microcrystalline cellulose

What is microcrystalline cellulose

Microcrystalline cellulose also known as cellulose gel is a purified, partially depolymerized cellulose with shorter crystalline polymer chains (average particle size 50 µm) prepared by treating alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids 1. Microcrystalline cellulose [E 460(i)] is a fine, white or almost white, odorless, free flowing crystalline powder with not more than 10% of the material has a particle size of less than 5 mm. According to European Commission Regulation (EU) No 231/2012, microcrystalline cellulose is purified, partially depolymerised cellulose prepared by treating α‐cellulose, obtained as a pulp from strains of fibrous plant material, with mineral acids. The degree of polymerization is typically < 400; the molecular weight is about 36,000 g/mol. Microcrystalline cellulose is a fine, white, odorless, crystalline powder. The particles are insoluble but able to swell in water, in dilute alkali and acids, and in most organic solvents. The substance is soluble in NaOH solution 2. At concentrations below 1%, microcrystalline cellulose forms colloidal solutions, and above 1%, thixotropic gels 3.

Cellulose is a linear glucose homopolymer consisting of glucopyranose units linked by β‐1,4‐glycosidic bonds; its molecular formula is (C6H10O5)m, with the degree of polymerisation dependent on the origin of the cellulolytic material. Cellulose molecular weight has been calculated to be approximately in the range 50,000–2,500,000. In modified celluloses, the chemical and physical characteristics of the native substances are modified in order to confer different technological properties for particular food applications.

Microcrystalline cellulose [E 460(i)] is prepared by the controlled hydrolysis of highly purified α‐cellulose, obtained as a pulp from strains of fibrous plant material, while powdered cellulose [E 460(ii)] is obtained by purification and mechanical disintegration of α‐cellulose. Hydrolysis is performed with a dilute mineral acid, e.g. hydrochloric acid. Cellulose is thereby converted into an acid‐soluble fraction and an acid‐insoluble crystalline material. The amorphous regions of the cellulose are completely hydrolysed. Resultant water‐soluble cello‐oligosaccharides and glucose are removed by subsequent rinsing and filtration. The remaining wet cake contains only pure crystalline regions of natural cellulose. Mechanical shearing in a water slurry is used to free the microcrystals from their fibrous, packed structure, in the form of short, rod‐like particles. These are dried and ground to a fine, white, free‐flowing crystalline powder 4. The degree of polymerization is predominantly ≥ 1,000 and greater, corresponding to a molecular weight of > 160,000 5. In Commission Regulation (EU) No 231/2012, the substance is described as a white, odourless powder, which is insoluble in water, ethanol, ether and dilute mineral acids, but slightly soluble in sodium hydroxide solution. Powdered cellulose [E 460(ii)] is able to swell in water, dilute acid and most solvents, while alkali solutions lead to swelling and dissolution of the present hemicelluloses 2.

Haafiz et al. described a method for the isolation of microcrystalline cellulose from oil palm empty fruit pulp (OPEFB‐pulp). The pulp was hydrolysed with 2.5 N HCl (ratio pulp‐liquor 1:20) at 105°C for 30 min under constant agitation. The reaction mixture was filtered and washed repeatedly first with distilled water and subsequently with 5% diluted NH4OH solution. Finally, distilled water was used to rinse the mixture until it was free from acid. The microcrystalline cellulose so obtained was dried at 105°C under vacuum until constant weight, and further ground into a fine powder, snowy‐white in appearance.

Microcrystalline cellulose [microcrystalline cellulose (E 460(i)), powdered cellulose (E 460(ii)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465), sodium carboxy methyl cellulose (E 466), enzymatically hydrolysed carboxy methyl cellulose (E 469) and cross‐linked carboxy methyl cellulose (E 468)] are used as food additives as an emulsifier, stabilizer, thickener,  anticaking and dispersing agent.

Methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464) and ethyl methyl cellulose (E 465) are celluloses obtained synthetically from fibrous plant material. Each of the celluloses is partially etherified with methyl groups, ethyl groups, hydroxypropyl groups and contains a small degree of hydroxypropyl substitution, and methyl and ethyl groups, respectively.

The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) and the Scientific Committee on Food (SCF) established an acceptable daily intake (ADI) ‘not specified’ for unmodified and modified celluloses 6. Celluloses are not absorbed and are excreted intact in the feces; in addition, microcrystalline cellulose, powdered and modified celluloses could be fermented by the intestinal flora in animals and humans.

