Regulatory Toxicology and Pharmacology最新文献

Analysis of predictive value of animal repeated dose toxicity study results for clinical safety of US FDA-approved anticancer drugs between 2019 and 2023 动物重复剂量毒性研究结果对2019 - 2023年美国fda批准的抗癌药物临床安全性的预测价值分析

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.yrtph.2026.106031

Gyeyoung Choi , Seungjin Bae , Kyung-Min Lim

The translational relevance of nonclinical animal studies in predicting clinical safety outcomes remains poorly understood in oncology drug development. This study aimed to qualitatively assess the concordance between toxicological findings from animal repeat-dose toxicity studies and treatment-emergent adverse events (TEAEs) in clinical trials of 63 anticancer drugs approved by the U.S. FDA from 2019 to 2023. We extracted nonclinical and clinical safety data from FDA review documents and categorized observations across 20 organ systems using a Concordant Positive/Concordant Negative/Animal-only Positive/Clinical-only Positive classification framework. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by organ class and animal species. Among 63 anti-cancer drugs analyzed, hematologic, hepatobiliary, and gastrointestinal systems exhibited high concordance (notably high PPV and sensitivity), while bone/tooth and lymphatic systems showed low translational predictivity. Predictive performance was similar across rats, dogs, and monkeys, with no statistically significant interspecies differences. These findings suggest that current animal models offer organ-specific, but not species-specific, translational value for anti-cancer drugs. A shift toward validated, human-relevant alternative models is recommended for organ classes with low predictive performance in animal studies, to enhance translational accuracy while reducing animal sacrifice.

在肿瘤药物开发中，非临床动物研究在预测临床安全性结果中的转化相关性仍然知之甚少。本研究旨在定性评估2019年至2023年美国FDA批准的63种抗癌药物临床试验中动物重复剂量毒性研究毒理学结果与治疗发生不良事件（teae）之间的一致性。我们从FDA审查文件中提取了非临床和临床安全性数据，并使用协和阳性/协和阴性/仅动物阳性/仅临床阳性分类框架对20个器官系统的观察结果进行了分类。按器官分类和动物种类计算敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）。在分析的63种抗癌药物中，血液系统、肝胆系统和胃肠道系统表现出高度的一致性（特别是高PPV和敏感性），而骨/牙齿和淋巴系统表现出较低的翻译预测性。大鼠、狗和猴子的预测性能相似，在物种间没有统计学上的显著差异。这些发现表明，目前的动物模型为抗癌药物提供了器官特异性而非物种特异性的转化价值。对于动物研究中预测性能较低的器官类别，建议转向经过验证的、与人类相关的替代模型，以提高翻译准确性，同时减少动物牺牲。

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引用次数: 0

Nonclinical development of advanced therapies: Best practices for translational and regulatory success 先进疗法的非临床开发：转化和监管成功的最佳实践

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.yrtph.2026.106032

Piyan Zhang

Advanced therapeutics—including cell and gene therapies, antibody–drug conjugates, and RNA-based medicines—present unique in vivo pharmacology, safety, and translational challenges that require tailored nonclinical programs aligned with global regulatory expectations. This review synthesizes best practices for designing IND/CTA-enabling studies, integrating biodistribution, pharmacokinetics/pharmacodynamics, immunogenic assessment, safety pharmacology, toxicology, and dose selection into a cohesive strategy. Regulatory frameworks from the FDA, EMA, and PMDA emphasize early engagement, modality-specific risk assessment, and harmonization through ICH guidance (e.g., S12). Key recommendations include using relevant animal models, novel analytical methods, and conservative first-in-human dosing to mitigate translational uncertainties. Distinct considerations for oncology versus non-oncology indications are highlighted, reflecting differing risk tolerances and data requirements. Case studies of clinical holds and successful submissions underscore the importance of anticipating regulatory concerns, ensuring manufacturing readiness, and implementing robust risk mitigation. By adopting these integrated scientific and regulatory strategies, developers can streamline translation from preclinical studies to human trials, ultimately accelerating the delivery of safe, effective advanced therapies.

