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SYNTHESIS ARTICLE - ARTICOLE DE SINTEZA -ARTICLES DE SYNTHÈSE - ОБЗОРНЫЕ СТАТЬИ
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POSSIBLE ALGORITHMS FOR DETERMINING ADVERSE REACTIONS CAUSED BY FOOD SUPPLEMENTS IN ROMANIA
Irina Mihaela MATRAN1, Daniela Lucia MUNTEAN1, Cristina NICULAS2, Roxana Maria MARTIN-HADMAS1, Monica TARCEA1
'iGeorge Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania 2Richter Pharmacy no 7, Cluj-Napoca, Romania
Corresponding author: Irina Mihaela Matran, e-mail: matran.irina-mihaela.20@stud.umfst.ro
DOI: 10.38045/ohrm.2021.4.01
CZU: [615.32.065+613.292](498)
Keywords: nutriv-igilence, algorithms, food supplements, side effects.
Cuvinte cheie: nutrivigilentä, algoritmi, supli-mente alimentare, efecte secundare.
Introduction. The advertising of food supplements on various media channels or in special ty stores with natural products and other places, as well as the lack of informative and educational programs for the population upon side effects and the interaction of food supplements with food and drugs, have led to the development of uncontrolled marketing of these products.
Material and methods. PubMed, ResearchGate and EUR-Lex databases were analyzed during 2015-2021, based on search criteria based on: adverse reactions, ingredient new food, food supplements, algorithms.
Results. Certain dietary supplements can cause multiple side effects, such as: impaired platelet function by decreased platelet aggregation, gastrointestinal side effects (diarrhea vomiting), decreased wound healing/epithelialization, bacterial or fungal sepsis, mos common in patients older. Herbal resources such as Aloe vera, Matricaria recutita, Taraxacum officinale and others, can cause dermatological side effects and inhibit the eliminatior of dermatological drugs metabolised by cytochrome P-450 (e.g. terbinafine). Matricaria recutita, Allium sativum, Mentha piperita L. and others, inhibit the enzyme CYP2C9. Another enzyme with a role in the metabolism of dermatological drugs and which is inhibited by plant resources is CYP3A4.
Conclusions. It is imperative to legislate the reporting of adverse reactions caused by fooc supplements, including their interaction with food or drugs.
ALGORITMIPOSIBILIPENTRUDETERMINAREA REACTIILOR ADVERSE CAUZATEDE SUPLIMENTELE ALIMENTARE IN ROMANIA
Introducere. Promovarea suplimentelor alimentare in diverse surse media sau de catre unele magazine, in special de cele specializate in comercializarea produselor naturale, pre-cum si lipsa programelor informative si educationale pentru populatie cu privire la efectele secundare si interactiunea suplimentelor alimentare cu alimentele si medicamentele, au dus la dezvoltarea comercializarii necontrolate a acestor produse.
Material si metode. Bazele de date PubMed, Research Gate si EUR -Lex au fost analizate in perioada 2015-2021, pe baza criteriilor de cautare: reactii adverse, ingrediente alimentart noi, suplimente alimentare, algoritmi.
Rezultate. Anumite suplimente alimentare pot provoca efecte secundare multiple, cum arfi afectarea functiei trombocitelor prin scaderea agregarii plachetare, efecte secundare gas trointestinale (diaree, varsaturi), scaderea vindecarii/epitelizarii ranilor, sepsis bacteriar sau fungic, atestate cel mai frecvent la pacientii cu varsta inaintata. Resursele vegetale pre cum Aloe vera, Matricaria recutita, Taraxacum officinale si altele, pot provoca reactii adverse dermatologice si inhiba eliminarea medicamentelor dermatologice metabolizate de citocromul P-450 (de exemplu terbinafina). Matricaria recutita, Allium sativum, Mentha piperita L. si altele, inhiba enzima CYP2C9. O alta enzima cu rol in metabolismul medicamentelor dermatologice si care este inhibata de resursele vegetale este CYP3A4. Concluzii. Este imperativ sa se reglementeze raportarea reactiilor adverse cauzate de su plimentele alimentare, inclusiv interactiunea acestora cu alimentele sau medicamentele.
ORRM
INTRODUCTION
Advertising of food supplements on various media channels or in specialty stores with natural products, as well as the lack of information and educational programs of the population, on adverse reactions and interaction of food supplements with food and drugs, have led to uncontrolled development of marketing these products.
Although in the US, the FDA (Food and Drug Administration) only authorizes food and drugs, the 1994 Dietary Supplement Health and Education Act (DSHEA) monitors the side effects (SE) of post-market food supplements (1). Under this law, food supplements are orally ingested foods that include botanical products (such as herbal remedies) and non-botanical substances, such as minerals, amino acids, vitamins and microbial products, and traditional cultural remedies, including Asian plants (2). Although the prohibition on the statement that "food supplement (FS) may be used for the treatment or prevention of a disease" is valid in Romania, in the USA, the mention regarding general well-being and health is allowed provided that on the packaging/label is "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease" (1).
SE has been found and reported in vitamin food supplements:
• doses higher than 500 mg/day pyridoxine (vitamin B6) - photosensitivity, neurotoxicity,
• chronic sensory polyneuropathy associated with pyridoxine,
• bleeding associated with antiplatelet action at doses 800-1200 mg/day,
• diarrhea, weakness, blurred vision and gonadal dysfunction at doses higher than 1200 mg/day a-tocopherol (vitamin E) and
• increased recurrence of cancer in the first 3.5 years (1).
The "Retinol Efficacy Trial" and "ATBC" studies demonstrated the toxicity of (3-carotene (vitamin A) supplements by significantly increasing the risk of lung cancer in male smokers (1). Following the study "Teratogenicity of high vitamin A intake" (1), researchers Rothman KJ, Moore LL, Singer MR et al. suggested the association of dietary supplements containing vitamin A with adverse effects on bone health and decreased bone density, thus increasing the risk of fracture.
Side effects have also been found with mineral supplements, omega 3/fish oil, soy protein, soy protein, plant nutrients, antioxidants, anti-inflammatory, supplements for weight loss or bodybuilding, various botanical supplements (3). Multi-skeletal distortion, fatigue, pain and gastrointestinal symptoms and hepatic adverse events have been reported with the nutraceutical ingredient RYR (red yeast rice) at the doses recommended by EFSA (European Food Safety Authority) (4).
With the exception of "classic" foods (hazelnuts, nuts, eggs, etc.) known to cause certain side effects such as allergies, the development of the food industry has led to the emergence of foods eaten especially by teenagers, such as energy drinks. Frequent consumption of this type of drink (>7 times a week) was significantly associated with asthma, allergic rhinitis and atopic dermatitis (3), high stress, lack of sleep, poor school performance and suicide attempts in Korean adolescents (5).
