Scientific Opinion on additional scientific data related to the safety of monacolins from red yeast rice submitted pursuant to Article 8(4) of Regulation (EC) No 1925/2006

EFSA Journal. 2025;23:e9276. | 1 of 17 https://doi.org/10.2903/j.efsa.2025.9276 efsa.onlinelibrary.wiley.com/journal/1831-4732 SCIENTIFIC OPINION Scientific Opinion on additional scientific data related to the safety of monacolins from red yeast rice submitted pursuant to Article 8(4) of Regulation (EC) No 1925/2006 EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) | Dominique Turck | Torsten Bohn | Montaña Cámara | Jacqueline Castenmiller | Stefaan DeHenauw | Karen Ildico HirschErnst | Ángeles Jos | Inge Mangelsdorf | Breige McNulty | Androniki Naska | Kristina Pentieva | Alfonso Siani | Frank Thies | Leonard Matijević | Silvia Valtueña Martinez | Alexandre Maciuk Adopted: 29 January 2025 DOI: 10.2903/j.efsa.2025.9276 Abstract The Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the safety of monacolins from red yeast rice (RYR), which have been placed under Union scrutiny in Part C of Annex III in accordance with Article 8(4) of Regulation (EC) No 1925/2006. The NDA Panel reviewed the additional scientific data submitted during the period of scrutiny, which included analytical data on the composition of RYR supplements, the intake of monacolins from other dietary sources, invitro bioaccessibility and cytotoxicity data of monacolins vs. other statins, nutrivigilance/postmarketing data, case reports and clinical studies. Based on the new nutrivigilance data provided, the NDA Panel reiterates the concerns of the ANS Panel (EFSA ANS Panel, 2018) that exposure to monacolin K from RYR at intake levels as low as 3 mg/day could lead to severe adverse effects on the musculoskeletal system, including rhabdomyolysis, and on the liver. The NDA Panel concludes that the data submitted by interested parties during the Union scrutiny period do not allow establishing the safety of monacolins in RYR supplements below 3 mg/day or to identify a daily intake of monacolins from RYR in food supplements that does not raise safety concerns for the general population or vulnerable subgroups thereof. KEYWORDS food supplements, lovastatin, monacolins, Monascus purpureus, red yeast rice This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. © 2025 European Food Safety Authority. EFSA Journal published by Wiley-VCH GmbH on behalf of European Food Safety Authority. Correspondence: [email protected] The declarations of interest of all scientific experts active in EFSA's work are available at https:// open. efsa. europa. eu/ experts 2 of 17 | MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY CONTENTS Abstract................................................................................................................................................................................................................................1 1. Introduction ..............................................................................................................................................................................................................3 1.1. Background and Terms of Reference as provided by the requestor .........................................................................................3 1.1.1. Background ....................................................................................................................................................................................3 1.1.2. Terms of Reference.......................................................................................................................................................................3 1.2. Interpretation of the Terms of Reference ............................................................................................................................................3 1.3. Previous EFSA assessments on monacolins from RYR ....................................................................................................................3 2. Data and Methodologies ......................................................................................................................................................................................4 2.1. Data ...................................................................................................................................................................................................................4 2.2. Methodologies..............................................................................................................................................................................................6 3. Assessment ................................................................................................................................................................................................................6 3.1. Analytical data about the characterisation of RYR preparations ................................................................................................6 3.2. Data on the dietary intake of monacolins from food sources other than RYR ......................................................................8 3.3. In vitro data of RYR/monacolin K vs. other statins ...........................................................................................................................8 3.4. Nutrivigilance/postmarketing data on adverse events related to the use of RYR products ...........................................9 3.5. Case reports of adverse events from the scientific literature ....................................................................................................11 3.6. New clinical data including safety endpoints .................................................................................................................................11 4. Discussion................................................................................................................................................................................................................ 