Commission Implementing Regulation (EU) 2024/1052 of 10 April 2024 authorising the placing on the market of calcidiol monohydrate as a novel food and amending Implementing Regulation (EU) 2017/2470

THE EUROPEAN COMMISSION,

Having regard to the Treaty on the Functioning of the European Union,

Having regard to 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 ¹, and in particular Article 12(1) thereof,

Whereas:

• (1) Regulation (EU) 2015/2283 provides that only novel foods authorised and included in the Union list of novel foods may be placed on the market within the Union.

• (2) Pursuant to Article 8 of Regulation (EU) 2015/2283, Commission Implementing Regulation (EU) 2017/2470 ² has established a Union list of novel foods.

• (3) On 16 May 2018, the company DSM Nutritional Products Ltd. (‘the applicant’) submitted an application to the Commission pursuant to Article 10(1) of Regulation (EU) 2015/2283 to place calcidiol monohydrate on the Union market as a novel food. The applicant requested for calcidiol monohydrate to be used as a novel food in food supplements as defined in Directive 2002/46/EC of the European Parliament and of the Council ³, intended for the general population above 3 years of age. The novel food was proposed for use in food supplements at levels of up to 10 μg/day for persons above 11 years of age and at levels of up to 5 μg/day for children from 3 to 10 years of age. The applicant also requested for calcidiol monohydrate to be added to the list of vitamin D forms specified in Annex II to Directive 2002/46/EC as a form of vitamin D.

• (4) On 16 May 2018, the applicant also made a request to the Commission for the protection of proprietary data for a number of studies submitted in support of the application, namely, master data for calcidiol ⁴; a comparison of 25(OH)D concentration in human serum/plasma following oral supplementation of calcifediol or cholecalciferol ⁵; the comparative metabolism of [14C]-calcifediol and [14C]-cholecalciferol following multiple oral administration in the intact male han wistar rat ⁶; the comparative metabolism of [14c]-calcifediol and [14c]-cholecalciferol following single oral administration in the bile duct cannulated male han wistar rat ⁷; calcifediol: acute oral toxicity study in rats ⁸; an in-vitro skin irritation test with DSMO47J 17 using a human skin model ⁹; an evaluation of the eye hazard potential of DSMO47J 17 using the bovine corneal opacity and permeability test ¹⁰; an evaluation of the mutagenic activity of D5M0471 17 in an in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells ¹¹; assessment of skin sensitization to DSMO471J7 in the mouse (Local Lymph Node Assay) – pre-screen test ¹²; a micronucleus test in bone marrow cells of the rat with DSM047117 ¹³; a Salmonella typhimurium and Escherichia coli reverse mutation assay ¹⁴; a chromosome aberration test in human lymphocytes in vitro with calcifediol ¹⁵; a 90-day oral toxicity study with DSM0471 17 by dietary administration in the rat followed by a 28-day recovery period ¹⁶; a 3-month oral toxicity study with Rovimix® D3-500 by dietary administration followed by a 4-week recovery period in Wistar rats ¹⁷; a dose finding study in physically non-frail and (pre-)frail elderly to measure 25(OH) vitamin D levels after supplementation with HY.D calcifediol 25 SD/S and vitamin D3 ¹⁸; response of serum 25-hydroxyvitamin D to different doses of Calcifediol 0,25 SD/S compared to vitamin D3 supplementation: a randomized, controlled, double blind, long term pharmacokinetic study ¹⁹; a report on the particle size distribution and its annexes ²⁰.

• (5) On 14 December 2018, the Commission requested the European Food Safety Authority (‘the Authority’) to carry out an assessment of calcidiol monohydrate as a novel food. The Commission also requested the Authority to evaluate, following the outcome of the novel food assessment, the safety and bioavailability of the novel food when added for nutritional purposes as a source of vitamin D to food supplements.

• (6) On 25 May 2021, the Authority adopted its scientific opinion on the ‘Safety of calcidiol monohydrate produced by chemical synthesis as a novel food pursuant to Regulation (EU) 2015/2283’ ²¹ in accordance with Article 11 of Regulation (EU) 2015/2283.

• (7) In its scientific opinion, the Authority concluded that calcidiol monohydrate is safe under the proposed conditions of use at use levels of up to 10 μg/day for the general population, excluding infants and children under 11 years of age. For children from 3 to 10 years of age the Authority concluded that combined intake of the novel food (5 μg/day) and of calcidiol from the background diet, added to the background intake of vitamin D, would approach the Tolerable Upper Intake Level (UL) for vitamin D (D2 and D3). Furthermore, as the novel food is proposed for use as a preparation containing 0,25 % to 0,275 % w/w of calcidiol, the UL for children of this age could be exceeded. Given the uncertainties, the Authority could not conclude on the safety of consumption of the novel food for children from 3 to 10 years of age at the proposed daily intake.

