7523000G PRONALEN BIO-PROTECT ZNSN Version: 22-07/JAN/2016 1. PRODUCT IDENTIFICATION Trade Name: PRONALEN BIO-PROTECT ZNSN Manufacturer: PROVITAL Responsible for the Safety Assessment: Lourdes Mayordomo Tf./Fax: 3493-7192350/7190294 e-mail: l.mayordomo@provitalgroup.com Kind of Raw Material: Active Ingredient Function of the Ingredient (PCPC Inventory): Skin-Conditioning Agent - Miscellaneous Function of the Ingredient (UE Inventory): Skin Conditioning; Moisturising; Buffering; Detangling; Emollient; Hair Conditioning; Skin Protecting; Tonic. INCI approved in: Registered in EU, USA, Japan Japanese Name: JCSL: Apple Juice, Peach Juice, Barley Extract, Ginseng Extract, Wheat Germ Extract Japanese translation available in PCPC. 2. PRODUCT COMPOSITION Components Breakdown (INCI). Including actives, solvents, preservatives, antioxidants and other additives: [EU] CAS EINECS Aqua 30-50 % 7732-18-5 231-791-2 Propanediol 30-50 % 504-63-2 207-997-3 26264-14-2 Pyrus Malus Juice 5-10 % 85251-63-4 286-475-7 Prunus Persica Juice 5-10 % 84012-34-0 281-678-7 Triticum Vulgare Seed Extract 5-10 % 84012-44-2 281-689-7 Hordeum Vulgare Seed Extract 5-10 % 85251-64-5 286-476-2 Panax Ginseng Root Extract 1-5 % 84650-12-4 283-493-7 Additives Glyceryl Caprylate 0,68-0,99 % 26402-26-6 247-668-1 Glyceryl Undecylenate 0,08-0,165 % --- --- ------------------------------------------------------------------------------------------------------------- PCPC [CTFA] CAS EINECS Water 30-50 % 7732-18-5 231-791-2 Propanediol 30-50 % 504-63-2 207-997-3 26264-14-2 Pyrus Malus (Apple) Juice 5-10 % --- --- Prunus Persica (Peach) Juice 5-10 % --- --- Triticum Vulgare (Wheat) Seed Extract 5-10 % 84012-44-2 281-689-7 Hordeum Vulgare Seed Extract 5-10 % 85251-64-5 286-476-2 Panax Ginseng Root Extract 1-5 % 50647-08-0 --- Additives Glyceryl Caprylate 0,68-0,99 % 26402-26-6 247-668-1 Glyceryl Undecylenate 0,08-0,165 % 123759-97-7 --- 62285-15-8 Impurities: 1
Heavy Metals (as Pb) Pesticides Less than 20 ppm. Non applicable. 3. TOXICOLOGICAL INFORMATION Data obtained in our own toxicological tests and/or bibliographical research Animal testing: This product has not been the subject of animal testing or retesting for cosmetic purposes by or on behalf of this company. General information: The apple is used mainly as food. It shows a great nutritional value and its consumption is considered to be a source of health benefits. The peach is used mainly as food. It shows a great nutritional value and its consumption is considered to be a source of health benefits. The following herbs have been approved by the German Commission E Monographs: Panax Ginseng Root (Published January 17, 1991) The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the ingredient Panax ginseng root extract is safe as cosmetic ingredients in the presents practices of use and concentration. (CIR Final report, October 2012) The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the Glyceryl Undecylenate is safe as cosmetic ingredients in the presents practices of use and concentration (IJT 23 (Suppl. 2:55-94,)2004) The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the Glyceryl Caprylate is safe as cosmetic ingredients in the presents practices of use and concentration (IJT 23 (Suppl. 