CHEMICAL NAME SODIUM IRON (III) EDTA (ethylenediaminetetraacetate)/ Ferric Sodium EDTA CHEMICAL FORMULA EDTA FeNa . 3H2O MOLECULAR WEIGHT 421.1 CAS Number 15708-‐41-‐5 (anhydrous) 18154-‐32-‐0 (trihydrate) SpeciﬁcaQons Appearance yellow or yellowish brown crystalline powder Odour Odourless Iron content 19.5-‐20.5 Free iron 0.05 Max. Sulphates 0.06% Max. pH of a 1% w/v aqueous soluJon 4.5-‐5.5 Loss on drying 12.5-‐13.5 % Heavy metals as Pb 20 mg/Kg Max. Free disodium EDTA 1% Max. IdenJﬁcaJon pass FERRISTAT TM is approved for food forJﬁcaJon. Manufacture is made in strict accordance with HACCP and FS22000. FERRISTAT TM is a stable, free-‐ﬂowing, yellow-‐brown powder, soluble in water and inherently biodegradable. Packing: For informaJon on packing possibiliJes, please contact us or your nearest sales ND Pharma & Biotech representaJve Storage: Store in original packaging at a dry place. Opened bags and containers must be closed properly. Shelf life in opJmal condiJons is 36 months or 3-‐years equivalent.
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Recommendations on Wheat and Maize Flour Fortification Meeting Report: Interim Consensus Statement
THE FFI SECOND TECHNICAL WORKSHOP ON WHEAT FLOUR FORTIFICATION
This statement is based on scientific reviews prepared for a Flour Fortification Initiative (FFI) technical workshop held in Stone Mountain, GA, USA in 2008 where various organizations actively engaged in the prevention and control of vitamin and mineral deficiencies and various other relevant stakeholders met and discussed specific practical recommendations to guide flour fortification efforts being implemented in various countries by the public, private and civic sector. This joint statement reflects the position of the World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), The United Nations Children’s Fund (UNICEF), Global Alliance for Improved Nutrition (GAIN), The Micronutrient Initiative (MI) and FFI. It is intended for a wide audience including food industry, scientists and governments involved in the design and implementation of flour fortification programs as public health interventions.
Nearly 100 leading nutrition, pharmaceutical and cereal scientists and milling experts from the public and private sectors from around the world met on March 30 to April 3, 2008 in Stone Mountain, GA, USA to provide advice for countries considering national wheat and/or maize flour fortification. This Second Technical Workshop on Wheat Flour Fortification: Practical Recommendations for National Application was a follow up to a FFI, the US Centers for Disease Control and Prevention (CDC) and the Mexican Institute of Public Health, first technical workshop entitled “Wheat Flour Fortification: Current Knowledge and Practical Applications,” held in Cuernavaca, Mexico in December 2004 (FFI, 2004). The purpose of this second workshop was to provide guidance on national fortification of wheat and maize flours, milled in industrial roller mills (i.e. >20 metric tons/day milling capacity), with iron, zinc, folic acid, vitamin B12 and vitamin A and to develop guidelines on formulations of premix based on common ranges of flour consumption. A secondary aim was to agree on the best practices guidelines for premix manufactures and millers. Expert work groups prepared technical documents reviewing published efficacy and effectiveness studies as well as the form and levels of fortificants currently being added to flour in different countries. The full reviews will be published in a supplement of Food and Nutrition Bulletin in 2009 and the summary recommendations of this meeting can be found in http://www.sph.emory.edu/wheatflour/ atlanta08/ (FFI, 2008).
