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 oxidised starch (E 1404), monostarch phosphate (E 1410), distarch phosphate (E 1412), phosphated distarch phosphate (E 1413), acetylated distarch phosphate (E 1414), acetylated starch (E 1420), acetylated distarch adipate (E 1422), hydroxypropyl starch (E 1440), hydroxypropyl starch phosphate (E 1442), starch sodium octenyl succinate (E 1450), acetylated oxidised starch (E 1451) and starch aluminium octenyl succinate (E 1452) when used as food additives.
The aforementioned modified starches are authorised as food additives in accordance with Regulation (EC) No 1333/2008.
Starch typically consists of two polymers of glucose, namely amylose, with an almost linear structure, and amylopectin, which is highly branched. In amylose, the glucose monomers (pyranosic form) are linked by α-1,4-glycosidic links, while amylopectin contains additionally α-1,6-glycosidic bonds. Commercial starches are composed of about 20–25% amylose and 75–80% amylopectin. High amylose starches typically consist of 50–80% amylose and 20–50% amylopectin. Starches for commercial use are generally produced from potatoes, cereals or other sources.
In modified starches, the chemical and physical characteristics of the native substances are altered in order to improve the functional properties for particular food applications: the observed effects on such properties depend on the type and extent of the modification (e.g. degree of substitution (DS)) and the source starch (e.g. cereal, potato, tapioca). In general, the extent of modification required to distinctly alter the functional characteristics of native starches is low, as imposed by Commission Regulation (EU) No 231/2012. In conclusion, for a large number of food applications, modified starches are used because of their superior properties compared to the native substances.
Modified starches have been previously evaluated by the Scientific Committee for Food (1976, 1981, 1990 and 1995) and by the Joint FAO/WHO Expert Committee on Food Additives (1969, 1971, 1973, 1982, 2014 and 2016). An acceptable daily intake (ADI) ‘not specified’ was allocated by both committees.
Data on in vitro degradation of modified starches by digestive enzymes indicated that their digestibility was slightly reduced or showed no differences when compared to corresponding unmodified starches. In vivo data are in agreement with in vitro studies indicating that the two major components of starches, amylose and amylopectin, would be fermented during their passage through the large intestine by strains of bacteria found in the human colon. The main end products of this colonic anaerobic digestive process are short-chain fatty acids (SCFA) such as acetic, propionic and butyric acids, which are absorbed from the colon. Despite the absence of absorption, distribution, metabolism and excretion (ADME) data for two modified starches (E 1451 and E 1452) and the absence of in vivo studies in humans for some other modified starches, the Panel considered this database sufficient to conclude that modified starches would not be absorbed intact but significantly hydrolysed by intestinal enzymes and then fermented by intestinal microbiota in humans.
Toxicity data were not available for all of the modified starches evaluated in the present opinion and for all endpoints. In general, the most complete data sets were available for acetylated distarch phosphate (E 1414) and acetylated distarch adipate (E 1422). However, given their structural, physicochemical and biological similarities, it is possible to read-across between all the modified starches.
Data concerning acute oral toxicity are available for several animal species for distarch phosphate (E 1412) only. These indicate low oral acute toxicity.
Short-term and/or subchronic (90-day) studies were available in rats for all modified starches, except monostarch phosphate (E 1410). Occasionally also, studies in dogs, pigs or hamsters were available. The modified starches were given at dietary levels up to 70%. The test duration was up to 90 days. Effects on body weight and feed consumption were not observed up to dietary levels of 25%. Caecum weight was increased at exposure levels of 30% and higher, but histopathological changes were not observed. The only frequently observed significant histopathological change was the presence of pelvic and/or corticomedullary mineralisation in the kidneys, which was observed with modified as well as unmodified starches, and occurred more pronounced in females than in males.
In a 90-day study with acetylated oxidised starch (E 1451) in rats, a no-observed-adverse-effect level (NOAEL) of 10% in the diet, equal to 5,900 mg/kg per day, was determined based on hyperplasia of the transitional epithelium of the urinary bladder and the kidneys.
