GRAS status of CD derivatives

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The question raised at the webinar held on Dec. 6, on the food application of CDs, if CD derivatives can be used in food products. See the answer below:

Fact: All parent cyclodextrins are accepted as food additives and “generally recognized as safe” (GRAS).
As dietary supplement, the total daily oral dose of α-CD may reach 6000 mg/day, for β-CD 500 mg/day and for γ-CD 10 000 mg/day, and for HP-β-CD as oral pharmaceutical 8000 mg/day (Ref: Loftsson, T., Brewster, M.E., ‘Pharmaceutical applications of cyclodextrins: basic science and product development’, J. Pharmacy and Pharmacology, Vol. 62, 2010, p. 1607-1621). In a recent evaluation of European Medicinal Agency (EMA) only the parent CDs are mentioned as food additives, the derivatives not: “In 2000-2004, α-CD, β-CD and γ-CD were introduced into the generally regarded as safe (GRAS) list of the FDA for use as a food additive. Alpha- and beta-CD are approved as novel food ingredients by the Commission. Beta-CD is approved in Europe as a food additive (E 459) with an ADI (acceptable daily intake) of 5 mg/kg/day.”

Preclinically, oral NOELs after a year of HP-β-CD are 500 mg/kg/day for rats and 1000 mg/kg/day for dogs . Ref: Gould, S., Scott, R.C., 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review, Food Chem Toxicol., Vol. 43(10), 2005, p. 1451-1459).

Oral NOAELs (no –observed-effect-level) of SBE-β-CD in rats and dogs after 3 months are both 3600 mg/kg/day (Ref: Stella, V.J., He, Q., Cyclodextrins, Toxicol Pathol Vol. 36, 2008, p. 30-42).

Random Methyl-β-CD has no oral application. (I have no offical data)

Not highly relevant, but may be of interest: oral safety data on children with HPBCD
Very few data on children under two years of age treated with oral solutions of itraconazol with up to 200 mg HP-β-CD/kg/day for 2 weeks were well tolerated and considered safe. The oral availability of HP-β-CD was less than 1% (Ref: Grigull, L., Kuehlke, O., Beilken, A., Sander, A., Linderkamp, C., Schmid, H., Seidemann, K., Sykora, K.W., Schuster, F.R., Welte, K., ‘Intravenous and oral sequential itraconazole antifungal prophylaxis in paediatric stem cell transplantation recipients: A pilot study for evaluation of safety and efficacy’, Pediatric Transplantation, Vol. 11(3), p. 261-266;
Ref: De Repentigny, L., Ratelle, J., Leclerc, J-M., Cornu, G., Sokal, E.M., Jacqmin, P., De Beule, K., ‘Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children’, Antimicrobial Agents and Chemotherapy, Vol. 42(2), 1998, p. 404–408).

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