First report of the HoA working group

“Food Supplements”

© BVL, 6. June 2024

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© Heads of Food Safety Agencies [2024]

This report was elaborated under the Heads of European Food Safety Agencies (HoA) by a working group of
26 Members, chaired and coordinated by the Federal Office of Consumer Protection and Food Safety (BVL)
GERMANY and Netherlands Food and Consumer Product Safety Authority (NVWA) THE NETHERLANDS.
Responsibility for the information and views set out in this document lies entirely with the authors.
Reproduction is authorised provided the source is acknowledged.

Publisher:
Bundesamt für Verbraucherschutz und Lebensmittelsicherheit (BVL)
Bundesallee 51
38116 Braunschweig

Cover illustration: © AdobeStock/Botamochy

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First report of the HoA working group “Food Supplements”

Summary

The use of ‘other substances’ with a nutritional or physiological effect in food and/or food supple-
ments is only partially harmonized within the EU. Only for substances listed in Annex III of Regula-
tion (EC) No 1925/20061 on fortified foods and in the Regulation (EU) 2017/24702 on authorized
novel foods a harmonization exists. It was determined that an agreed list of ‘other substances’ which
should be prohibited or restricted in food supplements would be very beneficial to provide a higher
level of consumer protection. This agreed list would also support a harmonized approach for regula-
tion of food supplements due to the absence of a uniform risk management approach and in the view
of the free movement of goods in the EU.

Therefore, the Heads of European Food Safety Agencies (HoA) established the working group “Food
Supplements” (HoA WG FS), with members from 26 states, to agree on a common approach for the
management and assessment of certain ‘other substances’.
The members of the HoA WG FS collected information regarding the risks (including risk assess-
ments), their assumed status as Novel Foods in accordance with Regulation (EU) 2015/22833 and
other relevant aspects, for a total of 117 substances.
The HoA recommends achieving legal status in EU food law for any agreed substances via the ‘Arti-
cle 8 procedure’ in Regulation (EC) No 1925/2006 and their addition to Annex III of the Regulation.
Therefore, the substances for which sufficient scientific information was available were reviewed
with regard to their eligibility for an ‘Article 8 procedure’. It was concluded that a proposed list of 13
of the 117 substances should be prioritized as these are considered to pose a (possible) health risk to
consumers, especially in the view of an enhanced intake via food supplements (daily dose) compared
to the balanced and varied diet. The recommendation for an initiation of the ‘Article 8 procedure’ for
these substances together with the underlying information could either be submitted by HoA or indi-
vidual member states from the EU and EEA to EU COM, which may then initiate the ‘Article 8 proce-
dure’.
The HoA further recommends that substances assumed ‘novel’4 according to the available infor-
mation (including national lists and RASFF notifications) should be forwarded by the HoA or the HoA

1 Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and min-

erals and of certain other substances to foods.

Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32006R1925
2 Commission Implementing Regulation (EU) 2017/2470 of 20 December 2017 establishing the Union list of novel foods in accordance with

Regulation (EU) 2015/2283 of the European Parliament and of the Council on novel foods. Online available: https://eur-lex.europa.eu/le-
gal-content/EN/TXT/?uri=CELEX%3A32017R2470
3 Regulation (EU) 2015/2283 of the European Parliament and of the Council of 25 November 2015 on novel foods, amending Regulation

(EU) No 1169/2011 of the European Parliament and of the Council and repealing Regulation (EC) No 258/97 of the European Parliament
and of the Council and Commission Regulation (EC) No 1852/2001. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?uri=CELEX%3A32015R2283
4 In the entire report this term refers to substances, the HoA WG FS assumes to be novel and which are not authorized in accordance with

Reg. (EU) 2015/2283.

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First report of the HoA working group “Food Supplements”

WG FS to the EU COM (CAFAB5 WG on Novel Food). Due to the large number, the substances should
be grouped by priority before being submitted to the EU COM.

The recommendations of the HoA are in no way intended to duplicate or precede the work of
corresponding working groups of EU COM or to prejudge their decisions. They are solely in-
tended to support EU COM and EU/EEA-MS in determining appropriate EU legislative require-
ments.

The information compiled in this report follows the terms of reference established by HoA
who oversee and conclude on the results of the accomplished work.

5 CAFAB: Competent Authority Food Assessment Body

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First report of the HoA working group “Food Supplements”

Table of contents

1 Background on legal situation of the use of substances with a nutritional or physiological effect
in food supplements .................................................................................................................................................... 7

1.1 Legal framework ............................................................................................................................................... 7

1.1.1 EU legislation ............................................................................................................................. 7
1.1.2 National regulations................................................................................................................. 9
1.1.3 Mutual recognition ................................................................................................................ 10
1.1.4 Challenges for competent authorities .............................................................................. 10
1.1.5 Other factors affecting competent authorities............................................................... 11

1.2 Establishment of the HoA Working group “Food Supplements” and its tasks .............................. 11

2 Accomplished milestones ........................................................................................................................... 14

2.1 Approach ......................................................................................................................................................... 14

2.2 Results.............................................................................................................................................................. 16
2.2.1 Reviewed substances ............................................................................................................ 16
2.2.2 Substances assumed to be ‘novel’ ..................................................................................... 20
2.2.3 Prioritization of substances assumed to be ‘not novel’ or ‘not NFS’ ......................... 21
2.2.4 RASFF notifications ............................................................................................................... 23

2.3 Conclusion of the review of substances................................................................................................... 24

3 Suggestion for next steps ............................................................................................................................ 25

3.1 Possible ways to regulate substances assumed to be ‘not novel’ or ‘not NFS’............................... 25

3.2 Possible ways to handle substances assumed to be ‘novel’ ................................................................ 26

3.3 Proposals for further actions ...................................................................................................................... 26

4 References....................................................................................................................................................... 27

5 Annexes ........................................................................................................................................................... 31

Annex A ....................................................................................................................................................................... 31

Annex B........................................................................................................................................................................ 35

Annex C ....................................................................................................................................................................... 37
Actaea racemosa .................................................................................................................................. 37
Coumarin in plant preparations........................................................................................................ 38
Curcumin in Curcuma spp.-preparations ....................................................................................... 39
Hypericum perforatum ....................................................................................................................... 41
Lepidium meyenii................................................................................................................................. 42
Melaleuca spp.-essential oils ............................................................................................................ 44
Melatonin............................................................................................................................................... 46
Ocimum tenuiflorum .......................................................................................................................... 47

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First report of the HoA working group “Food Supplements”

Piperine .................................................................................................................................................. 48
p-Synephrine in Citrus spp.-preparations ...................................................................................... 49
Tribulus terrestris................................................................................................................................. 51
Tryptophan ............................................................................................................................................ 52
Withania somnifera ............................................................................................................................. 53

Annex D ....................................................................................................................................................................... 55
Coumarin in plant preparations ........................................................................................................ 55
Curcumin in Curcuma spp.-preparations ....................................................................................... 55
Hypericum perforatum ....................................................................................................................... 56
Piperine .................................................................................................................................................. 56

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First report of the HoA working group “Food Supplements”

1 Background on legal situation of the use of substances with a nutritional or physio-

logical effect in food supplements

1.1 Legal framework

The use of certain other substances with a nutritional or physiological effect in conventional foods and food
supplements (hereinafter referred to as food and/or food supplements) may be regulated by legislation of the
European Union (EU) as well as national regulations.

1.1.1 EU legislation

In the EU food supplements are per definition foods and therefore all regulations applicable to food especially
Regulation (EC) No 178/20026 (General Food Law Regulation) apply. According to this legislation, food has to
be safe, which is the responsibility of the food business operator (FBO).

According to the Directive 2002/46/EC7 (Food Supplements Directive), food supplements are concentrated
sources of nutrients or other substances with a nutritional or physiological effect, alone or in combination.
These substances comprise e. g. vitamins, minerals, amino acids, fibres, bacteria, fungi, plant extracts or other
substances with a nutritional or physiological effect.
These other substances are defined in Article 2 (2) of Regulation (EC) No 1925/2006 8 (Fortified Food Regula-
tion) as “substances other than vitamins and minerals with a nutritional or physiological effect” (hereinafter re-
ferred to as ‘other substances’).
The permitted vitamin and mineral substances that may be used in food supplements are defined in Annex I and
II of Directive 2002/46/EC. For the use in foods, other than food supplements, the permitted vitamin and mineral
substances are defined in Annex II of Regulation (EC) No 1925/2006. However, no common maximum levels for
daily intake of vitamins and minerals have been established in the EU, yet.
The European Commission (EU COM) is currently developing a model for setting safe maximum levels for vita-
mins and minerals in food supplements and fortified foods.

According to Recital 8 of Directive 2002/46/EC, specific rules concerning ‘other substances’ with a nutritional
or physiological effect’ used as ingredients of food supplements should be specified at a later stage. However,
the EU COM stated in 2008 that the community’s legal instruments already provided sufficient legal basis for

6 Regulation (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. Online
available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32002R0178
7 Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the Member

States relating to food supplements. Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32002L0046

8 Regulation (EC) No 1925/2006 of the European Parliament and of the Council of 20 December 2006 on the addition of vitamins and min-

erals and of certain other substances to foods.

Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32006R1925

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First report of the HoA working group “Food Supplements”

the regulation of ‘other substances’ and therefore did not consider it appropriate to lay down specific rules for
substances other than vitamins or minerals for use in foodstuffs9.

Further specific provisions for the regulation of ‘other substances’ are outlined in Article 8 of Regulation (EC)
No 1925/2006 which provides a procedure to address the safety concerns associated with any substances other
than vitamins and minerals used in food, including food supplements.
On its own initiative or on the basis of information provided by member states of the European Union and the
European Economic Area (hereinafter referred to as EU/EEA MS), the EU COM may initiate the ‘Article 8 proce-
dure’ in order to include a certain substance on a list to prohibit (Annex III Part A), restrict (Annex III Part B) or
to put it under community scrutiny to be reviewed within four years (Annex III Part C). Although Regulation
(EC) No 1925/2006 has been applicable since 1st July 2007, only nine substances are listed in Part A and B, and
five substances in Part C of Annex III. Momentarily, five substances have currently been submitted for an ‘Arti-
cle 8 procedure’ (berberine, Garcinia cambogia (accepted scientific name: Garcinia cowa Roxb. ex Choisy), alfa-
lipoic acid and estragole together with Foeniculum vulgare Mill.).

In addition to Directive 2002/46/EC and Regulation (EC) No 1925/2006, Regulation (EU) 2015/2283 of the Eu-
ropean Parliament and of the Council on novel foods 10 (Novel Food Regulation) is applicable when it comes to
the use of ‘other substances’ in food supplements.
Novel Food is defined as food that had not been used for human consumption to a significant degree in the EU
before 15th of May 1997 and is falling under at least 1 of 10 categories mentioned in the regulation (e. g. foods
consisting of, isolated from or produced from plants or their parts). The obligation to verify whether food in-
tended to be placed on the EU market is ‘novel’ or ‘not novel’, lies with the FBO.
Any food which meets the definition of ‘novel’ falls under the scope of the Novel Food Regulation and needs a
pre-market approval at EU level. Food supplements containing for instance a plant extract which is regarded
‘novel’ may not enter the market until the ingredient has been authorized by the EU COM.
The purpose of the legislation is to ensure the safety of food and food ingredients with no significant history of
consumption in the EU. The Commission Implementing Regulation (EU) 2017/247011 (Union List of authorized
Novel Foods) establishes a list of all the authorized Novel Foods in the EU, including their conditions of use,
labelling requirements and their specifications.
This Regulation is amended following each new authorization.
Since Article 1 paragraph 3 (b) of Regulation (EC) No 1925/2006 states that this Regulation shall apply without
prejudice to specific provisions laid down in Community legislation concerning Novel Foods and Novel Food
ingredients, the specific directions of the Novel Food Regulation apply with priority.

9 Report from the commission to the council and the European Parliament on the use of substances other than vitamins and minerals in
food supplements. COM, 5.12.2008, COM(2008) 824 final. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?qid=1563793210387&uri=CELEX:52008DC0824
10 Regulation (EU) 2015/2283 of the European Parliament and of the Council of 25 November 2015 on novel foods, amending Regulation

(EU) No 1169/2011 of the European Parliament and of the Council and repealing Regulation (EC) No 258/97 of the European Parliament
and of the Council and Commission Regulation (EC) No 1852/2001. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?uri=CELEX%3A32015R2283
11 Commission Implementing Regulation (EU) 2017/2470 of 20 December 2017 establishing the Union list of novel foods in accordance

with Regulation (EU) 2015/2283 of the European Parliament and of the Council on novel foods. Online available: https://eur-lex.eu-
ropa.eu/legal-content/EN/TXT/?uri=CELEX%3A32017R2470

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Besides this, the Novel Food Status catalogue12 (NFSC) of the EU COM contains information made available to
competent authorities on the status of some substances/of different foods as Novel Food. However, information
in the NFSC is neither conclusive nor legally binding. Therefore, the status of a substance not listed in NFSC is
not always apparent, for those listed it may be contested.
Implementing Regulation (EU) No 307/201213 specifies which requirements have to be fulfilled for substances
being subjected to the ‘Article 8 procedure’. According to Article 8, the substance has either to be added as an
ingredient to foods or used in the manufacture of food. Therefore, Novel Foods would not meet this requirement
for an ‘Article 8 procedure’.

Certain ‘other substances’, if they are being added to food for technological purposes, e. g. for colouring or pro-
longing the shelf-life of the food, are subject to the provisions of Regulation (EC) No 1333/200814 (Food additive
Regulation) and Regulation (EU) No 231/201215 (Food additive Specification Regulation). ‘Other substances’ with
flavouring properties, in turn, are subject to the provisions of Regulation (EC) No 1334/200816 (Food flavourings
Regulation). These regulations define the specifications (synonyms, definition and purity) and any restrictions
linked with their use (maximal quantities and specific food categories to which these substances may be added).
As a rule, the addition for technological purposes is either 'quantum satis' or in precisely specified small quanti-
ties. Adding the same substances for nutritional or physiological purposes however, is usually done in larger
quantities.

1.1.2 National regulations

For ‘other substances’ with a nutritional or physiological effect which are not or not yet restricted at EU level
specific national laws can be applied in EU/EEA MS ensuring a high level of consumer protection.
Currently, some EU/EEA MS and Switzerland have developed national policies or guidelines to authorize, pro-
hibit or restrict the use of certain substances in food and/or food supplements.
Some EU/EEA MS and Switzerland have specific national laws in place for 'other substances ' than vitamins and
minerals. However, many of these national legal instruments are based traditionally on 'expert opinions' only,
and not on proper scientific risk assessments.
At the same time, some EU/EEA MS only have guidelines, that are not legally binding, and some EU/EEA MS
have no regulations nor guidance at all.
This leads to a non-harmonized approach that uses a mix of guidelines, which may be based on varying assess-
ment criteria in each EU/EEA MS.

12 Novel Food Status catalogue of the EU COM: https://food.ec.europa.eu/safety/novel-food/novel-food-status-catalogue

13 Commission Implementing Regulation (EU) No 307/2012 of 11 April 2012 establishing implementing rules for the application of Article 8
of Regulation (EC) No 1925/2006 of the European Parliament and of the Council on the addition of vitamins and minerals and of certain
other substances to foods. Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32012R0307
14 Regulation (EC) No 1334/2008 of the European Parliament and of the Council of 16 December 2008 on flavourings and certain food in-

gredients with flavouring properties for use in and on foods and amending Council Regulation (EEC) No 1601/91, Regulations (EC) No
2232/96 and (EC) No 110/2008 and Directive 2000/13/EC. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?uri=CELEX%3A32008R1334
15 Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in Annexes II and III to

Regulation (EC) No 1333/2008 of the European Parliament and of the Council. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?uri=CELEX%3A32012R0231
16 Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives.

Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32008R1333

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1.1.3 Mutual recognition

Products that are not or not fully harmonized by European regulations are subject to the free movement of
goods in accordance with Article 28 et seq. of the Treaty on the Functioning of the European Union 17 (TFEU;
see in particular Article 34) and thus the principle of mutual recognition applies. The mutual recognition princi-
ple ensures market access for goods that are not or only partly subject to EU harmonization legislation. EU/EEA
MS may not prohibit the sale of goods on their territory that do not fall under Union harmonization legislation
but which have been lawfully marketed in another EU/EEA MS. This even applies if the good does not comply
with the technical rules of the other country. However, there may be exceptions to this principle whenever
public safety, health protection or the environment are concerned. Directive 2001/83/EC18 of the European
Parliament and of the Council applies where a product, taking into account all its characteristics, may fall within
the definition of ‘medicinal product’ as laid down in Article 1(2) of that Directive. In that respect, in the case a
EU/EEA MS classifies a product as a medicinal product in accordance with Directive 2001/83/EC, it may restrict
placing on the market of that product in accordance with Union law.
Regulation (EU) 2019/51519 applies to goods or aspects of goods that are not exhaustively covered by Union
harmonization rules. The subject of the ordinance is, in particular, to describe the formal procedures of the mu-
tual recognition.
In general products are on the market of EU/EEA MS without a proper risk assessment or pre-market assess-
ment by authorities. However, the fact that a product is on the market does not necessarily mean that it is legal.
Due to the principle of mutual recognition, it is often not possible to stop the sale of products containing sub-
stances of concern as long as the competent authority does not claim issues regarding public safety, health pro-
tection or the environment. With a harmonization of rules to regulate substances and goods containing these
‘other substances’ the need of mutual recognition for these substances would not be necessary any longer.

1.1.4 Challenges for competent authorities

For ‘other substances’ with a nutritional or physiological effect, only general food law and provisions under the
general food law are applicable throughout the EU such as the Fortified Food Regulation, Novel Food Regula-
tion, etc. As no additional effective regulations are in place for most ‘other substances’ their surveillance may
pose challenges for the competent authorities.
The general requirement that all foods must be safe also applies to food supplements (Article 14 of Regulation
(EC) No 178/2002) and is the primary responsibility of the FBO. However, based on Article 14 of Regulation
(EC) No 178/2002 competent authorities may perform or initiate a risk assessment in order to evaluate the po-
tential risk to consumers of foods or foods supplements. This will be done on a case-by-case basis, which is
challenging and time consuming. Often information on hazard characterization and exposure is absent or lim-
ited and resources for scientific support cannot be provided.

17 Consolidated version of the treaty on the functioning of the European Union. Online available: https://eur-lex.europa.eu/LexUriS-

erv/LexUriServ.do?uri=CELEX:12012E/TXT:en:PDF
18 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal

products for human use. Online available: https://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX%3A02001L0083-20220101

19 Regulation (EU) 2019/515 of the European Parliament and of the Council of 19 March 2019 on the mutual recognition of goods lawfully

marketed in another Member State and repealing Regulation (EC) No 764/2008. Online available: https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/?uri=CELEX%3A32019R0515

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Unfortunately, the current framework of EU regulations in conjunction with national laws is not quite effective,
neither for the food business operators (FBO), who want to place their products on several EU/EEA MS mar-
kets, nor for the authorities.

As outlined before, according to legislation non-authorized Novel Foods shall not be placed on the EU market.
The responsibility lies with the FBO, but e. g. due to the often unknown status as a non-authorized Novel Food,
competent authorities have to deal with the occurrence of such Novel Foods on the market.

Substances, other than vitamins and minerals may also be classified as medicinal in some EU/EEA MS because
of the non-harmonized medicine legislation in the EU. This means that some substances may or may not be
used in food supplements in different EU/EEA MS. This creates even more challenges for the FBO and for the
food control authorities also in the context of mutual recognition.

1.1.5 Other factors affecting competent authorities

Infringements of EU food and feed legislation posing a direct or indirect risk to human health are reported
through the Rapid Alert System for Food and Feed (RASFF) in accordance with Article 50 of Regulation
(EC) No 178/2002. During recent years, several notifications and warnings concerning unsafe ‘other substances’
in food supplements (second most common reason for an alert) have been alerted via RASFF 20 underlining the
fact, that regulation of these substances is insufficient or is not complied with.

Regulation (EU) 2023/91521 (Contaminant Regulation, repealing Regulation (EC) No 1881/200622) already sets
maximum levels for some toxic substances originating from plants (e. g. hydrocyanic acid). However, in order to
set further maximum levels within the framework of this regulation, monitoring data for the respective sub-
stances in foods are needed, which are often not present and difficult to collect. Thus, only a few substances that
this working group has been working on could be suitable for inclusion in this regulation.

Attempts were made in the past to establish harmonized rules for the use of some ‘other substances’ through-
out the EU. However, no consensual decision was reached.
Overall, there is a tremendous need to find common ways to manage or regulate these substances.

1.2 Establishment of the HoA Working group “Food Supplements” and its tasks

As outlined before, the use of ‘other substances’ with a nutritional or physiological effect in food and/or food
supplements is only partially and not effectively harmonized within the EU apart from those listed in Annex III

20 Annual report on RASFF notification 2022. Online available: https://food.ec.europa.eu/system/files/2023-08/acn_annual-re-

port_2022.pdf
21 Commission Regulation (EU) 2023/915 of 25 April 2023 on maximum levels for certain contaminants in food and repealing Regulation

(EC) No 1881/2006. Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32023R0915

22 Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. No

longer in force. Online available: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32006R1881

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First report of the HoA working group “Food Supplements”

of Regulation (EC) No 1925/2006. In view of a uniform risk management approach in the EU, it is important to
agree on a harmonized list of ‘other substances’ which should be prohibited or restricted in food supplements.
Therefore, at the meeting of the Heads of European Food Safety Agencies (HoA) held in Dublin on March 28th
in 2019 it was agreed to establish the working group “Food Supplements” (WG FS) to tackle this task. Terms of
Reference (ToR) with a mandate to form a WG tackling this problem were established (see enclosed Attach-
ment ‘ToR of WG FS’).

The main objective of the working group is to elaborate a common approach for the management and assess-
ment of ‘other substances’ with a nutritional or physiological effect used in or as food and/or food supple-
ments. For most other categories of substances including food additives, flavourings or contaminants the legal
provisions are fully harmonized. The respective EU regulations provide maximum permitted quantities or maxi-
mum levels of these substances for different food groups. In addition, for permitted food improvement agents,
chemical specifications for these substances are laid down in the current legislation, e. g. Regulation No.
231/2012.

At a national level, 18 (thereof 16 EU MS) of 26 members23 of the HoA WG FS reported that they had drawn up
positive and/or negative lists of ‘other substances’ which can or cannot be used in food and/or food supple-
ments. However, those lists are not always legally binding. In some cases, the use of the substances in question
is subject to compliance with technical conditions, such as maximum limits, type of extract or combination of
ingredients.
Many substances mentioned on the national lists and their possible restrictions differ from state to state. How-
ever, some of the listed substances are assessed uniformly by several or most HoA WG FS members.
Therefore, harmonization could be initiated by drawing up a common negative list of ‘other substances’ which
may not be used in food and/or food supplements based on the consensus of national lists and available risk
assessments.
Eventually, suggested prioritized substances from this list could be included in Annex III Part A or B of Regula-
tion (EC) No 1925/2006 leading to an increased legal certainty for the food business operators and facilitating
the work of the competent authorities.
For this reason, the HoA WG FS first focussed on commonalities between the listings of the members of the
working group and identified consistent assessments.

Based on the data available, the most feasible way seemed to be the approach to identify those substances
which are not suitable for use in food and/or food supplements, primarily due to toxicity. Another argument for
this approach is that such a list would provide the basis for harmonized measures to prohibit or restrict those
substances which possess the highest potential to present a risk to the consumer.

23 Members of the HoA WG FS, members which have national lists are underlined: Austria, Belgium, Bulgaria, Czechia, Denmark, Estonia,
Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Poland, Portugal,
Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland.

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First report of the HoA working group “Food Supplements”

Additionally, it could serve as a basis for further harmonization of substances assessed and managed differently
between EU/EEA MS and Switzerland.

Thus, the first main objective of the WG was to identify substances which are possibly injurious to health and
thus should be “prohibited or restricted in food and/or food supplements”. ToR were adopted accordingly (see
enclosed Attachment ‘ToR of WG FS’).

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First report of the HoA working group “Food Supplements”

2 Accomplished milestones

2.1 Approach

The main objective of the HoA WG FS was to identify substances in food and/or food supplements that may
lead to (concerns for) adverse health effects and therefore need to be prohibited or restricted (depending on
dose and food matrix) regarding their use in food and/or food supplements. At first, the DACH-list24 was used
as a starting point. The DACH-list had been established by Germany (D), Austria (A) and Switzerland (CH) with
the objective to provide all parties involved in the trade of goods with a decision guidance for the assessment of
substances regarding their use as food or food ingredients.

The members of the HoA WG FS were asked to review 20 substances at a time. However, it became apparent
that it is difficult to review all the substances as suggested. The members were not able to draw a conclusion on
each substance as the underlying information (e. g. risk assessment) was often not available. It also became ap-
parent that it would not be realistic to perform a risk assessment for each individual substance due to the large
amount of time and resources needed and the general lack of data. Therefore, the members of the HoA WG FS
decided to modify their approach.

First, existing risk assessments and other relevant contributions containing information on the possible health
risks of the substances on the DACH-list were collected by asking members of the HoA WG FS to provide this
information. Subsequently, members of the HoA WG FS submitted these to the HoA platform and added risk
assessments for further relevant substances. Second, the subgroup ‘risk assessment’ was established for decid-
ing on the best utilization of the collected information for enabling a prioritization of the substances regarding
their suitability for an ‘Article 8 procedure’ under Regulation (EC) No 1925/2006. Currently, the subgroup con-
sists of nine risk assessors25.

In parallel to the work of the subgroup, the members of the HoA WG FS reviewed all available substances on
the HoA platform regarding their status as a Novel Food. The members checked all information available to
them (national lists, e-mail archives etc.) and assigned an assumed Novel Food status to each substance (Annex
A) to the best of their knowledge. The assumed status will still have to be confirmed by the competent expert
group on EU level (CAFAB26 WG on Novel Food).
As outlined in section 1.1.1, substances that are considered Novel Foods cannot be legally put on the market
unless they are authorized and included in the Union list. Authorized Novel Foods can be legally put on the
market only in accordance with the conditions and specifications set in the Union list. Therefore, HoA WG FS
considered these substances least relevant for further considerations by the HoA WG FS regarding a prohibition
or restriction due to possible risks.

24 See www.bvl.bund.de/stofflisten for detailed information and online availablitity.

25 Risk assessors from Belgium, Estonia, France, Germany, the Netherlands, Sweden and Switzerland.
26 CAFAB: Competent Authority Food Assessment Body

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For an initiation of the ‘Article 8 procedure’ for prohibiting, restricting or putting substances under Community
scrutiny in accordance with Regulation (EC) No 1925/2006 and Commission Implementing Regulation (EU) No
307/2012, the substance has to fulfil the following requirements (Table 1).

Table 1. Overview of the requirements needed in order to start an ‘Article 8 procedure’.

Requirement Yes No
1. The substance is actually added to food products or used in the manufacture of food.
2. Evidence demonstrating that the intake of the substance greatly exceeds normal intake from a
balanced and varied diet and/or
3. Evidence demonstrating a potential risk to consumers from consumption of the substance.

Concerning question 1 (Q1) “Is the substance actually added to food products or used in the manufacture of
food?” it was presumed that substances assumed to be ’not novel’ or only ‘not novel in food supplements’ (not
NFS) are actually being used in food and/or food supplements on the market and thus, the first requirement is
met.
Substances assumed to be ’novel’ 27 were given the lowest priority as they should presumably not be found on
the market and thus not meet the first requirement. Therefore, the HoA WG FS decided a further review of
these substances regarding the second and third requirements does not constitute a priority due to the above-
mentioned restrictions linked with Novel Foods.

The HoA WG FS asked the subgroup ‘risk assessment’ to answer the second and third question (requirements)
in order to prioritize the substances that might be suitable for an ‘Article 8 procedure’. The subgroup ‘risk as-
sessment’ agreed on a pragmatic approach for which only the information present on the HoA platform was
used. Although the subgroup ‘risk assessment’ was aware that additional risk assessments (e. g. Monographs by
European Medicines Agency (EMA)) and scientific literature might be present, it was decided to perform no ad-
ditional literature search and to include no risk assessments that were not available on the HoA platform. Each
substance was reviewed by two separate risk assessors, who discussed their findings and came to a common
conclusion.

For question 2 (Q2) “Is there evidence demonstrating that the intake of the substance greatly exceeds normal
intake from a balanced and varied diet?” one of the following answers was selected: “yes”, “likely yes”, “no” and
“not possible to answer due to limited information”.

The second option “likely yes” was chosen when there was limited information on dietary intake available on
the HoA platform, but a quick search on the internet revealed that the substance is available in food supple-
ments on the market in Europe. Thus, more research is needed to get an accurate overview of the intake. The
intake of substances via food supplements leads to an intake of a concentrated dose of ingredients. It can be
presumed that per definition the intake of food supplements leads potentially to higher plasma levels (above

27 In the entire report this term refers to substances, the HoA WG FS assumes to be novel and which are not authorized in accordance with

Reg. (EU) 2015/2283.

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toxic threshold) compared with normal intake from a balanced and varied diet (with food matrix, throughout
the day and not daily).

For question 3 (Q3) “Is there evidence demonstrating a potential risk to consumers from consumption of the
substance?” one of the following answers was selected: “yes, due to risks”, “yes, due to hazards”, “no” and “not
possible to answer due to limited information”.

The first option “yes, due to risk” was chosen when a risk was identified in the risk assessment (based on hazard
and exposure information, e. g. exposure > health-based-guidance-value (HBGV); however, exposure from food
supplements may considerably differ between products (e. g. due to recommended dose) which affects the out-
come of the risk assessment). In the cases where only hazard information was available, the second option
(“yes, due to hazards”) was chosen.

Substances assigned the highest priority regarding a needed regulation were the substances with the following
answer combination: Q2 = “yes” or “likely yes” & Q3 = “yes, due to risk”. Subsequently, the subgroup ‘risk as-
sessment’ made short summaries of the substances with the highest priority in order to further substantiate the
concerns and to identify substances with (possible) carcinogenic, mutagenic or reprotoxic properties.

In addition to the information directly available to the authorities (e-mail conversations, complaints, etc.), the
HoA WG FS has sought out further sources from which information on the use of ‘other substances’ (with pos-
sible risks) in food can be obtained. In the RASFF, alerts are published when an authority, e. g. in the context of
a monitoring program or during an inspection, finds a product that is legally not permissible, e.g. due to an in-
gredient. Possible reasons for an alert may include “unsafe ingredients” or “prohibited substances” or “unau-
thorized Novel Food ingredients”. Therefore, all available RASFF alerts from 2017 until May 2022 on food sup-
plements and fortified foods were collected and sorted by the reason of the alert (e. g. “unauthorized Novel
Food ingredient”). Alerts were grouped based on identical reasons for an alert. For further analysis, only alerts
due to "composition", "natural toxins" and "Novel Foods" were taken into account.