Specific toxicity data were not always available for all the celluloses evaluated and for all endpoints. Given their structural, physicochemical and biological similarities, the European Food Safety Authority Panel considered it possible to read‐across between all the celluloses. The acute toxicity of celluloses was low and there was no genotoxic concern. Short‐term and subchronic dietary toxicity studies performed with microcrystalline cellulose (E 460(i)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), sodium carboxy methyl cellulose (E 466) and enzymatically hydrolysed carboxy methyl cellulose (E 469) at levels up to 10% did not indicate specific treatment related adverse effects. In chronic toxicity studies performed with microcrystalline cellulose (E 460(i)), methyl cellulose (E 461), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465) and sodium carboxy methyl cellulose (E 466), the no observed adverse effect level (NOAEL) values reported ranged up to 9,000 mg/kg body weight per day. No carcinogenic properties were detected for microcrystalline cellulose and modified celluloses. Adverse effects on reproductive performance or developmental effects were not observed with celluloses at doses greater than 1,000 mg/kg body weight by gavage (often the highest dose tested). The combined exposure to celluloses (E 460–466, E 468 and E 469) at 95th percentile of the refined (brand‐loyal) exposure assessment for the general population was up to 506 mg/kg body weight per day. The European Food Safety Authority Panel concluded that there was no need for a numerical acceptable daily intake (ADI) and that there would be no safety concern at the reported uses and use levels for the unmodified and modified celluloses [microcrystalline cellulose (E 460(i)), powdered cellulose (E 460(ii)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465), sodium carboxy methyl cellulose (E 466), enzymatically hydrolysed carboxy methyl cellulose (E 469) and cross‐linked carboxy methyl cellulose (E 468)]. The European Food Safety Authority Panel considered an indicative total exposure of around 660–900 mg/kg body weight per day for microcrystalline, powdered and modified celluloses.

Figure 1. Microcrystalline cellulose

microcrystalline cellulose

Manufacturing process

The raw materials for the production of the different types of celluloses are mainly wood chips. Chemical wood pulping involves the extraction of cellulose from wood by dissolving the lignin that binds the cellulose fibres together. Several processes used in chemical pulping have been described, among these, ‘kraft pulping’ and ‘sulfite pulping’ being the most important. The choice of a pulping process is determined by the desired product, the wood species available, and by economic considerations.

In ‘kraft pulping’ wood chips are digested at elevated temperature and pressure in ‘white liquor’, being an aqueous solution of sodium sulfide (Na2S) and sodium hydroxide (NaOH). During digestion the lignin fraction is dissolved. When cooking is complete, the content of the digester is transferred to an atmospheric tank where the spent cooking liquor is separated from the pulp. The pulp then proceeds through various stages of washing, and possibly bleaching, after which it is pressed and dried into the finished product (wood pulp).

In ‘sulfite pulping’ wood chips are digested under high pressure in the presence of sulfurous acid. To buffer the cooking solution, either sodium bisulfite (NaHSO3), magnesium bisulfite (Mg(HSO3)2), calcium bisulfite (Ca(HSO3)2) or ammonium bisulfite 7.

In these processes, wood chips are digested, at high temperature (> 100°C), by treatment with a mixture of sodium hydroxide (NaOH), sodium sulfide (Na2S) and sodium sulfite (Na2SO3) in various concentrations. During this treatment, the lignin fraction is removed. The product so obtained is extracted washed, concentrated and bleached by treatment with chlorine dioxide (ClO2). After bleaching, the extract is subjected to a second digestion with sodium hydroxide at lower temperature (< 50°C). The resulting product is centrifuged and washed with oxalic acid to neutralise the residual alkali and to facilitate the extraction of other residuals and colouring impurities. Finally, the extract consists of α‐cellulose at a concentration of > 97% 8.

Chemically modified celluloses

Methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464) and ethyl methyl cellulose (E 465) are celluloses obtained synthetically from fibrous plant material. Each of the celluloses is partially etherified with methyl groups, ethyl groups, hydroxypropyl groups and contains a small degree of hydroxypropyl substitution, and methyl and ethyl groups, respectively (Figure 2).

The manufacturing processes of modified celluloses are detailed in literature. In general terms, cellulose pulp is dispersed in alkali solution (generally sodium hydroxide, 5–50%) to form alkali cellulose. Alkali celluloses are compounds with given stoichiometric relations between alkali and cellulose 9. Subsequently, alkali cellulose is treated with appropriate reagents, under strictly controlled conditions, to substitute the anhydroglucose monomers of the cellulose chain. In this reaction step, the hydroxy groups of the anhydroglucose monomers of the cellulose chain are etherified according to a nucleophilic substitution reaction (SN2 reaction; Williamson synthesis), a bimolecular reaction with simultaneous a bond‐making and a bond‐breaking step.

