Assessment of the feed additive neohesperidine dihydrochalcone (2b959) for piglets, pigs for fattening, calves, sheep, fish and dogs for the renewal of its authorisation (Adisseo S.A.S., ADM International Sàrl, Lucta S.A. and Norel S.A.)

TL;DR

This paper assesses the safety and authorization renewal of neohesperidine dihydrochalcone, a feed additive, for various animals including pigs, calves, and fish.

Contribution

The paper confirms the continued safety of neohesperidine dihydrochalcone without requiring re-evaluation of its efficacy.

Findings

The additive remains safe for target species, consumers, and the environment.

No modifications to the production process or efficacy were proposed.

The additive is not irritating to skin or eyes and is not a skin sensitiser.

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 neohesperidine dihydrochalcone as a sensory feed additive for piglets and pigs for fattening, calves, sheep, fish and dogs. The additive is already authorised for use in calves, sheep, fish, dogs and certain categories of pigs (2b959). The applicant provided evidence that the additive currently in the market complies with the existing conditions of the authorisation and that the production process has not been modified. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the additive remains safe for the target species, consumers and the environment. Neohesperidine dihydrochalcone is not irritant to skin and eyes and is not a skin sensitiser. The present application for renewal of the authorisation does not include any modification proposal that would have an impact on the efficacy of the additive, and therefore, there is no need to re‐assess the efficacy.

Tables

TABLE 1. Data on the batch‐to‐batch variation, impurities and physical properties of NHDC obtained from bitter orange (product A), pomelo (product B) and grapefruit (product C). The data presented are average values and ranges for batch‐to‐batch variation, and ranges for all other parameters. The number of batches is indicated in [].

	Product A (bitter orange)	Product B (pomelo)	Product C (grapefruit)
Specifications 1
Neohesperidine dihydrochalcone (% on dry basis)	≥ 96%	≥ 96%	≥ 96%
Ethanol (mg/kg)	5000	5000	5000
Batch‐to‐batch variation
Neohesperidine dihydrochalcone (% on dry basis)	98.4 (96.3–100.2) [17]	97.1 (96.2–98.9) [10]	96.8 (96.6–96.9) [5]
Water content (%)	6.81 (2.61–10.05) [9]	–	–
Loss on drying (%)	8.58 (7.53–10.27) [8]	7.36 (4.6–10.07) [10]	6.14 (5.46–7.21) [5]
Sulfated ash (%)	0.07 (0.0001–0.1) [7]	0.08 (0.02–0.19) [10]	0.05 (0.004–0.14) [5]
Substance‐related impurities 2
Neodiosmin (impurity B, %)	< 0.1 [3]	–	–
Naringin dihydrochalcone (impurity D, %)	0.11–1.46 [7]	–	–
Any other impurity (%)	< 0.1–0.13 [3]	–	–
Total impurities apart from neodiosmin (%)	0.3–1.45 [3]	–	–
Impurities
Lead (mg/kg)	< 0.05 [3]	< 0.02–< 10 [3]	< 0.05 [3]
Mercury (mg/kg)	< 0.005 [3]	< 0.001–< 0.1 [3]	< 0.001 [3]
Cadmium (mg/kg)	< 0.01 [3]	< 0.002–< 1 [3]	< 0.002 [3]
Arsenic (mg/kg)	< 0.1 [3]	< 0.002–< 1 [3]	< 0.002 [3]
Aflatoxins (B1, B2, G1, G2), (μg/kg)	< 1 [3]	< 1 [2]	–
Dioxins and furans (upper bound, 88% DM) 3
PCDD/Fs (ng WHO2005‐TEQ/kg)	0.114–0.124 [3]	0.121–0.126 [3]	0.061–0.078 [3]
PCDD/Fs + PCBs (ng WHO2005‐TEQ/kg)	0.176–0.191 [3]	0.185–0.282 [3]	0.086–0.100 [3]
nDL‐PCBs (μg/kg)	0.109–0.118 [3]	0.115–1.740 [3]	0.110 [3]
Residual solvents (mg/kg)
Ethanol	90.1–100.7 [3]	< 7 [2]	< 7.0–15.1 [3]
Methanol	6–8.5 [3]	< 3 [2]	< 3.0–10 [3]
Pesticides	Not detected [3]	Not detected [3]	Not detected [3]
Microbial contamination
Enterobacteriaceae (CFU/g)	< 10 [3]	< 10 [2]	–
Total aerobic counts (CFU/g)	< 10–40 [9]	< 10–30 [9]	< 10–85 [3]
Yeast and moulds (CFU/g)	≤ 10 [9]	< 10 [9]	< 10 [3]
Coliforms (CFU/g)	–	< 10 [7]	< 10 [3]
Escherichia coli (CFU/g or per 25 g)	Not detected [6]	Not detected [6] < 10 [1]	< 10 [3]
Staphylococcus aureus (per 25 g)	–	Not detected [1]	Not detected [3]
Salmonella spp. (per 25 g)	Not detected [9]	Not detected [9]	Not detected [3]
Physical properties
Bulk density (kg/m3)	409–526 [5]	399 [1]	398–480 [3]
Tap density (kg/m3)		–	460–570 [3]
Dusting potential (Stauber Heubach) (mg/m3)	1951–5742 [2]	1799 [1]	777–1218 [3]
Particle size distribution (laser diffraction)
D90 μm	22.8–51.4	– 4	57.2‐73.4
D50 μm	7.9–9.6		19.6–27.2
D10 μm	2.2–3.0 [2]		7.1–9.9 [3]
Shelf‐life (% recovery)
25°/60%RH, 36 months	98.9–99.3 [3]	100 [1]	–
40°C/75%RH, 6 months	99.8 [3]	–	–