2.2 Results

2.2.1 Reviewed substances

The starting point of the review was a collection of 117 substances, which consisted of substances from the
DACH-list and other substances suggested by the members of the HoA WG FS. Figure 1 provides an overview
of the steps taken by the members of the HoA WG FS during the review of substances available on the HoA
platform.

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Future prioritization by
Assumed Novel
HoA WG FS
N=65
N=65

No information available on
the HoA platform
N=4

'Article 8 procedure' was

already started
N=2
Substances Assumed Not Novel
(DACH-list and others)
N=49
N=117
Recent EFSA opinion
N=1

Prioritization for suitability

for an 'Article 8 procedure'
by subgroup risk
assessment
N=42

On Annex III
Regulation 1925/2006 No action needed
N=3

Figure 1. An overview of the steps taken by the members of the HoA WG FS during the review of substances present on
the HoA platform. The orange boxes represent the route of the substances that were prioritized for suitability for an ‘Ar-
ticle 8 procedure’.

Of the initial 117 substances, 65 substances were assumed to be ‘novel’, 49 were assumed to be ‘not novel’ or
‘not NFS’ by HoA WG FS to the best of their knowledge. In the meantime, 3 substances have already been in-
cluded in Annex III of Regulation 1925/2006: Monascus purpureus (monacoline K) which is included in PART B
and C as well as Aloe ferox and Aloe vera, both included in PART A. A complete overview of the reviewed sub-
stances and their status can be found in Annex A of this report. The complete scientific names of each botani-
cal substance including the corresponding author 28, 29 and the reviewed plant part or substance details, if
specified, are stated in the overview in Annex A and Annex C, as well as in Table 2. In the continuous text as
well as other tables and annexes however, they are omitted for pragmatic reasons.

Some parts of Angostura trifoliata, Annona muricata, Aquilegia vulgaris and Arnica montana were considered
‘not novel’ by the HoA WG FS, but no risk information was available on the HoA platform. Therefore, these
substances were not reviewed by the subgroup risk assessment.

28 Authors according to https ://powo.science.kew.org

29 In this report, the abbreviation “spp.” refers to more than one not further defined species of the same genus.

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Recently, the European Food Safety Authority (EFSA) has published an opinion regarding the dietary exposure
to heavy metals and iodine intake via consumption of seaweeds and halophytes in the European population
(EFSA, 2023). Iodine could be considered as a contaminant or a mineral but not as an ‘other substance’. There-
fore, iodine was not reviewed by the subgroup risk assessment, either.

EU COM has started an ‘Article 8 procedure’ for berberine and Garcinia cambogia (designated in the report with
the accepted name Garcinia cowa Roxb. ex Choisy), already. Therefore, these substances were also not re-
viewed by the subgroup risk assessment.

Table 2 provides an overview of the 42 substances that were reviewed by the subgroup ‘risk assessment’ based
on the information for these substances available on the HoA platform. It states the complete scientific name,
including the author, and the assessed plant part or substance details, if specified. In addition, Annex B provides
an overview of available EFSA opinions and monographs/assessment reports by EMA regarding the substances
in Table 2. Only EFSA opinions on food were included. Opinions for health claims or feed were not considered.
Furthermore, only EMA monographs/assessments on human use were included. No monographs/assessment
regarding veterinary use were added.

Table 2. Overview of the substances reviewed by the subgroup ‘risk assessment’ and the available information on the
HoA platform. Abbreviation RA stands for risk assessment.

Name of substance Substance details Available information

Substance
(as used in RA) (as assessed in RA) on HoA platform
N-Acetyl-Cysteine N-Acetyl-Cysteine not applicable (AECOSAN, 2015a; BLV,
2021)
Actaea racemosa L. Actaea racemosa L. rhizomes (DTU, 2009; RIVM, 2013;
BuRO, 2020)
Alisma plantago-aquat- Alisma plantago-aquatica fresh, dried rhizomes (DTU, 2011b;2015)
ica L. L. including Alisma plan- and various preparations
tago-aquatica L. ssp. ori- thereof
entale
Artemisia cina O.Berg Artemisia cina dried flower buds (van de Bovenkamp et al.,
2009)
Artemisia maritima L. Artemisia maritima dried flower buds, (van de Bovenkamp et al.,
shoots and leaves 2009)
Carica papaya L. Carica papaya L. leaves (FOD, 2020b)
Carlina acaulis L. Carlina spp. roots (FOD, 2020e)
Chelidonium majus L. Chelidonium majus extracts of plant parts (RIVM, 2009)
growing underneath and
above the ground
Cinnamomum verum Cinnamomum verum bark and essential oils (FOD, 2020c)
J.Presl J.Presl thereof
Coumarin in plant prep- Coumarin not applicable (BfR, 2012b; ANSES,
arations 2021)
Cucurbitacins in prepa- Extracts of Cucurbitaceae roots, fruits (Gry et al., 2006)
rations of Cucurbitaceae containing Cucurbitacins

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Name of substance Substance details Available information

Substance
(as used in RA) (as assessed in RA) on HoA platform
Curcumin in Curcuma Curcuminoids and extracts rhizome and extracts (FOD, 2019; AESAN,
spp.-preparations of Curcuma longa L., Cur- thereof 2020; BVL & BfArM,
cuma xanthorrhiza Roxb., 2020; BfR, 2021; ANSES,
2022a)
Curcuma zedoaria
(Christm.) Roscoe
Gentiana lutea L. Gentiana lutea L. roots, leaves (DTU, 2022)
Ginkgo biloba L. Ginkgo biloba L. leaves (Pelgrom et al., 2007)
Griffonia simplicifolia Griffonia simplicifolia no specific plant parts (FOD, 2004)
(Vahl ex DC.) Baill. (Vahl ex DC.) Baill. are mentioned in the RA
Huperzin A in Huperzia Huperzin A not applicable (DTU, 2016)
serrata Thunb.-prepara-
tions
Hypericum perforatum L. Hypericum perforatum L. aerial parts or dried (de Wit et al., 2019; DTU,
flowering tops 2019a)
Juglans regia L. Juglans regia L. whole plant excl. nuts (van de Bovenkamp et al.,
2009)
Lavandula angustifolia Lavandula officinalis Chaix flowering tops and es- (FOD, 2020a)
subsp. angustifolia sential oils thereof
Lepidium meyenii Walp. Lepidium meyenii Walp. root or germ stem (hy- (DTU, 2011a;2020a;2021)
pocotylene) or prepara-
tions thereof
Lycopus europaeus L. Lycopus europaeus L. no specific plant parts (van de Bovenkamp et al.,
are mentioned in the RA 2009)
Melaleuca spp.-essential Melaleuca alternifolia leaves and essential oils (ANSES, 2020)
oils (Maiden & Betche) Cheel, thereof
Melaleuca quinquenervia
(Cav.) S.T. Blake and Mela-
leuca cajuputi Maton &
Sm. ex R.Powell
Melatonin30 Melatonin not applicable (ANSES, 2018)
Mentha × piperita L. Mentha × piperita L. leaves and essential oils (FOD, 2021)
thereof
Morus alba L. Morus alba L. leaves, fruits, root bark (ZESPÓŁ DO SPRAW
and stem SUPLEMENTÓW DIETY,
2019)
Mutarda nigra (L.) Bernh. Brassica nigra roots, seeds and oil of (van de Bovenkamp et al.,
the seeds 2009)
Ocimum basilicum L. Ocimum basilicum L. Essential oils of aerial (FOD, 2022)
parts
Ocimum tenuiflorum L. Ocimum tenuiflorum L. dried leaves (DTU, 2019b)
Piper methysticum Piper methysticum G.Forst. roots (van de Bovenkamp et al.,
G.Forst. 2009; ZESPÓŁ DO
SPRAW SUPLEMENTÓW
DIETY, 2021a)
Piperine* Piperine not applicable (DTU, 2019c; ANSES,
2022b; ZESPÓŁ DO
SPRAW SUPLEMENTÓW
DIETY, 2022)

30 See footnote 37 in Annex C.

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Name of substance Substance details Available information

Substance
(as used in RA) (as assessed in RA) on HoA platform
Podophyllum peltatum L. Podophyllum peltatum L. roots, rhizomes, resin (van de Bovenkamp et al.,
2009)
Rhodiola rosea L. Rhodiola rosea L. preparations of roots (ZESPÓŁ DO SPRAW
SUPLEMENTÓW DIETY,
2021b)
Rhododendron tomento- Ledum palustre L. no specific plant parts (van de Bovenkamp et al.,
sum (Stokes) Harmaja are mentioned in the RA 2009)
Salvia rosmarinus Spenn. Rosmarinus officinalis L. essential oils of aerial (FOD, 2020d)
parts
Solanum dulcamara L. Solanum dulcamara L. leaves, stems, roots, (van de Bovenkamp et al.,
fruits 2009)
p-Synephrine in Citrus Citrus spp. especially Citrus peel (epicarp and meso- (Hammerling, 2012;
spp.-preparations* x aurantium L. carp) and other parts and ANSES, 2014; DTU,
extracts thereof 2014a; Tiesjema et al.,
2017; BuRO, 2018)
Tanacetum vulgare L. Tanacetum vulgare or leaves, flowers, stems (van de Bovenkamp et al.,
Chrysanthemum vulgare and oil of leaves and 2009)
flowering tops
Teucrium chamaedrys L. Teucrium chamaedrys L. no specific plant parts (van de Bovenkamp et al.,
are mentioned in the RA 2009)
Tribulus terrestris L. Tribulus terrestris L. fruits, plant shoots and (DTU, 2014b; AECOSAN,
extracts thereof 2015b; ZESPÓŁ DO
SPRAW SUPLEMENTÓW
DIETY, 2021c)
Tryptophan Tryptophan not applicable (AESAN, 2012)
Vinca minor L. Vinca minor L. no specific plant parts (van de Bovenkamp et al.,
are mentioned in the RA 2009)
Withania somnifera (L.) Withania somnifera (L.) roots (DTU, 2020b; ZESPÓŁ
Dunal Dunal DO SPRAW
SUPLEMENTÓW DIETY,
2020)
*A few risk assessments were initially added on the HoA platform, but later vanished for unknown reasons and therefore

were not included in the review, being Bakhiya et al., 2017; Ziegenhagen et al., 2021.

2.2.2 Substances assumed to be ‘novel’

Of the initial 117 substances 65 were assumed to be ‘novel’ to the best of the working group´s knowledge (An-
nex A).
HoA WG FS considered substances that were assumed to be ‘novel’ by the HoA WG FS with the lowest priority.
As already mentioned, they should not be found on the market, as they are per definition not marketable with-
out prior authorisation. If they are considered to be placed on the market, the Novel Food Regulation will apply
primarily.
Due to the large number of substances, the HoA WG FS suggests to perform a prioritization of these substances
before confirmation by CAFAB WG on Novel Food status is requested (see 3.2 and 3.3) and prior to further pro-
cessing.

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2.2.3 Prioritization of substances assumed to be ‘not novel’ or ‘not NFS’

Of the initial 117 substances 49 were assumed to be ‘not novel’ or ‘not NFS’ to the best of the working group´s
knowledge (Annex A).
The subgroup ‘risk assessment’ concluded that most of the available risk assessments on the HoA platform
were of good quality and were written by risk assessors of reputable institutes. However, it was noted that
some contributions contained limited information and were outdated. Overall, the assessments were consid-
ered suitable for priority setting and as a good starting-point for a final risk assessment of the selected sub-
stances by EFSA (presumably during the ‘Article 8 procedure’). Eventually, the subgroup ‘risk assessment’ prior-
itized the 42 substances that were assumed to be ‘not novel’ or ‘not NFS’.

Table 3 provides an overview of 13 substances with the highest priority; those are the substances considered to
pose a (possible) risk to consumers and for which the intake via food supplements exceeds normal intake. The
substances in Table 3 are listed alphabetically based on reply to Q2, consequently the order of these does not
indicate a prioritization.
It has to be noted that substances which have not been prioritized in this review process, might still pose a risk
to consumers. They may therefore be considered in future reviews.
For these 13 substances CAFAB WG on Novel Food has already been contacted and the status as ‘not novel’ or
‘not NFS’ has been confirmed.

Table 3. An overview of substances which were considered to be a risk for the consumer (yes to Q3) and to greatly exceed
normal intake from a balanced and varied diet (yes or likely yes to Q2).

Substance Q2 Q3
Yes Likely yes Yes, risk
Coumarin in plant preparations x x
Curcumin in Curcuma spp.-preparations x x
Hypericum perforatum x x
Melaleuca spp.-essential oils x x
Melatonin*, 31 x x
Piperine x x
p-Synephrine in Citrus spp.-preparations x x
Tryptophan x x
Actaea racemosa x x
Lepidium meyenii x x
Ocimum tenuiflorum x x
Tribulus terrestris** x x
Withania somnifera*** x x
*BfR has recently completed a risk assessment, which will be published in 2024 online. Information from this document was
included in the detailed description of melatonin (Annex C).
**RIVM currently works on a risk assessment that will be published in 2024. This assessment is not finalized and therefore

not included in this document.

***RIVM currently works on a risk assessment that will be published in 2024. Also ANSES works on a risk assessment that

will be published in 2024. These assessments are not finalized and therefore not included in this document.

31 See footnote 37 in Annex C.

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Short summaries of these substances with more detailed information can be found in Annex C of this report.
These summaries have been prepared following previous mandates from the EU COM to EFSA to initiate ‘Arti-
cle 8 procedures’. Of the substances from Table 3 Curcumin in Curcuma spp.-preparations, Lepidium meyenii,
Melaleuca spp.-essential oils, Ocimum tenuiflorum, piperine, Tribulus terrestris and Withania somnifera exhibit
(possible) carcinogenic, mutagenic or reprotoxic properties.

The 13 prioritized substances were also reviewed regarding existing permissions as food additives or food fla-
vourings. Information on the findings can be found in Annex D of this report.

The Novel Food status of the remaining substances assumed to be ‘not novel’ or ‘not NFS’ will still have to be
confirmed by CAFAB WG on Novel Food. Whether any regulations for their use as food additives or food fla-
vourings exist, has not been reviewed yet.

Table 4 provides an overview of substances which raise concern based on their hazard characteristics and which
(might) exceed normal intake from a balanced and varied diet. More information on exposure is needed in order
to fulfil a risk assessment. The substances in Table 4 are listed alphabetically based on reply to Q2, conse-
quently the order of these does not indicate a prioritization.

Table 4. An overview of substances which raise concern based on their hazard characteristics and which (might) exceed
normal intake from a balanced and varied diet.

Substance Q2 Q3
Yes Likely Not possible to answer due to Yes, hazard
yes limited information
Juglans regia x x
Alisma plantago-aquatica x x
Carica papaya x x
Chelidonium majus x x
Gentiana lutea x x
Mutarda nigra x x
Solanum dulcamara x x
Tanacetum vulgare x x
Artemisia cina x x
Artemisia maritima x x
Cinnamomum verum x x
Ginkgo biloba x x
Huperzin A in Huperzia serrata- x x
preparations*
Lycopus europaeus x x
Ocimum basilicum x x
Piper methysticum x x
Podophyllum peltatum x x
Rhododendron tomentosum x x
Teucrium chamaedrys x x
Vinca minor x x
RIVM currently works on a risk assessment that will be published in 2024.
*

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Table 5 provides an overview of the remaining substances which were reviewed. Based on the information
available on the HoA platform, four substances (Q3 answered with ‘no’) were considered not being a risk for
consumers. These four substances will therefore not undergo further prioritization in the HoA WG FS at this
moment. For the other substances it was not possible to assess the risk due to the limited information available.
The substances in Table 5 are listed alphabetically based on reply to Q3, consequently the order of these does
not indicate a prioritization.

