpineol to Sprague-Dawley rats for 90 days α-松油醇对sd大鼠90 d的影响。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-20 DOI: 10.1016/j.yrtph.2025.106017

Michel Aubanel , Christopher Choi , Jan Demyttenaere , Maodo Malick Diop , Sylvain Etter , Alexandra Blanchard , Christie L. Harman , Mihoko Koyanagi , Gerhard Krammer , Gregory Ladics , Severin Müller , George Pugh , Mark R. Bauter , Shannon E. Beck , Jeanne M. Davidsen , Suzanne F. Wilson , Sean V. Taylor

α-Terpineol is a flavoring ingredient that occurs naturally in spices and foods. It has been evaluated by regulatory and scientific expert bodies such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1999 and the European Food Safety Authority (EFSA) in 2006 and has been determined safe under the conditions of intended use. To ensure the continued safety of high-usage flavoring ingredients, a 90-day Organization for Economic Co-operation and Development (OECD) 408 and Good Laboratory Practice (GLP) compliant study was conducted in Sprague-Dawley (SD) rats (10/sex/groups) at target dietary intakes to achieve doses of 0, 50, 150 or 500 mg/kg bw/day. There were no unscheduled deaths and no adverse changes in ophthalmological examinations, body weight, food consumption, food efficiency, hematology, serum chemistry, urinalysis parameters and macroscopic and microscopic observations. While not statistically significant, excessive fragmentation of sperm (head and tail separating) was observed in high-dose males, resulting in reduced or zero sperm mobility. Based on the specific sperm abnormalities observed, the no-observed-adverse-effect level (NOAEL) was determined to be the middle dose, 146 mg/kg bw/day for male SD rats and 500 mg/kg bw/day, the highest dose tested, for female SD rats.

α-松油醇是一种天然存在于香料和食品中的调味成分。1999年粮农组织/世卫组织食品添加剂联合专家委员会（JECFA）和2006年欧洲食品安全局（EFSA）等监管和科学专家机构对其进行了评估，并确定其在预期使用条件下是安全的。为了确保高用量调味料的持续安全性，我们对Sprague-Dawley （SD）大鼠（10只/性别/组）进行了一项为期90天的符合经济合作与发展组织（OECD） 408和良好实验室规范（GLP）要求的研究，这些大鼠的目标膳食摄入量分别为0、50、150或500毫克/千克体重/天。无意外死亡，眼科检查、体重、食物消耗、食物效率、血液学、血清化学、尿液分析参数及宏观和微观观察均无不良变化。虽然没有统计学意义，但在高剂量雄性中观察到精子过度碎片化（头尾分离），导致精子活动性降低或零。根据所观察到的特定精子异常，确定无观察到不良反应水平（NOAEL）为中等剂量，雄性SD大鼠为146 mg/kg bw/天，雌性SD大鼠为500 mg/kg bw/天，为最高剂量。

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引用次数: 0

Adulterated cough syrup caused acute kidney failure deaths in children: lessons have still not been learnt 掺假止咳糖浆导致儿童急性肾衰竭死亡：至今仍未吸取教训。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-19 DOI: 10.1016/j.yrtph.2025.106015

Devaraj Ezhilarasan, Munusamy Karthick

In 2025, 24 children in India died after consuming COLDRIF, a paediatric cough syrup, due to acute kidney failure. Batch SR-13 from Sresan Pharmaceuticals in Tamil Nadu, India,was contaminated with 46.28 % diethylene glycol (DEG), a toxic solvent used in place of pharmaceutical-grade excipients. Kidney biopsies from children confirmed acute tubular necrosis. DEG toxicity, via its metabolites 2-hydroxyethoxyacetic acid and diglycolic acid, causes metabolic acidosis and nephrotoxicity. Global incidents highlight repeated risks of DEG adulteration in children medicines. Regulatory lapses and poor-quality control remain major contributors. Strict adherence to Good Manufacturing Practices and vigilant regulatory oversight are essential to prevent such fatal outbreaks.

