G BAICAPIL Version: 21-24/AUG/2015

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1 G BAICAPIL Version: 21-24/AUG/ PRODUCT IDENTIFICATION Trade Name: BAICAPIL Manufacturer: PROVITAL Responsible for the Safety Assessment: Lourdes Mayordomo Tf./Fax: / Kind of Raw Material: Active Ingredient Function of the Ingredient (PCPC Inventory): Skin-Conditioning Agents-Miscellaneous, Skin Bleaching Agents, Skin-Conditioning Agent-Humectant Function of the Ingredient (UE Inventory): Emollient, Skin Conditioning, Skin Protecting, Astringent, Humectant, Soothing INCI approved in: Registered in EU, USA, Japan Japanese Name: JCLS: Soy Extract, Wheat Germ Extract, Scutellaria Root Extract Japanese translation available in PCPC. 2. PRODUCT COMPOSITION Components Breakdown (INCI). Including actives, solvents, preservatives, antioxidants and other additives: [EU] CAS EINECS Propanediol % Aqua % Arginine 6-10 % Lactic Acid 5-10 % Glycine Soja Germ Extract 1-5 % Triticum Vulgare Germ Extract 1-5 % Scutellaria Baicalensis Root Extract 0,45-0,75 % Preservatives Sodium Benzoate 0,2-0,3 % Additives Gluconolactone 0,7-0,8 % Calcium Gluconate 0,008-0,012 % PCPC [CTFA] CAS EINECS Propanediol % Water % Arginine 6-10 % Lactic Acid 5-10 % Glycine Soja (Soybean) Germ Extract 1-5 % Triticum Vulgare (Wheat) Germ Extract 1-5 % Scutellaria Baicalensis Root Extract 0,45-0,75 %

2 Preservatives Sodium Benzoate 0,2-0,3 % Additives Gluconolactone 0,7-0,8 % Calcium Gluconate 0,008-0,012 % Impurities: Heavy Metals (as Pb) Pesticides Less than 20 ppm. No data available. Not expected to be found. 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: American Herbal Products Association: Scutellaria baicalensis root - Herbs that can be safely consumed when used appropriately (Class 1) The following substances are used as Food Additives permitted for human consume by FDA: L-arginine (21CFR ). The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the following ingredients are safe as used as described in this report: Arginine (Final report 09/12 available from CIR). The CIR Final Report on Safety Assessment of Sodium Benzoate (IJT, 20(S3):23-50, 2001, reopened 06/10) exists and includes all the toxicological data. Direct food substances affirmed as generally recognized as safe: Gluconolactone (21CFR ), Calcium gluconate (21CFR ) Classification according to Council of Europe (*): Glycine:3, Triticum:---, Scutellaria:--- *(1)- Non-recommended ingredients (2)-Ingredients which could not be assessed (3) Recommended ingredients Cytotoxicity: BAICAPIL (Cod.73800) at 20%: Neutral Red Release Assay performed using SIRC cell line. Results: CI50>50%, % of mortality at dilution 50% < 20%. Negligible cytotoxicity. Baicalin (RTECS no. LZ ): ICLo macrophage- mouse = mg/l/20h, 20 umol/l/20m; ICLo human - lung = 0.63 mmol/l/24h, mmol/l/24h, mmol/l/48h Skin Irritation: BAICAPIL (Cod.73800): Patch Test on 11 volunteers, occlusive patch for 48 hours. Product tested at 20%. The average irritant score of the product is Under these conditions, the product BAICAPIL can be considered as non-irritant regarding its primary skin tolerance. The antiallergic properties of a standardized aqueous extract of S. baicalensis were evaluated, and the skin toxicity of its dermal application was also determined. The in vivo and in vitro assays were performed by using the ß-hexosaminidase assay in rat basophilic leukemia cells (RBL-2H3) and cutaneous skin reaction in mice ( at doses of 0.5, 1 and 5 %), respectively. In addition, the acute dermal irritation/corrosion test was carried out in rabbits, and the skin sensitization test was conducted by Buhler's method in guinea pigs to estimate the safety of the extract for topical application. ß-Hexosaminidase release in RBL-2H3 was markedly decreased following treatment with the extract. It also ameliorated antigen-induced ear swelling compared with the control group in mice. In the toxicological studies, it did not induce any dermal irritation/corrosion in rabbits or skin sensitization in guinea pigs. (Planta Med 2013; 79(11): ) Propanediol (RTECS no. TY , 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: BAICAPIL (Cod.73800). Marzulli and Maibach Method: Human Repeated Insult Patch Test. Study in 50 2

