Safety of inulin‐propionate ester as a novel food pursuant to Regulation (EU) 2015/2283

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 inulin‐propionate ester as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF, which is the subject of the application, is a compound constituted by a natural polymer composed mainly of fructose moieties, polysaccharide inulin (65%–95% w/w), esterified with a short‐chain fatty acid (SCFA) moiety, propionic acid (5%–35% w/w). The NF is synthesised by the chemical reaction of inulin with propionic anhydride, under alkaline conditions and controlled temperature. The target population for the NF is the general population and it is intended to be used as an ingredient in cereal bars and fruit smoothie type beverages. Based on the provided studies investigating the metabolic fate of the NF, the Panel considers that the NF is not absorbed intact, but it is metabolised mainly in the large intestine to inulin and propionate which then exhibit normal metabolic fate of non‐digestible dietary fibre and SCFA, respectively. Taking into account physico‐chemical properties of the NF, the production process and metabolic fate of the NF, which do not raise safety concerns, and given that propionic acid and its salts were previously assessed by EFSA ANS Panel (2014), as well as that a large body of safety data were available on inulin, the Panel considers that no genotoxicity and subchronic toxicological studies are required on the NF. Despite the limitations of the provided human studies (primarily designed to investigate efficacy endpoints), the Panel notes that the NF, at doses up to 20 g/day for durations up to 12 months, appears to be generally well‐tolerated. The Panel concludes that the NF, inulin‐propionate ester, is safe for the general population under the proposed conditions of use.

1. INTRODUCTION

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

On 15 February 2018, Imperial College Hammersmith Campus submitted a request to the European Commission in accordance with Article 10 of Regulation (EU) N° 2015/2283 ¹ to place inulin‐propionate ester on the Union market as a novel food.

Inulin‐propionate ester is proposed for use in specific food categories, namely bread and rolls, cereal bars and fruit smoothie type beverages, intended to provide 5 g of inulin‐propionate ester per serving. The target population is the general population. Inulin‐propionate ester is not intended for use in infant or baby foods.

In accordance with Article 10(3) of Regulation (EU) 2015/2283, the European Commission asks EFSA to provide a scientific opinion on inulin‐propionate ester as a novel food.

1.2. Additional information

In 2014, the EFSA Panel on Food Additives and Nutrient Sources Added to Food (ANS) published an opinion on the re‐evaluation of propionic acid (E 280), sodium propionate (E 281), calcium propionate (E 282) and potassium propionate (E 283) as food additives. On the basis of a 90‐day study in dogs (BASF, 1988), the ANS Panel identified a no observed adverse effect level (NOAEL) of 0.3% propionic acid in the diet based on epithelial hyperplasia in the oesophagus in the 1% group (that recovered thereafter). This concentration was equivalent to the highest maximum permitted level (MPL) of propionic acid – propionates (3000 mg/kg) in food, in the category of bread and rolls. ² The ANS Panel also noted that the concentration provoking site of contact effect in the 90‐day study in dogs (1% propionic acid in the diet) was a factor of three times higher than the concentration of propionic acid – propionates in food at the highest permitted level. The ANS Panel concluded that an adequate daily intake (ADI) should not be derived because the only reported adverse effect to propionic acid exposure was observed at the site of contact and was a consequence of its irritating property. There was significant absorption of propionate anions but, despite some limitations in the available toxicological database, no systemic effects were reported in the toxicity studies. The overall conclusion of the ANS Panel was that for food as consumed, there would not be a safety concern from the maximum concentrations of propionic acid – propionates at their currently authorised uses and use levels as food additives (EFSA ANS Panel, 2014).

2. DATA AND METHODOLOGIES

2.1. Data

The safety assessment of this NF is based on data supplied in the application, information submitted by the applicant following EFSA's requests for supplementary and additional data identified by the Panel.

Administrative and scientific requirements for NF applications referred to in Article 10 of Regulation (EU) 2015/2283 are listed in Commission Implementing Regulation (EU) 2017/2469. ³

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, 2016). As indicated in this guidance, it is the duty of the applicant to provide all of the available (proprietary, confidential and published) scientific data, including both data in favour and not in favour to supporting the safety of the proposed NF.

In accordance with Article 38 of Regulation (EC) No 178/2002 ⁴ 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, ⁵ the non‐confidential version of the dossier has been published on Open.EFSA. ⁶

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: batch‐to‐batch analyses (including quantification of inulin and propionate, and in‐house analytical methods) and one human trial (Quinn et al., 2015, unpublished).

2.2. Methodologies

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

This assessment concerns only the risks that might be associated with 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.

In the context of this opinion, EFSA's definition of dietary fibre (i.e. non‐digestible carbohydrates plus lignin; EFSA NDA Panel, 2010) does not reflect the additional requirement of having a beneficial physiological effect demonstrated by generally accepted scientific evidence laid down in Annex I of Regulation (EC) 1169/2011 ⁷ for:

1. edible carbohydrate polymers which have been obtained from food raw material by physical, enzymatic or chemical means and,

2. edible synthetic carbohydrate polymers.

It is out of the scope of this opinion to establish whether the fraction of non‐digestible carbohydrates present in the NF meets the legal definition of dietary fibre in the EU or not.

3. ASSESSMENT

3.1. Introduction

This assessment refers to inulin‐propionate ester (IPE), produced by a chemical reaction between propionic anhydride and inulin, to be used as an ingredient in foods. The target population for the NF is the general population. The applicant indicated that, according to Article 3(2) of Regulation (EU) 2015/2283, this NF falls under the following category:

‘(i) food with a new or intentionally modified molecular structure, where that structure was not used as, or in, a food within the Union before 15 May 1997.’

3.2. Identity of the NF

The NF is a compound constituted by a natural polysaccharide polymer composed mainly of fructose moieties, inulin, partially esterified with a short‐chain fatty acid moiety, propionic acid. Inulin used in the production process of the NF is extracted from chicory root, following conventional manufacturing techniques and is a long‐chain inulin with a degree of polymerisation ≥ 23. According to the applicant, the targeted degree of esterification of the NF is 0.8, i.e. 26.6% of all hydroxyl groups are esterified. The final product is a fine, amorphous crystalline white to off‐white powder.

The presence of ester bonds was confirmed by Fourier transform infrared spectroscopy (FTIR). Analysis of free and bound (esterified) propionate in the NF was performed by gas chromatography (GC), before and after complete ester hydrolysis.

3.3. Production process

The NF is synthesised by the chemical reaction of inulin with propionic anhydride, under alkaline conditions and controlled temperature. After acidification, the ingredient is subjected to a series of purification steps (without using organic solvents) and spray‐dried to render an amorphous crystalline product. Upon the Panel's request, the applicant modified the purification process to reduce the sodium content (as a by‐product of the production process) in the NF.

The applicant provided certificates of analyses for inulin and propionic anhydride, which indicate purity of the two substances of at least 99.5% (dry matter) and 96.5%, respectively.

Regarding quality control of the manufacturing process, according to the applicant, it will be conducted in line with Good Manufacturing Practice (GMP) and Hazard Analysis and Critical Control Points (HACCP) principles. Steps of the quality control measures during the manufacturing process were provided.

The Panel considers that the production process is sufficiently described and does not raise safety concerns.

3.4. Compositional data

The applicant provided physico‐chemical (Table 1) and proximate (Table 2) analyses of the NF which were carried out using a number ⁸ of independently produced batches. As expected, the NF is largely comprised of carbohydrates with small amounts of water and sodium.