2025年，印度有24名儿童在食用COLDRIF（一种儿科止咳糖浆）后死于急性肾衰竭。批次SR-13被46.28%的二甘醇（DEG）污染，这是一种用于代替药用级赋形剂的有毒溶剂。组织病理学证实为急性肾小管坏死。DEG毒性通过其代谢物2-羟基乙氧基乙酸和二乙醇酸引起代谢性酸中毒和肾毒性。全球事件凸显了儿童药品中DEG掺假的反复风险。监管失误和质量控制不力仍然是主要原因。严格遵守良好生产规范和警惕的监管监督对于防止此类致命疫情至关重要。

引用次数: 0

Evaluation of chronic toxicity and carcinogenicity of HFPO-DA in mice HFPO-DA对小鼠的慢性毒性和致癌性评价。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-13 DOI: 10.1016/j.yrtph.2025.106014

Chad M. Thompson , Melissa M. Heintz , John M. Cullen , Laurie C. Haws

Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (HFPO-DA; CAS#: 62037-80-3) was tested for potential toxicity and carcinogenicity in CD-1 mice administered 0, 0.05, 0.1, 0.5, or 5 mg/kg-day HFPO-DA via oral gavage for 9 or 18 months. Histopathological examinations were conducted at each time point along with clinical chemistry measurements. Reduced survival was observed in male mice exposed to 5 mg/kg-day for 18 months but not 9 months. Hepatocellular hypertrophy was the most sensitive histopathological response to HFPO-DA and was significantly increased in both sexes at 9 and 18 months of exposure. At 18 months, hepatocellular hypertrophy was not observed below 0.1 mg/kg-day. Liver tumors were significantly increased at 5 mg/kg-day in males at both timepoints and in females at 18 months. No other treatment related tumors were observed. Consistent with previously published studies in mice, transcriptomic responses in the liver of both sexes showed enrichment of peroxisome proliferator-activated receptor alpha (PPARα) signaling pathways. These changes demonstrate that the tumor response in the liver is consistent with a PPARα mode of action. Other noncancer histopathological effects were limited to the adrenal gland (5 mg/kg-day at ≥9 months) and testes (≥0.5 mg/kg-day at 18 months) of male mice.

2,3,3,3-四氟-2-（七氟丙氧基）-丙酸铵（HFPO-DA; CAS#: 62037-80-3）通过灌胃0、0.05、0.1、0.5或5 mg/kg-day HFPO-DA，对CD-1小鼠进行了9或18个月的潜在毒性和致癌性测试。在每个时间点进行组织病理学检查并进行临床化学测量。5 mg/kg-day的雄性小鼠连续18个月而不是9个月的存活率降低。肝细胞肥大是HFPO-DA最敏感的组织病理反应，在暴露9个月和18个月时，肝细胞肥大在两性中显著增加。在18个月时，低于0.1 mg/kg-day时未观察到肝细胞肥大。在这两个时间点上，男性和女性在18个月时的肝脏肿瘤均显著增加。未观察到其他治疗相关肿瘤。与先前发表的小鼠研究一致，两性肝脏的转录组反应显示过氧化物酶体增殖激活受体α (PPARα)信号通路的富集。这些变化表明肝脏中的肿瘤反应与PPARα的作用模式一致。其他非癌性组织病理学影响仅限于雄性小鼠的肾上腺（≥9个月时5mg /kg-day）和睾丸（≥18个月时0.5 mg/kg-day）。

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引用次数: 0

Kinetics, tolerability and safety of (R)-1,3-butanediol (S)-lactate ester (LaKe): A randomized controlled cross-over trial in adults with obesity (R)-1,3-丁二醇(S)-乳酸酯（LaKe）的动力学、耐受性和安全性：一项成人肥胖患者的随机对照交叉试验。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-12 DOI: 10.1016/j.yrtph.2025.106013