先进疗法——包括细胞和基因疗法、抗体-药物偶联物和基于rna的药物——呈现出独特的体内药理学、安全性和转化挑战，需要量身定制符合全球监管期望的非临床项目。这篇综述综合了设计IND/ cta研究的最佳实践，将生物分布、药代动力学/药效学、免疫原性评估、安全药理学、毒理学和剂量选择整合到一个统一的策略中。FDA、EMA和PMDA的监管框架强调早期参与、特定模式的风险评估，以及通过ICH指导进行协调（例如，S12）。主要建议包括使用相关的动物模型、新的分析方法和保守的首次人体给药来减轻转化的不确定性。强调了肿瘤与非肿瘤适应症的不同考虑，反映了不同的风险承受能力和数据要求。临床持有和成功提交的案例研究强调了预测监管问题、确保生产准备和实施强有力的风险缓解的重要性。通过采用这些综合的科学和监管策略，开发人员可以简化从临床前研究到人体试验的转换，最终加速安全、有效的先进疗法的交付。

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引用次数: 0

Prolonged exposure to nitrate in drinking water does not adversely impact prenatal or birth outcomes in a rat model 在大鼠模型中，长期暴露于饮用水中的硝酸盐不会对产前或分娩结果产生不利影响

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-09 DOI: 10.1016/j.yrtph.2026.106030

Leaf R. Kardol , Avalon Gray , Amina Rhaman , Alexander N. Larcombe , Christine Jeffries-Stokes , Annette Stokes , Sarah Bourke , Sujata Shinde , Kevin Croft , Caitlin S. Wyrwoll

Nitrate (NO₃⁻) is a common drinking water contaminant associated with increased risks of adverse pregnancy outcomes at concentrations below the World Health Organisation (WHO) drinking water guidelines (50 mg/L NO₃⁻). However, causal evidence at relevant concentrations is sparse. This study aimed to characterise the effects of prolonged exposure to drinking water nitrate at concentrations relevant to human exposure on maternal, fetal, and birth outcomes. Wistar rats were exposed to 0, 50 or 100 mg/L NO₃⁻ as sodium nitrate in drinking water three weeks pre-conception and throughout gestation. At 21 days gestation, fetal and placental weights and morphology, maternal outcomes including plasma nitrate and nitrite, endocrine and inflammatory markers, and uterine artery haemodynamics were analysed. In a second cohort, birth timing and weight were assessed. While nitrate exposure substantially increased maternal plasma nitrate and nitrite concentrations, no consistent effects were seen on fetal or placental outcomes or endocrine/inflammatory markers. Several birth complications, small litters and higher uterine artery blood velocities were noted in nitrate-exposed groups, but these outcomes were highly variable. These results show that chronic exposure to nitrate at or above the WHO drinking water guidelines subtly impacts rat pregnancy and do not provide causal support for the findings of epidemiological studies.

硝酸盐（NO3−）是一种常见的饮用水污染物，浓度低于世界卫生组织（WHO）饮用水指南（50 mg/L NO3−）时，与不良妊娠结局的风险增加有关。然而，相关浓度的因果证据很少。本研究旨在描述长期暴露于与人类暴露浓度相关的饮用水硝酸盐对母体、胎儿和分娩结果的影响。Wistar大鼠在孕前三周和整个妊娠期间分别在饮用水中暴露于0、50或100 mg/L NO3−硝酸钠。在妊娠第21天，分析胎儿和胎盘的重量和形态，产妇结局包括血浆硝酸盐和亚硝酸盐，内分泌和炎症标志物，子宫动脉血流动力学。在第二个队列中，对出生时间和体重进行了评估。虽然硝酸盐暴露大大增加了母体血浆硝酸盐和亚硝酸盐浓度，但对胎儿或胎盘结局或内分泌/炎症标志物没有一致的影响。在硝酸盐暴露组中注意到一些分娩并发症，产仔少和子宫动脉血流速度加快，但这些结果变化很大。这些结果表明，长期暴露于达到或高于世卫组织饮用水指南的硝酸盐对大鼠妊娠有微妙的影响，并不能为流行病学研究的结果提供因果支持。

