Regulatory Toxicology and Pharmacology最新文献

{"title":"Using data on the uncertainty of LOAELs to model the probability of observing adverse effects in low-dose studies of the toxicity of chemical mixtures","authors":"Paul Price ,&nbsp;Shintaro Hagiwara ,&nbsp;Franco Momoli","doi":"10.1016/j.yrtph.2025.105843","DOIUrl":"10.1016/j.yrtph.2025.105843","url":null,"abstract":"<div><div>Studies of chemical mixtures toxicity are often designed to differentiate mixtures that follow dose-addition from those that follow response-addition. One design used for this purpose doses animals at levels below the levels that separately have been shown to cause a detectable occurence of a common effect. Under response addition, no effects are expected to be observed since no chemical would independently cause an observable response at the administered doses. Effects, however, could be observed if some or all of the chemicals follow dose addition. Thus, any observation of response can be taken as evidence of dose addition. A recent publication estimated interstudy variation in chemicals’ LOAELs. These estimates are here used to predict the probability of observing an effect in mixtures that follow response- or dose-addition models. Two case studies are presented. One is on a set of hypothetical mixtures containing from 2 to 20 chemicals. The second is on mixtures of anti-androgenic chemicals. In these studies, LOAEL uncertainty blurred the difference between dose and response models, and for many mixtures, it is not possible to determine whether response or dose additivity occurred. These findings suggest that caution should be taken when using these studies as evidence for dose addition.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105843"},"PeriodicalIF":3.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943342","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}

{"title":"Identifying human toxicodynamic variability: A systematic evidence map of the current knowledge","authors":"Annika Boye Petersen ,&nbsp;Lea Bredsdorff ,&nbsp;Natasha Tahir ,&nbsp;Marije Niemeijer ,&nbsp;George E.N. Kass ,&nbsp;Aiste Vitkauskaite ,&nbsp;Matthijs Moerland ,&nbsp;Frederic Y. Bois ,&nbsp;Nadia Quignot ,&nbsp;Bob van de Water ,&nbsp;Susanne Hougaard Bennekou","doi":"10.1016/j.yrtph.2025.105842","DOIUrl":"10.1016/j.yrtph.2025.105842","url":null,"abstract":"<div><div>Current chemical risk assessment uses a default uncertainty factor (UF) of 3.16 for toxicodynamic (TD) variability in humans. The objective was to create a systematic evidence map (SEM) of the human variability in TD by identifying and organizing the available empirical data to assess if a further refinement of the default UF of 3.16 for TD can be achieved. PubMed and Web of Science™ were searched from 2004 to 2023. Studies were screened according to the eligibility criteria. Inclusion criteria included studies, where TD could be separated from toxicokinetics (TK) to exclude an impact of TK on TD variability. The literature search retrieved 2408 studies. Manual screening identified 23 <em>in vitro</em> studies assessing human TD variability quantitively, of which only seven <em>in vitro</em> studies provided quantitative estimates of a TD variability factor. No <em>in vivo</em> study met the inclusion criteria. Several studies found TD UF of 3.16 not covering human variability; others did. However, the data were heterogeneous, and variability in Points of Departure (PODs) and methods used to estimate TD variability complicated comparisons across studies. A standardized approach for TDVFs determination is identified<em>.</em> This SEM underscores the scarcity of data assessing human variability in TD, while omitting the influence of TK.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105842"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928575","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}

