Diphosphates (E450)

What it is

Diphosphates are phosphate salts that make dough rise and keep acidity stable, widely used in biscuits and cakes ¹².

E 450 comprises disodium (i), trisodium (ii), tetrasodium (iii), tetrapotassium (v), dicalcium (vi), calcium dihydrogen (vii) and magnesium dihydrogen (ix) salts of diphosphoric acid, also called pyrophosphates; INS numbers are identical ¹.

How often it is used

In April 2019, 6,529 of 126,556 French packaged foods listed diphosphates, eighth among additives ².

Of 106,489 NutriNet-Santé adults, 64.36% consumed them, mean 178.33 mg/day; 0.02% exceeded the acceptable daily intake ³.

In the body

In the gut, diphosphates become ordinary phosphate, mostly absorbed, then excreted in urine ¹.

In rats, dietary tetrasodium diphosphate was almost completely hydrolysed; in humans, 80–90% of additive phosphorus is absorbed as orthophosphate ¹. Proximal tubules reabsorb 80% or more of filtered phosphorus, regulated by parathyroid hormone and FGF23 ¹.

Absorption and renal handling of phosphate from diphosphatesGut lumen, small-intestinal epithelium, plasma and renal proximal tubule

Diphosphate, gut lumen
Hydrolysis, shown in ratsRats fed diphosphate excrete orthophosphate, not diphosphate, in urine
Orthophosphate, gut lumen
several stepsApical NaPi-IIb (SLC34A2) with 3 Na⁺, plus passive diffusion
Orthophosphate, plasma
Glomerular filtrationAbout 200 mmol phosphorus filtered per day
Orthophosphate, glomerular filtrate
NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3), apical membrane3 Na⁺ (NaPi-IIa), 2 Na⁺ (NaPi-IIc)Parathyroid hormoneFGF23 with α-KlothoProximal tubules reabsorb 80% or more of filtered phosphorus
Orthophosphate, proximal tubule cell

What studies show

In short human studies, extra phosphate raised a phosphate-regulating hormone and briefly impaired artery widening ⁴⁵.

In 10 adults, a week of additive-rich food (606 mg/day more phosphorus, 58 mmol/day more sodium) raised FGF23 by 23% against a low-additive week ⁴. In 11 men, flow-mediated dilation 2 h after 1200 mg phosphorus was 5.02% against 8.42% after 400 mg ⁵. In 279 hyperphosphataemic haemodialysis patients, cluster-randomised advice to avoid phosphate additives changed serum phosphorus by −0.6 mg/dL (95% CI −1.0 to −0.1) against usual care over 3 months ⁶.

In NutriNet-Santé, diphosphate intake was not associated with cardiovascular disease or type 2 diabetes ⁷⁸. Over a mean 6.7 years, premenopausal breast cancer occurred in 113 of 19,382 people in the top intake third and 61 of 16,560 in the bottom (HR 1.45, 1.04 to 2.02; modelled risk at age 40, 2.5% against 1.7%) ⁹.

EFSA’s group acceptable daily intake for phosphates, 40 mg phosphorus/kg body weight/day, counts all dietary phosphorus and does not apply in moderate to severe renal impairment; estimated whole-diet intake exceeded it at the mean in infants, toddlers and children ¹.

Regulation

All four jurisdictions permit diphosphates ^1111213.

Jurisdiction	Rule
European Union	Phosphate group, 500 to 20,000 mg/kg as P₂O₅ or quantum satis (2019) ¹
United States	Sodium acid, tetrasodium and calcium pyrophosphate generally recognised as safe ¹¹
Japan	Four E 450 salts designated ¹²
China	Phosphate group, 15.0 g/kg as PO₄³⁻ in bakery wares; excluded from infant formulae ¹³

