Safety of benfotiamine as a Novel food pursuant to Regulation (EU) 2015/2283 and the bioavailability of benfotiamine as a source of thiamin in the context of Directive 2002/46/EC on food supplements

Abstract

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of benfotiamine as a novel food (NF) pursuant to Regulation (EU) 2015/2283 and on the bioavailability of benfotiamine as a source of thiamin in the context of Directive 2002/46/EC. The NF, which is produced by chemical synthesis, is proposed to be used in food supplements for adults at a maximum intake of 300 mg/day. The Panel notes that the identity of the NF has not been sufficiently demonstrated, including the possible presence of small particles and nanoparticles. The Panel also notes that the data provided were insufficient to demonstrate that the manufacturing process is reproducible and capable of consistently producing a product with the proposed characteristics. No conclusion could be drawn on the microbiological stability of the NF over the proposed shelf life. The information provided indicates that the bioavailability of thiamin from benfotiamine may be higher than that from water‐soluble forms of thiamin and thus benfotiamine may be used as a source of thiamin. Owing to the insufficient characterisation of the NF, unresolved uncertainties regarding small particles, including nanoparticles, the lack of adequate information on its metabolic fate, bioaccumulation and long‐term effects, and the limitations of the submitted toxicological data, the Panel concludes that the safety of benfotiamine as a NF cannot be established under the proposed conditions of use. The Panel also concludes that the higher bioavailability of benfotiamine compared with authorised or natural sources of thiamin has not been quantified to an extent that would allow the derivation of a conversion factor for labelling purposes.

1. INTRODUCTION

1.1. Background and Terms of Reference as provided by the requestor

The European Union legislation provides a list of nutritional substances that may be used for nutritional purposes in food supplements.

The relevant Union legislative measures are:

• Regulation (EU) 2015/2283 of the European Parliament and of the Council on novel foods,

• Directive 2002/46/EC of the European Parliament and of the Council laying down requirements on food supplements.

On 6 June 2023, the applicant ‘Gall Pharma GmbH’ submitted a request to the European Commission in accordance with Article 10 of Regulation (EU) 2015/2283 to authorise the placing on the market of ‘benfotiamine’ as a novel food.

The application requests the authorisation of the use of benfotiamine as a novel food in food supplements as defined by Directive 2002/46/EC for the adult population.

In accordance with Article 29(l)(a) of Regulation (EC) No 178/2002, the European Commission asks the European Food Safety Authority to provide a scientific opinion:

• −by assessing benfotiamine as a novel food in accordance with Article 10(3) of Regulation (EU) 2015/2283, and
• −following the outcome of the novel food assessment, by assessing the safety and bioavailability of benfotiamine when added for nutritional purposes to food supplements for the adult population in the context of Directive 2002/46/EC, and
• −by assessing the extent to which benfotiamine is bioavailable as compared to native forms of vitamin B1 naturally present in foods, or as compared to an authorised source of vitamin B1 for which the relative bioavailability versus one or more forms of the nutrient naturally present in foods is known, as well as by deriving a conversion factor that allows converting absolute amounts of this substance into the natural or authorised source used as a comparator.

1.2. Information on existing evaluations and authorisations

In 2008, the EFSA ANS Panel (2008) assessed the safety and bioavailability of benfotiamine, thiamin monophosphate chloride and thiamin pyrophosphate chloride as sources of vitamin B1 intended for use in food supplements. The ANS Panel noted that benfotiamine is not endogenous to humans, that in its dephosphorylated form is absorbed and bioavailable, and that the bioavailability of thiamin from benfotiamine is higher than that from other thiamin sources. The Panel further noted that several human intervention studies providing benfotiamine at dose levels from 40 up to 400 mg/day for several (3–12) weeks did not report adverse effects or changes in safety‐related biochemical parameters. The only exception was an open trial providing 40 mg benfotiamine in combination with 90 mg pyridoxine hydrochloride and 250 μg cyanocobalamin daily for 12 weeks to patients with diabetic polyneuropathy, in which 8.4% of the patients reported nausea, dizziness, stomach ache and weight gain at week 12 of the study. No toxicological studies were provided for benfotiamine to evaluate reproductive and developmental toxicity, genotoxicity or long‐term toxicity. The animal and clinical studies referred to, which were without adverse effects, were not designed to study possible adverse effects of benfotiamine. The Panel concluded that the submitted data were insufficient to demonstrate the safety of the proposed use and use levels for benfotiamine.

2. DATA AND METHODOLOGIES

The safety assessment of this NF is based on data provided in the application and the information submitted by the applicant in response to EFSA's requests for supplementary information.