Full text

INTRODUCTION

1

Background and Terms of Reference

1.1

Regulation (EC) No 1831/20031 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 Adisseo S.A.S, ADM International Sàrl (represented in the EU by ADM Specialty Ingredients), Lucta S.A. and Norel S.A.2 for the renewal of the authorisation of the additive consisting of neohesperidine dihydrochalcone, when used as a feed additive for piglets and pigs for fattening, calves, sheep, fish and dogs (category: sensory additives, functional group: flavouring compounds).

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 17 April 2024 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2024‐00245. The particulars and documents in support of the application were considered valid by EFSA as of 15 July 2024.

According to Article 8 of Regulation (EC) No 1831/2003, EFSA, after verifying the particulars and documents submitted by the applicant, 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 neohesperidine dihydrochalcone when used under the proposed conditions of use (see Section 3.1.2).

Additional information

1.2

The additive neohesperidine dihydrochalcone (NHDC) is currently authorised as a sensory feed additive (category: flavouring compound) for use in feed for calves, sheep, fish, dogs and certain categories of pigs (2b959).3 The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) issued two opinions on the safety and efficacy of NHDC when used in feed for these animal species (EFSA FEEDAP Panel, 2011, 2014). The FEEDAP Panel also adopted an opinion on the renewal of NHDC for piglets, pigs for fattening, calves, sheep, fish and dogs (EFSA FEEDAP Panel, 2025).

DATA AND METHODOLOGIES

2

Data

2.1

The present assessment is based on data submitted by the applicant in the form of a technical dossier4 in support of the authorisation request for the use of neohesperidine dihydrochalcone (2b959) as a feed additive.

In accordance with Article 38 of the Regulation (EC) No 178/20025 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 21 October to 11 November 2024, 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 19 July 2024 to 19 October 2024; the comments received were considered for the assessment.

The FEEDAP Panel used the data provided by the applicant 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 neohesperidine dihydrochalcone in animal feed are valid and applicable for the current application.7

Methodologies

2.2

The approach followed by the FEEDAP Panel to assess the safety and the efficacy of NHDC is in line with the principles laid down in Regulation (EC) No 429/20088 and the relevant guidance documents: Guidance on the renewal of the authorisation of feed additives (EFSA FEEDAP Panel, 2021).

ASSESSMENT

3

The additive neohesperidine dihydrochalcone (NHDC) is currently authorised as a sensory additive (functional group: flavouring compounds) for use in feed for piglets, pigs for fattening, calves, sheep, fish and dogs. The applicants are requesting the renewal of the authorisation.

Characterisation

3.1

Characterisation of the additive

3.1.1

The additive NHDC consists only of the active substance. Neohesperidine dihydrochalcone (International Union of Pure and Applied Chemistry (IUPAC) name: (1‐[4‐[(2S,3R,4S,5S,6R)‐4,5‐dihydroxy‐6‐(hydroxymethyl)‐3‐[(2S,3R,4R,5R,6S)‐3,4,5‐trihydroxy‐6‐methyloxan‐2‐yl]oxyoxan‐2‐yl]oxy‐2,6‐dihydroxyphenyl]‐3‐(3‐hydroxy‐4‐methoxyphenyl)propan‐1‐one) is identified with the Chemical Abstracts Service (CAS) number 20702‐77‐6, the European Community (EC) number 243‐978‐6 and the food flavouring EU flavour information system (FLAVIS) number 16.061. The molecular formula is C_28_H_36_O_15_ and the molecular weight is 612.58 g/mol.