{"title":"A tool to support food substance safety evaluations in the United States","authors":"Christine M. Crincoli ,&nbsp;Jennifer L.G. van de Ligt ,&nbsp;Alex K. Eapen ,&nbsp;Anthony T. Pavel ,&nbsp;Paul R. Hanlon ,&nbsp;Kelly Almond-Abbate ,&nbsp;Esther Haugabrooks ,&nbsp;Jason Hlywka ,&nbsp;Vivian Lu ,&nbsp;Fleur de Mooij ,&nbsp;Margaret Pandis ,&nbsp;Ross Peterson ,&nbsp;Jay S. Petrick ,&nbsp;Padhma Ranganathan ,&nbsp;Rayetta G. Henderson","doi":"10.1016/j.yrtph.2025.105838","DOIUrl":"10.1016/j.yrtph.2025.105838","url":null,"abstract":"<div><div>The US Food and Drug Administration (FDA) has published numerous regulations and guidance documents providing the foundation for establishing the safety of food substances. However, subject matter expertise is needed to interpret regulations and guidance documents commissioned to meet the regulatory standard of reasonable certainty that the substance is not harmful under the conditions of its intended use. To provide guidance for decision-making and communication within the food industry on safety determinations for food substances, a decision tree was developed to inform the user on what approach, supporting information, and documentation are needed. This framework has been developed by industry experts based on considerable experience substantiating safety with a wide range of food substances, to provide a structured approach to help navigate changes that have the potential to impact safety determinations. Several case studies applying the decision tree are presented. The objective of this manuscript is to serve as a reference to promote aligned practices using a decision tree for evaluating food substance safety throughout the food industry, as well as to function as a communication tool between food manufacturers, internal stakeholders, and consumers.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105838"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916122","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}

{"title":"Not yet nixing rabbit eyes from the six: the TTT is not predicting the full range of in vivo eye irritation classifications for agrochemical formulations","authors":"Susanne N. Kolle ,&nbsp;Peggy Haase ,&nbsp;Britta Wareing ,&nbsp;Monika Kemeny ,&nbsp;Stefan Stinchcombe ,&nbsp;Dorothee Funk-Weyer ,&nbsp;Robert Landsiedel","doi":"10.1016/j.yrtph.2025.105841","DOIUrl":"10.1016/j.yrtph.2025.105841","url":null,"abstract":"<div><div>Since its adoption as a test guideline (EIT, OECD test guideline (TG) 492) in 2015, the EpiOcular™ eye irritation test has been the in vitro method of choice to identify agrochemical formulations non-irritant to the eye (neither category 1 nor 2, according to the Globally Harmonized System of Classification and Labelling of Chemicals, GHS). For serious eye damage (GHS category 1), however, none of the in vitro test methods including the bovine cornea opacity and permeability test (BCOP, OECD TG 437, and protocol modifications), the isolated chicken eye test (ICE, OECD TG 438), the ocular irritation assay (OECD TG 496) or the hen's egg test on the chorioallantoic membrane (HET-CAM) assay proved sufficiently sensitive to correctly identify agrochemical formulations classified as seriously eye damaging in vivo. In 2022, the OECD adopted a new in vitro test guideline for identifying chemicals inducing serious eye damage, eye irritation, and chemicals not requiring classification for eye irritation (OECD TG 492B). However, within the formal validation study of this time-to-toxicity (TTT) test method, agrochemical formulations were not included. To assess the applicability of this test to agrochemical formulations 25 formulations with historical in vivo data were assessed in the TTT. The TTT correctly predicted 0 %, 90 % and 50 % of the agrochemical formulations which were classified by the in vivo data into the three categories 1, 2 and “not classified”, respectively. The overall accuracy of the TTT to predict agrochemical formulations of the three categories was 52 %. Therefore, to facilitate non-animal-based identification of the full range of ocular irritation of agrochemical formulations, testing protocols and/or prediction models must be revised or classification guidelines should be adjusted to align with human relevant in vitro testing rather than relying on in vivo Draize data as a reference point.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105841"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917609","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}