Administrative and scientific requirements for NF applications referred to in Article 10 of Regulation (EU) 2015/2283 are listed in the Commission Implementing Regulation (EU) 2017/2469. ¹

A common and structured format on the presentation of NF applications is described in the EFSA guidance on the preparation and presentation of a NF application (EFSA NDA Panel, 2016a). As indicated in this guidance, it is the duty of the applicant to provide all the available (proprietary, confidential and published) scientific data, (including both data in favour and not in favour) that are pertinent to the safety of the NF.

The applicant has submitted a confidential and a non‐confidential version of a dossier following the ‘EFSA guidelines on the preparation and presentation of a NF application’ (EFSA NDA Panel, 2016a) and the ‘Administrative guidance for the preparation of applications on novel foods pursuant to Article 10 of Regulation (EU) 2015/2283’ (EFSA, 2021).

In accordance with Article 38 of the Regulation (EC) No 178/2002 ² and taking into account the protection of confidential information and of personal data in accordance with Articles 39 to 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality, ³ the non‐confidential version of the dossier has been published on Open.EFSA. ⁴

According to Article 32c(2) of Regulation (EC) No 178/2002 and to the Decision of EFSA's Executive Director laying down the practical arrangements on pre‐submission phase and public consultations, EFSA carried out a public consultation on the non‐confidential version of the technical dossier from 2 February to 23 February 2026 for which no comments were received.

This NF application includes a request for protection of proprietary data in accordance with Article 26 of Regulation (EU) 2015/2283. The data requested by the applicant to be protected comprise genotoxicity study.

2.1. Methodologies

The assessment follows the methodology set out in the EFSA guidance on NF applications (EFSA NDA Panel, 2016a) and the principles described in the relevant existing guidance documents from the EFSA Scientific Committee. The legal provisions for the assessment of novel foods are laid down in Article 11 of Regulation (EU) 2015/2283 and in Article 7 of Commission Implementing Regulation (EU) 2017/2469. ⁵

This assessment concerns only the risks that might be associated with the consumption of the NF under the proposed conditions of use and is not an assessment of the efficacy of the NF with regard to any claimed benefit.

The evaluation of the bioavailability of benfotiamine was conducted in line with the principles laid down in the ‘Guidance on scientific principles and data requirements for the safety and relative bioavailability assessment of new micronutrient sources’ (EFSA ANS Panel, 2024).

3. ASSESSMENT

3.1. Introduction

The NF which is the subject of the application is benfotiamine, which refers to a synthetic derivative of thiamin.

According to Regulation (EU) 2015/2283, Article 3, the NF falls under the following category: ‘ix) vitamins, minerals and other substances used in accordance with Directive 2002/46/EC, Regulation (EC) No 1925/2006 or Regulation (EU) No 609/2013’.

The NF is produced by chemical synthesis from thiamin hydrochloride and consists of at least 98% weight per weight (w/w) benfotiamine.

The NF is intended to be used in food supplements. The target population is the general adult population, excluding pregnant and lactating women.

3.2. Identity of the NF

The NF is a chemical compound with a purity > 98% w/w (as determined by assay). Table 1 lists the main chemical identifiers of the NF. The chemical structure is shown in Figure 1.

TABLE 1.

Chemical identity of the benfotiamine.

Chemical substance
Chemical (IUPAC) name	S‐[2‐[(4‐amino‐2‐methylpyrimidin‐5‐yl)methyl‐formylamino]‐5‐phosphonooxypent‐2‐en‐3‐yl] benzenecarbothioate
Common name	Benfotiamine
Synonyms, trade names, abbreviations	Benfotiaminum, Benphothiamine, Biotamin
CAS number:	22457‐89‐2
Molecular formula:	C19H23N4O6PS
Molecular weight	466.45 g/mol

Abbreviations: CAS, chemical abstracts service; IUPAC, International Union of Pure and Applied Chemistry.

FIGURE 1.

Structural formula of the NF benfotiamine.

The identity test was performed using proton NMR analysis (¹H Nuclear Magnetic Resonance Spectroscopy) and carbon‐13 NMR analysis (¹³C Nuclear Magnetic Resonance Spectroscopy). Other analytical tests were provided to support the identity of the NF, including infrared spectroscopy, electrospray ionisation mass spectrometry (ESI–MS), elemental analysis and X‐Ray diffraction analysis.

Upon EFSA's request, the applicant stated that the chemical structure refers to the Z isomer, based on 2D‐NMR. However, The Panel noted that both isomers (Z and E) are mentioned throughout the dossier.

