green ginseng root

GREEN

Ginseng Root

CIR EXPERT PANEL MEETING

DECEMBER 12-13, 2011

November 11, 2011

MEMORANDUM

To: CIR Expert Panel and Liaisons From: Lillian C. Becker, M.S.

Scientific Analyst and Writer Subject: Draft Report for panax ginseng root and other ginseng root derived ingredients

used in cosmetics The Cosmetic Ingredient Review (CIR) announced the Scientific Literature Review (SLR) for ginseng in June, 2011. Comments and unpublished data have been received from industry and incorporated into the report. This safety assessment only addresses ingredients derived from ginseng root and does not include other plant parts. Ginseng root-derived ingredients have almost 650 uses, so the focus on root-derived deals with most of what is in use. Also, there is confusion enough just dealing with root-derived ingredients. For example, there is some confusion as to whether or not P. ginseng, P. quinquefolius, P. japonicas, and P. pseudoginseng are sources for ingredients used in cosmetics under their own names, all as P. ginseng, or interchangeably under the generic name “ginseng”. There is also speculation that there is no real difference between these plants as regards to cosmetic application. Perhaps because of the potential confusion, standard extracts from both P. ginseng and P. quinquefolium (G115 and CNT-2000) have been developed – standardized by the content of 6 saponins. We have not seen this for other plant-derived ingredients. The Panel should review the Draft Report and decide whether any additional data are needed in order to reach a safety conclusion for panx ginseng root and other ginseng root derived ingredients. Such data needs would be included in an insufficient data announcement. If no additional data are required, then the Panel should reach a tentative conclusion, with a rationale that would be included in the discussion section, and issue a tentative report for public comment.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

History of Panax Ginseng Root June, 2010 – It was announced that ginseng root is on the priority list. June, 2011 – SLR was posted for public comment. July, 2011 – The Council requested that the Draft Report be delayed until December,

2011 so that the use survey may be completed. This request was granted. December, 2011 – The Panel examines the Draft Report.



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Search Strategy for Ginseng Root

Terms USDA National Agriculture Library (6/10011)

ECETOC (1/2011)

SCCP & SCCN (1/2011

IUCLID (1/2011)

IARC (1/2011)

HPVIS (1,2/2011)

Dogpile (1,2/2011)

Gingeng; ginseng AND extraction after 1980

1200+ hits; no hits

0 0 0 0

CAS Nos & INCI names Hits on P. tetra C5-10 & C5-9 acid esters

CAS Nos. A few MSDS



Rep

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Draft Safety Assessment

Panax Ginseng Root-Related Ingredients as Used in Cosmetics

December 13, 2011 All interested persons are provided 60 days from the above date to comment on this Draft Report and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "

[email protected]



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TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................................................................................................................... i

INTRODUCTION ............................................................................................................................................................................................................................. 1

Chemistry .......................................................................................................................................................................................................................................... 1

Definitions.................................................................................................................................................................................................................................... 1

Method of Manufacture ............................................................................................................................................................................................................... 1

Analytical Methods ...................................................................................................................................................................................................................... 2

Impurities ..................................................................................................................................................................................................................................... 2

Physical and Chemical Properties ............................................................................................................................................................................................... 2

Constituents ................................................................................................................................................................................................................................. 2

USE .................................................................................................................................................................................................................................................... 3

Cosmetic ...................................................................................................................................................................................................................................... 3

Non-Cosmetic .............................................................................................................................................................................................................................. 4

TOXICOKINETICS .......................................................................................................................................................................................................................... 4

Absorption, Distribution, Metabolism, and Excretion ................................................................................................................................................................ 4

Dermal/Percutaneous/Inhalation ............................................................................................................................................................................................ 4

Oral/Intravenous/Intraperitoneal ............................................................................................................................................................................................ 4

Cytotoxicity ................................................................................................................................................................................................................................. 5

TOXICOLOGICAL STUDIES ......................................................................................................................................................................................................... 5

Acute Toxicity ............................................................................................................................................................................................................................. 5

Non-Human ............................................................................................................................................................................................................................ 5

Repeated Dose Toxicity ............................................................................................................................................................................................................... 5

Dermal .................................................................................................................................................................................................................................... 5

Oral - Non-Human ................................................................................................................................................................................................................. 5

Inhalation – Non-Human........................................................................................................................................................................................................ 6

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY .......................................................................................................................................................... 6

Genotoxicity ...................................................................................................................................................................................................................................... 6

CARCINOGENICITY ...................................................................................................................................................................................................................... 7

CANCER PREVENTION ................................................................................................................................................................................................................ 7

Irritation and sensitization ................................................................................................................................................................................................................. 7

Irritation ....................................................................................................................................................................................................................................... 7

Dermal-Nonhuman ................................................................................................................................................................................................................. 7

Dermal-Human ....................................................................................................................................................................................................................... 7

Sensitization ................................................................................................................................................................................................................................. 8

Phototoxicity ................................................................................................................................................................................................................................ 8

Clinical Use ....................................................................................................................................................................................................................................... 8

Oral – Human ......................................................................................................................................................................................................................... 8

Case Reports ................................................................................................................................................................................................................................ 9

SUMMARY ...................................................................................................................................................................................................................................... 9

TABLES AND FIGURES .............................................................................................................................................................................................................. 11

REFERENCES ................................................................................................................................................................................................................................ 32



1

INTRODUCTION Panax ginseng C. A. Meyer of the Araliaceae family is also called Chinese ginseng, Manchurian ginseng, or Korean

ginseng.1 It is a perennial herb indigenous to the mountainous forests of North China, Manchuria, and Korea. There are four other closely related plants of the Araliaceae family: Panax quinquefolius L. (American ginseng), Panax japonicus C. A. Meyer (chikusetsu ninjin or Japanese ginseng), and Panax pseudoginseng Wall (notoginseng, San-ch'i ginseng and Hirnalayan ginseng).

Many ginseng-derived materials are used in cosmetics. The majority of uses in cosmetics involve root-derived, as distinct from ingredients derived from other plant parts. This safety assessment focuses on those ginseng-derived ingredients that are derived from the root portion of the plant, and does not address ginseng derived ingredients that are prepared using other plant parts. The ingredients included are:

panax ginseng root extract, hydrolyzed ginseng root, hydrolyzed ginseng root extract, hydrolyzed ginseng saponins, panax ginseng root, panax ginseng root powder, panax ginseng root water,

panax ginseng root oil, panax ginseng root protoplast, panax japonicus root extract, panax notoginseng root, panax notoginseng root powder, and panax quinquefolium root extract.

. The cosmetic functions of these ingredients include: skin-conditioning agents - miscellaneous, fragrance

ingredients, skin conditioning agent-humectant, skin-conditioning agents - emollient, and cosmetic astringent. There is some confusion as to whether or not P. ginseng, P. quinquefolius, P. japonicas, and P. pseudoginseng are

used in cosmetics under their own names, all as P. ginseng, or interchangeably under the generic name “ginseng”. There is also speculation that there is no real difference between these plants in cosmetic application. Until this is cleared up, each of these ingredients will be referred to specifically in this safety assessment.

To address the difficulty in assessing the properties and biological effects of ginseng, standardized extracts of both P. ginseng C.A. Myer (G115) and P. quinquefolium (CNT-2000) have been developed.2 These extracts are standardized by the content of 6 saponins (Rb1, Re, Rc, Rd, Br2, and Rg1) and are used in several of the studies in this report. However, the composition of G115 and CNT-2000 is proprietary information and not available.3

CHEMISTRY

Definitions The names, CAS Registry Nos., functions, and definitions of the ingredients in this safety assessment are listed in Table 1. CAS No. 50647-08-0 is generic and used for several of the ginseng root ingredients, but several ingredients have no Cas Nos. The International Cosmetic Ingredient Dictionary and Handbook defines the terms extract, powder, oil, and water included in the names of these ingredients.4 Extract – Extracts are identified by the source of the material extracted. The INCI names for extracts represent the material extracted from. Many extracts are supplied with the extracting solvent and/or other diluents. Where evidence of isolation is presented, a botanical ingredient may be named as a chemical entity.

