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List of plants containing hydroxyanthracene derivatives permitted for use in food supplements in France ('Documentation provided to EFSA' n. 1)
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The Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the safety of hydroxyanthracene derivatives and to provide advice on a daily intake that does not give rise to concerns about harmful effects to health. Hydroxyanthracene derivatives are a class of chemical substances naturally occurrin...
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To develop a quantitative analysis of multicomponent by single-marker method for the simultaneous determination of fourteen components in Zhilou lotion, emodin was selected as an internal reference, and the relative correction factors of gallic acid, caffeic acid, polydatin, hyperoside, isoquercitrin, quercitrin, homoplantaginin, resveratrol, hispi...
Products based on plants containing hydroxyanthracene derivatives (HADs)—such as Rheum, Cassia, and Aloe species—are widely used in food supplements or nutraceuticals due to their laxative effects. A more restricted control of HAD contents in food supplements has been implemented by EU Regulation 2021/468, in order to increase the safety of these p...
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... The kit is a sandwich enzyme immunoassay for in vitro quantitative measurement of HSP70 in rat serum, plasma,tissue homogenates, cell lysates, cell culture supernates and other biological fluids (18). ...
The present study was undertaken to observe the effect of the aqueous leaf extract of Aloe vera gel of the Antioxidant and histological on liver and pancreas. Twenty_four male rats were divided into four groups (6rats/group) and treated as follows for 28 days.G 1 were intubated orally distal water serving as control while, G2 were administrating of Dexamethason -induced diabetic 1 mg/kg/bw. Intraperitoneally, G3 were administrating of diabetic rats given Dexamethason 1mg/kg/bw. + Aloe vera leaf gel extract (300 mg/kg) using an intragastric tube, G4)were administrating of diabetic rats given Dexamethasone 1mg/kg/bw. intraperitoneally + Aloe vera leaf gel extract (500 mg/kg) using an intragastric tube, the following criteria were measuredAntioxidant and histological on liver and pancreas. The findings show that Aloe Vera had a significant decrease influence in serumAntioxidant (MDA, ACE, and HSP70). In conclusion, this study mentioned a new evidence of the role of Aloe Vera on the decreasing of antioxidant.
... Therapeutic extracts of rhubarb are commonly obtained from its rhizome; the most representative components of these extracts include hydroxyanthracene derivates such as emodin, aloe-emodin and rhein. The safety of hydroxyanthracenes was evaluated by the Panel of the European Food Safety Authority, Food Additives and Nutrient Sources added to Food (EFSA-ANS Panel) in 2018, which concluded that "hydroxyanthracene derivatives should be regarded as genotoxic and carcinogenic unless there are specific data to the contrary, [.] and that there is a safety concern for extracts containing hydroxyanthracene derivatives although uncertainty persists" [5]. No genotoxic activity has been reported for rhein, physcion and chrysophanol. ...
... For mixtures that contain individual components for which there are concerns regarding potential genotoxicity, as suggested for hydroxyanthracene derivatives (EFSA-ANS Panel, 2018) [5], studies in Hsd:ICR (CD-1) male mice showed a lack of genotoxic activity in the comet assay in vivo in single cell preparations of kidney and colon following oral gavage of doses of 250, 500, 1000 and 2000 mg/kg bw/day high-titre aloe-emodin [15]. In addition, in three in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow cells of Wistar rats; mouse spot test [DBA/2 J × NMRI]) no indication of a genotoxic activity of aloe-emodin was found. ...
Hydroxyanthracene derivatives are widely distributed in the plant kingdom, mainly in botanicals such as the Hypericum, Rheum, Rhamnus and Aloe genera. For centuries, plants containing hydroxyanthracene derivatives have been used as herbal remedies, mainly as laxatives. The root and underground stem (rhizome) are used to make medicine, primarily for digestive complaints including constipation, diarrhoea, heartburn, stomach pain, gastrointestinal bleeding, and preparation for certain gastrointestinal diagnostic procedures. The use of hydroxyanthracene-containing botanicals has raised the attention of European Food Safety Authority (EFSA) for the potential genotoxicity activity, that in 2018 concluded “[.] and that there is a safety concern for extracts containing hydroxyanthracene derivatives although uncertainty persists”. No genotoxic activity has been reported with other constituents such as rhein, physcion and chrysophanol.
