Re-evaluation of celluloses

Re-evaluation of celluloses

Following a request from the European Commission, the EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion re-evaluating the safety of 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) as food additives. These celluloses are authorised as food additives in accordance with Annex II and Annex III of Regulation (EC) No 1333/2008.

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 (DP) 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 is purified, partially depolymerised cellulose prepared by treating α-cellulose, obtained as a pulp from strains of fibrous plant material, while powdered cellulose is purified, mechanically disintegrated cellulose prepared by processing α-cellulose.

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.

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 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 (JECFA, 1990), 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 (JECFA, 1999a,b) and an ADI ‘not specified’ was established. The ADI for cross-linked sodium carboxy methyl cellulose previously established by JECFA (2003) 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 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 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 (bw) 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 (Batt, 1992), in a gene mutation assay in mouse lymphoma cells (at thymidine kinase locus) (Cifone, 1992), in an in vitro test for unscheduled DNA synthesis (McKeon, 1992) and in the mouse bone marrow micronucleus assays (Murli, 1992). Negative results were also reported with other microcrystalline cellulose preparations in other unpublished studies (Documentation provided to EFSA no. 34, 35, 36, 37). Overall, the 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.

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 (Litton Bionetics Inc., 19751980, Blevins and Taylor, 1982; Ishidate et al., 1984). Negative results were also obtained in a chromosomal aberration assay in Chinese hamster fibroblasts (CHL) (Ishidate et al., 1984), only performed without metabolic activation, and in host-mediated assays with yeast and bacteria (Litton Bionetics Inc., 19741975).

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 (Litton Bionetics Inc., 1974).

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

The 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 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 bw per day. The 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 (FDLI, 19731975; Ferch, 1973a,b; Cannon Labs, 19751977; Kitagawa et al., 1978a,b; Fritz and Becker, 1981; Freeman, 1992b). Adverse effects on reproductive performance or developmental effects were not observed with modified and unmodified celluloses at doses greater than 1,000 mg/kg bw 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 Panel considered it possible to read-across between all the celluloses.

In addition, the 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 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 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 (Chassaing et al., 2015). 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 (Swidsinski et al., 2009a,b; Renz et al., 2012; Merga et al., 2014; Cani and Everard, 2015; Chassaing et al., 2015; Romano-Keeler and Weitkamp, 2015; Lecomte et al., 2016; Shah et al., 2017).

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 (EFSA ANS Panel, 2012).

The 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 bw 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 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 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 bw/day), human data and allowing for interindividual uncertainty. The Panel considered an indicative total exposure (daily consumption value) of around 660 to 900 mg/kg bw 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 EFSA (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 authorised in a wide range of foods. The Panel did identify brand loyalty to specific food categories in infants and toddlers (e.g. flavoured drinks). Further, the 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 authorised) 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, MPLs of E 466 for FSMP were used. The 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.

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 authorised. The 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 Panel noted that given the information from the Mintel’s Global New Products Database (GNPD), 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 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 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 (EFSA ANS Panel, 2014) 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 bw per day in toddlers (brand-loyal scenario)
  • an indicative high refined exposure assessment of up to 448 mg/kg bw per day for the elderly has been calculated at the 95th percentile among the population classes consuming food supplements

The Panel concluded that there was no need for a numerical 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 Panel further suggested an indicative total exposure (daily consumption value) of 660−900 mg/kg bw 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 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 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 13.1.5.1 and 13.1.5.2. The Panel noted that 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 labeled with E 466.

The 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 (E 460(i), E 460(ii), E 461, E 462, E 463, E 464, E 465, E 466, E 468 and E 469) 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.

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