The INCI names for plant extracts prepared by solvent extraction are assigned labeling names that identify the name of the plant and the solvent. When the extraction solvent is carbon dioxide, carbon dioxide is not included in the INCI name since it evaporates. Additionally, solvents are not identified in the INCI name in cases where the solvent has been driven off and not present in the final preparation. Powder - The term "powder" is applied to the names for botanical materials that have been mechanically ground, irrespective of particle size. Oil - The term may be used to name non-triglycerides when it applies to ingredients that are commonly recognized (e.g., panax ginseng root oil). Essential oils are prepared by a steam distillation process that yields two distinct fractions, a water-insoluble fraction and a water-soluble fraction. The water-insoluble fraction contains the term oil in the name, eg, panax ginseng root oil. Water - The term refers to the water soluble fraction from the steam distilled plant material and is identified by the term ‘Water” in the INCI name. The term water that refers to the instance wherein the water has come in contact with the named material does not apply here as it is different from an ingredient that is prepared by adding water to a material prepared by solvent extraction; the ingredient would then be called a mixture, eg, water (and) juniperus communis fruit extract.

Method of Manufacture In general, ginseng or ginseng root refers to the dried root of the P. ginseng, P. quinquefolius, P. japonicas, and P.



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pseudoginseng plants. The plants may be from wild or cultivated sources.5 If the root is raw or dried, then it is referred to as “white” ginseng. If it has been steamed and dried before extraction or pulverizing, it is referred to as “red” ginseng because of a change in coloring.6 If it is steamed and dried 9 times, the coloring darkens more and the product is referred to as “black ginseng”.7,8

ROOT EXTRACT - The extraction is performed by percolation with aqueous alcohol solution (60%) and then either concentration under vacuum to dryness or percolation with propylene glycol followed by concentrated under vacuum.9 The solvent for the root extract may be propylene glycol, propylene glycol + water, propylene glycol dicapryylate/dicaprate, butylene glycol, ethanol, ethanol + water, glycerin + water, caprylic/capric triglyceride, or helianthus annuus (sunflower) seed oil.10 One supplier reports “aging” the panax ginseng root in ethanol and butylene glycol (70% aqueous) for 6 weeks before filtering and evaporating the ethanol. This procedure results in a total of 4.61 ± 0.98 mg/g dry weight ginsenosides (2.75 ± 0.7 triol, 1.86 ± 0.3 diol, 0.73 ± 0.11 mg/g diol/triol). One manufacturer reported the extraction process to begin with grinding the whole dried red ginseng and placing the ginseng root into an extraction solvent of ethanol (70%) for 12 h at 20 -25°C.11 The solvent is then filtered and evaporated to remove the ethanol to < 1%. The product is then centrifuged, dried, and sterilized. One manufacturer reported the use of ultrahypothermia biotic extraction techniques to selectively yield ginsenosides.12 However, there is no further explanation about this process. SAPONINS - Saponin glycosides are extractable from the ginseng roots with hot water or alcohols.1

Saponins may be extracted from fresh raw P. quinquefolium root using methanol (30% - 100%) at room temperature, over heat, or under microwave conditions. Each of these conditions gives a different and ratio of saponins (i.e., Re, Fb1, mRb1) in the extract.13 Variation in yield and type of yield also depends on sample size, extraction time, sample to solvent ratio, and solvent concentration. Temperature influences the extraction kinetics, solvents viscosities, extraction efficiencies, and overall recoveries in ultrahigh pressure extraction.14 Using 70% aqueous ethanol at 200 MPa, 60ºC was optimal for saponin yields. Other temperature values led to a decreased yield of saponin compounds.

Analytical Methods Powdered ginseng may be detected by running it on thin-layer chromatography and comparing with a standard preparationunder UV light.7

Impurities

Analysis of a panax ginseng root extract concentrate showed lead, cadmium, and mercury were found at < 0.040, 0.051, and < 0.010 mg/kg, respectively.15 Aflatoxin B1 was measured at < 0.3 μ/lg. and B2, G1, and G2 at < 0.3 p/kg. Analysis of multiple pesticides showed that most of them were not detected except for DDE (0.02 mg/kg), total DDT (0.03 mg/kg), total HCH (0.030 mg/kg), Quintozen (0.020 mg/kg), and Pentachloranilin (0.020 mg/kg). Results of a microbiologic analysis, aerobic bacteria was found at 45000 CFU/g, fungus at 20 CFU/g, and Escherichia coli at <10 CFU/g.

A panax quinquefolium root extract was reported to have 20 ppm of heavy metals and 2 pm of arsenic.11

Ginseng root extract product mixtures may contain low concentrations of preservatives such as 0.5-0.7 % Bactiphen 2506 G (phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben).10

None of 35 fragrance allergens were detected in panax ginseng root extract.12

Physical and Chemical Properties The available physical and chemical properties of ginseng root-derived cosmetic ingredients are provided in Tables 2 and 3. Panax quinquefolium root extract is stable for 2 years in a sealed container.11 This extract was stable at 1%, 2%, and 3% in ethanol at pH 2-10 (time not specified) and at 1%, 3%, and 5% at 40 - 80°C for up to 120 min.

Saponins form colloidal solutions in water which foam upon shaking (frothing) and have a bitter taste.1

Constituents According to the Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants16, the

constituents of ginseng roots include: saponins and sapogenins, carbohydrates, organic acids (including amino acids), non-protein nitrogenous substances, peptides, minerals, and enzymes. The constituents of P. ginseng, P. quinquefolius, P. japonicas, and P. pseudoginseng roots, along with concentration in the plant root, are listed in Tables 4 - 7.

Saponins (or ginsengosides), a sweet-bitter material, usually exist in plants in the form of glycosides known as "saponin glycosides”.1 Saponin glycosides are macromolecules and are composed of a "sugar" (glycone) and a "non-sugar" (aglycone). The aglycone is also called genin. The aglycone of ginseng has been called sapogenin. The chemical structures of some of the saponins in ginseng are shown in Figure 1.

More than 40 different saponins have been identified and isolated from the root of P. ginseng.17 Each saponin has at least 2 (carbon-3 and -20) or 3 (carbon-3, -6 and -20) hydroxyl groups, which are free or bound to monomeric, dimeric, or trimeric sugars. Saponins also exist as stereoisomers depending on the position of hydroxyl group on carbon-20. Based on



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their chemical structures, saponins are generally divided into 2 groups: protopanaxadiols (PPD) and protopanaxatriols (PT). The sugar moities in the PPD group attach to 3-position of a dammarane-type triterpine as in Rb1, Rb2, Rc, Rd, Rg3, Rh2, and Rh3 (Fig. 1A), whereas the sugar moities in the PT group attach to 6-position of dammarane-type triterpine as in Re, Rf, Rg1, Rg2, and Rh1 (Fig. 1B). The pseudoginsenoside F11 belongs to PT group although the alkyl chain at the 20-position is replaced by a tetrahydrofuran ring (Fig. 1D) Analysis of commercially available panax ginseng root preparations (both powder and liquid) vary widely in the amount of saponins (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1).18 Panax ginseng root extract is reported to have a ginsenoside content of 0.2-0.3%.10 The saponins Rg1, Re, Rb1, Rc, Rb2, and Rd make up > 90% of the saponin content of P. ginseng root.19 Fresh roots have yielded higher amounts of panaxatriol (Re +Rf + Rg1 + Rg2 + Rh1; 2.8 mg/g DW) and panaxadiol (Rb1 + Rb2 + Rb3 +Rc +Rd + Rg3; 16 mg/g DW) saponins compared to dried roots and powdered roots.20

There are several chemical differences between P. ginseng and P quinquefolium root. Rf is present in P. ginseng but not P. quinquefolium. The opposite is true for pseudoginsenoside F11.21 Steaming the roots causes chemical degradation and conversion of original saponins to new compounds. Steaming is also associated with a decrease in the polar saponins Rg1, Re, Rb1, Rc, Rb2, Rb3, and Rd and an increase in the less polar Rg2, Rg3, Rg5, Rh2, Rk1, and Rs4.22-24

Table 8 shows the content of some of the saponins in both white (dried, unsteamed) and black (the steaming and drying process repeated 9 times) P. ginseng. The polyphenol content is greater in black ginseng (~ 35 mg/g) than in white ginseng (~ 20 mg/g).8 Table 9 shows a comparison of saponin content by extraction technique.10,12 OTHER GINSENG CONSTITUENTS Carbohydrates were reported to be obtained in the aqueous extract of ginseng root in small amounts, and were present as many different types of sugars or polysaccharide.25-28 The most common mono-sugars (monosaccharides) from ginseng sources were glucose and fructose. Maltose and sucrose were the most common di-sugars (disaccharides). Multi-sugar compounds such as trisaccharides, tetrasaccharides, and oligosaccharides were also found in ginseng root. Ginseng pectin, a crude polysaccharide, was also isolated from ginseng root.