TABLE 1.

Batch‐to‐batch analysis of the NF.

Parameter (unit)	Product analyses for the NF				Technique
	Batch no
	#1	#2	#3	#4
Physical characteristics
Colour	White to off‐white	White to off‐white	White to off‐white	White to off‐white	Visual
Form	Powder	Powder	Powder	Powder	Visual
Chemical characteristics
FTIR spectrum	Conforms to standard	Conforms to standard	Conforms to standard	Conforms to standard	FTIR spectroscopy
Free propionic acid (% wt/wt)	0.70	0.17	0.19	0.11	GC–FID
Degree of esterification	0.74	0.74	0.74	0.74	By calculation

Abbreviations: FTIR, Fourier transformed infrared spectroscopy; GC–FID, gas chromatography–flame ionisation detector.

TABLE 2.

Proximate analysis of the NF.

Parameter (unit)	Batch no					Technique
	#1	#2	#5	#6	#7
Moisture (g/100 g)	3.46	3.40	3.50	3.69	3.66	Gravimetry
Total nitrogen (g/100 g)	< 0.1	< 0.1	< 0.1	< 0.1	< 0.1	Kjeldahl
Ash (g/100 g)	0.1	< 0.1	< 0.1	< 0.1	0.2	Gravimetry
Carbohydrates (g/100 g)	95.2	95.8	93.4	94.6	95.7	Calculation
Total sugars (g/100 g) a	< 0.1	< 0.1	< 0.1	< 0.1	< 0.1	HPAEC‐PAD
Total fat (g/100 g)	< 0.5	< 0.5	< 0.5	< 0.5	< 0.5	Soxhlet extraction b
Sodium (mg/100 g)	78	43	26	18	42	ICS‐OES/AES

Abbreviations: HPAEC–PAD, high performance ion exchange chromatography with pulsed amperometric detection; ICP–OES, inductively coupled plasma–optical emission/atomic emission spectrometry.

^a Fructose, galactose, glucose, lactose, maltose and sucrose.

^b As laid down in Regulation (EC) No 152/2009 of 27 January 2009 laying down the methods of sampling and analysis for the official control of feed.

Initially, fat content was quantified by acid hydrolysis with heat, followed by gravimetric determination and nuclear magnetic resonance spectroscopy (NMR). Such analyses reported a total fat content above the limit of quantification (LOQ) in some batches and relatively high levels of trans‐fatty acids. Upon a request from EFSA, the applicant re‐analysed these batches using an accredited method: Soxhlet – fat analysis without acid hydrolysis, which is the method for the ‘Determination of crude oils and fats’ in feed [as laid down in Regulation (EC) 152/2009]. These repeated analyses resulted in fat levels below the LOQ (< 0.5 g/100 g) for all batches tested (Table 2).

Upon a request from EFSA, the applicant conducted analyses in order to quantify inulin and propionate content in the NF. The applicant developed and validated a method (UV–Vis spectrophotometry) for analysis of the total carbohydrate content of the NF as a determinant for the content of inulin. Total propionate was measured by complete hydrolysis of the ingredient using concentrated orthophosphoric acid and heat (80°C, 1 h) to release the total propionate content of the NF, which was analysed using HPLC with refractive index detection (RID). The free propionate parameter was measured directly as free sodium propionate, after extraction in the acidified aqueous mobile phase and analysis by HPLC with RI detection. The ‘esterified propionate’ (%) of the NF has been calculated as the difference between the measured ‘Total propionate’ and ‘Free propionate’ contents in five batches of the NF (Table 3).

TABLE 3.

Batch‐to‐batch analyses of the NF on inulin and propionate content.

Parameter (unit)	Batch no					Technique
	#1	#2	#5	#6	#7
Inulin (% w/w)	89.9	81.7	86.0	80.8	86.2	UV–Vis spectrophotometry
Total propionate (g/kg)	188.7	207.3	220.9	245.0	254.1	HPLC‐RID
Free propionate (mg/kg)	2800	760	< 250	680	1040	HPLC‐RID
Esterified propionate (%) a	18.59	20.65	22.07	24.43	25.31	Calculation
Sum inulin‐propionate ester (%)	108.49	102.35	108.07	105.23	111.51	Calculation

Abbreviation: RID, refractive index detection.

^a Total propionate − free propionate (mg/kg)/ × 10,000.

Regarding chemical and microbiological contaminants, the results (see Appendix A) showed that the NF contains only traces of heavy metals (arsenic and chromium) in some batches, which are not of safety concern.

The Panel considers that the information provided on the composition of the NF is sufficient and does not raise safety concerns.

3.4.1. Stability of the NF

The presence of free propionate was identified as a key indicator of degradation of the NF, over a period of up to 4 years under storage at room temperature. The gas chromatography with flame ionisation detection (GC–FID) analysis of free and bound propionate allowed the quantitation of propionate in the NF aqueous solution before and after complete ester hydrolysis. The applicant provided stability data for three batches of the NF stored for approximately 1, 3 and 4 years, respectively (Table 4).

TABLE 4.

Total and free propionic acid concentrations in the NF as key indicator of stability of the NF.

Parameter (unit)	Batch no
	#8		#9		#10
Storage time	0 month	10 months	0 month	32 months	0 month	45 months
Free propionate (g/100 g IPE) a	0.14	0.15	0.19	0.32	0.76	0.76
Sum of esterified and free propionate (g/100 g IPE) a	23.57	23.94	19.98	20.35	20.50	19.82

^a Calculated as a reference to internal standard (*2.375)

In addition to total and free propionic acid analyses, the applicant provided analyses on five independently produced batches to support microbiological stability of the NF during extended storage periods for up to 4 years at room temperature. The batches were stored for 2, 3, 6.5 months and one batch for 4 years (Table 5).

TABLE 5.

Microbiological testing of five independent batches of the NF.

Parameter (unit)	Batch No					Method of analysis
	#11	#12	#13	#14	#15
Storage time	2 months	3 months	3 months	6.5 months	4 years
Total aerobic count (CFU/g)	< 4000	< 4000	< 4000	< 4000	< 4000	BS EN ISO 4833‐2:2013
Enterobacteriaceae (CFU/g)	< 10	< 10	< 10	< 10	< 10	BS ISO 21528‐2:2004
E. coli (CFU/g)	< 10	< 10	< 10	< 10	< 10	BS EN ISO 16649‐2:2001
L. monocytogenes (/25 g)	Negative	Negative	Negative	Negative	Negative	BS EN ISO 11290‐1:1996

Abbreviation: CFU, colony forming units.

3.4.2. Stability under the intended conditions of use

To test the stability of the NF under the intended conditions of use, the applicant investigated physico‐chemical characteristics of different solutions of the NF under different temperatures and pH levels, which simulated food processing conditions. Mainly, changes in colour were observed in the NF solutions.

As the main criteria for stability of the NF in proposed food matrices (i.e. cereal bars and fruit smoothies; Table 6), the applicant analysed the content of free propionate, i.e. the release of propionate from the NF into a food matrix. In the selected food matrices, i.e. cereal bar (flapjack) and smoothie, free propionate was analysed by size‐exclusion ion chromatography with conductivity detection (LOD < 0.005 g/100 g). Inulin was used in control samples. All tests were done at the end of the shelf‐life of the tested food products, i.e. 14 days for cereal bars and 7 days for fruit smoothies, respectively.

TABLE 6.

Free propionate in representative food products for proposed use.

