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Toxicological Assessment of Higher Olefins in OECD TG 422 Repeated Dose and Reproductive /Developmental Toxicity Screening Tests in Han Wistar Rats. OECD TG 422重复给药和汉族Wistar大鼠生殖/发育毒性筛选试验中高级烯烃的毒理学评估。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-01 Epub Date: 2023-11-07 DOI: 10.1177/10915818231210856
Quan Shi, Juan-Carlos Carrillo, Michael G Penman, Hua Shen, Colin M North, Sophie Jia, Tilly Borsboom-Patel, Yuan Tian, Fabienne Hubert, Jason C Manton, Peter J Boogaard

Higher olefins (HO) are used primarily as intermediates in the production of other chemicals, such as polymers, fatty acids, plasticizer alcohols, surfactants, lubricants, amine oxides, and detergent alcohols. The potential toxicity of five HO (i.e., 1-Octene, Nonene, Decene, Hexadecene, and 1-Octadecene) with carbon ranging from C8 to C18 was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD TG 422). These five HO were administered to Han Wistar rats by gavage at 0 (controls), 100, 300, and 1000 mg/kg bw/day. As a group of substances, adaptive changes in the liver (liver weight increase without pathological evidence), as well as increased kidney weight in male rats, were observed in HO with carbon numbers from C8 to C10. The overall systemic no observed adverse effect level (NOAEL) for all HO was determined at 1000 mg/kg bw/day. In the reproductive/developmental toxicity assessment, offspring viability, size, and weights were reduced in litters from females treated with Nonene at 1000 mg/kg bw/day. The overall no observed effects level (NOEL) for reproductive toxicity was considered to be 300 mg/kg bw/day for Nonene and 1000 mg/kg bw/day for the other four HO, respectively. These data significantly enrich the database on the toxicity of linear and branched HO, allowing comparison with similar data published on a range of linear and branched HO. Comparisons between structural class and study outcome provide further supportive data in order to validate the read-across hypothesis as part of an overall holistic testing strategy.

高级烯烃(HO)主要用作生产其他化学品的中间体,如聚合物、脂肪酸、增塑剂醇、表面活性剂、润滑剂、胺氧化物和洗涤剂醇。在重复剂量和生殖/发育毒性联合筛选研究中,检测了五种HO(即1-辛烯、壬烯、癸烯、十六烯和1-十八烯)对C8至C18碳的潜在毒性(OECD TG 422)。这五种HO分别以0(对照)、100、300和1000 mg/kg bw/天灌胃给药于汉族Wistar大鼠。作为一组物质,在HO中观察到肝脏的适应性变化(在没有病理学证据的情况下肝脏重量增加),以及雄性大鼠肾脏重量增加,碳数从C8到C10。所有HO的全身无不良反应水平(NOAEL)测定为1000 mg/kg体重/天。在生殖/发育毒性评估中,用1000毫克/公斤体重/天的壬烯处理的雌性窝仔的后代生存能力、大小和重量都有所降低。生殖毒性的总体无观测效应水平(NOEL)被认为对壬烯分别为300毫克/公斤体重/天,对其他四种HO分别为1000毫克/公斤重量/天。这些数据显著丰富了关于线性和支链HO毒性的数据库,允许与一系列线性和支链HO的类似数据进行比较。结构类别和研究结果之间的比较提供了进一步的支持性数据,以验证作为整体测试策略一部分的跨读假设。
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引用次数: 0
In vitro Safety Assessment of Extracts and Compounds From Plants as Sunscreen Ingredients. 植物提取物和化合物作为防晒成分的体外安全性评估。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-01 Epub Date: 2024-01-06 DOI: 10.1177/10915818231225661
Silvia Juliana Flórez González, Elena E Stashenko, Raquel Elvira Ocazionez, María Pilar Vinardell, Jorge Luis Fuentes

This work investigated the safety of extracts obtained from plants growing in Colombia, which have previously shown UV-filter/antigenotoxic properties. The compounds in plant extracts obtained by the supercritical fluid (CO2) extraction method were identified using gas chromatography coupled to mass spectrometry (GC/MS) analysis. Cytotoxicity measured as cytotoxic concentration 50% (CC50) and genotoxicity of the plant extracts and some compounds were studied in human fibroblasts using the trypan blue exclusion assay and the Comet assay, respectively. The extracts from Pipper eriopodon and Salvia aratocensis species and the compound trans-β-caryophyllene were clearly cytotoxic to human fibroblasts. Conversely, Achyrocline satureioides, Chromolaena pellia, and Lippia origanoides extracts were relatively less cytotoxic with CC50 values of 173, 184, and 89 μg/mL, respectively. The C. pellia and L. origanoides extracts produced some degree of DNA breaks at cytotoxic concentrations. The cytotoxicity of the studied compounds was as follows, with lower CC50 values representing the most cytotoxic compounds: resveratrol (91 μM) > pinocembrin (144 μM) > quercetin (222 μM) > titanium dioxide (704 μM). Quercetin was unique among the compounds assayed in being genotoxic to human fibroblasts. Our work indicates that phytochemicals can be cytotoxic and genotoxic, demonstrating the need to establish safe concentrations of these extracts for their potential use in cosmetics.

