Assessment of the feed additives menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711) (vitamin K₃ ) for all animal species for the renewal of their authorisation (DSM Nutritional Products Ltd, KH Boddin GmbH, Oxyvit Kimya San. Ve Tic. A.Ş., Orffa Additives BV, FNF Ingredients EU BV, ADM International SàRL)

Abstract

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the assessment of the application for the renewal of the authorisation of vitamin K₃ in the form of menadione sodium bisulphite (MSB) and menadione nicotinamide bisulphite (MNB) as nutritional feed additives. The additives MSB (3a710) and MNB (3a711) are currently authorised for use in all animal species. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the use of vitamin K₃ in the form of MSB and MNB remains safe for the target animals, consumer and for the environment under the approved conditions of the authorisation. Regarding user safety, the Panel concluded that exposure by any route is considered a risk and should be minimised. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

1. INTRODUCTION

1.1. Background and Terms of Reference

Regulation (EC) No 1831/2003 ¹ establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 14(1) of that Regulation lays down that an application for renewal shall be sent to the Commission at the latest 1 year before the expiry date of the authorisation.

The European Commission received a request from DSM Nutritional Products Ltd. (represented in the EU by DSM Nutritional Products Sp. z o.o.), KH Boddin GmbH, Oxyvit Kimya San. Ve Tic. A.Ş. (represented in the EU by Cromital SpA), Orffa Additives BV, FNF Ingredients EU BV and ADM International SàRL (represented in the EU by ADM Specialty Ingredients (Europe) B.V.) ² for the renewal of the authorisation of menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711), when used as feed additives for all animal species and categories (category: nutritional additives; functional group: vitamins, pro‐vitamins and chemically well‐defined substances having a similar effect).

According to Article 7(1) of Regulation (EC) No 1831/2003, the Commission forwarded the application to the European Food Safety Authority (EFSA) as an application under Article 14(1) (renewal of the authorisation). The dossier was received on 18 December 2024 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2024‐00717. The particulars and documents in support of the application were considered valid by EFSA as of 02 April 2025.

According to Article 8 of Regulation (EC) No 1831/2003, EFSA, after verifying the particulars and documents submitted by the applicants, shall undertake an assessment in order to determine whether the feed additive complies with the conditions laid down in Article 5. EFSA shall deliver an opinion on the safety for the target animals, consumer, user and the environment and on the efficacy of the feed additive consisting of vitamin K₃ as menadione sodium bisulphite and menadione nicotinamide bisulphite, when used under the proposed conditions of use (see Section null).

1.2. Additional information

Vitamin K₃, in the form of menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711), is currently authorised as a nutritional additive for use in feed for all animal species. ³ EFSA issued an opinion on the safety and efficacy of these products when used in feed for all animal species (EFSA FEEDAP Panel, 2014).

2. DATA AND METHODOLOGIES

2.1. Data

The present assessment is based on data submitted by the applicants in the form of a technical dossier ⁴ in support of the authorisation request for the use of vitamin K₃ as menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711) as a feed additive.

In accordance with Article 38 of the Regulation (EC) No 178/2002 ⁵ and taking into account the protection of confidential information and of personal data in accordance with Articles 39 and 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality, ⁶ a non‐confidential version of the dossier has been published on Open.EFSA.

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 05 May to 26 May 2025 for which no comments were received.

The confidential version of the technical dossier was subject to a target consultation of the interested Member States from 07 April 2025 to 07 July 2025; the comments received were considered for the assessment.

The FEEDAP Panel used the data provided by the applicants together with data from other sources, such as previous risk assessments by EFSA or other expert bodies, peer‐reviewed scientific papers, other scientific reports and experts' knowledge, to deliver the present output.

The European Union Reference Laboratory (EURL) considered that the conclusions and recommendations reached in the previous assessment regarding the methods used for the control of the vitamin K₃ as menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711) in animal feed are valid and applicable for the current application. ⁷

2.2. Methodologies

The approach followed by the FEEDAP Panel to assess the safety and efficacy of vitamin K₃ as menadione sodium bisulphite and menadione nicotinamide bisulphite is in line with the principles laid down in Regulation (EC) No 429/2008 ⁸ and the relevant guidance documents: Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2021).

