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3 JECFA...15 FDA...15 (EU)

4 1

5 CAS JECFA 1970 ADI not specified ADI 2

6 1 GRAS GMPGood Manufacturing Practice 2% 5% 1) 2) EU 10 g/kg 10 g/kg dietary food supplement 3) FAO/WHO JECFA EU JECFA PTWI JECFA 2 3

7 2% 2% Calcium silicate 4)-10) CAS CaOSiO 2 Calcium metasilicatecasio Calcium orthosilicateca 2 SiO Tricalcium silicateca 3 SiO ) SiO % CaO % 6) JECFA ADI not limited 7)-19) 7)-10), 14), 16) Magnesium silicatesynthetic CAS ) MgO % 67.0% 14), 16) 4

8 Magnesium trisilicate2mgo3sio 2 XH 2 O Sodium aluminosilicate CAS ), 12), 17), 18) xna 2 OyAl 2 O 3 zsio 2 nh 2 O xy z 1:1:13 Sodium aluminium orthosilicate NaAlSiO Sodium aluminium silicate Al 2 O 3 Na 2 O6SiO ) SiO % Al 2 O % Na 2 O % 17) Aluminium calcium silicate 7), 8), 13), 18) CAS wna 2 OxCaO yal 2 O 3 zsio Calcium aluminium orthosilicate CaAl 2 Si 2 O Calcium dialuminoorthosilicate Ca 3 Al 2 SiO 3 Calcium dialumino metasilicate (AlOOCa) 2 SiO 3 13) SiO %Al 2 O %CaO %Na 2 O % 13) 5

9 1 2 SiO %Al 2 O % 9), 19) (b) JECFA hydrated aluminium silicate 11) M 2/n OAl 2 O 3 y SiO 2 wh 2 OM n y 2 2 A Na 12 [(AlO 2 ) 12 (SiO 2 ) 12 ] 27H 2 O 8), 9), 19),20) SiO %MgO 30.5% 8), 18), 19) (b) JECFA magnesium silicates 11), 15) SiO 2 [ H 2 SiO 3 ] 8), 9),18) [Si(OH) 4 ] H 2 SiO 3 SiO 2 nh 2 O 8),18) 6

10 (a) 5 g 20 ml mg SiO mg SiO 2 21) (b) 5 g 20 ml mg SiO 2 5 g9.2 mg SiO mg SiO 2 21) mg/kg 22) ,000 mg/kg / mg/kg / 16.8% 23) g g g mmol ) mg/kg / A30 mg/kg / (p<0.05) A AUC 22) 4 A ,000 mg/kg / 40 mg/kg 1.2% A 12.1% 72 7

11 23) 5 g 20 ml mg SiO mg SiO 2 21) 25)-27) 100 ppm Si(OH) 4 28), 29) 28) Yokoi Enomoto 28) 30) 24) 31) 32), 26) 1 µg/ml 32) 0.5 µg/ml 32), 33) µg/ ml (n=15) 34) 1 µg SiO 2 / ml 27) 8

12 33) 34) 25) mg SiO 2 /100 ml (n=6) (n=2) (n=6) (n=7) (n=6) (n=3) 35) 20.12±6.40 mg Si/(n=8) 36) 8.7±4.2 mg Si/ 36) 33.1±3.9 mg Si/ 36) mg Si(OH) 4 / 37) 32) 37) ml/ 2 ml/ 190 µg/ml1 mg/ml ) 39) 40) 100% 39)-41) 9

13 35), 42) 2 (a) ,2004,0005,000 mg/kg 5,000 mg/kg 1030 LD 50 5,000 mg/kg 43), 44) %(W/V) 5,000 mg/kg7 LD 50 5,000 mg/kg 20) ,0002,000 3,0004,0005,000 mg/kg 5,000 mg/kg 24 LD 50 3,400 mg/kg 20) (b) LD 50 1,050 mg/kg 45) (a) 25 mg 46) 10

14 10 mg/m ) (b) % ,250 mg/kg / % 1% 37) %50 mg/125 mg/kg / ) %05001,500 2,500 mg/kg / 1 3.0% 90 5% 37) mg/kg / 2 37) %01,875 3,7507,500 mg/kg / ) %06251,2502,500 mg/kg / JECFA 48) (kg) (g//) (g/kg /)

15 % 47) g/kg /1.3 g/kg / 2.4 g/kg /1.8 g/kg / 4 37), 49) JECFA 1973 ADI not limited ADI not limited 50) (a) ,600 mg/kg / 45) ,0001,250 1,500 1,600 mg/kg / 29 1,600 mg/kg / 13 20), 45) (b) 1,600 mg/kg /1,200 mg/kg /900 mg/kg / 12