Food product	Concentration of the NF in final product	Free propionate a – Range (g/100 g)	Shelf‐life	Storage conditions
Cereal bar (flapjack)
+ inulin (control)	6.25 g/100 g	< 0.05	14 days	Sealed and stored at room temperature
+ #1		0.0282–0.0421
+ #3		0.0180–0.0224
+ #4		0.0235–0.0275
Smoothie
+ inulin (control)	2.5 g/100 g	< 0.05	7 days	Sealed and stored at 4°C
+ #1		0.0115–0.0139
+ #3		0.0116–0.0140
+ #4		0.0105–0.0122

^a Analyses were conducted on 5 replicates of each batch of the NF.

The Panel notes that the concentrations used of the NF in food products in the provided stability tests were lower than the proposed use levels of the NF in food products ‘cereal bars’ and ‘fruit smoothies’ (see Section  3.7 Proposed uses and use levels, Table 9). Upon EFSA's request and in order to get maximum values of the free propionate content at proposed uses and use levels, the applicant provided estimates on a proportional basis (Table 7), using the results from the stability test (Table 6).

TABLE 9.

Proposed uses and maximum use levels of the NF.

FoodEx2 level	FoodEx2 code	Food category	Max use level (mg NF/100g)
3	A00EY	Cereal bars	17 g/100 g
4	A03DF	Fruit smoothies	3 g/100 mL

TABLE 7.

Theoretical content of free propionate at proposed use levels of the NF.

Proposed use	Theoretical content of free propionate at proposed use levels a based on analytical data from stability study b – Range (g/100 g) c
Cereal bars	0.049–0.114
Fruit smoothie type beverages	0.0126–0.0168

^a As proposed in Section  3.7 Proposed uses and use levels, Table 9.

^b Results presented in Table 6.

^c Calculated as (proposed use levels [g/100 g basis]/levels used in stability study [g/100 g basis]) × free propionate from stability study.

Taking into consideration proposed uses and use levels, the results of the stability test indicated that content of free propionate in food matrices would be up to 0.11% (Table 7).

The Panel considers that the NF is stable up to 45 months based on one batch tested.

3.5. Specifications

The specifications of the NF are indicated in Table 8.

TABLE 8.

Specifications of the NF.

Parameter (unit)	Specification	Technique
Description	Inulin‐propionate ester obtained by synthesis from inulin and propionic anhydride
Appearance (colour)	White to off‐white	Visual
Appearance (form)	Powder	Visual
FTIR spectrum	Conforms to standard	FTIR spectroscopy
Inulin (% w/w)	65 to 95	UV spectrophotometry
Free propionic acid (% w/w)	< 1.0	Gas chromatography
Esterified propionate (% w/w)	5 to 35	By calculation
Inulin‐propionate ester (% w/w)	100 to 112	By calculation
Total nitrogen (g/100 g)	< 0.1	Kjeldahl
Total fat (g/100 g)	< 0.5	Soxhlet extraction a
Sodium (% w/w)	< 0.1	Internal Method (ICP–OES)

Abbreviations: FTIR, Fourier transformed infrared spectroscopy; ICP–OES, inductively coupled plasma–optical emission spectrometry.

^a As laid down in Regulation (EC) 152/2009: Soxhlet – fat analysis without acid hydrolysis, which is the method for the ‘Determination of crude oils and fats’ in feed.

The Panel considers that the information provided on the specification of the NF is sufficient.

3.6. History of use of the NF and/or of its source

The NF does not have any previous history of use.

However, inulin and propionic acid, as source materials of the NF, both have a well‐known history of food use in the EU.

Inulin is a naturally occurring polysaccharide typical for many plant species and is classified as a dietary fibre.

The applicant stated that inulin, used in the preparation of the NF, is present in the current EU food supply. In addition, chicory‐derived inulin has a generally recognised as safe (GRAS) status in the USA since 2003 for use in variety of food applications ⁹ and is authorised to be used in all unstandardised foods in Canada. ¹⁰

Regarding the second constituent of the NF, propionic acid, it is produced by certain bacteria and occurs in various food and feedstuffs (EFSA ANS Panel, 2014). In addition, it is also used as a food additive (E 280), as its sodium, calcium and potassium salts (E 281–283). ¹¹

3.7. Proposed uses and use levels and anticipated intake

3.7.1. Target population

The target population proposed by the applicant is the general population.

3.7.2. Proposed uses and use levels

Initially, the applicants' intention was to use the NF as an ingredient in specific food categories (breads and rolls, cereal bars and fruit smoothies). However, due to stability issues, i.e. higher release of propionic acid in category ‘breads and rolls’ (0.55%), the applicant has decided to remove this food category from the proposed conditions of use. Therefore, two food categories (cereal bars and fruit smoothies, as defined using the FoodEx2 hierarchy ¹² ) remained to which the NF is proposed to be added in the amounts of 5 g per serving. The maximum use levels are expressed as g of NF/100 g or g of NF/100 mL (Table 9) and were obtained by converting use levels expressed on a serving basis (i.e. 5 g/serving) using the Food Portion Sizes (i.e. 30 g for cereal bars and 167 g for fruit smoothies, respectively) established by the UK Food Standards Agency (FSA, 2002).

3.7.3. Anticipated intake of the NF

EFSA performed an intake assessment of the anticipated daily intake of the NF based on the applicant's proposed uses and maximum proposed use levels (Table 9), using the EFSA Dietary Exposure (DietEx) Tool, ¹³ which is based on individual data from the EFSA Comprehensive European Food Consumption Database (EFSA, 2011). The lowest and highest mean and 95th percentile anticipated daily intake of the NF [on a mg/kg body weight (bw) and on an absolute basis], among the EU dietary surveys, are presented in Tables 10 and 11, respectively.

TABLE 10.

Daily intake estimate (on a body weight (bw) basis) of the NF resulting from its use as an ingredient in the intended food categories at the maximum proposed use levels.

Population group	Age group (years)	Mean intake (mg/kg bw per day)		P95 intake (mg/kg bw per day)
		Lowest a	Highest a	Lowest b , c	Highest b , c
Infants	< 1	0.2	14.0	0	0
Young children d	1 to < 3	0.9	16.7	0	107.6
Other children	3 to < 10	0.1	10.4	0	81.0
Adolescents	10 to < 18	0.9	7.6	0	62.5
Adults	≥ 18	0.5	5.5	0	47.2
Pregnant women	–	0.6	4.7	0	39.4
Lactating women	–	1.2	29.6	0	111.1
Vegetarians e	–	26.2	26.2	156.3	156.3

Abbreviation: bw, body weight.

^a Intakes are assessed for all EU dietary surveys available in the food comprehensive database on 4/6/2025. The lowest and the highest averages observed among all EU surveys are reported in these columns.

^b Intakes are assessed for all EU dietary surveys available in the food comprehensive database on 4/6/2025. The lowest and the highest P95th observed among all EU surveys are reported in these columns (P95 based on less than 60 individuals are not considered).

^c The value is 0 as less than 5% of individuals consumed the concerned foods.

^d Referred as ‘toddlers’ in the EFSA Food Consumption Comprehensive Database (EFSA, 2011).

^e https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/sp.efsa.2020.EN‐1923.

TABLE 11.

Daily intake estimate (on an absolute basis) of the NF resulting from its use as an ingredient in the intended food categories at the maximum proposed use levels.

