Calcium l‐methylfolate as a source of folate added for nutritional purposes to infant and follow‐on formula, baby food and processed cereal‐based food
2020; Wiley; Volume: 18; Issue: 1 Linguagem: Inglês
10.2903/j.efsa.2020.5947
ISSN1831-4732
AutoresDominique Turck, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch‐Ernst, John Kearney, Alexandre Maciuk, Inge Mangelsdorf, Harry J McArdle, Androniki Naska, Carmen Peláez, Kristina Pentieva, Alfonso Siani, Frank Thiès, Sophia Tsabouri, Marco Vinceti, Francesco Cubadda, Karl–Heinz Engel, Thomas Frenzel, Marina Heinonen, Rosangela Marchelli, Monika Neuhäuser‐Berthold, Morten Poulsen, Yolanda Sanz, Josef Rudolf Schlatter, Henk Van Loveren, Giovanni Bernasconi, Andrea Germini, Helle Katrine Knutsen,
Tópico(s)Trace Elements in Health
ResumoEFSA JournalVolume 18, Issue 1 e05947 Scientific OpinionOpen Access Calcium l-methylfolate as a source of folate added for nutritional purposes to infant and follow-on formula, baby food and processed cereal-based food EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Corresponding Author EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) nda@efsa.europa.eu Correspondence: nda@efsa.europa.euSearch for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJacqueline Castenmiller, Jacqueline CastenmillerSearch for more papers by this authorStefaan De Henauw, Stefaan De HenauwSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorJohn Kearney, John KearneySearch for more papers by this authorAlexandre Maciuk, Alexandre MaciukSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry J McArdle, Harry J McArdleSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this authorCarmen Pelaez, Carmen PelaezSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorFrank Thies, Frank ThiesSearch for more papers by this authorSophia Tsabouri, Sophia TsabouriSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorFrancesco Cubadda, Francesco CubaddaSearch for more papers by this authorKarl-Heinz Engel, Karl-Heinz EngelSearch for more papers by this authorThomas Frenzel, Thomas FrenzelSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorRosangela Marchelli, Rosangela MarchelliSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this authorMorten Poulsen, Morten PoulsenSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorJosef Rudolf Schlatter, Josef Rudolf SchlatterSearch for more papers by this authorHenk van Loveren, Henk van LoverenSearch for more papers by this authorGiovanni Bernasconi, Giovanni BernasconiSearch for more papers by this authorAndrea Germini, Andrea GerminiSearch for more papers by this authorHelle Katrine Knutsen, Helle Katrine KnutsenSearch for more papers by this author EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Corresponding Author EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) nda@efsa.europa.eu Correspondence: nda@efsa.europa.euSearch for more papers by this authorDominique Turck, Dominique TurckSearch for more papers by this authorJacqueline Castenmiller, Jacqueline CastenmillerSearch for more papers by this authorStefaan De Henauw, Stefaan De HenauwSearch for more papers by this authorKaren Ildico Hirsch-Ernst, Karen Ildico Hirsch-ErnstSearch for more papers by this authorJohn Kearney, John KearneySearch for more papers by this authorAlexandre Maciuk, Alexandre MaciukSearch for more papers by this authorInge Mangelsdorf, Inge MangelsdorfSearch for more papers by this authorHarry J McArdle, Harry J McArdleSearch for more papers by this authorAndroniki Naska, Androniki NaskaSearch for more papers by this authorCarmen Pelaez, Carmen PelaezSearch for more papers by this authorKristina Pentieva, Kristina PentievaSearch for more papers by this authorAlfonso Siani, Alfonso SianiSearch for more papers by this authorFrank Thies, Frank ThiesSearch for more papers by this authorSophia Tsabouri, Sophia TsabouriSearch for more papers by this authorMarco Vinceti, Marco VincetiSearch for more papers by this authorFrancesco Cubadda, Francesco CubaddaSearch for more papers by this authorKarl-Heinz Engel, Karl-Heinz EngelSearch for more papers by this authorThomas Frenzel, Thomas FrenzelSearch for more papers by this authorMarina Heinonen, Marina HeinonenSearch for more papers by this authorRosangela Marchelli, Rosangela MarchelliSearch for more papers by this authorMonika Neuhäuser-Berthold, Monika Neuhäuser-BertholdSearch for more papers by this authorMorten Poulsen, Morten PoulsenSearch for more papers by this authorYolanda Sanz, Yolanda SanzSearch for more papers by this authorJosef Rudolf Schlatter, Josef Rudolf SchlatterSearch for more papers by this authorHenk van Loveren, Henk van LoverenSearch for more papers by this authorGiovanni Bernasconi, Giovanni BernasconiSearch for more papers by this authorAndrea