Non-amino organic acids are present in alcohol extracts of ginseng roots. The most common organic acids are citric, fumaric, ketoglutaric, oleic, linoleic, linolenic, maleic, malic, pyruvic, succinic, and tartaric acids.29,30

The free amino acids found in ginseng are arginine, histidine, lysine, leucine, theonine, valine, phenylalanine, alanine, asparatic acid, glutamic acid, glycine, proline, tyrosine, and serine.31 The amount of amino acids in raw P. ginseng roots decreases when the roots are steamed, more so at 120ºC than 100ºC.32

Another nitrogenous substance in ginseng root is choline.33 Constituents reported for specific ingredients are:

PANAX GINSENG ROOT Calculated on the dried material of both raw and steamed roots, Panax ginseng root contains > 0.10% gensenoside

Rg1 and > 0.20% ginsenoside Rb1.7 PANAX GINSENG ROOT POWDER

Calculated on the dried material, Panax ginseng root powder contains > 0.10% gensenoside Rg1 and > 0.20% ginsendoside Rb1.7

The percentage of ginseng saponins from one sample of freeze-dried red ginseng extract powder was ~ 3.3%.34 Ginseng saponins present were Rb1 (15.8%), Rb2 (7.8%), Rc (8.1%), Rd (7.6%), Re (3.2%), Rf (4.7%), Rg1 (1.9%), Rg2 (22.2%), Rg3 (24.2%), Rh1 (4.7%) and other minor saponins. The concentration of saponins in ginseng root ingredients varies with the form. Ranges for food additives were found to be 4% - 8% saponins (calculated as Rg1) and actual root samples vary in their total saponin content from 0.5% - 3% (dry weight).35,36 PANAX GINSENG ROOT OIL

Ginseng oil contains volatile and non-volatile fractions. The low boiling fraction (boils from 71 to 110°C) contains the sesquiterpenes panacene and β-elemene (Figure 2). Panacene gives the characteristic fragrance of ginseng. The high boiling fraction (boils from l20 to 150°C) contains panaxynol.37,38

P. japonicas root oil yields were reported to be 0.451%, suggesting that one would need 15 pounds of root to produce 1 ounce of oil.39

USE

Cosmetic Data on ingredient usage are provided to the Food and Drug Administration (FDA) Voluntary Cosmetic Registration

Program (VCRP) and a survey conducted by the Personal Care Products Council (Council) has collected use concentrations for ingredients in this group.40,41

The total number of uses of panax ginseng root extract was 149 (102 leave-on products, 42 rinse-off products, and 5 diluted products; Table 10) at maximum concentrations of 0.000002% – 0.5% (maximum of 0.5 in leave-on products, 0.3 in rinse off products, and 0.0004% in diluted products). The Council further divided their survey and reported that white panax ginseng root extract is used up to 0.04% in leave-on, 0.0003% in rinse-off, and 0.00009% in diluted products. Red panax ginseng root extract was reported to be used up to 0.003% in both leave-on and rinse-off products.



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Panax ginseng root was reported to be used in 21 cosmetic products (15 leave-on and 6 rinse-off products); there were no use concentrations reported for this ingredient. Panax notoginseng root was reported to be used 0.0004% in rinse off products; there were no uses reported to the FDA for this ingredient. Panax quinquefolium root extract was reported to be used in 467 cosmetic products (317 leave-on, 146 rinse-off, and 4 diluted for bath products) at maximum concentrations of 0.002% in rinse-off products (no concentrations of use were reported for leave-on and diluted products).

There were no uses reported for panax ginseng root powder, hydrolyzed ginseng root, hydrolyzed ginseng root extract, hydrolyzed ginseng saponins, panax ginseng root powder, panax ginseng water, panax ginseng root oil, panax ginseng root protoplasts, panax japanicus root extract, or panax notoginseng root powder.

Non-Cosmetic

Ginseng root is widely used as an herbal medicine for its alleged tonic effect and possible curative and restorative effects.42-54 Modern therapeutic claims suggest that ginseng has beneficial effects on cognitive function, physical and psychomotor performance, immune-modulation, diabetes mellitus, and herpes simplex type-II infections.45,49,50,54-57 However, a systematic review of randomized controlled trials found that the efficacy of ginseng root extract could not be established for any of these effects.58

When used as a dietary supplement, unless otherwise prescribed, the recommended daily dose (taken in the morning) is dried root 0.5–2g by decoction; doses of other preparations would be calculated accordingly.59 Ginseng is often an ingredient in energy drinks.

TOXICOKINETICS

There were no dermal, percutaneous, or inhalation toxicity data discovered for any of the ginseng root-derived ingredients. The saponins were poorly absorbed when orally administered as root extract or as individual components.

Absorption, Distribution, Metabolism, and Excretion In some experiments studying the effects of ginseng, the metabolite of the saponin Rb1, “Compound K” (20-O-b-D-glucopyranosyl-20(S)-protopanaxadiol), is used. Rb1 is poorly absorbed from the gut. Compound K is produced from Rb1 by a stepwise degradation of sugar moieties by intestinal microflora.60-62 Dermal/Percutaneous/Inhalation No data were discovered on the dermal/percutaneous or inhalation absorption of ginseng root-derived ingredients. Oral/Intravenous/Intraperitoneal PANAX GINSENG ROOT

Panax ginseng root (1 to 2 g in capsules; G115) was orally administered to subjects (n = 2) on empty stomachs.63 Blood and urine were sampled before and periodically for up to 24 h after administration and were analyzed for saponins. In the plasma, at ~0.75-3.25 h, Rh1 was detected; ~3.75-5.25 h, hydrated Rh1; ~5.25-8.25 h, Rb1; ~7.5-10.75 h, compound k; ~8-11.75 h, f1/Rh1 (not distinguished between the two); ~8.75-10.25 h, hydrated compound k. In the urine at 0-3 h, Rg1, Rd, Re, Rb2, and Rc were detected. At 3-6 h, Rh1 was detected; 6-12 h, Rb1 and compound k; and at 12-24 h, f1/Rh1 and compound k were detected. GINSENG SAPONINS The absolute bioavailability of Panax saponins were reported to be poor (0.26% - 35%; Table 11).

The poor bioavailability of saponins may be attributable to their breakdown in the gastrointestinal tract, metabolism by intestinal microflora and excretion in bile or urine.64 It is also suggested that low membrane permeability may be an important factor in determining the extent of absorption.

The absolute bioavailability of 25-OH-PPD is 64.8±14.3% (range 44.1–75.9%) which is the highest among the reports on ginseng compounds.65 The higher absolute bioavailability is found in the rats and the author suggests that this can be explained by the deglycosylated mother aglycone structure, lower molecular weight, and higher hydrophobility of 25-OH-PPD compared to saponin Rg3.