这项研究调查了从哥伦比亚生长的植物中提取的萃取物的安全性,这些植物曾显示出紫外线过滤/抗原毒性特性。通过超临界流体(CO2)萃取法获得的植物提取物中的化合物采用气相色谱-质谱联用(GC/MS)分析法进行了鉴定。利用胰蓝排除法和彗星试验,分别研究了植物提取物和一些化合物在人成纤维细胞中的细胞毒性(以细胞毒性浓度 50%(CC50)计)和遗传毒性。Pipper eriopodon 和 Salvia aratocensis 的提取物以及化合物 trans-β-caryophyllene 对人类成纤维细胞具有明显的细胞毒性。相反,Achyrocline satureioides、Chromolaena pellia 和 Lippia origanoides 提取物的细胞毒性相对较低,CC50 值分别为 173、184 和 89 μg/mL。在细胞毒性浓度下,C. pellia 和 L. origanoides 提取物会产生一定程度的 DNA 断裂。研究化合物的细胞毒性如下,CC50 值越低,代表化合物的细胞毒性越强:白藜芦醇(91 μM)>松果菊素(144 μM)>槲皮素(222 μM)>二氧化钛(704 μM)。在所检测的化合物中,槲皮素对人类成纤维细胞的基因毒性是独一无二的。我们的研究结果表明,植物化学物质可能具有细胞毒性和基因毒性,因此有必要确定这些提取物的安全浓度,以便将其用于化妆品。
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引用次数: 0
Safety Assessment of Streptococcus salivarius UBSS-01 in Rats and Double-Blind Placebo-Controlled Study in Healthy Individuals 唾液链球菌 UBSS-01 在大鼠中的安全性评估和在健康人中的双盲安慰剂对照研究
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-27 DOI: 10.1177/10915818241247527
Bindhu S. Jatoth, Ziaur Rahman, Manoj P. Dandekar, Rajesh Venkataraman, Ravi K. Shivalingegowda, Gloriya G. Manuel
Streptococcus salivarius is a common, harmless, and prevalent member of the oral microbiota in humans. In the present study, the safety of S. salivarius UBSS-01 was evaluated using in silico methods and preclinical and clinical studies. In an acute toxicity study, rats were administered with 5 g/kg (500 × 109 CFU) S. salivarius UBSS-01. The changes in phenotypic behaviors and hematological, biochemical, electrolytes, and urine analyses were monitored. No toxicity was observed at 14 days post-treatment. The no observable effects limit (NOEL) of S. salivarius UBSS-01 was >5 g/kg in rats. In a 28-day repeat dose toxicity study, rats were administered S. salivarius UBSS-01 once daily at doses of 0.1, 0.5, and 1 g/kg (10, 50, and 100 billion CFU/kg, respectively) body weight. S. salivarius UBSS-01 did not influence any of the hematology parameters and clinical chemistry parameters in plasma and serum samples after 28-day repeated administration. No structural abnormality was observed in the histological examination of organs. Whole genome analysis revealed the absence of virulence factors or genes that may transmit antibiotic resistance. In the double-blind study with 60 human participants (aged 18–60 years), consumption of S. salivarius UBSS-01 for 30 days was found to be safe and results were comparable with placebo treatment These findings indicate that S. salivarius UBSS-01 may be safe for human consumption.