Table 5. An overview of the remaining substances which were reviewed.

Substance Q2 Q3
Yes Likely yes Not possible to No Not possible to
answer answer
due to limited in- due to limited infor-
formation mation
Carlina acaulis x x
Cucurbitacins in preparations of x x
Cucurbitaceae
Griffonia simplicifolia x x
Rhodiola rosea x x
Salvia rosmarinus x x
N-Acetyl-Cysteine* x x
Lavandula angustifolia subsp. x x
angustifolia
Mentha × piperita x x
Morus alba x x
*RIVM currently works on a risk assessment that will be published in 2024.

2.2.4 RASFF notifications

The evaluation of the approx. 1500 RASFF alerts 32 on food supplements and fortified foods with regard to
"composition", "natural toxins" and "Novel Foods" resulted in the selection of the following eight substances
that had caused an alert before and at the same time had already been identified by the HoA WG FS:
N-Acetyl-Cysteine (4 alerts), curcumin (14 alerts), huperzine A (17 alerts), melatonin (10 alerts), monacolin K
(32 alerts), piperine (18 alerts), p-synephrine (19 alerts), Tribulus terrestris (3 alerts) and Withania somnifera
(17 alerts). The presence of RASFF alerts for these substances identified by the HoA WG FS can additionally be
considered as an evidence that they are actually used in food and/or food supplements on the market.

Other substances that caused alerts may be of interest to the HoA WG FS but have not been considered further
yet, e. g. agmatine sulphate (101 alerts) and 1,3-dimethylamylamine (DMAA; 29 alerts). These could be included
in future work within the HoA WG FS, if deemed important (see 3.3).

32 RASFF alerts were taken into account from 1.1.2017 to 14.5.2022.

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RASFF alerts also occurred due to already forbidden substances like Yohimbe bark, emodin and Ephedra herb
(all in Annex III, Part A of Regulation (EC) No 1925/2006). The results of the evaluation can be found in the en-
closed Attachment ‘RASFF notifications‘.

2.3 Conclusion of the review of substances

The 13 substances that are most eligible for an ‘Article 8 procedure’, as they are considered posing a risk to
consumers and their intake through food supplements greatly exceeds normal intake from a balanced and var-
ied diet, are the following: Actaea racemosa, Coumarin in plant preparations, Curcumin in Curcuma spp.-prepa-
rations, Hypericum perforatum, Lepidium meyenii, Melaleuca spp.-essential oils, melatonin33, Ocimum tenuiflo-
rum, piperine, p-Synephrine in Citrus spp.-preparations, Tribulus terrestri, tryptophan and Withania somnifera
(Table 3).

Of these substances Curcumin in Curcuma spp.-preparations, Lepidium meyenii, Melaleuca spp.-essentials oils,
Ocimum tenuiflorum, piperine, Tribulus terrestris and Withania somnifera exhibit (possible) carcinogenic, muta-
genic or reprotoxic properties. Based on these properties the subgroup ‘risk assessment’ suggests, if necessary,
to prioritize these substances over the other substances in Table 3 when starting an ‘Article 8 procedure’.
Table 4 contains a list of substances which raise concern based on their hazard characteristics and which
(might) exceed normal intake from a balanced and varied diet. The fact that these substances are not eligible for
an ‘Article 8 procedure’ at the moment does not mean that there are no concerns. More information on hazard
and exposure is needed in order to fulfil a risk assessment and to proceed with an ‘Article 8 procedure’.

33 See footnote 37 in Annex C.

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3 Suggestion for next steps

As elaborated in the last paragraph the HoA WG FS has fulfilled the work mandate stated in the ToR (see en-
closed Attachment ’ToR of WG FS‘) compiling a list of substances that based on existing risk assessments
should be prohibited or restricted in food and/or food supplements.
Not included in the ToR, however, is neither the question in what way or through which legislation the use of
these substances in food can be prohibited or restricted, nor which substances should be prioritized for such
measures.

The recommendations of the HoA are in no way intended to duplicate or precede the work of corresponding
working groups of EU COM or to prejudge their decisions. They are solely intended to support EU COM and
EU/EEA-MS in determining appropriate EU legislative requirements.
The information compiled in this report follows the terms of reference established by HoA who oversee and
conclude on the results of the accomplished work.

3.1 Possible ways to regulate substances assumed to be ‘not novel’ or ‘not NFS’

Before further processing the CAFAB WG on Novel Foods should be enquired also for confirmation of the as-
sumed status as ‘not novel’ or ‘not NFS’ of the non-prioritized substances. This could either be done by HoA or
HoA WG FS.

The members of the HoA WG FS discussed by which means an implementation of measures on substances as-
sumed to be ‘not novel’ or ‘not NFS’ by the EU COM could be realized.
Two approaches were discussed, being:

 Approach 1: The Heads of Food Safety Agencies hand over the recommendations of this report to EU COM.
EU COM may initiate ‘Article 8 procedures’.

 Approach 2: Individual EU/EEA MS hand over the report to EU COM. EU COM may initiate ‘Article 8 proce-
dures’.

Approach 1 was supported by the majority of the HoA WG FS (15 of 19 members participating at the vote, two
members abstaining).
Approach 2 was supported by two members. Four additional members will support Approach 2, if the HoA is
unable to hand over the recommendations of the report to EU COM (Approach 1).
Furthermore, four members indicated their basic commitment to hand over the report to the EU COM, if ap-
proach 2 is followed. In this case handing over the report would be representative on behalf of all members of
the HoA WG FS.
Irrespective of the approach followed, all relevant information gathered by the HoA WG FS should be made
available to EU COM and EFSA to accelerate the process of ‘Article 8 procedures’.

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The members of the HoA WG FS agreed to elaborate alternative options, in the case that ‘Article 8 procedures’
will not be achieved for some or all of the substances, provided that HoA supports this proposal (see 3.3).

3.2 Possible ways to handle substances assumed to be ‘novel’

The substances that are assumed to be ‘novel’ could be forwarded by the HoA or by the HoA WG FS to the EU
COM (CAFAB WG on Novel Food).
This way the classification as a Novel Food could be verified by the COM WG and a corresponding entry in the
NFSC of the EU COM could be created. The publicly available NFSC, though not legally binding, provides the
needed clarity to FBOs and competent authorities. In the case FBOs can provide information on the use of a
certain substance in foods in the EU prior to 15th of May 1997 they can submit this information to EU/EEA MS
or EU COM. Validation provided the entry in the NFSC would be adopted accordingly. Further handling of
these substances by the HoA WG FS could then proceed as outlined in chapter 3.1.
Due to the large number of substances presumed to be ‘novel’, they should be submitted to the EU COM in
clusters. Therefore, some prioritization should be suggested beforehand. This prioritization could be done - alt-
hough not legally compliant (see 1.1.1., 1.1.4. and 2.2.1) - based on market availability in EU/EEA MS and Swit-
zerland (e. g. RASFF-notifications, complaints and online searches) as these are the most urgent cases with
doubt/incorrect information concerning the Novel Food status among FBOs. In case a substance is not on the
market, it could be investigated whether the substance is prohibited or restricted on a national level.

Afterwards, the verified prioritized list with assumed Novel Foods could be forwarded to EU COM (CAFAB WG
on E-Commerce) as a proposal for consideration in a future e-sweep project.

3.3 Proposals for further actions

Congruent with the ToR the HoA WG FS herewith submits a report of the proceedings.
However, the HoA WG FS has not yet completed the list of substances which shall either not or only with re-
strictions be added to FS. To proceed with the work, the HoA WG FS proposes to assign new tasks to the HoA
WG FS.

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4 References

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5 Annexes

Annex A

Table 6 provides and overview of the reviewed substances by the member of the HoA WG FS and the outcome
of the review. The table continues on the next three pages.

Table 6. An overview of the substances reviewed by the members of the HoA WG FS regarding the assumed ‘Novel Food
Status’ (specified for the plant part) including the outcome of the review.

Outcome of review, to be con-

Plant part(s) or substance
Substance firmed by CAFAB WG on Novel
details, if specified
Food
Abrus precatorius L. leaves, seeds Assumed ‘novel’
N-Acetyl-Cysteine (NAC) not applicable Assumed ‘not novel’ or ‘not NFS’
Aconitum carmichaelii Debeaux not specified Assumed ‘novel’
Aconitum kusnezoffii Rchb. not specified Assumed ‘novel’
Aconitum napellus L. all plant parts Assumed ‘novel’
Actaea racemosa L. rootstocks/rhizomes Assumed ‘not novel’ or ‘not NFS’*
all plant parts, especially fruits
Actaea spicata L. Assumed ‘novel’
and roots
Adenium spp. all plant parts Assumed ‘novel’
Adonis vernalis L. herb Assumed ‘novel
Aethusa cynapium L. all plant parts Assumed ‘novel’
Agapanthus spp. rhizomes, bulbs Assumed ‘novel’
Agrostemma githago L. all plant parts, seeds Assumed ‘novel’
Aleurites spp. all plant parts Assumed ‘novel’
rhizomes and preparations
Alisma plantago-aquatica L. Assumed ‘not novel’ or ‘not NFS’
thereof
Alkanna tinctoria Tausch roots Assumed ‘novel’
Aloe ferox Mill. leaf juice/gel On Annex III RE 1925/2006
Aloe vera (L.) Burm.f leaf juice/gel On Annex III RE 1925/2006
Amaryllis spp. all plant parts Assumed ‘novel’
Anacyclus pyrethrum (L.) Lag. roots Assumed ‘novel’
Anadenanthera spp. seeds Assumed ‘novel’
Anamirta cocculus (L.) Wight & Arn. fruits Assumed ‘novel’
Anchusa spp. herb Assumed ‘novel’
Andromeda spp. leaves, flowers Assumed ‘novel’
Anemone spp. all plant parts Assumed ‘novel’
Angostura trifoliata (Willd.) T.S. Elias all plant parts Assumed ‘not novel’ or ‘not NFS’
Annona muricata L. leaves Assumed ‘not novel’ or ‘not NFS’
Antiaris toxicaria Lesch. all plant parts Assumed ‘novel’
Aquilegia vulgaris L. all plant parts Assumed ‘not novel’ or ‘not NFS’
Areca catechu L. fruits Assumed ‘novel’
Argyreia nervosa (Burm. f.) Bojer seeds Assumed ‘novel’
Arisaema spp. rootstocks/rhizomes Assumed ‘novel’
Aristolochia spp. all plant parts Assumed ‘novel’
Arnica chamissonis Less. flowers Assumed ‘novel’
Arnica montana L. not specified Assumed ‘not novel’ or ‘not NFS’

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Outcome of review, to be con-

Plant part(s) or substance
Substance firmed by CAFAB WG on Novel
details, if specified
Food
Artemisia cina O.Berg flowers, fruits Assumed ‘not novel’ or ‘not NFS’
Artemisia maritima L. all plant parts Assumed ‘not novel’ or ‘not NFS’
Arum spp. all plant parts Assumed ‘novel’
Asarum canadense L. rootstocks/rhizomes Assumed ‘novel’
Asarum europaeum L. all plant parts Assumed ‘novel’
Aspidosperma quebracho-blanco
bark, wood Assumed ‘novel’
Schltdl.
Atropa belladonna L. all plant parts Assumed ‘novel’
Banisteriopsis caapi (Spruce ex Griseb.)
bark, wood Assumed ‘novel’
C.V.Morton
Berberine in preparations of Berberis
extracts from root, bark Assumed ‘not novel’ or ‘not NFS’
vulgaris L.
Bryonia alba L. roots Assumed ‘novel’
Calliandra angustifolia Spruce ex Benth. not specified Assumed ‘novel’
Carapichea ipecacuanha (Brot.) L.An-
roots Assumed ‘novel’
dersson
Carica papaya L. leaves Assumed ‘not novel’ or ‘not NFS’
Carlina acaulis L. roots Assumed ‘not novel’ or ‘not NFS’
Chamaeleon gummifer (L.) Cass. all plant parts Assumed ‘novel’
Chelidonium majus L. herb Assumed ‘not novel’ or ‘not NFS’
Cinnamomum verum J.Presl bark, essential oils Assumed ‘not novel’ or ‘not NFS’
Citrullus colocynthis (L.) Schrad. all plant parts Assumed ‘novel’
Colchicum autumnale L. all plant parts Assumed ‘novel’
Convallaria majalis L. herb Assumed ‘novel’
Convolvulus scammonia L. roots Assumed ‘novel’
different parts depending on
Coumarin in plant preparations Assumed ‘not novel’ or ‘not NFS’*
plant
Croton tiglium L. all plant parts Assumed ‘novel’
Cucurbitacins in preparations of Cucur-
not specified Assumed ‘not novel’ or ‘not NFS’
bitaceae
Curcumin in Curcuma spp.-preparations esp. rhizomes Assumed ‘not novel’ or ‘not NFS’*
Cytisus scoparius (L.) Link all plant parts Assumed ‘novel’
Datura stramonium L. all plant parts Assumed ‘novel’
Digitalis lanata Ehrh. all plant parts Assumed ‘novel’
Digitalis purpurea L. all plant parts Assumed ‘novel’
Dryopteris filix-mas (L.) Schott all plant parts Assumed ‘novel’
Dysphania ambrosioides (L.) Mosyakin &
seeds Assumed ‘novel’
Clemants
Garcinia cowa Roxb. ex Choisy fruits Assumed ‘not novel’ or ‘not NFS’
Genista tinctoria L. flowers Assumed ‘novel’
Gentiana lutea L. roots Assumed ‘not novel’ or ‘not NFS’
Ginkgo biloba L. leaves Assumed ‘not novel’ or ‘not NFS’
Griffonia simplicifolia (Vahl ex DC.) Baill. esp. seeds Assumed ‘not novel’ or ‘not NFS’
Huperzin A in Huperzia serrata Thunb.-
esp. aerial parts Assumed ‘not novel’ or ‘not NFS’
preparations
Hyoscyamus niger L. all plant parts Assumed ‘novel’
herb Assumed ‘not novel’ or ‘not NFS’*
Hypericum perforatum L.
flowers and leaves Assumed ‘not novel’ or ‘not NFS’*

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Outcome of review, to be con-