Germini, Andrea GerminiSearch for more papers by this authorHelle Katrine Knutsen, Helle Katrine KnutsenSearch for more papers by this author First published: 17 January 2020 https://doi.org/10.2903/j.efsa.2020.5947Citations: 1 Requestor: European Commission Question number: EFSA-Q-2018-00816 Panel members: Dominique Turck, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch-Ernst, John Kearney, Helle Katrine Knutsen, Alexandre Maciuk, Inge Mangelsdorf, Harry J McArdle, Androniki Naska, Carmen Pelaez, Kristina Pentieva, Alfonso Siani, Frank Thies, Sophia Tsabouri and Marco Vinceti. Adopted: 27 November 2019 AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the extension of use of calcium l-methylfolate to be used as a source of folate added for nutritional purposes to infant and follow-on formula, baby food and processed cereal-based food pursuant to Regulation (EU) 609/2013. In 2004, EFSA assessed the use of calcium l-methylfolate as a source of folate in foods for particular nutritional uses, food supplements and foods intended for the general population. The new alternative synthetic step proposed to produce the nutrient source, using platinum as a catalyst, did not raise any safety concern and the production process was found to consistently yield a product in line with the proposed specifications. Based on the studies assessed in the previous evaluation, it was concluded that calcium l-methylfolate is non-genotoxic and that subchronic and embryotoxicity/teratogenicity studies in rats did not reveal any adverse effects up to the highest doses tested. The Panel considered that no additional toxicological studies are required on the nutrient source. The intervention study in healthy infants provided by the applicant did not indicate differences in growth and tolerance parameters in infants who consumed either an infant formula supplemented with calcium l-methylfolate or with folic acid, and did not raise concerns regarding safety or tolerability of the infant formula with the proposed nutrient source. The study also provided further supporting evidence for the bioavailability of calcium l-methylfolate. The Panel considers that calcium l-methylfolate is a source from which folate is bioavailable and concludes that calcium l-methylfolate is safe under the proposed uses and use levels for infants and young children. 1 Introduction 1.1 Background and Terms of Reference as provided by the European Commission Background The European Union legislation lists nutritional substances that may be used for nutritional purposes in certain categories of foods as sources of certain nutrients. The Commission has received a request for the evaluation of calcium L-methylfolate as a source of folate added for nutritional purposes to infant and follow-on formula, baby food and processed cereal-based food. The relevant Union legislative measure is: Regulation (EU) No 609/2013 of the European Parliament and of the Council on food intended for infants and young children, food for special medical purposes, and total diet replacement for weight control and repealing Council Directive 92/52/EEC, Commission Directives 96/8/EC, 1999/21/EC, 2006/125/EC and 2006/141/EC, Directive 2009/39/EC of the European Parliament and of the Council and Commission Regulations (EC) No 41/2009 and (EC) No 953/20091. Terms of Reference In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002, the European Commission asks the European Food Safety Authority to provide a scientific opinion, based on its consideration of the safety and bioavailability of calcium L-methylfolate as a source of folate added for nutritional purposes to infant formula, follow-on formula, baby food and processed cereal-based food. 1.2 Information on existing evaluations and authorisations Calcium l-methylfolate is an authorised form of folate in food for special medical purposes and total diet replacement for weight control as per Regulation (EU) No 609/2013. It is also authorised for use in food supplements and for addition to foods as per Regulation (EC) No 1925/2006. In 2004, the European Food Safety Authority (EFSA) issued an opinion on calcium l-methylfolate (EFSA AFC Panel, 2004) concluding that its use as a source of folate in foods for particular nutritional uses, food supplements and foods intended for the general population, at level of 1 mg/adult person/day does not raise safety concerns in line with the tolerable upper level (UL) for folic acid for adults defined by the Scientific Committee on Food (2000). Additionally, in 2013 EFSA issued another opinion on (6S)-5-methyltetrahydrofolic acid (5-MTHF), glucosamine salt as an alternative source of folate added for nutritional purposes to food supplements. The Panel concluded that the proposed use levels (up to 1.8 mg/day, which equates to 1 mg 5-MTHF and 0.8 mg glucosamine) are not of safety concern (EFSA ANS Panel, 2013). In 2014, EFSA provided an opinion on the dietary reference values for folate (EFSA NDA Panel, 2014). For infants aged 7–11 months an adequate intake (AI) for folate was set at 80 μg dietary folate equivalents (DFE)/day but no UL could be defined. For children aged 1–3 years, the average requirement (AR) and the population reference intake (PRI) were set at 90 and 120 μg DFE/day respectively, and the UL of 200 μg/day for synthetic folic acid previously defined by the SCF (2000) was confirmed. 