BACKGROUND WHO and FAO published in 2006 the Guidelines on Food Fortification with Micronutrients (WHO/FAO, 2006). These general guidelines, written from a nutrition and public health perspective are a resource for governments and agencies implementing or considering food fortification and a source of information for scientists, technologists and the food industry. Some basic principles for effective fortification programs along with fortificants’ physical characteristics, selection and use with specific food vehicles are described. Fortification of widely distributed and consumed foods has the potential to improve the nutritional status of a large proportion of the population, and neither requires changes in dietary patterns nor individual decision for compliance. Technological issues to food fortification need to be fully resolved especially with regards to appropriate levels of nutrients, stability of fortificant, nutrient interactions, physical properties and acceptability by consumers (WHO/FAO, 2006). Worldwide, more than 600 million metric tons of wheat and maize flours are milled annually by commercial roller mills and consumed as noodles, breads, pasta, and other flour products by people in many countries. Fortification of industrially processed wheat and maize flour, when appropriately implemented, is an effective, simple, and inexpensive strategy for supplying vitamins and minerals to the diets of large segments of the world’s population. It is estimated that the proportion of industrial-scale wheat flour being fortified is 97% in the Americas, 31% in Africa, 44% in Eastern Mediterranean , 21% in South-East Asia , 6% in Europe, and 4% in the Western Pacific regions in 2007 (FFI, 2008).
RECOMMENDATIONS FOR WHEAT AND MAIZE FLOUR FORTIFICATION Wheat and maize flour fortification is a preventive food-based approach to improve micronutrient status of populations over time that can be integrated with other interventions in the efforts to reduce vitamin and mineral deficiencies when identified as public health problems. However, fortification of other appropriate food vehicles with the same and/or other nutrients should also be considered when feasible. Wheat and maize flour fortification should be considered when industrially produced flour is regularly consumed by large population groups in a country. Wheat and maize flour fortification programmes could be expected to be most effective in achieving a public health impact if mandated at the national level and can help achieve international public health goals. Decisions about which nutrients to add and the appropriate amounts to add to fortify flour should be based on a series of factors including the nutritional needs and deficiencies of the population; the usual consumption profile of “fortifiable” flour (i.e. the total estimated amount of flour milled by
industrial roller mills, produced domestically or imported, which could in principle be fortified); sensory and physical effects of the fortificant nutrients on flour and flour products; fortification of other food vehicles; population consumption of vitamin and mineral supplements; and costs. Flour fortification programs should include appropriate Quality Assurance and Quality Control (QA/QC) programs at mills as well as regulatory and public health monitoring of the nutrient content of fortified foods and assessment of the nutritional/health impacts of the fortification strategies. Though the wheat and maize flours can be fortified with several micronutrients, the technical workshop focused on iron, folic acid, vitamin B12, vitamin A and zinc, which are five micronutrients recognized to be of public health significance in developing countries. 1. IRON The suggested levels for fortification of wheat flour with iron were reviewed by experts from published efficacy and effectiveness studies with various ironfortified foods (Hurrell R et al, 2009). The authors estimated the daily amounts of selected iron compounds, including NaFeEDTA, ferrous sulphate, ferrous fumarate and electrolytic iron that have been shown to improve iron status in populations. The selection of the type and quantity of vitamins and minerals to add to flour, either as a voluntary standard or a mandatory requirement, lies with national decision makers in each country and therefore the choice of compounds as well as quantities should be viewed in the context of each countryâ€™s situation. Based on available data from the Food Balance Sheets of FAO and World Bank-supported Household Income and Expenditure Surveys (HIES), it was proposed that four wheat flour average consumption ranges be considered in designing flour fortification programs: >300 g/day, 150-300 g/day, 75-150 g/day and <75 g/day.