3. ASSESSMENT

Vitamin K₃ in the form of menadione sodium bisulphite (MSB) (3a710) and menadione nicotinamide bisulphite (MNB) (3a711) is currently authorised as a nutritional additive (functional group: vitamins, pro‐vitamins and chemically well‐defined substances having a similar effect) for use in feed for all animal species. The present application is for the renewal of the above authorisations.

3.1. Characterisation

MSB and MNB are produced by chemical synthesis, and they appear as free‐flowing white to yellowish crystalline powder and powder, respectively. Both additives shall be incorporated into feed in the form of a premixture. ⁹

3.1.1. Menadione sodium bisulphite

MSB (International Union of Pure and Applied Chemistry (IUPAC name) sodium 2‐methyl‐1,4‐dioxo‐3H‐naphthalene‐2‐sulfonate trihydrate) is identified with the Chemical Abstracts Services (CAS) number 6147‐37‐1, and the European Community (EC) number 685‐346‐6. It has a molecular formula C₁₁H₉NaO₅S·3H₂O and a molecular mass of 330.29 g/mol.

The additive is obtained by chemical synthesis. The applicants stated that the manufacturing process of MSB remained unchanged since the previous authorisation. ¹⁰

MSB is currently authorised with a minimum purity of 96% which corresponds to a minimum of 50% menadione. The regulation also specifies that the additive contains not more than 45 mg/kg chromium. ¹¹

The data provided by the applicants on the batch‐to‐batch variation, impurities ¹² and physical properties ¹³ of the additive are reported in Table 1.

TABLE 1.

Data on the batch‐to‐batch variation, impurities and physical properties of menadione sodium bisulphite. The data presented are average values and (range) for batch‐to‐batch variation and ranges for impurities. The number of batches analysed or group of parameters is indicated in [].

Specification 1
Menadione sodium bisulphite (%)	≥ 96
Menadione (%)	≥ 50
Chromium (total, mg/kg)	≤ 45
Batch‐to‐batch variation	[13]
Menadione sodium bisulphite (%)	98.9 (98–99.9)
Menadione (%)	51.6 (51.1–52.1)
Chromium (total, mg/kg)	27.3 (13.4–41.2)
Water (%)	11.4 (10.7–12.21)
Free sodium bisulphite (%)	1.8 (0.03–4.5) [12]
Impurities (mg/kg)
Lead	< 0.02 (LOD)–< 5 [9]
Mercury	< 0.01–< 0.1 (LOD) [6]
Cadmium	< 0.003–< 0.1 (LOD) [6]
Arsenic	< 0.005 (LOD)–< 1 [12]
Residual solvents (mg/kg)
n‐Butanol	1.87–48 [4]
Ethanol	< 10 [3]
Physico‐chemical properties
Physical form	Crystalline powder
Bulk density (kg/m3)	580–700 [2]
Particle size distribution (laser diffraction) (% of particles below, v/v)
< 50 μm	37.27–47.14 [3]
< 10 μm	8.85–11.96 [3]

Note: <: means below the limit of quantification, unless otherwise indicated.

¹ Specifications set in Regulation (EU) No 2015/2307.

The data provided by the applicants showed compliance with the specifications set in the authorisation. The FEEDAP Panel considers that the amounts of the detected impurities do not raise safety concerns. The Panel notes that the levels of residual solvents are below the limits set by VICH (2023) and are of no concern.

Since the composition and the manufacturing process of the additive have not been changed since the last authorisation, the data on physico‐chemical properties, shelf‐life, stability and homogeneity previously assessed in the context of previous assessment are still considered valid (EFSA FEEDAP Panel, 2014). The applicants submitted new data on the shelf‐life and stability to feed processing which support the previous observations. ¹⁴

3.1.2. Menadione nicotinamide bisulphite

MNB (IUPAC name 2‐methyl‐1,4‐dioxo‐3H‐naphthalene‐2‐sulfonic acid;pyridine‐3‐carboxamide) is identified with the CAS number 73581‐79‐0, and the EC number 277‐543‐7. It has a molecular formula C₁₇H₁₆N₂O₆S and a molecular mass of 376.4 g/mol.