Evaluation of genotoxicity of the modified starches evaluated in the present opinion was performed in silico, since no genotoxicity studies were available. The Panel concluded that the in silico analyses of the substructures of modified starch moieties did not identify any relevant alert for genotoxicity, and concluded that modified starches do not raise concern for genotoxicity.
Two chronic (52-week) studies were available, one with acetylated distarch phosphate (E 1414) and one with acetylated distarch adipate (E 1422). At necropsy, relative organ weights showed no differences between the groups, except for caecal enlargement. Histopathological examination of kidneys demonstrated the presence of treatment-related pelvic nephrocalcinosis. A clear correlation was observed between the increased incidence of pelvic nephrocalcinosis, increased accumulation of calcium in the kidneys and increased urinary excretion of calcium.
Carcinogenicity studies were available for E 1413, E 1414, E 1420, E 1422, E 1442 and E 1450 in rats and for E 1442 in mice. There was no evidence for carcinogenicity. The long-term studies in rats did not reveal any significant effect, except for caecal enlargement. As this effect was observed without associated histopathological changes, it was considered to be of no toxicological significance for humans.
Kidney lesions (pelvic and corticomedullary mineralisation) occurred in rats (sub)chronically fed high levels (up to 62% in the diet, equivalent to 31,000 mg/kg body weight (bw) per day) of phosphated distarch phosphate (E 1413), acetylated distarch phosphate (E 1414), acetylated starch (E 1420), acetylated distarch adipate (E 1422) and hydroxypropyl distarch phosphate (E 1442). The lesions were considered to be associated with an imbalance of Ca/P and Mg in the diet. The mechanism is considered to be related to increased calcium absorption in the lower intestine caused by the formation of absorbable breakdown products. As the rat is a particularly sensitive species for pelvic nephrocalcinosis, while these lesions were not observed in the hamster and the pig, it was considered to be of no relevance for risk assessment in humans.
Dietary reproductive toxicity studies in rats were available for phosphate distarch phosphate (E 1413), acetylated distarch phosphate (E 1414), acetylated starch (E 1420) and acetylated distarch adipate (E 1422). No effects on reproductive performance or maternal and developmental effects were observed in the three-generation reproductive toxicity studies at dietary levels of up to 62% (equivalent to 31,000 mg/kg bw per day).
No developmental toxicity studies were available.
Studies in healthy human volunteers with phosphated distarch phosphate (E 1413), acetylated distarch phosphate (E 1414) and acetylated starch (E 1420) reported no adverse effects at doses of 60,000 mg/person.
Starch sodium octenyl succinate (E 1450) up to a single dose of 25,000 mg was well tolerated by fasting healthy adults. However, the Panel noted reports on gastrointestinal symptoms conducted in infants with hypoallergenic formula containing 2% octenyl succinic anhydride (OSA)-modified starch (24,000 mg/person).
To assess the dietary exposure to modified starches (E 1404–E 1451) from their use as food additives, the combined exposure was calculated based on (1) maximum reported use levels 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).
Modified starches are authorised in a wide range of foods. The Panel did identify brand loyalty to specific food categories in infants and toddlers (e.g. processed cereal baby foods, unflavoured fermented milk products and flavoured fermented milk products). Further, the Panel considered that the non-brand-loyal scenario covering other population groups was appropriate and realistic scenario for risk characterisation because it is 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 purposes (FSMP) for infants and young children (FC 188.8.131.52 Dietary foods for infants for special medical purposes and special formulae for infants and FC 184.108.40.206 Dietary foods for babies and young children for special medical purposes as defined by Commission Directive 1999/22/EC) was also performed to estimate exposure of infants and toddlers who may be on a specific diet. Considering that this diet is required due to specific needs, it is assumed that consumers are loyal to the food brand; therefore, the refined brand-loyal estimated exposure scenario was performed.
A specific food supplement consumers only scenario was 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 supplement consumers may be low depending on populations and surveys.