16 45) 100 mg/kg / ) (a) Salmonella typhimurium TA1530 G46 Saccharomyces cerevisiae D ,5005,000 mg/kg 5 in vitro 51) µg/ml µg/ml 52) WI µg/ml 51) ,5005,000 mg/kg ) ,5005,000 mg/kg 5 51) (b) S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 Escherichia coli WP mg/plates9 mix 53) S. typhimurium TA98, TA100, TA1535, TA1537, TA1538E. coli WP mg/plates9 mix 13

17 53) S. typhimurium TA1530 G46 S. cerevisiae D ,000 mg/kg 5 in vitro 54) WI µg/ml 54) ,000 mg/kg ) ,000 mg/kg 5 54) S. typhimurium TA98, TA100, TA1535, TA1537, TA1538 E. coli WP mg/plates9 mix 53) 55) 12% g/ 34 11,000 37) g 37) ), 56) 20 40) ) 14

18 mg Si/l 41) JECFA ADI not limited 11) ) ADI not limitedjecfa ADI not limitedadi ADI not specifiedadi 50), 37) ADI 58) ADI not specifiedadi 30) JECFA ADI 48) ADI FDA FDA GRAS 1979 FDA

19 45) EU SCF 1990 ADI ADI not specified EFSA kg 2050 mg mg/kg / 55% 55) 131 ppm8.2 ppm 22.5 ppm 2.0 ppm7.1 ppm 27) NAS/NRC ) 3 mg// 0.5 mg// 18 mg// ) 60 kg 9.8 mg// 16

20 7.3 mg// 0.5 mg(al )// mg mg 60) ADI 61) mg 62) 20 mg/l 63) JECFA 1970 ADI not specified ADI 17

21 1) Food and Drug Administration, HHS. 21CFR, Subpart C -Anticaking Agents Aluminum calcium silicate, Calcium silicate, Magnesium silicate, Sodium aluminosilicate. 21CFR Ch.I ( Edition). 2) Food and Drug Administration, HHS. 21CFR, Subpart E -Anticaking Agents, Calcium Silicate. 21CFR Ch I. ( Edition). 3) Office for Official Publications of the EC. European parliament and council directive No 95/2/EC of 20 February 1995 on food additives other than colours and sweeteners. CONSLEG: 1995L /07/2003, pp.1-7, ) Compedium of calcium silicate. Prepared at the 17th JECFA (1973), Published in FNP 4 (1978) and in FNP 52 (1992). 5) Institute of Medicine of the National Academies. FCC V Monographs /Calcium Silicate. Food Chemicals Codex : ) Official Journal of the European Communities. Commission Directive 2000/63/EC of October Amending directive 96/77/EC/ laying down specific purity criteria on food additives other than colours and sweeteners (. O J L277/1-4, L277/ ).. 9.(1993) : 103, 104, 302, 303, ) Calcium Aluminosilicate, Calcium Silicate, Kaolin, Magnesium Silicate, Silicon Dioxide, Talc, Zeolites. THE MERCK INDEX, Thirteenth Edition. (2001):277, 284, 945, , , 1613, ). Calcium SilicateSilica Gel) Zeolite)(Magnesium Trisilicate) Silicon DioxideFine))Kaolin) (2005): 16-17, , 184, , ). ph. ( No.Q-0456). 11) Thirteenth Report of the JECFA. Specifications for the identity and purity of food additives and their toxicological evaluation. WHO Technical Report Series 445, FAO Nutrition Meetings Report Series 46. (1970). 12) Compedium of sodium aluminosilicate. Prepared at the 17th JECFA (1973), Published in FNP 4 (1978) and in FNP 52 (1992). 13) Compedium of calcium aluminium silicate. Prepared at the 28th JECFA (1984), Published in FNP 31/2 (1984) and in FNP 52 (1992). 14) Compedium of magnesium silicate (synthetic). Prepared at the 61th JECFA (2003), Published in FNP 52 Add 11 (2003). 18

