ORIGINAL SUBMISSION AM IN T ALATI & UPADHYE ATTO R NEYS AT LAW GRN oootot,6 As hish R. Talati 312.327.3381 Tel Ashish@A minTalati. com 312.884 .735 2 Fax A ugust 16, 20 I 6 Office of Food Add iti ve Safe ty (H FS-200) Cente r fo r Food a fety and Applied utrition Food A nd Drug Adm in istration 500 1 Campus Drive College Park, MD 20740-3835 Rc: Gener ally Rec~ed As Safe ("GRAS") Notification for Chondroitin Sodium Sulfa te Dear S ir/Madam : Pursuant to proposed 2 I CFR 170 .36, o ur clie nt, Gnosis S .p.A. (" Gnosis"), thro ugh Amin Talati & Upadhye, LLC as its attorneys, here by provides notice ofa claim that the food ingredi ent cho ndroitin sulfate sodium, described in the enclosed notification document, is exempt from the premarket approval requirement of the Federal Food, D ru g, and Cosme tic Act because it has been determined to be Generally Recognized As Safe (GRAS), based on scientific proced ures. As required, pl ease find encl osed three co pi es ofthe notification. Please do not hesitate to contact me at Ashish@ A minTalati.com or 312-327-338 1 if you have any questions or require addi tional info rmation. S incerely, (b) (6) ~~CG~D '¥~[Q) AUG 1 7 2016 OFFICE OF FOOD ADDITIVE SAFETY Amin Talat i & Upadhye, LLC • 100 South Wacker D rive, Su ite 2000 • Chicago, IL 60606 · Office (3 12) 466- 1033 • Fax (3 12) 884- 7352 • www.AminTalati.com GRAS NOTIFICATION I. Claim of GRAS Status A. Claim of Exemption from the Requirement for Premarket Approval Requirements Pursuant to Proposed 21 CFR § 170.36(c)(l) Gnosis S.p.A., Italy has determined that chondroitin sulfate sodium is Generally Recognized As Safe, consistent with Section 20l(s) of the Federal Food, Drug, and Cosmetic Act. This determination is based on scientific procedures as described in the following sections, under the conditions of its intended use as a food ingredient. Therefore, the use of chondroitin sulfate sodium is exempt from the requirement of premarket approval. Signed, (b) (6) Ashish Talati, J.D., M.S ., RAC Attorney for: Gnosis S.p.A. Via Lavoratori Autobianchi, 1 20832 Desio (MB), Italy Page I of8 r--------~~~~-- ------- -~ B. Narne and Address of N otifier: Marco Bema Gnosis S.p.A. Via Lavoratori Autobianchi 1 20832 Desio (MB) ITLY C. Common or Usual Name of the Notified Substance: The common name ofthe substance ofthis notification is chondroitin sulfate sodium. D. Conditions of Intended Use in Food Chondroitin sulfate sodium is intended for use as a nutrient [21 CFR 170.3(o)(20)] 1 in conventional foods such as beverage and beverage bases, milk and milk products, and chewing gum at use levels ranging from 50 to 200 mg/serving (reference amounts customarily consumed, 21 CFR 101.12). Chondroitin sulfate sodium is not proposed for uses in foods that are intended for infants and toddlers, such as infant formulas or foods formulated for babies or toddlers, as well as it is not intended for use in meat and poultry products that come under USDA jurisdictions. The intended use of chondroitin sulfate sodium in the above mentioned food categories, is estimated to result in a maximum daily intake of 1200 mg /person [20 mg/kg body weight (bw)/day for an individual weighing 60 kg]. E. Basis for GRAS Determination: In accordance with 21 CFR 170.30, the intended use of chondroitin sulfate sodium has been determined to be Generally Recognized As Safe (GRAS) based on scientific procedures. The determination is supported by the opinion of the Expert Panel. A comprehensive search of the scientific literature through July 2016 was also utilized for this determination. There exists sufficient qualitative and quantitative scientific evidence, including animal and human data to determine safety-in-use for chondroitin sulfate sodium. Chondroitin sulfate as a component of connective tissue is found in human body and is commonly consumed as a dietary supplement. The safety determination of chondroitin sulfate sodium is based on the totality of available evidence. The safety of chondroitin sulfate sodium is supported by multiple well designed human clinical trials and animal studies with chondroitin sulfate. In the published literature, several double-blind, placebo-controlled trials were found. In these studies, the use levels of chondroitin sulfate ranged from 800 to 1200 mg/day for long duration. Additionally, several animal and in vitro studies further corroborate the safety in use of chondroitin sulfate sodium at the intended use levels. The findings from a series of specifically designed subchronic toxicity and mutagenicity studies that followed standard regulatory guidelines, supports the safety in use of chondroitin sulfate sodium, subject of present GRAS. Based on the subchronic study, the no-observed-adverse-effect level (NOAEL) for