Simon K. Kjær , Nikolaj Rittig , Jens M. Bruun , Niels Møller , Mads Svart

Hyperketonemia and hyperlactatemia can be induced by exogenous supplementation of each individual compound. In this study we examined the safety profile of (R)-1,3-butanediol (S)-lactate ester, a new lactate-ketone ester (LaKe). We hypothesized that 4 weeks of LaKe supplementation would induce hyperketonemia, hyperlactatemia, be feasible, tolerable, and safe. In this randomized, double-blind, placebo-controlled cross-over study, otherwise healthy adults with obesity (N = 10) received 25 mL (∼27.75 g) LaKe or taste-matched non-caloric placebo twice daily for 28 days, followed by an additional dose in a laboratory setting on day 29 with fasting and continuous blood sampling. Compliance was ≥80 % with no dropouts. 28 days of LaKe consumption was overall well tolerated but associated with mild to moderate gastrointestinal side effects without affecting organ function biomarkers. Following a 25 mL dose of LaKe, beta-hydroxybutyrate (βHB) and lactate concentrations peaked at 0.6 mmol/L (IQR 0.5–0.675 mmol/L) and 2.15 mmol (IQR 1.5–2.65 mmol/L), respectively, while blood gases and and electrolytes remained within normal ranges. LaKe elevates blood concentrations of both βHB and lactate. The consumption of LaKe twice daily for 28 days is well tolerated and safe, although associated with mild to moderate gastrointestinal side effects.

高酮血症和高乳酸血症可通过外源性补充每个单独的化合物引起。在这项研究中，我们检查了(R)-1,3-丁二醇(S)-乳酸酯的安全性，这是一种新的乳酸酮酯（LaKe）。我们假设补充4周的LaKe会诱发高酮血症和高乳酸血症，这是可行的、可耐受的和安全的。在这项随机、双盲、安慰剂对照的交叉研究中，肥胖的健康成年人（N=10）每天两次接受25 mL (~ 27.75 g) LaKe或口味匹配的无热量安慰剂，持续28天，然后在第29天在实验室环境中额外剂量，禁食和连续抽血。依从性≥80%，无退出。28天的LaKe消费总体耐受良好，但与轻度至中度胃肠道副作用相关，不影响器官功能生物标志物。在25 mL的LaKe剂量下，β -羟基丁酸（βHB）和乳酸浓度分别达到0.6 mmol/L （IQR 0.5-0.675 mmol/L）和2.15 mmol/L (IQR 1.5-2.65 mmol/L)，而血气和电解质保持在正常范围内。湖升高血中βHB和乳酸浓度。尽管与轻度至中度胃肠道副作用相关，但每日两次连续28天的LaKe耐受性良好且安全。

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引用次数: 0

Methoxyflurane exposure in ambulances: a controlled laboratory study on paramedic safety 救护车中甲氧基氟醚暴露：护理人员安全的对照实验室研究。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-11 DOI: 10.1016/j.yrtph.2025.106012

Michael A. Austin , Somalin Mao , Jonathan MacLeod , Zachary Cantor

Methoxyflurane, a self-administered fluorinated hydrocarbon, provides rapid, relief for traumatic pain. While low-dose methoxyflurane poses minimal risk, paramedics may experience intermittent exposure. This study assesses occupational risks to enhance paramedic safety, health standards, and patient care directives.

Active air sampling was conducted in a Ministry of Health-approved ambulance, in the driver and patient compartment, under controlled conditions, both with and without ventilation. Twelve healthy participants inhaled for 15 min, with samples collected per EPA and ISO standards. Results were adjusted for time weighted average (TWA) exposure.

Twenty-four air samples were collected (median age 30.5 years, 50 % female). Exposure concentrations remained below 8-h TWA occupational limits and NIOSH 60-min ceiling limits. With ventilation, 8-h TWA levels were 0.001 ppm (driver) and 0.033 ppm (patient compartment), rising to 0.017 ppm and 0.057 ppm without ventilation. Maximum TWA levels for 22 transports (30-min duration) reached 0.019 ppm (driver) and 0.736 ppm (patient) with ventilation, increasing to 0.377 ppm and 1.254 ppm without. These were based upon worst-case assumptions of 22 treatment and transport events, each lasting 30 min, over a 12 h work shift. Ventilation significantly reduced exposure, with 99.1 % protocol adherence and no adverse events.