Plant part(s) or substance
Substance firmed by CAFAB WG on Novel
details, if specified
Food
Iodine (Macroscopic Algae) not applicable/not specified Assumed ‘not novel’ or ‘not NFS’
Ipomoea purga (Wender.) Hayne all plant parts Assumed ‘novel’
leaves, (green) fruits, seeds,
Juglans regia L. Assumed ‘not novel’ or ‘not NFS’
skins
Juniperus sabina L. all plant parts Assumed ‘novel’
Lavandula angustifolia subsp. angusti-
essential oils of flowering tops Assumed ‘not novel’ or ‘not NFS’
folia
Leipidium meyenii Walp. roots Assumed ‘not novel’ or ‘not NFS’*
Lobelia inflata L. all plant parts Assumed ‘novel’
Lycopus europaeus L. herb Assumed ‘not novel’ or ‘not NFS’
Lysimachia arvensis (L.) U.Manns & An-
herb Assumed ‘novel’
derb.
Mallotus philippensis (Lam.) Müll. Arg. fruits Assumed ‘novel’
Mandragora officinarum L. roots Assumed ‘novel’
Melaleuca spp.-essential oils essential oils, leaves Assumed ‘not novel’ or ‘not NFS’*
Melatonin not applicable Assumed ‘not novel’ or ‘not NFS’*
Mentha × piperita L. leaves (essential oil) Assumed ‘not novel’ or ‘not NFS’
Monacoline K (Monascus purpureus) not applicable On Annex III RE 1925/2006
Morus alba L. leaves Assumed ‘not novel’ or ‘not NFS’
Mutarda nigra (L.) Bernh. seeds Assumed ‘not novel’ or ‘not NFS’
Nerium oleander L. leaves Assumed ‘novel’
Ocimum basilicum L. herb, seeds Assumed ‘not novel’ or ‘not NFS’
herb Assumed ‘not novel’ or ‘not NFS’*
Ocimum tenuiflorum L.
seeds Assumed ‘novel’
Pilocarpus jaborandi Holmes leaves Assumed ‘novel’
Piper methysticum G.Forst. rootstocks Assumed ‘not novel’ or ‘not NFS’
Piperine not applicable Assumed ‘not novel’ or ‘not NFS’*
Podophyllum peltatum L. roots, resin Assumed ‘not novel’ or ‘not NFS’
Pulsatilla pratensis (L.) Mill. all plant parts Assumed ‘novel’
Pulsatilla vulgaris Mill. all plant parts Assumed ‘novel’
Rauvolfia serpentina (L.) Benth. ex Kurz roots Assumed ‘novel’
Rhodiola rosea L. herb Assumed ‘not novel’ or ‘not NFS’
Rhododendron tomentosum (Stokes)
herb Assumed ‘not novel’ or ‘not NFS’
Harmaja
Ricinus communis L. seeds Assumed ‘novel’
Rubia tinctorum L. roots Assumed ‘novel’
not specified, possibly aerial
Salvia rosmarinus Spenn. Assumed ‘not novel’ or ‘not NFS’
parts
Scopolia carniolica Jacq. all plant parts Assumed ‘novel’
Solanum dulcamara L. esp. stems Assumed ‘not novel’ or ‘not NFS’
Strophanthus kombe Oliv. not specified Assumed ‘novel’
Strychnos nux-vomica L. seeds Assumed ‘novel’
p-Synephrine in Citrus spp.-
esp. pulp and peel Assumed ‘not novel’ or ‘not NFS’*
preparations
Tanacetum vulgare L. flowers, herb Assumed ‘not novel’ or ‘not NFS’
Teucrium chamaedrys L. all plant parts Assumed ‘not novel’ or ‘not NFS’
Tribulus terrestris L. fruits Assumed ‘not novel’ or ‘not NFS’*
Tryptophan not applicable Assumed ‘not novel’ or ‘not NFS’*

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Outcome of review, to be con-

Plant part(s) or substance
Substance firmed by CAFAB WG on Novel
details, if specified
Food
Urginea maritima (L.) Baker bulbs Assumed ‘novel’
Vinca minor L. herb Assumed ‘not novel’ or ‘not NFS’
whole plant Assumed ‘not novel’ or ‘not NFS’
Withania somnifera (L.) Dunal
roots Assumed ‘not novel’ or ‘not NFS’*
* CAFAB WG NF has already been contacted to confirm the Novel Food Status (bold = confirmed status).

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Annex B

Table 7 provides an overview of available EFSA opinions and monographs/assessment reports by the European
Medicines Agency (EMA) on the substances reviewed by the subgroup ‘risk assessment’. Only EFSA opinions on
food were included. No opinions for health claims or feed (additives) were considered for the table below. Fur-
thermore, only EMA monographs/assessments on human use were included. Monographs/assessment regard-
ing veterinary use were not considered for the table below.

Table 7. An overview of available EFSA opinions and monographs/assessment reports by EMA.

Substance EFSA EMA

N-Acetyl-Cysteine Opinion of the Scientific Panel on -
Food Additives, Flavourings, Pro-
cessing Aids and Materials in Con-
tact with Food (AFC) on a request
from the Commission related to
N-Acetyl-L-cysteine for use in
foods for particular nutritional
uses and in foods for special med-
ical purposes | EFSA (europa.eu)
Actaea racemosa L. - Cimicifugae rhizoma - herbal me-
dicinal product | European Medi-
cines Agency (europa.eu)
Coumarin in plant preparations Coumarin in flavourings and other -
food ingredients with flavouring
properties - Scientific Opinion of
the Panel on Food Additives, Fla-
vourings, Processing Aids and Ma-
terials in Contact with Food (AFC)
| EFSA (europa.eu)
Curcumin in Curcuma spp.-prepa- Scientific Opinion on the re-eval- Curcumae longae rhizoma | Euro-
rations uation of curcumin (E 100) as a pean Medicines Agency (europa.eu)
food additive | EFSA (europa.eu)
Gentiana lutea L. - Gentianae radix | European Medi-
cines Agency (europa.eu)
Ginkgo biloba L. - Ginkgo folium | European Medicines
Agency (europa.eu)
Hypericum perforatum L. - Hyperici herba | European Medi-
cines Agency (europa.eu)
Juglans regia L. - Juglandis folium | European Medi-
cines Agency (europa.eu)
Lavandula angustifolia subsp. an- - Lavandulae aetheroleum | European
gustifolia Medicines Agency (europa.eu)

Lavandulae flos | European Medi-

cines Agency (europa.eu)
Melaleuca spp.-essential oils - Melaleucae aetheroleum | European
Medicines Agency (europa.eu)

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Substance EFSA EMA

Melatonin - Circadin | European Medicines
Agency (europa.eu)
Mentha × piperita L. - Menthae piperitae aetheroleum |
European Medicines Agency (eu-
ropa.eu)
Ocimum basilicum L. - Public Statement on the use of
HMP cont. estragole | HMPC (eu-
ropa.eu)

Public Statement on the use of

HMP cont. methyleugenol | HMPC
(europa.eu)
Ocimum tenuiflorum L. Scientific Opinion on a Qualified Public Statement on the use of
Presumption of Safety (QPS) ap- HMP cont. estragole | HMPC (eu-
proach for the safety assessment ropa.eu)
of botanicals and botanical prepa-
rations | EFSA (europa.eu) Public Statement on the use of
HMP cont. methyleugenol | HMPC
(europa.eu)
Piper methysticum G.Forst. - Piperis methystici rhizoma | Euro-
pean Medicines Agency (europa.eu)
Piperine Scientific Opinion on Flavouring -
Group Evaluation 86, Revision 2
(FGE.86Rev2): Consideration of al-
iphatic and arylalkyl amines and
amides evaluated by JECFA (65th
meeting) | EFSA (wiley.com)
Rhodiola rosea L. - Rhodiolae roseae rhizoma et radix |
European Medicines Agency (eu-
ropa.eu)
Salvia rosmarinus Spenn. Refined exposure assessment of Rosmarini aetheroleum | European
extracts of rosemary (E 392) from Medicines Agency (europa.eu)
its use as food additive | EFSA (eu-
ropa.eu)
Solanum dulcamara L. - Solani dulcamarae stipites | Euro-
pean Medicines Agency (europa.eu)
p-Synephrine in Citrus spp.-prep- Safety of caffeine | EFSA (eu- -
arations ropa.eu)
Tribulus terrestris L. - Tribuli terrestris herba | European
Medicines Agency (europa.eu)
Withania somnifera (L.) Dunal - Withaniae somniferae radix | Euro-
pean Medicines Agency (europa.eu)

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Annex C

This Annex includes short summaries with more detailed information on the 13 substances of Table 3 in Chap-
ter 2.2.3. Those are the substances considered to pose a (possible) risk to consumers and for which the intake
via food supplements exceeds normal intake and are therefore prioritized. The summaries have been prepared
following previous mandates from the EU COM to EFSA to initiate ‘Article 8 procedures’. They could therefore
serve as a template for new mandates from the EU COM to EFSA.

Actaea racemosa
Based on national risk assessment from the Netherlands, the HoA WG FS raised concerns regarding a potential
risk to consumers linked to the consumption of foods containing preparations or extracts of Actaea racemosa L.
(hereinafter referred to as Actaea racemosa) synonym Cimicifuga racemosa (L) Nutt.34, rhizoma due to hepato-
toxicity. Most important substances are triterpene glycosides, phenols and flavonoids. However, no toxicologi-
cal data are available to link specific substances or groups of substances to the effects reported. In general, the
intake of 40 mg Actaea racemosa, rhizoma per day (0.57 mg/kg body weight per day) for 6 months does not
pose a risk for the consumer. This dose, however, may be largely exceeded with consumption of food supple-
ments containing Actaea racemosa, as supplements on the market contain up to 2500 mg Actaea racemosa.
However, possible idiosyncratic hepatotoxicity might occur in individuals at unknown intake. From this view
point there is no safe dose. According to the European Medicines Agency Actaea racemosa rhizoma should not
be taken for more than 6 months without medical advice. This concern leads to the following questions:
1. Is there a link between consumption of Actaea racemosa, rhizoma and/or preparations or extracts
thereof and adverse effects on health including hepatoxicity?
2. What is the maximum level of total dietary exposure of Actaea racemosa, rhizoma unlikely to pose a
risk of adverse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by Actaea racemosa?

Substance Preparations or extracts of rhizome/rootstocks of Actaea racemosa L. Most important

constituents are triterpene glycosides, phenols and flavonoids.

Synonyms: Cimicifuga racemosa (L) Nutt, Botrophis serpentaria Raf., Cimicifuga serpentaria
Pursh, Macrotrys racemosa (L.) Sweet, Megotrys serpentaria Raf., Thalictrodes racemosa (L.)
Kuntze
Common name: black cohosh
Medicinal use Yes (HMPC, 2018a)
Most critical Animal studies showed effects on bone marrow, thymus and liver. Worldwide severe cases
endpoint of hepatotoxicity are reported. However they cannot be causally linked with the intake of
Actaea racemosa L., rhizome (BuRO, 2020).
Toxicological Lowest observed adverse effect level of 62.5 mg Actaea racemosa L. /kg body weight was
reference found in a 90-day study with mice (increased haematological parameters) (BuRO, 2020).
point

34 The risk assessments always refer to the synonym Cimicifuga racemose.

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Health Based In general, the intake of 40 mg Actaea racemosa L., rhizome per day (0.57 mg/kg body
Guidance weight per day) for 6 months does not pose a risk for the consumer. The margin of expo-
Value sure is 110.
However, possible individual idiosyncratic hepatotoxicity might occur at unknown intake.
From this view point there is no safe dose (BuRO, 2020).
Exposure Most extracts of Actaea racemosa L., rhizoma used in clinical trials are standardized and
contain 40 mg Actaea racemosa L. rhizoma. However, on the internet supplements with 20
to 2500 mg Actaea racemosa L. rhizoma extract are available. These are probably not
standardized (BuRO, 2020).
Remarks According to the European Medicines Agency Actaea racemosa L. rhizoma should not be
taken for more than 6 months without medical advice (HMPC, 2018a).
Possible sensitive subgroups are (BuRO, 2020):
- Patients with a history of liver injuries or disease.
- Patients who receive or have received treatment for breast cancer or other hor-
mone dependent tumours.
- People who are hypersensitive to substances in Actaea racemosa L. rhizoma.

Coumarin in plant preparations

Based on national risk assessments from Germany and France, the HoA WG FS raised concerns regarding a po-
tential risk to consumers linked to the consumption of foods containing coumarin due to hepatotoxicity. Some
food supplements available on the market of the EU, especially those containing Neolitsea cassia (L.) Kosterm
(synonym: Cinnamomum cassia (L.) J.Presl), lead to exposure exceeding the tolerable daily intake (TDI) derived
by EFSA of 6 mg / day for a 60 kg adult (hepatotoxic effects) (EFSA AFC panel, 2008). This concern leads to the
following questions:
1. Is there a link between consumption of coumarin or plant preparations containing coumarin and ad-
verse effects on health?
2. What is the maximum level of total dietary exposure of coumarin or plant preparations containing
coumarin unlikely to pose a risk of adverse health effects to humans (i.e. is the TDI still appropriate)?
3. What is the maximum level of exposure of coumarin or plant preparations containing coumarin via
food supplements unlikely to pose a risk of adverse health effects to humans?
4. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by coumarin or plant preparations containing coumarin?

Substance Coumarin is a natural aromatic compound found in certain plants such as Neolitsea cassia
(L.) Kosterm (synonym: Cinnamomum cassia (L.) J.Presl, common name: Cinnamon; but
also other Cinnamomum spp.), Galium odoratum (L.) Scop. (common name: sweet wood-
ruff), Dipteryx odorata (Aubl.) Forsyth f. (common name: tonka bean) and Melilotus offici-
nalis (L.) Lam. (common name: sweet clover). This list is not exhaustive.
Neolitsea cassia (L.) Kosterm or preparations and extracts thereof are often used in FS and
are particularly rich in coumarin.

Also synthetically produced coumarin may be relevant.

Medicinal use Two herbal medicinal products containing sweet clover have a marketing authorization in
France: One for venotonic purposes (Esberiven Fort®) and the other as a sedative (Sedo-
pal®) (ANSES, 2021).
Most critical Hepatotoxic effects in animal studies. The liver toxicity of coumarin at high doses
endpoint (> 25 mg/day in humans) was confirmed by the available toxicological data (BfR, 2012b;
ANSES, 2021).

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Toxicological NOAEL: coumarin dose of 10 mg/kg body weight per day (in a 2 years study with Beagle
reference dogs: necropsies were observed at a coumarin dose of 25 mg/kg body weight per day but
point no effect at the dose of 10 mg/kg bw per day) (BfR, 2012b; ANSES, 2021).
Health Based TDI is 0.1 mg/kg body weight by oral intake i.e. 6 mg/day for a 60 kg adult (hepatotoxic ef-
Guidance fects) (BfR, 2012b; ANSES, 2021).
Value
Exposure For the populations most exposed via food, exposure to coumarin through food consump-
tion can be as much as 20 % of the TDI of 0.1 mg/kg body weight per day. On the market,
dietary supplementation can range from 3 to 24 mg of coumarin per day. With these doses,
the TDI of 0.1 mg/kg body weight per day (i.e. 6 mg/day for a 60 kg adult) may therefore
be largely exceeded and a risk to human health cannot be ruled out (ANSES, 2021).
Remarks According to ANSES, a limit of max 4.8 mg/day of coumarin intake by food supplements is
needed in order to comply with TDI (this dose can be reached through daily consumption
of food supplements containing around 1.6 g of cinnamon).
A risk assessment encompassing all exposure routes, including also respiratory and dermal
exposure, is not available yet (ANSES, 2021).
Possible sensitive subgroups are:
- Individuals with a history of liver disease.
- Individuals taking medicines known to cause adverse liver effects.