Population group	Age group (years)	Mean intake (mg/day)		P95 intake (mg/day)
		Lowest a	Highest a	Lowest b , c	Highest b , c
Infants	< 1	1.8	119	0	0
Young children d	1 to < 3	12.0	210.6	0	1500
Other children	3 to < 10	2.9	260.2	0	2267
Adolescents	10 to < 18	44.2	373.5	0	3090
Adults	≥ 18	35.0	372.1	0	3400
Pregnant women	–	44.1	310.9	0	2250
Lactating women	–	81.0	1910	0	6000
Vegetarians e	–	1674	1674	8500	8500

^a Intakes are assessed for all EU dietary surveys available in the food comprehensive database on 4/6/2025. The lowest and the highest averages observed among all EU surveys are reported in these columns.

^b Intakes are assessed for all EU dietary surveys available in the food comprehensive database on 4/6/2025. The lowest and the highest P95 observed among all EU surveys are reported in these columns (P95th based on less than 60 individuals are not considered).

^c The value is 0 as less than 5% of individuals consumed the concerned foods.

^d Referred as ‘toddlers’ in the EFSA Food Consumption Comprehensive Database (EFSA, 2011).

^e https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/sp.efsa.2020.EN‐1923.

The estimated daily intake of the NF for each population group from each EU dietary survey is available in the Excel file annexed to this scientific opinion (under Supporting Information).

As reported in Table 10, the highest estimates of mean and high‐level (on 95th percentile) chronic intake on a body weight basis (mg NF/kg bw per day) were noted for lactating women (29.6 and 111.1 mg/kg bw per day, respectively) and vegetarians (26.2 and 156.3 mg/kg bw per day, respectively). Regarding the estimates on an absolute basis (Table 11), mean and high‐level intakes for the same two sub‐groups were 1910 and 6000 mg/day for lactating women and 1674 and 8500 mg/day for vegetarians.

3.7.4. Precautions and restrictions of use

Individuals with rare genetic disorders of propionate metabolism (propionic acidaemia) should be advised to avoid the consumption of the NF because it is a source of propionate.

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

The applicant provided a series of human intervention studies to address the fate of the NF upon human consumption.

Two studies conducted with 10 g of the NF in healthy normal‐weight and overweight individuals, which used ¹³C‐labelled inulin‐propionate ester, show that the NF dissociates in the GI tract to the soluble fibre inulin and the SCFA propionic acid, and that propionic acid becomes then available for absorption and metabolism, being oxidised to CO₂ within 24 h (Chambers et al., 2015; Polyviou et al., 2016). A third intervention study comparing 10 g of the NF versus 10 g of inulin in non‐obese individuals also showed that serum SCFA (acetate, propionate, butyrate) did not differ between the interventions at 240 min post ingestion. Only serum concentrations of butyrate significantly increased at 240 min versus baseline in both groups (Byrne et al., 2016).

The Panel notes that inulin is not hydrolysed by human digestive enzymes due to its β(2 → 1) and β(2 → 6) glycosidic linkages (Flamm et al., 2001). As a non‐digestible carbohydrate, inulin passes intact into the colon where it is subject to fermentation by colonic microbiota, resulting in the production of gases (e.g. hydrogen, carbon dioxide) and short‐chain fatty acids (SCFAs), including propionic acid. The Panel also notes that SCFAs, including propionic acid, are utilised as energy sources by the resident microbiota in the colon or are absorbed by colonocytes, where they are used as source of energy (especially butyrate) and/or are released into the circulation (Den Besten et al., 2013). After that, SCFAs are transported to the liver via the portal circulation and are extensively metabolised, with approximately 80% being oxidised to carbon dioxide and excreted by exhalation (EFSA ANS Panel, 2014).

The Panel considers that the NF is not absorbed intact, but it is metabolised mainly in the large intestine to inulin (a dietary fibre which is not absorbed) and propionic acid (a SCFA which is systemically available). A smaller fraction of propionic acid seems to be released from the NF before entering the colon and is available for absorption in the small intestine (Chambers et al., 2015). Available studies indicate that a major part of propionic acid, once absorbed, undergoes oxidation to CO₂ within 24 h (Chambers et al., 2015; Polyviou et al., 2016).

3.9. Nutritional information

The Panel notes that the NF consists of inulin (a non‐digestible carbohydrate which is fermented by colonic bacteria) and propionic acid (SCFA).

The dietary reference values (DRVs) expressed as adequate intakes (AIs) for fibre amount to 25 g/day for adults and 10 to 21 g/day for children aged 1 to 17 years and were established to ensure a normal laxation (EFSA NDA Panel, 2010).

The Panel notes that the observed highest mean and 95th percentile intakes of the NF (Table 11) are below the AI for fibre. Thus, the intake of the non‐digestible carbohydrate inulin, which accounts for approximately 85% of the NF (see Table 3), is not of nutritional concern.

The Panel considers that the amount of sodium in the NF produced by the final production process is negligible for the total daily intake.

The Panel considers that at the proposed levels of intake, the NF is not nutritionally disadvantageous.

3.10. Toxicological information

3.10.1. General considerations

Inulin is a dietary fibre and as such, high intakes have not been associated with any adverse health effects other than gastrointestinal symptoms (Carabin & Flamm, 1999; Mysonhimer & Holscher, 2022). EFSA ANS Panel (2014) considered that the mode of action of propionic acid causing adverse effects in animal studies (i.e. reversible diffuse epithelial hyperplasia in the oesophagus) was due to its concentration in the animal feed, and not the dose. Based on the findings in a 90‐day study on Beagle dogs, the LOAEL was considered to be 1% and the NOAEL 0.3% propionic acid in the diet, respectively. Since the only reported adverse effect to propionic acid exposure was observed at the first site of contact (irritating property), no ADI was established for propionic acid – propionates.

Taking into account physico‐chemical properties of the NF, the production process, metabolic fate and the proposed conditions and use levels of the NF, which do not raise safety concerns, the Panel considers that no genotoxicity and subchronic toxicological studies on the NF are required.

Thus, the main consideration of the Panel was stability of the NF under proposed conditions of use, i.e. release of the propionic acid in relevant food matrices. As shown in the Section  3.4.2 Stability under the intended conditions of use, maximum release of propionic acid can be up to 0.11%, which is below the established NOAEL of 0.3% of propionic acid in the diet (EFSA ANS Panel, 2014).

The only animal study, submitted by the applicant, was on a chemical compound similar to the NF; a dietary study in rats (Peters, 2010), described in the following section.

3.10.2. Other animal studies

Peters (2010) conducted a battery of studies using a product named ‘propionate inulin ester’ with a lower degree of esterification (0.25 and 0.5) compared to the NF (0.74). The Panel notes that these studies were not designed to assess toxicological profile of the test substance, but rather focused on specific endpoints (i.e. intestinal effects).

In these studies, no adverse changes in gut architecture of rats and mice have been reported following administration of propionate inulin ester in the diet at a concentration up to 10% for 21 days. The applicant calculated that this concentration of propionate inulin ester of 10% w/w (100 g/kg) is equivalent to 20 g/kg bw per day, using a food conversion factor of 0.2 for subacute study on mice (EFSA SC, 2012). Feeding rats with diets containing > 10% propionate inulin ester resulted in diarrhoea, reductions in food consumption and body weight, as well as an enlargement of the caecum. These effects are known phenomena associated with high intake of fibre and they were not statistically different from those observed following administration of inulin.