In the present study, Rhubarb ethanolic extract of ground rhubarb rhizome (hydroxyanthracene total content 1.39%) was tested in the Ames Assay in Salmonella typhimurium and Escherichia coli, up to 5000 µg/plate and up to 5000 µg/mL in human lymphocytes Micronucleus Test (OECD 471 and 487 respectively) in vitro mutagenic and genotoxic effects. Under the experimental conditions used, the rhubarb rhizome extract showed no genotoxic activity.
... The toxicity issue, including genotoxicity, of Aloe genus species, is complicated as the literature presents both for and against arguments [31][32][33][34]. Researchers assume plant genotoxicity often points to hydroxyanthracene derivatives (e.g., aloin, aloe-emodin) as compounds responsible for this effect [35]. An argument supporting this theory is that non-decolorized Aloe vera, without the reduced content of hydroxyanthracene derivatives, administered orally to mice and rats, caused intestinal lesions [36]. ...
The present study assessed the genotoxicity, the possibility of inhibiting selected enzymes, and the microbial activity of lyophilisate from 3-year-old A. arborescens leaves obtained from controlled crops. The lyophilisate from 3-year-old A. arborescens leaves was standardized for aloin A and aloenin A content. Moreover, concentrations of polyphenolic compounds and phenolic acids were determined. The first stage of the research was to determine genotoxicity using the comet test, which confirmed the safety of A. arborescens. Assays of enzymatic inhibition were performed for hyaluronidase (IC50 = 713.24 ± 41.79 µg/mL), α-glucosidase (IC50 = 598.35 ± 12.58 µg/mL), acetylcholinesterase and butyrylcholinesterase (1.16 vs. 0.34 µM of eserine/g d.m., respectively). The next stage of the research was to determine the ability of the healing properties using the scratch test, which showed a positive response using the extract. Microbial activity was evaluated and obtained against Gram-negative and Gram-positive bacteria and yeasts. We concluded that A. arborescens leaf gel meets the important conditions for plant raw materials to obtain semi-solid forms of herbal medicinal products.
... For example, extracts from the leaves of Aloe species containing HADs have been placed on the list of prohibited substances (Annex III, Part A), together with the anthraquinones aloe-emodin, emodin and danthron, due to potentially severe harmful effects on health, including genotoxicity and because the safe daily dose of HADs was unknown. These statements originate from an assessment of the safety of HADs for use in foods carried out by the EFSA and published on 22 November 2017 (EFSA, 2018) [5]. ...
... The EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS) concluded that emodin and aloe-emodin, tested as single substances, have shown reliable evidence of in vitro genotoxicity [6][7][8], whereas rhein and sennosides resulted in nonmutagen in all or the majority of in vitro tests taken into account [8,9]. Furthermore, the Panel deemed aloe-emodin to also be genotoxic in vivo based on the results of a single study obtained by comet assay regarding the pure molecule [10], whereas in several other in vivo experiments performed by Heidemann et al., aloe-emodin did not result in genotoxicity [6]; however, those studies were not considered sufficiently reliable by EFSA [5]. After the EFSA alert, other studies have been published. ...
... On the other hand, some data suggest an increased risk for colorectal cancer associated with the general use of laxatives, several of which contain HADs, [13], whereas others sustain that the correlation is unproven [14,15]. In light of these ambiguities, the Panel concluded that HADs should be considered genotoxic and carcinogenic unless there are specific data to the contrary, such as for rhein, and that there is a safety concern for extracts containing HADs, although uncertainty persists [5]. ...
A genotoxicological study was carried out on a substance-based medical device (SMD) containing anthraquinones in order to evaluate its potential mutagenic effect. The “In Vitro Mammalian Cell Micronucleus Test” was performed on human TK6 cells by flow cytometry. Cultures were treated with concentrations of SMD tested in the range of 0–2 mg/mL for short treatment time (3 h) both in the absence and presence of an exogenous metabolic activation system, followed by a recovery period in fresh medium (23 h) and for extended treatment time (26 h) without an exogenous metabolic activation system. At the end of both treatment times, cytotoxicity, cytostasis, apoptosis and micronuclei (MNi) frequency were analysed in treated cultures and then compared with those measured in concurrent negative control cultures. The SMD did not induce a statistically significant increase MNi frequency under any of experimental conditions tested. The negative outcome shows that the SMD is non-mutagenic in terms of its ability to induce chromosomal aberrations both in the absence and presence of an exogenous metabolic activation system. The study ended by analyzing intracellular ROS levels to exclude the pro-oxidant ability, typically linked to DNA damage. On the contrary, our results demonstrated the ability the SMD to counteract oxidative stress.