This controlled study confirms methoxyflurane's safe use in ambulances with exposure well below safety thresholds. Ventilation minimizes potential risk(s), ensuring paramedic safety and uninterrupted pain management.

甲氧基氟醚是一种自行使用的氟化碳氢化合物，能迅速缓解创伤性疼痛。虽然低剂量甲氧基氟醚的风险最小，但护理人员可能会间歇性接触。本研究评估职业风险，以提高护理人员的安全、健康标准和病人护理指示。在一辆卫生部批准的救护车上，在驾驶员和病人车厢内，在受控条件下进行了主动空气采样，有和没有通风。12名健康参与者吸入15分钟，并根据EPA和ISO标准收集样本。结果根据时间加权平均（TWA）暴露进行调整。收集了24份空气样本（中位年龄30.5岁，50%为女性）。暴露浓度仍低于8小时TWA职业限值和NIOSH 60分钟上限限值。在通风条件下，8小时TWA水平为0.001 ppm（驾驶员）和0.033 ppm（患者室），在不通风的情况下上升到0.017 ppm和0.057 ppm。22次运输（持续时间30分钟）的最大TWA水平在有通风的情况下达到0.019 ppm（驾驶员）和0.736 ppm（患者），在没有通风的情况下增加到0.377 ppm和1.254 ppm。这些是基于22个治疗和运输事件的最坏情况假设，每个事件持续30分钟，超过12小时的轮班。通气显著减少暴露，99.1%的人遵守协议，无不良事件发生。这项对照研究证实，甲氧基氟醚在远低于安全阈值的救护车中使用是安全的。通气可将潜在风险降至最低，确保护理人员安全和不间断的疼痛管理。

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引用次数: 0

Use of human data for risk assessment of pesticides: A review including an evaluation of trichlorfon as case study 使用人类数据进行农药风险评估：一项审查，包括对敌百虫作为个案研究的评价。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-09 DOI: 10.1016/j.yrtph.2025.106011

Giulia Collatuzzo , Paolo Boffetta

Pesticides are suspected to cause health effects in humans, but human-based data on their toxicity are often insufficient to establish associations and quantify risks. We reviewed literature on trichlorfon and investigated methodological aspects of risk assessment for pesticides based on human data. We provided an overview of epidemiology of pesticide toxicity, with focus on methodological features of the available studies, combined with a systematic review of the health effects of the pesticide, trichlorfon in humans, focusing on studies published after 1990. Studies on dichlorvos, the metabolite of trichlorfon, as well as metrifonate, a medication with the identical formula as trichlorfon, were included. A total of 60 publications were identified on health effects of trichlorfon, dichlorvos and metrifonate. Studies on acute effects (N = 23 publications) comprised mainly case-reports related to accidents and suicidal attempts, and were connoted by cholinergic syndrome, gastrointestinal and general symptoms. Evidence on chronic effects derived from analyses of the Agricultural Health Study (28 publications), as well as case-control and cross-sectional studies (9 publications). Evidence of possible associations between trichlorfon or dichlorvos exposure and various outcomes was heterogeneous and insufficient to establish causality. Critical features of epidemiology studies used for pesticide risk assessment include study design, exposure misclassification, lack of quantitative exposure data, and lack of consideration to potential confounders. Few high-quality epidemiology studies are available on potential health effects of trichlorfon. Future studies conducted according to established guidelines and supported by artificial intelligence might help to fill the gap on human health risks from pesticides.