2 Data and methodologies 2.1 Data The safety assessment of calcium l-methylfolate as a new source of folate for use in infant and follow-on formula, baby food and processed cereal-based food is based on data supplied in the application and information submitted by the applicant following an EFSA request for supplementary information. 2.2 Methodologies The evaluation of the safety and bioavailability of calcium l-methylfolate was conducted in line with the principles contained in the 'Guidance on safety evaluation of sources of nutrients and bioavailability of nutrient from the sources' (EFSA ANS Panel, 2018). 3 Assessment 3.1 Introduction This opinion deals with the safety and bioavailability of calcium l-methylfolate as a new source of folate added for nutritional purposes to infant and follow-on formula, baby food and processed cereal-based food. The nutrient source (NS) calcium l-methylfolate is produced by chemical synthesis starting from folic acid as described in Section 3.3. 3.2 Identity of the nutrient source The NS is calcium l-methylfolate, commercialised by the applicant as Metafolin®. The chemical name according to the IUPAC nomenclature is calcium;(2S,6S)-2-[[4-[(2-amino-5-methyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioate. Two CAS registry numbers are available for the NS: 129025-21-4 for calcium salt with an unspecified ratio of l-methylfolate and Ca2+, and 151533-22-1 for calcium salt with a specified 1:1 ratio of l-methylfolate and Ca2+. Synonyms, trade names and abbreviations commonly used for calcium l-methylfolate include: calcium l-5-methyltetrahydrofolate; l-methylfolate, calcium; l-5-methyltetrahydrofolic acid, calcium salt [l-5-MTHF-Ca]; (6S)-5-methyltetrahydrofolic acid, calcium salt [(6S)-5-MTHF-Ca]; (6S)-5-methyl-5,6,7,8-tetrahydropteroyl-l-glutamic acid, calcium salt; and Metafolin®. Calcium l-methylfolate has a molecular weight of 497.5 g/mol; its molecular formula is C20H23CaN7O6 and its structural formula is given in Figure 1 below. Figure 1Open in figure viewerPowerPoint Structural formula of calcium l-methylfolate Calcium l-methylfolate has two chiral carbon atoms: the α-C atom in the l-glutamic acid moiety and the C-atom in position 6 of the pteroyl moiety. According to the specifications provided, the stereoisomer configuration of calcium l-methylfolate is (6S, αS). In fact, the α-C atom in the l-glutamic acid moiety originates from the starting material folic acid and its configuration (αS or L) and remains unchanged during the chemical synthesis used by the applicant. The (6S, αS) and (6R, αS) diastereoisomers obtained in the first step of the chemical synthesis are separated afterwards by crystallisation and further purification steps to isolate the (6S, αS) isomer only, which corresponds to the natural form of folate. The particle size of the manufactured calcium l-methylfolate, subject of this opinion, has been measured by laser diffraction and electron microscopy. The latter indicated the presence of few small-sized particles (including particles in the nanoscale), which however, based on the water solubility of the nutrient source in its formulation, the Panel consider that they are likely to readily and entirely dissolve. The manufactured calcium l-methylfolate has been characterised by the applicant by means of ultraviolet-visible (UV-Vis) spectroscopy, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, X-ray diffraction and elemental analysis. Upon request of the Panel the applicant also provided a chiral high-performance liquid chromatography (HPLC) analysis of the novel food which demonstrated that the manufactured calcium l-methylfolate corresponds to the natural diastereoisomer (6S, αS). 