According to the applicant, the NF is insoluble in water, alcohol 96% or chloroform. With regard to the assessment of small particles, including nanoparticles, potentially present in the NF, the applicant submitted a particle size distribution analysis conducted using a ■■■■■ method. According to the relevant EFSA guidance (EFSA Scientific Committee, 2021a, 2021b), light scattering methods are not considered appropriate for particle size characterisation. Considering that the NF is a liposoluble substance, the applicant was requested to provide information supporting the uptake route of lipids and their partitioning into physiological hydrophobic environments (EFSA Scientific Committee, 2021a, 2021b). As no data for this appraisal route were provided, the Panel considers the available evidence insufficient to rule out the presence of small particles, including nanoparticles, in the NF. Consequently, the data are not adequate to conclude on the identity of the NF.

3.3. Production process

According to the information provided, the NF is produced in line with good manufacturing practice (GMP) and hazard analysis critical control points (HACCP) principles.

The NF is produced by chemical synthesis in two steps. The first step is a chemical reaction of thiamin hydrochloride with benzoyl chloride, orthophosphoric acid and polyphosphoric acid. The second step consists of the purification of crude benfotiamine in the presence of methanol and acetic acid. Further processing includes drying, milling, sifting and packaging. According to the applicant, excess methanol is removed by centrifugation and subsequently dried.

3.4. Compositional data

The NF consists of > 98% w/w benfotiamine.

To demonstrate that the manufacturing process is reproducible and capable of consistently producing a product with the proposed characteristics on a commercial scale, the applicant provided proximate analyses and analytical data on chemical and microbiological parameters for three independently produced batches of the NF, as well as analytical data on heavy metals for six independently produced batches (Tables 2, 3, 4).

TABLE 2.

Batch to batch analysis of the NF.

Parameter (unit)	Batch number			Method of analysis
	Batch #1	Batch #2	Batch #3
Appearance	White to pale yellow‐white crystalline powder	White to pale yellow‐white crystalline powder	White to pale yellow‐white crystalline powder	Visual
Identification	Positive	Positive	Positive	HPLC
Assay benfotiamine (%)	99.8	99.4	100.3	HPLC
Related substances (%)				HPLC‐UV
Benzoic acid	0.03	0.03	0.03
Thiamine HCl	N.D.	N.D.	N.D.
Other impurities	0.09	0.07	0.08
Total	0.41	0.36	0.36
Loss on drying (%, w/w)	0.57	0.45	0.47	USP 731
Residual solvents (mg/kg)
Methanol	572	< 402	< 402	GC
Acetic acid	< 397	N.D.	< 1207	GC

Abbreviations: GC, gas spectrometry; HCl, chlorhydric acid; HPLC, high‐performance liquid chromatography; HPLC‐UV, high‐performance liquid chromatography with ultraviolet detector; N.D., not detected.

TABLE 3.

Metals and other elements.

Parameter (unit)	Batches						Method of analysis
Metals and other elements (μg/g)	Batch #4	Batch #5	Batch #6	Batch #7	Batch #8	Batch #9
Lead	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	USP 231 (ICP‐MS)
Arsenic	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
Cadmium	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■
Mercury	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■	■■■■■

Abbreviations: ICP–MS, inductively coupled plasma mass spectrometry; N.D., not detected; USP, United States Pharmacopeia.

TABLE 4.

Analytical data on microbiological parameters of the NF.

Parameter (unit)	Batches			Method of analysis
	Batch #7	Batch #8	Batch #9
Total aerobic plate count (CFU/g)	10	< 10	< 10	Ph. Eur. 5.1.4, 2.6.12 & 2.6.13 USP Chapter 61 and 62
Total yeasts and moulds (CFU/g)	< 10	< 10	< 10
S. aureus in 1 g	N.D.	N.D.	N.D.
P. aeruginosa in 1 g	N.D.	N.D.	N.D.
Salmonella spp. in 10 g	N.D.	N.D.	N.D.
E. coli in 1 g	N.D.	N.D.	N.D.

Abbreviations: CFU, colony forming units; N.D., not detected; USP, United States Pharmacopeia.

The Panel notes that one batch of the NF was above the regulatory limit for mercury in food supplements. ⁶ Upon EFSA's request, the applicant provided analytical data for three additional batches on the content of metals and other elements, with mercury levels below the regulatory limit. The applicant was also requested to provide quantitative analytical data for two additional independently produced batches of the NF, including data on related substances, moisture content and residual solvents. In response, analytical data were provided for one additional batch, including results for benzoic acid and thiamine monophosphate. However, the Panel considered that the information provided was insufficient to fully establish the reliability of the analytical data. Further microbiological data for three additional independently produced batches of the NF, including total aerobic plate counts, total yeasts and moulds, S. aureus, P. aeruginosa, Salmonella spp. and E. coli, were also requested. The applicant provided data for only one batch for these parameters. The Panel considers these data inadequate because the methodology employed lacked appropriate validation and quality control criteria and did not provide quantitative results.

The Panel notes that the analyses were conducted in‐house and validation of the methods was provided. However, no information was provided on the accreditation of the laboratory which performed the NMR analysis.