3.10.3. Human data

The applicant provided eight publications reporting on human intervention studies using the NF as the test substance (Byrne et al., 2016, 2019; Chambers et al., 2015; Chambers, Byrne, Morrison, et al., 2019; Chambers, Byrne, Rugyendo, et al., 2019; Malkova et al., 2020; Polyviou et al., 2016; Pugh et al., 2024). The key characteristics of these eight publications (some including multiple studies) are summarised in the Appendix B.

The NF was typically provided as a powder in sachets, either mixed into the habitual diet (n = 2), beverages such as drinks, water or smoothies (n = 3), or incorporated into bread rolls (n = 1). In several studies, it was administered with a meal, such as breakfast or lunch (n = 3). Doses of the NF ranged from 10 to 20 g/day. The intervention duration varied from acute (single dose) studies (n = 2) to short‐term interventions of 7 days (n = 2), 4 weeks (n = 1), 6 weeks (42 days) (n = 2) and longer‐term interventions of 24 weeks (n = 1) and up to 12 months (n = 1). The number of subjects per study assigned to the NF (or completing the IPE arm) ranged from 9 to 135 (in the IPE arm of the largest study, Pugh et al., 2024, which enrolled 270 subjects in total).

Most studies assessed gastrointestinal (GI) tolerance, commonly using visual analogue scales (VAS) for symptoms such as nausea, bloating, flatulence and stomach discomfort, or through general adverse event reporting. Several studies assessed clinical chemistry parameters (e.g. fasting glucose, lipids, liver function tests, HbA1c, C‐reactive protein) and vital signs (blood pressure, pulse). Hormones related to appetite regulation (e.g. PYY, GLP‐1) were frequently measured, as well as inflammatory markers. The systematic reporting of a comprehensive list of haematological parameters was not provided across the studies.

The most frequently reported adverse effects related to the consumption of the NF were gastrointestinal in nature, such as bloating, flatulence, increased bowel movement frequency, nausea or stomach discomfort. These effects were generally described as mild and were comparable to those observed with the control group. Pugh et al. (2024) reported a statistically significant but small increase in fasting glucose in the IPE group compared to the inulin control group; however, glucose concentrations remained within the normal range and the change was considered unlikely to be of clinical relevance by the study authors. Four serious adverse events (SAEs) occurred (two in the IPE arm), none of which were considered related to the study intervention by the study authors. Attrition rates varied, with reasons including intolerance (to IPE or control), non‐compliance or withdrawal for personal reasons. No other consistent adverse effects on clinical chemistry or vital signs were reported across the studies.

The Panel notes the limitations of these human intervention studies for the safety assessment of the NF, which were primarily designed to investigate efficacy endpoints (e.g. changes in appetite, body weight, metabolic markers), with safety and tolerability often assessed as secondary outcomes.

Despite these limitations, the Panel notes that the NF, at doses up to 20 g/day for up to 12 months, appears to be generally well‐tolerated. The primary adverse effects observed are mild and transient gastrointestinal symptoms, which are common with non‐digestible fibres and comparable to those seen with inulin.

3.11. Allergenicity

Batch‐to‐batch proximate analysis (Table 2) showed that the NF does not contain quantifiable levels of proteins measured by Kjeldahl method (LOQ < 0.1 g/100 g). Furthermore, the applicant stated that the NF is free from known allergens listed in Annex II of Regulation (EU) 1169/2011 ¹⁴ and that exposures to inulin from the regular diet have not been associated with any allergenic risk.

However, the Panel identified three case reports of allergic reactions possibly caused by inulin.

In a letter to the editor, Gay‐Crosier et al. (2000) reported a case of a 39 year old male who had four episodes of anaphylaxis a few minutes after consumption of inulin‐containing foodstuffs (salsify, artichoke leaves, margarine containing inulin extracted from chicory and a candy containing inulin or oligofructose, a hydrolysate of inulin). On skin‐prick testing (SPT), he showed a very strong reaction to a commercially available inulin extracted from chicory (Raftiline HP®, average degree of polymerisation of 24) and strong reactions to the above‐mentioned inulin‐containing foodstuffs. SPTs with the inulin extract in 10 controls were negative. A follow‐up double‐blind placebo‐controlled food challenge (DBPCFC) confirmed anaphylaxis to the inulin extract (10 g in mint syrup containing rice flour), but not to the control (mint syrup containing rice flour alone). An open oral challenge with 40 g of oligofructose was negative.

Franck et al. (2005) described a case of a 50 year old woman with a history of allergy to artichoke who had two episodes of immediate allergic reactions: generalised urticaria after eating a biscuit with 0.38 g of the Raftiline HP® and a severe anaphylactic shock after eating a yogurt with 2.5 g of Raftiline HP®. SPTs were strongly positive for inulin‐containing foodstuffs (raw and cooked artichoke, salsify and yogurt), but negative to the Raftiline HP®. A subsequent DBPCFC was positive to inulin‐containing yogurt. Dot blot analysis and inhibition tests were also performed with inulin‐containing yogurt, milk, bovine serum albumin (BSA) heated in the presence of Raftiline HP® and artichoke puree. The results of these tests indicated the presence of IgE specific to inulin‐protein compounds formed by heating during the manufacturing of inulin‐containing foodstuffs, rather than to residual chicory proteins in the inulin extract or to carbohydrate determinants.

In an abstract, Streeks et al. (2017) described a case of a young child with an anaphylactic reaction to inulin following multiple exposures. SPTs to an inulin extract and to artichoke were positive. Authors claimed that appropriate positive and negative controls were used. No further details were available from this abstract.

Concerning propionic acid, the available data did not indicate that propionic acid and its salts may trigger allergic reactions (EFSA ANS Panel, 2014).

The Panel notes that inulin or its sources are not among the allergic foods subject to mandatory allergen labelling in the EU as per Regulation (EU) No 1169/2011. The Panel also notes that only three cases of allergic reactions to inulin have been reported in the literature, of which only two have been well documented, despite the wide use of inulin extracted from chicory as ingredients. In this context, the Panel considers that the risk of allergic reaction is low and similar to that associated with inulin‐containing foods already on the market.

4. DISCUSSION

The NF, which is the subject of the application, is a compound constituted by a natural polysaccharide polymer composed mainly of fructose moieties, inulin, esterified with a short‐chain fatty acid moiety, propionic acid. Both moieties are naturally present in the food and in the current EU and global food supply for different purposes (as food additives, food supplements etc.).

The target population for the NF is the general population and it is intended to be used as an ingredient in cereal bars and fruit smoothie type beverages.

Based on the provided studies investigating metabolic fate of the NF, the Panel considers that the NF is not absorbed intact, but it is metabolised mainly in the large intestine to its two main components: inulin (a dietary fibre which is not absorbed) and propionic acid (SCFA, which is readily absorbed). A smaller fraction of propionic acid seems to be released from the NF before entering the colon and is available for absorption in the small intestine. The Panel considers that the inulin and propionic acid from the NF exhibit normal metabolic fate of non‐digestible dietary fibre and SCFA, respectively.

Taking into account the composition of the NF and the proposed conditions of use, consumption of the NF is not nutritionally disadvantageous.

Excessive intakes of non‐digestible fibre such as inulin have not been associated with any adverse health effects other than gastrointestinal symptoms. Regarding toxicity of propionic acid, a safety assessment of the use of propionic acid and its salts as food additives concluded that propionic acid has a local effect at the first site of contact within the body (EFSA ANS Panel, 2014). Based on epithelial hyperplasia in the oesophagus observed in a 90‐day study in dogs, a NOAEL of 0.3% and LOAEL of 1% in the diet were derived. Thus, the Panel considered the stability of the NF at the proposed conditions of use as pivotal such that the release of free propionic acid from the NF should not increase the concentration of propionic acid in the diet above 0.3%, which has been confirmed by the provided stability tests.