... More than 700 different natural HADs have been reported; 200 are present in flowering plants, and the remainder in lichens and fungi [1]. Plants containing HADs are numerous and belong to different botanical families and genera [2]. HADs are distributed in roots, rhizomes, fruits, flowers, and leaves, where they can be found in free form or conjugated with sugar moieties, with glycosylation being a strategy used by plants to favour their accumulation and storage [3]. ...
... leaves and fruits contain chrysophanol, physcion, and rhein. The content of HAD glycosides in the most used Cassia senna L. is in general over 2.5%, expressed as sennoside B [2]. Cassia senna L. seeds contain aloe emodin, emodin, emodin anthrone, and physcion, and the amount of HAD glycosides is at least 3.4%. ...
... Cassia senna L. seeds contain aloe emodin, emodin, emodin anthrone, and physcion, and the amount of HAD glycosides is at least 3.4%. In Aloe spp., aloe emodin, aloenin, aloin A, and aloin B are present, and HADs reach a minimum concentration of 18% in the dried drug, expressed as barbaloin [2]. In Rhamnus frangula Mil., the minimum content of glucofrangulis in bark is 7.0%, expressed as frangulin A, and in the bark of Rhamnus purshiana DC the minimum content of HAD glycosides is 8.0%, expressed as cascaroside A [2]. ...
Products based on plants containing hydroxyanthracene derivatives (HADs)—such as Rheum, Cassia, and Aloe species—are widely used in food supplements or nutraceuticals due to their laxative effects. A more restricted control of HAD contents in food supplements has been implemented by EU Regulation 2021/468, in order to increase the safety of these preparations. Due to their toxicity, aloin A, aloin B, aloe emodin, emodin, and the synthetic derivative danthron have been listed as prohibited substances in food supplements, being tolerated in amounts < 1 mg kg−1 in marketed products. In this work, we report the development of a sensitive and fast LC–DAD–MS-based procedure for the determination of these five compounds in food supplements and plant materials or extracts. The entire procedure includes a simple sample preparation step, where target analytes are concentrated by means of solvent extraction and evaporative concentration (solid samples), or by lyophilisation (liquid samples). The average LOQ of 0.10 mg/L, LOD of 0.03 mg/L, accuracy, and precision with CVs below 12.72 were obtained for the studied analytes. This method is suitable for assessing the compliance of commercial products and raw materials with EU Regulation 2021/468. Furthermore, the proposed method can represent a starting point for the development of a unique and standardised analytical approach for the determination of other HADs under the attention of EU authorities.
... However, despite the commonly diffused conception that NP are usually safe and well-tolerated, several reports highlight the potential toxicity of NP already available on the food supplements market, pointing out the importance of a careful chemical and biological evaluation of these products prior to their distribution. As an example, the European Food Safety Authority (EFSA) recently provided a scientific opinion on the safety of hydroxyanthracene derivatives (HADs) [5] due to concerns about the possible harmful effects associated with long-term consumption of HAD-containing preparations. HADs are characteristic constituents of Rheum, Cassia, and Aloe species that are widely used in food supplements or nutraceuticals for their laxative effects. ...
... HADs are characteristic constituents of Rheum, Cassia, and Aloe species that are widely used in food supplements or nutraceuticals for their laxative effects. Four naturally occurring HADs, namely aloin A, aloin B, aloe-emodin, and emodin, have been listed as prohibited substances in food supplements by EFSA that, on the basis of epidemiological data, stated that they should be considered as genotoxic and carcinogenic unless there are specific data demonstrating to the contrary [5]. ...
Historically, mankind has used plants and their derivatives as food and medicine for thousands of years [...]
... Flavonoids have been reported in A. marlothii A.Berger and A. melanacantha A.Berger (Bachheti et al., 2021). Nevertheless, the hydroxyanthracene derivatives in leaf extracts of different Aloe species, e.g., A. vera and A. ferox and its hybrids, have drawn genotoxicity concerns if present in foods and supplements (Baldi et al., 2021;Younes et al., 2018). ...