The appropriate etherifying reagents are: (i) in case of methyl cellulose (E 461), methyl chloride; (ii) in case of ethyl cellulose (E 462), ethyl chloride; (iii) in case of ethyl methyl cellulose (E 465) a mixture of ethyl and methyl chloride; (iv) in case of hydroxypropyl cellulose (E 463), propylene oxide; (v) in case of hydroxypropyl methyl cellulose (E 464), a mixture of propylene oxide and methyl chloride.

Figure 2. Chemically modified celluloses

Chemically modified celluloses

Footnote: General chemical structure of modified celluloses E 461–466 and E 468 and E 469, where R represents hydrogen or specific groups, as indicated. In this structure, ‘n’ represents the number of anhydrocellobiose repeating units

[Source 6 ]

Sodium carboxy methyl cellulose (E 466) is the partial sodium salt of a carboxymethyl ether of cellulose.

Cross‐linked sodium carboxy methyl cellulose (E 468) is obtained from carboxy methyl cellulose by acidifying and heating the aqueous suspension.

Enzymatically hydrolysed carboxy methyl cellulose sodium salt (E 469) is obtained from carboxy methyl cellulose by enzymatic digestion with a cellulase produced by Trichoderma longibrachiatum (formerly Trichoderma reesei).

All modified celluloses are derived from cellulose. They carry the cellulose backbone which consists of a polymer of β‐(1→4) linked d‐glucopyranose units (also called anhydroglucose unit (AGU)) 10. The hydroxyl groups at the carbon atoms C‐2, C‐3 and C‐6 of the glucopyranose are more or less completely etherified depending on the used substitution reagent and conditions during manufacturing 11.

The average number of hydroxyl groups substituted per glucopyranose unit is known as degree of substitution. A complete substitution would provide a degree of substitution of 3. In the case of hydroxypropyl cellulose (E 463) and hydroxypropyl methyl cellulose (E 464), the degree of substitution can be higher than 3 because the hydroxypropyl group added also contains a hydroxyl group which can be etherified 12.

Chemically modified celluloses are white or slightly yellowish, odourless and tasteless powders. However, the physical appearance of the modified celluloses depends on the type of substitution, the degree of polymerisation and the degree of substitution 13.

All modified celluloses, except ethyl cellulose (E 462) and cross‐linked sodium carboxy methyl cellulose (E 468), are water‐soluble polymers. Ethyl cellulose (E 462) is the only modified cellulose not soluble in water but soluble in ethanol. Hydroxypropyl cellulose (E 463) and ethyl methyl cellulose (E 465) are both soluble in water and ethanol 14. However, the solubility of the modified celluloses is influenced by the degree of substitution, e.g. sodium carboxy methyl cellulose (E 466) with a degree of substitution < 0.3 is only soluble in alkali. As the degree of substitution approaches 0.7, sodium carboxy methyl cellulose (E 466) can is easily be dissolved in water, above a degree of substitution of 1, sodium carboxy methyl cellulose (E 466) is less water soluble 2.

The European Food Safety Authority Panel noted that the data provided by industry indicated that the majority of particles of individual modified celluloses were in the range of 10–100 μm. In addition, based on the known ability of cellulose particles to swell in water, the presence of nanoscale material after ingestion is highly unlikely.

Aqueous solutions of modified celluloses are highly viscous, depending on concentration, temperature, average chain length of the macromolecule (degree of polymerisation), and the presence of salts or other additives 14.

Microcrystalline cellulose uses

Microcrystalline cellulose is used as a thickener, stabilizer or emulsifiers. Microcrystalline cellulose is also used in cosmetics as an abrasive, absorbent, anti-caking agent, aqueous viscosity increasing agent, binder, bulking agent, emulsion stabilizer, slip modifier, and texturizer, which can be found in various hair and skin care products as well as makeup.

The microcrystalline cellulose is a valuable additive in pharmaceutical, food, cosmetic and other industries. Different properties of microcrystalline cellulose are measured to qualify its suitability to such utilization, namely particle size, density, compressibility index, angle of repose, powder porosity, hydration swelling capacity, moisture sorption capacity, moisture content, crystallinity index, crystallite size, and mechanical properties such as hardness and tensile strength.

Table 1. Maximum permitted levels of E 460–466 and E 468 and E 469 in foods in the European Union