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引用次数: 0

Analysis of occupational exposure limits for hazardous chemical agents of African countries: A comparative study 非洲国家危险化学剂职业接触限值分析：比较研究

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.yrtph.2026.106029

Nadia Suzette Botha, Ilzé Engelbrecht, Suranie Rachel Horn

Occupational exposure limits (OELs) are a valuable tool used by occupational hygiene professionals to assess exposure and determine when measures should be employed to control exposure to hazardous chemical agents (HCAs) in the workplace. Many countries have OELs that are included in their respective occupational health and safety legislation. In South Africa, the Regulations for Hazardous Chemical Substances (RHCS SA, 1995) were first published in 1995. It was repealed and replaced with the Regulations for Hazardous Chemical Agents (RHCA SA, 2021). This study aimed to comparatively evaluate the progress of OELs in South Africa for certain HCAs as stated in the RHCA SA 2021 in terms of the previous version (RHCS SA, 1995) and other countries in Africa with OELs. This was done to provide insights into the gap in OEL development in Africa. The findings show that of the 54 countries in Africa, only 10 have OELs included in their occupational health and safety legislation. Legislative documents from five African countries were compared to the RHCA SA 2021 using the geometric mean method. The results indicate that South Africa has less stringent OELs than the other African countries to which it was compared, with the exception of Lesotho. This highlights the work that still needs to be done to improve OELs in African countries.

职业暴露限值（OELs）是职业卫生专业人员用来评估暴露和确定何时应采取措施来控制工作场所危险化学剂（hca）暴露的宝贵工具。许多国家在各自的职业健康和安全立法中都纳入了OELs。在南非，1995年首次出版了《危险化学物质条例》（RHCS SA, 1995）。它被废除并被《危险化学剂条例》（RHCA SA, 2021）所取代。本研究旨在对比评估南非在RHCA SA 2021中所述的某些HCAs的OELs进展与之前版本（RHCS SA, 1995）和其他具有OELs的非洲国家。这样做是为了深入了解非洲OEL发展的差距。调查结果表明，在非洲54个国家中，只有10个国家的职业健康和安全立法中纳入了OELs。使用几何平均方法将五个非洲国家的立法文件与RHCA SA 2021进行了比较。结果表明，除莱索托外，南非的OELs比与之比较的其他非洲国家不那么严格。这凸显了改善非洲国家OELs的工作任重而道远。

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引用次数: 0

Development and evaluation of a novel consensus in silico model within the OECD GL497 defined approach for skin sensitization prediction 在OECD GL497定义的皮肤致敏预测方法中开发和评估一种新的共识硅模型。

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2026-01-05 DOI: 10.1016/j.yrtph.2026.106028

Mika Imamura , Ryoichi Murakami , Masakazu Tateshita , Yasushi Hikida

Skin sensitization is a key endpoint in chemical safety assessment, involving multiple key events (KEs) in the adverse outcome pathway. The integrated testing strategy defined approach (ITS-DA) in OECD GL497 combines non-animal methods addressing KE1 and KE3 with an in silico component to predict sensitization. We developed a novel consensus in silico model integrating a rule-based system with metabolic simulation and two statistical models trained on local lymph node assay (LLNA) and guinea pig maximization test (GPMT) data.

When applied as the in silico element of the ITS-DA, the model achieved balanced accuracies of 77 % for LLNA and 70 % for human data, surpassing existing in silico approaches. Furthermore, we developed a rule- and statistics-based KE1 replacement model (RSRKE1) that estimates protein-binding potential without in chemico KE1 assays. Combining RSRKE1 with the human Cell Line Activation Test (h-CLAT, KE3) and the consensus model yielded sensitivities of ∼80 % and potency classification accuracies of ∼70 % for LLNA, with similar performance for human data.

These results demonstrate that the consensus model and RSRKE1 can maintain predictive performance comparable to established ITS-DA workflows, while eliminating the need for certain in vitro assays. This approach supports regulatory acceptance of non-animal testing strategies for skin sensitization assessment.