References

Regulator
EFSA Panel on Food Additives and Flavourings (FAF), Younes M, Aquilina G, Castle L, Engel KH, Fowler P, et al. Re-evaluation of phosphoric acid–phosphates – di-, tri- and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use EFSA Journal, 2019.
doi:10.2903/j.efsa.2019.5674 PubMed 32626329
Funding and finding
Funding
European Food Safety Authority; requestor: European Commission; question numbers EFSA-Q-2011-00532 to -00543, EFSA-Q-2011-00618 to -00626, EFSA-Q-2011-00628 to -00630 and EFSA-Q-2018-00597; adopted 4 June 2019.
Finding
E 450 comprises disodium diphosphate (E 450(i)), trisodium diphosphate (E 450(ii)), tetrasodium diphosphate (E 450(iii)), tetrapotassium diphosphate (E 450(v)), dicalcium diphosphate (E 450(vi)), calcium dihydrogen diphosphate (E 450(vii)) and magnesium dihydrogen diphosphate (E 450(ix)); JECFA specifications carry the same INS sub-numbers. Formulae are Na2H2P2O7, Na3HP2O7, Na4P2O7, K4P2O7, Ca2P2O7, CaH2P2O7 and MgH2P2O7; synonyms include disodium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium salt of diphosphoric acid, calcium pyrophosphate and acid calcium and acid magnesium pyrophosphate. Diphosphate, also named pyrophosphate, is M4P2O7; sodium diphosphates are made by neutralising phosphoric acid with sodium hydroxide and drying above 200 °C, which condenses phosphate groups. JECFA functional classes (Appendix A) include raising agent for E 450(i), (ii), (vi), (vii) and (ix), sequestrant for (i) and (iii), emulsifier for (ii), (iii), (v) and (vii), emulsion stabiliser for (ii), (vii) and (ix) and buffer, including acidity regulator, for (iii) and (vi). Phosphate additives are assumed to dissociate in the gastrointestinal tract; inorganic phosphorus from food additives is absorbed at about 80 to 90% as free orthophosphate, without metabolism, by passive diffusion and sodium-dependent active transport; NaPi-IIb (SLC34A2) predominates in the intestine and is modulated by active vitamin D and low phosphorus intake. About 200 mmol of phosphorus is filtered daily, 80% or more is reabsorbed in proximal tubules mainly via NaPi-IIa, and PTH and FGF-23 with Klotho influence reabsorption; excretion is via the kidney. In rats fed 5% tetrasodium diphosphate, diphosphate was undetected in faeces and urine, hydrolysis to orthophosphate in the gut was almost complete and about 85% was absorbed; toxicokinetic data on dicalcium and calcium dihydrogen diphosphate are lacking. The only significant adverse effect of phosphates in animal studies was kidney calcification and tubular nephropathy; a 90-day rat study of tetrasodium diphosphate gave a NOAEL of 500 mg/kg bw per day (116 mg P/kg bw per day). A group ADI of 40 mg/kg bw per day, expressed as phosphorus, was derived for E 338–341, E 343 and E 450–452 from a chronic rat NOAEL of 76 mg P/kg bw per day plus 91 mg P/kg bw per day background diet (167 mg P/kg bw per day) divided by an adjustment factor of 4; it covers phosphorus from all sources, natural ones included, and does not apply to people with moderate to severe reduction in renal function. Mean whole-diet exposure estimated from analytical data ranged across surveys from 16 mg P/kg bw per day in adults and the elderly to 85 mg P/kg bw per day in infants aged 12 weeks to 11 months; it exceeded the ADI at the mean for infants, toddlers and children, and at the 95th percentile also for adolescents (highest 95th percentile 123 mg P/kg bw per day, in toddlers). Exposure from food additives indicatively contributed 6 to 21% of total mean intake in all groups except infants and 12 to 30% in infants aged 12 weeks to 11 months. In the EU, phosphates (E 338–341, E 343, E 450–452) were authorised with maximum permitted levels of 500 to 20,000 mg/kg expressed as P2O5 in 104 uses and at quantum satis in four.
Independent research
Chazelas E, Deschasaux M, Srour B, Kesse-Guyot E, Julia C, Alles B, et al. Food additives: distribution and co-occurrence in 126,000 food products of the French market Scientific Reports, 2020.
doi:10.1038/s41598-020-60948-w PubMed 32132606
Funding and finding
Funding