Food category nameRestrictions/exceptionsMaximum permitted level (mg/L or mg/kg as appropriate)
Unflavoured fermented milk products, heat‐treated after fermentationQuantum satis
Flavoured fermented milk products including heat‐treated productsQuantum satis
Unflavoured pasteurised cream (excluding reduced fat creams)Quantum satis
Unflavoured live fermented cream products and substitute products with a fat content of less than 20%Quantum satis
Other creamsQuantum satis
Unripened cheese excluding products falling in category 16Only grated and sliced mozzarellaQuantum satis
Unripened cheese excluding products falling in category 16Except mozzarellaQuantum satis
Ripened cheeseOnly sliced and grated ripened cheeseQuantum satis
Whey cheeseOnly grated and sliced cheeseQuantum satis
Processed cheeseQuantum satis
Cheese products (excluding products falling in category 16)Quantum satis
Cheese products (excluding products falling in category 16)Only grated and sliced ripened products and unripened productsQuantum satis
Dairy analogues, including beverage whitenersQuantum satis
Other fat and oil emulsions including spreads as defined by Council Regulation (EC) No 1234/2007 and liquid emulsionsQuantum satis
Vegetable oil pan sprayQuantum satis
Edible icesQuantum satis
Entire fresh fruit and vegetablesOnly for citrus fruit, melons and pomegranates in order to:
repeat all or some of the mandatory information particulars required by the Union legislation and/or national law and/or
provide on a voluntary basis brand name, production method, PLU‐code, QR‐code and/or barcode
10
Dried fruit and vegetablesQuantum satis
Fruit and vegetables in vinegar, oil, or brineQuantum satis
Fruit and vegetable preparations excluding compoteQuantum satis
Nut butters and nut spreadsQuantum satis
Processed potato productsQuantum satis
Cocoa and Chocolate products as covered by Directive 2000/36/ECOnly energy‐reduced or with no added sugarQuantum satis
Other confectionery including breath freshening microsweetsQuantum satis
Chewing gumQuantum satis
Decorations, coatings and fillings, except fruit‐based fillings covered by category 4.2.4Quantum satis
StarchesQuantum satis
Breakfast cerealsQuantum satis
Dry pastaOnly gluten free and/or pasta intended for hypoproteic diets in accordance with Directive 2009/39/ECQuantum satis
Potato gnocchiExcept fresh refrigerated potato gnocchiQuantum satis
Fillings of stuffed pasta (ravioli and similar)Quantum satis
NoodlesQuantum satis
BattersQuantum satis
Pre‐cooked or processed cerealsQuantum satis
Bread and rollsExcept products in 7.1.1 and 7.1.2Quantum satis
Fine bakery waresQuantum satis
Non‐heat‐treated meat productsQuantum satis
Heat‐treated meat productsExcept foie gras, foie gras entier, blocs de foie gras, Libamáj, libamáj egészben, libamáj tömbbenQuantum satis
Casings and coatings and decorations for meatQuantum satis
Processed fish and fishery products including molluscs and crustaceansQuantum satis
Fish roeOnly processed fish roeQuantum satis
Processed eggs and egg productsQuantum satis
Other sugars and syrupsQuantum satis
Table‐top sweeteners in liquid formQuantum satis
Table‐top sweeteners in powder formQuantum satis
Table‐top sweeteners in powder form50000
Table‐top sweeteners in tabletsQuantum satis
Table‐top sweeteners in tablets50000
Salt substitutesQuantum satis
Herbs and spicesOnly when dried
Seasonings and condimentsQuantum satis
VinegarsQuantum satis
MustardQuantum satis
Soups and brothsQuantum satis
SaucesQuantum satis
Salads and savoury‐based sandwich spreadsQuantum satis
Yeast and yeast productsQuantum satis
Protein products, excluding products covered in category 1.8Quantum satis
Dietary foods for infants for special medical purposes and special formulae for infantsFrom birth onwards in products for the dietary management of metabolic disorders10000
Dietary foods for babies and young children for special medical purposes as defined in Directive 1999/21/ECFrom birth onwards in products for the dietary management of metabolic disorders10000
Dietary foods for special medical purposes defined in Directive 1999/21/EC (excluding products from food category 13.1.5)Quantum satis
Dietary foods for weight control diets intended to replace total daily food intake or an individual meal (the whole or part of the total daily diet)Quantum satis
Foods suitable for people intolerant to gluten as defined by Regulation (EC) No 41/2009Including dry pastaQuantum satis
Fruit juices as defined by Directive 2001/112/EC and vegetable juicesOnly vegetable juicesQuantum satis
Fruit nectars as defined by Directive 2001/112/EC and vegetable nectars and similar productsOnly vegetable nectarsQuantum satis
Fruit nectars as defined by Directive 2001/112/EC and vegetable nectars and similar productsOnly traditional Swedish and Finnish fruit syrups from citrusQuantum satis
Flavoured drinksQuantum satis
OtherExcluding unflavoured leaf tea; including flavoured instant coffeeQuantum satis
Cider and perryQuantum satis
Fruit wine and made wineQuantum satis
MeadQuantum satis
Spirit drinks as defined in Regulation (EC) No 110/2008Except whisky or whiskeyQuantum satis
Aromatised winesQuantum satis
Aromatised wine‐based drinksQuantum satis
Aromatised wine‐product cocktailsQuantum satis
Other alcoholic drinks including mixtures of alcoholic drinks with non‐alcoholic drinks and spirits with less than 15% of alcoholQuantum satis
Potato‐, cereal‐, flour‐ or starch‐based snacksQuantum satis
Processed nutsQuantum satis
Desserts excluding products covered in category 1, 3 and 4Quantum satis
Food supplements supplied in a solid form including capsules and tablets and similar forms, excluding chewable formsQuantum satis
Food supplements supplied in a solid form including capsules and tablets and similar forms, excluding chewable forms30000
Food supplements supplied in a liquid formQuantum satis
Food supplements supplied in a syrup‐type or chewable formQuantum satis
Processed foods not covered by categories 1–17, excluding foods for infants and young childrenQuantum satis