The Panel notes that the data provided are insufficient to conclude on the composition of the NF.

3.4.1. Stability

The applicant performed stability tests with five independently produced batches of the NF (Table 5). The tests were carried out at accelerated conditions at 40°C ± 2°C and at 75% ± 5% RH for a period of 6 months. The batches were analysed for identification, related substances and microbiological parameters, packed in double polythene bags and stored in HDPE drums. Loss on drying was determined at 80°C for 3 h. A long‐term stability study was also provided for five independently produced batches of the NF (Table 6). The tests were carried out at 25°C ± 2°C and at 60% ± 5% RH for a period of 60 months. The shelf‐life proposed by the applicant is 60 months.

TABLE 5.

Stability testing under accelerated conditions.

Parameter (unit)	Batches															Analytical method
	Batch #10			Batch #11			Batch #12			Batch #13			Batch #14
Timepoints* (months)	0	3	6	0	3	6	0	3	6	0	3	6	0	3	6
Appearance	White to pale yellow‐white crystalline powder			White to pale yellow‐white crystalline powder			White to pale yellow‐white crystalline powder			White to pale yellow‐white crystalline powder			White to pale yellow‐white crystalline powder			Visual
Identification	Positive			Positive			Positive			Positive			Positive			IR, HPLC
Loss on drying (80°C for 3 h), % w/w	0.72	0.75	0.77	0.64	0.71	0.72	0.56	0.58	0.60	1.29	1.33	1.32	1.14	1.15	1.15	USP 731
Assay benfotiamine (%, w/w basis)	98.5	98.3	98.6	99.9	99.5	99.7	98.5	98.5	98.6	99.9	100.3	99.2	100	99.5	99.5	HPLC
Related substances (%)
Benzoic acid	0.16	0.17	0.18	0.12	0.16	0.15	0.13	0.17	0.16	0.04	0.10	0.07	0.07	0.11	0.08	HPLC‐UV
Thiamin HCl	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.
Total impurities	0.34	0.34	0.35	0.35	0.36	0.35	0.32	0.36	0.37	0.51	0.54	0.57	0.96	0.94	0.78

Abbreviations: HPLC, high‐performance liquid chromatography; HPLC‐UV, high‐performance liquid chromatography with ultraviolet detector; IR, Infrared spectroscopy; N.D., not detected; USP, United States Pharmacopeia.

^*The applicant provided data also for timepoint 1 and 2 months.

TABLE 6.

Stability testing under long‐term conditions.

Parameter (unit)	Batches																				Analytical method
	Batch #10				Batch #11				Batch #12				Batch #13				Batch #14
Timepoints* (months)	0	12	24	60	0	12	24	60	0	12	24	60	0	12	24	60	0	12	24	60
Appearance	White to pale yellow‐white crystalline powder				White to pale yellow‐white crystalline powder				White to pale yellow‐white crystalline powder				White to pale yellow‐white crystalline powder				White to pale yellow‐white crystalline powder				Visual
Identification	Positive				Positive				Positive				Positive				Positive				IR, HPLC
Loss on drying (80°C for 3 h), % w/w	0.72	0.75	0.79	0.77	0.64	0.67	0.68	0.68	0.56	0.60	0.65	0.63	1.29	1.34	1.31	1.33	1.14	1.15	1.19	1.20	USP 731
Assay benfotiamine (%, w/w basis)	98.5	98.0	99.1	98.6	99.9	98.9	99.2	98.8	98.5	98.8	98.9	98.8	99.9	100.1	100.6	100.5	100	100.4	100.3	100.2	HPLC
Related substances (%)
Benzoic acid	0.16	0.17	0.16	0.13	0.12	0.15	0.17	0.13	0.13	0.15	0.17	0.13	0.04	0.01	0.011	0.05	0.07	0.13	0.16	0.07	HPLC‐UV
Thiamin HCl	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.
Total impurities	0.34	0.38	0.40	0.30	0.35	0.39	0.41	0.30	0.32	0.41	0.43	0.29	0.60	0.63	0.55	0.75	0.96	0.93	0.88	1.0
Microbiological parameters
TAPC (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	10	10	20	20	10	< 10	10	10	Ph. Eur. 5.1.4, 2.6.12 & 2.6.13 USP Chapter 61 and 62
TYM (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10
S. aureus (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.
P. aeruginosa (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.
Salmonella spp. in 10 g (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.
E. coli (CFU/g)	/	/	/	/	/	/	/	/	/	/	/	/	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.	N.D.

Abbreviations: ‘/’, not provided; HPLC, high‐performance liquid chromatography; HPLC–UV, high‐performance liquid chromatography with ultraviolet detector; IR, Infrared spectroscopy; N.A., not analysed; N.D., not detected; TAPC, total aerobic plate counts; TYM, total yeasts and moulds; USP, United States Pharmacopeia.