唾液链球菌是人类口腔微生物群中常见、无害且普遍的成员。本研究采用硅学方法和临床前及临床研究对唾液链球菌 UBSS-01 的安全性进行了评估。在急性毒性研究中,大鼠每公斤摄入 5 克(500 × 109 CFU)唾液酸酵母菌 UBSS-01。研究人员监测了大鼠的表型行为变化以及血液、生化、电解质和尿液分析。治疗后 14 天未观察到毒性。唾液腺单胞菌 UBSS-01 对大鼠的无观测效应限(NOEL)为 5 克/千克。在一项为期 28 天的重复剂量毒性研究中,按 0.1、0.5 和 1 克/千克(分别为 100、500 和 1000 亿 CFU/千克)的体重剂量给大鼠每天注射一次唾液球菌 UBSS-01。重复给药 28 天后,唾液球菌 UBSS-01 没有影响血浆和血清样本中的任何血液学参数和临床化学参数。器官组织学检查未发现结构异常。全基因组分析表明,不存在可能传播抗生素耐药性的毒力因子或基因。在对 60 名人类参与者(18-60 岁)进行的双盲研究中发现,连续 30 天食用唾液腺战士 UBSS-01 是安全的,其结果与安慰剂治疗相当。
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引用次数: 0
Zinc Phenolsulfonate. 苯酚磺酸锌。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-25 DOI: 10.1177/10915818241249416
Regina Tucker, Wilma F Bergfeld, Donald V Belsito, David E. Cohen, Curtis D. Klaassen, Allan E. Rettie, David Ross, Thomas J. Slaga, Paul W. Snyder, Susan Tilton, Monice Fiume, Bart Heldreth
The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1986 and a previous re-review in 2004, along with updated information regarding product types and concentrations of use. Considering this information, the Panel confirmed that Zinc Phenolsulfonate is safe as a cosmetic ingredient in the present practices of use and concentration as described in this report.
化妆品成分安全专家小组审查了自 1986 年首次评估和 2004 年再次审查以来的最新研究成果,以及有关产品类型和使用浓度的最新信息。考虑到这些信息,专家小组确认,按照本报告所述的当前使用方法和浓度,苯酚磺酸锌作为化妆品成分是安全的。
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引用次数: 0
Laneth Acetates. 乙酸拉奈斯酯。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-23 DOI: 10.1177/10915818241249398
Priya Cherian, Wilma F Bergfeld, Donald V Belsito, David E. Cohen, Curtis D. Klaassen, Allan E. Rettie, David Ross, Thomas J. Slaga, Paul W. Snyder, Susan Tilton, Monice Fiume, Bart Heldreth
The Expert Panel for Cosmetic Ingredient Safety reviewed newly available studies since their original assessment in 1982 and a previous re-review in 2002, along with updated information regarding product types and concentrations of use. Considering this information, the Panel confirmed that Laneth-9 Acetate and Laneth-10 Acetate are safe for topical application to humans in the present practices of use and concentration as described in this report.