2. FOLIC ACID Well conducted studies from the United States (Williams LJ et al, 2002), Canada (De Wals P et al, 2007), and Chile (Hertrampf E & Cortes F, 2004) have documented decreases of 26%, 42%, and 40%, respectively, in the rate of neural tube defects (NTD) affected births after implementation of national regulations mandating wheat flour fortification with folic acid. Wheat and maize flour fortification with folic acid increases the intake of folate by women and can reduce the risk of neural tube and other birth defects. 3. VITAMIN B12 An unpublished pilot study testing the feasibility of adding B-complex vitamins and iron to flour in Israel showed that vitamin B12 added to flour was stable during baking, did not affect the quality of the bread, and increased plasma B12 concentrations slightly within six months (Allen L et al, 2008). However, evidence is still lacking about the population impact of fortification of wheat flour with vitamin B12 to improve vitamin B12 status. Nevertheless, fortifying flours with vitamin B12 could be a feasible approach to improve vitamin B12 intake and the status of populations as there are no known adverse consequences of vitamin B12 fortification, and there are no known adverse effects of high intakes of the vitamin. 4. VITAMIN A Wheat and maize flour can technically be fortified with vitamin A as vitamin A is stable in flour without producing organoleptic changes. As is the case for some other vitamins, high humidity and high temperatures can adversely affect vitamin A content during the preparation of wheat and maize flour products. Experience with vitamin A fortification of wheat and maize flour in developing
Table 1. Average levels of nutrients to consider adding to fortified wheat flour based on extraction, fortificant compound, and estimated per capita flour availability Nutrient
Level of nutrient to be added in parts per million (ppm) by estimated average per capita wheat flour availability (g/day)1 <752 g/day
Low or High
Low or High
Low or High
Vitamin A Palmitate
Flour Extraction Rate
These estimated levels consider only wheat flour as main fortification vehicle in a public health program. If other mass-fortification programs with other food vehicles are implemented effectively, these suggested fortification levels may need to be adjusted downwards as needed. Estimated per capita consumption of <75 g/day does not allow for addition of sufficient level of fortificant to cover micronutrients needs for women of childbearing age. Fortification of additional food vehicles and other interventions should be considered. NR = Not Recommended because very high levels of electrolytic iron needed could negatively affect sensory properties of fortified flour. These amounts of zinc fortification assume 5 mg zinc intake and no additional phytate intake from other dietary sources.
countries is increasing. Although vitamin A is most often used in the fortification of oils and fats, currently 11 countries are fortifying or propose to fortify wheat and/or maize flour with this vitamin. Two published efficacy trials have reported the impact of vitamin A fortified wheat flour on vitamin A nutritional status but there are no published studies that have evaluated the effectiveness of this intervention on a national scale (West KP et al, 2009). Wheat and, more broadly, other cereal grain flour (e.g. maize) can be considered as a vehicle for delivery of vitamin A to populations at risk of vitamin A deficiency. 5. ZINC Unpublished results from a trial of wheat flour fortification in China suggests that zinc fortified flour could improve zinc status in women of childbearing age (Brown K et al, 2009). Fortification of other foods with zinc has shown that zinc intake and absorption increase when some zinc fortified foods are consumed but the impact as a public health intervention remains unknown. More research on efficacy and effectiveness of large scale zinc fortification programs is needed. The levels of nutrients to consider adding to fortified wheat flour based on extraction, fortificant compound, and estimated per capita flour availability are presented in Table 1. These levels and compounds could theoretically improve the nutritional status of the populations consuming the fortified wheat flour regularly in different preparations.
SUMMARY OF STATEMENT DEVELOPMENT This statement was prepared by the core group from WHO’s Department of Nutrition for Health and Development in close collaboration with FAO, the nutrition section of UNICEF, GAIN, MI and FFI. The core group members were: Dr Francesco Branca (WHO), Dr Juan Pablo Pena-Rosas (WHO), Mr Brian Thompson (FAO), Mr Arnold Timmer, (UNICEF), Dr Regina Moench-Pfanner (GAIN), Dr Annie Wesley (MI) and Dr Glen Maberly (FFI). The core group evaluated the commissioned scientific reviews prepared by international nutrition, pharmaceutical and cereal scientists and milling experts from the public and private sector working in the area of micronutrients, milling and food fortification, as well as the summary of discussions and conclusions from the consultation. This position statement is based on these documents and was initiated at WHO headquarters and further discussed and reviewed by members of the core group who provided technical and editorial advice. This statement contains all the consensus recommendations of the core group.