• (8) The Authority also concluded that the novel food is a bioavailable source of the biologically active form of vitamin D (1,25-dihydroxyvitamin D). For the safety assessment, the Authority took a conservative approach for the theoretical calculation and used a factor of 5 set by the Panel on Additives and Products or Substances used in Animal Feed to convert calcidiol to vitamin D. However, the Authority also noted that a systematic review of data, to assess the extent to which oral calcidiol is more bioavailable than oral vitamin D3 in all population groups and the dietary context was outside the remit of that opinion and the data provided by the applicant did not permit that question to be answered for the proposed daily intake of 5 or 10 μg/day.

• (9) Annex II to Directive 2002/46/EC lists the substances that may be used as forms of vitamins and minerals in the manufacture of food supplements. Article 6(3) of that Directive provides that the amount of nutrients or substances with a nutritional or physiological effect present in the product shall be declared on the labelling in numerical form. Concerns have been raised by the Member States that the absence of a conversion factor that would allow to convert the amount of calcidiol monohydrate into vitamin D3 might cause difficulties for the national competent authorities to enforce compliance with the Article 6(3) of Directive 2002/46/EC. In addition, both Regulation (EU) No 1169/2011 of the European Parliament and of the Council ²² and Directive 2002/46/EC provide that the information on vitamins and minerals in a product is to be expressed as a percentage of the daily reference intakes. Annex XIII of Regulation (EU) No 1169/2011 lists these daily reference intakes, including that for vitamin D, without providing for a conversion factor that would allow to convert the amount of calcidiol monohydrate into vitamin D. Therefore, on 25 February 2022, the Commission requested the Authority to assess the extent to which calcidiol monohydrate is bioavailable as compared to native vitamin D3, as well as to derive a conversion factor that allows converting absolute amounts of this nutrient form into vitamin D3.

• (10) On 5 July 2023, the Authority adopted its ‘Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate’ ²³. The opinion concerned an updated exposure assessment for vitamin D and proposed a factor of 2,5 for the conversion of calcidiol monohydrate into vitamin D3 for labelling purposes and for doses up to 10 μg/day.

• (11) Following that opinion, in accordance with Article 31 of Regulation (EC) No 178/2002 of the European Parliament and of the Council ²⁴, the Commission asked the Authority to provide scientific and technical assistance as regards the evaluation of calcidiol monohydrate as a novel food, in particular to reconsider the outcome of the opinion on the safety of calcidiol monohydrate.

• (12) On 25 January 2024 the Authority published the scientific and technical report ‘Scientific and technical assistance to the evaluation of the safety of calcidiol monohydrate as a novel food’ ²⁵.

• (13) In its report, the Authority concluded that the novel food calcidiol monohydrate proposed for use in food supplements is a bioavailable source of the biologically active metabolite of vitamin D (1,25-dihydroxyvitamin D) and that a conversion factor of 2,5 reflects the relative bioavailability of calcidiol monohydrate as compared to vitamin D3 under the proposed conditions of use and use levels. The Authority further concluded that the novel food calcidiol monohydrate proposed for use in food supplements is safe under the proposed conditions of use and use levels (up to 10 μg/day) for children from 11 years of age and for adults, including pregnant and lactating women, as well as under the proposed conditions of use and use levels (up to 5 μg/day) for children from 3 to 10 years of age.

• (14) The opinions and the report of the Authority give sufficient grounds to establish that calcidiol monohydrate when used at levels of up to 10 μg/day in food supplements intended for children from 11 years of age and for adults, including pregnant and lactating women, and when used at levels of up to 5 μg/day in food supplements intended for children from 3 to 10 years of age fulfils the conditions for its placing on the market in accordance with Article 12(1) of Regulation (EU) 2015/2283.

• (15) In its 2021 scientific opinion, the Authority noted that ‘calcifediol’ (calcidiol) is used in the Union as a human medicinal product, approved in the Member States and in some countries outside the Union. Directive 2001/83/EC of the European Parliament and of the Council ²⁶ applies where a product, considering all its characteristics, may fall both within the definition of ‘medicinal product’ as laid down in Article 1(2) of that Directive and within the definition of a ‘food’ covered by Regulation (EU) 2015/2283. In that respect, where a Member State establishes, in accordance with Directive 2001/83/EC, that a product is a medicinal product, it may restrict the placing on the market of that product as a food in accordance with Union law.