化妆品成分安全专家小组审查了自 1982 年首次评估和 2002 年再次审查以来的最新研究结果,以及有关产品类型和使用浓度的最新信息。考虑到这些信息,专家小组确认,按照本报告所述的现行使用方法和浓度,Laneth-9 Acetate 和 Laneth-10 Acetate 可安全地用于人体局部护理。
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引用次数: 0
Dose Range-Finding Toxicity Study in Rats With Recombinant Human Lactoferrin Produced in Komagataella phaffii 用 Komagataella phaffii 生产的重组人乳铁蛋白对大鼠进行剂量范围毒性研究
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-22 DOI: 10.1177/10915818241247013
Ross Peterson, Robert B. Crawford, Lance K. Blevins, Norbert E. Kaminski, June S. Sass, Bryce Ferraro, Roma Vishwanath-Deutsch, Anthony J. Clark, Carrie-Anne Malinczak
The oral toxicity of recombinant human lactoferrin (rhLF, Helaina rhLF, Effera™) produced in Komagataella phaffii was investigated in adult Sprague Dawley rats by once daily oral gavage for 14 consecutive days. The study used groups of 3–6 rats/sex/dose. The vehicle control group received sodium citrate buffer, and the test groups received daily doses of 200, 1000, and 2000 mg of rhLF in sodium citrate buffer per kg body weight. Bovine LF at 2000 mg/kg body weight per day was used as a comparative control. Clinical observations, body weight, hematology, clinical chemistry, iron parameters, immunophenotyping, and gross examination at necropsy were used as criteria for detecting the effects of treatment in all groups and to help select dose levels for future toxicology studies. Quantitative LF levels were also analyzed as an indication of bioavailability. Overall, administration of Helaina rhLF by once daily oral gavage for 14 days was well tolerated in rats at levels up to 2000 mg/kg/day, or 57 × Helaina’s intended commercial use in adults, and indicating that a high dose of 2000 mg/kg/day is appropriate for future definitive toxicology studies.
研究人员以成年 Sprague Dawley 大鼠为研究对象,连续 14 天每天一次口服 Komagataella phaffii 中生产的重组人乳铁蛋白(rhLF、Helaina rhLF、Effera™)。研究采用 3-6 只大鼠/性别/剂量分组。载体对照组接受柠檬酸钠缓冲液,试验组接受柠檬酸钠缓冲液中的 rhLF,每日剂量分别为每公斤体重 200、1000 和 2000 毫克。每天每公斤体重 2000 毫克的牛血清磷脂作为对比对照。临床观察、体重、血液学、临床化学、铁参数、免疫分型和尸体解剖时的大体检查被用作检测所有组治疗效果的标准,并帮助选择未来毒理学研究的剂量水平。此外,还分析了LF的定量水平,作为生物利用率的指标。总体而言,大鼠对每日一次口服海拉那(Helaina)rhLF 14天的耐受性良好,最高剂量为2000毫克/千克/天,相当于海拉那(Helaina)在成人中的预期商业用量的57倍,这表明2000毫克/千克/天的高剂量适合用于未来的确定性毒理学研究。
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引用次数: 0
Recovery Animals in Toxicology Studies: An Innovation and Quality Consortium Perspective on Best Practices With Case Study Examples 恢复毒理学研究中的动物:创新与质量联合会的最佳实践视角及案例研究实例
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-12 DOI: 10.1177/10915818241243350
Smita Salian-Mehta, James D. Smith, Thierry D. Flandre, Amy L. Lambert, Joan H. Lane, Alan H. Stokes, Kathy Orsted, Natalie A. Bratcher-Petersen, Kyathanahalli S. Janardhan, Elizabeth G. Tonkin
The inclusion of recovery animals in nonclinical safety studies that support clinical trials is undertaken with a wide diversity of approaches even while operating under harmonized regulatory guidance. While empirical evaluation of reversibility may enhance the overall nonclinical risk assessment, there are often overlooked opportunities to reduce recovery animal use by leveraging robust scientific and regulatory information. In the past, there were several attempts to benchmark recovery practices; however, recommendations have not been consistently applied across the pharmaceutical industry. A working group (WG) sponsored by the 3Rs Translational and Predictive Sciences Leadership Group of the IQ Consortium conducted a survey of current industry practice related to the evaluation of reversibility/recovery in repeat dose toxicity studies. Discussion among the WG representatives included member company strategies and case studies that highlight challenges and opportunities for continuous refinements in the use of recovery animals. The case studies presented in this paper demonstrate increasing alignment with the Society of Toxicologic Pathology recommendations (2013) towards (1) excluding recovery phase cohorts by default (include only when scientifically justified), (2) minimizing the number of recovery groups (e.g., control and one dose level), and (3) excluding controls in the recovery cohort by leveraging external and/or dosing phase data. Recovery group exclusion and decisions regarding the timing of reversibility evaluation may be driven by indication, modality, and/or other scientific or strategic factors using a weight of evidence approach. The results and recommendations discussed present opportunities to further decrease animal use without impacting the quality of human risk assessment.