chondroitin sulfate sodium was determined to be 1000 mg/kg bw/day, the highest dose tested. On the basis of '"Nutrient supplements": Substances which are necessary for the body's nutritional and metabolic processes. Page 2 of8 - -----------------------------, scientific procedures 2 , Gnosis S.p.A. considers the consumption of chondroitin sulfate sodium, as a food ingredient to be safe at levels up to 1200 mg/person/day. F. Availability of Information: The data and information that forms the basis for this GRAS determination will be provided to Food and Drug Administration upon request or will be available for FDA review and copying at reasonable times at the above mentioned offices of the notifier (Section I, B) or at the offices of: Madhu G. Soni, PhD, FATS Soni & Associates Inc 749 46th Square Vero Beach, FL 32068 Telephone:+ 1- 772-299-0746 Email: [email protected] II. Detailed Information About the Identity of the Notified Substance: Chondroitin sulfate sodium is a standardized amorphous white to off-white powder produced by fermentation of a particular strain of E. coli to produce the K4 polysaccharide that is further chemically transformed to chondroitin sulfate sodium. The product is chemically pure. A. Chemical name: Chondroitin sulfate is a glycosaminoglycan, a linear polymer constituted of random sequences ofrepeated disaccharide units of: 2-acetylamino-2-deoxy-4-0-sulfate- 3 -0-~-D-glucopyranurosyl-D-galactose 2-acetylamino-2-deoxy-6-0-sulfate- 3 -0-~-D-glucopyranurosyl-D-galactose 2-acetylamino-2-deoxy-4,6-0-disulfate-3-0-~-D-glucopyranurosyl-D-galactose 2-acetylamino- 2-deoxy-6-0-sulfate-3 -0-~-2'-0-sulfate-D-glucopyranurosyl-D-galactose B. Chemical Abstract Registry and other Number: Chondroitin Sulfate Sodium Salt: [CAS: 9082-07-9] Chondroitin sulfate C: [12678-07-8], [25322-46-7] Chondroitin sulfate mixture of regioisomers A, C, E: [9007 -28-7] C. Chemical Formula and Molecular Weight: Monosulfated disaccharide unit: Cr4Hr9NNa20 14S (molecular weight= 503.3) Bisulfated disaccharide unit: Cr4H2oNNa3017S2 (molecular weight= 605.4) Monosulfated polymer: (Cr4Hr9NNa2014S)nH20; n> 1 [molecular weight= (503.3)n+18] Bisulfated polymer: (C 14H2oNNa30r 7Si)nH20; n> 1 [molecular weight = (605 .4)n+ 18] 2 21 CFR §170.3 Defmitions. (h) Scientific procedures include those human, animal, analytical, and other scientific studies, whether published or unpublished, appropriate to establish the safety of a substance. Page 3 of8 D. Structure: The structural formula of chondroitin sulfate is presented in Figure II-D. _...[4)-p-0-GicA-( I + 3)-p-0-GaiNAc(1_.Jn Chondroitin Sulfate Chemical Formula : (C1. H 19NNa20 14S)n H20 Molecular Weight: (503,34)n + 18 R4,R6=H or S03Na Ft. different from R6 Figure 11-D. Chemica l Structure of Chondroitin Sulfate Sodium E. Physical Characteristics Chondroitin sulfate sodium is an amorphous white to off-white powder. F. Identity and Specifications Food grade specifications of chondroitin sulfate sodium are presented in Tables II-G.l. The product is highly pure and contains >95% chondroitin sulfate sodium. The identity of chondroitin sulfate sodium is confirmed by employing N uclear Magnetic Resonance (NMR) spectra. Chondroitin sulfate sodium is the only main ingredient present in the product. Analytical data from three nonconsecutive manufacturing lots are presented in Appendix I. Page 4 of8 Table ll-F. Specifi ca tio ns of C ho ndroitin Sulfate Sodium ( MythocondroTM) Tests Limits Limits Ref. Analytical M ethods Ref. Appearance White to lo-house USP monograph off-white powder Identification : USP monograph USP monograph -IR Positive -Sodium Positive Clarity and Color ofsolution ~ 0.35 USP monograph USP monograph (5% aqueous solution, abso rbance at 420 nrn) Specifi c Optical Rotation -7.0° to - 19.0° d.b. In-house USP monograph (3% aqueous solution) pH ( 1% aqueous solution) 5.5 to 7.5 USP monogr!iJ>h USP monograph Loss on drying ~ 10.0 % USP monog raph USP monograph (105 °C for 4 hours) Residue on ign ition 20.0% to 30.0 % d.b. USP monograph USP monograph Chloride < 0.50 % USP monograph USP mon ograp h Sulfate < 0 .24 % USP monograph USP monograph Heavy metals < 0.002 % USP monograph USP monograph Lead ~ 0.5 ppm USP <23 3> USP <233 > Cadmium < 0 .5 ppm USP <23 3> USP <233> Mercury < 0 . 1 ppm US P <233> USP <233> Arsenic < 1.5 ppm US P <233> USP <233 > Electrophoretic purity: US P monograp h USP monograph -any ind ividual impurity < 2% Microbial enumeration: USP monograph USP monog raph - Tota l bacterial count S 103 CFU/g -Total combined yeasts and molds S 102 CFU/g - Salmone lla s p. Absent I 10 g -Escherichia coli Absent/tO g Limit of prote in < 0 .5% d.b. In-house USP monograph Content of chondroitin s ul fate 95 .0 % to 105.0% d.b. In-house USP monograph sod ium G.