The additive is obtained by chemical synthesis. The applicants stated that the manufacturing process remained unchanged since the previous authorisation. ¹⁵

MNB is currently authorised with a minimum purity of 96% which corresponds to minimum of 43.9% menadione and minimum of 31.2% nicotinamide. The regulation also specifies that the additive contains not more than 142 mg/kg chromium. ¹⁶

The data provided by the applicants on the batch‐to‐batch variation, impurities ¹⁷ and physical properties ¹⁸ of the additive are reported in Table 2.

TABLE 2.

Data on the batch‐to‐batch variation and impurities of menadione nicotinamide bisulphite. The data presented are average values and (range) for batch‐to‐batch variation and ranges for impurities. The number of batches analysed or group of parameters is indicated in [].

Specification 1
Menadione nicotinamide bisulphite (%)	≥ 96
Menadione (%)	≥ 43.9
Nicotinamide (%)	≥ 31.2
Chromium (total, mg/kg)	≤ 142
Batch‐to‐batch variation	[19]
Menadione nicotinamide bisulphite (%)	97.6 (96.8–98.9)
Menadione (%)	44.6 (44.3–45.3)
Nicotinamide (%)	31.7 (31.3–32.2)
Chromium (total, mg/kg)	73.9 (29.6–128)
Water (%)	0.3 (0.1–0.5)
Impurities (mg/kg)
Lead	< 0.02 (LOD)–< 5 [13]
Mercury	< 0.01–< 0.1 (LOD) [7]
Cadmium	< 0.003–< 0.5 [7]
Arsenic	< 0.005 (LOD)–< 1 [18]
Residual solvents (mg/kg)
n‐Butanol	10.6–108.5 [5]
Ethanol	< 10–37 [3]
Physico‐chemical properties
Physical form	Powder
Bulk density (kg/m3)	570–710 [5]
Dusting potential (Stauber Heubach) (g/m3)	1.54–2.64 [2]
Particle size distribution (laser diffraction) (% of particles below, v/v)
< 50 μm	20.60–23.66 [3]
< 10 μm	5.58–9.31 [3]

Note: <: means below the limit of quantification, unless otherwise indicated.

¹ Specifications set in Regulation (EU) No 2015/2307.

The data provided by the applicants showed compliance with the specifications set in the authorisation. The FEEDAP Panel considers that the amounts of the detected impurities do not raise safety concerns. The Panel notes that the levels of residual solvents are below the limits set by VICH (2023) and are of no concern.

Since the composition and the manufacturing process of the additive have not been changed since the last authorisation, the data on physico‐chemical properties, shelf‐life, stability and homogeneity previously assessed in the context of previous assessment are still considered valid (EFSA FEEDAP Panel, 2014). The applicants provided new data on the shelf‐life of the additive which are in line with those reported in the previous opinion. ¹⁹ Also, new data were submitted on the stability of MNB during feed processing (pelleting or extrusion), which showed recoveries ranging approximately 75%–85%. ²⁰

3.1.3. Conditions of use

The additives are currently authorised for use in feed for all animal species with no minimum or maximum use levels. Under other provisions of the authorisation, ²¹ it is specified that:

1. The additive shall be incorporated into feed in the form of a premixture.

2. In the directions for use of the additive and premixtures, indicate the storage and stability conditions.

3. The following equivalency shall be used if the amount of the additive is labelled: 1 mg vitamin K₃ = 1 mg of menadione = 2 mg of menadione sodium bisulphite or 2.27 mg of menadione nicotinamide bisulphite.

4. Appropriate measures shall be taken to avoid the chromium emission in the air and prevent the exposure by inhalation or by dermal route. If such measures are technically not feasible or not sufficient, protective measures shall be taken according to national regulations implementing Union legislation on health and safety at work including Directives 89/391/EEC, 89/656/EEC, 92/85/EEC, 98/24/EC and Directive 2004/37/EC of the European Parliament and of the Council.

5. Appropriate protective gloves, respiratory and eye protection according to Council Directive 89/686/EEC shall be worn during handling.