Is microcrystalline cellulose safe?

Microcrystalline cellulose (E 460(i)) and powdered cellulose (E 460(ii)) have been previously evaluated by the Scientific Committee on Food (SCF), the most recent evaluation dating in 1999. In 1999, the SCF assessed additional toxicological data and confirmed the ‘ADI not specified’, established in 1978. As a matter of precaution, the Committee repeated the advice given in 1995, according to which, the particle size should not be lower than 5 μm with a tolerance of 10% by the number of particles.

The latest safety evaluation of methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), methyl ethyl cellulose (E 465), carboxy methyl cellulose (E 466) by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) was done in 1989 15, where an acceptable daily intake (ADI) ‘not specified’ was established for each modified cellulose. Latest evaluation of enzymatically hydrolysed carboxy methyl cellulose (E 469) was done in 1998 16 and an acceptable daily intake (ADI) ‘not specified’ was established. The ADI for cross‐linked sodium carboxy methyl cellulose previously established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) 17 is ‘not specified’ based on the substance being poorly absorbed and of low toxicity, with which is in agreement with the known low toxicity of other modified celluloses.

Animal and human data clearly demonstrated that microcrystalline cellulose (E 460(i)) and powdered cellulose (E 460(ii)) are not absorbed intact in the gastrointestinal tract and could be fermented during their passage through the large intestine by strains of bacteria found in the human colon. Data for methyl cellulose (E 461), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465), sodium carboxy methyl cellulose (E 466), cross‐linked sodium carboxy methyl cellulose (E 468) and enzymatically hydrolysed carboxy methyl cellulose (E 469) demonstrated that these modified celluloses are not absorbed intact, not fermented and are excreted intact via the faeces. The European Food Safety Authority Panel noted that microcrystalline, powdered and modified celluloses would not be absorbed intact and would be less fermented than other polysaccharides such as gums, starches or pectins.

Specific toxicity data were not always available for all the celluloses evaluated in the present opinion and for all endpoints. In general, the most complete data sets were available for microcrystalline cellulose (E 460(i)) and sodium carboxy methyl cellulose (E 466). However, given their structural, physicochemical and biological similarities, the European Food Safety Authority Panel considered it possible to read‐across between all the celluloses.

Data on acute oral toxicity are available for microcrystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxy methyl cellulose. These indicate a low oral acute toxicity.

Short‐term and subchronic toxicity studies have been performed with microcrystalline cellulose (E 460(i)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), sodium carboxy methyl cellulose (E 466) and enzymatically hydrolysed carboxy methyl cellulose (E 469). In the majority of studies, animals were dosed via diet at levels up to 10%. Effects on body weight at the highest dose tested (10%) were reported in some, but not all studies, which may reflect nutritional constraints rather than toxicity. No adverse effects were reported with most of the tested celluloses, except for local effects on caecal size due to the presence of undigested fibre. Groups of 20 Albino Wistar outbred rats per sex were dosed with carboxy methyl cellulose (E 466) or enzymatically hydrolysed carboxy methyl cellulose (E 469) via diet with 0%, 2.5%, 5% and 10% (up to 6,800 mg/kg body weight per day) for up to 102 days. Effects on caecal weight, urothelial hyperplasia, pelvic nephrocalcinosis, corticomedullary nephrocalcinosis and increased incidence of diffuse epithelial hyperplasia in the urinary bladder were observed. However, the findings in kidneys and urinary bladder were attributed to the concentration of sodium, which was up to fourfold higher in the test diet compared with the basal diet. The Panel noted that this was a plausible explanation for the reported findings.

Avicel® RCN‐15 (a mixture of 85% microcrystalline cellulose with 15% guar gum) did not induce mutagenic effects in the presence or absence of a metabolic activation system in bacterial reverse mutation assays 18, in a gene mutation assay in mouse lymphoma cells (at thymidine kinase locus) 19, in an in vitro test for unscheduled DNA synthesis 20 and in the mouse bone marrow micronucleus assays 21. Negative results were also reported with other microcrystalline cellulose preparations in other unpublished studies 6. Overall, the European Food Safety Authority Panel concluded that microcrystalline cellulose (E 460(i)) and powdered cellulose (E 460(ii)), which only differs for polymerisation degree, do not raise concern for genotoxicity 6.