12 5. Conclusions ............................................................................................................................................................................................................. 12 6. Steps taken by EFSA ............................................................................................................................................................................................. 13 Abbreviations ................................................................................................................................................................................................................. 13 Acknowledgements ..................................................................................................................................................................................................... 14 Requestor .........................................................................................................................................................................................................................14 Question number ..........................................................................................................................................................................................................14 Copyright for nonEFSA content.............................................................................................................................................................................. 14 Panel members ..............................................................................................................................................................................................................14 References........................................................................................................................................................................................................................ 14 Appendix A ...................................................................................................................................................................................................................... 17 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 3 of 17 MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY 1 | INTRODUCTION 1.1 | Background and Terms of Reference as provided by the requestor 1.1.1 | Background Regulation (EC) No 1925/20061 establishes the rules governing the addition of vitamins and minerals and of certain other substances to foods and, in particular, Article 8 thereof defines the procedure to be followed for prohibiting, restricting, or placing under Community scrutiny a given substance. 1.1.2 | Terms of Reference On 1 June 2022, pursuant to Article 1(2) of Commission Regulation (EU)2022/860,2 amending Annex III, Part C, of Regulation (EC) No 1925/2006, the Commission has placed under Union scrutiny ‘Monacolins from red yeast rice’. The European Commission (EC) requests the European Food Safety Authority's (EFSA) opinion on whether the scientific data contained in the files submitted or to be submitted for evaluation by food business operators or any other interested parties demonstrate the safety of substances placed under Union scrutiny mentioned above. 1.2 | Interpretation of the Terms of Reference As safety concerns were raised in relation to the consumption of monacolins from red yeast rice (RYR) in food supplements at doses of 10 mg/day, and individual cases of severe adverse reactions had been reported at doses as low as 3 mg/day (EFSA ANS Panel,2018), monacolins from RYR were placed under Union scrutiny (Commission Regulation (EU) 2022/860) and Annex III (Part B) to Regulation (EC) No 1925/2006 was amended to indicate that the individual portion of the product for daily consumption shall provide less than 3 mg of monacolins from RYR. The main reasons for placing monacolins from RYR food supplements under Union scrutiny (Recital 18 of Commission Regulation (EU) 2022/860) were the scientific uncertainties in relation to the possibility of harmful effects on health associated with the use of monacolins from RYR and that EFSA (EFSA ANS Panel,2018) could not identify a level of intake that does not give rise to concerns about harmful effects to health for the general population, and as appropriate, for vulnerable subgroups of the population. In the context of the terms of reference and the reasons given in the recitals of Commission Regulation (EU) 2022/860 for placing monacolins from RYR under Union scrutiny, the Panel understands that EFSA is requested to assess whether the data provided by food business operators (FBO) or any other interested parties during the scrutiny period are sufficient to: a. address the scientific uncertainties raised by the EFSA ANS Panel (2018) in relation to the safety assessment of monacolins from RYR; and b. allow the identification of a daily intake of monacolins from RYR in food supplements3 that does not raise safety concerns for the general population or vulnerable subgroups thereof. Therefore, this assessment needs to be read in conjunction with the EFSA ANS Panel opinion(2018), where all the information and data available in relation to the safety of monacolins from RYR up to the scrutiny period is presented and assessed, including the chemical homology with the cholesterollowering medication lovastatin and a (comparative) assessment of the ADME and reported adverse effects in humans. This assessment concerns the safety of monacolins from RYR in food supplements only. Potential beneficial health effects of monacolins from RYR and risk–benefit analyses are out of the scope of this mandate. This assessment does not concern quality aspects of RYR products available in the market, such as the potential presence of contaminants (e.g. fungi and their mycotoxins such as citrinin) or adulterants (e.g. addition of synthetic statins). 