PhD grant from Paris 13 University (E. Chazelas); post-doctoral fellowship from the Fondation pour la Recherche Médicale (ARF201809007046, M. Deschasaux); French Ministry of Health (DGS Arrêté 29 Novembre 2019); French National Cancer Institute (INCa_14059); European Research Council (ERC CoG ADDITIVES_864219). Researchers were independent from funders. Funders had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit the article for publication. Open Food Facts is a non-profit association.
Finding
53.8% of products contained at least one additive and 11.3% five or more. Appendix 7, products containing each additive: citric acid E 330 18,302; lecithins E 322 13,102; E 14XX modified starches 10,100; sodium carbonates E 500 8587; ascorbic acid E 300 7919; xanthan gum E 415 7327; sodium nitrite E 250 7144; diphosphates E 450 6529; pectins E 440 6504; mono- and diglycerides of fatty acids E 471 6060. Specific starches: E 1442 209, E 1422 173, E 1414 55, E 1450 30, E 1412 27, E 1420 19, E 1404 18, E 1440 5, E 1410 1. The footnote and the Discussion state that the number of products containing each specific modified starch may be underestimated because packaging often states only 'modified starch'. E 500 had the highest squared loading (0.64) in cluster 3, 'stabilizers and emulsifiers mostly used in biscuits and cakes'; sodium carbonate (E 500), diphosphates (E 450) and lecithins (E 322) co-occurred in 1667 products, mostly biscuits. The authors describe E 500, E 450, E 503 and E 422 as widely used in biscuits and cakes as acidity regulators, stabilizers and emulsifiers. Additive doses were not available.
Independent research
Chazelas E, Druesne-Pecollo N, Esseddik Y, de Edelenyi FS, Agaesse C, De Sa A, et al. Exposure to food additive mixtures in 106,000 French adults from the NutriNet-Santé cohort Scientific Reports, 2021.
doi:10.1038/s41598-021-98496-6 PubMed 34608173
Funding and finding
Registration
NCT03335644
Participants
106,489
Funding
NutriNet-Santé: Ministère de la Santé, Santé Publique France, INSERM, INRAE, CNAM and University Sorbonne Paris Nord. E. Chazelas: doctoral funding from University Sorbonne Paris Nord; C. Debras: French National Cancer Institute. Project: European Research Council (Horizon 2020, grant agreement No 864219), French National Cancer Institute (INCa_14059), French Ministry of Health (arrêté 29.11.19) and IdEx Université de Paris (ANR-18-IDEX-0001). Researchers were independent from funders; funders had no role in the study design, the collection, analysis and interpretation of data, the writing of the report, and the decision to submit the article for publication.
In-kind support
Some of the 2677 ad hoc laboratory assays of additive doses were ordered by the consumers' association UFC Que Choisir.
Finding
Intakes of 90 additives were estimated from repeated 24-h records matched to brand-level composition data (OQALI, Open Food Facts, Mintel GNPD), with doses from 2677 laboratory assays, EFSA dose data by food category or Codex GSFA levels; descriptive analyses were weighted to the 2016 French census. Table 1, % consumers; median, 95th percentile and mean (SD) in mg/day; mean (SD) in mg/kg bw/day: modified starches E 14xx 91.48%; 1304.66, 4270.38, 1596.45 (1394.44); 24.33 (21.84). Citric acid E 330 91.15%; 1380.84, 6193.84, 1956.51 (2231.41); 29.84 (34.31). Lecithins E 322 86.57%; 35.36, 168.33, 53.94 (71.99); 0.83 (1.1). Xanthan gum E 415 79.74%; 303.60, 1401.31, 439.26 (508.65); 6.62 (7.62). Mono- and diglycerides of fatty acids E 471 78.07%; 101.90, 547.24, 160.8 (197.42); 2.44 (2.98). Sodium carbonates E 500 67.10%; 560.00, 4950.00, 1267.46 (1913.51); 19.62 (29.73), with median 8.51 and 95th percentile 76.73 mg/kg bw/day. The ADI column reads NA for all six. Diphosphates E 450 64.36%; 62.86, 715.67, 178.33 (308.05); 2.74 (4.67); ADI 40 mg/kg bw/day, exceeded by 0.02% of all participants and 0.03% of consumers. Additives without a specified ADI can be used quantum satis, that is with no limitations other than current good manufacturing practice. The authors state that information on the health impact of regular and cumulative intake of food additives in humans, and on effects of their mixtures, is still missing.
Independent research
Gutiérrez OM, Luzuriaga-McPherson A, Lin Y, Gilbert LC, Ha SW, Beck GR Jr. Impact of Phosphorus-Based Food Additives on Bone and Mineral Metabolism The Journal of Clinical Endocrinology and Metabolism, 2015.