^*The applicant provided data also for timepoint 9, 18, 36, 48 months.

The Panel notes that no chemical or physical degradations were observed during the reported tests. As the microbial stability was provided only for three independently produced batches, no conclusion can be drawn with regard to the microbial stability during the proposed shelf‐life. The benfotiamine content remained between 98% and 101% w/w.

3.5. Specifications

The specifications of the NF as proposed by the applicant are shown in Table 7.

TABLE 7.

Specifications of the NF.

Description: Benfotiamine
Parameter	Specification
Appearance	White to pale yellow‐white crystalline powder
Assay, % w/w	98–102
Clarity of solution	Should be clear
Chloride, %	< 0.05
Sulphate, %	< 0.01
Loss on drying, % w/w	< 1.5
Related substances
Benzoic acid, %	0.5
Thiamin HCl, %	0.5
Total impurities, %	1.5
Metals and other elements	20
Lead (mg/kg)	≤ 0.5
Cadmium (mg/kg)	≤ 0.5
Mercury (mg/kg)	≤ 3
Arsenic (mg/kg)	1.5
Cobalt (mg/kg)	5
Vanadium (mg/kg)	10
Nickel (mg/kg)	20
Residual solvents
Methanol (mg/kg)	3000
Acetic acid (mg/kg)	5000

3.6. History of use of the NF

According to the applicant, several medicinal products containing benfotiamine as an active pharmaceutical ingredient have been authorised in Germany and Austria since 1998 and 2005, respectively. In particular, benfotiamine has been sold in Germany since 1998 under the name ‘Milgamma mono 50 mg’ and ‘Milgamma mono 150 mg’, and from 2005 as ‘Benfo 300 mg’, ‘Milgamma protekt’ or ‘Milgamma mono 300 mg’ for the treatment of neurological diseases, neuropathy and back pain. The applicant also provided surveillance data reports which were of limited value for the safety assessment of the NF.

The Panel notes that there is no history of safe use of benfotiamine as foodstuff.

3.7. Proposed uses and use levels and anticipated intake

3.7.1. Target population

The target population proposed by the applicant is adults, excluding pregnant and lactating women.

3.7.2. Proposed uses and use levels

The applicant intends to market the NF as a source of thiamin (vitamin B1) for use in food supplements at a maximum dose of 300 mg per day, which corresponds to an equimolar amount of 170 mg thiamin per day. The NF is intended to be sold as a food supplement in the form of capsules, tablets and powders.

3.7.3. Precautions and restrictions of use

The applicant indicated that the NF is not intended for children and adolescents under 16 years of age, due to lack of safety data for these population groups, and for pregnant and lactating women.

3.7.4. Estimate of exposure to undesirable substances

The Panel notes that benzoic acid was detected among the related substances of the NF. Based on the specification limit of 0.5 mg benzoic acid/kg and assuming that the daily intake of the NF would be up to 300 mg per day, the daily exposure for a 70‐kg body weight adult would be 2.14 × 10⁻⁶ mg/kg bw per day, which is below the ADI of 20 mg/kg bw per day for total exposure (JECFA, 2021(5)) or 5 mg/kg bw per day when used as food additive (EFSA ANS Panel, 2016), so it would not be of concern.

While the estimated exposure to benzoic acid at the proposed maximum use level is low and unlikely to be of toxicological concern, the Panel considers that it should be included in the impurity profile and appropriately controlled in the specifications of the NF.

3.8. Absorption, distribution, metabolism and excretion (ADME)

3.8.1. Absorption, distribution, metabolism and excretion (ADME)

The ADME of benfotiamine as compared to the ADME of natural sources of thiamin (EFSA NDA Panel, 2016a, 2016b) is briefly described below

Thiamin is a water‐soluble vitamin composed of a thiazole and a pyrimidine ring linked by a methylene group. It naturally occurs in its free form (plant foods) and in phosphorylated forms (foods of animal origin), which are hydrolysed in the intestine to free thiamin before absorption. Free thiamin is absorbed through the mucosal membrane by an active specific saturable transport system. Absorption efficiency decreases at thiamin intakes > 5 mg/day. In blood, thiamin is transported by a high‐affinity transporter into erythrocytes, where it is phosphorylated to thiamin monophosphate (TMP) and diphosphate (TDP), a fraction of which is further converted to thiamin triphosphate (TTP). About 80% of circulating thiamin is in erythrocytes as TDP or TTP, whereas concentrations of free thiamin in plasma are relatively low. Free thiamin is taken up by cells in tissues by an active transport system and converted to TDP, the active form of the vitamin which acts as cofactor for several energy‐yielding enzymatic processes. The concentrations of total thiamin (free thiamin and its phosphate esters) in whole blood, serum and erythrocytes are not related to the observed habitual thiamin intake and their response to thiamin supplementation is modest, whereas TDP concentrations in whole blood and erythrocytes, and the erythrocyte transketolase activity coefficient (α‐ETK) are good markers of thiamin status. Thiamin is excreted in urine mostly as free thiamin and its metabolites, the rate of excretion rapidly increasing with increasing intakes (EFSA NDA Panel, 2016a, 2016b).