{"title":"Colemanite and biological disruptions: Behavioral, neurological, and physiological findings","authors":"Hasan Türkez ,&nbsp;Özlem Özdemir Tozlu ,&nbsp;Melik Saraçoğlu ,&nbsp;Edanur Yıldız ,&nbsp;Cem Baba ,&nbsp;Cemil Bayram ,&nbsp;Burak Çınar ,&nbsp;Serkan Yıldırım ,&nbsp;Metin Kılıçlıoğlu ,&nbsp;Berrah Gözegir ,&nbsp;Kenan Çadırcı","doi":"10.1016/j.yrtph.2025.105840","DOIUrl":"10.1016/j.yrtph.2025.105840","url":null,"abstract":"<div><div>Colemanite (COL), a boron-containing mineral, has shown potential therapeutic applications, particularly in the fields of drug delivery and bone health. However, despite its promising bioactive properties, there is a lack of comprehensive toxicological data on its safety, especially regarding its potential medical use. Previous studies have primarily focused on its industrial applications, with limited investigation into its biological effects. This gap in knowledge prompted the current study, which aimed to investigate the subacute toxicity of colemanite in rats using behavioral, hematological, biochemical, genotoxic, and histopathological analyses. Over a 7-day period, rats were treated with doses of 10, 30, and 300 mg/kg. Behavioral assessments, including locomotor activity and elevated plus maze tests, indicated enhanced exploratory behaviors, indicating heightened curiosity or activity and no alterations in motor coordination or anxiety-like behaviors. Hematological findings revealed dose-dependent reductions in hematocrit, hemoglobin, and red blood cell counts, while biochemical analyses showed elevated aspartate aminotransferase, lactate dehydrogenase, and cholesterol levels at higher doses, suggesting hepatotoxicity and lipid metabolism disruption. Genotoxicity analysis demonstrated increased micronucleus formation at 30 and 300 mg/kg, indicative of chromosomal instability possibly linked to oxidative stress. Histopathological evaluations revealed mild hepatocyte degeneration and hyperemia in the liver and brain tissues at the highest dose. Importantly, no significant toxic effects were observed at the 10 mg/kg dose. These findings highlight the dose-dependent toxicity of colemanite, with low doses exhibiting a favorable safety profile. This study underscores the need for dose optimization and further research to elucidate the molecular mechanisms underlying colemanite's toxicological effects, including its impact on various organs over both short-term and long-term exposures. Additionally, future studies should focus on assessing the human relevance of these effects to ensure its safe and effective therapeutic application.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105840"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924759","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}

{"title":"Verification of health-based guidance values for carbendazim.","authors":"Takako Iso, Takaaki Umano, Kei-Ichi Sugiyama, Kenichi Masumura, Mariko Matsumoto","doi":"10.1016/j.yrtph.2025.105839","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105839","url":null,"abstract":"<p><p>Carbendazim is registered on the Japanese positive list (PL) for food contact materials (food utensils, containers, and packaging; UCP). However, to ensure food safety, a dietary risk assessment of carbendazim is necessary. The safety of carbendazim has been evaluated by several risk assessment bodies, from which health-based guidance values (HBGVs) have been established, mainly based on the no observed adverse effect level (NOAEL) approach. However, as most of the reviewed studies were not conducted in accordance with Good Laboratory Practice (GLP) or OECD test guidelines (TGs), they may not have fully met quality standards. Following the results of periodic re-evaluations, some HBGVs have been withdrawn owing to insufficient toxicological information. Therefore, we verified the HBGVs of carbendazim from the perspective of genotoxicity. The point of departure (PoD) for aneugenicity was calculated based on a dose-response analysis from in vivo micronucleus tests using the benchmark dose (BMD) approach. Overall, the HBGV based on the PoD of aneugenicity was comparable with the existing HBGV based on developmental toxicity tests in rats and rabbits using the NOAEL approach.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105839"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014181","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}