doi:10.1210/jc.2015-2279 PubMed 26323022
Funding and finding
Registration
NCT01394146
Participants
10
Follow-up
2 weeks of study diets after a 2-week run-in
Funding
Grants UL1TR00165, P30DK079626 and P30DK056336 from the National Institutes of Health; O.M.G.: grants R03DK095005 and R01NS080850; G.R.B.: Biomedical Laboratory Research & Development Service Award I01BX002363 from the VA Office of Research and Development and R01CA136716.
Finding
Non-randomised fixed-sequence feeding study: 1 week of a low-additive diet followed by 1 week of an additive-enhanced diet with identical food items containing phosphorus additives. Measured phosphorus was 1070 ± 58 and 1677 ± 167 mg/day (difference 606 ± 125 mg/day, P < .001) and sodium 89 ± 28 and 148 ± 28 mmol/day (difference 58 ± 27 mmol/day, P = .02); calcium, potassium and energy did not differ significantly. After the additive-enhanced week, plasma FGF23 was 23% higher than at the end of the low-additive week (P = .03), and osteopontin and osteocalcin were 10% and 11% higher (P = .01 and .04); mean sclerostin fell over time (P = .02 for the main effect of time) but not significantly against the preceding diet period (P = .10). Over the 2 weeks, changes in serum phosphorus, calcium, PTH, P1NP, CTX and FGF23 (main effect of time P = .19) were not statistically significant. In mice, a 1.8% against a 0.2% phosphorus diet raised serum FGF23, osteopontin and osteocalcin at 5 and 15 weeks, lowered sclerostin at 15 weeks and reduced bone mineral density.
Independent research
Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M, et al. Dietary phosphorus acutely impairs endothelial function Journal of the American Society of Nephrology, 2009.
doi:10.1681/ASN.2008101106 PubMed 19406976
Funding and finding
Registration
UMIN000000803
Participants
11
Follow-up
2 hours after each test meal, with flow-mediated dilation also measured at 24 hours
Funding
Grants-in-Aid for Scientific Research on Priority Areas (17790554), for Young Scientists (19680030, 18790567), for Scientific Research (B) (18300232), for Exploratory Research (17650225) and Knowledge Cluster Initiative from the Ministry of Education, Culture, Sports, Science, and Technology in Japan; the Uehara Memorial Foundation; the Kidney Foundation (JKFB08-22); the 21st Century COE Program 'Human Nutritional Science and Stress Control'; and the Initiatives for Attractive Education in Graduate School, University of Tokushima. The investigators and sponsors in the University of Tokushima, University of Tokyo and Hiroshima University contributed to the design and execution of the study.
Finding
Double-blind crossover study on two days separated by more than 1 day: breakfast meals containing 400 mg (P400) or 1200 mg (P1200) phosphorus. Mean ± SEM serum phosphorus 2 h after the meal was 3.66 ± 0.2 mg/dL after P400 and 4.56 ± 0.1 mg/dL after P1200, above the normal range in 8 of 11 men. Flow-mediated dilation of the brachial artery was 8.81 ± 0.3% before and 8.42 ± 0.5% 2 h after P400, and 9.26 ± 0.4% before and 5.02 ± 0.3% 2 h after P1200 (P < 0.0001 between meals); it was 8.60 ± 0.2% 24 h after P1200. After P1200, flow-mediated dilation correlated inversely with serum phosphorus (Spearman rs = -0.42, P = 0.006). In bovine aortic endothelial cells, raised extracellular phosphate increased reactive oxygen species production, which the sodium-phosphate transport inhibitor phosphonoformic acid reduced, and inhibited bradykinin-stimulated nitric oxide production, with protein kinase C-dependent phosphorylation of endothelial nitric oxide synthase at Thr497; preincubation in 2.4 mM against 1.2 mM phosphate reduced acetylcholine-induced relaxation of rat aortic rings by 70%.
Independent research
Sullivan C, Sayre SS, Leon JB, Machekano R, Love TE, Porter D, et al. Effect of food additives on hyperphosphatemia among patients with end-stage renal disease: a randomized controlled trial JAMA, 2009.
doi:10.1001/jama.2009.96 PubMed 19211470
Funding and finding
Registration
NCT00583570
Participants
279
Follow-up
3 months
Funding