1.3 | Previous EFSA assessments on monacolins from RYR The EFSA NDA Panel has assessed two health claim applications on monacolin K from RYR and maintenance of normal blood LDLcholesterol concentrations with a favourable outcome (EFSA NDA Panel,2011, 2013). To obtain the claimed effect, 1Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and minerals and of certain other substances to foods. OJ L 404, 30.12.2006, p. 26–38. 2Commission Regulation (EU) 2022/860 of 1 June 2022 amending Annex III to Regulation (EC) No 1925/2006 of the European Parliament and of the Council as regards monacolins from red yeast rice. OJ L 151, 2.6.2022, p. 37–41. 3According to recital 6 of Regulation (EC) No 2022/860, the use of RYR preparations in other food categories is subject to an authorisation under Regulation (EC) 2015/2283 on novel foods. 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 17 | MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY 10 mg of monacolin K from fermented RYR should be consumed daily. The target population was adults in the general population. In the framework of Regulation (EC) No 1924/2006, a safety assessment is not foreseen in health claim evaluations. In relation to the restrictions of use, the NDA Panel referred to the opinion by the EFSA CONTAM Panel on citrinin (a nephrotoxic mycotoxin), which can be produced by some strains of Monascus purpureus (EFSA CONTAM Panel,2012). The maximum level of citrinin (100 μg/kg) in food supplements based on rice fermented with the red yeast Monascus purpureus is regulated [Regulation (EU) 2023/915]. In relation to the restrictions of use, the NDA Panel also referred to the Summary of Product Characteristics (SmPC) for lovastatincontaining medicinal products available on the EU market, as monacolin K in lactone form is identical to lovastatin. The SmPC, among others, includes special warnings and precautions for use that refer to the risk of myopathy/rhabdomyolysis, which is increased by concomitant use of lovastatin with certain other medicinal products, and discourages the use of lovastatin by pregnant and lactating women [EFSA NDA Panel,2011, 2013; Regulation (EU) 2022/860]. In that context, Member States raised potential safety concerns associated with the consumption of foods containing monacolins from RYR (ANSES,2014; CSS,2016; DFG, 2016). Consequently, in 2017, the European Commission initiated the procedure under Article 8(2) of Regulation (EC) No 1925/2006 and asked EFSA to: • review the existing scientific data on the possible link between the intake of monacolins from RYR and harmful effects on health. • provide advice on a daily intake of monacolins from RYR that does not give rise to concerns about harmful effects to health, for the general population, and as appropriate, for vulnerable subgroups of the population. In 2018, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) issued an opinion on the safety of monacolins in RYR (EFSA ANS Panel,2018) within the framework of Article 8(2) of Regulation (EC) No 1925/2006. In its opinion, the EFSA ANS Panel(2018) noted that monacolin K in lactone form is identical to lovastatin, the active ingredient of several medicinal products authorised for the treatment of hypercholesterolemia in the EU. Monacolin K from RYR is available in food supplements at varying recommended daily intakes for its effect on the maintenance of normal blood LDL cholesterol levels. The estimated exposure to monacolin K was within the range of therapeutic doses of lovastatin. The ANS Panel noted that the profile of adverse effects of RYR was similar to that of lovastatin. Based on case reports, the most important target organs/tissues for adverse events were musculoskeletal and connective tissues (including rhabdomyolysis), liver, nervous system, gastrointestinal tract, skin and subcutaneous tissue, in descending order of occurrence. The available information on the adverse effects reported in humans was judged to be sufficient to conclude that monacolins from RYR in food supplements were of significant safety concern at the use level of 10 mg/day. The ANS Panel further noted that individual cases of severe adverse reactions (rhabdomyolysis, hepatitis and skin disorders) to monacolins from RYR which required hospitalisation had been reported at intakes as low as 3 mg/day taken for periods of between 2 weeks and 1 year. On the basis of the information available and the several uncertainties highlighted in its opinion, the ANS Panel was unable to identify a level of intake of monacolins from RYR in food supplements that does not give rise to concerns about harmful effects to health, for the general population, and as appropriate, for vulnerable subgroups of the population (EFSA ANS Panel,2018). In 2019, the European Commission asked EFSA to provide technical assistance on two scientific publications that were submitted to the Commission by an interested party following the adoption of the scientific opinion by the ANS Panel(2018). These were a systematic review and metaanalysis of randomised controlled trials (RCT) on the safety of RYR supplementation (Fogacci etal.,2019) and a narrative review and expert opinion aiming at weighing the risks and benefits of using RYR in food supplements and the drug lovastatin as blood cholesterollowering agents (Banach etal.,2019). EFSA noted that the RCTs provided were not designed to detect adverse effects as the sample size was not sufficient for that purpose, and that comparative risk–benefit analyses were not useful in addressing the safety concerns raised by the available case reports of adverse effects associated with the consumption of RYR in humans. 2 | DATA AND METHODOLOGIES 2.1 | Data During the period of Union scrutiny, foreseen by Article 8(4) of Regulation (EC) No 1925/2006, four interested parties [Società Italiana di Scienze Applicate alle Piante Officinali e ai Prodotti per la Salute (SISTE), European Federation of Associations of Health Product Manufacturers (EHPM), Linneus Consulting Services and Hylobates Consulting srl as representative of Asociación Española de Complementos Alimenticios (AFEPADI)] submitted data. All the documents submitted by each interested party are listed in alphabetical order of the first author. 