This present research is aimed at displaying the algorithms that can be applied to determine adverse reactions caused by the consumption of food supplements and foods in Romania, the need to initiate a legislative project and its implementation regarding the reporting of these adverse reactions and implementation of information/education programs on the population when consuming these products. The implementation of the nutrition surveillance system may be one of the methods of re-evaluation of food additives approved by EFSA and European Commission (EC).
The purpose of this paper was to implement nu-trivigilence in Romania.
MATERIAL AND METHODS
The PubMed, ResearchGate and EUR-Lex databases (online portal offering access to EU legislation) were analyzed during 2015-2021, starting from the search criteria like: side effects, new food ingredients, supplements food, algorithms. Herbal resources that may influence the clearance of dermatological drugs metablized by cy-tochrome P-450 have been identified (enzymes CYP2C9, and CYP3A4).
RESULTS
Of the total of 5696 European Union Regulations and/or Decisions published during this period, 39 refer to the authorization of novel food ingredients in the European Union, which are presented in Tables 1, 2 and 3.
Table 1. Adverse reactions caused by new food ingredients authorized by EFSAinthe European Union, in the period 2015-2017.
Ingredient/substance approved as a novel food ingredient in the EU EU Decision/ Regulation Category of products for which it has been authorized or action - Maximum dose/day (mg or g/day), according to EU Decision/ Regulation Adverse reactions/Warnings Consumption mode (e.g. mono-ingredient)
(6S) -5-methyltetrahydrofolic acid, the glucosamine salt, as a source of folate (6) Reg. [EU)* no. 414/2015 (6) FS (6) SE* reported for patients taking 15 mg folic acid for 1 month: - gastrointestinal: nausea, abdominal distension and flatulence; - nervous system: bitter taste, sleep changes, difficulty concentrating, hyperactivity, impaired thinking; - metabolic: anorexia; - other: decrease in serum diphenyl-hydantoin in patients taking 5 or 15 mg of folic acid daily (7). Multi-ingredient (7)
Oil extracted from mi-croalgae Schizochytri-um sp. (ATCC PTA-9695) (8) EU Decision no. 545/2015 (8) FS: • 250 nig DHA* per day, as recommended by the manufacturer for the normal population; • 450 mg DHA per day, as recommended by the manufacturer for pregnant and lactating women. Foods intended for use in low-calorie diets for weight loss within the meaning of Directive 96/8/EC: • 250 mg per meal replacement. Other foodstuffs for particular nutritional uses as defined in Directive 2009/39/EC, with the exception of infant formulas and follow-on formulas: • 200 mg /100 g. Dietary foods for special medical purposes: • according to the specific nutritional needs of the persons for whom the products are intended (8). Possible side effects: - buckling, slight increase in cholesterol; - pregnant women: dose > 3g/day slowing blood clotting and increasing the chances of bleeding; - respiratory sensitivity, in the case of people sensitive to aspirin; - diabetes: Increased blood sugar before meals in people with type 2 diabetes; - tension: decreased blood pressure (9); - respiratory infection and gastroesophageal reflux (10). Mono-ingredient (9)
Oil rich in DHA and EPA, extracted from microalgae Schizo-chytrium sp. (11) EU Decision no. 546/2015 (11) FS: •3000 mg as recommended by the manufacturer, for the adult population, except for pregnant and lactating women (11). Possible SE: - belching, slight increase in cholesterol (9); - pregnant women: dose> 3g/day slowing blood clotting and increasing the chances of bleeding (9); - respiratory sensitivity, in the case of people sensitive to aspirin (9); - diabetes: Increased blood sugar before meals in people with type 2 diabetes (9); - blood pressure: decreased blood pressure (9); - respiratory infection and gastroesophageal reflux (10). Mono-ingredient (9)
Flavonoids from Glycyr-rhiza glabra L. (12) EU decision no.1213/2015 (12) Foods intended for use in low-calorie diets for weight loss (only for products presented as a substitute for the whole daily diet): • daily consumption of 120 mg. Dietary foods for special medical purposes: • daily intake of 120 mg (12). - dose-dependent increase in plasma renin, Na, concomitant decrease in plasma Cortisol, ACTH *, aldosterone and K (13); - hipertensiune, hipokalimie, edem (13); - contraindicated with co-administration with laxatives or diuretics (13). Mono-ingredient (13)
Refined Buglossoides arvensis seed oil (14) EU Decision no. 1290/2015 (14) FS as defined in Directive 2002/46/EC, with the exception of food supplements for infants and young children: • a daily dose of 500 mg, as recommended by the manufacturer. Foods intended for special medical purposes as defined in Directive 1999/21 /EC, with the exception of dietary foods for infants and young children: • in accordance with the specific nutritional needs of the persons for whom the products are intended. Foods intended for use in low-calorie diets for weight loss within the meaning of Directive 96/8/EC: • 250 mg/food substitute (14). No side effects have been reported (15). Mono-ingredient (15)
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Lacto-N-neotetraosis (16) EU Decision no. 375/2016 (16) Dietary foods intended for special medical purposes as defined in Directive 1999/21/EC: • in accordance with the specific nutritional needs of the persons for whom the products are intended. FS, as defined in Directive 2002/46/EC, with the exception of infant food supplements: • 1.5 g/day for the general population 0.6 g/day for young children, etc. (16). No adverse reactions have been reported (17,18). Mono-ingredient (17,18)
2 '-O-fuc osyl-lactose (19) EU decision no. 376/2016 (19) Dietary foods intended for special medical purposes, as defined in Directive 1999/21/EC: • in accordance with the specific nutritional needs of the persons for whom the products are intended. Foods used in low-calorie diets for weight loss as defined in Directive 96/8/EC (only for products presented as a substitute for the whole daily diet): • 4.8 g/1 in beverages and 40 g/kg in bars. FS, as defined in Directive 2002/46/EC, with the exception of infant food supplements: • 3.0 g/day for the general population and 1.2 g/day for young children, etc. (19). Mild side effects: • flatulence; • stomach ache; • diarrhea Severe side effects not reported (20). Mono-ingredient (20).
Traiis-resveratrol (21) EU Decision no. 1190/2016 (21) FS in the form oftablets or capsules intended adults, in maximum dose: • 150 mg per day (21). No side effects have been reported (22). Mono-ingredient (22).