In lipophilic thiamin derivatives of chemical synthesis, including benfotiamine, the thiazole ring is open, facilitating their passive and dose‐dependent transport across cell membranes in the intestinal mucosa, where benfotiamine is dephosphorylated to S‐benzoylthiamin and converted into the water‐soluble thiamin by hydrolysis of the benzoyl group. The benzoyl group is metabolised in the liver to benzoic acid, which is conjugated with glycine to form hippuric acid. Hippuric acid is then excreted in urine and the available data suggest that it does not accumulate in the body after multiple doses (Loew, 1996; Sheng et al., 2021; Xie et al., 2014).

3.8.2. Bioavailability of the NF

The applicant provided several publications identified in the literature to support the bioavailability of benfotiamine. These include an in vitro study on the determination of the dissociation constant (pKa) at several pH values between 2.96 and 5.42 (Angelov, 2021), an in vitro study comparing two different lipophilic thiamin analogues, sulbutiamine and benfotiamine, with respect to intracellular concentrations of TPP and PDH phosphorylation levels in cancer cells (Jonus et al., 2020), a study in mice with one oral dose of benfotiamine repeated for 14 days which measured thiamin derivatives in different tissues (Volvert et al., 2008), and one human intervention study investigating the effect of single oral doses (150, 300, 600, 900 or 1200 mg) and multiple ascending oral doses (150, 300, 600 mg once per day for 3 days and twice per day thereafter until day 10) of benfotiamine vs. placebo (unspecified) on TMP, TDP and TTP concentrations in whole blood (Sheng et al., 2021). The applicant also provided a review (Loew, 1996) of bioavailability studies comparing the pharmacokinetics of water‐soluble vs. lipophilic thiamin sources, including benfotiamine. These studies collectively show higher absorption, higher concentrations in blood and tissues, and longer retention rates (up to 8 days) of thiamin from benfotiamine as compared to water‐soluble forms (Woelk et al., 1998; Loew, 1996; Bitsch et al., 1991). The Panel notes that none of the studies compared oral doses of benfotiamine vs. water‐soluble forms of thiamin in equimolar amounts.

The Panel considers that the studies mentioned above support the bioavailability of benfotiamine as a source of thiamin in humans and provide evidence that the bioavailability of thiamin from benfotiamine may be higher than that from water‐soluble forms of thiamin.

3.8.3. Relative bioavailability of the NF and derivation of a conversion factor for labelling purposes

The applicant claims that maximum plasma levels of thiamin are about 5 times higher after benfotiamine intake and that the bioavailability is about 3.6 times higher than that of thiamin hydrochloride. The applicant provided one animal study and two human intervention studies identified in the literature to support the derivation of a conversion factor (CF) for benfotiamine.

One human study (Greb & Bitsch, 1998) compared three forms of liposoluble thiamin (benfotiamine, fursultiamin and thiamin disulfide), administered at a dose of 100 mg each. The Panel notes that this study did not include a water‐soluble thiamin reference and, therefore, cannot be used to derive a CF for benfotiamine.

A relative bioavailability study in broiler chickens compared two water‐soluble sources of thiamin (thiamin mononitrate and thiamin hydrochloride at doses of 1.5 and 1.8 mg/kg of feed each) and benfotiamine (at doses of 1.2 and 1.5 mg/kg of feed) administered for 21 days in relation to thiamin concentrations in blood, plasma and the liver, and the αETK (Geyer et al., 2000). Biochemical indices of thiamin status were significantly higher with benfotiamine than with the two water‐soluble thiamin forms, which did not significantly differ from each other. The authors note, however, that the difference between benfotiamine and water‐soluble thiamin cannot be quantified, which would require a dose‐titration experiment at lower doses.

The second human intervention study had an open label, randomised, two‐way crossover design that compared the effects of a single dose of benfotiamine (300 mg) with those of equimolar amounts of thiamin hydrochloride (220 mg) on thiamin, TMP and TDP concentrations in blood, plasma and erythrocytes (blood draw at baseline and 12 time points post dose over 24 h), as well as the 24‐h urinary excretion of hippuric acid, in 20 healthy young male volunteers (Xie et al., 2014). The Panel notes that the results of this study confirm a higher bioavailability of thiamin from benfotiamine as compared to thiamin hydrochloride. However, the Panel also notes that this relative bioavailability study was conducted only in males, that only one dose of benfotiamine and of the thiamin reference was used, and that only hippuric acid, and not free thiamin and thiamin metabolites, were assessed in urine.