22 15) JECFA. Toxicological evaluation of some food colours, emulsifiers, stabilizers, anti-caking agents and certain other substances. FAO Nutrition Meetings Report Series 46A WHO/FOOD ADD/ (1969). 16) Institute of Medicine of the National Academies. FCC V Monographs /Magnesium Silicate. Food Chemicals Codex : ) Institute of Medicine of the National Academies. FCC V Monographs /Sodium Aluminosilicate. Food Chemicals Codex : ). 4. (1987): 51, , 239, , 495, ).. (1999): 130, 316, ) Cosmetic Ingredient Review Expert Panel. Final report on the safety assessment of aluminum silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate, magnesium trisilicate, sodium magnesium silicate, zirconium silicate, attapulgite, bentonite, Fuller's earth, hectorite, kaolin, lithium magnesium silicate, lithium magnesium sodium silicate, montmorillonite, pyrophyllite, and zeolite. Int. J. Toxicol. (2003) 22: ) King EJ, McGeorge M. The biochemistry of silicic acid. : The solution and excretion of silica. Biochem. J. (1938) 32: ) Cefali EA, Nolan JC, McConnell WR, Walters DL. Pharmacokinetic study of zeolite A, sodium aluminosilicate, magnesium silicate, and aluminum hydroxide in dogs. Pharm. Res. (1995) 12: ) Benke GM, Osborn TW. Urinary silicon excretion by rats following oral administration of silicon compounds. Food Cosmet. Toxico. (1979) 17: ) Dobbie JW, Smith MB. Silicate nephrotoxicity in the experimental animal: the missing factor in analgesic nephropathy. Scott. Med. J. (1982) 27: ) Bellia JP, Birchall JD, Roberts NB. Beer: a dietary source of silicon. The Lancet. (1994) 343: ) Calomme MR, Vanden Berghe DA. Supplementation of calves with stabilized orthosilicic acid. Effect on the Si, Ca, Mg, and P concentrations in serum and the collagen concentration in skin and cartilage. Biol. Trace Elem. Res. (1997) 56: ) Baumann H. Verhalten der kieselsäure im menschlichen blut und harn. Z Physiol Chemie. (1960) 320: ) Yokoi H, Enomoto S. Effect of degree of polymerization of silicic acid on the gastrointestinal absorption of silicate in rats. Chem. Pharm. Bull. (1979) 27: ) Meyers P. Behavior of silica - technologies available and how they rate. Water Conditioning & Purificationl (2004) 46: ) Twenty-ninth Report of the JECFA. Evaluation of certain food additives and 19

23 contaminants. WHO Technical Report Series 733. (1986). 31) SECTION 9: Reactions to Environmental Agents. HANDBOOK OF PHYSIOLIGY, American Physiological Society, BETHESDA, MARYLAND (1977) : ) Carlisle EM. Silicon. Biochemistry of the Essential NY: Plenum Press. (1984): ) Carlisle EM. Silicon as a trace nutrient. The Sci.Total Environ. (1988) 73: ) Saldanha LF, Gonick HC, Rodriguez HJ, Marmelzat JA, Repique EV, Marcus CL. Silicon-related syndrome in dialysis patients. Nephron. (1997) 77: ) King EJ, Stantial H, Dolan M. The biochemistry of silicic acid.. The presence of silica in tissues. Biochem. J. (1933) 27: ) Reffitt DM, Jugdaohsingh R, Thompson RP, Powell JJ. Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion. J. Inorg. Biochem. (1999) 76: ) JECFA. Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. WHO Food Additives Series 5. (1974): ) Baily CB. Silica metabolism and silica urolithiasis in ruminants: A review. J. Anim. Sci. (1981) 61: ) Farrer JH, Rajfer J. Silicate urolithiasis. J. Urol. (1984) 132: ) Haddad FS, Kouyoumdjian A. Silica stones in humans. Uro. Int. (1986) 41: ) Nishizono T, Eta S, Enokida H, Nishiyama K, Kawahara M, Nakagawa M. Renal silica calculi in an infant. In. J. Uro. (2004) 11: ) Carlisle EM. Silicon: an essential element for the chick. Science. (1972) 178: ). R. No. T ( ). 44). R. No. T ( 11 9 ). 45) FDA. Evaluation of the health aspects of certain silicates as food ingredients. National Technical Information Service (NTIS), PB FDA Contract No /2004. (1979). 46) Bolton RE, Addison J, Davis JM, Donaldson K, Jones AD, Miller BG, Wright A. Effects of the inhalation of dusts from calcium silicate insulation materials in laboratory rats. Environ. Res. (1986) 39: ) Takizawa Y, Hirasawa F, Noritomi E, Aida M, Tsunoda H. Oral ingestion of SYLOID to mice and rats and its chronic toxicity and carcinogenicity. Acta Medica et Biologica. (1988) 36: ) Principles for the safety assessment of food additives and contaminants in food. Environmental Health Criteria 70. IPCS in cooperation with the JECFA. World Health 20