3.3 Production process The nutrient source is produced according to Good Manufacturing Practice (GMP) principles. Calcium l-methylfolate is produced by a three-step chemical synthesis starting from folic acid. The first synthetic step is a reduction of the folic acid to produce a mixture of (6S, αS)- and (6R, αS)-tetrahydrofolic acid benzenesulfonate. For this first synthetic step two alternatives exist and are used: a catalytic hydrogenation or a reduction with sodium borohydride. The pure (6S, αS)-diastereoisomer is then isolated by crystallisation with benzenesulfonic acid. In the second step, the first isolated intermediate, (6S, αS)-tetrahydrofolic acid benzenesulfonate, is then methylated in the 5-position by condensation with formaldehyde and subsequent reduction with sodium borohydride to form (6S, αS)-5-methyltetrahydrofolic acid. The third and last synthetic step is the crystallisation of the second isolated intermediate – (6S, αS)-5-methyltetrahydrofolic acid – as calcium salt to produce the final product (6S, αS)-5-methyltetrahydrofolic acid, calcium salt (calcium l-methylfolate). According to the applicant, the manufacturing process is the same as the one assessed by EFSA in the opinion of 2004, apart from the first synthetic step where a catalytic hydrogenation, using platinum as catalyst, can be used as alternative to the sodium borohydride reduction step assessed in the previous opinion (both techniques can be used in the production process). Then, the second and third synthetic steps are equivalent to those previously assessed. The Panel assessed the new alternative first synthetic step (namely, the hydrogenation with platinum catalyst) and the experimental analytical data provided by the applicant to demonstrate the equivalent profiles of the production batches obtained by the two alternative synthetic steps. In particular, the Panel evaluated: (i) the content of the residual platinum catalyst, (ii) the overall impurity profile including the compliance with the same product specifications and (iii) the stability of the different production batches as further described below. The applicant provided the concentration of platinum for four different batches produced by hydrogenation with platinum as first synthetic step. The results indicated that the NS had a measured concentration of platinum ranging from < 0.1 to 0.14 mg/kg. With regard to the overall impurity profile and the compliance with the same product specifications for the production batches obtained by the two alternatives for the first synthetic step, the applicant reported analytical data for both manufacturing methods (i.e. hydrogenation or reduction). The Panel notes that both manufacturing methods lead to a final product with quality and impurity profiles within the specification limits provided by the applicant. Finally, in relation to the stability of the final product, the Panel considers that no influence on the stability is expected using the two alternatives as first synthetic step (catalytic hydrogenation or reduction with borohydride). Considering the quality and impurity profiles reported for the first intermediates obtained by these two synthetic alternatives and the fact that the last two synthetic steps are equivalent, the Panel considers that the physical properties of the final product are not influenced by the manufacturing process applied. This is also confirmed by the stability results of the product obtained with the catalytic hydrogenation step provided by the applicant. The Panel considers that the production process is sufficiently described and does not raise safety concerns. Further considerations on the safety of the residual amounts of platinum are reported in Section 3.7.5 ('Estimate of exposure to undesirable substances'). 3.4 Compositional data In order to confirm that the manufacturing process is reproducible and adequate to yield on a commercial scale a product with the required characteristics, the applicant provided a certificate of analysis for three independent batches of the NS produced by the reduction step with sodium borohydride (see Table 1). Table 1. Batch-to-batch analysis of the NS Parameter Batch number LMCG045801 LMCG046801 LMCM048001 Calcium l-methylfolatea (6S, αS-diastereoisomer) 101.0% 100.6% 100.5% Water 13.0% 12.1% 12.3% Total calciuma 8.0% 8.0% 8.0% Calcium d-methylfolate (6R, αS-diastereoisomer) 0.6% 0.5% 0.5% Other folates and related substances 1.08% 1.10% 0.91% Lead < LOQ (1 mg/kg) < LOQ (1 mg/kg) < LOQ (1 mg/kg) Total viable aerobic counts < LOQ (10 CFU/g) < LOQ (10 CFU/g) < LOQ (10 CFU/g) CFU: colony forming unit; LOQ: limit of quantification. a Dry basis. Information was provided on the accreditation of the laboratories that conducted the analyses presented in the application. The applicant reported the different impurities identified in the final commercial batches of calcium l-methylfolate, both in terms of residual solvents, inorganic and other potential elemental impurities, organic impurities derived from the chemical synthesis and microbial impurities. The Panel notes that the compositional data and the impurity profile is consistent for the three commercial batches analysed and in line with the specifications provided to EFSA in 2004, and with