Safety and efficacy of a feed additive consisting of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one for all animal species other than dogs and cats (ADISSEO France SAS, ADM International Sàrl, Laboratoires Phodé S.A.S., LUCTA S.A., Norel, S.A.)

TL;DR

The paper evaluates the safety of a feed additive for animals other than dogs and cats, concluding it is safe at proposed levels but may cause irritation.

Contribution

The study confirms the safety of 4-hydroxy-2,5-dimethylfuran-3(2H)-one in feed for non-dog and non-cat animals at specified levels.

Findings

The additive is safe for all animal species other than dogs and cats at 10 mg/kg feed.

It is irritant to skin, eyes, and respiratory tract, and a dermal and respiratory sensitiser.

No further efficacy testing is needed as it is already authorised for cats and dogs.

Abstract

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the authorisation of a feed additive consisting of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one for all animal species other than dogs and cats. 4‐Hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is currently authorised for use as a sensory additive (functional group: flavouring compounds) for cats and dogs at a recommended maximum content of 18 and 25 mg/kg complete feed, respectively. The FEEDAP Panel concludes that the use of the additive 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one at the maximum use level proposed by the applicants (10 mg/kg complete feed) is safe for all animal species other than cats and dogs. 4‐Hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is safe for consumer and environment, however, it is irritant to skin, eyes and is a dermal and respiratory sensitiser. It should be considered irritant to the respiratory tract. Any exposure is considered a risk. 4‐Hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is used in food as a flavouring and its function in feed is essentially the same as that in food. Moreover, the Panel notes that the additive is already authorised in feed for cats and dogs. Therefore, no further demonstration of efficacy is necessary.

Tables

TABLE 1. Data on the batch‐to‐batch variation, impurities and physical properties of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one.

Parameter	Specification	Analysis
		Average	Range	# batches
Batch‐to‐batch variation
4‐Hydroxy‐2,5‐dimethylfuran‐3(2H)‐one 1 (%)	98	99.7	99.1–99.9	15
Impurities (mg/kg)
Lead			< 0.05	3
Mercury			< 0.005	3
Cadmium			< 0.01	3
Arsenic			< 0.10	3
Physical properties
Physical form		Solid
Bulk density (kg/m3)		1049
Solubility (g/L)			176 (at 20°C) 315 (at 25°C)
Dusting potential (Stauber Heubach) (mg/m3)			8–24	3
Shelf‐life (% recovery)
22°C – 24 months			99.8	1

TABLE 2. Maximum safe concentration in complete feed of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one for target animal species and categories calculated from the NOAEL of 200 mg/kg bw per day derived from a 2‐year carcinogenicity study in rats, as reference point.

Animal category	Default values for daily feed intake (g dry matter/kg)	Maximum safe use level (mg/kg complete feed) a
Chickens for fattening	79	22
Laying hens	53	33
Turkeys for fattening	59	30
Piglets	44	40
Pigs for fattening	37	48
Sows lactating	30	58
Veal calves (milk replacer)	19	100
Cattle for fattening	20	88
Dairy cows	31	57
Sheep/goat	20	88
Horses	20	88
Rabbits	50	35
Salmons	18	101
Ornamental fish	5	391

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 4(1) of that Regulation lays down that any person seeking authorisation for a feed additive or for a new use of feed additive shall submit an application in accordance with Article 7.

The European Commission received a request from Lucta S.A., ADM International Sàrl (represented in the EU by ADM Specialty Ingredients (Europe) BV), Norel S.A., Adisseo France S.A.S., Laboratoires Phodé SAS2 for the authorisation of the authorisation of the additive consisting of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one, when used as a feed additive for all animal species (except dogs and cats) (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 4(1) (authorisation of a feed additive or new use of a feed additive). The dossier was received on 14 November 2023 and the general information and supporting documentation are available at https://open.efsa.europa.eu/questions/EFSA‐Q‐2023‐00722. The particulars and documents in support of the application were considered valid by EFSA as of 05 March 2024.