This work was supported by grant DK51472 from the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and by the Leonard C. Rosenberg Renal Research Foundation, Cleveland, Ohio. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Finding
Cluster randomisation by dialysis shift (or by facility for 2 single-shift facilities). Intervention participants (n = 145) received about 30 minutes of education on avoiding phosphorus-containing additives, with a magnifier case listing them (among them pyrophosphate and sodium acid pyrophosphate) and fast-food handouts; control participants (n = 134) continued usual care. Baseline mean serum phosphorus was 7.2 and 7.1 mg/dL. After 3 months serum phosphorus fell by 1.0 mg/dL in the intervention group (P < .001) and 0.4 mg/dL in the control group (P = .02); the difference was 0.6 mg/dL larger with the intervention (95% CI -1.0 to -0.1 mg/dL). Missing data from 28 participants were multiply imputed. No adverse events were associated with the intervention; dietary intake and adherence were not measured.
Independent research
Sellem L, Srour B, Javaux G, Chazelas E, Chassaing B, Viennois E, et al. Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study BMJ, 2023.
doi:10.1136/bmj-2023-076058 PubMed 37673430
Funding and finding
Registration
NCT03335644
Participants
95,442
Follow-up
median 7.4 years
Funding
NutriNet-Santé: Ministère de la Santé, Santé Publique France, INSERM, INRAE, Conservatoire National des Arts et Métiers and University Sorbonne Paris Nord. Project: European Research Council (grant agreement 864219), French National Cancer Institute (INCa_14059), French Ministry of Health, IdEx Université de Paris (ANR-18-IDEX-0001) and a Bettencourt-Schueller Foundation research prize 2021. Researchers were independent from funders. The funders had no role in the design; collection, analysis, and interpretation of data; writing of the report; and decision to submit the article for publication.
Finding
1995 cardiovascular events over 666,509 person-years. Hazard ratios per 1 SD of intake: total celluloses (E460-E468) 1.05 (95% CI 1.02 to 1.09) for cardiovascular disease and 1.07 (1.02 to 1.12) for coronary heart disease; carboxymethylcellulose (E466, SD 32.0 mg/day) 1.03 (1.01 to 1.05) and 1.04 (1.02 to 1.06); total mono- and diglycerides of fatty acids (E471 and E472) 1.07 (1.04 to 1.11) for cardiovascular disease. Supplementary eTable2: total mono- and diglycerides of fatty acids (E471, E472, E472a, E472b, E472c and E472e; SD 287.5 mg/day) 1.07 (1.04 to 1.11), 1.08 (1.03 to 1.14) for coronary heart disease and 1.07 (1.01 to 1.13) for cerebrovascular disease; E471 alone (SD 208.6 mg/day) 1.03 (0.98 to 1.09), P = 0.2, for cardiovascular disease, and 1.03 (0.96 to 1.11) for coronary heart disease and for cerebrovascular disease. E471 was consumed by 81.6%, mean 161.2 mg/day. Diphosphates (E450) were consumed by 72.6%, mean 244.5 (SD 338.2) mg/day; eTable2 hazard ratios per SD (349.7 mg/day) were 0.99 (0.93 to 1.04) for cardiovascular disease, 0.96 (0.89 to 1.04) for coronary heart disease and 1.01 (0.93 to 1.09) for cerebrovascular disease. Trisodium phosphate (E339) was associated with coronary heart disease, 1.06 (1.00 to 1.12) per SD (58.4 mg/day), P = 0.03, not significant after correction for multiple testing (adjusted P = 0.3). Carrageenans and lecithins were not associated. Mean E466 intake 3.8 mg/day, consumed by 10.8%; E433 consumed by 1.1% and not analysed individually. Absolute risks by intake level are not reported.
Independent research
Salame C, Javaux G, Sellem L, Viennois E, de Edelenyi FS, Agaësse C, et al. Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study The Lancet Diabetes & Endocrinology, 2024.
doi:10.1016/S2213-8587(24)00086-X PubMed 38663950
Funding and finding
Registration
NCT03335644
Participants
104,139
Follow-up
mean 6.8 years
Funding
NutriNet-Santé public institutions (Ministère de la Santé, Santé Publique France, INSERM, INRAE, CNAM, University Sorbonne Paris Nord); European Research Council (grant agreement 864219, ADDITIVES); French National Cancer Institute (INCa_14059); French Ministry of Health; IdEx Université de Paris (ANR-18-IDEX-0001); Bettencourt-Schueller Foundation Research Prize 2021. The funders had no role in study design; the collection, analysis, and interpretation of data; the writing of the report, or the decision to submit the manuscript for publication.