The National Toxicology Program reported that the degradation and metabolism of saponins has been studied in animals and in vitro using acids, enzymes, and intestinal bacteria.61,66-69 After oral administration, the protopanaxatriol saponins are hydrolyzed to saponin Rh1 and its hydrated form under acidic conditions similar to gastric fluid. Protopanaxadiol saponins (Rb1) are metabolized to M1 [20-O-B-D-glucopyranosyl-20(S)-protopanaxadiol] or compound-K in rats and humans by intestinal anaerobes via stepwise cleavage of the sugar moieties.67 Strains of the intestinal bacteria Prevotella oris hydrolyze Rb1.70 Protopanaxadiol is formed from Rh2 as a result of deglycosylation by B16 melanoma cells in vitro.71

The absorption of Rb1 from the intestine of rats was low.61 In mice, after an oral dose of Rb1 or M1, a metabolite of protopanaxadiols, the M1 level in the serum gradually increased, peaked at 8 hours after oral administration of Rb1, and decreased with time; intact Rb1 was not detected in the serum.72 Rg1 was rapidly absorbed (30% after 1 hour) and metabolized by mice after oral administration. Mouse urine and feces contained little unchanged Rg1 but did contain high levels of metabolites including Rh1 and saponin Rg1 (protopanaxatriol) showed an extremely short half-life of 27 min after intravenous administration to mini-pigs. In contrast, the protopanaxadiol saponin Rb1 showed a half-life in the β-phase of 16



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hours.73 In several experiments using male New Zealand White rabbits, saponins (A1, Rg1, Rd, Re, Rb2) were administered

by oral, intraperitoneal (ip), and intravenous (iv) routes (Table 12).74 In the oral experiment, no saponins were observed in the plasma, urine, or feces. The authors suggested that this is due to poor absoption in the gastro-intestinal tract, binding within the gastro-intestinal tract, microorganism metabolism, or an unreliable animal model.

In humans, saponins are present in urine after oral ingestion.75,76 About 1.2% of the dose was recovered in 5 days. Generally, saponins are very poorly absorbed following oral administration in vivo.

Cytotoxicity PANAX GINSENG ROOT EXTRACT Panax ginseng root extract (0, 100, 250, 500, 1000 μg/ml in ethanol) was not cytotoxic to human dermal fibroblast cells.77

TOXICOLOGICAL STUDIES The oral LD50 for rats was 750 mg/kg and 200 mg/kg for mice for panax ginseng root. P. ginseng root extract was nontoxic to rats up to 5000 mg/kg/d for up to 105 weeks, up to 5000 mg/kg for life for mice, and 15 mg/kg/d for 90 days for dogs.

Acute Toxicity Non-Human PANAX GINSENG ROOT EXTRACT The LD50 values using rodents for the root itself and for various forms and fractions of panax ginseng root extract administered orally and intraperitoneally (ip) are listed in Table 13.

Repeated Dose Toxicity Dermal In an efficacy test of red panax ginseng root extract concentrate (0.2 ml) and Rg2 (1%; 0.2 ml), the test material was applied to the backs of 5-week-old female C57BL/6 mice after “shav[ing] with hair removal tape” for 14 days. No adverse effects were observed during treatment.11 Oral - Non-Human

Male Wistar rats (n = 5) were orally administered P. ginseng root water extract, heat-treated P. ginseng root water extract, P. quinquefolius root water extract, or heat-treated P. quinquefolius root water extract (0, 100 mg/kg/d) by gavage for 15 days.78 The extracts were heat treated by autoclave at 120ºC for 3 h then placed in an oven at 50ºC for 3 days. Blood and urine were collected. No clinical signs or decreases in renal or hepatic function parameters of the treated rats were observed. F344/N rats (n = 5/sex) were administered P. ginseng root extract (extracted with 80% aqueous ethanol; 0, 125, 250, 500, 1000, or 2000 mg/kg in 0.5% aqueous methylcellulose) by gavage 5 days/week for 16 days.79 All rats survived to the end of the study. Mean body weight gain of 2000 mg/kg males was greater than that of the vehicle controls. There were no chemical-related gross or microscopic findings attributed to the administration of ginseng. B6C3F1 mice (n = 5/sex) were administered P. ginseng root extract (0, 125, 250, 500, 1000, or 2000 mg/kg in 0.5% aqueous methylcellulose) by gavage 5 days per week for 17 days.79 All mice survived to the end of the study. The final mean body weight of 1,000 mg/kg males was significantly less than that of the vehicle controls. There were no statistically significant chemical-related gross or histopathologic changes in dosed mice. Panax ginseng root extract in the form of G115 (0, 1.5, 5, or 15 mg/kg/day) was administered in the feed of Beagle dogs (n = 4/sex) for 90 days. No consistent, dose-response relationship occurred and all values were within normal physiological ranges for Beagle dogs. Gross and microscopic examinations of major organs revealed no morphological or pathological effects. No evidence of toxicity was observed. The highest dose, 15 mg/kg, is approximately twice the recommended dose for humans.80 F344/N rats (n = 10/sex) were administered panax ginseng root extract (0, 1000, ,000, 3000, 4000, or 5000 mg/kg) in sterile water by gavage 5 days/week for 14 weeks.79 All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. No lesions that were observed by gross or histopathologic examination were attributed to the administration of panax ginseng root extract. B6C3F1 mice (n = 10/sex) mice were administered panax ginseng root extract (0, 1000, 2000, 3000, 4000, or 5000 mg/kg) 5 days per week for 14 weeks.79 All mice survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Although sporadic incidences of lesions were observed in the vehicle control and 5,000 mg/kg groups, there were no chemical-related gross or microscopic findings in dosed mice. Rats (n and species not provided) were orally administered panax ginseng root extract (105-210 mg/kg/d) for 25 weeks.81 No toxic effects were observed. No further details on this study were provided. F344/N rats (n = 50/sex) were administered panax ginseng root extract (0, 1250, 2500, or 5000 mg/kg) in sterile water by gavage for 5 days/week for 104-105 weeks.79 Survival of 5000 mg/kg females was statistically significantly less



6

than that of the vehicle controls; however, the deaths were not attributed to the administration of ginseng. Mean body weights of high dose females were less than those of the vehicle controls after week 61 of the study, and mean body weights of other dosed groups of rats were similar to those of the vehicle controls throughout the study. No increases in the incidences of neoplasms or nonneoplastic lesions were attributed to the administration of ginseng. The incidence of mammary gland fibroadenoma was statistically significantly decreased in the high dose females. B6C3F1 mice (n = 50/sex) mice were administered panax ginseng root extract (0, 1250, 2500, or 5000 mg/kg) 5 days/week for 105 weeks.79 Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of dosed mice were similar to those of the vehicle controls. No neoplasms or nonneoplastic lesions were attributed to the administration of ginseng. The incidence of mammary gland fibroadenoma was significantly decreased in the high dose female group. LACa mice (n = 90) were administered panax ginseng root extract (8 mg/kg/d; 40 mg of whole root) in drinking water 1) from 8 weeks of age throughout life, 2) from 52 weeks throughout life, and 3) none.82 There were no differences in mean weights or survival observed in the mice. Increased behavioral responses to mild stress were observed in the treatment groups. Inhalation – Non-Human No data was discovered on the repeated dose inhalation toxicity of ginseng root-derived ingredients. However, a material safety data sheet stated that panax quinquefoium root extract may be irritating or toxic if inhaled.11

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY There were no adverse effects reported in an oral reproductive study at 15 mg/kg/d and one developmental study up

to 20 mg/kg/d panax ginseng root extract using rats. In embryo emersion studies using rats and mice, the total morphological scores of embryos exposed to 30 mg/ml of the saponin Rb1 were reduced. The total morphological scores of rat embryos exposed to 30 mg/ml of the saponin Re were reduced. There were no adverse effects to embryos exposed to Rc. PANAX GINSENG ROOT EXTRACT

There were no adverse effects reported in 2 reproductive/developmental studies of panax ginseng root extract using rats (Table 14).