The Panel considers that the data provided by this study are insufficient to derive a CF for benfotiamine as compared to thiamin hydrochloride for the general population across the dose‐range up to 300 mg consumed as food supplements.

3.8.4. Conclusions on ADME

The Panel considers that the evidence provided by the applicant is sufficient to establish that benfotiamine is bioavailable in humans, that it can be used as a source of thiamin and that it is more bioavailable than water‐soluble forms of thiamin. However, the Panel also considers that the data provided are insufficient to derive a CF for benfotiamine for labelling purposes.

3.9. Nutritional information

The NF consists of benfotiamine (> 98%) and is proposed to be used as a source of thiamin in food supplements intended for adults (≥ 18 years of age, providing up to 170 mg thiamin/day), excluding pregnant and lactating women.

Since thiamin requirements are dependent on energy intake, Dietary Reference Values for thiamin have been established on that basis (EFSA NDA Panel, 2016a, 2016b). A Population Reference Intake (PRI) of 0.1 mg/MJ (about 0.4 mg/1000 kcal) has been derived for adults, corresponding to daily intakes between 0.68 and 1.4 mg/day, considering average requirements (AR) for energy derived for adult men and non‐pregnant, non‐lactating women at different physical activity levels (PAL) (EFSA NDA Panel, 2016b). No tolerable upper intake level (UL) has been established for thiamin. The Scientific Committee on Food (SCF) noted that orally ingested thiamin has a very low risk of adverse effects because with intake levels higher than 5 mg, absorption rapidly declines and absorbed thiamin is actively excreted in the urine (SCF, 2001). The SCF also noted that no evidence of toxicity at oral intakes up to 500 mg/day (for 1 month), and that no adverse effects had been observed in humans, despite the fact that relatively high doses of thiamin up to 50–200 mg daily have been used therapeutically over long periods of time (months) as well as the widely available supplements providing intakes up to 50 mg/day without prescription (SCF, 2001).

The Panel notes that, unlike for water‐soluble thiamin, benfotiamine absorption is dose‐dependent and proportionally increases at high intakes (Section 3.8.4). The Panel also notes that a CF for benfotiamine vs. thiamin cannot be derived from the data provided for the whole range of intake under the proposed conditions of use (Section 3.7), and that the proposed maximum intake of 300 mg/day of the NF results in a thiamin intake that is more than 100 times above the PRI for thiamin for adults.

Based on the information and data provided, the Panel cannot conclude whether the consumption of the NF is nutritionally disadvantageous under the proposed conditions of use.

3.10. Toxicological information

The applicant provided an opinion of a pharmacologist as the main argument to address the safety concerns expressed by the EFSA ANS Panel (2008).

In this individual's opinion it is stated that, based on the minimum and median (L50) lethal doses for benfotiamine in rats established in the 1950–1960s (5 g/kg bw and 15 g/kg bw), which are higher than the OECD limit test dose of at least 1000 mg/kg bw per day, toxicological studies are not considered necessary. The opinion states that there are no genotoxicity, sub‐chronic toxicity, chronic toxicity and carcinogenicity, reproductive and development toxicity studies conducted with benfotiamine.

The applicant referred to a sub‐chronic toxicity study conducted in rats and mice in which 1428 mg/kg bw per day of thiamin disulphide monohydrate given orally for 8 weeks did not cause adverse effects (Szirmai et al., 1977). However, the Panel notes that the study was not conducted with benfotiamine and does not provide information on repeated dose toxicity of benfotiamine.

Due to uncertainties related to the characterisation of the NF and the lack of information on its metabolic fate, potential bioaccumulation and repeated dose toxicity effects, the applicant was requested to conduct in vitro genotoxicity studies in line with EFSA's guidance. Instead, the applicant referred to a published study (Schmid et al., 2008). The Panel considers that this study is not suitable for assessing the genotoxic potential of the NF because benfotiamine was tested only in combination with a genotoxic agent and the study investigated anti‐mutagenic rather than genotoxic effects. Therefore, the request for appropriate genotoxicity studies was reiterated by EFSA to the applicant, together with the request for information on the potential presence of small particles, including nanoparticles.

The applicant provided a bacterial reverse mutation (Ames) test performed using Salmonella Typhimurium strains TA98, TA100, TA1535, TA1537 and E. coli strain WP2 uvrA (pKM101) following OECD TG 471 (1997, corrected 2020), in a study compliant with the principles of GLP. ■■■■■

Owing to the lack of a correct characterisation of the fraction of small particles, including nanoparticles, of the NF (EFSA Scientific Committee, 2021a, 2021b), the Panel cannot confirm whether the toxicological testing strategy for the genotoxicity studies used by the applicant is appropriate to assess the safety of the NF.