Curcumin in Curcuma spp.-preparations35

Based on national risk assessments from Germany, France and Spain, the HoA WG FS raised concerns regarding
a potential risk to consumers linked to the consumption of foods containing curcumin in Curcuma spp.-prepa-
rations or curcuminoids (often referred to as curcumin or curcumins) due to hepatotoxicity in humans and ani-
mals (at very high doses), although the mechanism is unknown. An acceptable daily intake (ADI) of 3 mg curcu-
min/kg body weight per day i.e. a maximum intake of 180 mg per day of curcumin for a 60 kg adult was derived
by EFSA (based on reprotoxic effects). Some food supplements available on the market of the EU lead to expo-
sures exceeding the ADI. Further, the established ADI is not appropriate for curcumin preparations with in-
creased bioavailability. Also, curcumin is reported to interact with anticoagulant and anticancer drugs. This con-
cern leads to the following questions:
1. Is there a link between consumption of curcumin or plant preparations or extracts containing curcu-
min without increased bioavailability and adverse effects on health?
2. Is there a link between consumption of curcumin or plant preparations or extracts containing curcu-
min with increased bioavailability and adverse effects on health?
3. What is the maximum level of total dietary exposure of curcumin or plant preparations or extracts
containing curcumin, with and without increased bioavailability, unlikely to pose a risk of adverse
health effects to humans?
4. What is the maximum level of total dietary exposure of curcumin or plant preparations or extracts
containing curcumin in food supplements unlikely to pose a risk of adverse health effects to humans?
5. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by curcumin or plant preparations or extracts containing curcumin?

35 The abbreviation “spp.” refers to more than one not further defined species of the same genus.

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Substance Curcumin belongs to the curcuminoids, a class of plant secondary metabolites which also
includes demethoxycurcumin, and bisdemethoxycurcumin. Curcuminoids are found in the
rhizomes of various Curcuma species (e.g. Curcuma longa L., Curcuma zanthorrhiza Roxb.,
Curcuma zedoaria (Christm.) Roscoe). This list is not exhaustive. Curcumin is the principal
curcuminoid (75-80 %) of Curcuma longa L. (turmeric). Commercial curcumin (spice) con-
tains curcumin and the structurally analogous compounds. The available risk assessments
often refer to curcuminoids as ‘curcumin’.

Also synthetically produced curcumin may be relevant.

Medicinal use Medicinal uses for two species containing curcumin: Curcuma longa L. (synonym: Curcuma
domestica Valeton) and for Curcuma zanthorrhiza Roxb. for their digestive properties
(HMPC, 2014;2018b).
Most critical Reprotoxicity: Wistar rodents study
endpoint Hepatotoxicity: Case reports of hepatotoxicity have been reported in humans (and in ani-
mal studies, although doses used in animal studies were very high) but mechanism is un-
known. In some of these cases analysis points to the use of curcumin in combination with
other medicines, the use of multi-ingredient food-supplement or pre-existence of liver
function problems.
With regard to clinical trials conducted with curcumin: no hepatotoxicity reported (how-
ever, in many clinical trials, liver function was not assessed or reported) (ANSES, 2022a).
Drug interaction highly suspected: interactions of curcumin have been reported with anti-
coagulant and anticancer drugs (ANSES, 2022a).
Toxicological NOAEL: 250-320 mg/kg in a reprotoxicity study with Wistar rodents (AESAN, 2020; BVL &
reference BfArM, 2020; BfR, 2021; ANSES, 2022a).
point
Health Based ADI: 3 mg curcumin/kg body weight per day i.e. a maximum intake of 180 mg per day of
Guidance curcuminoids for a 60 kg adult (should only be used in view of curcumin preparations with
Value no increased bioavailability) (AESAN, 2020; BVL & BfArM, 2020; BfR, 2021; ANSES, 2022a).
Exposure The study of exposure to curcumin in the French population shows that this exposure
through food is low. The estimated daily exposure to curcumin in the French population
could be as high as 0.45 mg/kg body weight per day in adults and 0.77 mg/kg body weight
per day in children (at the 95th percentile). EFSA exposure estimation: 0.2-0.6 mg/kg body
weight per day. Food supplements on the French market generally provide 1 to 3 g of dry
rhizome per day or 0.g to 1 g of curcumin per day. In Spain, "only 36 of the 106 supple-
ments (34 %) provide information on its content, with 950 mg and 1.57 mg being the maxi-
mum and minimum daily amounts established, respectively". Increased exposure with for-
mulations with improved bioavailability (ANSES, 2022a).
Remarks According to ANSES, the ADI can be greatly exceeded when consuming a food supple-
ment, especially if the bioavailability is modified. Due to the increased absorption of curcu-
min in the gastrointestinal tract and/or a reduced metabolization, a higher systemic bioa-
vailability and thus in principle an increase in toxicity must be considered for these prepara-
tions.
More research is needed, especially with regard to hepatotoxicity.
The existing ADI for such products is not very conservative and may not ensure a sufficient
level of protection for consumers. Novel Food status has to be considered for products
with improved bioavailability.
Warnings on the products have been mentioned in certain EU MS with regard to not use
curcumin in case of liver or bile function problems, as well as to not use supplements in
case of pregnancy, lactation or < 18 yr (FOD, 2019; AESAN, 2020; ANSES, 2022a).

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Hypericum perforatum
Based on national risk assessments from Denmark and the Netherlands, the HoA WG FS raised concerns re-
garding a potential risk to consumers linked to the consumption of food supplements and herbal teas contain-
ing (preparations or extracts of) the herb of Hypericum perforatum L. (hereinafter referred to as Hypericum per-
foratum) due to phototoxicity and pharmacological effects that may occur. In addition, there are indications for
genotoxicity, reprotoxicity and developmental toxicity with Hypericum perforatum and its constituents, how-
ever, the data are not sufficient to adequately conclude on those endpoints. From this view point, it is currently
not possible to derive a safe dose level or health-based guidance value.

Based on the reported hypericin content of some food supplements containing Hypericum perforatum available
on the market of the European Union, the estimated exposure to hypericin by consumers ranges from 1.4 to
41 µg/kg body weight per day for a 70 kg person. This estimated exposure exceeds the dose of 31 µg hyperi-
cin/kg body weight per day at which enhanced phototoxicity was observed in humans. This indicates that pho-
totoxicity can occur when using food supplements with Hypericum perforatum. This concern leads to the fol-
lowing questions:
1. Is there a link between consumption of supplements (and herbal tea) containing Hypericum perfora-
tum and adverse effects on health?
2. Has Hypericum perforatum genotoxic properties?
3. Is Hypericum perforatum able to induce reprotoxic effects and/or developmental toxicity?
4. What is the maximum level for acute (single dose) and chronic dietary exposure of supplements (and
herbal tea) containing Hypericum perforatum unlikely to pose a risk of adverse health effects to hu-
mans?
5. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by Hypericum perforatum?

Substance Supplements containing (preparations or extracts of) the herb of Hypericum perforatum L.

Hypericin, pseudohypericin and hyperforin are generally thought to be the most relevant
constituents for the pharmacological effects of Hypericum perforatum L.

Hyperforin is the constituent related to drug interactions (de Wit et al., 2019).

Synonyms: Hypericum officinale Gaterau, Hypericum officinarum Crantz, Hypericum

perforatum var. vulgare Spenn., Hypericum perforatum subsp. vulgare (Spenn.) A.Fröhl.,
Hypericum vulgare Lam.
Common name: St. John’s wort
Medicinal use Yes, see Hyperici herba | European Medicines Agency (europa.eu)
Most critical Concerns are raised for the following endpoints (de Wit et al., 2019; DTU, 2019a):
endpoint - Serious drug interactions mainly due to hyperforin.
- Phototoxicity induced by hypericin.
- Indications for genotoxicity, reprotoxicity and developmental toxicity.
- Pharmacological effects may occur when exposure via supplements is in the same
range as via herbal medicines.
Toxicological It is not possible to derive a toxicological reference point as for the most serious effects the
reference data are not sufficient.
point

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For phototoxicity, a LOAEL of 31 µg hypericin/kg body weight per day in humans was iden-
tified.
Health Based Not possible to derive health based guidance value for Hypericum perforatum L. or the
Guidance main constituents, due to gaps in the toxicological data available (de Wit et al., 2019).
Value
EMA has established that for daily doses containing less than 1 mg hyperforin clinically rel-
evant interactions are not reported (Hyperici herba | European Medicines Agency (eu-
ropa.eu)).
Exposure Based on the reported hypericin content of some food supplements containing Hypericum
perforatum L. that are available in the Netherlands, the estimated exposure to hypericin by
consumers ranges from 1.4 to 41 µg/kg body weight per day for a 70 kg person.
The estimated exposure exceeds the dose of 31 µg hypericin/kg body weight at which en-
hanced phototoxicity was observed in humans. This indicates that phototoxicity can occur
when using food supplements with Hypericum perforatum L.
Remarks Adverse effects have been reported including dizziness, diarrhoea, skin reactions and psy-
chiatric symptoms.

Concerns about contamination with pyrrolizidine alkaloids (which are genotoxic carcino-
gens) (de Wit et al., 2019).

Lepidium meyenii
Based on a national risk assessment from Denmark, the HoA WG FS raised concerns regarding a potential risk
to consumers linked to the consumption of foods containing Lepidium meyenii Walp. (hereinafter referred to as
Lepidium meyenii), root or germ stem (hypocotylene) or its preparations due to effects on sex hormones, repro-
duction in rodents and hormonal effects on menopausal women. Most important substances are glucosin-
olates, macamides and imidazolalkaloids. However, no toxicological data are available to link specific constitu-
ents of Lepidium meyenii to the effects on the reproductive and endocrine systems, reported in experimental
animals. A health based guidance value was not derived but DTU concludes based on human studies that doses
of 2 g/day may have hormonal effect on menopausal women. This concern leads to the following questions:
1. Is there a link between consumption of Lepidium meyenii, root or germ stem (hypocotylene) or its
preparations and adverse effects on health?
2. What is the maximum level of total dietary exposure of Lepidium meyenii, root or germ stem (hypocot-
ylene) or its preparations unlikely to pose a risk of adverse health effects to humans?
3. What are, besides menopausal women, other possible subgroups of the general population that are
more vulnerable or more sensitive to the adverse effects caused by Lepidium meyenii?

Substance Roots or germ stems (hypocotylene) or preparations thereof of Lepidium meyenii Walp.
Most important substances are glucosinolates, macamides and imidazolalkaloids (DTU,
2020a).

Macamides (N-alkyl-amides) are considered as a group of substances that have bioactive

properties and may be responsible for the effects attributed to L. meyenii (DTU, 2020a).

Different phenotypes of Lepidium meyenii Walp. are typically referred to as yellow, red, vio-
let and black maca. Maca preparations can have different compositions of plant constitu-
ents depending the plant variety, origin of the plant material as well as depending on the
drying and extract-manufacturing process (DTU, 2020a).

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Synonyms: Lepidium affine Wedd., Lepidium gelidum Wedd., Lepidium meyenii var. affine
Thell., Lepidium meyenii subsp. gelidum (Wedd.) Thell., Lepidium meyenii var. gelidum
(Wedd.) Hosseus, Lepidium meyenii f. rhombicum Thell., Lepidium meyenii f. rotundatum
Thell., Lepidium peruvianum G.Chacón, Lepidium weddellii O.E.Schulz
Common name: Maca
Medicinal use No
Most critical Effects on sex hormones (mice, rats), male reproduction in animals (genitals, spermatogen-
endpoint esis, sperm count), female reproduction (sex hormones in rats/mice without ovaries),
weight loss in male rats. Based on the animal studies described, it is not possible to estab-
lish a dose at which these effects are not seen (DTU, 2020a).

Human studies: increase in estradiol in menopause women, some studies show effects and
some do not on FSH, LH, PG - Effects in human individuals with metabolic syndrome in a
randomised placebo controlled trial with dose 0.6 g dry root/day for 90 days (increased di-
astolic blood pressure in men and women and increased diastolic and systolic blood pres-
sure in women) (DTU, 2020a).
Toxicological No NOAEL or LOAEL was established (DTU, 2020a).
reference
point
Health Based A HBGV was not derived and DTU considers that it is not possible to determine a dose
Guidance from the described animal experiments where adverse effects can be ruled out. However,
Value based on human studies, it cannot be excluded that 2 g of Leipidum meyenii Walp. per day
as a food supplement may affect hormone levels in peri- and postmenopausal women
(DTU, 2020a).
Exposure The roots of the maca plant have long been consumed (history of use) as food in certain re-
gions of South America, however no quantitative data is available (BfR, 2024 in prepara-
tion).

Extracts from Lepidium meyenii Walp. roots as well as dried roots are marketed as food
supplements. The daily doses of the extracts vary from 150 to 4000 mg (BfR, 2024 in prepa-
ration).

A quick search on the internet revealed that supplements with Leipidum meyenii Walp. are
available in Sweden. The recommended daily dose are for example 400 mg, 1 teaspoon to 1
tablespoon, or sold as powder with no given dose other than e. g. “mix powder with water
or add it to a smoothie, salad or yoghurt”
Remarks No toxicological data are available to link specific constituents of Lepidium meyenii Walp.
to the effects on the reproductive and endocrine systems, reported in experimental ani-
mals.

There are several human studies in which the aim has been to investigate Leipidum meyenii
Walp.’s effects on sex hormones. DTU considers that it cannot be excluded that 2 g Leipi-
dum meyenii Walp. per day may affect hormone levels in peri- and postmenopausal women
(DTU, 2020a).

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Melaleuca spp.-essential oils36

Based on a national risk assessment from France, the HoA WG FS raised concerns regarding a risk to consumers
linked to the consumption of the essentials oils of the leaves and other parts of Melaleuca alternifolia (Maiden
& Betche) Cheel, Melaleuca quinquenervia (Cav.) S.T. Blake and Melaleuca cajuputi Maton & Sm. ex R.Powell
(hereinafter referred to as Melaleuca alternifolia, Melaleuca quinquenervia, Melaleuca cajuputi) as food supple-
ments due to the presence of 1,8-cineol, methyleugenol and terpinene-4-ol. These substances might also be
present in other plant-based foods or food supplements. 1,8 cineol has possible neurotoxic properties, the gen-
otoxicity and carcinogenicity of methyleugenol have been demonstrated and terpinene-4-ol has effects on the
reproductive system. This concern leads to the following questions:
1,8-Cineol
1. Is there a link between consumption of 1,8-cineol and adverse effects on health?
2. What is the maximum level of total dietary exposure of 1,8-cineol unlikely to pose a risk of adverse
effects to humans?
3. What is the maximum level of total dietary exposure of 1,8-cineol in food supplements unlikely to
pose a risk of adverse effects to humans?
4. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by 1,8-cineol?
Methyleugenol
1. Is there a link between consumption of methyleugenol and adverse effects on health?
2. What is the maximum level of total dietary exposure of methyleugenol unlikely to pose a risk of ad-
verse effects to humans?
3. What is the maximum level of total dietary exposure of methyleugenol in food supplements unlikely to
pose a risk of adverse effects to humans?
4. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by methyleugenol?
Terpinen-4-ol
1. Is there a link between consumption of terpinen-4-ol and adverse effects on health?
2. What is the maximum level of total dietary exposure of terpinen-4-ol unlikely to pose a risk of adverse
effects to humans?
3. What is the maximum level of total dietary exposure of terpinen-4-ol in food supplements unlikely to
pose a risk of adverse effects to humans?
4. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by terpinene-4-ol?
Melaleuca spp.-essential oils
1. Is there a link between consumption of essentials oils of Melaleuca alternifolia, Melaleuca quinquener-
via and Melaleuca cajuputi as a food supplement and adverse effects on health?

36 The abbreviation “spp.” refers to more than one not further defined species of the same genus.

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2. What is the maximum level of total dietary exposure of essentials oils of Melaleuca alternifolia, Mela-
leuca quinquenervia and Melaleuca cajuputi as a food supplement unlikely to pose a risk of adverse ef-
fects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by essentials oils of Melaleuca alternifolia, Melaleuca quinquenervia and
Melaleuca cajuputi?