Subcutaneous administration of a ginseng extract enhanced the mating behavior of male rats.83 The extract further stimulated spermatogenesis in rat, and rabbit testes, and increased the motility and survival of rabbit sperm outside the body.84 SAPONINS In screening tests with whole immersion of embryos, the saponins Rb1 (30-50 µg/ml) and Re (50 µg/ml) yielded changes in morphological scores in rat and mice embryos (Table 15). Rc (5, 50 µg/ml) had no effect on the morphological scores of rat embryos. Saponins (6 mg/2 ml injection; composition not provided) injected into male rats (n = 10; strain not provided) for 7 consecutive days did not increase testosterone levels in the plasma.85

GENOTOXICITY Panax ginseng root extract, up to 75 ppm in feed, did not increase the number of aberrant crypt foci in rat colons.

Panax ginseng root extract, panax ginseng root powder, and panax ginseng quinquefolius root extract were not mutagenic in Ames tests, rec-assay, and microsome reversion assay. Panax ginseng saponins were not mutagentic to S. typhimurium up to 36 mg/ml. PANAX GINSENG ROOT EXTRACT Panax ginseng root extract (0-1 mg/ml) produced inhibitory effects on DNA synthesis/mutagenesis, measured by thymidine incorporation into V79 Chinese hamster lung cells.86 PANAX GINSENG QUINQUEFOLIUS A water extract of P. quinquefolius roots (up to 36 mg/ml) was not mutagenic in Salmonella typhimurium (TM677) with or without metabolic activation.87 In an Ames test of panax ginseng quinquefoius (30% - 70%) using S. typhimurium (strains TA98, TA100) did not demonstrate a potential for mutagenicity.11 PANAX GINSENG ROOT POWDER Dried Panax ginseng root powder dissolved in water (100 mg/ml) were negative in genotoxicity tests using Bacillus subtilis strains H17Rec+ and M45Rec- and in S. typhimurium (TA98, TA100) with or without PCB-induced rat liver S9.88 GINSENG SAPONINS In an assay of the effects of saponins on mitosis, Rg1 stimulated mitosis in the bulb and seedling root tip cells of Allium cepa . It was the most effective at 0.002 - 0.006 mg/ml. In contrast, saponin Rb1 (0 - 0.01 mg/ml) inhibited mitosis in the same cell line in a dose dependent manner.89 An aqueous and a 1-butanol extract containing saponins from P. quinquefolius roots (up to 36 mg/ml) was not mutagenic in Salmonella typhimurium (TM677) with or without metabolic activation.87



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CARCINOGENICITY Panax ginseng root extract (0, 50, 75 ppm in feed) did not increase the number of aberrant crypt foci in rat colons (n = 10).90

CANCER PREVENTION

P. ginseng root extract suppressed TPA-induced skin tumor promotion in mice. Antitumor effects have not been established in humans. PANAX GINSENG ROOT A number of in vitro and in vivo studies indicate that ginseng root and its extracts or its purified constituents have antitumor properties.45,53,91-93 For example, the topical application of either the methanol extract of heat-processed P. ginseng or the purified saponin Rg3 to the shaved backs of female ICR mice suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion.91 P. ginseng appears to inhibit tumor development, especially tumor promotion and progression, through anti-inflammatory, antioxidant, and apoptotic mechanisms involving changes in gene expression.51,92,94-

96 Other pertinent mechanisms under investigation involve the potential for ginseng and its constituents to influence immuno-surveillance and neurotransmission.92 However, the evidence for the antitumor effects of ginseng in humans is not conclusive, and no clinical trials have yet confirmed the efficacy of ginseng treatments in cancer patients.

IRRITATION AND SENSITIZATION Irritation

Panax ginseng root extract was not irritating to mice up to 0.1% or humans up to 100 mg/ml. Falcarinol at 0.5 mg, Rb1 at 0.05%, Re at 0.05%, Rh1 at 0.05%, Rg5 at 0.05%, Rh3 at 0.05%, Rh2 at 0.1%, Rh3 at 0.1%, Rg3 at 0.05%, Rf at 0.05%, and compound K at 0.05% were not dermally irritating to mice. Dermal-Nonhuman PANAX GINSENG ROOT EXTRACT Inclusion of panax ginseng root extract (red; 0.1%) in a sermal test of 2-chloro-1,3,5-trinitrobenzene (TNCB) reduced the appearance of severe erythema/hemorrhage, edema, excoriation/erosion and scaling/dryness compared to TCNB in verhicle alone using female NC/Nga mice (n = 7).97 In an ear thickness test, panax ginseng root extract (red; 0.02%) applied to oxazolone-induced dermatitis on female ICR mice did not cause irritation and reduced the irritation effects of the oxazolone.98 GINSENGS SAPONINS AND OTHER CONSTITUENTS Saponin Rb1 (0.05%) or the metabolite compound K (0.2, 0.05%) was administered to the ears of ICR mice (n = not provided) after sensitization to oxazolone.99 Then a total of 20 μl of 1% oxazolone in a mixture of acetone and olive oil (4 :1) was applied to both sides of the mouse ear every 3 days starting 7 days after sensitization. Ear thickness was measured. Seventy-two h after each application of the oxazolone, Rb1 was topically applied in a total volume of 20 μl to both sides of the ear 30 min before and 3 h after each application of oxazolone. There were no irritation effects reported for Rb1 or compound K. The above experiment was repeated with saponin Re (0.01%, 0.05%) and its mebabolite Rh1 (0.01%, 0.05%) on 12-O-tetradecanoylphorbol- and oxazolone-induced dermatitis.100 There were no irritation effects reported for either compound. The above experiment was repeated with saponin Rg5 (0.05%) and its mebabolite Rh3 (0.02%, 0.05%) on oxazolone-induced dermatitis.21 There were no irritation effects reported for either compound. Inclusion of panax ginseng root extract constituents Rh2 (0.1%) and Rh3 (0.1%) in a sermal test of TNCB reduced the appearance of severe erythema/hemorrhage, edema, excoriation/erosion and scaling/dryness compared to TCNB in verhicle alone using female NC/Nga mice (n = 7).97 In an ear thickness test, panax ginseng root extract saponins Rg3(0.02%, 0.05%), Rf (0.02%, 0.05%), and Rh2 (0.05%[sic] applied to oxazolone-induced dermatitis on female ICR mice did not cause irritation and reduced the effects of the oxazolone.98 Dermal-Human PANAX GINSENG ROOT EXTRACT In a human patch test (n = 30) of panax ginseng root extract (0, 1, 10, 20, 100 mg/ml in petrolatum), the patch was left in place for 48 h. There were no reactions observed at 1 and 24 h after removal.77 In a human patch test (n = 30) of panax ginseng root extract (concentration not provided, assumed to be 100%), The patch was left in place for 48 h. There were no reactions observed at 30 min and 24 and 48 h after removal.12 In a human efficacy test (n = 15) of panax ginseng root extract (concentration not provided, assumed to be 100%), there were no adverse effects reported at the time of treatment and at 4 and 8 weeks.12 GINSENGS SAPONINS AND OTHER CONSTITUENTS Falcarinol (0.5 mg in ethanol) strongly aggravated histamine induced edema, but did not induce edema by itself, in skin prick tests (n = 4).101 The test was repeated on 2 of the subjects 1 week later with the same results.



8

Sensitization In a human repeated insult patch test (HRIPT; n = 99) of a cuticle serum containing Panax ginseng root extract (1%) resulted in no dermal irritation or allergic contact sensitization.102 In a HRIPT (n = 10) of panax quinquefoium root extract (10% aqueous), there were no signs of irritation or sensitization observed.11

Phototoxicity Panax ginseng root extract was not phototoxic in C. albicans assays up to 100%. Panax ginseng root extract was

not phototoxic to mice when administered dermally up to 0.2 mg/cm2, intraperitoneally at 25 mg/kg, or orally up to 2.25%. Dermally applied Rb1 was not phototoxic to mice up to 1 ng/mouse. PANAX GINSENG ROOT EXTRACT An ethanol extract of P. ginseng (100%; 30 μl) was not photoxic to Candida albicans exposed to 50 J/cm2 UVA radiation. Using the same treatment, hemolysis was observed in red blood cells.103

HaCaT cell were treated with ginseng root extract (0, 1%) for 24 h and were then exposed to UVB radiation (time not provided). At 24 h after UVB irradiation, survival was increased in the treatment group compared to controls.12

Panax ginseng root extract (10 pg/, 100 ng/mouse) or 3% vitamin C (1.5 mg/mouse) were applied topically to the dorsal region of each male albino hairless HOS: HR-1 mice (n = 6) daily for 12 weeks.104 The mice were exposed to 36 mJ/cm2 UVB radiation, which was subsequently increased to 54 mJ/cm2 at weeks 1–4, 72 mJ/cm2 at weeks 4–7, 108 mJ/cm2 at weeks 7–10, and finally to 122 mJ/cm2 at weeks 10–12. No phototoxic effects observed.