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 5 of 17 MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY SISTE submitted: • A narrative review including the analysis of serious adverse events (rhabdomyolysis and acute hepatitis), associated with the consumption of RYR reported to the US Food and Drug Administration (Banach & Norata,2023), which included reference to postmarketing nutrivigilance safety data for specific food supplements containing RYR (Banach etal.,2021). • An RCT on the effects (including adverse effects) of a food supplement containing RYR and providing total monacolins < 3 mg/day (Cicero etal.,2024). • A narrative review on the occurrence of muscle symptoms and liver dysfunction associated with the consumption of RYR supplements, using available data from adverse event reporting systems and metaanalyses (Norata & Banach,2024). EHPM submitted: • A final report of the Task Force for RYR of EHPM on nutrivigilance data (EHPM,2024), including an update on postmarketing nutrivigilance safety data for a specific food supplement containing RYR (Banach etal.,2024, unpublished). • A study about the phytochemical profile, pharmacological effects and safety of various RYR samples in comparison with lovastatin, using invitro/in silico models (Rigillo etal.,2025). Linneus Consulting Services submitted: • A report including the monacolin content in commercially available RYR products (food supplements) and invitro cytotoxicity assessments of RYR samples vs. lovastatin, and of monacolin K vs. simvastatin and atorvastatin, using a human HepG2 cell line model (Linneus Consulting Services,2024). • An analytical report of RYR metabolites in different ethanolic extracts (SUPPLEMENTARY_MATERIALS_TOT). Hylobates Consulting srl, representative of AFEPADI, submitted: • A summary report/document of the evidence for establishing a healthbased guidance value (HBGV) for RYR (< 3 mg/ day) (AFEPADI,2024), including a scientific statement from the American Heart Association (AHA) on statin safety and associated adverse events (Newman etal.,2019) and reference to a foodborne outbreak in Japan linked to the consumption of RYR products (Hashimoto etal.,2024). • A list of references included in the submission (AFEPADI20240703MonacolinReferenceProvided.pdf). • A published article about the lovastatin content in Pleurotus ostreatus, or oyster mushroom (edible mushroom) (Alarcón etal.,2003). • A published article about the influence of the gut microbiota on the conversion of monacolin K to its active βhydroxy acid form (BBeltrán etal.,2019). • A published article about the onlabel and offlabel uses of lovastatin as a drug (Duong & Bajaj,2023). • EFSA's external scientific report about the occurrence of citrinin in food (López Sánchez etal.,2017). • A narrative review about the use of statins in children (Fiorentino & Chiarelli,2023). • A narrative review about statins (Hajar,2011). • A cover letter from AFEPADI (Hylo2024SignedLetter.pdf). • A published article about a new analytical method [nuclear magnetic resonance (NMR) assay] for assessing total statin content and βHydroxy βmethylglutarylcoenzyme A (HMGCoA) reductase inhibition in RYR supplements (Lachenmeier etal.,2012). • A published systematic review and metaanalysis on the use of statins in children with familiar hypercholesterolaemia (Radaelli etal.,2018). • A published article on the content of mycotoxins and natural statins in commercially available RYR food supplements (Righetti etal.,2021). • A systematic review about the beneficial and adverse effects of Xuezhikang, a partially purified extract of fermented RYR, in the secondary prevention of coronary heart disease (CHD) combined with dyslipidaemia (Shang etal.,2012). • An analytical guideline for RYR, as a basis to establish the specifications for the product [SIFITLab Laboratorio d'analisi di Siena et al. (2018b) (translation in English) and SIFITLab Laboratorio d'analisi di Siena et al. (2018a) (original document in Italian)]. • A narrative review about citrinin occurrence in food supplements (Silva etal.,2021). • A published article about the quantification of lovastatin in Agaricus bisporus (mushroom species) (Tsiantas etal.,2021). • A published article containing the evaluation of the quality profile of food supplements containing RYR marketed in Italy (Vitiello etal.,2023). • A document about the first identification of M. purpureus (Went,1895). The Panel considers that the following documents submitted are not pertinent to the safety assessment of monacolins from RYR, which do not include quality aspects of RYR supplements in the market (see Section1.3), and will not be considered further in this opinion: 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 17 | MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY • The publications by Went(1895), Beltrán etal.(2019) and Silva etal.(2021); • Analytical guideline to establish the specifications for RYR products [SIFITLab Laboratorio d'analisi di Siena et al. (2018a) (original document in Italian) and SIFITLab Laboratorio d'analisi di Siena et al. (2018b) (translation in English)]; • Data related to a recent food intoxication outbreak in Japan that has been attributed to the contamination of RYR products during the fermentation stage with Penicillium adametzoides. This fungus produces puberulic acid, which can induce renal dysfunction (MHLW,2024); • Narrative reviews (Duong & Bajaj,2023; Fiorentino & Chiarelli,2023; Hajar, 2011), the systematic review (Radaelli etal.,2018) and the consensus statement from the AHA (Newman etal.,2019) on the safety of statins, which collectively address the tradeoff between beneficial and adverse effects of the onlabel and offlabel use of statins for the treatment of hypercholesterolaemia and/or the