Concerning methyl cellulose and sodium carboxy methyl cellulose, both substances were negative in Ames tests with different Salmonella Typhimurium strains, both with and without metabolic activation 22. Negative results were also obtained in a chromosomal aberration assay in Chinese hamster fibroblasts 22, only performed without metabolic activation, and in host‐mediated assays with yeast and bacteria 23.

Methyl cellulose was also tested with negative results in an in vitro chromosomal aberration assay in human embryonic lung cells (WI‐38), and in vivo in a chromosome aberration assay in rat bone marrow and in the dominant lethal assay in male rats 24.

Therefore, the European Food Safety Authority Panel concluded that methyl cellulose and sodium carboxy methyl cellulose do not raise concern for genotoxicity.

The European Food Safety Authority Panel also considered that read‐across from methyl cellulose (E 461) to the other modified celluloses bearing similar simple substituents (E 462, E 463, E 464, E 466) was scientifically justified, and supported by the in silico analysis, which did not highlight additional structural alerts for genotoxicity, and concluded that either these modified celluloses did not raise genotoxic concern. Similarly, the European Food Safety Authority Panel considered scientifically justified the read‐across from sodium carboxy methyl cellulose (E 466) to its products of enzymatic hydrolysis (E 469) or cross‐linking (E 468), which do not bear additional structural determinants of genotoxicity. Overall, the Panel concluded that microcrystalline and powdered cellulose (E 460(i) and E 460(ii)) and modified celluloses (E 461−E 469) do not raise concern for genotoxicity.

Chronic toxicity studies have been performed with microcrystalline cellulose (E 460(i)), methyl cellulose (E 461), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465) and sodium carboxy methyl cellulose (E 466). Although there were some inconsistencies in the data, the main effects seen were decreases in body weight gain at the highest dose, which are likely to be due to the amount/bulk of celluloses in the diet leading to nutritional imbalance. Furthermore, in a chronic feeding study with microcrystalline cellulose (E 460(i)), some dystrophic calcification of renal tubules was observed in the high dose group (15,000 mg/kg bw per day). The no observed adverse effect level (NOAEL) values reported ranged up to 9,000 mg/kg body weight per day. The European Food Safety Authority Panel concluded that microcrystalline cellulose and modified celluloses have no carcinogenic properties and that there was no reason to expect carcinogenic properties with powdered cellulose (E 460(ii)).

Concerning reproductive and developmental toxicity, data are available for microcrystalline cellulose (E 460(i)), methyl cellulose (E 461), hydroxypropyl cellulose (E 463) and sodium carboxy methyl cellulose (E 466). The substances were tested in mice, rats, hamsters and/or rabbits with oral dosing via gavage 25. Adverse effects on reproductive performance or developmental effects were not observed with modified and unmodified celluloses at doses greater than 1,000 mg/kg body weight by gavage (often the highest dose tested).

Specific toxicity data were not always available for all the celluloses for all endpoints. In general, the most complete data sets were available for microcrystalline cellulose (E 460(i)) and sodium carboxy methyl cellulose (E 466). Given the similarities in their structure, relevant physicochemical, metabolic and toxicological properties, the European Food Safety Authority Panel considered it possible to read‐across between all the celluloses.

In addition, the European Food Safety Authority Panel noted that methyl cellulose (E 461) and sodium carboxy methyl cellulose (E 466) were frequently used in the formulations for administration of xenobiotics by gavage in chronic, reproductive and developmental toxicity and carcinogenicity studies. In these studies, there should be a negative control group receiving the formulation alone. Although modified cellulose levels were usually only up to 2%, given the number of studies and group sizes in these studies, the overall number of animals tested would be very large. The European Food Safety Authority Panel considered that the absence of reported adverse effects from such vehicle control groups provided additional evidence of the lack of safety concern for modified celluloses at levels up to 2% in the vehicle.

There was evidence that repeated doses up to 35 g/person of microcrystalline cellulose or powdered cellulose did not adversely affect clinical chemistry and haematological parameters and had no effect on the absorption and/or the metabolism of dietary constituents.

Some modified celluloses have been used in patients suffering from diarrhoea or constipation. In general, it can be concluded that an oral ingestion of up to 6,000 mg/person per day for 8 months was well tolerated.

The European Food Safety Authority Panel noted that carboxy methyl cellulose was one of the food additives reported to alter the gut microbiota, promote gut inflammation, promote obesity and to impair glycaemic control in mice 26. In several studies, other emulsifiers have been reported to alter the gut microbiota, promote gut inflammation, promote obesity and to impair glycaemic control in experimental studies with animals 27.