The applicants did not request any change in the current conditions of the authorisation.

3.2. Safety

The safety of vitamin K₃ in the form of MSB and MNB was evaluated in its previous opinion (EFSA FEEDAP Panel, 2014). The FEEDAP Panel concluded that the additives are safe for all animal species at practical use levels in feed, for the consumers and for the environment. However, the Panel had concerns about the safety of MSB when administered via water for drinking because of the exposure of target animals to chromium (VI). Regarding user safety, the Panel concluded that MSB is an eye irritant; in the absence of adequate data, the additive should be considered a skin sensitiser. In the absence of data, MNB should be considered irritant to skin and eyes and a skin sensitiser. Considering the high dusting potential of MSB and MNB, the absence of data on inhalation toxicity and the chromium (VI) content of dust, inhalation exposure from handling of MSB and MNB could be hazardous.

The applicants declared that no incidents or safety issues for target animals, consumers, users and/or the environment have been documented or reported regarding the additives since their previous authorisation. ²²

For the present assessment, the applicants conducted an extensive literature search.

3.2.1. Extensive literature search

The applicants performed an extensive literature search (ELS) ²³ to provide evidence that, in the light of the current knowledge, the additive remains safe for the target species, consumers, users and the environment under the approved conditions. The literature search was conducted on five cumulative databases (OVID, PubMed, LIVIVO, PubChem, Toxinfo) and other sources (i.e. individual databases ²⁴ ) covering the period from 2013 to 2024. The search included terms relative to the safety of vitamin K₃ (e.g. menadione, hykinone, klotogen, etc.). The search strategy as well as the inclusion and exclusion criteria applied were properly described. A total of 20 hits were considered eligible and relevant by the applicants for the safety of the additive. These papers were screened by the FEEDAP Panel and those considered relevant for the safety for the current assessment are quoted in the corresponding chapters below.

3.2.2. Safety for the target species

In the previous opinion (EFSA FEEDAP Panel, 2014), the FEEDAP Panel concluded that MSB and MNB are safe for all animal species at practical use levels in feed and that it was not necessary to set a maximum content for either. Additionally, the Panel noted concerns regarding the use of MSB and MNB in water for drinking due to the potential increase in Cr(VI) exposure.

The ELS provided by the applicants identified eight publications of potential interest for the safety for the target animals. These papers were reviewed by the FEEDAP Panel, who considered two studies as relevant for the assessment of the safety for the target animals.

The two studies were conducted in finfish, either in largemouth bass (Wei et al., 2023) or in grass carps (Li et al., 2023). Wei et al. (2023) evaluated the effects of increasing levels of vitamin K₃ (from 0.78 to 20.85 mg/kg feed) on growth performance and antioxidant capacity. Results suggested that all measured parameters were improved for a certain range of vitamin K₃ supplementation (10.0–15.2 mg/kg feed), but the highest concentration (20.85 mg/kg feed) increased blood levels of malondialdehyde (MDA) and alanine aminotransferase (ALT), suggesting alterations in antioxidant capacity. Zootechnical performance was not adversely affected by vitamin K₃ supplementation at any concentration. Similar results were observed by Li et al. (2023) in which substantially higher levels of vitamin K₃ (25,000 mg/kg feed) were associated with increased oxidative stress and some alterations in immune parameters relative to the control group. It is noted that, when supplemented above the requirements, vitamin K₃ might lead to an impairment of the antioxidant capacity of some finfish. However, given the scarcity of data and the absence of clear adverse effects on performance or other key biomarkers, the FEEDAP Panel considers that there are no grounds that would lead to reconsider the previous conclusion.

3.2.2.1. Conclusions on safety for the target species

The FEEDAP Panel concludes that there is no new evidence to lead it to reconsider the previous conclusions that vitamin K₃ is safe for the target species under the authorised conditions of use.

3.2.3. Safety for the consumer and the environment

Considering that the manufacturing process and the composition of the additive have not been modified since the previous authorisation and no relevant new information was found in the literature search, the Panel concludes that the additives MSB and MNB remain safe for the consumer and the environment under the current conditions of the authorisation.