the current manufacturer specifications, as confirmed by the certificate of analysis provided for these three commercial batches of the NS. The Panel further notes that the applicant reported a list of potential organic impurities such as the residual starting material, by-products and degradation products obtained during the chemical synthesis of calcium l-methylfolate and identified them by HPLC. The analytical data reported by the applicant consistently confirmed the presence of the non-natural d-5-methylfolate diastereoisomer at a concentration below 1% and the overall concentration of 'other folates and related substances' below 2.5% in line with the purity of calcium l-methylfolate previously assessed by EFSA (EFSA AFC Panel, 2004) and the specifications from JECFA (2005). The applicant provided also analytical data for several consecutive batches produced using both alternatives for the first synthetic step (hydrogenation or reduction) showing that all batches have quality and impurity profiles within the provided specification limits. The Panel considers that the information provided on the composition and reported impurity profile of calcium l-methylfolate is sufficient and does not raise safety concerns. 3.4.1 Stability The applicant performed stability tests with fourteen independent batches of the NS. The tests were carried out at refrigerated conditions and room temperature (25°C, 60% RH) for up to 24 months. The batches were analysed for compliance with specifications for appearance, water content and diastereomeric purity. The applicant also provided information on the stability in powdered infant formula and follow-on formula, showing that the folate concentration was stable over the 18-month period tested. Moreover, the applicant also tested the stability in prepared liquid infant formula showing no loss of folate during the preparation process of the liquid infant formula. The Panel notes that the appearance of the tested batches did not change and complied with the proposed specifications for all tested parameters (HPLC assay of related compounds, water content, diastereomeric purity) for all time periods and for all samples stored at both temperatures. The Panel considers that the data provided sufficient information with respect to the stability of the NS for a period of 18 months. 3.5 Specifications The specifications of the NS as proposed by the applicant are reported in Table 2. Table 2. Specifications of the NS Description: the NS is a purified, white to yellow or beige powder that is produced by chemical synthesis Parameter Amount Method of analysis Calcium l-methylfolate (6S, αS-diastereoisomer) ≥ 95.0% (Dry basis) HPLC Water 6.0–17.0% Karl Fischer method Total calcium 7.0–8.5% (Dry basis) Titration Calcium d-methylfolate (6R, αS-diastereoisomer) ≤ 1.0% HPLC Other folates and related substances ≤ 2.5% HPLC Heavy metals and specified elemental impurities Lead ≤ 1 mg/kg ICP-MS Cadmium ≤ 0.5 mg/kg ICP-MS Mercury ≤ 1.0 mg/kg ICP-MS Arsenic ≤ 1.5 mg/kg ICP-MS Platinum ≤ 2 mg/kg ICP-MS Boron ≤ 10 mg/kg ICP-OES Microbiological TAMC ≤ 100 CFU/g Membrane filter technique TYMC ≤ 100 CFU/g Membrane filter technique CFU: colony forming unit; HPLC: high performance liquid chromatography; ICP-MS: inductively coupled plasma mass spectrometry; ICP-OES: inductively coupled plasma optical emission spectroscopy; TAMC: total aerobic microbial count; TYMC: total yeast and mould count. The Panel notes that the certificates of analysis provided for three representative commercial batches of the NS (Table 1) are compliant with the specifications indicated in the table above and reported for this application. The Panel considers that the information provided on the specifications of the NS is sufficient and does not raise safety concerns. 3.6 History of use of the NS l-Methylfolate is the predominant natural form of folates found in food (Friedrich, 1987) and breast milk (Page et al., 2017) and the major form in human plasma (Pfeiffer et al., 2015). Following the earlier assessment of calcium l-methylfolate (EFSA AFC Panel, 2004), the NS was authorised on the EU market as source of folate in food for special medical purposes and total diet replacement for weight control and in food supplements and fortified foods. Calcium l-methylfolate has a generally recognised as safe (GRAS) status in the USA, where it is also listed as a new dietary ingredient for use in dietary supplements. l-5-Methyltetrahydrofolate, calcium salt is registered as new dietary ingredient in Canada in the Natural Health Products Ingredients Database and l-5-methyltetrahydrofolate calcium salt is listed as a permitted form of folic acid for the fortification of specific foods in Australia and New Zealand. 