Finding
1056 incident cases of type 2 diabetes. Hazard ratios per 100 mg/day: total carrageenans 1.03 (95% CI 1.01 to 1.05), E407 1.03 (1.01 to 1.05); mean total carrageenan intake 59.0 mg/day. Associations were also reported for E340 (1.15, 1.02 to 1.31, per 500 mg/day), E472e, E331, E412, E414 and xanthan gum E415 (hazard ratio 1.08, 95% CI 1.02 to 1.14, per increment of 500 mg/day, p = 0.013). Xanthan gum was found in 5% of foods according to EFSA data cited by the authors. Appendix eTable3 (https://ars.els-cdn.com/content/image/1-s2.0-S221385872400086X-mmc1.pdf), per 500 mg/day, fully adjusted and mutually adjusted for other emulsifiers: E471 0.99 (0.91 to 1.08), p = 0.84, minimally adjusted 1.07 (0.98 to 1.16); total mono- and diglycerides of fatty acids 1.00 (0.95 to 1.05). E471 was consumed by 80.3%, mean 165.4 mg/day. eTable3, per 500 mg/day, fully adjusted: diphosphates E450 1.01 (0.98 to 1.04), p = 0.49; tripotassium phosphate E340 1.15 (1.02 to 1.31), p = 0.023, with a false-discovery-rate-adjusted p of 0.10 (Figure 4 legend); trisodium phosphate E339 1.03 (0.92 to 1.14), p = 0.64. E450 was consumed by 70.4%, mean 244.5 (SD 351.7) mg/day; E340 by 5.2%, mean 6.9 (SD 90.5) mg/day. Absolute risks by intake level are not reported.
Independent research
Sellem L, Srour B, Javaux G, Chazelas E, Chassaing B, Viennois E, et al. Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Santé cohort PLoS Medicine, 2024.
doi:10.1371/journal.pmed.1004338 PubMed 38349899
Funding and finding
Registration
NCT03335644
Participants
92,000
Follow-up
mean 6.7 years
Funding
NutriNet-Santé public institutions (Ministère de la Santé, Santé Publique France, INSERM, INRAE, CNAM, Université de Paris, University Sorbonne Paris Nord); European Research Council (grant agreement 864219); French National Cancer Institute (INCa_14059); French Ministry of Health; IdEx Université de Paris (ANR-18-IDEX-0001); Bettencourt-Schueller Foundation Research Prize 2021. Researchers were independent from funders. Funders had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, and the decision to submit the article for publication.
Finding
2604 incident cancers (750 breast, 322 prostate, 207 colorectal) over 615,749 person-years. Highest versus lowest intake of E471: overall cancer HR 1.15 (95% CI 1.04 to 1.27), breast 1.24 (1.03 to 1.51), prostate 1.46 (1.09 to 1.97); total carrageenans and breast cancer 1.32 (1.09 to 1.60). No emulsifier was associated with colorectal cancer. Modelled absolute risks at age 60 by intake category (eTable C): overall cancer 11.2%, 11.8% and 12.4% for E471; breast cancer 4.2%, 4.7% and 5.1% for E471 and 4.1%, 4.6% and 5.2% for total carrageenans; prostate cancer 3.6%, 4.2% and 4.9% for E471. E471 was coded in sex-specific thirds (cut-offs 34 and 187.3 mg/day in men, 40.4 and 177.8 mg/day in women; category means 7.16, 104.17 and 376.1 mg/day). eTable D, cases/participants by third of E471 intake: overall cancer 790/30,667, 1018/30,729 and 796/30,604, HR 1.00, 1.16 (1.05 to 1.27) and 1.15 (1.04 to 1.27), p-trend 0.01; breast cancer 211/24,090, 292/24,153 and 245/24,027; prostate cancer 86/6,577, 133/6,576 and 103/6,577. Total mono- and diglycerides of fatty acids (E471, E472, E472a, E472b, E472c, E472e) and overall cancer: HR 1.12 (1.02 to 1.23) and 1.03 (0.93 to 1.14), p-trend 0.4. Diphosphates (E450) were consumed by 72.6%, mean 246.7 (SD 341.0) mg/day, and coded in sex-specific thirds (cut-offs 47.3 and 259.5 mg/day in women, 28 and 264.3 mg/day in men; category means in women 4.85, 145.42 and 580.06 mg/day). eTable D, E450 by third: premenopausal breast cancer 61/16,560, 120/17,021 and 113/19,382, HR 1.00, 1.56 (1.13 to 2.15) and 1.45 (1.04 to 2.02), p-trend 0.03 (false-discovery-rate-adjusted p-trend 0.1); overall cancer 838/30,683, 1036/30,658 and 730/30,659, HR 1.00, 1.03 (0.94 to 1.13) and 0.98 (0.88 to 1.09), p-trend 0.97; breast cancer HR 1.14 (0.94 to 1.40) for the highest third, p-trend 0.08. eTable C modelled absolute risk of premenopausal breast cancer at age 40 by E450 third: 1.7%, 2.1% and 2.5%. Additive doses were estimated from laboratory assays, EFSA doses by food category or Codex GSFA doses; the study period was 2009 to 2021. The authors state that further human, epidemiological and preclinical studies are required to elucidate the potential underlying mechanisms.