在支持临床试验的非临床安全性研究中使用恢复期动物的方法多种多样,即使是在统一的监管指导下也是如此。虽然对可逆性的经验评估可能会加强整体的非临床风险评估,但人们往往忽视了通过利用可靠的科学和监管信息来减少复原动物使用的机会。过去,人们曾多次尝试为恢复实践制定基准;但是,这些建议并没有在整个制药行业得到一致应用。由 IQ 联合会 3Rs 转化和预测科学领导小组赞助的一个工作组(WG)对当前行业中与重复剂量毒性研究中的可逆性/恢复性评估相关的实践进行了调查。工作组代表讨论的内容包括成员公司的策略和案例研究,这些策略和案例研究突出了在使用恢复期动物方面不断改进所面临的挑战和机遇。本文中介绍的案例研究表明,与毒理学病理学会的建议(2013 年)越来越一致,即:(1) 默认排除恢复期队列(仅在科学上合理时才纳入);(2) 尽量减少恢复组的数量(例如对照组和一个剂量水平);(3) 利用外部和/或剂量阶段数据排除恢复队列中的对照组。恢复组的排除和有关可逆性评估时机的决定可能受适应症、方式和/或其他科学或战略因素的驱动,采用证据权重法。所讨论的结果和建议为在不影响人类风险评估质量的情况下进一步减少动物使用提供了机会。
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引用次数: 0
Editor’s Note 编者按
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-04 DOI: 10.1177/10915818241245479
Mary Beth Genter
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引用次数: 0
Safety Assessment of Zinc Salts as Used in Cosmetics. 化妆品中使用的锌盐的安全性评估。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-01-27 DOI: 10.1177/10915818241227124
Laura N Scott, Monice Fiume, Jinqiu Zhu, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Bart Heldreth

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 27 inorganic and organometallic zinc salts as used in cosmetic formulations; these salts are specifically of the 2+ (II) oxidation state cation of zinc. These ingredients included in this report have various reported functions in cosmetics, including hair conditioning agents, skin conditioning agents, cosmetic astringents, cosmetic biocides, preservatives, oral care agents, buffering agents, bulking agents, chelating agents, and viscosity increasing agents. The Panel reviewed the relevant data for these ingredients, and concluded that these 27 ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-irritating.

化妆品成分安全专家小组(专家小组)对化妆品配方中使用的 27 种无机和有机金属锌盐的安全性进行了评估;这些锌盐特别是锌的 2+ (II) 氧化态阳离子。据报告,本报告中的这些成分在化妆品中具有各种功能,包括头发调理剂、皮肤调理剂、化妆品收敛剂、化妆品杀菌剂、防腐剂、口腔护理剂、缓冲剂、膨松剂、螯合剂和增粘剂。专家小组审查了这些成分的相关数据,得出结论认为,按照本安全评估中所述的现行使用方法和浓度,这 27 种成分在配制成无刺激性的化妆品中是安全的。
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引用次数: 0
Safety Assessment of Alkane Diols as Used in Cosmetics. 化妆品中使用的烷二醇安全性评估。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-01-04 DOI: 10.1177/10915818231224234
Laura N Scott, Monice Fiume, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, Bart Heldreth

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 10 alkane diol ingredients as used in cosmetics. The alkane diols are structurally related to each other as small diols, and most are reported to function in cosmetics as solvents. The Panel reviewed the relevant data for these ingredients, and concluded that seven alkane diols are safe in cosmetics in the present practices of use and concentration described in this safety assessment, but that the available data are insufficient to make a determination of safety for three ingredients, namely 1,4-Butanediol, 2,3-Butanediol, and Octanediol.

化妆品成分安全专家小组(专家小组)评估了化妆品中使用的 10 种烷二醇成分的安全性。这些烷二醇在结构上相互关联,都是小的二元醇,据报道,大多数烷二醇在化妆品中起溶剂作用。专家小组审查了这些成分的相关数据,得出结论认为,按照本安全评估中所述的现行使用方法和浓度,七种烷二醇在化妆品中是安全的,但现有数据不足以确定三种成分(即 1,4-丁二醇、2,3-丁二醇和辛二醇)的安全性。
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引用次数: 0
期刊
International Journal of Toxicology
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