CONFLICTS OF INTEREST All members of the core group were asked to submit and sign Declaration of Interest statements which are on file. There were no known conflicts of interest disclosed among the core group members developing this statement.
PLANS FOR UPDATE It is anticipated that the recommendations in this statement will remain valid until December 2010. The Department of Nutrition for Health and Development at WHO headquarters in Geneva will be responsible for initiating a review following formal WHO Handbook for Guideline Development procedures at that time.
ACKNOWLEDGEMENT WHO wishes to thank the Government of Luxembourg for their financial support.
REFERENCES Allen L et al., eds. Guidelines on food fortification with micronutrients. Geneva, World Health Organization and Food and Agricultural Organization of the United Nations, 2006. Flour Fortification Initiative country database [online database], Flour Fortification Initiative. (http://www.sph.emory.edu/wheatflour/COUNTRYDATA/Master_Database.xls, accessed 21 August 2008). Report of the Workshop of Wheat Flour Fortification. Cuernavaca, Mexico, Flour Fortification Initiative, 2004. (http://www.sph.emory.edu/wheatflour/CKPAFF/ index.htm, accessed 21 August 2008). Second Technical Workshop on Wheat Flour Fortification: Practical Recommendations for National Application: Summary Report, Stone Mountain, GA, 30 March to 3 April 2008 . The Flour Fortification Initiative. (http://www.sph.emory.edu/ wheatflour/atlanta08/ , accessed 11 December 2008). Hurrell R, Ranum P, de Pee S, Biebinger R, Hulthen L, Johnson Q. Lynch S. Revised recommendations for the iron fortification of wheat flour and an evaluation of the expected impact of current national wheat flour fortification programs. Food and Nutrition Bulletin, 2009, (Supplement). For submission. Williams LJ et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology, 2002, 66:33-39. De Wals P et al. Reduction in neural-tube defects after folic acid fortification in Canada. New England Journal of Medicine, 2007, 357:135-142. Hertrampf E, Cortes F. Folic acid fortification of wheat flour: Chile. Nutrition Review, 2004, 62:S44-S48. Allen L and Vitamin B12 Working Group. Vitamin B12 fortification. Background Paper for the workshop, Stone Mountain, GA, 30 March to 3 April 2008. The Flour Fortification Initiative, 2008 (http://www.sph.emory.edu/wheatflour/atlanta08/papers.html, accessed 11 December 2008). West KP Jr., Klemm RDW, Dary O, Palmer AC, Johnson Q, Randall P, Ranum P, Northrop-Clewes C. Vitamin A Fortification of Wheat Flour—Considerations and Current Recommendations. Food and Nutrition Bulletin, 2009, (Supplement). For submission. Brown KH, Hambidge KM, Ranum P, Tyler V. and the Zinc Fortification Working Group. Zinc fortification of cereal flours: current recommendations and research needs. Food and Nutrition Bulletin, 2009, (Supplement). For submission.
WHO, FAO, UNICEF, GAIN, MI, & FFI. Recommendations on wheat and maize flour fortification. Meeting Report: Interim Consensus Statement. Geneva, World Health Organization, 2009 (http://www.who.int/nutrition/publications/micronutrients/wheat_maize_fort.pdf, accessed [date]).