Thus, taking into account physical–chemical properties of the NF, the production process and metabolic fate of the NF, which do not raise safety concerns and given that propionic acid and its salts were previously assessed by EFSA ANS Panel (2014), as well as that a large body of safety data were available on inulin, the Panel considers that no genotoxicity or subchronic toxicological studies are required on the NF.

Based on the proposed uses and use levels, the highest estimated (95th percentile) chronic intake of the NF is observed in the subgroup of vegetarians, up to 8.5 g/day.

Despite the limitations of the provided human studies (primarily designed to investigate efficacy endpoints), the Panel notes that the NF, at doses up to 20 g/day for up to 12 months, appears to be generally well‐tolerated. The primary adverse effects observed are mild and transient gastrointestinal symptoms, which are common with non‐digestible fibres and comparable to those seen with inulin.

5. CONCLUSIONS

The Panel concludes that the NF, inulin‐propionate ester, is safe for the general population under the proposed conditions of use.

5.1. Protection of proprietary data in accordance with Article 26 of Regulation (EU) 2015/2283

The Panel could not have reached the conclusion on the safety of the NF under the proposed conditions of use without the data claimed as proprietary by the applicant: batch‐to‐batch analyses (including quantification of inulin and propionate, and in‐house analytical methods).

ABBREVIATIONS

ADI

adequate daily intake

ADME

absorption, distribution, metabolism and excretion

AE

adverse event

AI

adequate intake

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ANS

Panel on Food Additives and Nutrient Sources added to Food

AST

aspartate aminotransferase

BIA

bioelectrical impedance analysis

BMI

body mass index

BOLD

blood oxygen level‐dependent

BP

blood pressure

BSA

bovine serum albumin

bw

body weight

CAS

Composite Appetite Score

CFU

colony forming unit

CRP

C‐reactive protein

DBPCFC

double‐blind placebo‐controlled food challenge

DRV

dietary reference value

EE

energy expenditure

F

female

FFM

fat‐free mass

FM

fat mass

FTIR

Fourier transform infrared spectroscopy

GC

gas chromatography

GC‐FID

gas chromatography–flame ionisation detector

GI

gastrointestinal

GLP‐1

glucagon‐like peptide‐1

GMP

Good Manufacturing Practice

GRAS

generally recognised as safe

HACCP

Hazard Analysis and Critical Control Points

HbA1c

haemoglobin A1c

HDL

high‐density lipoprotein

HE

high energy

HOMA–IR

homeostasis model assessment–insulin resistance

HPAEC–PAD

high performance ion exchange chromatography with pulsed amperometric detection

HPLC

high performance liquid chromatography

HPLC–RID

high performance liquid chromatography with refractive index detection

ICP–OES

inductively coupled plasma–optical emission/atomic emission spectrometry

IgA

immunoglobulin A

IgE

immunoglobulin E

IgG

immunoglobulin G

IgM

immunoglobulin M

IHCL

intrahepatocellular lipid

IPAQ

International Physical Activity Questionnaire

IPE

inulin‐propionate ester

IQR

interquartile range

LBP

lipopolysaccharide‐binding protein

LDL

low‐density lipoprotein

LE

low energy

LOAEL

lowest observed adverse effect level

LOD

limit of detection

LOQ

limit of quantification

M

male

MPL

maximum permitted level

MRI

magnetic resonance imaging

MRS

magnetic resonance spectroscopy

NAFLD

non‐alcoholic fatty liver disease

ND

not detected

NDA

Panel on Nutrition, Novel Foods and Food Allergens

NEFA

non‐esterified fatty acids

NF

novel food

NMR

nuclear magnetic resonance spectroscopy

NOAEL

no observed adverse effect level

PBMC

peripheral blood mononuclear cell

PYY

peptide YY

REE

resting energy expenditure

RER

respiratory exchange ratio

SAE

serious adverse effect

SCFA

short‐chain fatty acid

SD

standard deviation

SEM

standard error of the mean

SPT

skin‐prick testing

TBW

total body water

VAS

visual analogue scale

REQUESTOR

European Commission

QUESTION NUMBER

EFSA‐Q‐2018‐00225

COPYRIGHT FOR NON‐EFSA CONTENT

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PANEL MEMBERS

Dominique Turck, Torsten Bohn, María de la Montaña Cámara Hurtado, 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.

Supporting information

Annex A: Dietary exposure estimates to the Novel Food for each population group from each EU dietary survey

APPENDIX A. Batch‐to‐batch analyses of the NF on contaminants

Parameter (unit)	Batch No										Analytical method/technique
	#5	#6	#7	#16	#17	#18	#19	#20	#21	#22
Chemical parameters
Arsenic (mg/kg)	0.008	< 0.002	< 0.002	0.003	0.003	0.003	0.005	0.003	< 0.002	< 0.002	ICP–MS/OES
Cadmium (mg/kg)	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
Lead (mg/kg)	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005
Mercury (mg/kg)	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005	< 0.005
Chromium (mg/kg)	0.067	0.066	0.066	–	–	–	–	–	–	–
Microbiological parameters
Total aerobic count (CFU/g)	250	610	680	280	90	–	–	–	–	–	ISO 4833
Listeria (/25 g)	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ELISA
Escherichia coli (CFU/g)	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	ISO 16649‐2
Enterobacteriaceae (CFU/g)	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10	ISO 21528‐2

Abbreviations: CFU, colony forming units; ICP–MS/OES, inductively coupled–plasma mass/optical emission spectrometry; ND, not detected.