{"title":"Case Studies using the Probabilistic Aggregate Consumer Exposure Model (PACEM) for Cosmetics Ingredient Safety Assessment.","authors":"Camilla Alexander-White, Catherine Barratt, Dagmar Bury, Sabrina Fritz, Taryn Kirsch, Laure Michel, Hermine Dika Nguea, Arianna Giusti, Sarah Tozer","doi":"10.1016/j.yrtph.2025.105836","DOIUrl":"https://doi.org/10.1016/j.yrtph.2025.105836","url":null,"abstract":"<p><p>Case studies for cosmetic ingredients propyl paraben, salicylic acid, methyl salicylate, D5 and methylisothiazolinone have been used to assess the functionality and performance of the online webtool PACEM (Probabilistic Aggregate Consumer Exposure Model), which is free and publicly available. PACEM can be used by a consumer safety assessor to estimate consumer aggregate exposures (from cosmetic and household care products) to a single ingredient present in multiple product types, used simultaneously by a consumer in any one day. In this evaluation, only cosmetic product exposure assessment has been reviewed. The tool uses probabilistic mathematical modelling approaches, incorporating survey data on the habits and practices of product use from different European populations. The model is used by an exposure assessor to generate either a) an external exposure dose metric (mg/kg/day), b) an internal systemic exposure dose (SED) metric (mg/kg/day) or c) a dermal load (μg/cm²). The case studies performed, indicate that PACEM is a useful tool for the cosmetics safety assessor, and generates credible outputs for regulatory dossier submissions.</p>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":" ","pages":"105836"},"PeriodicalIF":3.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041939","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}

{"title":"Mode of action analysis for rat thyroid gland follicular cell tumor formation by MGK-264 and human relevance","authors":"Junji Yano ,&nbsp;Kensuke Kawamoto ,&nbsp;Yukako Shimotsuma ,&nbsp;Kohei Matsunaga ,&nbsp;Jun Abe ,&nbsp;Satoki Fukunaga ,&nbsp;Thomas G. Osimitz ,&nbsp;Brian G. Lake ,&nbsp;Hiroyuki Asano","doi":"10.1016/j.yrtph.2025.105834","DOIUrl":"10.1016/j.yrtph.2025.105834","url":null,"abstract":"<div><div>MGK-264 (N-(2-ethylhexyl)-5-norborene-2.3-dicarboximide or N-octyl bicycloheptene dicarboximide), an insecticidal synergist, produced thyroid gland follicular cell (TFC) tumors in male Sprague-Dawley (SD) rats in a carcinogenicity study. The purpose of this study was to evaluate the possible mode of action (MoA) for TFC tumor induction by MGK-264 and its relevance to humans. In short-term <em>in vivo</em> studies, the treatment of male SD rats with MGK<strong>-</strong>264 resulted in induction of hepatic UDPglucuronosyltransferase (UGT) activity towards thyroxine (T₄) as substrate (UGT activity), a decrease in serum T₄ levels, an increase in serum thyroid stimulating hormone levels, and TFC hypertrophy at MGK-264 dose levels where TFC tumors were noted in the carcinogenicity study. Other possible MoAs such as genotoxicity, thyroperoxidase inhibition, and sodium/iodide symporter inhibition were excluded. Therefore, it is reasonable to conclude that MGK-264 has mitogenic activity on TFCs via induction of hepatic UGT activity followed by perturbation of the hypothalamus-pituitary-thyroid axis, similar to other hepatic xenobiotic enzyme inducers like phenobarbital. Literature data demonstrates that there are marked species differences between rats and humans in the effects of hepatic xenobiotic enzyme inducers on thyroid hormones and the thyroid gland. Overall, the proposed MoA for MGK-264-induced rat TFC tumor formation is considered quantitatively not plausible for humans.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"160 ","pages":"Article 105834"},"PeriodicalIF":3.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906670","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}