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 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one, when used under the proposed conditions of use (see Section 3.1.2).

Additional information

1.2

EFSA issued an opinion on the safety and efficacy of furanones and tetrahydrofurfuryl derivatives: 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one, 4,5‐dihydro‐2‐methylfuran‐3(2H)‐one, 4‐acetoxy‐2,5‐dimethylfuran‐3(2H)‐one and linalool oxide (chemical group – CG 13) when used as flavourings for all animal species (EFSA FEEDAP Panel, 2012).

Another opinion has been issued by the FEEDAP Panel on the modification of the terms of authorisation regarding the maximum inclusion level of a feed additive consisting of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one for cats and dogs (EFSA FEEDAP Panel, 2024a).

The additive is currently authorised as a sensory additive (flavouring compounds) for use for cats and dogs (2b13010).3

DATA AND METHODOLOGIES

2

Data

2.1

The present assessment is based on data submitted by the applicants in the form of a technical dossier4 in support of the authorisation request for the use of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one as a feed additive.

The confidential version of the technical dossier was subject to a target consultation of the interested Member States from 8 March 2024 to 8 June 2024; the comments received were considered for the assessment.

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 17 July to 7 August 2024 for which no comments were received.

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 active substance in animal feed are valid and applicable for the current application.5

Methodologies

2.2

The approach followed by the FEEDAP Panel to assess the safety and the efficacy of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is in line with the principles laid down in Regulation (EC) No 429/20086 and the relevant guidance documents: Guidance on the assessment of the safety of feed additives for the users (EFSA FEEDAP Panel, 2023), Guidance on the assessment of the safety of feed additives for the consumer (EFSA FEEDAP Panel, 2017a), Guidance on the identity, characterisation and conditions of use of feed additives (EFSA FEEDAP Panel, 2017b), Guidance on the assessment of the safety of feed additives for the target species (EFSA FEEDAP Panel, 2017c), Guidance on the assessment of the efficacy of feed additives (EFSA FEEDAP Panel, 2024b), Guidance on the assessment of the safety of feed additives for the environment (EFSA FEEDAP Panel, 2019).

ASSESSMENT

3

The additive 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is currently authorised for use as a sensory additive (functional group: flavouring compounds) for cats and dogs with no minimum and no maximum content, but with a recommended maximum content of 18 mg/kg feed for cats and 25 mg/kg feed for dogs. The applicants are requesting the extension of the authorisation for all animal species other than dogs and cats.

Characterisation

3.1

Characterisation of the additive

3.1.1

4‐Hydroxy‐2,5‐dimethylfuran‐3(2H)‐one (racemate) (synonym: furaneol; strawberry furanone) is identified with the single Chemical Abstracts Service (CAS) number 3658‐77‐3, the EU Flavour Information System (FLAVIS) number 13.010. It has the molecular formula C_6_H_8_O_3_ and molecular weight 128.1 g/mol and belongs to the CG 13 for flavouring substances defined in Commission Regulation (EC) No 1565/2009 as ‘furanones and tetrahydrofurfuryl derivatives’.

The additive was characterised in a previous assessment (EFSA FEEDAP Panel, 2012). The applicants stated that no modifications in the composition or manufacturing process have been introduced since the previous assessment.

The additive is authorised for use in feed for cats and dogs with a purity of 98% and the applicants request to maintain the same specifications for the new use in all animal species (other than dogs and cats).

The data provided by the applicants on the batch‐to‐batch variation,7 impurities8 and physical properties9 ^,^ 10 ^,^ 11 of the additive are reported in Table 1.

The data provided showed compliance with the specifications of the current authorisation.

The FEEDAP Panel considers that the amounts of the detected impurities do not raise safety concerns.

Conditions of use

3.1.2

The additive is intended for use in feed for all animal species other than dogs and cats at a proposed maximum use level of 10 mg/kg feed.