Substance 1,8-cineol, methyleugenol and terpinen-4-ol present in essential oils of the leaves and
other parts of Melaleuca alternifolia (Maiden & Betche) Cheel, Melaleuca quinquenervia
(Cav.) S.T.Blake and Melaleuca cajuputi Powell (ANSES, 2020).

Melaleuca alternifolia (Maiden & Betche) Cheel

Synonyms: Melaleuca linariifolia var. alternifolia Maiden & Betche
Common name: Tea tree

Melaleuca quinquenervia (Cav.) S.T.Blake

Synonyms: Metrosideros quinquenervia Cav., Melaleuca leucadendra var. albida Cheel, Me-
laleuca leucadendra var. angustifolia L.f., Melaleuca leucadendra var. coriacea (Poir.) Cheel,
Melaleuca maidenii R.T.Baker, Melaleuca smithii R.T.Baker, Melaleuca viridiflora var.
angustifolia (L.f.) Byrnes, Melaleuca viridiflora var. rubriflora Pancher ex Brongn. & Gris,
Metrosideros albida Sieber ex DC., Metrosideros coriacea Poir.
Common name: Broad-leaved Paperbark

Melaleuca cajuputi Maton & Sm. ex R.Powell

Synonyms: Melaleuca saligna (J.F.Gmel.) Reinw. ex Blume, Melaleuca trinervis Buch.-Ham.,
Myrtus saligna J.F.Gmel., Pimentus saligna (J.F.Gmel.) Raf.
Medicinal use No
Most critical 1,8-cineol: possible neurotoxicity
endpoint
Methyleugenol: genotoxicity and carcinogenicity

Terpinen-4-ol: reprotoxicity (ANSES, 2020)

Toxicological 1,8-cineol: no toxicological reference point available due to the absence of precise toxico-
reference logical studies.
point
Methyleugenol: no toxicological reference point available due to genotoxicity and carcino-
genicity.

Terpinen-4-ol: a NOAEL of 250 mg/kg body weight (testicular and epididymal toxicity)
(ANSES, 2020).
Health Based 1,8-cineol: as no toxicological reference point is available also no health based guidance
Guidance value can be derived.
Value
Methyleugenol: no health based guidance value available due to genotoxicity and carcino-
genicity. MOE-approach applies.

Terpinen-4-ol: applying a safety factor of 100 to the NOAEL and an additional factor of 2
due to the short duration of the studies carried out, a corresponding maximum non-health
ingestion of 1.2 mg/kg body weight per day was set for terpinen-4-ol by EFSA in 2012
(ANSES, 2020).
Exposure There is no information regarding intake from a balanced diet: historical use has been de-
scribed as external, not oral. Melaleuca essential oils are not usually used in food. Moreo-
ver, their oral intake as a food supplement is recent (ANSES, 2020).

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Melatonin37
Based on national risk assessments from France and Norway, the HoA WG FS raised concerns regarding a po-
tential risk to consumers linked to the consumption of food supplements containing melatonin/adult per day
due to general (headaches, dizziness, drowsiness), cardiovascular, neurological, digestive and psychological
symptoms in humans. Melatonin is an endogenous hormone in humans and also used as medicinal drug (EMA
authorization for product containing 2 mg, see also Annex B). This concern leads to the following questions:
1. Is there a link between consumption of melatonin as a food supplement and adverse effects on
health?
2. What is the maximum level of total and acute exposure of melatonin as a food supplement unlikely to
pose a risk of adverse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by melatonin?

Substance Melatonin

Chemical name: N-acetyl-5-methoxytryptamine

Also synthetically produced melatonin may be relevant.

Medicinal use Yes
Circadin and Melatonin Neurim: 2 mg prolonged release tablets (see also Annex B)
Slenyto: 1-5 mg, mostly 2 mg/day, tablet
Most critical Human: general (headaches, dizziness, drowsiness), cardiovascular, neurological, digestive
endpoint and psychological symptoms (ANSES, 2018; VKM, 2021).

Mainly based on ANSES nutrivigilance system; not only “healthy persons taking melatonin
as a single ingredient in food supplements at proposed dose levels” (i.e. it included also
cases with other food supplement ingredients, concomitant medication, medical history,
overdoses in suicide attempts).
Toxicological Not possible to derive a toxicological reference point for children and adolescents. VKM
reference identified a NOAEL of 0.005 mg/kg bw/day (90-day toxicity study in rats) and a NOEAL of
point 0.4 mg/kg bw/day (6-month repeated dose study in dogs) (VKM, 2021).
Health Based No HBGV stated (ANSES, 2018). Recommendation not to exceed 2 mg melatonin per per-
Guidance son per day (ANSES, 2018). VKM cannot conclude on the safety of 1 mg/day of melatonin
Value for 3 months (VKM, 2021).
Exposure Melatonin in food supplements is marketed in several EU MS. Melatonin is also an endoge-
nous hormone. Melatonin is also known to be present in low amounts in food, but no die-
tary exposure data is currently available (BfR, 2024, in preparation).
Remarks Favourable EFSA opinion for two health claims relating to melatonin in foodstuffs, requir-
ing at least 0.5 mg or 1 mg of melatonin/portion, respectively (Commission Regulation (EU)
No 432/2012).

EMA advises against melatonin-intake by pregnant and breastfeeding women due to ef-
fects of melatonin on embryo-foetal development in rabbits and postnatal development in
rats. Melatonin passes into breast milk.

ANSES 2018 is mainly based on sufficiently documented nutrivigilance cases with likely
causality, however most cases are with medical history, other food supplement ingredients,
concomitant medication or overdoses (suicide attempts). ANSES considered the data from
French pharmacovigilance and toxicovigilance systems as well as cases from other EU MS,
Canada and the US FDA, to be too heterogeneous data (ANSES, 2018).

37 In many MS there is an urgent need to e. g. determine the maximum daily dose of melatonin, or to restrict products aimed at children.

However, as melatonin is considered medicinal in several MS, depending on e. g. the daily dose, the topic is highly complex. Thus, the HoA
WG FS suggests to put further processing and submission of melatonin to the EU COM on hold for now.

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Ocimum tenuiflorum
Based on a national risk assessment form Denmark, the HoA WG FS raised concerns regarding a potential risk
to consumers linked to the consumption of foods containing preparations or extracts of Ocimum tenuiflorum L.
(hereinafter referred to as Ocimum tenuiflorum), leaves extracts and other plant parts or preparations thereof
due to effects on genitals in rabbits (possible reprotoxicity). This concern leads to the following questions:
1. Is there a link between consumption of Ocimum tenuiflorum, leaves extracts and other plant parts or
preparations thereof and adverse effects on health?
2. What is the maximum level of total dietary exposure of Ocimum tenuiflorum, leaves extracts and other
plant parts or preparations thereof parts unlikely to pose a risk of adverse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by Ocimum tenuiflorum?

Substance Leaves and other plant parts (herb, flowers or seeds) and preparations or extracts thereof of
Ocimum tenuiflorum L.

Information on substances are not available in DTU 2019b. However, estragole and meth-
yleugenol are present in leaves and methyleugenol in live plants according to the EFSA
compendium of botanicals and ESCO 2009 (ESCO, 2009).

Synonyms: Geniosporum tenuiflorum (L.) Merr., Lumnitzera tenuiflora (L.) Spreng.,

Moschosma tenuiflorum (L.) Heynh., Ocimum flexuosum Blanco, Ocimum hirsutum Benth,
Ocimum inodorum Burm.f., Ocimum monachorum L., Ocimum sanctum L., Ocimum sanctum
var. cubensis Gomes, Ocimum sanctum var. hirsutum (Benth.) Hook.f., Ocimum
scutellarioides Willd. ex Benth., Ocimum subserratum B.Heyne ex Hook.f., Ocimum
tenuiflorum f. villicaulis Domin, Ocimum tomentosum Lam., Ocimum villosum Roxb.,
Plectranthus monachorum (L.) Spreng.
Common names: holy basil, Tulsi
Medicinal use No
Most critical Effects on genitals and fertility in rabbits (DTU, 2019b).
endpoint
Toxicological Negative effects on the genitals and on fertility in rabbits at 100-300 mg dried leaves (DTU,
reference 2019b).
point
Health Based Factor of 14-41 (100-300 mg dried leaves/day gives 1.4-4.3 mg/kg body weight for an adult
Guidance 70 kg). Normal praxis for biologically active substances is to use a factor of at least 100
Value when extrapolating from a No Observed Adverse Effect level, NOAEL, in experimental ani-
mals to humans. Therefore, DTU concludes that margin of safety of 14-41 is too small
(DTU, 2019b).
Exposure A quick search on the internet in Sweden learned that supplements with a recommended
daily dose of 600-1380 mg Ocimum tenuiflorum L. are available. These are probably not
standardized.
Remarks DTU performed a risk assessment in 2012 (not available) with the conclusion that it is not
possible to derive a safe dose of leaves extracts in food supplements. In 2019, DTU as-
sessed documentation from a company on the safety of five food supplements. The sub-
mitted documentation did not change DTU’s previous conclusion from 2012 (DTU, 2019b).

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Piperine
Based on national risk assessments from Denmark, France, Germany and Poland, the HoA WG FS raised con-
cerns regarding a potential risk to consumers linked to the consumption of food supplements containing piper-
ine. The national risk assessments differ in critical endpoint in rodents (reproductive toxicity, elevated choles-
terol plasma levels), point of departure, uncertainty factor and health based guidance value. Raised concerns
lead to the following questions:
1. Is there a link between consumption of piperine and adverse effects on health?
2. Is there a link between consumption of isolated, highly piperine-enriched pepper extracts as bolus in
food supplements and adverse effects on health?
3. What is the maximum level of total dietary exposure of piperine unlikely to pose a risk of adverse
health effects to humans?
4. What is the maximum level of total dietary exposure of piperine in highly piperine-enriched pepper
extracts as bolus in food supplements unlikely to pose a risk of adverse health effects to humans?
5. Does piperine increase the bioavailability of other ingredients in food supplements?
6. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by highly piperine-enriched pepper extracts as a bolus in food supple-
ments?

Substance Piperine

Natural ingredient of Piper nigrum L. (black pepper), Piper longum L. and some other Piper
species as well as Aframomum melegueta K.Schum (grains of paradise).
Isolated, highly piperine-enriched pepper extracts (frequently ≥ 95 %) as bolus in food sup-
plements (versus pepper for food seasoning or as flavouring agent) (Ziegenhagen et al.,
2021).

Chemical names: ((E,E)-piperine; IUPAC-name: (2E,4E)-5-(2H-1,3-benzodioxol-5-yl)-1-(pi-

peridin-1-yl)penta-2,4-dien-1-one; CAS-No. 94-62-2; FEMA-No. 2909)

Also synthetically produced piperine may be relevant.

Medicinal use Yes
Most critical Animal studies
endpoint - Spermatogenesis and accompanying effects on male reproductive organs in rats
(Ziegenhagen et al., 2021; ANSES, 2022b).
- Elevated cholesterol plasma level in rats (EFSA CEF Panel, 2015; VKM, 2016b; DTU,
2019c).
Toxicological Different point of departures (PODs) by EFSA 2008/2011/2015/2016, JECFA 2005/2006,
reference DTU 2019, VKM 2016 (EFSA CEF Panel, 2015; VKM, 2016b; DTU, 2019c; Ziegenhagen et
point al., 2021); none by ANSES 2022 (ANSES, 2022b).

EFSA, DTU, VKM: NOAEL 5 mg/kg body weight per day from rat oral 90-day study (ele-
vated cholesterol plasma level in male rats).

BfR: LOAEL 10 mg piperine/kg body weight per day oral, several animal studies with rats
and mice (male reproduction).

ANSES: no POD identified, as in-depth clarification of reproductive toxicity is needed.

Health Based Different HBGVs by the above mentioned authorities/committees differing in POD and UF:
Guidance
Value (HBGV)

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BfR: 2.3 mg piperine/person/day (70 kg bw, bolus; UF 300).

DTU: 1.75 mg/person/day (70 kg bw; UF 200, including 2 for subchronic-chronic extrapo-
lation).
VKM: 3.5 mg/person/day (UF 100 to NOAEL).
ANSES: none

Max. allowed daily dose in food supplements:

PL: max. 2 mg piperine/adult/day in food supplements excluding pregnant and lactating
women (among others based on the above mentioned authorities/committees) (ZESPÓŁ
DO SPRAW SUPLEMENTÓW DIETY, 2022).
Exposure Piperine in food supplements is marketed in several EU MS.
Exposure estimate for piperine from pepper in food preparations for male German popula-
tion: mean 24-36 mg piperine/day and P95 64-96 mg piperine/day (Ziegenhagen et al.,
2021).

Piperine content in food supplements frequently ranges 5-30 mg/day with single products
reaching 40 or 50-100 mg/day (Ziegenhagen et al., 2021).
Remarks Piperine is also used and promoted to increase bioavailability of other ingredients in food
supplements.

p-Synephrine in Citrus spp.-preparations38

Based on national risk assessments from Germany, France, the Netherlands, Sweden and Denmark, the HoA
WG FS raised concerns regarding a potential risk to consumers linked to the consumption of foods containing
Citrus spp.-preparations or extracts containing p-synephrine. p-Synephrine is a constituent of preparations or
extracts of different Citrus species and especially of preparations or extracts of bitter orange (Citrus x aurantium
L.), which are marketed as supplements for weight loss and enhancing athletic performance. The main health
concern about p-synephrine use in food and sports supplements refers to its potential as a sympathomimetic to
induce adrenergic (stimulant-related) adverse effects on the cardiovascular system. Animal and human studies,
as well as numerous case reports, provide evidence for cardiovascular effects due to ingestion of high p-
synephrine doses, especially in combination with caffeine and physical exertion. This concern leads to the fol-
lowing questions:
1. Is there a link between consumption of p-synephrine (e.g. from bitter orange extracts) as an ingredient
of food supplements and adverse (cardiovascular) effects on health?
2. What is the maximum level for acute (single dose) and chronic dietary exposure of p-synephrine, as an
ingredient of food supplements, unlikely to pose a risk of adverse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by p-synephrine (e.g. from bitter orange extracts) as an ingredient of food
supplements?
4. What are recommendations for the possible high-risk groups, including individuals who deliberately
take a lot of p-synephrine such as bodybuilders, athletes and people who want to lose weight and indi-
viduals who may be especially sensitive to the adverse effects, namely children, pregnant and lactating
women and people taking medication for their blood pressure?

38 The abbreviation “spp.” refers to more than one not further defined species of the same genus.

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Substance p-Synephrine in Citrus spp.-preparations or extracts and especially preparations or extracts

of Citrus x aurantium L. (common names: pummelo, Seville Orange, bitter orange).

p-Synephrine (also referred to as synephrine) is an alkaloid with adrenergic activity and is a

natural ingredient occurring in the pulp and peel (epicarp and mesocarp) of various citrus
fruits (Citrus spp.) especially of bitter orange (Citrus x aurantium L.). p-Synephrine from bit-
ter orange extracts is added to various products marketed as food, especially sports supple-
ments and slimming products (Bakhiya et al., 2017).

Also synthetically produced p-synephrine may be relevant.

Medicinal use No, but synthetic p-synephrine has been on the market since the 1930s as a drug for the
treatment of hypotension due to its sympathomimetic effect under the name Oxedrine or
Sympatol® (BfR, 2012a).
Most critical Animal studies on synephrine indicated acute cardiovascular effects as a critical toxicologi-
endpoint cal endpoint.