APPENDIX B. Overview of human studies

Reference	Study design	Subject characteristics at baseline	Duration of study	Intervention	Endpoints assessed	Safety‐related findings
Chambers et al. (2015)	Randomised, controlled, crossover design Acute human study: appetite regulation, hormone release, energy intake, gastric emptying & colonic delivery	Colonic delivery: Nine healthy subjects (8M/1F, mean age 32 ± 4 years, BMI 25.0 ± 1.3 kg/m2) Energy intake/hormones: 20 healthy subjects (15M/5F, mean age 31 ± 2 years, BMI 25.4 ± 0.8 kg/m2) Gastric emptying: 14 healthy subjects (8M/6F, mean age 32 ± 4 years, BMI 24.0 ± 0.9 kg/m2)	Acute	Single dose of 10 g IPE or 10 g inulin (control), given with a standardised breakfast For colonic delivery: 10 g IPE also containing 100 mg 13C‐labelled IPE For gastric emptying: 100 mg 13C‐octanoic acid with lunch	Energy intake (ad libitum buffet meal), plasma PYY, GLP‐1, glucose, insulin, leptin Subjective appetite ratings (VAS for hunger, satiety, nausea), gastric emptying rate (13CO2 breath test), colonic delivery (breath H2, 13CO2, plasma 13C propionate/acetate)	Subjective ratings of nausea were monitored via VAS (no significant difference reported). No other specific adverse events were detailed. The study stated acute IPE did not influence the rate of gastric emptying
	Randomised, double‐blind, placebo‐controlled, parallel design Efficacy study on the long‐term effects of IPE on weight gain, adiposity and related metabolic parameters in overweight adults	60 overweight adults (19M/30F, 40–65 years old, BMI 25–40 kg/m2). 49 completed the study (25 in IPE group, 24 in Inulin control group)	24 weeks	10 g/day IPE or 10 g/day inulin (control), mixed into the normal diet	Co‐primary outcomes: changes in body weight and food intake Secondary outcome: adipose tissue distribution (MRI/MRS, including intrahepatocellular lipid – IHCL) Other assessments: postprandial PYY, GLP‐1, glucose, insulin, leptin. Fasting blood tests: triglycerides, total cholesterol, LDL, HDL, HbA1c, C‐reactive protein (CRP), liver function tests (ALT, ALP, AST). Blood pressure, pulse. Subjective appetite ratings (VAS). Self‐reported food intake and physical activity Gastrointestinal adverse events	Adverse events were monitored at weeks 8, 16 and 24 Attrition: 11 participants (18%) did not complete the study; attrition rates were not significantly different between the groups Gastrointestinal (GI) symptoms (from Table S1): ratings of flatulence were significantly lower in the IPE group compared to the inulin control group (p = 0.004). No significant differences between groups were found for nausea, stomach discomfort, bloating, heartburn or belching Clinical chemistry and vital signs (from Table 1): no changes in the endpoints assessed which could be considered as adverse
Byrne et al. (2016)	Randomised, placebo‐controlled, within‐subject, single‐blind crossover Efficacy study on the acutely increased colonic propionate production on brain anticipatory reward responses (fMRI) during food picture evaluation and ad libitum energy intake	20 healthy non‐obese men (aged 18–65 years, BMI 20–35 kg/m2) 18 subjects had analysable fMRI data	Acute	Single dose of 10 g IPE or 10 g inulin (control), provided with a standard breakfast and lunch	Primary outcome: blood oxygen level‐dependent (BOLD) signal (fMRI) in a priori brain regions involved in reward processing during a food picture evaluation task (HE and LE foods) Other Endpoints: ad libitum energy intake (pasta meal). Subjective appeal of food pictures and reaction time. Breath hydrogen concentration, plasma PYY, GLP‐1, glucose, serum insulin, serum SCFAs (acetate, propionate, butyrate). Composite appetite score (VAS), mood (Positive and Negative Affect Schedule)	The paper does not explicitly report on adverse events beyond the VAS ratings for nausea etc. (which showed no difference)
Polyviou et al. (2016)	Randomised, controlled, crossover study For developing and testing inulin short‐chain fatty acid (SCFA) esters for site‐specific delivery to the colon, to optimise colonic propionate delivery in humans, and to determine its role in appetite regulation and food intake	Nine overweight healthy males [mean (± SEM): age 38 ± 9 years, weight 98.36 ± 3.0 kg, BMI 29.8 ± 1.5 kg/m2]	Each treatment period was 7 days, with at least a 2‐week washout between supplements	1. IPE with 27% propionate loading (IPE‐27), 10 g/day 2. IPE with 54% propionate loading (IPE‐54), 10 g/day 3. Inulin (control), 10 g/day On CRF study days, 13C‐labelled IPE variants were given with the respective unlabelled supplement and a standard breakfast	Primary outcome: area under the curve of breath 13CO2 enrichment Other endpoints: ad libitum food intake, plasma PYY and GLP‐1 concentrations (fasting and postprandial up to 7 h). Subjective ratings of hunger and fullness (VAS). Stool and urine 13C output Palatability of IPE in food products (chocolate drink, tomato soup) by 15 subjects (5M/10F) was also assessed	No issues were highlighted in the main text for the 7‐day supplementation period regarding VAS The study did not explicitly detail a systematic collection of all adverse events beyond VAS for appetite and implicitly palatability. However, no safety concerns were raised from the reported data
Byrne et al. (2019)	Randomised, double‐blind, crossover feeding study Efficacy study to confirm the appetite‐suppressing effects of elevated colonic propionate following a supplementation with IPE‐containing food products A secondary aim was to explore the effect of elevated colonic propionate on energy expenditure (EE) and substrate oxidation	23 participants, 21 completed all study visits (9M/12F, median [IQR] or mean ± SEM: age 60 [53.0, 64.0] years, weight 80.2 [76.3, 87.2] kg, BMI 29.07 ± 0.70 kg/m2)	Two 7‐day supplementation periods (6 days consumption, 7th day was study visit with test product) Washout periods: > 7 days after acclimatisation & baseline; > 14 days between supplementation arms	Participants consumed food products (bread roll and fruit smoothie) for 6 days, with the 7th dose on the study visit morning Three conditions in crossover: 1. IPE‐Food Product (IPE‐FP): containing 10 g/day IPE (5 g in bread roll, 5 g in smoothie) 2. Inulin‐Food Product (Inulin‐FP): containing 10 g/day inulin (positive control) 3. Control‐Food Product (Control‐FP): un‐supplemented food products (negative control, consumed on acclimatisation and baseline visits)	Ad libitum energy intake (assessed 420 min after test meal). Blood hormones (PYY, GLP‐1) and metabolites (glucose, insulin, NEFA, acetate, propionate, butyrate). Resting Energy Expenditure (REE) and substrate oxidation (indirect calorimetry). Breath H2. Taste and appearance ratings of food products. Composite Appetite Score (CAS) and individual appetite VAS (hunger, fullness, desire to eat, appetite for meal). Body composition (BIA: FFM, FM, TBW). IPAQ. Fasting blood lipids (total cholesterol, HDL, LDL, triglycerides). Food product satisfaction ratings (overall, appearance, aroma, flavour, texture)	Attrition: 2 participants withdrew before their first study visit (reasons not specified) Gastrointestinal side effects (Figure 1): assessed using 100 mm VAS for stomach discomfort, nausea, bloating, flatulence, heartburn, belching, toilet more often, toilet less often. Compared to control, both inulin‐FP and IPE‐FP supplementation significantly increased stomach discomfort, nausea, flatulence, heartburn and toilet frequency. However, there were no significant differences in these side effects between the inulin‐FP and IPE‐FP supplements. There was no difference in bloating and belching between any treatments Biochemical parameters: no changes in the endpoints assessed which could be considered as adverse
Chambers, Byrne, Rugyendo, et al. (2019)	Randomised, double‐blind, placebo‐controlled, parallel design To investigate the impact of raising colonic propionate production (via IPE) on hepatic steatosis	20 participants, 18 completed (9M/9F, aged 18–65 years, BMI 20–40 kg/m2), histological confirmation of NAFLD by liver biopsy within the previous 5 years, controlled blood glucose levels (HbA1c < 48 mmol/mol)	42 days (6 weeks)	20 g/day IPE (providing 5.4 g bound propionate and 14.6 g inulin), taken as two 10 g sachets mixed into habitual diet or 20 g/day inulin (control), taken as two 10 g sachets mixed into habitual diet	Primary outcome: change in intrahepatocellular lipid (IHCL) content (assessed by MRS) Other Endpoints: insulin resistance (HOMA‐IR). Postprandial glucose and insulin (from Mixed Meal Test – MMT). Fasting and postprandial SCFA. Breath hydrogen. Fasting blood tests: triglycerides, total cholesterol, LDL, HDL, HbA1c, alanine transaminase, C‐reactive protein. Inflammatory markers (IL‐6, IL‐8, IL‐10, IL‐12, IL‐17A). Body weight, fat mass (FM), fat‐free mass (FFM) (BIA). Self‐reported food intake, physical activity (IPAQ) and gastrointestinal adverse events (VAS)	Attrition: 2 participants did not complete the study 1 from inulin group due to changed medication, 1 from IPE group due to non‐compliance (Figure S1) Gastrointestinal adverse events (from Suppl. Material, assessed by VAS): ratings of GI side effects (e.g. stomach discomfort, nausea, bloating, flatulence, heartburn, belching) did not show adverse effects of the IPE Metabolic parameters (Table S2) and inflammatory markers (Table S4): no changes in the endpoints assessed which could be considered as adverse
Chambers, Byrne, Morrison, et al. (2019)	Randomised, double‐blind, placebo‐controlled, crossover trial To investigate the underlying mechanisms behind changes in glucose homeostasis with colonic propionate delivery by analysing gut bacterial composition, plasma metabolome and immune responses	14 non‐diabetic adults with overweight and obesity 12 completed all three study arms (3M/9F, age (mean ± SEM, range): 60 ± 1 years (49–65), BMI (kg/m2) (mean ± SEM, range): 29.8 ± 0.9 (26.2–37.0), HbA1c (mmol/mol) (mean ± SEM, range): 35.5 ± 1.0 (30–42))	Three 42‐day supplementation periods, separated by washout periods of at least 28 days (mean 44 days)	Participants received 20 g/day of one of three supplements, divided into two 10 g doses per day: 1. IPE (providing 14.6 g inulin and 5.4 g esterified propionate) 2. Inulin (as high‐fermentable fibre control) 3. Cellulose (as low‐fermentable fibre control/placebo)	Primary outcome: glucose homeostasis (HOMA2‐IR, Matsuda Insulin Sensitivity Index) Secondary outcomes: fasting insulin, glucose, NEFA, GLP‐1, PYY; plasma metabolome (1H NMR); stool and blood SCFAs. Stool bacterial composition (16S rRNA gene sequencing), bacterial diversity. Serum cytokines (IL‐6, IL‐8, IL‐10, IL‐12, etc.), C‐reactive protein, LBP, immunoglobulins (IgA, IgG, IgM); PBMC immune phenotyping. Body weight, compliance, self‐reported food intake, physical activity, gastrointestinal (GI) side effects	GI side effects: No statistically significant differences were observed between the three supplementation periods for self‐reported stomach discomfort, nausea, bloating, flatulence, heartburn or belching (assessed by 100 mm VAS, Table S4) No other specific adverse events (beyond the monitored GI symptoms) were detailed as being significantly different during the interventions
Malkova et al. (2020)	Single‐blinded, randomised, parallel study Efficacy study on IPE supplementation, in combination with a moderate intensity exercise training programme, on whole‐body fat oxidation and on plasma GLP‐1 and PYY in overweight women	20 healthy overweight women; IPE group (n = 9): body weight 77.3 ± 4.2 kg, body fat mass %: 37.7 ± 1.9% Placebo group (n = 11): body weight: 84.2 ± 4.3 kg, body fat mass %: 40.1 ± 1.9% Age: 25–45	4 weeks	One sachet per day with breakfast, containing: 10 g/day IPE or 10 g/day cellulose (placebo)	Primary outcome: whole‐body fat oxidation (measured by expired gas collection during 7‐h experimental trials) Secondary outcomes: carbohydrate oxidation, Respiratory Exchange Ratio (RER), Energy Expenditure (EE), plasma GLP‐1 and PYY concentrations (fasting and postprandial during 7‐h trials), body weight, body composition (BMI, body fat mass, body fat percentage, height), submaximal exercise test (to predict VO2max and set exercise intensity), dietary intake (3‐day record, replicated before second trial)	Reporting on adverse events was not provided. No changes in plasma concentrations of GLP‐1 and PYY
Pugh et al. (2024)	Multi‐centre, double‐blind, randomised, parallel‐group trial Efficacy study on the prevention of weight gain due to IPE supplementation	Adults aged 20–40 years (n = 270, 98M/172F, 135 per arm; 226 included in primary outcome analysis at 12 months). Mean (SD) age 30.2 (5.4) years. Overweight (BMI 23–27 kg/m2 for individuals of South Asian descent or 25–30 kg/m2 for those of other ethnicities; mean BMI 27.5 (1.5) kg/m2 at baseline). Participants were at risk of weight gain (defined by at least one factor: low physical activity, weight gain of ≥ 2 kg in the past year, consumption of > 1 sugar‐sweetened beverage/day or < 2 portions of fruit and vegetables/day)	12 months	10 g/day IPE or 10 g/day of inulin (control), administered as a powder in sachets, mixed in a cool drink or water	Primary outcome: weight gain from baseline to 12 months Secondary (including safety‐relevant) outcomes: weight gain at 2 and 6 months; Body composition (fat mass, fat‐free mass, body water); waist/hip circumference, BMI; fasting blood biochemistry (glucose, insulin, triglycerides, total cholesterol, LDL‐cholesterol, HDL‐cholesterol); blood pressure; physical activity; diet; lifestyle factors Safety‐specific: occurrence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Attrition: the overall study withdrawal rate was 16% (42/270); 16% (22/135) participants in the IPE arm and 15% (20/135) in the inulin control arm Adverse Events (AEs): similar rates of AEs were reported in both groups (56% IPE, 56% inulin). Common, expected and related AEs were gastrointestinal disorders such as bloating, cramping and gas. Gastrointestinal disorders were reported by 24% of participants in the IPE arm and 33% in the inulin control arm Serious Adverse Events (SAEs): four SAEs occurred during the study (two in the IPE arm, two in the control arm); none were considered related to the study intervention (IPE or inulin consumption) Blood biochemistry: fasting glucose was significantly elevated in the IPE arm by 0.11 mmol/L (95% CI: 0.01–0.21) at 12 months compared to the inulin control; however, levels remained within the normal range and the increase was considered unlikely to be of clinical relevance. No other changes in blood biomarkers (lipids, insulin, BP) were detected that raised safety concerns