The genus Aloe has attracted considerable research attention in the last two decades owing to its ethnomedicinal, nutraceutical, pharmaceutical, and cosmeceutical importance. This review aimed to evaluate the performance of research outputs, identify evolving trends and research hotspots, and present a detailed summary of recent research reports on the biological and clinical activities of Aloe species of the last two decades. Two databases (Scopus and Web of Science Core Collection) were searched to identify relevant literature on Aloe species spanning 2001 to 2020. The search and retrieval approaches were TITLE-ABS-KEY (Aloe) and TS (Biological AND Activit*). RStudio Inc. 1.1.463 and VOSviewer 1.6.15 were used to analyze the main bibliometric indicators such as annual publication evolution and trend, contributing authors, articles, countries, journals, collaborative network, and thematic domains. Information on biological and clinical activities was retrieved from relevant articles from January 2001 to September 2021 from different databases. A total of 8192 documents were retrieved. The number of publications in the study period showed an increasing trend, with a mean annual growth rate of 5%. India was the most productive country and had the greatest collaborative strength on Aloe research. Articles were predominantly published in the Journal of Ethnopharmacology. Gideon F. Smith made the most significant contributions to Aloe research. Three thematic research domains were identified: (i) pharmacological/toxicological studies, (ii) traditional/medicinal uses, and (iii) nutraceutical and cosmetic studies. Recent biological investigations were mainly in vitro and in vivo and focused on antimicrobial, anti-inflammatory, anti-diabetic, anti-cancer, wound-healing, antimalarial, antioxidant, analgesic, laxative, anti-erythema, and anti-skin wrinkling effects. The majority of human clinical investigations in the last two decades have been conducted using A. vera leaf gel. The results from the biological activities confirm that Aloe is indeed a promising medicinal genus. However, there is a need for more clinical trials to be conducted on different species and isolated bioactive compounds in this genus.
... Evidence that aloe emodin induces primary damage to DNA in the liver and kidneys of mice in in vivo comet analysis has also been associated with its being hepatotoxic and nephrotoxic [123]. In addition to all these, the informa-tion that aloe emodin is genotoxic was emphasized in the EFSA panel [124]. It turns out that studies elucidating the toxic effects of aloe emodin for clinical use are insufficient and risk assessment of aloe emodin exposure is necessary. ...
Cancer is one of the important causes of death worldwide. Despite remarkable improvements in cancer research in the past few decades, several cancer patients still cannot be cured owing to the development of drug resistance. Natural sources might have prominence as potential drug candidates. Among the several chemical classes of natural products, anthraquinones are characterized by their large structural variety, noticeable biological activity, and low toxicity. Aloe emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. This compound has proven its antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative potential as well as ability to prevent cancer metastasis and potential in reversing multidrug resistance of cancer cells. The anticancer property of aloe emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of inhibition of cell growth and proliferation, cell cycle arrest deterioration, initiation of apoptosis, antimetastasis, and antiangiogenic effect. In accordance with the strategy of developing potential drug candidates from natural products, aloe emodin’s low bioavailability has been tried to be overcome by structural modifications and nanocarrier systems. Consequently, this review summarizes the antiproliferative and anticarcinogenic properties of aloe emodin, as well as the enhanced activity of its derivatives and the advantages of drug delivery systems on bioavailability.
... The European Food Safety Authority (EFSA) reported that some AQ derivatives in food supplements represent a relevant health problem (Younes et al., 2018). The EFSA Panel on Food Additives and Nutrient Sources added to Food reviewed the available scientific evidence on a possible relationship between AQ derivatives exposure and carcinogenic effects. ...
... Furthermore, one study compared AQ laxatives use versus "other laxatives" (Charlton et al., 2013), and one study versus "no laxative" use (Nascimbeni et al., 2002) Considering MC, the role of AQ laxatives in its development could not be assessed. In fact, the association between AQ laxatives use and MC is mainly reported in the literature as anecdotal (i.e., case report, case series, endoscopy studies, etc.) description (Younes et al., 2018). Moreover, most of observational evidence incorrectly considers MC as a proxy of long-term use of laxatives, specific for AQ derivatives (Kassim et al., 2020;Siegers, Von Hertzberg-Lottin, Otte, & Schneider, 1993), but their use is only one of the factor involved in its aetiology (Yang et al., 2020). ...