Some of the effects associated with emulsifiers are not systematically studied as specific endpoints in toxicity studies performed according to current toxicity testing guidelines; therefore, they would have be investigated on a case‐by‐case basis if indicated by the results of the general toxicity testing, as recommended in the Guidance for submission of food additives 28.

The European Food Safety Authority Panel considered that based on the animal data, the toxicity of microcrystalline, powdered and modified celluloses was low and that NOAELs were generally the highest dose tested (up to at least 9,000 mg/kg body weight per day). In addition, the large cumulative group of exposed animals from use in control populations to 2% would indicate that there. There were no reasons why humans would be expected to be more sensitive than animals in toxicodynamics or. The available data in humans indicate that daily doses of up to 6,000 mg for around 8 months were not associated with adverse effects; however in line with many other dietary fibres, large bolus intakes of celluloses were occasionally associated with laxation, but there was a lack of dose–response data available.

The European Food Safety Authority Panel considered that in line with the conceptual framework, it would be useful if risk managers had an indicative total exposure (daily consumption value) for microcrystalline, powdered and modified celluloses used as food additives, which would not pose a health risk and uses up to this value would not require a further risk assessment. The European Food Safety Authority Panel considered this could be based on all the reported NOAELs from subchronic and chronic toxicity studies (ranging from 2100 to more than 9000 mg/kg body weight/day), human data and allowing for interindividual uncertainty. The European Food Safety Authority Panel considered an indicative total exposure (daily consumption value) of around 660 to 900 mg/kg body weight per day for microcrystalline, powdered and modified celluloses.

To assess the dietary exposure to celluloses (E 460–466, E 468 and E 469) from their use as food additives, the combined exposure was calculated based on (1) maximum levels of data provided to European Food Safety Authority (defined as the maximum level exposure assessment scenario) and (2) reported use levels (defined as the refined exposure assessment scenario brand‐loyal and non‐brand‐loyal consumer scenario).

Celluloses (E 460–466, E 468 and E 469) are authorized in a wide range of foods. The European Food Safety Authority Panel did identify brand loyalty to specific food categories in infants and toddlers (e.g. flavored drinks). Further, the European Food Safety Authority Panel considered that the non‐brand‐loyal scenario covering other population groups was appropriate and a realistic scenario for risk characterisation because it was assumed that the population would probably be exposed long‐term to the food additive present at the mean reported use in processed food.

A refined estimated exposure assessment scenario taking into account the food for special medical purpose (FSMP) for infants and young children (Food category (FC) 13.1.5.1 dietary foods for infants for special medical purposes and special formulae for infants and 13.1.5.2 dietary foods for babies and young children for special medical purposes as defined by Commission Directive 1999/22/EC in which E 466 is authorized) was also performed to estimate exposure for infants and toddlers who may be on a specific diet. However, no reported use levels were made available by industry for these food categories. Thus, maximum permitted levels of sodium carboxy methyl cellulose (E 466) for food for special medical purpose (FSMP) were used. The European Food Safety Authority Panel noted that according to Mintel, very few baby foods were on the European market containing E 466. This was in line with the fact that no data were submitted for the food categories 13.1.5.1 and 13.1.5.2.

  • Food of category 13.1.1: Infant formulae as defined by Directive 2006/141/EC;
  • Food of category 13.1.5.1: Dietary foods for infants for special medical purposes and special formulae for infants. This interpretation also applies to those food additives in food category 13.1.5.2 (Dietary foods for babies and young children for special medical purposes as defined in Directive 1999/21/EC) for which exceptional uses in food for infants under the age of 12 weeks are indicated.

A refined estimated exposure assessment scenario taking into account the consumption of food supplements for consumers only, were also performed to estimate exposure for children, adolescents, adults and the elderly, as exposure via food supplements may deviate largely from that via food, and the number of food supplements consumers may be low depending on populations and surveys.

The refined estimates were based on 26 out of 84 food categories in which celluloses (E 460–466, E 468 and E 469) are authorized. The European Food Safety Authority Panel considered that the uncertainties identified would, in general, result in an overestimation of the exposure to celluloses (E 460–466, E 468 and E 469) as food additives in European countries for the refined scenario if it is considered that the food additives may not be used in food categories for which no usage data have been provided.

The European Food Safety Authority Panel noted that given the information from the Mintel’s Global New Products Database, it may be assumed that celluloses (E 460–466, E 468 and E 469) are used in food categories for which no data have been provided by food industry. The main food categories, in terms of amount consumed, not taken into account were processed fermented milk products, cheeses (unripened, processed), fish and fishery products and breakfast cereals. However, according to the Mintel GNPD, in the European Union (EU) market, a small percentage (< 1%) of food products belonging to these food categories are labelled with celluloses (E 460–466, E 468 and E 469). Therefore, the Panel considered that if these uncertainties were confirmed, it would result in a slight underestimation of the exposure.