Enzymatic preparation ofprolyl-3-oligopeptidase produced with a genetically modified strain of Aspergillus nifjer (23) EU decision no. 1387/2017 (23) FS as defined in Directive 2002/46/EC: • 120 PPU*/day (2.7 g of enzyme preparation/day); • (2x106 PPI*/day) for the general adult population (23). No side effects have been reported (24). Multi-ingredient (7)
Beta glucans in yeast * (25) EU Decision no. 2078/2017, for the extension of FS, as defined in Directive 2002/46/EC, with the exception of food supplements for infants and young children: Possible side effects: • dermal hypersensitivity (26) Multi-ingredient (26)
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the field of use according to Decision no. Commission Regulation (EC), no. 762/2011 (25) • 1,275 g/day for children older than 12 years and the adult population in general; • 0.675 g/day for children under 12 years of age; Substitutes for a total diet for weight control as defined in Regulation (EU), No 182/2011. 609/2013: • 1,275 g/day; Foods intended for special medical purposes, as defined in Regulation (EU), No 182/2011. 609/2013, except for foods intended for special medical purposes for infants and young children: • 1,275 g/day (25).
Taxifolin Rich Extract * (27, 28) EU Decision no. 2079/2017 (27, 28) FS, as defined in Directive 2002/46/EC, with the exception of food supplements for infants and young children, children and adolescents under 14 years of age: • 100 mg/day (27, 28). No adverse reactions have been reported (29). Multi-ingredient (29)
2'-fticosyl-lactose * (30) EU Decision no. 2201/2017 (30) Starting formulas and follow-on formulas: • 1,2 grams of 2'-fucosyl-lactose per liter of final product, ready to use, marketed as such or reconstituted according to the manufacturer's instructions (30). Not mentioned Not mentioned
Calanus finmarchicus oil * (31) EU Decision no. 2353/2017 (31) FS as defined in Directive 2002/46/EC: . 2.3 g/day (31) Mild side effects: - increased incidence of eczema (32). Possible side effects: - gastrointestinal disorders, in case of an amount greater than 2.3 g/day; - intolerance (33). Mono-ingredient (32)
Cilia seeds (Salvia hispánico) (34) EU Decision no. 2354/2017 (34) Yogurt: • 1.3 g of whole chia seeds per 100 g yogurt; • 4.3 g of whole chia seeds per 330 g of yogurt (portion). Bakery: • 5 g of whole seeds per 100 grams of bak- No side effects have been reported. Mono/multi-ingredient (34)
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ery products. Breakfast cereals; mixes of fruits, nuts and seeds, as well as prepacked cilia seeds as such: • 5 g of whole seeds per 100 grams of breakfast cereals (34).
Ultraviolet-treated mushrooms * (Agaricus bisporus) (35} EU Decision no. 2355/2017 (35) Marketed fresh (35) Not mentioned Not mentioned
*SE - Side effects; RYR - Red yeast rice fermented with Monascus purpureus; monocholine - monocholine ofK, Reg. (UE) - Regulation (EU); FS -Food supplements; DHA -docosahexaenoic acid; PPU - Prolyl peptidase units or proline protease units; PPI - Protease Picomole International; beta glucans in yeast - human studies are very limited (27); taxifolin-rich extract - obtained from Dahurian larch wood [Larix gmelinii (Rupr.) Rupr]; 2'-fucosyl-lactose - produced with Escherichia coli BL21 strain (31); Calanus finmarchicus oil - oil obtained from the shellfish (marine zooplankton) Calanus finmarchicus harvested in the Norwegian Economic Zone, and in the Jan Mayen area (32).
Tab e 2. Adverse reactions caused by new food ingredients authorized by EFSA in the European Union during 2018.
Ingredient/substance approved as a novel food ingredient in EU EU Decision/ Regulation Category of products for which it has been authorized or action - Maximum dose/day (mg or g/day), according to EU Decision/Regulation Adverse reactions/ Warnings Consumption mode (eg: mono-ingredient)
RYR * - monocholine K * (36) EFSA Journal 2018; 16 (8): 5368 (36) Maintaining the normal concentration of LDL-cholesterol in the blood: • 10 mg monocholine K from RYR/day (36). - multicellular-skeletal distortion; - fatigue; - pain and gastrointestinal symptoms; - hepatic side effects (37). Mono and multi-ingredients (37)
Florotanins from Ecklonia cava* (38) EU Regulation no. 460/2018 (38) Food supplements, as defined in Directive 2002/46/EQ intended for the general population, except for children under 12 years of age: • 163 mg/day for adolescents between 12 and 14 years old; • 230 mg/day for adolescents over 14 years of age; • 263 mg/day for adults (38). EFSA Warning *: the intake of iodine from food supplements containing fluorotanins from Ecklonia cava may be of concern to people at risk of thyroid disease and for those who are not at risk for thyroid disease but consuming food supplements containing fluorotanins from Ecklonia cava in addition to other dietary supplements containing iodine, since their total iodine intake may exceed the upper limit established for iodine (38). Mono and multi-ingredients (38)
L-ergotionein (39) Reg. (EU) no. 462/2018 (39) Food supplements, as defined in Directive 2002/46/EC: • 30 mg/day for the general population (except pregnant and lactating women); • 20 nig / day for children older than 3 years (39). No possible side effects have been reported (39). Mono and muhi-ingredients (39)
Extract from the roots of three plants (Cynanchum wilfordii Hemsley, Phlomis umbrosa Turcz. and Angelica gigas Nakai) (40) Reg. (EU) no. 469/2018 (40) Food supplements, as defined in Directive 2002/46/EQ intended for the adult population: • 175 mg/day (40) Possible allergic side effects (40). Mono and multi-ingredients (39)
Yeast for ultraviolet-treated bakery (Saccha-romyces cerevisiae) (41) Reg. (EU) no. 1018/2018 (41) Food supplements, as defined in Directive 2002/46/EC: • CN (41). No possible side effects have been reported (41). Multi-ingredients (41)
Quinoa pyrroloquinoline disodium salt * (42) Reg. (EU) no. 1122/2018 (42) Food supplements, as defined in Directive 2002/46/EQ intended for the adult population, with the exception of pregnant women and lactating women: • 20 mg/day (42). - no side effects have been reported (42); - no comprehensive assessment of renal function has been performed (43); - pro-oxidant activity (43); - no information on allergenicity has been provided (43). Multi-ingredients (43)
Dry aerial parts of Hoodia parviflora (43) Reg. (EU) no. 1113/2018 (43) Food supplements, as defined in Directive 2002/46/EQ intended for the adult population: • 9.4 mg/day (43). Insufficient characterization of novel food, limited allergenicity assessment, insufficient data to exclude risk to children over 12 years of age, insufficient information on specifications, stability, consumption assessment and toxicological data (43). Multi-ingredients (43)
Cranberry extract in powder form (44) Reg. (EU) no. 1631/2018 (44) Food supplements, as defined in Directive 2002/46/EQ intended for the adult population: • 350 mg/day (44). Possible nutritional risks associated with excessive consumption of polyphenols in children aged one to three years, resulting from the intake of polyphenols in novel foods and other sources of polyphenols in children's diets (44). Insufficient data to exclude the risk for young children aged one to three Mono-/multin gredient (44)
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years, the incomplete nature of the novel food specification and the lack of information on the protein content needed to exclude the risk of allergy (44). Possible side effects: Gastroesophageal reflux, nausea, digestive disorders (45).