3 volunteers, product tested at 20%. No irritation or sensitisation reaction was registered. Under the test conditions, the product BAICAPIL can be considered Non-irritating and No-sensitizing. The antiallergic properties of a standardized aqueous extract of S. baicalensis were evaluated, and the skin toxicity of its dermal application was also determined. The in vivo and in vitro assays were performed by using the ß-hexosaminidase assay in rat basophilic leukemia cells (RBL-2H3) and cutaneous skin reaction in mice ( at doses of 0.5, 1 and 5 %), respectively. In addition, the acute dermal irritation/corrosion test was carried out in rabbits, and the skin sensitization test was conducted by Buhler's method in guinea pigs to estimate the safety of the extract for topical application. ß-Hexosaminidase release in RBL-2H3 was markedly decreased following treatment with the extract. It also ameliorated antigen-induced ear swelling compared with the control group in mice. In the toxicological studies, it did not induce any dermal irritation/corrosion in rabbits or skin sensitization in guinea pigs. (Planta Med 2013; 79(11): ) 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: It was realized a battery of tests to determine the ocular irritation potential of BAICAPIL (Cod.73800) at a concentration of 20%: The Hen's Eggs Test on the Chorioallantoic Membrane (HET-CAM), Mean Irritation Index = 3.0. Bovine Cornea Opacity and Permeability Test (BCOP), Irritation Index at 30 min = 0.5, Irritation Index 4 h = 9.3. Study of cytotoxicity in rabbit corneal fibroblasts (SIRC),Neutral Red Release Assay, IC50> 50%,% of mortality at dilution 50% < 20%. All these results show that the product can be considered Non-Irritant at Ocular level. 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: BAICAPIL (Cod.73800): Genic Mutation Bacteria In Vitro Test (Ames Test), using 5 strains of Salmonella typhimurium (TA1535, TA1537, TA98, TA100 and TA102), both in the presence and absence of metabolic activation system (S-9). The product was tested at five dose levels between 0.05 and 5 ul/plate. No significant increase in the number of revertants was noted in any of the strains. The trial product can be considered as: No mutagenic. Extracts of Scutellariae Radix and its major components, wogonin, baicalin, and baicalein were evaluated in in vivo micronucleous and UDS assay. None of these products induced micronuclei and UDS. It is concluded that these products had no genotoxicity in vivo. (Environmental Mutagen Research 24(1), 1-15, 2002) Mutagenic assay in E.coli uvrb; uvrb umuc;uvrb LexA, strains at a concentration of L-arginine 348 µg/ml, negative results (-S9). Assay in chromatid sisters exchange in human lymphocytes concentration up to 246 µg/ml (3 doses tested), positive results (-S9); this result is considered that is due to a metabolic response to genotoxic response. Assay sister exchange in humans peripheral blood lymphocytes, concentration up to 100 µg/ml, 3 doses tested, negative results (-S9).(RepotThe EFSA Journal (2008) 87,1-46). 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: Crude drug extract from Scutellaria baicalensis (RTECS no. RI ): TDLo p.o. rat = 200 mg/kg Baicalin (RTECS no. LZ ): TDLo p.o. mouse = 15 mg/kg, LD50 i.t. rat = 11g/kg, TDLo i.p. mouse = 50 mg/kg, TDLo i.p. mouse = 100 mg/kg, TDLo oral rat = 40 mg/kg, TDLo s.c. rat = 20 mg/kg, TDLo i.c. rat = ng/kg, TDLo i.c. rat = ng/kg. Several studies of the acute toxicity of various preparations from the root of Scutellaria baicalensis concluded that such preparations have very low toxicity when given orally. (Adverse Effects of Herbal Drugs, vol. 2, pp 291, Springer-Verlag Berlin Heidelberg 1993) Baicalin was reported to have an intraperitoneal LD50 of 3 g/kg in mice. (Adverse Effects of Herbal Drugs, vol. 2, pp 291, Springer-Verlag Berlin Heidelberg 1993) L-Arginine: LD50 oral, rat mg/kg (EFSA Journal (2006) 373,1-48). Propanediol (RTECS no.ty , 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 = mg/kg, dermal in rat LD50 > 4200 mg/kg and inhalation in rat, DL > 5000 mg/m3. (Supplier data) 3