The refined estimates were based on 36 out of 72 food categories in which modified starches are authorised. The Panel considered that the uncertainties identified would, in general, result in an overestimation of the exposure to modified starches as a food additive in European countries for the maximum level exposure scenario. However, the Panel noted that given the information from the Mintel’s Global New Products Database (GNPD), it may be assumed that modified starches are used in food categories (n = 13) 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 fish and fishery products, including molluscs and crustaceans, breakfast cereals, salads and savoury-based sandwich spreads. According to the Mintel GNPD, in the European Union (EU) market, these categories are labelled with modified starches. Therefore, the Panel considered that if these uncertainties were confirmed, it would therefore result in an underestimation of the exposure.
The Panel further noted that the exposure to modified starches (E 1404–E 1451) from their use according Annex III to Regulation (EC) No 1333/2008 (Parts 1, 3 and 5) was not considered in the exposure assessment.
Separate scenarios were carried out for the exposure assessment of starch aluminium octenyl succinate (E 1452), taking into account the consumption of food supplements for consumers only and based on the maximum permitted level (MPL) (regulatory maximum exposure assessment scenario) and on the maximum reported use level (maximum reported level exposure assessment scenario). Exposure to aluminium from the use of E 1452 as a food additive was also estimated.
Exposure to aluminium from the use of E 1452 in the regulatory maximum level exposure assessment scenario ranged for all population groups from 0.8% to 26% of the tolerable weekly intake (TWI) of 1 mg aluminium/kg bw established by EFSA (2008) at the mean, and up to 47% at the 95th percentile. For the maximum reported level exposure assessment scenario, based on the usage levels provided by food industry, exposure to aluminium from E 1452 ranged from < 0.1 at the mean, up to 2.5% for the 95th percentile across population groups. Furthermore, according to the information provided by industry, the content of aluminium in E 1452 is significantly lower than the limit set in the EU specifications for E 1452.
The Panel also noted that the refined exposure estimates are based on information provided on the reported levels of use of modified starches. 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:
- adequate combined exposure data were available; in the general population, the 95th percentile of the refined exposure, calculated based on the use levels reported from food industry, was up to 3,053 mg/kg bw per day for toddlers (brand-loyal consumer scenario);
- an indicative refined exposure to modified starches (E 1404–E 1451) of up to 991 mg/kg bw per day has been calculated at the 95th percentile for children, for the population consuming food supplements;
- exposure to starch aluminium octenyl succinate (E 1452) for food supplement consumers only at the 95th percentile was 22.1 mg/kg bw per day (regulatory maximum level exposure assessment scenario) and 1.2 mg/kg bw per day (maximum reported level exposure scenario) in the elderly;
- their structural, physicochemical and biological similarities, allow for read-across between all the modified starches;
- the ADME database is sufficient to conclude that, in humans, modified starches would not be absorbed intact, but significantly hydrolysed by intestinal enzymes and then fermented by the intestinal microbiota;
- using the read-across approach, adequate data on short- and long-term toxicity and carcinogenicity and reproductive toxicity are available;
- no treatment-related effects relevant for human risk assessment were observed in long-term studies in rats fed very high levels of modified starches (up to 31,000 mg/kg bw per day);
- although no genotoxicity data on the modified starches evaluated in the present opinion were available, modified starches are not of genotoxic concern based on in silico analysis;
- modified starches (i.e. E 1413, E 1414, E 1420 and E 1450) were well tolerated in adults up to a single daily dose of 60,000 mg/person (860 mg/kg bw);
the Panel concluded that there is no safety concern for the use of modified starches as food additives at the reported uses and use levels and that there is no need for a numerical ADI.