The additive is an off‐white, odourless, crystalline powder with a characteristic, intense sweet taste. The additive is slightly soluble in water (0.4–0.5 g/L at 22°C) and the solubility in water increases with the temperature.

The additive is authorised with a content of at least 96% (on a dried basis) of NHDC and a maximum content of ethanol of 5000 mg/kg.9

The additive NHDC is obtained by the catalytic hydrogenation of the flavanone glycoside neohesperidine, which is extracted from the immature fruit of bitter orange (Citrus aurantium). An alternative starting material for the synthesis of NHDC is naringin, which is obtained from grapefruit (Citrus paradisi). Naringin can be converted to phloroacetophenone‐4′‐β‐neohesperidoside and further condensed with isovanillin, leading to the formation of neohesperidine (Borrego & Montijano, 2001). The applicants stated that the manufacturing process and the composition of the additive have not been modified since the previous authorisation.10 However, the applicants stated that the additive can also be obtained from naringin obtained from pomelo (Citrus maxima, previously Citrus grandis Osbeck). According to the applicants, the manufacturing process is independent of the botanical sources of the starting material and proceeds through the same intermediate stages and leads to the final product of NHDC that complies with the existing authorisation.11

The applicants provided data on the analysis of the batch‐to‐batch variation of the content of the active substance, impurities and physical properties for the additive under assessment manufactured with different starting materials (neohesperidine from bitter orange, naringin from pomelo or grapefruit), which are summarised in Table 1.12, 13, 14

In addition to the data reported above, more information was included in the certificates of analysis stating compliance with specifications for residual solvents and microbial contamination, in the absence of actual analytical data, these results were not considered in the table above.

The data provided showed compliance of the additive with the specifications set in the authorising regulation in terms of active substance and ethanol. The FEEDAP Panel notes that the use of naringin derived from pomelo as starting material does not result in a change in the concentration of the active substance in the additive. The Panel considers that the microbial contamination and the levels of the impurities15 analysed in the additive are of no concern.

Considering that the manufacturing process and the composition of the additive have not been changed since the previous authorisation, the data on physico‐chemical properties evaluated in the previous assessment (EFSA FEEDAP Panel, 2011) still apply. However, the applicants provided some additional data which are reported in Table 1.

Conditions of use

3.1.2

Neohesperidine dihydrochalcone is currently authorised for use in feed for piglets, pigs for fattening, calves, sheep, fish and dogs, with a maximum content of 35 mg/kg of complete feedingstuff.

Under other provisions of the authorisation,16 it is specified that:

1. In the directions for use of the additive and premixture, indicate the storage conditions.
2. For safety: breathing protection, safety glasses and gloves should be worn during handling.

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

Safety

3.2

The safety of NHDC for the target species, consumers, users and the environment was evaluated in previous opinions (EFSA FEEDAP Panel, 2011, 2014). The FEEDAP Panel considered that the additive was safe for the target animals, consumers and the environment under the proposed conditions of use. The additive was considered as a respiratory irritant.

The applicants state that no adverse effect notifications were received since the previous authorisation with respect to the safety for target animals, consumers, users/workers and the environment.17

The applicant performed an extensive literature search (ELS)18 to confirm that the additive remains safe for target species, consumers, users and the environment under the approved conditions. The search covered the period from 2010 to September 2023. Three cumulative databases (LIVIVO, OVID and PubMed), 13 single databases and publishers' search facilities, including Elsevier, Ingenta, Springer and Wiley, were used. The search terms and the inclusion/exclusion criteria were provided. In addition to the automatic ELS, an independent manual search of relevant articles for the safety of NHDC was conducted. The ELS and the manual search identified a total of 550 publications potentially relevant for the safety assessment of the additive under assessment. After the screening, 44 hits were considered eligible and relevant by the applicant. The FEEDAP Panel assessed all the publications and concluded that none of them identified new information that would lead to reconsider its previous conclusions. The only relevant reference is the opinion of the EFSA Panel on Food Additives and Flavourings (EFSA FAF Panel, 2022), which is briefly described in the next section.

Safety for the target species, consumer and the environment

3.2.1

The FAF Panel adopted an opinion on the re‐evaluation of NHDC (E959) as a food additive (EFSA FAF Panel, 2022). The information considered relevant for the current assessment of the safety of the target species and the consumer is briefly summarised below.

‘Based on the available in vivo studies in rats, the FAF Panel considered that, also in humans, NHDC is likely to be absorbed’ (partially unchanged and after hydrolysis in the gastrointestinal tract of the glycosidic moiety) ‘to become systemically available, both as the parent compound and as metabolites, which are excreted primarily with urine’. The FAF Panel also ‘concluded that NHDC does not raise a concern regarding genotoxicity’ based on the negative outcome of bacterial reverse mutation and in vitro micronucleus assays.