2:55-94,)2004) Classification according to Council of Europe (*): Pyrus malus:---, Prunus persica:---, Triticum vulgare: ---, Hordeum vulgare: ---, Panax ginseng:3 *(1)- Non-recommended ingredients (2)-Ingredients which could not be assessed (3) Recommended ingredients Cytotoxicity: No data available. Skin Irritation: Test performed with other products of Provital: Pronalen Bio-Protect (Cod.75200):Patch Test IIP(30 min)=0%, IP(48h)=0% Propanediol (RTECS no. TY2010000, Last Updated:200608): Standard Draize Test in human skin, product at 100% for 48 hours and 7 days, moderate Propanediol. Skin irritation tests in NZW rabbit: undiluted product at 0.5ml was considered to be a Slight irritant. (Supplier data) Skin Sensitization: Propanediol. Skin sensitization tests: Studies performed in guinea pigs by Landsteiner/Draize method and by Magnusson-Kligman method considered the product to be non-sensitizing. Studies in human at product concentration of 50% in 112 volunteers and 75% in 207 volunteers considered the product not to be a primary skin irritant or a sensitizing agent. (Supplier data) Eye Irritation: Test performed with other products of Provital: Pronalen Ginseng (Cod. 42910): In-vitro Irritation Index: Eytex (UMA): 30.1, mild/moderate.; Pronalen Ginseng (Cod. 42910): In-vitro Irritation Index: HET-CAM (con. 100%): 1.8.; Apple Extract D.C. (Cod. 48840): In-vitro Irritation Index: HET-CAM (con. 100%): 2.9. Propanediol. Eye irritation tests in NZW rabbit: undiluted product at 0.1ml was considered to be Non-irritating and at 0.2 ml was considered to be Practically non-irritating. (Supplier data) Mutagenicity: Test performed with other products of Provital: Pronalen Bio-Protect (Cod.7520): Ames Test: negative (all strains, with and without S9) Triticum vulgare Extract (RTECS no. YM0110000): Unscheduled DNA synthesis, mouse lymphocyte = 30 mg/l; mouse fibroblast = 30 mg/l. Ginseng: Hepatocyte-DNA repair test showed no genotoxicity of ginseng at concentrations 0.1-10 mg/ml (ESCOP MONOGRAPHS, Second Edition, 2003). Panax ginseng: Ames test negative (RATPHYT 272, 98). 2
Ginseng root -neutral saponins (RTECS no. LY9534000): Mutagenesis test, i.p. rat = 50 mg/kg. Ginsenoside (RTECS no. LY 9535000): Morphological transformation, rat liver 20 mg/l. Ginsenoside RB1 (RTECS no. LZ5856000): Mutagenesis test, i.p. rat = 50 mg/kg. Ginsensid Rc (RTECS no. LY9536300): Mutation test, i.p. rat = 50 mg/kg. Propanediol. Genetic toxicity tests: This product was considered non-mutagenic in the Ames Test (OECD method no.471), in the HPRT Test (OECD method no. 476), in the chromosome aberrations test (OECD method no.473) and in the in vivo mouse micronucleus test (92/69/EEC Method) (Supplier data) Acute toxicity: Hordeum vulgare extract (RTECS no. MT1662500): LD i.p. mouse > 1g/kg. Ginsenoside RB1 (RTECS no. LZ5856000): LD50 i.p. mouse = 1110 mg/kg; LD50 i.v. mouse = 243 mg/kg; TDLo p.o. 25 mg/kg; TDLo i.p. mouse = 5 mg/kg; TDLo skin, mouse = 40 ng/kg/24h; TDLo p.o. mouse = 10 mg/kg; TDLo p.o. mouse = 50 mg/kg. Ginsenoside RG2 (RTECS no. LZ6430000): LD50 i.p. mouse = 1340 mg/kg; TDLo i.p. mouse = 12.5 mg/kg; TDLo i.v. rat = 2.5 mg/kg. Ginseng root - neutral saponins (RTECS no. LY9534000): LDLo i.p. rat = 200 mg/kg; LD50 i.p. mouse = 545 mg/kg; LD50 i.v. mouse = 367 mg/kg; LDo (mg/kg) parental: mouse = 32500 mg/kg, frog =8500 mg/kg; TDLo i.p. mouse =100 mg/kg; TDLo p.o. rat = 10 mg/kg. Panax ginseng (RTECS no. LY9531500): LD50 p.o. rat = 750 mg/kg; LD50 p.o. mouse = 200 mg/kg; LD50 i.p. mouse = 54 mg/kg; TDLo p.o. mouse = 90 mg/kg; LD50 p.o. mammal unspecified species > 10000 mg/kg; TCLo inhalation, rat = 150 mg/m3/4h; TCLo inhalation, rat = 300 mg/m3/4h; TDLo p.o. mouse = 1200 mg/kg. Panax ginseng, standardized extract (RTECS no. RT8520000): TDLo p.o. human = 2857 mg/kg. Ginsenoside B2 (RTECS no. LY9536700): LD50 i.p. mouse = 405 mg/kg, LD50 s.c. mouse > 1500 mg/kg; LD50 i.v. mouse = 130 mg/kg. Ginsenoside R0 (RTECS no. FM337500): LD50 i.p. mouse = 656 g/kg, LD50 i.v. mouse = 278 mg/kg. Ginsenoside F (RTECS no. LY9533000): LD50 p.o. mouse > 5 g/kg; i.p. mouse = 402 mg/kg; i.v. mouse = 381 mg/kg. Ginsenoside No.3 (RTECS no. LY9535500): LD50 i.p. mouse = 910 mg/kg. Ginsenoside Rb3 (RTECS no. LZ5857000): LD50 i.p. mouse = 637 mg/kg. Ginsenoside