{"title":"HESI GTTC ring trial: Concordance between Ames and rodent carcinogenicity outcomes for N-nitrosamines (NAs) with rat and hamster metabolic conditions","authors":"Joel Bercu ,&nbsp;Alejandra Trejo-Martin ,&nbsp;Connie Chen ,&nbsp;Maik Schuler ,&nbsp;Jennifer Cheung ,&nbsp;Tetyana Cheairs ,&nbsp;Anthony M. Lynch ,&nbsp;Dean Thomas ,&nbsp;Andreas Czich ,&nbsp;Aisar Atrakchi ,&nbsp;Timothy J. McGovern ,&nbsp;Robert H. Heflich ,&nbsp;Alisa Vespa ,&nbsp;Roland Froetschl ,&nbsp;Yi Yang ,&nbsp;Raj D. Gandhi ,&nbsp;Joanne Elloway ,&nbsp;Verena Ziegler ,&nbsp;Anna Hellmann ,&nbsp;Michelle Schaefer ,&nbsp;Raechel Puglisi","doi":"10.1016/j.yrtph.2025.105835","DOIUrl":"10.1016/j.yrtph.2025.105835","url":null,"abstract":"<div><div>A multi-sector study (i.e., Ring Trial) was designed to improve the <em>in vitro</em> detection of <em>N</em>-nitrosamine (NA)-associated mutagenicity by optimizing the bacterial reverse mutation (i.e., Ames) assay protocol and testing various conditions on the sensitivity and specificity for the prediction of rodent carcinogenicity. A total of 29 NAs and 3 <em>N</em>-nitroso drug-like compounds from different structural classes and carcinogenicity outcomes were tested (two independent laboratories per compound) across 5 bacterial strains using a 30-min pre-incubation protocol. To evaluate the impact of different metabolic activating systems (MASs), testing conditions included the use of 10 or 30 % liver S9 fractions prepared from rats or hamsters pretreated with inducers of enzymatic activity. Results indicate that <em>E. coli</em> and <em>Salmonella typhimurium</em> strains detecting single base pair mutations, coupled with MASs containing 30 % hamster S9s were the most sensitive (90 %) for identifying NAs that are rodent carcinogens. Regarding MAS combinations, the highest sensitivity was 30 % rat and 30 % hamster (93 %), but has low specificity (45 %), with good laboratory agreement for the Ames calls (91 %). DMSO and water were considered suitable solvents, except for small-molecular weight alkyl NAs. These results will support harmonized Ames testing of NAs, giving high confidence for a negative result.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105835"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928693","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}

{"title":"Ninety-day repeated oral toxicity and genetic toxicity studies of powderized Aurantii Fructus Immaturus","authors":"Soyoung An ,&nbsp;Songyeon Kim ,&nbsp;Si-Whan Song ,&nbsp;Hye-Seon Heo ,&nbsp;Changwook Park ,&nbsp;Minseob Kim ,&nbsp;Wooju Lee ,&nbsp;Yujin Park ,&nbsp;Jae-Ho Shin ,&nbsp;Beom Seok Han ,&nbsp;Wan-Seob Cho","doi":"10.1016/j.yrtph.2025.105837","DOIUrl":"10.1016/j.yrtph.2025.105837","url":null,"abstract":"<div><div>Aurantii Fructus Immaturus (AFI) has been widely used as an herbal medicine for health promotion and the treatment of various diseases but there is little information on its toxicity. Herein, we performed general and genetic toxicity studies on the powdered form of AFI. The lethal dose 50 % (LD₅₀) of AFI powder in Sprague-Dawley (SD) rats was &gt;4000 mg/kg for both sexes. The 28-day repeated oral toxicity study of AFI powders at 0, 125, 250, 500, 1000, and 2000 mg/kg/day showed some occasional changes including soiled perineal region, loss of fur, and weight loss. However, these changes were not considered treatment-related because the values were within the control range and responses were not dose-dependent. The 90-day repeated oral toxicity study with a 4-week recovery period of AFI powders in rats at 0, 125, 250, 500, 1000, and 2000 mg/kg/day also showed no treatment-related toxicity outcomes, although some endpoints showed significant changes such as loss of fur, increased MCH and MCV levels, and increased liver weight. Therefore, the no-observed-adverse-effect level (NOAEL) of AFI powders in rats was 2000 mg/kg/day. Finally, a battery of three genotoxicity tests showed that the AFI powder was not a genotoxic material.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"161 ","pages":"Article 105837"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907703","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}