3.10.1. Human data

No human studies investigating the safety of the NF have been provided by the applicant.

3.11. Allergenicity

The Panel considers that, owing to the synthetic nature of the NF and because the raw materials used in the production process do not contain proteins, peptides or other protein‐derived substances, it is unlikely that the NF will trigger allergic reactions in the target population under the proposed conditions of use.

4. DISCUSSION

The NF that is the subject of the application, benfotiamine, is proposed by the applicant for use in food supplements for adults, excluding pregnant and lactating women.

The safety of benfotiamine as a new nutrient source had been previously assessed by the EFSA ANS Panel (2008) and the data submitted were insufficient to demonstrate its safety at the proposed use and use levels.

The Panel notes that there is no history of safe use of benfotiamine as foodstuff.

No data were provided by the applicant to exclude potential concerns related to the presence of small particles, including nanoparticles, which remain an unaddressed uncertainty. In addition, the Panel considers that the NF is insufficiently characterised.

The studies provided by the applicant support the bioavailability of benfotiamine as a source of thiamin in humans and show that the bioavailability of thiamin from benfotiamine may be higher than that from water‐soluble forms of thiamin. However, the data provided were considered insufficient to derive a conversion factor for benfotiamine for labelling purposes.

The Panel notes the lack of data regarding the metabolic fate, bioaccumulation and repeated dose toxicity of benfotiamine, as well as the inadequacy of the genotoxicity study conducted with benfotiamine. In this respect, the Panel notes that the applicant provided insufficient toxicological data on benfotiamine.

Finally, owing to the above shortcomings, the Panel considers that the data submitted are insufficient to demonstrate the safety of the NF at the proposed use and use levels.

5. CONCLUSIONS

The Panel concludes that the safety of the NF, benfotiamine, cannot be established under the proposed conditions of use and that, although benfotiamine is a bioavailable source of thiamine in humans, a conversion factor for labelling purposes cannot be derived with the available data.

ABBREVIATIONS

ADME

absorption, distribution, metabolism and excretion

ANS

EFSA Panel on Food Additives and Nutrient Sources added to Food

bw

body weight

CF

conversion factor

CFU

colony forming units

DRV

dietary reference values

ESI‐MS

electrospray ionisation mass spectrometry

GMP

good manufacturing practice

HACCP

hazard analysis critical control points

HPLC–UV

high‐performance liquid chromatography‐ultraviolet detection

ICP–MS

inductively coupled plasma mass spectrometry

IR

infrared spectroscopy

IUPAC

International Union of Pure and Applied Chemistry

NDA

EFSA Panel on Nutrition, Novel Foods and Food Allergens

NF

novel food

NMR

Nuclear Magnetic Resonance Spectroscopy

NOAEL

no observed adverse effect level

OECD

Organisation for Economic Co‐operation and Development

SCF

Scientific Committee on Food

TAPC

total aerobic plate counts

TDP

thiamin diphosphate

TMP

thiamin monophosphate

TTP

thiamin triphosphate

TYM

total yeasts and moulds

UL

tolerable upper intake level

UL

upper levels

USP

United States Pharmacopeia

w/w

weight/weight

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2024‐00115

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PANEL MEMBERS

Dominique Turck, Torsten Bohn, Montaña Cámara, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch‐Ernst, Ángeles Jos, Alexandre Maciuk, Inge Mangelsdorf, Breige McNulty, Androniki Naska, Kristina Pentieva, Alfonso Siani and Frank Thies.

LEGAL NOTICE

Relevant information or parts of this scientific output have been blackened in accordance with the confidentiality requests formulated by the applicant pending a decision thereon by EFSA. The full output has been shared with the European Commission, EU Member States (if applicable) and the applicant. The blackening may be subject to review once the decision on the confidentiality requests is adopted by EFSA and in case it rejects some of the confidentiality requests.

EFSA NDA Panel (EFSA Panel on Nutrition, Novel Foods and Food Allergens) , Turck, D. , Bohn, T. , Cámara, M. , Castenmiller, J. , De Henauw, S. , Jos, Á. , Maciuk, A. , Mangelsdorf, I. , McNulty, B. , Naska, A. , Pentieva, K. , Siani, A. , Thies, F. , Cubadda, F. , Frenzel, T. , Gundert‐Remy, U. , Marcon, F. , McArdle, H. J. , … Hirsch‐Ernst, K. I. (2026). Safety of benfotiamine as a Novel food pursuant to Regulation (EU) 2015/2283 and the bioavailability of benfotiamine as a source of thiamin in the context of Directive 2002/46/EC on food supplements. EFSA Journal, 24(10), e10301. 10.2903/j.efsa.2026.10301