prevention of cardiovascular diseases in different population groups, including children and adolescents and do not provide relevant information for the safety assessment of monacolins from RYR, including the identification of a daily dose of monacolin K from RYR in food supplements that does not raise safety concerns for humans. In accordance with Article 38 of Regulation (EC) No 178/20024 and taking into account the protection of confidential information and of personal data in accordance with Articles 39, 39a to 39e of the same Regulation and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality,5 the nonconfidential versions of the data submitted by the interested parties are published in OpenEFSA.6 According to Art. 32c (2) of Regulation (EC) No 178/2002 and according to the Decision of EFSA's Executive Director laying down the practical arrangements on the presubmission phase and public consultations, EFSA carried out a public consultation (PC1090) from 13 August to 03 September 2024 on the nonconfidential version of the submissions by interested parties. No comments were received. 2.2 | Methodologies The scientific evaluation was based on the data submitted during the period of scrutiny, and it was performed in line with the principles described in the EFSA Guidance on transparency in the scientific aspects of risk assessment (EFSA,2009) and followed the relevant existing guidance documents from the EFSA Scientific Committee. The risk assessment was performed according to the EFSA Guidance on safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements (EFSA Scientific Committee,2009). 3 | ASSESSMENT The data submitted by interested parties to EFSA aim at addressing the uncertainties identified by the ANS Panel(2018), which precluded establishing a HBGV for monacolins in RYR food supplements. The NDA Panel considers as pertinent for that purpose: • Analytical data about the characterisation of RYR preparations (Lachenmeier etal.,2012; Linneus Consulting Services,2024; Righetti etal.,2021; Rigillo etal.,2025; Vitiello etal.,2023); • Data on the dietary intake of monacolins from food sources other than RYR (AFEPADI,2024); • In vitro/in silico data of RYR/monacolin K vs. other statins (Linneus Consulting Services,2024; Rigillo etal.,2025); • Nutrivigilance/postmarketing data on adverse events related to the use of RYR products (Banach & Norata,2023; Banach etal.,2021; Banach etal.,2024, unpublished; Norata & Banach,2024; EHPM,2024; AFEPADI,2024); • Case reports of adverse events from the scientific literature (Banach & Norata,2023); • New clinical data including safety endpoints (Shang etal.,2012; Cicero etal.,2024, unpublished). 3.1 | Analytical data about the characterisation of RYR preparations The following uncertainties in relation to the characterisation of RYR preparations were highlighted by the ANS Panel(2018): a. the composition and content of monacolins (and their relative abundance) in food supplements containing RYR; b. monacolins in RYR are used in multiingredient botanical preparations, the components of which have not been fully evaluated individually or in combination; and c. the ratio between monacolin K lactone and monacolin K hydroxy acid (HA) is variable in food supplements containing RYR. 4Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L 31, 1.2.2002, pp. 1–48. 5Decision available online: https:// www. efsa. europa. eu/ en/ corpo ratepubs/ trans paren cyregul ation - pract icalarran gements. 6The nonconfidential version of the dossier, following EFSA's assessment of the applicant's confidentiality requests, is published on Open.EFSA and is available at the following link: https:// open. efsa. europa. eu/ quest ions/ EFSAQ202300424 . 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 7 of 17 MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY Rigillo etal.(2025) analysed 14 commercialgrade RYR food supplements with a declared total monacolin K content ranging from < 0.15% to 5% w/w using a highperformance liquid chromatography with diode array detection (HPLCDAD) method, which allows quantifying the content of total monacolin K (as the sum of monacolin K in lactone and HA forms) and the content of other monacolins (as the sum of monacolin M, monacolin L, monacolin L HA, monacolin X, compactin, dihydromonacolin K and dehydromonacolin K). Total monacolin K ranged from 0.05% to 5.25% w/w in the analysed samples, showing deviations from the declared amounts (from −5% to +20%), while other monacolins showed high variability, accounting for 3%–30% (mean 23%) of total monacolins. The ratio between monacolin K in lactone form and monacolin K in HA form ranged from approximately 1:1–34:1 in the tested samples. The average content of total polyphenols and total triterpenes was 0.92% and 3.63% w/w, respectively, and did not correlate with the total content of monacolins. In the report by Linneus Consulting Services(2024), phytochemical analyses were conducted in 27 samples of RYR food supplements commercially available on the Italian market and supplied by different companies. The content of monacolin K in lactone (MKL), HA (MKHA) and dehydro- (DMK) forms and the content of other monacolins (MSEC; the sum of monacolin L, compactin, monacolin J, monacolin L HA, monacolin X and monacolin M) were quantified using HPLCDADMS/MS and highresolution mass spectrometry (HRMS) methods. The measured content of total monacolins (from 0.45% to 7.84% w/w), including all forms of monacolin K and other monacolins, differed from the declared content (from –37% to +62% w/w) in most samples for which this information was available. The ratio MKL:MKHA varied from 2.5:1 to 114:1 across RYR samples. Based on the ratio between each monacolin measured (MKL, MKHA, DMK and MSEC) and the sum of MKL and MKHA (MKL/MKL+MKHA; MKHA/MKL+MKHA; DMK/MKL+MKHA; MSEC/MKL+MKHA), a hierarchical cluster analysis (HCA) was used to identify the different patterns of relative monacolin abundance across RYR samples. The four clusters identified on such bases