The backs of SKH-1 hairless mice (n = 20) were exposed to UV lamps (80% UVB and 20% UVA).34 The mice were exposed to 90 mJ/cm2 3 times/week. The dose was increased by 10%/week until the dose reached 175 mJ/cm2 at 22 weeks. The experimental groups were (a) untreated control, (b) UV-irradiated control (i.p. with saline vehicle), (c) red ginseng root extract (25 mg/kg) i.p. in combination with UV-irradiation, (d) UV-irradiated control (topical administration with cream base vehicle), (e) red ginseng root extract topical (0.2%) administration in combination with UV-irradiation. The i.p. injections were administered 24 h prior to each UV irradiation. Topical creams (0.2 mg/cm2) were applied at least 15 min before UV irradiation. Topical and i.p. treatment with red ginseng root extract reduced the incidence of tumors, reduced turmor multiplicity, and delayed the time of first turmor appearance. Panax ginseng root extract (0, 0.5%, 2.5%) was administered in the feed of male SKH-1 hairless mice.105 The backs of the mice were exposed to ∼30% UVA; they were also exposed to UVB radiation 3 times a week for 12 weeks. The amount of irradiation was progressively increased from 100 mJ/cm2 per exposure at week 1 (1 minimal erythematous dose = 100 mJ/cm2) to 400 mJ/cm2 at week 7. The authors reported a reduction in UV-induced wrinkle formation in both groups fed red ginseng extract compared with animals exposed to UV radiationwithout ginseng in their feed. No adverse effects were reported in the animals administered ginseng alone. SAPONINS

Panax ginseng root extract saponin Rb1 (100 fg,10 pg, and 1 ng/mouse) or 3% vitamin C (1.5 mg/mouse) were applied topically to the dorsal region of male albino hairless HOS: HR-1 mouse (n = 6) every day for 12 weeks.104 The mice were exposed to 36 mJ/cm2 UVB, which was subsequently increased to 54 mJ/cm2

at weeks 1–4, 72 mJ/cm2 at weeks 4–7,

108 mJ/cm2 at weeks 7–10, and finally to 122 mJ/cm2

at weeks 10–12. There were no phototoxic effects observed.

CLINICAL USE The characteristic signs and symptoms of overexposure to ginseng, “ginseng abuse syndrome” include morning diarrhea, skin eruptions, sleeplessness, nervousness, and hypertension. Oral – Human In multiple studies of orally administered panax ginseng root extract to test for efficacy for treatment or prevention of various maladies, the adverse effects attributable to the extract in placebo-controlled (150 - 11250 mg; Tables 16 and 17), comparative (200 mg; Table 18), and uncontrolled (105 - 4500 mg; Table 19) studies included flu/cold, headache, gastrointestinal complaints, nausea, diarrhea, and vomiting.55 GINSENG ABUSE SYNDROME

The characteristic signs and symptoms of overexposure to ginseng, “ginseng abuse syndrome” include morning diarrhea, skin eruptions, sleeplessness, nervousness, and hypertension.106

In a study of ginseng abuse syndrome, subjects (n = 133) using ginseng regularly for at least one month were surveyed.107 It was not possible to differentiate those using Panax ginseng and subjects using Siberian ginseng. Ginseng doses varied from 8 - 10 g 3 times a day for capsules; 0.5 - 3 g twice a day for roots, 1 - 2 g 3 times a day for ground powders, and 2.5 - 5 ml a day for extracts. Most subjects experienced central nervous system excitation and arousal. Fourteen subjects who ingested Panax ginseng roots experienced hypertension, nervousness, sleeplessness, skin eruptions, and morning diarrhea; 5 had edema; 10 became euphoric, restless, agitated, and insomniac. Ten subjects taking high doses (15 g) felt depersonalization and confusion. The average daily dose of ginseng roots was 3 g for persons experiencing ginseng abuse syndrome. One user reported that abrupt withdrawal precipitated hypotension, weakness, and tremor. Ginseng abuse syndrome appeared periodically in the first 12 months of ginseng use but was rarely reported in follow-up



9

examinations at 18 and 24 months. The author suggested that, taken together, these effects mimicked those of corticosteroid poisoning, strongly suggesting a steroidal mechanism of action.

Case Reports

PANAX GINSENG ROOT EXTRACT Panax ginseng root extract was believed to cause mastalgia with diffuse mammary nodularity and vaginal bleeding

in postmenopausal women.106 A 44-year old woman using ginseng face cream developed an episode of postmenopausal bleeding. Her follicular

stimulating hormone (FSH) level was 36 mIU; one month after she stopped using the face cream, her FSH level increased to 70 mIU. When she began using a measured amount of face cream, her FSH level decreased, and she had another bleeding episode. An endometrial biopsy specimen showed a disordered proliferative pattern, and she stopped using the ginseng cream. One year later, she had not experienced any further bleeding.108

A 39-year old man developed hypertension, dizziness, and inability to concentrate during long-term ingestion of ginseng. He stopped taking ginseng, became normotensive within 5 days, and remained normotensive without treatment; after 3 months his symptoms resolved.109

A 28-year old woman developed a severe headache after ingesting a large quantity of ethanol-extracted ginseng. Cerebral angiograms showed a "beading" appearance in the anterior and posterior cerebral and superior cerebellar arteries, consistent with cerebral arteritis.110. PANAX GINSENG ROOT POWDER A woman (70-years-old) presented with swollen, tender breasts with diffuse nodularity.111 She had been consuming ginseng powder for 3 weeks. The symptoms ceased after she stopped using ginseng. She began consuming the ginseng 2 more times with the same result. The authors suggest ginseng may have mild hormonal activity.

SUMMARY This is a safety assessment of the ginseng root-derived cosmetic ingredients: panax ginseng root extract, hydrolyzed ginseng root, hydrolyzed ginseng root extract, hydrolyzed ginseng saponins, panax ginseng root, panax ginseng root powder, panax ginseng root water, panax ginseng root oil, panax ginseng root protoplast, panax japonicus root extract, panax notoginseng root, panax notoginseng root powder, and panax quinquefolium root extract. The cosmetic uses of these ingredients include: skin-conditioning agents - miscellaneous, fragrance ingredients, skin-conditioning agents - miscellaneous, skin conditioning agent-humectant, skin-conditioning agents - emollient, and cosmetic astringent. If the root is raw or dried, it is referred to as “white” ginseng. If it has been steamed and dried before extraction or pulverizing, it is referred to as “red” ginseng because of a change in coloring. If it is steamed and dried 9 times, the coloring darkens more and the product is referred to as “black ginseng”. The constituents of ginseng roots include: saponins and sapogenins, carbohydrates, organic acids (including amino acids), non-protein nitrogenous substances, peptides, minerals, and enzymes.

The total number of uses of panax ginseng root extract was 51 (27 leave-on and 14 rinse-off products; Table 8). Panax ginseng root was reported to be used in 21 cosmetic products (17 leave-on and 4 rinse-off). Panax quinquefolium root extract was reported to be used in 467 cosmetic products (317 leave-on and 150 rinse-off). There were no uses reported for panax ginseng root powder, hydrolyzed ginseng root, hydrolyzed ginseng root extract, hydrolyzed ginseng saponins, panax ginseng root powder, panax ginseng water, panax ginseng root oil, panax ginseng root protoplasts, panax japanicus root extract, panax nonotginseng root extract, or panax notoginseng root powder.