Safety

3.2

No studies conducted with the additive under assessment were carried out by the applicants. In support of the safety of the additive, the applicants submitted some papers found in the literature. Those that have been considered relevant for the current assessment by the FEEDAP Panel are cited in the sections below.

Safety for the target species

3.2.1

In the previous assessment (EFSA FEEDAP Panel, 2012), the FEEDAP Panel concluded that 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one was safe at the maximum concentration proposed by the applicant of 5 mg/kg complete feed for all target species. Subsequently, the applicant requested the increase of the maximum recommended content to 25 mg/kg in cats and dogs. In its last opinion (EFSA FEEDAP Panel, 2024a), the Panel concluded that the additive is safe for dogs at the maximum use level of 25 mg/kg feed and for cats at 18 mg/kg complete feed. These maximum safe concentrations of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one in feed were derived from the lowest no observed adverse effect level (NOAEL) of 200 mg/kg body weight (bw) per day identified in a 2‐year carcinogenicity study in rats exposed to the additive under assessment. The NOAEL was identified based on reduced body weight gain and reduced survival in male rats at 400 mg/kg bw per day (Kelly & Bolte, 2003).12

The assessment of genotoxicity potential of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one was performed in a previous EFSA opinion, in which it was concluded that there was no concern for genotoxicity (EFSA CEF Panel, 2011).

The NOAEL of 200 mg/kg bw per day, identified and applied in the previous evaluation (EFSA FEEDAP Panel, 2012), is still considered valid for the current assessment. Applying an uncertainty factor (UF) of 100 to the NOAEL, the safe daily dose for the target species was derived following the EFSA FEEDAP Guidance on the safety of feed additives for the target species (EFSA FEEDAP Panel, 2017b), and thus the maximum safe feed concentration of the additive in complete feed was calculated (Table 2).

The maximum use level proposed by the applicants of 10 mg 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one/kg complete feed is safe for all the species listed in Table 2. These levels are extrapolated to related species in the same physiological stage. For other species not covered above, the lowest safe value of 18 mg/kg complete feed derived for cats in the previous opinion (EFSA FEEDAP Panel, 2024a) is considered as safe.

Therefore, the maximum use level of 10 mg 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one/kg complete feed is considered safe for all animal species (other than dogs and cats).

Conclusions on safety for the target species

3.2.1.1

The FEEDAP Panel concludes that the use of the additive 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one at the maximum use level proposed by the applicants (10 mg/kg complete feed) is safe for all animal species other than cats and dogs.

Safety for the consumer

3.2.2

In its previous assessment (EFSA FEEDAP Panel, 2012), the FEEDAP Panel considered that the safety of 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one for the consumers was already assessed by the CEF Panel (EFSA, 2008a, 2008b, 2011) and JECFA (2005) which concluded that the substance is safe for use in food. In its previous opinion (EFSA FEEDAP Panel, 2012), the Panel concluded that the use of the additive in feed for mammals is safe for the consumer. However, since the metabolic pathway(s) for 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one was not established in poultry and fish, and in the absence of residues in these target animals, the Panel could not conclude on the safety of the additive for the consumer when used in feed for birds and fish.

For the current assessment, no data were provided by the applicants on the absorption, distribution, metabolism, excretion and residues (ADMER) of the additive in the target species, and in particular in birds and fish. Instead, the applicants provided some data from the literature which indicates that, in humans and mice, 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is rapidly and extensively conjugated and excreted in urine as glucuronides (Roscher et al., 1997; Smith et al., 2018). Food‐producing animals, including ruminants, pigs, fish and birds are able to carry out conjugation reactions with sulphate and glucuronic acid (Gusson et al., 2006; James, 1987; Watkins III & Klaassen, 1986), producing water‐soluble derivatives that are eliminated with the bile and excreta. Therefore, mammals, fish and birds can also be assumed to have the ability to metabolise and excrete 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one and therefore, it is unlikely that 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one or metabolites would accumulate in tissues and cause a concern for consumer safety.