3.7 Proposed uses and use levels and anticipated intake Calcium l-methylfolate is intended to be used as a source of folate in infant formula, follow-on formula, processed cereal-based food and baby food. Calcium l -methylfolate is intended as an alternative to folic acid, currently the only authorised form of folate added to infant formula, follow-on formula, processed cereal-based food and baby food. 3.7.1 Target population The target population proposed by the applicant is infants (< 12 months) and young children (12–< 36 months). 3.7.2 Proposed uses and maximum use levels The applicant proposes to use calcium l-methylfolate to meet the compositional requirements for folate in infant formula and follow-on formula and in processed cereal-based food and baby food. Infant formula and follow-on formula are regulated to contain folate at concentrations of 3.6–11.4 μg DFE/100 kJ or 15–47.6 μg DFE/100 kcal, where 1 μg DFE corresponds to 1 μg of food folate and to 0.6 μg of folic acid2 (see Section 3.8). Based on this, the amount of folic acid needed to meet the compositional requirements for folate in infant formula and follow-on formula corresponds to 2.2–6.8 μg/100 kJ or 9.0–28.6 μg/100 kcal. In the case of processed cereal-based food and baby food for infants and young children, no minimum compositional requirements are set for folic acid,3 but these products are regulated to contain a maximum level of folic acid of 50 μg/100 kcal. 3.7.3 Anticipated intake of the nutrient source The EFSA AFC Panel concluded that folic acid and calcium l-methylfolate have similar bioavailability at equimolar doses of supplementation (EFSA AFC Panel, 2004). Therefore, the amount of calcium l-methylfolate to be added to meet the compositional requirements for folate can be calculated on the basis of the respective molecular weights of calcium l-methylfolate (497.5 g/mol) and folic acid (441.4 g/mol). In the case of infant formula and follow-on formula, the compositional requirements for folate would be met by 2.5–7.7 μg/100 kJ or 10.1–32.2 μg/100 kcal of calcium l-methylfolate. By applying the energy density value of 280 kJ/100 mL (67 kcal/100 mL) for formula for infants below 16 weeks of age (EFSA Scientific Committee, 2017), infant formula may contain calcium l-methylfolate up to 21.6 μg/100 mL. In the case of processed cereal-based food and baby food for infants and young children, the maximum limit of folic acid permitted is 50 μg/100 kcal, which would correspond to 56 μg calcium l-methylfolate/100 kcal. Upon request of EFSA, the applicant provided a refined exposure assessment for the nutrient source in the target population groups. Infants below 16 weeks of age The applicant estimated the exposure for a scenario based on the 95th percentile (P95) of formula intake per kg body weight for different age ranges in line with (EFSA Scientific Committee, 2017). Using the average body weights of different age ranges and their infant formula consumption at the P95 level as described in (EFSA Scientific Committee, 2017), the applicant estimated the intakes of folic acid and calcium l-methylfolate corresponding to their occurrence at the maximum permitted amount of total folate (Table 3). Table 3. Estimated intake of folic acid and calcium l-methylfolate from infant formula by 1- to 16-week-old infants based on the P95 of formula consumption and maximum permitted total folate levels Age (days) Average body weighta (kg) P95 formula intakeb Folic acid intakec (μg/day) Calcium l-methylfolate intaked (μg/day) (mL/kg bw per day) (mL/day) Boys 8–13 3.5 254 889 169 192 14–27 4.0 261 1,044 198 226 28–41 4.6 251 1,155 219 250 42–55 5.1 238 1,214 231 262 56–83 5.7 211 1,203 229 260 84–111 6.5 195 1,268 241 274 Girls 8–13 3.3 251 828 157 179 14–27 3.7 257 951 181 205 28–41 4.2 253 1,063 202 230 42–55 4.7 233 1,095 208 237 56–83 5.3 212 1,124 214 243 84–111 6.0 195 1,170 222 253 a Based on WHO Child Growth Standards (https://www.who.int/childgrowth/standards/en/). b Data for formula intake in units of mg/kg body weight (bw)/day based on (EFSA SC, 2017). c Concentration in formula 0.190 μg/mL. d Calculated from folic acid intake. At the highest permitted level of total folate in infant formula, exclusively formula-fed infants at the P95 of formula consumption could ingest up to 241 μg/day of folic acid assuming a scenario in which total folate is present exclusively as synthetic folic acid. Assuming a scenario where calcium l-methylfolate would replace entirely other sources of folates in infant formula, infants below 16 weeks of age may be exposed to up to 274 μg/day of calcium l-methylfolate. This intake corresponds to an intake of calcium of 22 μg/day. Infants above 16 weeks of age and young children The applicant performed a market survey for follow-on formula, processed cerea
Referência(s)