Whey Protein Isolate from Cow's Milk (46) Reg. (EU) no. 1632/2018 (46) Starting formulas, as defined in Regulation (EU) No. 609/2013: • 30 mg/100 g (powder); • 3.9 nig/100 ml (reconstituted). Follow-up formulas as defined in Regulation (EU) no. 609/2013: • 30 mg/100 g (powder); • 4.2 mg/100 ml (reconstituted). Substitutes for a total diet for weight control as defined in Regulation (EU) no 182/2011. 609/2013: • 300 mg/day. Foods intended for special medical purposes, as defined in Regulation (EU) no 182/2011. 609/2013: • 58 mg/day for young children; • 380 mg/day for children and adolescents aged 3 to 18 years; • 610 nig/day for adults (46). Clinical studies with basic whey protein isolate from bovine milk have not been provided. The most clinical studies were related to the main components of the whey protein basic protein isolate: bLF * and bLP * (47). Allergies (47). Mono-ingredient (47)
Refined shrimp peptide concentrate* (48) Reg. (EU) no. 1633/2018 (48) Food supplements, as defined in Directive 2002/46/EC, for the adult population: • 1,200 mg/day (48). No possible RAs have been reported regarding the blood pressure and interaction of the concentrate with the drugs used in treatment of blood pressure disorders (48, 49). Allergen (49). Mono-ingredient (48, 49)
Egg Membrane Hydro ly-zate (50) Reg. (EU) no. 1647/2018 (50) Food supplements, as defined in Directive 2002/46/EQ for the general adult population: • 450 mg/day (50). Adverse reactions reported in subjects included in the clinical trial: - hypertension; - allergies (51). Mono-ingredient (51)
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Xylo-oligosaccharide Reg. (EU) Breakfast cereals: Reported side effects: Mono-/Multi-ingredient
(52) no. 1648/2018 • 14g/kg. - transient gastrointestinal disorders: diarrhea (53). (53)
(52) Chocolate confectionery: • 30 g/kg (52). RA possible: - allergy (low probability) (53).
Ultraviolet-treated mushrooms (Agaricus bisporus) - with high levels of vitamin D2 (35); Ecklortia cava - edible seaweed (38); EFSA - Authority European Food Safety Authority; quinine pyrroloquinoline disodium salt - produced from the bacterium Hyphomicrobium denitrificans; bLF - bovine lactoferrin; bLP - lactoperoxidase, the refined peptic concentrate of shrimp - by enzymatic hydrolysis of the shells and heads of northern shrimp (Pandalus borealis).
Table 3. Adverse reactions caused by new food ingredients authorized by EFSA in the European Union, in the period 2019-2021.
Ingredient/ substance approved as a novel food ingredient in EU EU Decision/ Regulation Category of products for which it has been authorized or action - Maximum dose/day (mg or g/day), according to EU Decision/Regulation Adverse reactions/ Warnings Consumption mode (eg mono-ingredient)
Schizochytrium sp. Oil (54) Reg. (EU) no. 109/2019 (54) Food supplements, as defined in Directive 2002/46/EC: • 250 mgDHA/day for the general population; • 450 nig DHA/day for pregnant and lactating women. Replacements of a total diet for weight control, as defined in Regulation (EU) no. 609/2013 and substitute s for a weight c ontrol table: • 250 mg/portion. Milk-based beverages and similar products for young children: • 200 mg/100 g (54). No side effects/possible side effects reported (55). Mono-ingredient (55)
Allanblackia seed oil (56) Reg. (EU) no. 110/2019 (56) Yellow spreadable fats and cream products: • 30 g/100 g. Mixtures of vegetable oils (*) and milk (falling into the food category: Dairy products, including beverage bleaching preparations): . 30 g/100 g (56). No side effects/possible side effects reported (57). Mono-ingredient (57)
Yarrowia lipolytica yeast biomass (58) Reg. (EU) no. 760/2019 Food supplements, as defined in Directive 2002/46/EC, with the exception of food supple- No clinical studies have been presented on the safety of Yarrowia lipolytica Multi-ingredient (58, 59)
(58) ments for infants and young children: • 6 g/day for children over 10 years of age, adolescents and the general adult population; • 3 g/day for children aged 3 to 9 years (58). yeast biomass in humans. Possible side effects: - allergies (59).
Tlie mixture of 2'-fucosyl-lactose/ difucosyl-lactose * (60) Reg. (EU) no. 1979/2019 (60) Replacements of a total diet for weight control, as defined in Regulation (EU) no. 609/2013: • 4.0 g/1 (drinks); • 40 g/kg (products other than beverages). Foods intended for special medical purposes, as defined in Regulation (EU) No 182/2011. 609/2013: • in accordance with the specific nutritional needs of the persons for whom the products are intended. Food supplements, as defined in Directive 2002/46/EQ intended for the general population, except infants: • 4.0 g/day (60). No clinical trials have been reported to verify the safety of the mixture 2'-fuc osyl-lac tose/difuc osyl-lactose. Studies performed with 2'-fucosyl-lactose alone, in amount of 20 g/day, over 2 weeks were provided. Gastrointestinal RAs have been reported: - nausea; - ballooning; - diarrhea (61). Mono-ingredient (61)
Partially defatted cilia seed powder (Salvia hispanica) (62) Reg. (EU) no. 500/2020 (62) Food supplements within the meaning of Directive 2002/46/EQ with the exception of food supplements for infants and young children: • 7.5 g/day (62). There are no clinical studies to verify the safety of Chia seeds in humans. The studies followed the benefits and few parameters for safety (eg blood pressure, histological parameters). Allergies may occur. No side effects have been reported (63). Mono-ingredient (63)
Mushroom powder with vitamin D2 (64) Reg. (EU) no. 1163/2020 (64) Maximum vitamin D2 levels. Meal substitutes in the form of bars and drinks: • 2.25 jig of vitamin D2/100 g/1; • 125 (ig of vitamin D2/100 ml (drinks). Foods intended for special medical purposes, as defined in Regulation (EU) no. 609/2013, except for those for infants: • 15 ug/day. No specific studies have been provided on the safety of vitamin D2 fungus in humans. The studies made available to the Authority * by the applicant were performed with similar products. These studies show a little evidence in assessing the potential health effects of vitamin D2 mushroom powder. Regarding allergenicity, the applicant
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Food supplements, as defined in Directive 2002/46/EQ intended for the general population, except infants: • 15 ng/day (64). referred to EFSA's conclusion on ultraviolet-treated mushrooms* (Agari-cusbisporus (35)) (65).