Conclusions on safety for the consumer

3.2.2.1

The FEEDAP Panel considers that the use of the additive in animal species at the maximum dose proposed is safe for the consumer.

Safety for the user

3.2.3

In the previous assessment (EFSA FEEDAP Panel, 2012), and in absence of data, the FEEDAP Panel concluded that it was prudent to treat 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one as irritant to skin, eyes and the respiratory tract and as skin sensitiser.

Based on the highest dusting potential measured value (see Section 3.1.1), the FEEDAP Panel considered that the exposure of users through inhalation is likely.

Based on the information present in the safety data sheet,13 the additive is irritant to the skin and eye and is a dermal and respiratory sensitiser. It should be considered irritant to the respiratory tract. Therefore, any exposure is considered a risk.

Safety for the environment

3.2.4

In the previous assessment on the safety and efficacy of the additive for all animal species, the FEEDAP Panel concluded that the use of the additive was safe for the terrestrial compartment when used at 0.5 mg/kg complete feed. Regarding the safety of the additive for the aquatic compartments, in the absence of ecotoxicity data or any well validated quantitative structure–activity relationships (QSAR) models for furans, it was not possible to assess the risk for surface water and groundwater (EFSA FEEDAP Panel, 2012).

For the current assessment, the applicants submitted results from a literature search including data on the natural occurrence of the additive in different environment compartments14 and a new ready biodegradability study15 conducted with the additive under assessment and in accordance with the OECD Testing Guideline 310.

The data from the literature demonstrate that 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is naturally present in several European plant species at concentration ranging from 0.016 (tomatoes, Mayer et al., 2002) to 37 mg/kg (ripen strawberry, Perez et al., 1996).

In addition, the biodegradation study, performed with the additive under assessment, showed that 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is readily biodegradable under aerobic conditions. Consequently, no safety concerns are expected from the use of the additive in terrestrial animals. In addition, since the substance is volatile and biodegradable, it is not expected to accumulate in marine sediments when used in feed for marine aquaculture.

Based on the new information available, the FEEDAP Panel concludes that 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is safe for the environment when used in animal nutrition under the proposed conditions of use.

Efficacy

3.3

In the previous assessment (EFSA FEEDAP Panel, 2012), the FEEDAP Panel concluded that since 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is used in food as a flavouring and its function in feed is essentially the same as that in food no further demonstration of efficacy is necessary. Moreover, the Panel notes that the additive is already authorised in feed for cats and dogs. The FEEDAP Panel reiterates the previous conclusions.

CONCLUSIONS

4

The FEEDAP Panel concludes that the use of the additive 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one at the maximum use level proposed by the applicants (10 mg/kg complete feed) is safe for the target species.

The use of the feed additive in animal nutrition under the conditions of use proposed is of no concern for the safety of the consumer and the environment.

The additive is irritant to the skin, eyes and respiratory tract and is a dermal a respiratory sensitiser. Any exposure is considered a risk.

Since 4‐hydroxy‐2,5‐dimethylfuran‐3(2H)‐one is used in food as a flavouring and in feed for cats and dogs, no further demonstration of efficacy is necessary.ABBREVIATIONSADMERabsorption, distribution, metabolism, excretion and residuesBWbody weightCASChemical Abstracts ServiceCEFEFSA Scientific Panel on Food Contact Materials, Enzymes, Flavourings and Processing AidsCGchemical groupEURLEuropean Union Reference LaboratoryFEEDAPEFSA Scientific Panel on Additives and Products or Substances used in Animal FeedFLAVISThe EU Flavour Information SystemNOAELno observed adverse effect levelOECDOrganisation for Economic Co‐operation and DevelopmentQSARquantitative structure–activity relationshipUFuncertainty factor

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2023‐00722

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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.

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.