FOR FURTHER INFORMATION PLEASE CONTACT Department.of Nutrition for Health and Development (NHD) World Health Organization 20, Avenue Appia, 1211 Geneva, Switzerland Email: email@example.com WHO home page: http://www.who.int © World Health Organization 2009
The Joint FAO/WHO Expert Committee on Food Additives (JECFA) met in Geneva from 19 to 28 June 2007. The meeting was opened by Susanne Weber-Mosdorf, Assistant Director General, World Health Organization (WHO), on behalf of the Directors General of WHO and the Food and Agriculture Organization of the United Nations (FAO). Mrs Weber-Mosdorf acknowledged the important role the work of the Committee plays in the establishment of international food safety standards and its contribution to sustainable development. She informed the Committee of the six-point agenda that the new Director General of WHO, Dr Margaret Chan, has proposed for the organization. This agenda also refers to using evidence to define strategies and measure results, and in this context the work of the Committee is an important contribution to the goals of WHO. Mrs Weber-Mosdorf informed the Committee that the 50th World Health Assembly approved an increased budget for the areas of food safety and nutrition and for public health and the environment, which illustrated the importance the Member States give to these work areas. She emphasized that FAO and WHO consider the provision of scientific advice in food safety an important and core activity. 1.1
Declarations of interests The Secretariat informed the Committee that all experts participating in the sixty-eighth meeting of JECFA had completed declaration-of-interest forms and that no conflicts had been identified. The following declared interests and potential conflicts were discussed by the Committee. Professor Andrew Renwick consulted for the International Sweeteners Association and hence did not participate in the discussions on steviol glycosides. Professor Gary Williams declared an interest in steviol glycosides and did not participate in the discussions. The employer of Dr Ian Munro receives part of its revenues from consulting on the safety assessment of food additives. The company, but not Dr Munro himself, prepared submissions regarding the assessments of sodium iron ethylenediaminetetraacetic acid (EDTA) and of acidified sodium chlorite (ASC).
In a 13-week study of toxicity in rats, no significant treatment-related effects were seen when the LEC was administered by oral gavage at doses up to and including 575 mg TOS/kg bw per day. Therefore, 575 mg TOS/kg bw per day, the highest dose tested, was taken to be the NOEL. The LEC was not mutagenic in an assay for mutagenicity in bacteria in vitro and was not clastogenic in an assay for chromosomal aberrations in mammalian cells in vitro. Assessment of dietary exposure
Based on a maximum mean daily consumption of 44 g of cheese (GEMS/ Food Consumption Cluster Diet E) by a 60-kg adult and on the assumptions that the enzyme is used at the maximum recommended use level of 350 lecitase units/l milk and that all TOS originating from the enzyme preparation remain in the cheese, the dietary exposure would be 0.03 mg TOS/kg bw per day. Evaluation
Comparing the conservative exposure estimate with the NOEL from the 13-week study of oral toxicity, the margin of safety is >19 000. The Committee allocated an ADI “not specified” for phospholipase A1 from this recombinant strain of A. oryzae, used in the applications specified and in accordance with good manufacturing practice. An addendum to the toxicological monograph was prepared. The existing specifications were maintained. 3.1.8 Sodium iron(III) ethylenediaminetetraacetic acid (sodium iron EDTA)
At the request of CCFAC at its thirty-eighth session (7), the Committee reevaluated the safety of sodium iron(III) ethylenediaminetetraacetic acid trihydrate (in short, sodium iron EDTA) as to its use for iron fortification. The Committee had previously evaluated sodium iron EDTA at its forty-first and fifty-third meetings for its specific application in supervised food fortification programmes in populations in which iron deficiency anaemia is endemic (Annex 1, references 107 and 143). It was concluded that sodium iron EDTA could be considered safe for use in such programmes, providing daily intakes of iron and EDTA of approximately 0.2 and 1 mg/kg bw, respectively. This opinion has been perceived as being restrictive to the use of sodium iron EDTA as a source of iron for food fortification (i.e. preventing it from being used at levels higher than 0.2 mg iron/kg bw per day and other than “under supervision only”). The Committee at its present meeting was therefore asked to re-evaluate the safety of sodium iron EDTA for iron fortification. 48
In addition to the studies already evaluated by the Committee at its earlier meetings, several new studies on the biochemical and toxicological aspects and on the efficacy of sodium iron EDTA were submitted. The new data provided on the biochemical aspects following administration of sodium iron EDTA corroborate the findings from earlier studies, i.e. that
the iron in sodium iron EDTA dissociates from the chelate and is released into the common non-haem iron pool before absorption;
only a very small fraction of the sodium iron EDTA complex (less than 1–2%) is absorbed intact and is rapidly and completely excreted via the kidneys in the urine;
iron from sodium iron EDTA is generally more efficiently absorbed than iron from alternative sources such as iron(II) sulfate, with less influence of inhibitory factors present in the diet (e.g. phytic acid, polyphenols);
the same enhancing effect on iron absorption can be achieved by adding disodium EDTA to other soluble iron fortificants, such as iron(II) sulfate.