The European Food Safety Authority Panel further noted that the exposure to celluloses (E 460–466, E 468 and E 469) from their use according the Annex III to Regulation (EC) No 1333/2008 was not considered in the exposure assessment.

The European Food Safety Authority Panel also noted that the refined exposure estimates were based on information provided on the reported levels of use of celluloses (E 460–466, E 468 and E 469). If actual practice changes, this refined estimates may no longer be representative and should be updated.

Following the conceptual framework for the risk assessment of certain food additives re‐evaluated under Commission Regulation (EU) No 257/2010 29 and given that:

  • their structural, physicochemical and biological similarities, allows for read‐across between all the celluloses
  • animal and human data demonstrate that microcrystalline cellulose (E 460(i)) and powdered cellulose (E 460(ii)) are not absorbed intact in the gastrointestinal tract but could be fermented by intestinal microbiota. Chemically modified celluloses are not absorbed intact, nor fermented, but are excreted intact via the faeces
  • using the read‐across approach, adequate data on short‐ and long‐term toxicity and carcinogenicity and reproductive toxicity are available,
  • despite the limitations of some of the studies, the available data do not indicate a genotoxic concern for microcrystalline cellulose, methyl cellulose and carboxy methyl cellulose, and by read‐across, of the other modified and unmodified celluloses
  • no adverse effects were reported after repeated doses up to 35 g/person of microcrystalline cellulose or powdered cellulose; oral ingestion of some modified celluloses up to 6,000 mg/person per day for 8 months in patients suffering from diarrhoea or constipation was well tolerated;
  • adequate combined exposure data were available; in the general population, the highest 95th percentile refined exposure assessment estimates calculated based on the reported data from food industry was 506 mg/kg body weight per day in toddlers (brand‐loyal scenario)
  • an indicative high refined exposure assessment of up to 448 mg/kg body weight per day for the elderly has been calculated at the 95th percentile among the population classes consuming food supplements

The European Food Safety Authority Panel concluded that there was no need for a numerical acceptable daily intake (ADI) and that there would be no safety concern at the reported uses and use levels for the unmodified and modified celluloses (E 460(i); E 460(ii); E 461–466; E 468 and E 469). The European Food Safety Authority Panel further suggested an indicative total exposure (daily consumption value) of 660−900 mg/kg body weight per day where these conclusions would remain valid.

Concerning the use of sodium carboxy methyl cellulose (E 466) in ‘dietary foods for special medical purposes and special formulae for infants’ (FC 13.1.5.1) and in ‘dietary foods for babies and young children for special medical purposes as defined in Directive 1999/21/EC’ (FC 13.1.5.2), and given that:

  • for infants and toddlers consumers only of food for special medical purpose (FSMP), the highest 95th percentile refined exposure estimate was 1,557 mg/kg bw per day in infants;
  • no adequate specific studies addressing the safety of use of sodium carboxy methyl cellulose (E 466) in this population under certain medical conditions were available;

The European Food Safety Authority Panel concluded, that the available data did not allow for an adequate assessment of the safety of use of sodium carboxy methyl cellulose (E 466) in infants and young children consuming foods belonging to the categories – food for special medical purpose (FSMP). The European Food Safety Authority Panel noted that sodium carboxy methyl cellulose (E 466) seemed not to be used in these food categories as no use or use levels were submitted by industry and only very few food belonging to these categories appeared to be labelled with sodium carboxy methyl cellulose (E 466).

The European Food Safety Authority Panel recommended that the European Commission considers lowering the maximum limits for the toxic elements arsenic, lead, mercury and cadmium present as impurities in the EU specifications for unmodified and modified celluloses re‐evaluated in the present opinion [microcrystalline cellulose (E 460(i)), powdered cellulose (E 460(ii)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465), sodium carboxy methyl cellulose (E 466), enzymatically hydrolysed carboxy methyl cellulose (E 469) and cross‐linked carboxy methyl cellulose (E 468)] should be revised to ensure that these food additives will not be a significant source of exposure to these toxic elements in food, in particular for infants and children.

Microcrystalline cellulose side effects

None known in the literature search.

Microcrystalline cellulose allergy

No microcrystalline cellulose allergy was found in the literature search, in fact there was 1 clinical trial using microcrystalline cellulose topical nasal spray for allergic rhinitis 30. Microcrystalline cellulose topical nasal spray did not prove to be significantly better than placebo in treating seasonal allergic rhinitis symptoms.

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