were used to select six RYR samples that were representative of RYR supplements available on the market for untargeted analyses and invitro cytotoxicity testing (see Section3.3). The Panel notes that the four clusters identified widely differed in the relative abundance of MKL, MKHA, DMK and MSEC. The six RYR samples selected underwent ethanol extraction at different concentrations (30%, 50% and 75%), followed by untargeted analysis by ultrahighperformance liquid chromatographyhighresolution mass spectrometry (UHPLCHRMS) methodology. The major groups of compounds found in the ethanol extracts were monacolins (25%–30%), azaphilones (19%–23%) and polyketides (10%–15%), the amounts of which varied depending on the extract. Other compounds such as fatty acids, lignans, glycosides, steroids, amino acids, coumarins, decalins, terpenoids, alkaloids and flavonoids were also quantified. An 1HNMR study (Lachenmeier etal.,2012) provided information about the monacolin content in five commercially available RYR products obtained from webshops. Total monacolin content (the sum of the lactone and HA forms of monacolin K and other monacolins containing the hexahydronaphthalene moiety, including monacolins J, L, M or X) ranged between 1.5 and 8 mg/capsule (0.45%–1.33% w/w), leading to daily doses of 1.5–24 mg based on the manufacturer's recommendations. In the study by Righetti etal.(2021), 37 RYR food supplements as monoor multiingredient formulations available on the Italian market were analysed for their content of mycotoxins (e.g. citrinin), MKL and MKHA. Among these, nine RYR products had a total monacolin K content below the label statement (from −27 to −83%), with three products having a negligible content, while the content of total monacolin K was higher than reported (from 10% to 266%) in 25 products. In four products, the total monacolin K content would result in a daily intake below 3 mg following the manufacturer recommendations, while in 20 products, the daily dose would exceed 10 mg, reaching 36 mg in one product. The ratio MKHA/ MKL+MKHA across samples varied from 0.03 to 0.64. The authors noted that variable but small amounts of simvastatin (0.1–7.5 μg per daily dose) were also found in 30 RYR food supplements. Vitiello etal.(2023) tested 14 RYR food supplements commercially available on the Italian market with a declared monacolin K content from 1.45 to 10 mg/unit of product (filmcoated or uncoated tablets, hardshell capsules, soft gels). The authors found that, in all products tested, the measured content of monacolin K deviated from the declared one (from −20.8% to +1.4%) and showed high variability across products (from 1.47 to 10.14 mg total monacolin K/unit of product). The Panel acknowledges that some information has been provided regarding the identification and quantification of compounds other than monacolins in selected RYR samples and the identification and quantification of monacolins and their relative abundance (Linneus Consulting Services,2024; Rigillo etal.,2025), including the total monacolins (Lachenmeier etal.,2012), the amount of total monacolin K (Vitiello etal.,2023) and the ratio between its lactone and HA form (Linneus Consulting Services,2024; Righetti etal.,2021; Rigillo etal.,2025). The Panel also notes, however, that: a. commercially available RYR food supplements show high variability in total monacolin K content (from < 0.15% to 7.48%, w/w), as well as in the amount of total monacolins/monacolin K measured vs. declared on the product label; and b. the ratio between monacolin K in its lactone form (chemically identical to lovastatin) and its HA form shows significant variability in food supplements containing RYR, with reported ratios ranging from 1:1 to 114:1. The Panel considers that, although the data provided contribute to the knowledge on the composition and total monacolin profile of commercially available RYR supplements, it also strengthens the concerns expressed by the EFSA ANS Panel(2018) about the uncertainties regarding the characterisation of these products, particularly in relation to the variability in content of total monacolin K and to the relative abundance of its lactone and HA forms, as these two forms of monacolin K are most likely responsible for the adverse health effects reported in relation to the consumption of RYR supplements. 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 17 | MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY 3.2 | Data on the dietary intake of monacolins from food sources other than RYR In the document by AFEPADI(2024), it is argued that monacolins (including monacolin K in lactone form) are naturally occurring substances found not only in RYR but also in various species of edible mushrooms (Alarcón etal.,2003; Chen etal.,2013; Kała etal.,2020; Lam & Okello,2015; Lee etal.,2006; Lin etal.,2013; Lo etal.,2012; Tsiantas etal.,2021). Consequently, the interested party argued that any risk assessment or risk management actions concerning monacolins from RYR should also consider and apply to other dietary sources. The Panel notes the opinion of the Joint Expert Committee BVL/BfArM (BVL/BfArM,2016), which evaluated the occurrence of monacolins in food sources and provided intake estimates. Their review of the available literature on monacolin content in several edible mushroom species identified several methodological shortcomings, particularly concerning sample preparation and analytical methods used. To address these limitations, the Committee conducted an internal study using a validated method to measure the monacolin content in mushrooms. This study concluded that the intake of monacolin K lactone would range from approximately 4 to 11 μg per 100–200 g of fresh mushrooms consumed. The Panel notes that these intake levels are several orders of magnitude lower than the currently allowed maximum daily doses of monacolin K from RYR when consumed as food supplements [Regulation (EC) 2022/860]. Therefore, the Panel considers that the daily intake of monacolin K from