Moreover, it was demonstrated that the human body maintains iron levels through down-regulating systems, which control the amount of iron absorbed and protect against the possibility of iron overload: more iron is absorbed when the body is in a state of iron deficiency (with an inverse relation between absorption and concentration of serum ferritin) and less when the body iron stores are replete. Besides, a 3-fold increase in the level of iron fortification resulted in a decreased percentage of iron absorption from sodium iron EDTA in healthy adults. Also, in iron-replete subjects, non-haem iron absorption was reduced to a larger extent than the absorption of haem iron, whereas absorption of iron during states of iron depletion was comparable for the two different forms of iron. This tight regulation of non-haem iron absorption is of importance, given that iron from sodium iron EDTA will join the nonhaem iron pool before absorption. These findings support the conclusion that dietary iron fortification with sodium iron EDTA does not increase the risk for iron accumulation beyond normal physiological requirements in ironreplete individuals. Studies have also provided additional evidence that dietary intake of sodium iron EDTA has no negative influence on the absorption of other minerals, such as zinc. From the new toxicological studies provided, it can be concluded that sodium iron EDTA is of low acute oral toxicity and that it does not induce gene mutations in bacteria and mammalian cells in vitro, unless tested at high, cytotoxic concentrations.
The results of new intervention studies in populations with a high prevalence of anaemia and iron deficiency in Viet Nam, China and Kenya demonstrated the efficacy of sodium iron EDTA-fortified condiments (soy sauce and fish sauce) and sodium iron EDTA-fortified whole maize flour in reducing iron deficiency and/or iron deficiency anaemia and the prevalence of anaemia. Evaluation
The Committee considered the new data submitted to be in support of the earlier conclusions by the Committee at its fifty-third meeting that once the nutritional requirement for iron is satisfied, administration of iron in the form of sodium iron EDTA will not result in greater uptake of iron than from other iron fortificants (such as iron(II) sulfate), as a result of down-regulating systems in the body. The Committee also noted that the new data submitted provide additional evidence that dietary intake of sodium iron EDTA has no adverse effects on the absorption of other minerals, such as zinc. The Committee concluded that sodium iron EDTA is suitable for use as a source of iron for food fortification to fulfil the nutritional iron requirements, provided that the total intake of iron from all food sources including contaminants does not exceed the provisional monthly tolerable daily intake (PMTDI) of 0.8 mg/kg bw (Annex 1, reference 62). Additionally, the total intake of EDTA should not exceed acceptable levels, also taking into account the intake of EDTA from the food additive use of other EDTA compounds. An ADI of 0–2.5 mg/kg bw was previously established for the calcium disodium and disodium salts of EDTA, equivalent to up to 1.9 mg EDTA/kg bw (Annex 1, reference 32). A preliminary exposure assessment based on suggested levels of fortification for sodium iron EDTA indicates that the intake of EDTA in infants and children up to the age of 13 already is at or exceeds the upper limit of the ADI for EDTA. As previously noted for ferrous glycinate (Annex 1, reference 166), products, including sodium iron EDTA, that are intended to provide a source of additional iron should not be consumed by individuals with any type of iron storage disease, except under medical supervision. An addendum to the toxicological monograph was prepared. 3.1.9 Steviol glycosides
Steviol glycosides are natural constituents of the plant Stevia rebaudiana Bertoni. Stevioside and rebaudioside A are the component glycosides of principal interest for their sweetening properties.
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