Sugars derived from cocoa pulp (Theobroma cacao L.) (66) Reg. (EU) no. 1634/2020 (66) Used as an ingredient for the population as a whole (66). The Commission considers that, in the case of the current application, it is not necessary for EFSA to do so (66).
Alga Euglena gracilis * (67) Reg. (EU) no. 1820/2020 (67) Food supplements, as defined in Directive 2002/46/EQ with the exception of infant food supplements: • 100 mg/day for young children; • 150 mg/day for children aged 3 to 9 years; • 225 mg/day for children aged 10 years and adolescents (up to 17 years); • 375 mg/day for adults (67). Based on the results, EFSA considers that the highest dose that has been tested and at which an adverse effect may occur is 3300 mg of seaweed Euglena gracilis desicatga/kg body weight/day (68).
Extract of Panax noto-ginseng and Astragalus membranaceus (AstraGin™) [69) Reg. (EU) no. 1821/2020 (69) Food supplements, as defined in Directive 2002/46/EQ for the general adult population, excluding food supplements for pregnant women: • 35 mg/day (69). The applicant did not provide clinical trials and there were no extensive human studies published in the literature on the safety of Panax noto-ginseng and Astragalus membranaceus in humans. Possible side effects: allergies (70).
Yeast Biomass (Yarrowia lipolytica) with chromium content (71) Reg- (EU) no. 1822/2020 (71) Food supplements as defined in Directive 2002/46/EQ with the exception of food supplements for infants and young children: • 2 g/day for children aged 3 to 9 years, which means 46 |ig of chromium per day; • 4 g/day for children over 10 years of age, adolescents and adults, which means 92 |.ig of chromium per day (71). Possible side effects: - allergies (low risk) (72). Mono-ingredient (72)
Selenium-containing yeast biomass (Yarrowia lipolytica) (73) Reg. (EU) no. 1993/2020 (73) Food supplements, as defined in Directive 2002/46/EQ with the exception of food supplements for infants and children under 4years of age: • 50 mg/day for children aged 4 to 6 years, which means 10 pg of selenium per day; • 100 mg/day for children aged 7 to 10 years, which means 20 |ig of selenium per day; • 500 mg/day for adolescents aged 11 to 17 years, which means 100 tig of selenium per day; Possible side effects: - Allergies (low risk) (72,74). Mono-ingredient (72, 74)
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• 800 nig/day for adults, which means 160 fig of selenium per day (73").
Partially defatted rape-seed powder of Brassica rapa L. and Brassica napusL. * (75) Reg. (EU) no. 120/2021 (75) Grain mix sticks: • 20 g/100 g. Bread and buns with special ingredients added (such as seeds, raisins, herbs): • 7 g/100 g (75). Possible side effects: - Allergies, in the case of people allergic to mustard (76).
Schizochytrium sp oil - oil extracted from Schizochytrium sp microalgae; 2'-fucosyl-lactose/difucosyl-lactose mixture - obtained by fermentation microbial with a genetically modified strain of Escherichia coli Kl2 DH1; Authority - EFSA, Commission - European Commission, alga Euglena gracilis - whole cells dried by Euglena gracili
ORRM
In addition to the product categories mentioned in Table 1, the oil extracted from the microalga Schizochytrium sp. (ATCC PTA-9695) may be added to dairy products, other than milk-based beverages, for cheeses, dairy products, excluding beverages or, for cheese-like products, spreada-ble fat and salad dressings, bakery products (bread and buns), sweet biscuits, cereal bars, cooking fats, non-alcoholic beverages (including similar dairy products and milk-based drinks), preparations for infants and preparations for young children - used in accordance with Directive 2006/141/EC, cereal-based preparations and baby foods for infants and young children, including those used in accordance with Directive 2006/125 (8).
Regarding food supplements, special medical foods and foods for use in low-calorie diets listed in Table 1, refined Buglossoides arvensis seed oil is approved as a novel food ingredient in dairy products and the like, beverages, cheese and cheeses, butter and other fat and oil emulsions, including spreads (not for cooking or frying), breakfast cereals (14).
The European Commission has approved lacto-N-neotetraose (tab. 1) (16) as a novel food ingredient in pasteurized and sterilized milk products (including UHT), non-flavored, non-flavored fermented milk products, beverages and other products than beverages, flavored fermented milk products, including heat-treated products in beverages and non-beverages, cereal bars, table-top sweeteners, infant formulas, as defined in Directive 2006/141/EC.
In vitro and in vivo studies suggest that trans-resveratrol sulphate may inhibit CYP enzymes in humans and may interact with drugs that are primarily metabolised by CYP2C9 (22).
Other authorized uses for yeast beta glycans (Saccaromyces cerevisiae) are the following: beverages based on fruit juice and/or vegetable juice including concentrated and dehydrated juice, fruit flavored beverages, powdered form for cocoa-based beverages, breakfast cereals, breakfast cereals, whole grain breakfast cereals (instant hot cooking), cookies, crackers, milk drinks, dairy products fermented milk, similar dairy products, dehydrated milk/milk powder, soups and mixes for soups, chocolate and sweets, protein bars and protein powder, jam, marmalade and other fruit spreads (25).
The extended conditions under which taxifolin-rich extract may be used are the plain yogurt/fruit yoghurt (when used in dairy products, taxifolin-rich extract may not replace, in whole or in part, any constituent of milk), kefir, sour milk, powdered milk, cream, fermented cream, cheese, butter, chocolate confectionery, soft drinks (28).
Commercially grown Agaricus bisporus mushrooms are subjected to ultraviolet treatment after harvest, which results in a vitamin D2 content of < 10 |ig/100 g fresh weight. UVB radiation: a process of radiation in ultraviolet light with a wavelength in the range 290-320 nm. Vitamin D2 in the finished product: 5-10 [j.g/100 g fresh weight at the end of the shelf life (35).