RYR would greatly exceed the amount of monacolin K that would be reasonably expected to be consumed in the context of a balanced and varied diet. 3.3 | In vitro data of RYR/monacolin K vs. other statins In the study by Rigillo etal. (2024), the pharmacokinetic differences between 1 mL of selected RYR solutions with a total monacolin K content between 1.55 and 5.25% w/w (see Section3.1) and an equivalent concentration of pure lovastatin were evaluated in an invitro model of simulated digestion. The median bioaccessibility rate of lovastatin, expressed as % of recovery after sample digestion compared to the initial (predigestion) amount used, was 65.23% ± 18.45%, which was explained by the poor solubility of lovastatin in the digestive environment. When replicating the simulated digestion without enzymes, but only changing the pH, a comparable recovery was obtained. Bioaccessibility of monacolin K from RYR samples varied, but it was higher than for lovastatin (only one sample had a slightly lower value), exceeding 80% in some samples and reaching 100% in one sample, with a total monacolin content of 3.5% w/w. The authors noted that the bioaccessibility of RYR samples was positively associated with the content of other monacolins and triterpenes and not with the content of monacolin K. The invitro cytotoxic effects of 14 RYR samples, differing in monacolin K content (from 0.05% to 5.25% w/w), total polyphenols, and triterpenes, as well as pure lovastatin, were assessed using the cell counting kit8 (CCK8) assay (Rigillo etal.,2025). Cytotoxicity was measured at concentrations ranging from 10 to 200 μg/mL in various immortalised or cancerderived cell lines, including human intestinal (Caco2), hepatic (HepG2), kidney (HEK293) cells and mouse muscle (C2C12) cells. The results were expressed as IC50 values, representing the concentration required to reduce 50% of cell viability. Most RYR samples showed IC50 values exceeding the highest concentration tested, i.e. 200 μg/mL in all cell lines. IC50 values above 100 μg/mL were shown in HEK293 cells by two samples and in C2C12 cells by four samples. When compared with lovastatin, the only remarkable difference was that the highest cytotoxicity of lovastatin was observed in the C2C12 myoblast cell line. To investigate the molecular mechanisms of statininduced toxicity in muscle cells, the authors compared the effects of selected RYR samples and lovastatin on the expression of genes involved in muscle function and metabolism, including myoblast determination protein 1 (MyoD), muscle creatine kinase (MCK) and interleukin6 (IL6). The C2C12 muscle cells were treated for 24 h with lovastatin (1 μg/mL) or RYRs at the equivalent monacolin K concentration, corresponding to 1 μg/mL. The mRNA levels of the selected genes were measured by quantitative reverse transcription polymerase chain reaction (RTqPCR) and in the case of IL6, also at protein levels. Lovastatin treatment significantly downregulated MyoD and upregulated MCK and IL6 compared to controls and RYR samples, suggesting targeted effects on muscle physiology. In contrast, RYR samples showed minimal or sporadic effects, indicating a more limited and variable impact. Additionally, the expression of autophagy- (Atg5 and Atg7) and atrophyrelated genes (Fbxo32 and Trim63) was analysed. Lovastatin significantly upregulated Atg7 and Trim63 mRNA levels compared to control, while RYR samples did not affect the expression of these genes (Rigillo etal.,2025). In the Linneus Consulting Services report(2024), an invitro Alamar Blue cytotoxicity assay was conducted on liver HepG2 cells exposed for 24 h to various concentrations (0.1–100 μM) of simvastatin, atorvastatin, monacolin K and six RYR preparations with varying monacolin compositions (0.45–7.84% w/w; see Section3.1). Simvastatin caused significant cytotoxicity at higher concentrations (97% at 100 μM, 70% at 50 μM), while atorvastatin was less cytotoxic (49% at 100 μM). Monacolin K caused 20% cell death only at 100 μM. RYR preparations exhibited higher cytotoxicity overall, with 72%–96% cell death at 100 μM and up to 95% at 50 μM. Notably, three RYR samples showed slight cytotoxicity (13%–18%) even at 0.1 μM. Increased cytotoxicity correlated with higher dehydromonacolin K content. These findings suggest that RYR preparations are more cytotoxic than pure monacolin under these conditions. The Panel notes that, based on the submitted studies, RYR preparations (with total monacolin K content ranging from 0.05% to 5.25% w/w) demonstrate variable cytotoxic effects, which are generally less pronounced than those observed for lovastatin, particularly in muscle C2C12 cells. However, the IC50 values reported for RYR preparations are predominantly 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | 9 of 17 MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY threshold values (i.e. > 200 μg/mL), indicating no cytotoxicity within the tested concentration range. Consequently, the actual IC50 values could be any value higher than 200 μg/mL, rendering any definitive conclusion inappropriate. The analysis of transcriptional levels of target genes involved in muscle function and metabolism provides a plausible mechanism for the greater toxicity of lovastatin in muscle cells compared to RYR preparations. The Panel also notes the higher invitro cytotoxicity of RYR samples as compared to monacolin K and other statins (Linneus Consulting Services report,2024) in the HepG2 cell line, the same cell line that showed a lack of cytotoxic effects with both lovastatin and RYR samples up to 200 μg/mL in the Rigillo etal. (2024) study. These contrasting findings highlight the variability in RYR sample compositions, which may hamper cytotoxicity assessments. The Panel acknowledges that, while invitro cytotoxicity studies may offer valuable mechanistic insights, their predictive value for invivo toxicity is limited, especially when using immortalised cell lines, as in the submitted studies. The Panel considers that, given these limitations, these studies are of limited value for the safety assessment of monacolins in RYR for human consumption. 