RD (RTECS no. LZ5858000): LD50 i.p. mouse = 324 mg/kg. Ginsenoside RF (RTECS no. LY9536900): LD50 i.p. mouse = 1340 mg/kg; TDLo p.o. mouse = 25 mg/kg; TDLo skin, mouse = 10 mg/kg. Ginsenoside RG1 (RTECS no. LY9537200): LD50 i.p. mouse = 405 mg/kg; TDLo p.o. mouse = 10 mg/kg. Ginsenoside RG3 (RTECS no. LY9537300): LD50 i.p. mouse = 1250 mg/kg; TDLo p.o. mouse = 25 mg/kg; TDLo i.p. mouse = 10 mg/kg. Ginsenoside RC (RTECS no. LY9536300): LD50 i.p. mouse = 410 mg/kg. Ginsenoside RB2 (RTECS no. LZ5779240): LD50 i.p. mouse = 305 mg/kg. Ginsenoside (RTECS no. LY9535000): LD50 (mg/kg) i.p. rat = 40; mouse = 40. Propanediol (RTECS no.ty2010000, Last Updated:200608): LDLo p.o rat = 10g/kg, LDLo i.m. rat = 6 g/kg, LD50 i.p. mice = 4780 mg/kg, LDLo p.o cat = 3 g/kg, LDLo i.v. rabbit = 3 g/kg, LD50 p.o mice = 4500 mg/kg Propanediol. Acute toxicity tests: p.o. in rat LD50 = 15800 mg/kg, dermal in rat LD50 > 4200 mg/kg and inhalation in rat, DL > 5000 mg/m3. (Supplier data) Subchronic and chronic toxicity: The 28-day-long study on rats with a diet based on barley beta-glucan purified at concentrations of 1%, 5% and 10% showed that levels of up to 10% were tolerated without showing any signs of toxicity (Food Chem Toxicol. 2010, Jan; 48(1): 422-428). Grain dust (RTECS no. MD7900000): TCLo inhalation, rabbit = 20 mg/m3/7h/26w-i. Ginsenosides (RTECS no. LY9537250): TDLo p.o. rat 7000 mg/kg/10w-i; TDLo i.p. mouse 40 mg/kg/10d-i; TDLo mouse 8 mg/kg/2d-i. Ginsenoside RB1 (RTECS no. LZ5856000): TDLo p.o. mouse = 155 mg/kg/14d-i; TDLo i.p. rat = 140 mg/kg/14d-i; TDLo skin mouse = 0.004 ng/kg/3d-c. Ginsenoside RG2 (RTECS no. LZ6430000): TDLo p.o.mouse = 75 mg/kg/3d-i. Ginseng root - neutral saponins (RTECS no. LY9534000): TDLo i.p. rat = 1200 mg/kg/120d-i; p.o. rat = 353 mg/kg/5d-i; TDLo p.o. mouse = 75 mg/kg/3d-i. Panax ginseng (RTECS no. LY9531500): TDLo p.o. mouse = 500 mg/kg/10d-i; TDLo p.o. mouse = 850 mg/kg/5w-i; TCLo inhalation, guinea pig = 20 mg/m3/30d-i; TCLo inhalation, rat = 6.18 mg/m3/122d-i; TCLo inhalation, rat = 3
6.18 mg/m3/61d-i; TCLo inhalation, rat = 60.3 mg/m3/30d-i; TCLo inhalation, rat = 60.3 mg/m3/122d-i; TDLo p.o. man = 92.82 mg/kg/13d-i; TDLo p.o. mouse = 1800 mg/kg/9d-i; TDLo p.o. mouse = 1000 mg/kg/5d-i. Panax ginseng, standardized extract (RTECS no. RT8520000): TDLo p.o. rat = 9100 mg/kg/13w-i; TDLo p.o. rat = 9 mg/kg/90d-i; TDLo p.o. rat = 9 g/kg/90d-i; TDLo p.o. rat = 119 mg/kg/7d-i Ginsenoside RF (RTECS no. LY9536900): TDLo skin, mouse = 1.44 mg/kg/9d-i Ginsenoside RG1 (RTECS no. LY9537200): TDLo i.p. rat = 50 mg/kg/5d-i; TDLo i.p. rat = 120 mg/kg/4d-i; TDLo i.p. rat = 120 mg/kg/4d-i; TDLo i.p. rat = 120 mg/kg/12d-i. Ginsenoside RG3 (RTECS no. LY9537300): TDLo skin, mouse = 2.67 mg/kg/6d-i; TDLo p.o. mouse = 75 mg/kg/3d- I. Ginsenoside (RTECS no. LY 9535000): TDLo p.o. rat = 33.6 mg/kg/6w(i). Propanediol. Repeat-Dose Toxicity tests: p.o. in rat for 90 days NOEL = 1000 mg/kg/day and inhalation in rat after 9 exposures NOEL= 1800 mg/m3. (Supplier data) Reproductive effects: Wheat extract (RTECS no. ZC3619500): TDLo p.o. mammal = 1400 mg/kg in female 7 day pre-mating. Panax ginseng: Negative results in teratogenicity tests on rats and rabbits (RATPHYT 272, 98). Ginseng (RTECS no. LY9531500): TDLo p.o. rat = 352 g/kg male, 60 days before pre-mating. Panax ginseng - Pregnancy category A: no evidence for an increase of the frequency of malformation or other harmful effects on the foetus, despite the consumption by a large number of women (The Essential Guide to Herbal Safety, Simon Mills and Kerry Bone, Elsevier, First edition 2005, pp. 433). The use of Panax ginseng is compatible with breastfeeding (The essential guide to herbal safety, Elsevier, First edition, 2005, pp. 433). Propanediol. Prenatal development