Expert consensus
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Kidney International Supplements, 2017.
doi:10.1016/j.kisu.2017.04.001 PubMed 30675420
Funding and finding
Funding
not stated; the guideline was published by KDIGO, which contracted the Johns Hopkins University as Evidence Review Team.
Finding
Recommendation 4.1.8: 'In patients with CKD G3a–G5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with other treatments (2D). It is reasonable to consider phosphate source (e.g., animal, vegetable, additives) in making dietary recommendations (Not Graded).' The rationale states that food additives contain inorganic phosphate, which is more readily absorbed and likely to be underreported in nutrient databases, and that efforts to restrict dietary phosphate must not compromise adequate protein intake. A 2017 erratum (doi 10.1016/j.kisu.2017.10.001) corrected Supplementary Table S21 only.
Regulator
US Food and Drug Administration. Sodium acid pyrophosphate, sodium pyrophosphate, tetra sodium pyrophosphate and calcium pyrophosphate, 21 CFR 182.1087, 182.6787, 182.6789 and 182.8223: substances generally recognized as safe Code of Federal Regulations, title 21, part 182, subparts B (Multiple Purpose GRAS Food Substances), G (Sequestrants) and I (Nutrients), read in the electronic Code of Federal Regulations, up to date as of 20 October 2026, 2026.
https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-182
Funding and finding
Funding
US Food and Drug Administration; the text is federal regulation codified by the Office of the Federal Register.
Finding
Section 182.1087 (subpart B, multiple purpose GRAS food substances) lists sodium acid pyrophosphate; sections 182.6787 and 182.6789 (subpart G, sequestrants) list sodium pyrophosphate and tetra sodium pyrophosphate; section 182.8223 (subpart I, nutrients) lists calcium pyrophosphate. Each states: 'This substance is generally recognized as safe when used in accordance with good manufacturing practice.'
Regulator
The Japan Food Chemical Research Foundation. List of Designated Food Additives The Japan Food Chemical Research Foundation; English list of the designated food additives in Appended Table 1 of the Enforcement Regulations under the Food Sanitation Act, as of 1 March 2024, 2024.
https://www.ffcr.or.jp/en/tenka/lists-of-additives/list-of-designated-additives.html
Funding and finding
Funding
Published by the Japan Food Chemical Research Foundation, which translated the substance names from the original Japanese table; the English page of the Consumer Affairs Agency on food additives links to this list as its List of Designated Additives.
Finding
Designated additives are those designated by the Prime Minister (by the Minister of Health, Labour and Welfare until March 2024) under Article 12 of the Food Sanitation Act as unlikely to harm human health; 476 in total as of 1 March 2024. The list includes No. 251 Sodium Bicarbonate (Sodium Hydrogen Carbonate or Bicarbonate Soda) and No. 252 Sodium Carbonate (Crystal: Carbonate Soda, Anhydrous: Soda Ash). It also includes No. 341 Potassium Pyrophosphate (Tetrapotassium Pyrophosphate), No. 342 Calcium Dihydrogen Pyrophosphate (Acid Calcium Pyrophosphate), No. 343 Disodium Dihydrogen Pyrophosphate (Acid Disodium Pyrophosphate) and No. 345 Sodium Pyrophosphate (Tetrasodium Pyrophosphate), besides No. 344 Ferric Pyrophosphate.
Regulator
National Health Commission of the People's Republic of China; State Administration for Market Regulation. 食品安全国家标准食品添加剂使用标准 (National food safety standard: Standard for uses of food additives), GB 2760—2024 National standard of the People's Republic of China, issued 8 February 2024, in force from 8 February 2025, replacing GB 2760—2014, 2024.
https://file.jgvogel.cn/134/upload/resources/file/595476.pdf
Funding and finding
Funding
Issued by the National Health Commission and the State Administration for Market Regulation; the standard carries no funding statement. The text was read in a copy hosted by a third party, as the issuing bodies' sites refused automated access; its title page, contents and Table A.1 are those of GB 2760—2024.