3.4 | Nutrivigilance/postmarketing data on adverse events related to the use of RYR products A narrative review (Norata & Banach,2024) reported on adverse events related to muscle and liver as target organs associated with the consumption of products containing RYR. The FDA Adverse Event Reporting System (FAERS) (as of September 2023) and CFSAN Adverse Event Reporting System (CAERS) (as of June 2023) were used as sources of data. A total of 28 cases of adverse events, of which 25 were classified as serious events, were retrieved from FAERS. These included eight cases of musculoskeletaland connective tissuerelated adverse events, of which three were cases of rhabdomyolysis. Seven women and one man (from 51 to 78 years of age) were affected. In all cases, RYR was one among other active ingredients in the product suspected to be responsible for the adverse effects, and in three cases, the concomitant use of other products/medications was noted. Four cases of liverrelated adverse events were reported, including three cases of hepatic cytolysis and one case of liver damage (not better specified). Only males (from 45 to 68 years of age) were affected. The concomitant use of other products/medications was noted in all cases. The analysis of the CAERS database retrieved 223 cases of adverse events in relation to RYR supplement use. These included 53 cases of musclerelated adverse events, with myalgia and muscle spasms being the most common symptoms, and 29 cases of liverrelated adverse events, with abnormal liver function tests being the most common finding. Multiple adverse effects were often reported by the same person. In 34 cases of musclerelated adverse events and 10 cases of liverrelated adverse events, RYR was one among other active ingredients in the products suspected to be responsible for the adverse effects, while in all other cases, RYR was used in concomitance with the suspected product (other than RYR). When RYR was reported as the suspected product, adverse events were more frequent in women. The age of affected individuals ranged from 36 to 91 years (median age: 64 years). The Panel notes that neither the FAERS nor the CAERS database allows concluding on causal relationships between the use of RYRcontaining products and the reported adverse events. The Panel also notes that FAERS does not provide information on the doses of RYR consumed, while CAERS reports a dose of 600 mg of RYR in several cases but reports no information on the monacolin content of these products. The paper by Banach etal.(2021) reports on postmarketing safety data for the RYRcontaining food supplements Armolipid® (standard) and Armolipid® Plus (enhanced), at the recommended dose of one tablet/day for 1 year. One tablet of Armolipid (standard) contained RYR (200 mg, of which 3 mg of monacolin K), folic acid (0.2 mg), CoQ10 (2 mg), astaxanthin (0.5 mg) and, in some countries, policosanols (10 mg). One tablet of Armolipid Plus (enhanced) contained Berberis aristata extract (588 mg, of which 500 mg of berberine chloride), RYR (200 mg, of which 3 mg of monacolin K), policosanol (10 mg), folic acid (0.2 mg), CoQ10 (2.0 mg) and astaxanthin (0.5 mg). Postmarketing information was collected in a voluntary nutrivigilance system established by the manufacturing company (Meda Pharma SpA, a Viatris Company, Monza, Italy) from 1 October 2004 to 31 December 2019. This system captured cases of suspected adverse effects spontaneously reported by consumers, healthcare professionals or health authorities, regardless of causality. A total of 542 notifications/cases reporting on 855 adverse events were received related to the use of Armolipid® (standard) and Armolipid® Plus (enhanced). The number of musculoskeletal adverse events (% of the total) was 148 (17.3%), and the number of hepatic adverse events was 26 (3%). Serious adverse events occurred in nine cases, two related to rhabdomyolysis and seven to serious hepatitis. One case of rhabdomyolysis occurred in an elderly woman who took Armolipid® Plus (enhanced) while using sertraline and rosuvastatin. The second case was a consumer (unknown sex) with a history of rhabdomyolysis in response to simvastatin who developed rhabdomyolysis requiring hospitalisation after starting Armolipid® Plus (enhanced). The authors claim that, in both cases, the labelling warnings against concomitant use of RYR supplements and other statins without medical supervision were not respected by the consumers. As for the seven cases of serious hepatitis, causality was assessed as probable (in two cases), possible (in two cases) and unlikely (in three cases) by the reporter based on the WHOUMC system criteria (WHO,2018). The authors (Banach etal.,2021) calculated the total reporting rate of adverse events and serious adverse events notified in relation to the consumption of Armolipid® (standard) and Armolipid® Plus (enhanced) by estimating the number of exposed consumers based on the number of tablets manufactured over 15 years, assuming a consumption of one tablet per day for 1 year (n = 2,287,449). The total reporting rate (number of cases among total consumers) was 0.0374% for any 18314732, 2025, 2, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2025.9276 by Readcube (Labtiva Inc.), Wiley Online Library on [13/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 16 of 17 | MONACOLINS FROM RED YEAST RICE PLACED UNDER UNION SCRUTINY MHLW (Ministry of Health, Labour and Welfare). (2024). Information on Adverse Events associated with Benikoji (Red Yeast Rice) related Products. https:// www. mhlw. go. jp/ stf/ seisa kunit suite/ bunya/ kenkou_ iryou/ shoku hin/ daiet to/ index_ 00005. html Newman, C. B., Preiss, D., Tobert, J. A., Jacobson, T. A., Page, R. L., 2nd, Goldstein, L. B., Chin, C., Tannock, L. R., Miller, M., Raghuveer, G., Duell, P. B., Brinton, E. A., Pollak, A., Braun, L. T., Welty, F. 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