There were no dermal, percutaneous, or inhalation toxicokinetic data discovered. The saponins were poorly absorbed when orally administered as root extract or as individual components.

Panax ginseng root extract was not cytotoxic to human dermal fibroblasts up to 1000 μg/ml. The acute oral LD50 for rats was 750 mg/kg and 200 mg/kg for mice for panax ginseng root, but no data were available for extracts. Oral administration of P. ginseng root extract was nontoxic to rats up to 5000 mg/kg/d for up to 105 weeks, up to 5000 mg/kg for life for mice, and 15 mg/kg/d for 90 days for dogs.

There were no adverse effects reported in an oral reproductive study at 15 mg/kg/d and one developmental study up to 20 mg/kg/d panax ginseng root extract using rats. In embryo emersion studies using rats and mice, the total morphological scores of embryos exposed to 30 mg/ml of the saponin Rb1 were reduced. The total morphological scores of rat embryos exposed to 30 mg/ml of the saponin Re were reduced. There were no adverse effects to embryos exposed to Rc.

Panax ginseng root extract, up to 75 ppm in feed, did not increase the number of aberrant crypt foci in rat colons. Panax ginseng root extract, panax ginseng root powder, and panax ginseng quinquefolius root extract were not mutagenic in ames tests. Panax ginseng saponins were not mutagentic to S. typhimurium up to 36 mg/ml.

P. ginseng root extract suppressed TPA-induced skin tumor promotion in mice. Antitumor effects have not been established in humans.

Panax ginseng root extract was not irritating to mice up to 0.1% or humans up to 100 mg/ml. Falcarinol at 0.5 mg, Rb1 at 0.05%, Re at 0.05%, Rh1 at 0.05%, Rg5 at 0.05%, Rh3 at 0.05%, Rh2 at 0.1%, Rh3 at 0.1%, Rg3 at 0.05%, Rf at



10

0.05%, and compound K at 0.05% were not dermally irritating to mice. Panax ginseng root extract was not phototoxic in C. albicans assays up to 100%. Panax ginseng root extract was not

phototoxic to mice when administered dermally up to 0.2 mg/cm2, intraperitoneally at 25 mg/kg, or orally up to 2.25%. Dermally applied Rb1 was not phototoxic to mice up to 1 ng/mouse.

In multiple studies of orally administered panax ginseng root extract to test for efficacy for treatment or prevention of various maladies, the adverse effects attributable to the extract in humans included flu/cold, headache, gastrointestinal complaints, nausea, diarrhea, and vomiting. The characteristic signs and symptoms of overexposure to ginseng, “ginseng abuse syndrome”, include morning diarrhea, skin eruptions, sleeplessness, nervousness, and hypertension.



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TABLES AND FIGURES

Figure. 1. Structure of selected saponins. A. protopanaxadiols (PPD). B. protopanaxatriols (PT). C. derivatives of PPD and PT. D. saponins. Glc, β-D-glucose; Rha, α-L-rhamnose; Ara(p), αL-arabinose(pyranose); Ara(f), α-L-arabinose(furanose);

Xyl, β-D-xylose; GlcUA, β-D-glucuronic acid; mal, malonyl; Ac, acetyl.17

Figure 2. A) Panacene and B) β-elemene.

CH3

O C

O

H

C C

H

R

R

R

H

Br

CH2

CH2

CH2

BA

CH3

CH3

R

SS

CH3



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Table 1. The names, CAS Registry Nos. functions, and definitions of the ginseng root-derived ingredients in this safety assessment.4

Ingredient CAS No. Function(s) Definition Panax Ginseng Root Extract

50647-08-0 Skin-conditioning agents - miscellaneous

The extract of the roots of Panax ginseng.

Hydrolyzed Ginseng Root Skin-conditioning agents - miscellaneous

The hydrolysate of Panax Ginseng Root (q.v.) derived by acid, enzyme or other method of hydrolysis.

Hydrolyzed Ginseng Root Extract

Skin-conditioning agents - miscellaneous

The hydrolysate of Panax Ginseng Root Extract (q.v.) derived by acid, enzyme or other method of hydrolysis.

Panax Ginseng Root 50647-08-0 (generic)


The roots of P. ginseng

Panax Ginseng Root Powder

50647-08-0 (generic)


The powder obtained from the dried, ground roots of P. ginseng.

Panax Ginseng Root Water

50647-08-0 (generic)

Fragrance ingredients An aqueous solution of the steam distillate obtained from the roots of P. ginseng.

Panax Ginseng Root Oil 50647-08-0 (generic)


The volatile oil obtained from the roots of P. ginseng.

Panax ginseng root protoplasts

Skin conditioning agent-humectant

The protoplasts derived from the roots of P. ginseng.

Panax japonicus root extract


The extract of the roots and rhizomes of P. japonicus

Hydrolyzed Ginseng Saponins

Skin-conditioning agents - emollient

The saponins derived from ginseng that are hydrolyzed by acid, enzyme or other method of hydrolysis.

Panax notoginseng root extract

Skin conditioning agent-humectant

The extract of the roots of P. notoginseng

Panax notoginseng root powder


The powder obtained from the dried, ground roots of P. notoginseng.

Panax quinquefolium root extract

90045-38-8 Cosmetic astringent The extract of the roots of P. quinquefolium.

Table 2. Physical and chemical properties of ginseng root ingredients. Property Value Reference

Panax ginseng root extract Color Pale yellow 11 Odor Typical 11 pH (10% solution) 4.0-7.0 11 Specific gravity 0.980-1.100 11

Hydrolyzed ginseng root Odor Characteristic 112

Hydrolyzed ginseng root extract None found

Hydrolyzed ginseng saponins None found

Panax ginseng root Physical Form Powder 112,113 Color Yellowish white 112,113

Panax ginseng root powder Physical form Powder 112

Color Light yellowish wite to light yellowish brown

112

Odor Characteristic 112

Panax ginseng root water None found

Panax ginseng root oil Physical Form Oil 39 Color Pale white 39

Panax ginseng root protoplast None found

Panax japonicas root extract None found



13

Panax nonoginseng root None found

Panax notoginseng root powder None found

Panax quinquefolium root extract Liquid 11 Color Pale yellow 11 Odor Typical 11 Specific gravity 0.980-1.100 11 Solubility in water Soluble 11 pH (10% aqueous) 4.0-7.0 11

Table 3. Physical and chemical properties of saponins. Property Value Reference

Ro Physical Form Needles 114 Color Colorless 114 Melting Point oC 239-241 114

Rb1 Physical Form Powder 114 Color White 114 Melting Point oC 197-198 114

Rb2 Physical Form Powder 114 Color White 114 Melting Point oC 200-203 114

Rc Physical Form Powder 114 Color White 114 Melting Point oC 199-201 114

Rd Physical Form Powder 114 Color White 114 Melting Point oC 206-209 114

Re Physical Form Needles 115 Color Colorless 115 Melting Point oC 201-203 115

Rf Physical Form Powder 115 Color White 115 Melting Point oC 197-198 115

Rg1 Physical Form Powder 115 Color Colorless 115 Boiling Point oC 194-196 115

Rg2 Physical Form Powder 115 Color Colorless 115 Melting Point oC 187-189 115



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Table 4. Chemical constituents of Panax ginseng root.16

Constituent Part Lo (ppm) Hi (ppm)

(-)-BETA-PANASINSENE Root Essent. Oil 1,8-CINEOL Root Essent. Oil

10-ACETYL-PANAXYTRIOL Root

1-O-ALPHA-GLUCOSIDE-PROPAN-2-ON-1-OL Root 20-(S)-DIHYDRO-PROTOPANAXATRIONE Root

20(S)-PROTOPANAXADIOL-3-O-BETA-D-GLUCOPYRANOSIDE

Root 10

20-GLUCOSYL-GINSENOSIDE Root 50

20(R)-GINSENOSIDE-RH-1 Rhizome 2-5-DIMETHYL-TRIDECANE Root Essent. Oil

2-6-DIETHYL-PYRAZINE Root

2-6-DITERT-BUTYL-4-METHYL-PHENOL Root Essent. Oil 14000 2-ETHYL-5-METHYL-PYRAZINE Root