Abbreviations: 1H NMR, proton nuclear magnetic resonance; AEs, adverse events; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BIA, bioelectrical impedance analysis; BMI, body mass index; BOLD, blood oxygen level‐dependent; BP, blood pressure; CAS, composite appetite score; CRP, C‐reactive protein; EE, energy expenditure; FFM, fat‐free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GI, gastrointestinal; GLP‐1, glucagon‐like peptide‐1; HbA1c, haemoglobin A1c; HDL, high‐density lipoprotein; HE, high energy; HOMA2‐IR, homeostasis model assessment 2–insulin resistance; HOMA‐IR, homeostasis model assessment–insulin resistance; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; IHCL, intrahepatocellular lipid; IL‐10, interleukin‐10; Inulin‐FP, inulin‐food product; IPAQ, International Physical Activity Questionnaire; IPE, inulin‐propionate ester; IPE‐27, IPE with 27% propionate loading; IPE‐54, IPE with 54% propionate loading; IQR, interquartile range; LBP, lipopolysaccharide‐binding protein; LDL, low‐density lipoprotein; LE, low energy; M/F, male/female; MMT, mixed meal test; MRI/MRS, magnetic resonance imaging/magnetic resonance spectroscopy; NAFLD, non‐alcoholic fatty liver disease; NEFA, non‐esterified fatty acids; PBMC, peripheral blood mononuclear cell; PYY, peptide YY; REE, resting energy expenditure; RER, respiratory exchange ratio; SAEs, serious adverse events; SCFA, short‐chain fatty acid; SD, standard deviation; SEM, standard error of the mean; TBW, total body water; VAS, visual analogue scale.

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