The Scientific Opinion issued by EFSA on monacolin K in RYR (3 6), it has the same structure as lovastatin, the active ingredient in several medicines authorized to treat hypercholesterolemia in the EU. With the help of the Mintel Global New Products (MintelGNPD) database, which lists the contents of all product labels containing monacolin K from RYR, 40 products containing monacolin K from RYR were identified and included in the category "Vitamins and dietary supplements". Approximately 25% of the total products identified provided the daily intake of 10 mg monacolin K recommended by EFSA, and only 8 products were identified as mono-ingredients, containing only RYR preparation (36). Although studies underlying this scientific opinion have shown that monacolin K and lovastatin rapidly convert from the lactone form to an identical form of hydroxy acid (HA), the latter being responsible for the inhibition of 3-hydroxy-3. Methylglutaryl-coenzyme A (HMG-CoA) enzyme reductase involved in cholesterol biosynthesis, and the acid form occurs naturally in RYR. The bioavailability of lovastatin increases by 30-50% when taken as a standard dose. Due to the involvement of the CYP3A4 isoform in its metabolism, there have been found interactions with drugs or food ingredients with inhibitors of this enzyme, leading to increased plasma statin levels and a possible increased risk of toxic effects (36).
The WHO, FDA, EMA, and ANSES have published common side effects for RYR and lovastatin: damage to musculoskeletal and connective tissue, liver, nervous system, gastrointestinal tract, skin, and subcutaneous tissue (4, 36).
ORRM
The case reports used to carry out the aforementioned scientific opinion, specified the daily intake of monacolin K in which SE (rhab-domyolysis, hepatitis and skin disorders) occurred was 3 mg/day for a period between 2 weeks and 1 year (36).
L-ergothioneine is also accepted as a novel food ingredient in the following food categories: nonalcoholic beverages, milk-based beverages, fresh dairy products - maximum 0.040 g/kg (when used in dairy products, L-ergothioneine cannot replace, in whole or in part, any milk constituent), cereal bars. The name of the novel food mentioned on the label of foods containing it is "L-ergothioneine" (39).
In addition to food supplements, the European Commission and EFSA have approved yeast for ultraviolet-baked bread (Saccharomyces cere-visiae) and for the addition of yeast-leavened bread and buns, yeast-leavened bakery products, fresh or dried pre-packaged yeast for home baking (41).
In accordance with Article (5) of Regulation (EU) no. 1133/2018 (43), in its opinion, the Authority did not confirm the safety of dry aerial parts of Hoodia parviflora in food for the uses and use levels proposed by the applicant, as consumption would exceed the level considered safe (0.134 mg/kg body weight). However, the Authority concluded that the dry aerial parts of Hoodia parviflora are safe for adults when added to food supplements in a maximum daily dose of 9.4 mg, which corresponds to the safe level of consumption of an adult with a body weight of 70 kg.
In the case of refined shrimp peptic concentrate -by enzymatic hydrolysis of shells and heads of northern shrimp (Pandalus borealis) (48), according to point (13) of Regulation (EU) no. 1633 of 2018, data from the 90-days oral toxicity study served as a basis for assessing the toxicity profile of refined shrimp peptide concentrate and for establishing the level at which no adverse effects are observed. Data from the study evaluating the antihypertensive effects and safety of the refined peptide concentrate in shrimp in healthy subjects with mild to moderate hypertension, as well as data from the parallel doubleblind, placebo-controlled study on the evaluation of the antihypertensive effect and safety dietary supplement with refined shrimp peptide concentrate in the case of healthy individuals with mild
or moderate hypertension, served as a basis for establishing the safety of the novel food for this category of consumers.
Therefore, it is considered that, in the absence of data from the unpublished reports of those studies, it would not have been possible to reach these conclusions on the safety of the refined shrimp peptide concentrate. In carrying out this study, the applicant replied that some Member States had objected to the safety of refined shrimp peptide concentrate in the case of hypo-, normo- and hypertensive consumers given its alleged antihypertensive effects, its potential side effects related to its presumed ability to inhibition of angiotensin converting enzyme (ACE) and its potential cardiac effects, and on potential drug interactions used in the treatment of blood pressure disorders (48).
Powder with a high content of partially defatted chia seed protein (Salvia hispanica) (62), in addition to food supplements (tab. 1) may also be added in unflavored fermented dairy products, including unflavored natural sour milk (excluding sterilized sour milk), untreated after fermentation, non-flavored fermented milk products, heat-treated after fermentation, flavored fermented milk products, including heat-treated products, confectionery, fruit juices within the meaning of Directive 2001/112/EC and vegetable juices, fruit nectars within the meaning of Directive 2001/112/EC and vegetable nectars and similar products, flavored beverages. Powder with a high content of partially defatted chia seed fibers (Salvia hispanica) is accepted by EF-SA for addition to confectionery, fruit juices within the meaning of Directive 2001/112/EC and vegetable juices, fruit nectars within the meaning of Directive 2001/112/EC and vegetable nectars and similar products, flavored beverages (62).
Given the clinical trials conducted by various teams of specialists, EFSA considers that in the case of yeast biomass (Yarrowia lipolytica) (72) containing selenium, it should be re-evaluated (74).
Probiotics that can cause human sepsis, generally in elderly patients and those suffering from chronic diseases, are Lactobacilli (strains of L. rhamnosis, due to its high translocation potential) (77), Lactobacillus sp. bacteremia which is sometimes fatal (77), infectious endocarditis
ORRM
(77) caused by L. rhamnosus, L. casei, L. acidophilus, L. jensenii, L. plantarum and L. paracasei (77). They can cause anaphylactic response in patients who have undergone cardiovascular surgery (77) or localized infection in diabetes associated with old age and liver transplantation (77).
Thus, for terbinafine (78) which is metabolised by the enzyme CYP3A4 and the clearance (or intracellular concentration) of this drug may be influenced by dietary supplements/other products containing Agaricus blazei Murrill, Aloe vera, Artemisia annua, Andrographis paniculata, Matricaria recutita, Chrysanthemum morifolium, Vitex agnus castus, Taraxacum officinale, Echinacea purpurea, Tanacetum parthenium, Zingiber officinale, Allium sativum, Hydrastis Canadensis, Centella asiatica, Commiphora mukul, Crataegus mo-nogyna, Cymbopogon citratus , Artemisia annua, Urtica dioica, Mentha piperita L, 3,3', 4', 5,7-pentapentahydroxyflavone (quercetin), Monas-cus purpureus (Red Yeast Rice), Trifolium pratense, 3,5, 4'-trihydroxystilbene (resveratrol), Rhodiola rosea, Serenoa repens, Glycine max (Soy), Turmeric longa (79).