3.2.4. Safety for the user

In its previous opinion, the Panel concluded, based on studies, that MSB is not an irritant to skin but is an eye irritant. In the absence of adequate data, the additive was also considered a skin sensitiser. Similarly, in the absence of data, MNB was considered as irritant to skin and eyes and as a skin sensitiser. Considering the high dusting potential of MSB and MNB, the absence of data on inhalation toxicity and the chromium (VI) content of dust, inhalation exposure from handling of MSB and MNB could be hazardous.

No additional studies were submitted in the present application.

Based on the dusting potential measured (EFSA FEEDAP Panel, 2014), the FEEDAP Panel considers that the exposure of users through inhalation is likely.

One paper, retrieved by the literature search performed by the applicants, reports a case study in a pig farm worker who showed allergic contact dermatitis following exposure to MSB (Bianchi et al., 2015).

Based on the information present in the safety data sheet (SDS), ²⁵ MNB is an irritant to the skin and eyes.

In the absence of data of speciation of chromium present in the additive, the FEEDAP Panel considers that part of it might be chromium (VI). Chromium (VI) is classified under the CLP regulation as Carc. 1B and Skin Sens.1.

Considering the above, the Panel concludes that exposure by any route is considered a risk and should be minimised.

3.3. Efficacy

The present application for renewal of the authorisation does not include a proposal for amending or supplementing the conditions of the original authorisation that would have an impact on the efficacy of the additive. Therefore, there is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

3.4. Post‐market monitoring

The FEEDAP Panel considers that there is no need for specific requirements for a post‐market monitoring plan other than those established in the Feed Hygiene Regulation ²⁶ and good manufacturing practice.

4. CONCLUSIONS

The applicants provided evidence that the additives MSB and MNB currently in the market comply with the existing conditions of the authorisation.

The FEEDAP Panel concludes that the use of the additives under assessment remains safe for the target species, consumers and the environment under the authorised conditions of use.

Regarding user safety, exposure of users to the additives MSB and MNB by any route is considered a risk and should be minimised.

There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

5. RECOMMENDATION

Considering the content of non‐speciated chromium in MSB and MNB, the FEEDAP Panel reiterates its recommendation that the chromium content of all production batches be monitored and that the content of hexavalent chromium be reduced as much as possible.

ABBREVIATIONS

CAS

Chemical Abstracts Service

CLP

Classification, Labelling and Packaging

EEC

European Economic Community:

EURL

European Union Reference Laboratory

FEEDAP

EFSA Scientific Panel on Additives and Products or Substances used in Animal Feed

IUPAC

International Union of Pure and Applied Chemistry

LOD

limit of detection

MNB

menadione nicotinamide bisulphite

MSB

menadione sodium bisulphite

SDS

safety data sheet

VICH

Veterinary International Conference on Harmonisation

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2024‐00717

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PANEL MEMBERS

Roberto Edoardo Villa, Giovanna Azimonti, Eleftherios Bonos, Henrik Christensen, Mojca Durjava, Birgit Dusemund, Ronette Gehring, Boet Glandorf, Maryline Kouba, Marta López‐Alonso, Francesca Marcon, Carlo Nebbia, Alena Pechová, Miguel Prieto‐Maradona, Ilen Röhe, and Katerina Theodoridou.

EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed), Villa, R. E. , Azimonti, G. , Bonos, E. , Christensen, H. , Durjava, M. , Dusemund, B. , Gehring, R. , Glandorf, B. , Kouba, M. , López‐Alonso, M. , Marcon, F. , Nebbia, C. , Pechová, A. , Prieto‐Maradona, M. , Röhe, I. , Theodoridou, K. , Ørnsrud, R. , Galobart, J. , … Gkimprixi, E. (2025). Assessment of the feed additives menadione sodium bisulphite (3a710) and menadione nicotinamide bisulphite (3a711) (vitamin K₃ ) for all animal species for the renewal of their authorisation (DSM Nutritional Products Ltd, KH Boddin GmbH, Oxyvit Kimya San. Ve Tic. A.Ş., Orffa Additives BV, FNF Ingredients EU BV, ADM International SàRL). EFSA Journal, 23(12), e9792. 10.2903/j.efsa.2025.9792