24 Organization, Geneva. (1987). 49) Newberne PM, Wilson RB. Renal damage associated with silicon compounds in dogs. Proc. Nati. Acad. Sci. (1970) 65: ) Seventeenth Report of the JECFA. Toxicological evaluation of certain food additives with a review of general principles and of specification. WHO Technical Report Series 539, FAO Nutrition Meetings Report Series 53. (1974). 51) Litton Bionetics, Inc. Mutagenic evaluation of compound FDA 71-41, calcium silicate. National Technical Information Service (NTIS), PB (1974). 52) Aslam M, Rahman O. Cytotoxic and genotoxic effects of calcium silicates on human lymphocytes in vitro. Mutat. Res. (1993) 300: ) Prival MJ, Simmon VF, Mortelmans KE. Bacterial mutagenicity testing of 49 food ingredients gives very few positive results. Mutat. Res. (1991) 260: ) Litton Bionetics, Inc. Mutagenic evaluation of compound FDA 71-45, synthetic silica sodium silicoaluminate. National Technical Information Service (NTIS), PB (1974). 55) European Food Safety Authority (EFSA). Opinion of the scientific panel on dietetic products, nutrition and allergies on a request from the commission related to the tolerable upper intake level of silicon. The EFSA Journal. (2004) 60: ) Lee MH, Lee YH, Hsu TH, Chen MT, Chang LS. Silica stone - development due to long time oral trisilicate intake. Scand. J. Uro. Nephrol. (1993) 27: ) Ichiyanagi O, Sasagawa I, Adachi Y, Suzuki H, Kubota Y, Nakada T. Silica urolithiasis without magnesium trisilicate intake. Urol. Int. (1998) 61: ) Twenty-sixth Report of the JECFA. Evaluation of certain food additives and contaminants. WHO Technical Report Series 683. (1982). 59) Ministry of Agriculture, Fisheries and Food. Dietary Intake of Food Additives in the UK : Initial Surveillance. Food Surveillance Paper No ) Jugdaohsingh R, Anderson SH, Tucker KL, Elliott H, Kiel DP, Thompson RP, Powell JJ. Dietary silicon intake and absorption. Am. J. Clin. Nutr. (2002) 75: ) EU Commission. Report from the commission on dietary food additive intake in the European Union. ( 62) ).. (2002):

25 25 mg mg/kg 45 / , 4, 5 g/kg 5 g/kg 1030 LD 50 = 5 g/kg , 4, 5 g/kg 1030 LD 50 = 5 g/kg 5 g/kg 24.1% 7 20 LD 50 = 5 g/kg , 0.5, 1, 2, 3, 4, 5 g/kg 24 5g/kg LD 50 = 3.4 g/kg LD 50 = 1.05 g/kg , 0.2, 1.0, 2.5 % 1, 2.5% 37 ( ,250 mg/kg / 1) ) mg/ 37 (125 mg/kg / 1 ) , 1.0, 3.0, 5.0 % 37 (05001,5002,500 mg/kg / 1 ) mg/kg / 37 No , 1.25, 2.5, 5.0 % 5 g/kg (01,8753,750 7,500 mg/kg/ 1 ) , 1.25, 2.5, 5.0 % (06251,2502,500 mg/kg / 1 ) 2.5, 5.0 %12, Na 0.8 g/kg / Na Mg 37 Mg 1.3 g/kg / 0.8 g/kg / 49 Al 1.3 g/kg / 4 6 Na Mg 9 Al 1 10 mg/m mg/kg mg/kg 45 22

26 / 2 6 0, 250, 500, 750, ,000, 1,250, 1,500, 45 1,600 mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg / In vitro TA1530 G46 D3 In vitro In vitro WI-38 TA1530 In vitro TA98 TA100 TA1535 TA1537 (+/ TA1538 S9mix) WP2 54In vitro TA98 TA100 TA1535 TA1537 (+/ TA1538 S9mix) WP2 In vitro G46 D3 No 15, 150, 1,500, 5, mg/kg µg/ml µg/ml , 10., 100µg/ml 51 15, 150, 1,500, 5,000 6, 24, 48 mg/kg 5 15, 150, 1,500, 5,000 mg/kg mg/ S9mix mg/ S9mix , 42.5, ,000 mg/kg In vitro WI-38 1, 10, 100 µg/ml 54 23

27 In vitro TA98 TA100 TA1535 TA1537 (+/ TA1538 S9mix) WP2 34 / , 42.5, , 24, ,000 mg/kg , 42.5, ,000 mg/kg % g/ 1/ mg/ S9mix 53 No g JECFA 48) (kg) (g//) (g/kg /)

HydroxypropylcelluloseCellulose 2-hydroxypropyl ether CH 2 OR R=H H O O H CH H 3 OR H CH 2 CH O m H OR m1 n 30,000n 100 1,000,000n 2,500 13) 1 14 C 14

HPC 1), 2), 3) HPC 4) 5) 6), 7), 8) GMPGood Manufacturing Practice EU 9) 10), 11) GMP 9) FAO/WHO JECFA 1989 35 7 HPC ADI not specified 12) 14 7 JECFA EU 46 HPC 16 8 16 EU - 1 - HydroxypropylcelluloseCellulose