The CYP2C9 enzyme metabolizes dermatological drugs such as voriconazole (80) and can be inhibited by dietary supplements/other products containing Andrographis paniculata, Sulphydryl
proteolytic enzyme, cysteine proteinase, Matricaria recutita, Harpagophytum procumbens, Tanacetum parthenium, Allium sativum, Centella asiatica, Cymbopogon citratus (Lemongrass), Magnolia officinalis, Urtica dioica, Mentha piperita L. (Peppermint), Trifolium pratense, 3,5,4'-trihydroxystilbene (resveratrol), Serenoa repens, Eleutherococcus senticosus (79).
As regarding "Nutrivigilance that is a new activity referring to dietary supplements" (2), the authors Morgan C, Ghibu S, Juncan AN et al presented the current use of SE and the interaction with drugs of certain substances or herbs, such as Aloe Vera, Aristolochic acids/Aristolochia sp, Chelidonium majus, Citrus sp, Cytisus sp, Echinacea purpurea, Ginkgo biloba, Green tea extract, Camellia sinensis, Hypericin St. John's wort/Hy-pericum perforatum, Lamiaceae sp. With high contents in Rosmarinic acid, Valeriana officinalis, etc.
To establish the severity-causality relationship in the case of SA, authors such as Kazuki I, Hiro-shi Y, Mamoru K et al. (79) propose the use of algorithms used in pharmacovigilance, for drug-induced RA: Naranjo scale, FDA, Kramer scale, Liverpol scale, WHO scale.
Table 4 and Figure 1 show the Naranjo and FDA algorithms.
Table 4. Naranjo algorithm (81).
Nr. No The question Yes* Not* I do not know *
1 Is there a notification about the reaction, on the label or in the package leaflet food supplement?
2 Did the side effect occur after taking the food supplement?
3 Did the adverse reaction improve when the suspected food supplement was discontinued?
4 Did the adverse event recur when the food supplement was given?
5 Are there any causes other than the dietary supplement that could have caused side effects?
6 Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
7 Did the consumer have a similar adverse reaction to the similar food supplement in the previous exposure?
8 Has the adverse event been confirmed by any objective evidence?
* Scores applied: > 9 most likely, 5 - 8 likely, 3 - 4 very likely, 1 - 2 possible, < 0 unlikely.
ORRM
I don't know
DISCUSSIONS
Given that new food ingredients can be added to food supplements and a wide range of foods, in which new food ingredients, the lifestyle of many people can be added, there is a risk of reaching and/or exceeding the maximum allowable dose and challenging AR identified or unidentified up to date. A major risk is the large amount of commercial information on the benefits of various plant resources, without a possible and scientifically proven/clinically proven AR and their interaction with food or medicine.
Nutrivigilence is also important from the perspective of CYP's transformation of certain plant components into toxic or mutagenic
substances and reactive, carcinogenic metabolites by 1'-hydroxylation to allylic side chains and the bioactivation of alkylbenzenes, such as
CYP1A1, CYP1A2, and CYP1A2, and by their high catalytic capacity they contributed to the metabolic activation of elemicin, by the formation of 1'-hydroxyelemicine (82). Thus, excessive intake of foods and spices containing elemicin can lead to cellular toxicity. This is an argument why nu-trivigilence is important in both the food and food supplements, dietetics and nutrition and pharmaceutical industries.
We propose the application of the algorithm model for drug-induced RA to food supplements. One method of collecting information on possible ARs caused by FS is by telephone survey, including the following criteria: the substance involved, the age of the patient (adult/paediatric), the type of ingestion (accidental or intentional), the food consumed and their approximate amount, where he bought FS (hypermarket, health food store, community pharmacy, online pharmacy or vari-
ORRM
ous websites), the symptoms recorded, evaluated according to severity and causality.
Another method of collecting information about AR caused by FS are online questionnaires distributed through social networks, or through companies organizing medical events or otherwise.
We joined the signal sent by colleagues Morgan C, Ghibu S, Juncan AN et al (2) and supported the urgent need to legislate the reporting of adverse reactions caused by dietary supplements, including their interaction with food or medicine. The veracity of the practical applicability of the legislation and the existence of an educational program of the population, proved that this intervention is not to be null and void.
We consider that the formation of multidiscipli-nary teams of regional specialists, as well as
CONCLUSIONS
their cooperation on a regular basis, might have a constructive brainstorming for data collection (adverse reactions, age, etc.), the database formation and the identification of severity-causality, which could be a good start for implementing nutrivigilance in Romania.
Given the mandatory pharmacovigilance process in pharmaceutical companies, a similar system of nutrivigilance is needed in food and food supplement factories in Romania. The implementation of the nutrition surveillance system may be one of the methods of re-evaluation of food additives and ingredients approved by the European Food Safety Authority (EFSA) and European Commission.
Due to the complexity of nutrivigilence, this article has the following weaknesses: the methodology of approaching the problem and the existing scientific basis.
1. The formation of territorial teams of specialists and their involvement in risk assessment, monitoring and management of unauthorized exposure to food supplements, especially among vulnerable population groups, can have a constructive impact on the collection of medical and pharmaceutical data (adverse reactions, age, etc.).
2. The formation of a pharmacovigilence database and the identification of the causality of the reported side effects could be a good start in implementing nutrivigilence in Romania.
3. We recommend conducting a pilot study in Romania and possibly in collaboration with colleagues from the Republic of Moldova, to test the two algorithms and adapt to the conditions in this area.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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ORRM
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25. European Commission. Commission Implementing Decision (EU) No 2078/2017 of 10 November 2017 authorizing the extension of the scope of use of beta glucans in yeast as a novel food ingredient in accordance with Regulation (EC) No 1234/2007 Regulation (EC) No 258/97 of the European Parliament and of the Council. Official Journal of the European Union.2017: L295/77.
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38. European Commission. Commission Implementing Regulation (EU) 460/2018 of 20 March 2018 authorizing the placing on the market of eclonia cava florotanines as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2010/2470. Official Journal of the European Union. 2018: L78/2.
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44. European Commission. Commission Implementing Regulation (EU) 1631/2018 of 30 October 2018 authorizing the placing on the market of cranberry extract in powder form as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council, and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2018: L272/17.
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on the safety of cranberry extract powder as a novel food ingredient pursuant to Regulation (EC) No 258/97. EFSA Journal. 2017;15(5):4777, 17 pp. doi:10.2903/j.efsa.2017.4777
46. European Commission. Commission Implementing Regulation (EU) 1632/2018 of 30 October 2018 authorizing the placing on the market of whey protein basic protein isolate as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2018: L272/23.
47. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D, Bresson J-L, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M et al. 2018. Scientific Opinion on the safety of Whey basic protein isolates as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2018;16(7):5360, 18 pp. doi:10.2903/j.efsa.2018.5360
48. European Commission. Commission Implementing Regulation (EU) 1633/2018 of 30 October 2018 authorizing the placing on the market of refined shrimp peptide concentrate as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending of Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2018: L272/29.