Based on the toxicological data set (consisting of studies on subchronic and prenatal developmental toxicity in rodents, none of which showed adverse effects up to the highest dose tested) and applying a weight of evidence analysis, the FAF Panel ‘considered it unlikely that NHDC can lead to adverse effects on health in animals in the dose ranges tested’. ‘The Panel derived an acceptable daily intake (ADI) of 20 mg/kg body weight (bw) per day based on a no observed adverse effect level (NOAEL) of 4000 mg/kg bw per day from a 13‐week study in rat, applying the standard default factors of 100 for inter‐ and intraspecies differences and of 2 for extrapolation from subchronic to chronic exposure. Considering the derived ADI of 20 mg/kg bw per day, the exposure estimates were below the reference value in all age groups. Therefore, the FAF Panel concluded that dietary exposure to the food additive neohesperidine dihydrochalcone at the reported uses and use levels would not raise a safety concern.’ The FEEDAP Panel notes that the ADI derived by the FAF Panel is higher than the previous ADI of 5 mg/kg bw per day set by the Scientific Committee on Food (SCF). Considering the limitations in the available data set, to derive the ADI the SCF selected the lowest NOAEL value of 500 mg/kg bw per day (the only dose tested) from all the studies available at that time (European Commission, 1989). The assessment of the FAF Panel is based on a body of evidence consisting of three animal studies, which were evaluated for different endpoints in a weight of evidence analysis, showing with high confidence that exposure to NHDC at the doses tested is not associated with adverse effects on health. Therefore, the data from the three animal studies evaluated were considered sufficient to establish a new ADI, corresponding to the highest dose tested. The FEEDAP Panel agrees with the conclusions of the FAF Panel.

None of the papers reviewed (including the published opinion on the re‐evaluation of NHDC made by the FAF Panel) provided information relevant to the safety for the target species, consumers and the environment that would lead the Panel to modify its previous conclusions. Therefore, the FEEDAP Panel concludes that the additive NHDC remains safe for the target species, consumers and environment under the current conditions of the authorisation.

Safety for the user

3.2.2

In the previous assessment, the FEEDAP Panel concluded: ‘No data relevant to an assessment of user safety were made available. The applicant considers that the additive in solid form is a possible respiratory irritant’ (EFSA FEEDAP Panel, 2011).

The dusting potential measured (Table 1) indicates that the exposure of users through inhalation is likely.

The applicant provided the report of two studies on skin and eye irritation in rabbits19 and a skin sensitisation study.20 Although the studies do not comply with the corresponding OECD TG, the results indicated are non‐irritant to skin and eyes, and it is not a skin sensitiser.

Based on the available evidence, the FEEDAP Panel concludes that the additive NHDC is not an irritant to skin or eyes and that it is not a dermal sensitiser.

Efficacy

3.3

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

CONCLUSIONS

4

The applicant provided evidence that the feed additive neohesperidine dihydrochalcone currently on the market complies with the existing conditions of authorisation.

The FEEDAP Panel concludes that the use of the additive in animal nutrition remains safe for the target animals, consumers and for the environment under the approved conditions of the authorisation.

The additive is not irritant to the eyes and the skin, and it is not a skin sensitiser.

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

ABBREVIATIONSADIacceptable daily intakeBWbody weightCASChemical Abstracts ServiceCFUcolony‐forming unitDL‐PCBsdioxin‐like polychlorinated biphenylsDMdry matterELSextensive literature searchEURLEuropean Union Reference LaboratoryFAFEFSA Panel on Food Additives and FlavouringsFEEDAPEFSA Scientific Panel on Additives and Products or Substances used in Animal FeedFLAVISThe EU Flavour Information SystemFL‐noFLAVIS numberIUPACInternational Union of Pure and Applied ChemistrynDL‐PCBsNon‐dioxin‐like polychlorinated biphenylsNHDCneohesperidine dihydroichalconeNOAELno observed adverse effect levelOECDOrganisation for Economic Co‐operation and DevelopmentPCBspolychlorinated biphenylsPCDDspolychlorinated dibenzo‐p‐dioxinsPCDFspolychlorinated dibenzofuransRHrelative humiditySCFScientific Committee on foodTEQtoxic equivalentWHOWorld Health Organization

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2024‐00245

COPYRIGHT FOR NON‐EFSA CONTENT

EFSA may include images or other content for which it does not hold copyright. In such cases, EFSA indicates the copyright holder and users should seek permission to reproduce the content from the original source.

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.