Finding
Table A.1, ascorbic acid (vitamin C), CNS 04.014, INS 300, functions flour treatment agent and antioxidant: used in various foods in appropriate amounts according to production needs (按生产需要适量使用), except the food categories numbered 1 to 5, 10 to 62 and 68 in Table A.2, which comprise milks, fermented milk, milk powder and cream, butter, fresh fruit, vegetables, fungi and algae, cereals, rice, flours and raw noodles, fresh meat, aquatic products, eggs, sugars, honey, salt, spices, infant formulae and complementary foods for infants, drinking waters, fruit and vegetable juices, tea and coffee; maximum 5.0 g/kg in peeled or pre-cut fresh fruit (04.01.01.03) and in peeled, cut or shredded vegetables (04.02.01.03), 0.2 g/kg in wheat flour (06.03.01) and 1.5 g/kg in fruit and vegetable juices (14.02.01), as ready to drink. Table A.1, sodium carbonate (碳酸钠, CNS 01.302, INS 500(i)), function acidity regulator: according to production needs in various foods except categories 1 to 30 and 33 to 68 in Table A.2, and in fermented rice products; categories 31 and 32 are raw wet and raw dry noodle products. Sodium hydrogen carbonate (碳酸氢钠, CNS 06.001, INS 500(ii)), functions raising agent, acidity regulator and stabiliser: according to production needs in various foods except categories 1 to 56 and 58 to 68 in Table A.2, and in fermented rice products; category 57 is cereal-based complementary foods for infants and young children. Sodium sesquicarbonate (碳酸氢三钠, also named 倍半碳酸钠, CNS 01.305, INS 500(iii)), function acidity regulator: according to production needs in dairy products other than listed exceptions, only goat milk, and in pastries (07.02) and biscuits (07.03). Table A.1, phospholipids (磷脂, CNS 04.010, INS 322), functions antioxidant and emulsifier: according to production needs in various foods, except the categories numbered 1 to 4, 6, 8 to 53 and 59 to 68 in Table A.2, which comprise pasteurised and sterilised milk, fermented milk, milk and cream powder, vegetable oil, animal fats, butter, fresh fruit, vegetables, fungi and algae, cereals, rice, flours and noodle products, fresh, chilled and frozen meat, aquatic products, eggs, sugars, honey, salt, spices, drinking waters, fruit and vegetable juices, wines, and tea and coffee; cream (category 5), hydrogenated vegetable oil (7) and infant formulae and complementary foods for infants (54 to 58) are not among the exceptions. Table A.1, mono- and diglycerides of fatty acids (单,双甘油脂肪酸酯, CNS 10.006, INS 471), functions emulsifier and coating agent (乳化剂、被膜剂): according to production needs in various foods, except the 59 categories numbered 1 to 4, 6 to 11, 13 to 14, 16 to 30, 32 to 53 and 59 to 68 in Table A.2; cream (5), surface-treated fresh fruit (12) and vegetables (15), raw wet noodle products (31) and infant formulae and complementary foods for infants (54 to 58) are not among the exceptions; maximum 20.0 g/kg in butter and concentrated butter (02.02.01.01), 30.0 g/kg in raw dry noodle products (06.03.02.02), 6.0 g/kg in brown sugar, raw sugar, other sugars and syrups (11.01.02) and 5.0 g/kg in spices (12.09). Table A.1, phosphoric acid and phosphates (磷酸及磷酸盐), a group entry that includes disodium dihydrogen pyrophosphate (焦磷酸二氢二钠), tetrasodium pyrophosphate (焦磷酸钠), tetrapotassium pyrophosphate (焦磷酸四钾), trisodium monohydrogen diphosphate (焦磷酸一氢三钠) and calcium acid pyrophosphate (酸式焦磷酸钙); its INS numbers include 450(i), 450(ii), 450(iii), 450(v) and 450(vii); functions water-retention agent, raising agent, acidity regulator, stabiliser, coagulant and anticaking agent (水分保持剂、膨松剂、酸度调节剂、稳定剂、凝固剂、抗结剂). Maximum levels apply singly or in combination, expressed as phosphate (PO4 3-), for example 5.0 g/kg in dairy products other than listed exceptions, 15.0 g/kg in bakery wares (07.0), 5.0 g/kg in prepared and cooked meat products, 20.0 g/kg in non-dairy creamer and compound seasonings and 80.0 g/kg in seasoning packets for instant wet noodles (12.10.01.03); in infant formulae (13.01.01, 13.01.02) and complementary foods for infants and young children (13.02), 1.0 g/kg using only calcium hydrogen phosphate and sodium dihydrogen phosphate.

Updated 2026-10-21