toxicity test in rat (OECD method no. 414), the product administered at 250 and 1000 mg/kg by oral gavage on gestation days 6-15, was considered non-toxic. Study on effects during reproduction in rats after a 90-day oral administration, there were no effects to reproductive organs and differences in fertility. (Supplier data) Other data: Pyrus malus: Whole-apple extracts inhibit the growth of colon- and liver- cancer cells in vitro in a dosedependent manner (Nature 405, 903-904, 2000). Consumption of fruits and vegetables has been associated with reduced risk of chronic diseases such as cardiovascular disease and cancer. The study was designed to investigate the profiles of total phenolic components of apple (272.1 mg phenolic/100g) on the proliferative activity of human cells liver cancer HEPG2 in vitro. The product showed antiproliferative effects at a median effective concentration (CE50) of 49.4 mg/l (J Agric Food Chem 2002 4, 50(25): 7449-54). The pericarp extract of Prunus persica at a dose of 500 mg/kg, p.o., showed a significant protection against the acute nephrotoxicity and hepatotoxicity induced by a single administration of cisplatin in mice. (Med Food 2008, 11(2):302-6) 4. ECOLOGICAL DATA Biodegradability: Propanediol: BOD5 = 1160000 mg/l (Supplier data) Aquatic Toxicity: Propanediol. Acute toxicity tests: Fish (Pimephales promelas) LC50 = 7417 mg/l, Daphnia magna EC50 = 7417 mg/l and growth inhibition of algae EC50 > 10000 mg/l (Supplier data) Other data: No data available. 5. CONCLUSION The European cosmetics legislation (Regulation (EC) No 1223/2009) establishes the need to assess the safety of cosmetic products, taking into account the toxicological profile of the ingredients. To do this, in the case of possible systemic effects, it is necessary to obtain the NOAEL (no observed adverse effects level) for the calculation of MoS (margin of safety). The absence of these considerations shall be duly justified. 4
The NOAEL value, or else other data used for the same purpose (LOAEL, LD50, etc.), can only be calculated experimentally from toxicological studies that require the use of animals. Since Provital does not perform any animal testing, it has established a system to ensure the safety of its products without the need of NOAEL and the subsequent calculation of MoS. This systematic, in the case of natural complex substances (NCS) has been endorsed by international organisms and renowned toxicologists. The safety of this ingredient is then established based on the following information: known uses of the active in different fields (medicine, food, cosmetics, etc.), profile of the chemical compounds of the ingredient and bibliographic toxicological information available for the active and its components. The integration and study of all these data allows for a conclusion on the safety of the ingredient. The components of this product have registered adverse effects neither in its described uses nor in the historical marketing of this company. These data and the available toxicological information lead to the conclusion that the use of this product, under the normal conditions of cosmetic use, involves no risk for consumers. This information is based on Provital's current knowledge and experience and Provital has no legal obligation or liability in relation to any damage, loss or offense, including in regard to patent rights. Risks and liabilities arising from the use of this information, the product or its applications are accepted by the user according to current local laws. Provital does not guarantee efficacy experimental results under conditions other than those specified. Provital also reserves the right to make changes to this document due to technical progress or further developments. 5