皮肤致敏是化学品安全性评估的关键终点，涉及不良结果通路中的多个关键事件（KEs）。OECD GL497中的综合测试策略定义方法（ITS-DA）将非动物方法与硅成分结合起来，解决KE1和KE3的问题，以预测致敏性。我们开发了一个新的共识硅模型，集成了基于规则的代谢模拟系统和两个基于局部淋巴结测定（LLNA）和豚鼠最大化试验（GPMT）数据训练的统计模型。当应用于ITS-DA的计算机元素时，该模型在LLNA和人类数据上实现了77%的平衡精度，超过了现有的计算机方法。此外，我们开发了一个基于规则和统计的KE1替代模型（RSRKE1），该模型可以在没有化学KE1检测的情况下估计蛋白质结合潜力。将RSRKE1与人类细胞系激活试验（h-CLAT, KE3）和共识模型结合使用，LLNA的灵敏度为80%，效力分类精度为70%，对人类数据具有相似的性能。这些结果表明，共识模型和RSRKE1可以保持与已建立的ITS-DA工作流程相当的预测性能，同时消除了对某些体外检测的需要。这种方法支持监管机构接受非动物试验策略进行皮肤致敏评估。

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引用次数: 0

Four-year monitoring of pesticide residues in Egyptian sweet peppers 埃及甜椒四年农药残留监测

IF 3.5 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.yrtph.2025.106027

Farag Malhat , Shokr Abdel Salam Shokr , Fawzy Eissa

This study monitored pesticide residues in 1826 sweet pepper samples from Egyptian markets (2021–2024), screening for 430 pesticides using QuEChERS extraction with LC-MS/MS and GC-MS/MS. Results revealed concerning contamination trends, with samples exceeding EU Maximum Residue Limits (MRLs) increasing from 14.95 % (2021) to 37.38 % (2023), before declining to 28.74 % (2024). Between 42 and 97 different pesticides were detected annually, with acetamiprid consistently the most prevalent (21.5–29.51 %). Neonicotinoids dominated detections, representing two to four compounds in annual top-10 rankings. Multiple residue contamination escalated dramatically from 45.79 % (2021) to 69.35 % (2023), with samples containing up to 16 pesticides simultaneously. Chlorpyrifos and bifenazate showed severe MRL violations, exceeding limits by 6.2-fold and 25.9-fold, respectively. Despite extensive contamination, chronic dietary risk assessment across 13 population groups indicated acceptable exposure levels, with all calculated %ADI values below the 100 % safety threshold. The highest exposure corresponded to 3.47 % of the ADI for chlorpyrifos in the GEMS/Food G15 population. While current consumption poses negligible health risks, the high prevalence of MRL violations and multiple residues highlights urgent needs for enhanced agricultural practices and regulatory enforcement to ensure long-term food safety.

本研究对埃及市场1826份甜椒样品（2021-2024）的农药残留进行了监测，采用QuEChERS萃取、LC-MS/MS和GC-MS/MS对430种农药进行了筛选。结果显示了污染趋势，超过欧盟最大残留限量（MRLs）的样品从14.95%（2021年）增加到37.38%（2023年），然后下降到28.74%（2024年）。每年共检出42 ~ 97种农药，其中以啶虫脒的检出率最高（21.5 ~ 29.51%）。新烟碱类在检测中占主导地位，在年度前10名中占2到4个化合物。多重残留污染从45.79%（2021年）急剧上升至69.35%（2023年），样品中同时含有多达16种农药。毒死蜱和联苯肼严重违反MRL，分别超标6.2倍和25.9倍。尽管存在广泛的污染，但对13个人群进行的慢性饮食风险评估表明，暴露水平是可以接受的，所有计算出的%ADI值都低于100%安全阈值。在GEMS/Food G15人群中，毒死蜱的最高暴露量相当于每日摄入量的3.47%。虽然目前的消费构成的健康风险可以忽略不计，但严重违反MRL规定和多种残留的情况突出表明，迫切需要加强农业实践和监管执法，以确保长期食品安全。

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引用次数: 0

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