Concerning the use of starch sodium octenyl succinate (E 1450) in ‘dietary foods for special medical purposes and special formulae for infants’ (food category 220.127.116.11) and of E 1404, E 1410, E 1412, E 1413, E 1414, E 1420, E 1450 and E 1451 in food belonging to food category 18.104.22.168 and given that:
- for populations consuming foods for special medical purposes and special formulae, the 95th percentile of exposure calculated based on the maximum use levels reported from food industry was up to 5,286 mg/kg bw per day for infants;
- infants and young children consuming foods belonging to these food categories may show a higher susceptibility to the gastrointestinal effects of modified starches than their healthy counterparts due to their underlying medical condition;
- no effects on body weight and food intake were observed in male and female neonatal pigs exposed to 10,000 mg/kg bw per day of OSA-modified starch (E 1450) in formula for 21 days;
- OSA-modified starch (E 1450), up to a single dose of 25,000 mg/person, was well tolerated by fasting healthy adults, but gastrointestinal symptoms were reported in infants with hypoallergenic formula containing 2% of OSA-modified starch (about 24,000 mg/person);
- available information on the clinical studies in infants is limited and results refer to the feeding of formula containing OSA-modified starch in concentrations below 2%, the current authorised MPL,
the Panel concluded, that the available data do not allow for an adequate assessment of the safety of the use of starch sodium octenyl succinate (E 1450) in ‘dietary foods for special medical purposes and special formulae for infants’ (food category 22.214.171.124) or of E 1404, E 1410, E 1412, E 1413, E 1414, E 1420, E 1450 and E 1451 in foods belonging to food category 126.96.36.199, in infants and young children consuming these foods at the presently authorised maximum use levels of 20,000 or 50,000 mg/kg, respectively.
The Panel recommended that:
- the European Commission considers revising the maximum limits for the toxic elements arsenic, lead and mercury present as impurities in the EU specifications for all modified starches re-evaluated in the present opinion (E 1404, E 1410, E 1412, E 1413, E 1414, E 1420, E 1422, E 1440, E 1442, E 1450, E 1451 and E 1452) to ensure that these food additives will not be a significant source of exposure to these toxic elements in food;
- the European Commission considers revising specifications, including harmonisation of microbiological criteria for polysaccharides such as modified starches and gums, and taking into account future availability of specific methods of analysis of modified starches;
- the European Commission seeks confirmation on the actual use of starch aluminium octenyl succinate (E 1452) in its currently permitted use limited to food supplements (only vitamin preparations for encapsulation purposes);
- additional data should be generated to assess the potential health effects of starch sodium octenyl succinate (E 1450) when used in ‘dietary foods for special medical purposes and special formulae for infants’ (food category 188.8.131.52) or of E 1404, E 1410, E 1412, E 1413, E 1414, E 1420, E 1450 and E 1451 in foods belonging to food category 184.108.40.206;
- due to the discrepancies observed between the data reported from industry and the Mintel database, where modified starches (E 1404–E 1451) are labelled in more products than in food categories for which data were reported from industry, the Panel recommended collection of data on usage and use levels of modified starches (E 1404–E 1451) in order to perform a more realistic exposure assessment.
The present opinion deals with the re-evaluation of the safety of oxidised starch (E 1404), monostarch phosphate (E 1410), distarch phosphate (E 1412), phosphated distarch phosphate (E 1413), acetylated distarch phosphate (E 1414), acetylated starch (E 1420), acetylated distarch adipate (E 1422), hydroxypropyl starch (E 1440), hydroxypropyl distarch phosphate (E 1442), starch sodium octenyl succinate (E 1450), acetylated oxidised starch (E 1451) and starch aluminium octenyl succinate (E 1452) when used as food additives. These modified starches are authorised food additives in the EU according to Annex II and Annex III to Regulation (EC) No 1333/20081.
1.1 Background and Terms of Reference as provided by the European Commission
Regulation (EC) No 1333/2008 of the European Parliament and of the Council on food additives requires that food additives are subject to a safety evaluation by the European Food Safety Authority (EFSA) before they are permitted for use in the European Union (EU). In addition, it is foreseen that food additives must be kept under continuous observation and must be re-evaluated by EFSA.