农药被怀疑对人类健康造成健康影响，但基于人类的毒性数据往往不足以建立关联和量化风险。我们回顾了有关敌百虫的文献，并调查了基于人体数据的农药风险评估的方法学方面。我们概述了农药毒性的流行病学，重点介绍了现有研究的方法学特点，并对农药敌百虫对人类健康的影响进行了系统审查，重点介绍了1990年以后发表的研究。对敌百虫的代谢物敌敌畏以及配方与敌百虫相同的药物三氟膦酸盐进行了研究。共确定了60份关于敌百虫、敌敌畏和三氟膦酸盐对健康影响的出版物。关于急性效应的研究（N=23篇出版物）主要包括与事故和自杀企图有关的病例报告，并伴有胆碱能综合征、胃肠道和一般症状。关于慢性影响的证据来自农业健康研究（28篇出版物）以及病例对照和横断面研究（9篇出版物）的分析。暴露于敌百虫或敌敌畏与各种结果之间可能存在关联的证据参差不齐，不足以确定因果关系。用于农药风险评估的流行病学研究的关键特征包括研究设计、暴露错误分类、缺乏定量暴露数据以及缺乏对潜在混杂因素的考虑。关于敌百虫对健康的潜在影响的高质量流行病学研究很少。未来根据既定准则并在人工智能支持下进行的研究可能有助于填补农药对人类健康风险的空白。

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引用次数: 0

Subchronic oral toxicity and genotoxicity of Aurantii Fructus Immaturus water extract 枳实水提取物的亚慢性口服毒性及遗传毒性研究。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-09 DOI: 10.1016/j.yrtph.2025.106010

So-Young An , Si-Whan Song , Hyun-Suk Heo , Chang-Wok Park , Min-Sub Kim , Woo-Joo Lee , Yoo-Jin Park , Jae-Ho Shin , Beom Seok Han , Wan-Seob Cho

Aurantii Fructus Immaturus (AFI) water extract has been utilized in traditional medicine; however, its toxicity data are still lacking. In this study, we evaluated the general and genetic toxicity of the AFI water extract as a project of the Korea National Toxicology Program (KNTP). Naringin and neohesperidin, marker compounds of AFI, contained in the AFI water extract were 7.63 % and 4.51 %, respectively. These levels were higher than AFI powders, which contain about 4 % naringin and 3 % neohesperidin. The acute oral toxicity study in rats, conducted at doses of 2500–10000 mg/kg, demonstrated that the median lethal dose (LD₅₀) of AFI water extract exceeds 10000 mg/kg. Subacute oral toxicity tests at doses up to 5000 mg/kg/day and subchronic toxicity studies conducted over 13 weeks at similar dose ranges showed no treatment-related adverse effects. Thus, the no-observed-adverse-effect level (NOAEL) of AFI water extract in rats was 5000 mg/kg bw/day. Additionally, three genotoxicity assays (bacterial reverse mutation, in vitro chromosomal aberration, and in vivo micronucleus tests) confirmed that the AFI water extract is not genotoxic. These results will provide the toxicity data for the risk assessment of AFI water extract for human consumption.

枳实（AFI）水提物已被广泛应用于传统医学；然而，其毒性数据仍然缺乏。在本研究中，作为韩国国家毒理学计划（KNTP）的一个项目，我们评估了AFI水提取物的一般毒性和遗传毒性。AFI水提物中柚皮苷和新橙皮苷的含量分别为7.63%和4.51%。这些含量高于AFI粉末，后者含有约4%的柚皮苷和3%的新橙皮苷。2500 ~ 10000 mg/kg大鼠急性口服毒性研究表明，AFI水提取物的中位致死剂量（LD50）超过10000 mg/kg。剂量高达5000 mg/kg/天的亚急性口服毒性试验和在类似剂量范围内进行的超过13周的亚慢性毒性研究显示，没有与治疗相关的不良反应。因此，AFI水提物对大鼠的无观察不良反应水平（NOAEL）为5000 mg/kg bw/day。此外，三种遗传毒性试验（细菌反向突变、体外染色体畸变和体内微核试验）证实AFI水提取物没有遗传毒性。这些结果将为人类食用AFI水提取物的毒性风险评估提供依据。

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引用次数: 0