49. Turck D, Bresson JL, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M et al., 2018. Scientific Opinion on the safety of shrimp peptide concentrate as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2018;16(5):5267, 17 pp. doi:10.2903/j.efsa.2018.5267
50. European Commission. Commission Implementing Regulation (EU) 1647/2018 of 30 October 2018 authorizing the placing on the market of egg membrane hydrolysate as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending of Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2018: L274/51.
51. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D, Bresson J-L, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M et al. 2018. Scientific opinion on the safety of egg membrane hydrolyzate as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2018;16(7):5363, 13 pp. doi:10.2903/j.efsa.2018.5363
52. European Commission. Commission Implementing Regulation (EU) 1648/2018 of 29
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53. Turck D, Bresson J-L, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M et al. - Scientific opinion on the safety of xylo-oligosaccharides (XOS) as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2018;16(7):5361. doi:10.2903/j.efsa.2018.5361
54. European Commission. Commission Implementing Regulation (EU) 109/2019 of 24 January 2019 authorizing an extension of the use of Schizochytrium sp. as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2019: L23/7.
55. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2014. Scientific Opinion on the extension of use for DHA and EPA-rich algal oil from Schizochytrium sp. as a Novel Food ingredient. EFSA Journal. 2014;12(10):3843, 17 pp. doi:10.2903/j.efsa.2014.3843
56. European Commission. Commission Implementing Regulation (EU) 110/2019 of 24 January 2019 authorizing the placing on the market of the use of Allanblackia seed oil as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amendment of Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2019: L23/11.
57. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), Turck D, Bresson J-L, Burlingame B, Dean T, Fairweather-Tait S, Heinonen M et al. 2018. Draft scientific opinion on the safety of Allanblackia seed oil for extended uses in vegetable oils and milk and in yellow fat and cream-based spreads up to 30% (w/w). EFSA Journal. 2018;16(8):5362, 11 pp. doi:10.2903/j.efsa.2018.5362
58. European Commission. Commission Implementing Regulation (EU) 760/2019 of 13 May 2019 authorizing the placing on the market of yeast biomass Yarrowia lipolytica as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending of Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2019: L125/13.
59. EFSA NDA Panel (EFSA Panel on Nutrition, Novel
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60. European Commission. Commission Implementing Regulation (EU) 1979/2019 of 26 November 2019 authorizing the placing on the market of the mixture 2'-fucosyl-lactose/difucosyl-lactose as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2019: L308/62.
61. EFSA NDA Panel (EFSA Panel on Nutrition, Novel Foods and Food Allergens), Turck D, Castenmiller J, De Henauw S, Hirsch-Ernst KI, Kearney J, Maciuk A et al. 2019. Scientific Opinion on the safety of 2'-fucosyllactose/difucosyllactose mixture as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2019;17(6):5717. doi:10.2903/j.efsa.2019.5717
62. European Commission. Commission Implementing Regulation (EU) 500/2020 of 6 April 2020 authorizing the placing on the market of chia seeds (Salvia hispanica) partially defatted as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2020: L109/2.
63. Turck D, Castenmiller J, de Henauw S, HirschErnst KI, Kearney J, Maciuk A et al. Scientific Opinion on the safety of chia seeds (Salvia hispanica L.) powders, as novel foods, pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2019;17(6):5716.
64. European Commission. Commission Implementing Regulation (EU) 1163/2020 of 6 August 2020 authorizing the placing on the market of vitamin D2 mushroom powder as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amendment of Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2020: L258/1.
65. Turck D, Castenmiller J, de Henauw S, HirschErnst K-I, Kearney J, Maciuk A et al. Scientific Opinion on the safety of vitamin D2mushroom powder as a novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal.
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66. European Commission. Commission Implementing Regulation (EU) 1634/2020 of 4 November 2020 authorizing the placing on the market of sugars obtained from cocoa pulp (Theobroma cacao L.) as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union.2020: L367/39.
67. European Commission. Commission Implementing Regulation (EU) 1820/2020 of 02 December 2020 authorizing the placing on the market of dried seaweed Euglena gracilis as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2020: L406/29.
68. Turck D, Castenmiller J, De Henauw S, HirschErnst KI, Kearney J, Maciuk A et al. Scientific Opinion on the safety of dried whole cell Euglena gracilis asa novel food pursuant to Regulation (EU) 2015/2283. EFSA Journal. 2020;18(5):6100. doi:10.2903/j.efsa.2020.6100
69. European Commission. Commission Implementing Regulation (EU) 1821/2020 of 02 December 2020 authorizing the placing on the market of an extract of Panax notoginseng and Astragalus membranaceus as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union.2020: L406/34.
70. Turck D, Castenmiller J, De Henauw S, HirschErnst KI, Kearney J, Maciuk A et al. Scientific Opinion on the safety of a botanical extract derived from Panax notoginseng and Astragalus membranaceus (AstraGinTM) as a novel food pursuant toRegulation (EU) 2015/2283. EFSA Journal. 2020;18(5):6099. doi:10.2903/j.efsa.2020.6099
71. European Commission. Commission Implementing Regulation (EU) 1822/2020 of 02 December 2020 authorizing the placing on the market of yeast biomass (Yarrowia lipolytica) containing chromium as a novel food pursuant to Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union.2020: L406/39.
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73. European Commission. Commission Implementing Regulation (EU) 1993/2020 of 4 December 2020 authorizing the placing on the market of selenium-containing yeast biomass (Yarrowia lipolytica) as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union.2020: L410/62.
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75. European Commission. Commission Implementing Regulation (EU) 1993/2020 of 4 December 2020 authorizing the placing on the market of powdered rapeseed from Brassica rapa L. and Brassica napus L. as a novel food under Regulation (EU) 2015/2283 of the European Parliament and of the Council and amending Commission Implementing Regulation (EU) 2017/2470. Official Journal of the European Union.2021: 37/11.
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Date of receipt of the manuscript: 31/05/2021 Date of acceptance for publication: 13/09/2021
Irina Mihaela MATRAN, ORCID ID: 0000-0001-5491-0796, Web of Science Researcher ID: 0-3431-2019, SCOPUS Author ID: 55941866400
Daniela Lucia MUNTEAN, ORCID ID: 0000-0002-6263-0708 Cristina NICULAS, ORCID ID: 0000-0003-2879-5813
Roxana Maria MARTIN-HADMAS, ORCID ID: 0000-0003-1499-5398, SCOPUS Author ID: 23670523500 Monica TARCEA, ORCID ID: 0000-0001-7299-118x, Web of Science Researcher ID: AAB-8622-2019, SCOPUS: Author ID 24401852300