For this purpose, a programme for the re-evaluation of food additives that were already permitted in the European Union before 20 January 2009 has been set up under Regulation (EU) No 257/20102. This Regulation also foresees that food additives are re-evaluated whenever necessary in light of changing conditions of use and new scientific information. For efficiency and practical purposes, the re-evaluation should, as far as possible, be conducted by group of food additives according to the main functional class to which they belong.
The order of priorities for the re-evaluation of the currently approved food additives should be set on the basis of the following criteria: the time since the last evaluation of a food additive by the Scientific Committee on Food (SCF) or by EFSA, the availability of new scientific evidence, the extent of use of a food additive in food and the human exposure to the food additive taking also into account the outcome of the Report from the Commission on Dietary Food Additive Intake in the EU3 of 2001. The report ‘Food additives in Europe 2000’ submitted by the Nordic Council of Ministers to the Commission, provides additional information for the prioritisation of additives for re-evaluation.
In 2003, the Commission already requested EFSA to start a systematic re-evaluation of authorised food additives. However, as a result of adoption of Regulation (EU) 257/2010, the 2003 Terms of References are replaced by those below.
1.1.2 Terms of Reference
The Commission asks EFSA to re-evaluate the safety of food additives already permitted in the Union before 2009 and to issue scientific opinions on these additives, taking especially into account the priorities, procedures and deadlines that are enshrined in Regulation (EU) No 257/2010 of 25 March 2010 setting up a programme for the re-evaluation of approved food additives in accordance with Regulation (EC) No 1333/2008 of the European Parliament and of the Council on food additives.
1.1.3 Interpretation of Terms of Reference
The Panel on Food Additives and Nutrient Sources added to Food (ANS) described its risk assessment paradigm in the Guidance for submission for food additive evaluations in 2012 (EFSA ANS Panel, 2012). This Guidance states, that in carrying out its risk assessments, the Panel sought to define a health-based guidance value, e.g. an acceptable daily intake (ADI) (IPCS, 2004) applicable to the general population. According to the definition above, the ADI as established for the general population does not apply to infants below 12 weeks of age (JECFA, 1978; SCF, 1998). In this context, the re-evaluation of the use of starch sodium octenyl succinate (E 1450) in food for infants below 12 weeks represents a special case for which specific recommendations were given by the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 1972a, 1978) and by the SCF (1996, 1998). The Panel endorsed these recommendations.
In the current EU legislation (Regulation (EC) No 1333/2008), use levels of additives in food for infants under the age of 12 weeks in categories 13.1.1 and 220.127.116.11 (Annex II) and uses of food additives in nutrient preparations for use in food for infants under the age of 12 weeks and maximum levels for the carry-over from these uses (Annex III, Part 5, section B) are included. The Panel considers that these uses would require a specific risk assessment in line with the recommendations given by JECFA and the SCF and endorsed by the Panel in its current Guidance for submission for food additives evaluations (EFSA ANS Panel, 2012). Therefore, risk assessments for the general population are not considered applicable for infants under the age of 12 weeks and will be performed separately.
This re-evaluation refers exclusively to the uses of modified starches as food additives in food, including food supplements and does not include a safety assessment of other uses of modified starches.
1.2 Information on existing authorisations and evaluations
Oxidised starch (E 1404), monostarch phosphate (E 1410), distarch phosphate (E 1412), phosphated distarch phosphate (E 1413), acetylated distarch phosphate (E 1414), acetylated starch (E 1420), acetylated distarch adipate (E 1422), hydroxypropyl starch (E 1440), hydroxypropyl distarch phosphate (E 1442), starch sodium octenyl succinate (E 1450), acetylated oxidised starch (E 1451) and starch aluminium octenyl succinate (E 1452) are listed in Commission Regulation (EC) No 1333/2008 as authorised food additives in the EU and have been previously evaluated by JECFA and by the SCF. An acceptable daily intake (ADI) ‘not specified’ was allocated by both committees in their evaluations.