... As reported in EFSA scientific opinion (Younes et al., 2018), previous epidemiological evaluations suggested an increased risk for CRC associated with the general use of laxatives (Sonnenberg & Muller, 1993), some of which contain AQ derivatives (Nusko T A B L E 2 Full-text manuscripts included in the meta-analysis of colorectal cancer and anthracene laxatives use (quantitative evidence) , 1993;Siegers et al., 1993). To the best of our knowledge, this is the first systematic review and meta-analysis investigating the role of AQ laxatives alone on the risk of gastrointestinal neoplasia. ...
This systematic review and meta-analysis were conducted to determine the effects of anthraquinone (AQ) laxatives on colorectal cancer (CRC). We searched PubMed, Embase, Google Scholar, and CENTRAL from inception until March 2021, for randomized controlled trials (RCTs) and observational studies. Through the systematic review, we identified 8 observational studies evaluating AQ laxatives use as a risk factor for CRC development, and 5 studies on CRC risk were included in the meta-analysis using a random-effects model. Through the meta-analysis, we found that a history of AQ laxatives use compared with “other” and “no laxatives” use was associated with CRC development (OR: 1.41; 95% CI: 0.94–2.11), although not at a statistically significant level. The possible association persists even after removal of the outlier studies (OR: 1.51; 95% CI: 0.97–2.34). Selection of cases and controls was judged at low or unclear risk of bias across almost all studies, and the quality of evidence was from moderate to low. In conclusion, it is not possible to associate the use of AQ laxatives with the development of CRC. However, the trend toward an increased risk of CRC provides a strong indication for investigating this issue by performing further high-quality studies.
... The estimated exposure to hydroxyanthracene derivatives from the recommended daily doses of food supplements indicates intakes of 24.83 mg/person per day of sennoside B, 78.8 mg/person per day of rhein, 26 mg/person per day of glucofrangulin A, 24 mg/person per day of barbaloin and 51 mg/person per day of aloin A + B.; the data relating to exposure to emodin and aloe-emodin are not known and are likely to be on the same order of magnitude [6]. ...
... The European Food Safety Authority (EFSA) Food Additives and Nutrient Sources added to Food (ANS) Panel concluded that "hydroxyanthracene derivatives should be regarded as genotoxic and carcinogenic unless there are specific data to the contrary, [...] and that there is a safety concern for extracts containing hydroxyanthracene derivatives although uncertainty persists" [6]. The only study judged reliable by the ANS Panel was the one in which aloe-emodin was administered by the oral route to male (OF1) mice at doses of 500, 1000 and 2000 mg/kg bw in an in vivo rodent comet assay conducted in accordance with unspecified international recommendations [7]. ...
... The European Commission proposed placing aloe-emodin and all the extracts in which this substance is present and leaf extracts of Aloe species containing hydroxyanthracene derivatives in Part A (ban on the use in food) of Annex III of Regulation (EC) no. 1925/2006 of the European Parliament and of the Council, due to alleged genotoxic and carcinogenic effects of hydroxyanthracene derivatives identified by the EFSA [6]. ...
Aloe ferox Mill is widely used as a traditional herbal medicine for the treatment of a broad spectrum of illnesses given its laxative, anti-inflammatory, bitter tonic, anti-oxidant, antimicrobial and anti-cancer properties.
Using the in vivo alkaline comet assay in animals (OECD 489), this study investigated the potential in vivo genotoxicity of dried Aloe ferox juice at dose levels of 500, 1000, and 2000 mg/kg/day in mice. Aloe ferox showed no genotoxic activity in preparations of single cells from the colon of the treated Hsd:ICR (CD-1) male mice. No statistically significant increase in DNA migration over the negative control was observed by analysis of variance for both comet parameters, tail moment and tail intensity, apart from the positive control ethyl methanesulphonate that induced clear and statistically significant increases in DNA migration parameters over the concurrent controls. The new reported scientific evidence unequivocally demonstrates that dried Aloe ferox juice containing hydroxyanthracene derivatives does not induce DNA damage in preparations of single cells from colon in in vivo comet genotoxicity studies. This suggests that the hyperplastic changes and mucosal hyperplasia observed after long-term administration of Aloe vera non-decolourised whole leaf extract may be attributed to an epigenetic effect of the material under investigation.