• (16) In its 2021 scientific opinion, the Authority noted that its conclusion on the safety of the novel food was based on scientific data from the master data and the product specifications, the studies on absorption, distribution, metabolism and excretion (ADME studies), the toxicity studies, the human studies and the analytical reports, including the annexes, without which it could not have assessed the novel food and reached its conclusion.

• (17) The Commission requested the applicant to further clarify the justification provided with regard to their proprietary claim over those studies and to clarify their claim to an exclusive right of reference to them in accordance with Article 26(2), point (b), of Regulation (EU) 2015/2283.

• (18) The applicant declared that they held proprietary and exclusive rights of reference for all studies submitted, at the time they submitted the application and therefore third parties could not lawfully access, use or refer to those studies.

• (19) The Commission assessed all the information provided by the applicant and considered that they have sufficiently substantiated the fulfilment of the requirements laid down in Article 26(2) of Regulation (EU) 2015/2283. Therefore, the master data for calcidiol; the comparison of 25(OH)D concentration in human serum/plasma following oral supplementation of calcifediol or cholecalciferol; the comparative metabolism of [14C]-calcifediol and [14C]-cholecalciferol following multiple oral administration in the intact male han wistar rat; the comparative metabolism of [14C]-calcifediol and [14C]-cholecalciferol following single oral administration in the bile duct cannulated male han wistar rat; the acute oral toxicity study on calcifediol in rats; the evaluation of the mutagenic activity of D5M0471 17 in an in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells; the micronucleus test in bone marrow cells of the rat with DSM047117; the Salmonella typhimurium and Escherichia coli reverse mutation assay; the chromosome aberration test in human lymphocytes in vitro with calcifediol; the 90-day oral toxicity study with DSM0471 17 by dietary administration in the rat followed by a 28-day recovery period; the 3-month oral toxicity study with Rovimix® D3-500 by dietary administration followed by a 4-week recovery period in Wistar rats; the dose finding study in physically non-frail and (pre-)frail elderly to measure 25(OH) vitamin D levels after supplementation with HY.D calcifediol 25 SD/S and vitamin D3; the response of serum 25-hydroxyvitamin D to different doses of calcifediol 0,25 SD/S compared to vitamin D3 supplementation: a randomized, controlled, double blind, long term pharmacokinetic study; the report on the particle size distribution and its annexes should be protected in accordance with Article 27(1) of Regulation (EU) 2015/2283. Accordingly, only the applicant should be authorised to place calcidiol monohydrate on the market within the Union during a period of five years from the entry into force of this Regulation.

• (20) However, restricting the authorisation of calcidiol monohydrate and the reference to the data contained in the applicant’s file for their sole use does not prevent subsequent applicants from applying for an authorisation to place on the market the same novel food provided that their application is based on legally obtained information supporting such an authorisation.

• (21) It is appropriate that the inclusion of calcidiol monohydrate as a novel food in the Union list of novel foods contains the information referred to in Article 9(3) of Regulation (EU) 2015/2283. In line with the conditions of use of food supplements containing calcidiol monohydrate as proposed by the applicant and assessed by the Authority, it is necessary to inform the consumers in that regard by appropriate labelling about the uses of food supplements containing calcidiol monohydrate.

• (22) Calcidiol monohydrate should be included in the Union list of novel foods set out in Implementing Regulation (EU) 2017/2470. The Annex to Implementing Regulation (EU) 2017/2470 should therefore be amended accordingly.

• (23) The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Plants, Animals, Food and Feed,

HAS ADOPTED THIS REGULATION:

Article 1

Calcidiol monohydrate shall be included in the Union list of novel foods set out in Implementing Regulation (EU) 2017/2470.

Article 2

Only the company DSM Nutritional Products Ltd. ²⁷ is authorised to place on the market within the Union the novel food referred to in Article 1, for a period of 5 years from 1 May 2024, unless a subsequent applicant obtains an authorisation for that novel food without reference to the scientific data protected pursuant to Article 3 or with the agreement of DSM Nutritional Products Ltd.

Article 3

The scientific data contained in the application file and fulfilling the conditions laid down in Article 26(2) of Regulation (EU) 2015/2283 shall not be used for the benefit of a subsequent applicant for a period of 5 years from the date of entry into force of this Regulation without the agreement of DSM Nutritional Products Ltd.

Article 4

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 10 April 2024.

For the Commission

The President

Ursula VON DER LEYEN

ANNEX

The Annex to Implementing Regulation (EU) 2017/2470 is amended as follows:

• (1) in Table 1 (Authorised novel foods), the following entry is inserted:

• (2) in Table 2 (Specifications), the following entry is inserted:

ELI: http://data.europa.eu/eli/reg_impl/2024/1052/oj

ISSN 1977-0677 (electronic edition)