4 Subchronic and chronic toxicity: Glycine max, seed, 40% ethanol dry extract (RTECS nº mc ): TDLo p.o. rat = 40 mg/kg/5d-i. Crude drug extract from Scutellaria baicalensis (RTECS no.ri ): TDLo p.o. rabbit= 175 mg/kg/5d-c, TDLo oral human-man 2 g/kg/11d-i Baicalin (RTECS no. LZ ): TDLo p.o. mouse= 180 mg/kg/12d-i, TDLo i.p. rat = 2.5 mg/kg/5d-i An effective part isolated from Scutellaria baicalensis (RTECS no.lz ): TDLo p.o. mouse= 2350 mg/kg/47d-i Scutellaria baicalensis, extract (RTECS no.vr ): TDLo p.o. mouse= 12 ml/kg/12d, TDLo p.o mouse = 2.1 g/kg/7d-i, TDLo oral mouse = 5000 mg/kg/10d-i 90-day oral toxicity study in rats was realized with a standardized plant composition, with baicalin from the roots of Scutellaria baicalensis and catechin from the Acacia catechu. Four groups of animals (10 males and females per group) of dose levels of 250, 500, and 1000 mg/kg/day, as well as a control (0.5% carboxymethylcellulose) were tested. A dose of 1000 mg/kg/day was identified as the NOAEL in this study. (Food Chem Toxicol. 2010, May; 48(5): ) Arginine (RTECS no. CF ): TDLo p.o. rat = 21 g/kg/1w-i, TDLo p.o. rat= 63 g/kg/3w-i, TDLo i.m. rat= 1400 mg/kg/2w-i, TDLo rat= 21 g/kg/1w-c, TDLo p.o. rat = 14 g/kg/7d-i, TDLo p.o. rabbit = mg/kg/12w-i, TDLo p.o. rat = 2625 mg/kg/21d-i, TDLo p.o. rat = 700 mg/kg/7d-i, TDLo p.o. rat = 700 mg/kg/7d-i, TDLo i.p. mouse = 7 g/kg/13d-i, TDLo p.o. rabbit = mg/kg/16w-c, TDLo p.o. rat = 45 g/kg/20d-i, TDLo man = 903 mg/kg/3w-i, TDLo i.p. rat = mg/kg/10d-i Study of 13 weeks in rats, administration of L-Arginine in diet at concentrations of 0, 1.25, 2.5 y 5%( equal 0,843, 1690 y 3320 mg/kg, bw/day in males and 0, 975, 2000 y 3880 mg/kg, bw /day in females), NOAEL M: 5.0% (3320 mg/kg bw/day) F: 5.0% (3880 mg/kg bw/day).( EFSA Journal (2006) 373, 1-48). 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. ZC ): TDLo p.o. mammal = 1400 mg/kg in female 7 day pre-mating. An aqueous extract of Scutellaria baicalensis administered subcutaneously to female mice for 5 days, did not caused decrease fertility. (Adverse Effects of Herbal Drugs, vol. 2, pp 293, Springer-Verlag Berlin Heidelberg 1993) This study aims to evaluate the effects of S.baicalensis aqueous root extract on embryonic development in mice. Pregnant mice were randomly divided into a four groups. The oral doses were: 2, 8 and 32 g/kg/day from gestation day 6 to15. The parameters evaluated were: live and dead fetuses, resorptions, external and skeletal malformed fetuses, maternal body weight, maternal liver, kidneys, and heart weights. There was no significant difference in fetal parameters among groups. The study concluded that oral administration of the product at or below 32 g/kg/day to mice during organogenesis did not cause significant fetal external or skeletal malformations. However, 32 g/kg/day presented potential maternal toxicity. (Birth Defects Res B Dev Reprod Toxicol. 2009, Apr; 86(2):79-84.) Crude drug extract from Scutellaria baicalensis (RTECS no.ri ): TDLo oral rat = 2750 mg/kg, female 7-17 days after conception. Arginine (RTECS no CF ): TDLo rat = 800 mg/kg, female 8-11 days after conception, TDLo i.p. rat = 40 mg/kg, male 1 day pre-mating 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: It was studied the anticancer in vitro and in vivo activity of Sctuellaria baicalensis on head and neck squamous cell carcinoma (HNSCC). Two human HNSCC cell lines (SCC-25 and KB) and a nontumorigenic cell line (HaCaT) were tested. Scutellaria demonstrated a strong growth inhibition in both tested human HNSCC cell lines and no growth inhibition of HaCaT cells were observed; la IC 50 were 150ug/ml. The in vivo test were performed in mice with inoculation of KB cells and treated with Scutellaria at 75 mg/kg p.o. for 7 weeks. A 66% reduction in tumor mass was observed was observed in nude mice. (J Cancer Research 63, , 2003) Effect of oral administration of methanolic extract from Scutellaria baicalensis root on the development of oxazolone-induced atopic dermatitis-like skin lesions in mice was investigated. Mice were orally administered at 4

5 doses of 250, 500 mg/kg/day for 33 days. The product alleviates atopic dermatitis via the inhibition of mast cells infiltration. (Journal of the Korean Society for Applied Biological Chemistry, 55(2), , 2012) Growth of induced mammary tumors by DMBA in rats was inhibited by feeding rats with ariginine-enriched diet containing 5% of L-arginine. The diet significantly reduced both the rate of tumor induction and the number of tumors induced per rat.(cancer Research , 1975) Arginine: Non-toxic ingestion (Hazardous Substances Databank no.: 1429) 4. ECOLOGICAL DATA Biodegradability: Propanediol: BOD5 = mg/l (Supplier data) L-arginine readily biodegradable (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 > 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. 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

PRONALEN BIO-PROTECT ZNSN

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