Animal studies involving oral administration clearly showed that supplementation with p-
synephrine (in the form of Citrus x aurantium L. extract or as purified phytochemical) can
lead to elevated blood pressure, and ingestion of synephrine in combination with caffeine
can induce considerable cardiovascular effects with additional alteration of heart rate.

The available mechanistic data indicate that effects of p-synephrine on the cardiovascular
system are attributable to adrenergic stimulation.

The scientific literature describes a number of cases of serious effects that were associated
with the ingestion of preparations containing p-synephrine (case reports of ischemic stroke
and cardiotoxicity including tachyarrhythmia, cardiac arrest, syncope, angina, myocardial
infarction, ventricular arrhythmia, and death in otherwise healthy patients). Most cases in-
volved preparations of p-synephrine, caffeine and other substances (BfR, 2012a; ANSES,
2014; Tiesjema et al., 2017).
Toxicological Animal studies do not allow the identification of a no observed adverse effect level (NO-
reference AEL), as the effects (on the cardiovascular system) were observed at all doses tested (BfR,
point 2012a).
Health Based Currently no HBGV available.
Guidance
Value According to EFSA's Qualified Presumption of Safety (QPS) approach, p-synephrine intake
is considered safe when consumed orally in amounts commonly found in foods.

The BfR (Germany) recommends that supplements should provide no more than 6.7 mg of
p-synephrine daily, which is equivalent to the median dietary intake from conventional
foods in Germany, and is presumed to represent a safe intake of supplements (BfR, 2012a).

The French ANSES concludes that intake levels of p-synephrine through food supplements
must remain below 20 mg/day (ANSES, 2014).

NL BuRO advises to set the maximum intake of p-synephrine from herbal preparations at
27 mg of p-synephrine per day (BuRO, 2018).
Exposure The total daily intake of p-synephrine via conventional food, estimated for the German
population under consideration of maximum concentrations of p-synephrine, amounts to
6.7 mg/day for average consumers and to 25.7 mg/day for high consumers (95th percentile).
Estimations for the French population considering the maximum levels in citrus fruits
yielded an average p-synephrine intake of 4.3 and 17.7 mg/day at the 95th percentile (BfR,
2012a; ANSES, 2014).
Remarks Synephrine is frequently present in products in combination with caffeine and/or multiple
herbal ingredients. The adverse effects of p-synephrine on the cardiovascular system may
be enhanced when used in combination with other stimulants (such as caffeine).

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In its opinion on the risk assessment of caffeine (EFSA NDA Panel, 2015), EFSA was man-
dated to assess the risks for consumption of caffeine together with p-synephrine. EFSA
concluded, that the question of whether or not p-synephrine modifies the acute cardiovas-
cular effects of single doses of caffeine has not been adequately investigated in humans,
particularly if consumed shortly before intense physical exercise, and therefore no conclu-
sions could be drawn.

p-Synephrine is considered a banned substance by the National Collegiate Athletic Associ-

ation (NCAA)39.

Tribulus terrestris
Based on national risk assessments from Spain and Denmark, the HoA WG FS raised concerns regarding a po-
tential risk to consumers linked to the consumption of foods containing preparations or extracts of different
parts of Tribulus terrestris L. (hereinafter referred to as Tribulus terrestris) due to possible genotoxic and estro-
genic activity. In its natural form it contains various active substances, the most notable of which are steroidal
saponins, β-carboline alkaloids, flavonoids and lignanamides. However, no toxicological data are available to
link specific substances or groups of substances to the effects reported. In Spain supplements with high con-
centrations (250 and 1500 mg) Tribulus terrestris preparation or extract are on the market. This concern leads to
the following questions:
1. Is there a link between consumption of Tribulus terrestris preparations or extracts and adverse effects
on health?
2. What is the maximum level of total dietary exposure of Tribulus terrestris unlikely to pose a risk of ad-
verse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by Tribulus terrestris?

Substance Fruits, plant shoots and preparations or extracts thereof of Tribulus terrestris L.
In its natural form it contains various active substances, the most notable of which are ste-
roidal saponins, β-carboline alkaloids, flavonoids and lignanamides (AECOSAN, 2015b).

Common names: puncture vine, Gokshura

Medicinal use Yes? Tribuli terrestris herba are currently under review by EMA. There has been a call for
data (see Tribuli terrestris herba | European Medicines Agency (europa.eu)).
Most critical A clear critical endpoint cannot be identified. Clinical observations associate the intake of
endpoint Tribulus terrestris L. with neuronal, hepatic and renal toxicity. These toxic effect are also
seen in animal studies. In vitro studies indicated cytotoxicity as well as genotoxicity and es-
trogenic activity from Tribulus terrestris L. extracts (AECOSAN, 2015b).
Toxicological Not possible to derive a toxicological reference point.
reference
point
Health Based Not possible to derive a health based guidance value.
Guidance
Value
Exposure In Spain supplements are on the market containing Tribulus terrestris extract between 250
and 1500 mg, which could lead to a daily intake between 250 and 9000 mg (AECOSAN,
2015b).

39 See NCAA Banned Substances - NCAA.org

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Tryptophan
Based on national risk assessments from Spain and Norway, the HoA WG FS raised concerns regarding a poten-
tial risk to consumers linked to the consumption of food supplements containing tryptophan in doses of
3 g/day and higher leading to adverse effects such as appetite suppression, nausea and vomiting, faintness, diz-
ziness, drowsiness, tremor, fatigue, and headache. In the European Union supplements with high concentra-
tions (500 to 1000 mg) of tryptophan are available on the market. In the Norwegian assessment it was con-
cluded that in adults (≥ 18 years), adolescents and children, the intake of the specified doses (250, 300 and
450 mg/day) in food supplements may represent a risk of adverse health effects.
This concern leads to the following questions:
1. Is there a link between consumption of L-tryptophan and adverse effects on health?
2. What is the maximum level of total chronic dietary exposure of L-tryptophan unlikely to pose a risk of
adverse health effects to humans?
3. What is the maximum level of exposure to L-tryptophan via food supplements unlikely to pose a risk
of adverse health effects to humans?

Substance Tryptophan is an essential amino acid that intervenes in protein synthesis and is the bio-
chemical precursor of serotonin, melatonin, niacin and the coenzymes, NAD and NADP
(AESAN, 2012).

Chemical name: 2-amino-3-(1H-indol-3-yl) propionic acid

Also synthetically produced Tryptophan may be relevant.

Medicinal use No
Most critical According to previous reports, short-term supplementation with L-tryptophan
endpoint supplements in doses of 3 g/day and higher have led to adverse effects including appetite
suppression, nausea and vomiting, faintness, dizziness, drowsiness, tremor, fatigue, and
headache. A suspected, but not established, increased risk of cataract has also been re-
ported. There is a lack of data concerning long-term supplementation (VKM, 2016a).
Toxicological Several doses associated with observed adverse effects have been referred to in the litera-
reference ture, the lowest being 3 g/day, which represents a LOAEL. A NOAEL of 2228 mg/day has
point been identified, based on monitoring of patients treated with tryptophan prescribed as an
antidepressant in the UK who did not report side effects (VKM, 2016a).
Health Based VKM will use 220 mg/day as a value for comparison in the risk characterisation of L-trypto-
Guidance phan. This value is based on the NOAEL described above and an uncertainty factor of 10.
Value
Exposure The Norwegian Food Safety Authority has requested a risk assessment of the doses
250 mg/day, 300 mg/day and 450 mg/day of L-tryptophan in food supplements for chil-
dren 10 years and older, adolescents and adults (VKM, 2016a).
Remarks The Scientific Committee concludes that, based on the information available to date and
taking into account the considerations reflected in this report, the AESAN proposal of a
maximum daily amount of 300 mg of L-tryptophan is acceptable from the safety point of
view for use as a food supplement (AESAN, 2012; VKM, 2016a).

VKM concludes that in adults (≥ 18 years), adolescents and children the specified doses
250, 300 and 450 mg/day L-tryptophan in food supplements may represent a risk of ad-
verse health effects (AESAN, 2012; VKM, 2016a).

It should not be consumed by pregnant women, or those individuals receiving treatment

with antidepressants or who suffer from kidney failure.

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First report of the HoA working group “Food Supplements”

A crucial point is that adverse effects are exacerbated when tryptophan is administered in
combination with antidepressant medications with serotonergic actions (i.e. which increase
brain serotonin levels), including MAOIs, SSRIs, SNRIs tricyclic antidepressants and other
drugs.

Withania somnifera
Based on a national risk assessment from Denmark, the HoA WG FS raised concerns regarding a potential risk
to consumers linked to the consumption of supplements containing roots, herbs, flowers and preparations or
extracts thereof of Withania somnifera (L.) Dunal (hereinafter referred to as Withania somnifera) due to (poten-
tial) effects on reproduction, thyroid hormones, acetylcholinesterase, the immune system and due to liver tox-
icity. The toxicity data are limited and not sufficient to derive a safe dose level or health-based guidance value.
Besides in supplements, Withania somnifera is also used in herbal teas.
This concern leads to the following questions:
1. Is there a link between consumption of food supplements (and herbal teas) containing (preparations or
extracts of) Withania somnifera and adverse effects on health?
2. What is the maximum level of total dietary exposure of Withania somnifera unlikely to pose a risk of
adverse health effects to humans?
3. What are possible subgroups of the general population that are more vulnerable or more sensitive to
the adverse effects caused by Withania somnifera?

Substance Supplements and herbal teas containing roots, herbs, flowers and preparations or extracts
thereof of Withania somnifera (L.) Dunal.

Main constituents are withanolides and alkaloids (DTU, 2020b).

Synonyms: Alicabon somniferum (L.) Raf., Physalis somnifera L., Physaloides somnifera (L.)
Moench, Hypnoticum somniferum Rodr. ex Boiss., Larnax morrisonii (Dunal) Miers, Physalis
alpini J.Jacq., Physalis arborescens Thunb., Physalis flexuosa L., Physalis scariosa Webb &
Berthel., Physalis somnifera var. communis Nees, Physalis somnifera var. flexuosa (L.) Nees,
Physalis sugunda Buch.-Ham. ex Wall., Physalis tomentosa Thunb., Physalis villosa Moench
ex Steud., Withania arborescens Dunal, Withania chevalieri A.E.Gonç., Withania kansuensis
Kuang & A.M.Lu, Withania macrocalyx (Chiov.) Chiov., Withania microphysalis Suess.,
Withania morisonii Dunal, Withania mucronata Chiov., Withania obtusifolia Täckh.,
Withania sicula Lojac., Withania somnifera var. communis (Nees) Dunal, Withania somnifera
var. flexuosa (L.) Dunal, Withania somnifera var. macrocalyx Chiov., Withania somnifera
subsp. obtusifolia (Täckh.) Abedin & al.
Common names: Ashwagandha, winter cherry
Medicinal use Yes, although EMA concluded that it was not possible to establish a community herbal
monograph on traditional herbal medicinal products (Withaniae somniferae radix | Euro-
pean Medicines Agency (europa.eu)).
Most critical Reported effects include (DTU, 2020b):
endpoint - Effects on (male) reproduction via effects on levels of sex hormones.
- Effects on thyroid hormones.
- Inhibition of acetylcholinesterase.
- Effects on the immune system.
- Liver toxicity (based on case studies).
Toxicological N/A
reference
point

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First report of the HoA working group “Food Supplements”

Health Based Not possible to derive HBGV for Withania somnifera (L.) Dunal. or the main constituents
Guidance (DTU, 2020b).
Value
Exposure Withania somnifera Withania somnifera (L.) Dunal. in food supplements is marketed in sev-
eral EU MS.
Remarks There is information that women have used Withania somnifera (L.) Dunal. as an abortifa-
cient; doses are not reported. Therefore, WHO advises not to use Withania somnifera (L.)
Dunal. during pregnancy or lactation (DTU, 2020b).

There are several RASFF notifications on Withania somnifera (L.) Dunal.; for example recent
(March 2023) notifications by Denmark 40, 41, 42.

40 https://webgate.ec.europa.eu/rasff-window/screen/notification/601523
41 https://webgate.ec.europa.eu/rasff-window/screen/notification/602102
42 RASFF Window - Notification detail (europa.eu)

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First report of the HoA working group “Food Supplements”

Annex D

Result of the review of the 13 prioritized substances regarding existing permissions as food additives or food
flavourings.

Coumarin in plant preparations

Coumarin is a phytotoxin and is categorized as an ‘active principle’. These are undesirable naturally occurring
substances that may not be used as flavourings. However, spices and other food ingredients with flavouring
properties that may naturally contain such ‘active principles’ may be used.
Coumarin is included in Annex III Part A of Regulation (EC) No 1334/2008 in the list of "Substances which shall
not be added as such to foods".
As the substance is naturally present in flavourings and food ingredients with flavouring properties or in certain
ready-to-eat foods to which flavourings and/or food ingredients with flavouring properties have been added,
coumarin may be present in certain foods at a specified maximum level 43.

According to Article 6(2) of Regulation (EC) No 1334/2008, without prejudice to Regulation (EC) No 110/2008,
maximum levels of certain substances, naturally present in flavourings and/or food ingredients with flavouring
properties, in the compound foods listed in Part B of Annex III shall not be exceeded as a result of the use of
flavourings and/or food ingredients with flavouring properties in those foods. The maximum levels of the sub-
stances set out in Annex III shall apply to foods as marketed, unless otherwise stated. By way of derogation
from this principle, for dried and/or concentrated foods which need to be reconstituted, the maximum levels
shall apply to the food as reconstituted according to the instructions on the label, taking into account the mini-
mum dilution factor.

Three Coumarin derivatives are also approved as flavouring substances without restrictions/exemptions and are
listed in Annex I of Regulation (EC) No. 1334/2008:
- 3,4-Dihydrocumarin [Fl No. 13.009]
- 6-Methylcumarin [Fl No. 13.012]
- Octahydrocumarin [Fl No. 13.161]

Curcumin in Curcuma spp.-preparations

Curcumin (E 100) is listed as an approved food additive in Group III: "Colours with combined maximum limits"
in Regulation (EC) No. 1333/2008. Curcumin is extracted mainly from Curcuma-species.

43 Maximum levels of coumarin as listed in Annex III Part B of Regulation (EC) No 1334/2008: Traditional and/or seasonal bakery ware con-

taining a reference to cinnamon in the labelling 50 mg/kg; Breakfast cereals including muesli 20 mg/kg; Fine bakery ware, with the excep-
tion of traditional and/or seasonal bakery ware containing a reference to cinnamon in the labelling 15 mg/kg; Desserts 5 mg/kg.

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Hypericum perforatum
Hypericum perforatum L. is listed in Annex IV Part B of Regulation (EC) No 1334/2008 as a source material
whose use is restricted in the production of flavourings and food ingredients with flavouring properties. Ac-
cording to Article 7(2) of Regulation (EC) No 1334/2008, flavourings and/or food ingredients with flavouring
properties produced from the source materials listed in Part B of Annex IV may only be used under the condi-
tions set out in that Annex. Flavourings and food ingredients with flavouring properties produced from Hyperi-
cum perforatum L. may only be used for the production of alcoholic beverage.

Piperine
Piperine [Fl No. 14.003] is listed as an approved flavouring substance in the Union list in Annex I Part B of Regu-
lation (EC) No. 1334/2008 without any restrictions. Piperine is extracted mainly from Piper nigrum L.

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