A group of modified starches was evaluated by the SCF in 1976 (SCF, 1976). The starches E 1404–1422 were assigned to group B: ‘starches may be used temporarily until 31 December 1980 but the numbers and amounts used should be limited in infant foods. For these latter foods every effort should be made to work within a maximum of 3.5%. If technologically necessary for the manufacture of certain products, the Committee could accept a maximum of 5%’. The starches E 1440 and E 1442 were assigned to Group C (starches that should not be allowed in infant foods). They were acceptable for use in food, other than that prepared for infants, on a temporary basis until 31 December 1980, subject to a limit for total chlorohydrins of 1 mg/kg in the relevant specifications.
The group of modified starches was evaluated a second time by the SCF in 1981 (SCF, 1982). Additional short-term, long-term and reproductive toxicity studies on starches previously classified into group B or C5 were reviewed. The SCF considered the appearance and mechanism of corticomedullary and of pelvic nephrocalcinosis (PN) as a finding to be specific for the rat as the most sensitive species and to have little relevance for the safety assessment of modified starches for man. The SCF considered that E 1440 and E 1442 could be transferred to group B provided residues of chlorohydrin did not exceed 0.1 mg/kg as determined by an agreed method. The Panel noted that according to the current specifications, the residues of propylene chlorohydrin should not exceed 1 mg/kg (Commission Regulation (EU) No 231/20126).
Starch sodium octenyl succinate (E 1450; octenyl succinic anhydride (OSA)-modified starch) was evaluated by the SCF in 1990 (SCF, 1994), and acetylated oxidised starch (E 1451) was evaluated by the SCF in 1995 (SCF, 1997) and were included among the other modified starches in group B, for which use was considered acceptable and for which the establishment of individual ADIs was judged by the SCF to be unnecessary, provided the technological usage remained at present-day levels.
The group of ‘modified starches’ was discussed by JECFA in 1969 (JECFA, 1970), in 1971 (JECFA, 1972b), in 1973 (JECFA, 1974c) and in 1982 (JECFA, 1982a). The group ‘modified starches’ comprised the following substances: E 1404, E 1410, E 1412, E 1413, E 1414, E 1420, E 1422, E 1440, E 1442 and E 1450. At this meeting, JECFA established an ADI ‘not specified’ for all modified starches listed above except for acetylated oxidised starch (E 1451), for which an ADI ‘not specified’ was established at the 57th JECFA meeting (JECFA, 2002a).
Starch sodium octenyl succinate (OSA-modified starch; E 1450) was evaluated at the 79th JECFA meeting (JECFA, 2015). Since the 26th meeting, where an ADI ‘not specified’ was assigned to OSA-modified starch, new data became available, including a 90-day oral toxicity study, genotoxicity studies and a long-term toxicity and carcinogenicity study. The Committee confirmed the low toxicity of the additive and also confirmed the ADI ‘not specified’ for the general population. The Committee ‘took into account the overall low toxicity of OSA-modified starch, the conservatism in the no-observed-adverse-effect level (NOAEL), which was the highest dose tested in a study in neonatal animals, and in the exposure assessments, as well as the supporting evidence from clinical trials and post-marketing surveillance and concluded that the consumption of OSA-modified starch in infant formula or formula for special medical purposes intended for infants is not of concern at use levels up to 20 g/L’.
Additionally, in 2010, the EFSA Panel on Dietetic Products, Nutrition and Allergies (EFSA NDA Panel, 2010) evaluated phosphated distarch phosphate for use as a novel food ingredient. The starch was prepared with a novel maize starch source. The NDA Panel concluded that the novel ingredient was safe at the proposed conditions of use and intake levels.
In 1979, the Federation of American Societies for Experimental Biology (FASEB, 1979) evaluated starch and modified starches for status as generally recognised as safe (GRAS) food ingredients.
In 2008, the safety of aluminium from dietary intake has been evaluated by the EFSA Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials (AFC). The Panel established a tolerable weekly intake (TWI) for aluminium of 1 mg/kg body weight (bw) per week (EFSA, 2008).
In 2011, JECFA established a provisional tolerable weekly intake (PTWI) for aluminium of 2 mg/kg bw per week (JECFA, 2012).
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