2-ETHYL-6-METHYL-PYRAZINE Root

2-GLUCOGINSENOSIDE-RF Root 50 2-ISO-BUTYL-3-METHOXY-PYRAZINE Root

2-ISO-PROPYL-3-METHOXY-PYRAZINE Root 2-ISO-PROPYL-5-METHYL-ANISOLE Root

2-METHYL-HEXANOIC-ACID-EHTYL-ESTER Root

2-METHYL-TETRADECANE Root Essent. Oil 29000 2-SEC-BUTYL-3-METHOXY-PYRAZINE Root

3-9-10-TRIACETOXY-HEPTADECA-1-16-DIENE-4-6-DIYNE

Root

3-ISO-PROPYL-2-METHOXY-5-METHYL-PYRAZINE Root

3-SEC-BUTYL-2-METHOXY-5-METHYL-PYRAZINE Root 4-METHYL-THIAZOLE-5-ETHANOL Root

4-OXY-OCT-6-ENOIC-ACID-METHYL-ESTER Root

5-ETHYL-2-3-DIMETHYL-PYRAZINE Root 9-10-EPOXY-HEPTADEC-1-16-DIENE-4-6-DIYN-3-ONE Root

9-10-EPOXY-HEPTADECA-1-16-DIENE-4-6-DIYN Root

ACETYL-PANAXYDOL Root 2.1 ADENINE Root

ADENOSINE Root 90

ADENOSINE Rhizome ADENYL-CYCLASE Root

ALANINE Root

ALLO-AROMADENDRENE Root Essent. Oil ALPHA-AMYLASE Root

ALPHA-FRUCTOSE Root ALPHA-GAMMA-DIPALMITIN Root

ALPHA-GLUCOSE Root

ALPHA-GUAIENE Root ALPHA-GUAIENE Root Essent. Oil 40000

ALPHA-HUMULENE Root Essent. Oil

ALPHA-MALTOSE Root ALPHA-MALTOSYL-BETA-D-FRUCTOFURANOSIDE Root

ALPHA-NEOCLOVENE Root Essent. Oil

ALPHA-PANASINSENE Root 17.6 ALPHA-PANASINSENE Root Essent. Oil

ALPHA-PHELLANDRENE Root

ALPHA-PHELLANDRENE Root Essent. Oil ALPHA-PINENE Root

ALPHA-PINENE Root Essent. Oil

ALPHA-PYRROLIDONE Root ALPHA-SANTALENE Root Essent. Oil

ALPHA-SELINENE Root Essent. Oil

ALUMINUM Root 5 22 AMINO-ACIDS Root

ARACHIDIC ACID Root



15



ARGININE Root AROMADENDRENE Root Essent. Oil

ARSENIC Root

ASCORBIC-ACID Root 0 ASH Root 10600 50000

ASPARTASE Root

ASPARTIC-ACID Root BEHENIC-ACID Root

BENZYL-BETA-PRIMEVEROSIDE Root 47

BETA-AMYLASE Root BETA-BISABOLENE Root Essent. Oil

BETA-CAROTENE Root

BETA-ELEMENE Root BETA-ELEMENE Root Essent. Oil 150000

BETA-EUDESMOL Root Essent. Oil BETA-FARNESENE Root

BETA-FARNESENE Root Essent. Oil 85000

BETA-FRUCTOSE Root BETA-GLUCOSE Root

BETA-GUAIENE Root Essent. Oil

BETA-GURJUNENE Root Essent. Oil 60000 10,503 BETA-HUMULENE Root Essent. Oil

BETA-MAALIENE Root

BETA-MALTOSE Root BETA-NEOCLOVENE Root Essent. Oil

BETA-PANASINSENE Root 10.2

BETA-PATCHOULENE Root BETA-PATCHOULENE Root Essent. Oil

BETA-SELINENE Root Essent. Oil 80000

BETA-SITOSTEROL Root BETA-SITOSTEROL Rhizome

BETA-SITOSTEROL-3-O-BETA-D-GLUCOSIDE Root

BICYCLOGERMACRENE Root BIOTIN Root 0.9

CAFFEIC ACID Root

CALCIUM Root 611 4140 CAMPESTEROL Root

CAMPESTEROL-6'-LINOLENYLGLUCOSIDE Root CAMPESTEROL-6'-LINOLYLGLUCOSIDE Root

CAMPESTEROL-6'-OLEYLGLUCOSIDE Root

CAMPESTEROL-6'-PALMITYLGLUCOSIDE Root CAMPESTEROL-6'-STEARYLGLUCOSIDE Root

CAPROIC-ACID-BUTYL-ESTER Root

CAPROIC-ACID-PROPYL-ESTER Root CARBOHYDRATES Root 176808 834000

CARBON-DISULFIDE Root 1500

CARYOPHYLLENE Root Essent. Oil CARYOPHYLLENE ALCOHOL Root Essent. Oil

CATALASE Root

CELLULASE Root CEREBROSIDE Root

CHOLINE Root 1000 2000

CHROMIUM Root 0.2 1.1 CHROMIUM Root 1.1

CIS-CARYOPHYLLENE Root Essent. Oil

CITRAL Root CITRAL Root Essent. Oil

CITRIC-ACID Root

COBALT Root 0.7 3.1



16



COBALT Root 3.1 COPPER Root 17

CYSTEINE Root

CYSTINE Root DAUCOSTERINE Root

DAUCOSTEROL Root

DAUCOSTEROL Rhizome DELTA-CADINENE Root

DENSICHINE Root

D-FRUCTOSE Root D-GLUCOSE Root

DIGLYCOSYL DIGLYCERIDE Root

DI-ISO-PROPYL-SULFIDE Root DISACCHARIDES Root 33000

D-SUCROSE Root ELEMENE Root

EO Root 100 500

EPSILON MUUROLENE Root Essent. Oil EREMOPHILENE Root Essent. Oil 23000

ERUCIC-ACID Root

ESTRADIOL Root ESTRIOL Root

ESTRONE Root

EUGENOL Root Essent. Oil FALCARINOL Root 0.9 310

FALCARINOL Rhizome

FAT Root 3752 17700 FERULIC-ACID Root

FIBER(CRUDE) Root 72000

FIBER(DIETARY) Root 301000 FLUORIDE Root 26.3

FOLIC-ACID Root

FRUCTOSE Root 200 6000 FUMARIC-ACID Root

GADOLEIC-ACID Root

GALACTOSE Root GALANIN Root

GAMMA AMINOBUTYRIC ACID Root GAMMA-ELEMENE Root Essent. Oil 60000 100000

GAMMA-PATCHOULENE Root Essent. Oil

GAMMA-SELINENE Root Essent. Oil GE Root

GENSENOSIDE RD [sic] Root

GENTISIC-ACID Root GERMANIUM Root 0.12 320

GINSENAN-PA Root 235

GINSENAN-PB Root 170 GINSENAN-S-I-A Root 106.6

GINSENAN-S-II-A Root 90

GINSENG-POLYPEPTIDE Root GINSENG-POLYPEPTIDE-GPP Root

GINSENOL Root 9.6

GINSENOSIDE Root 47000 GINSENOSIDE-K Root

GINSENOSIDE-NG-R-2 Root

GINSENOSIDE-RA Root 100 300 GINSENOSIDE-RA-1 Root 100 300

GINSENOSIDE-RA-2 Root 300

GINSENOSIDE-RA-3 Root 50



17



GINSENOSIDE-RA-O Root GINSENOSIDE-RB Root 11300 40000

GINSENOSIDE-RB Rhizome

GINSENOSIDE-RB-1 Root 1700 83000 GINSENOSIDE-RB-1 Rhizome 8800 14,000

GINSENOSIDE-RB-1 Root Bark

GINSENOSIDE-RB-2 Root 100 23000 GINSENOSIDE-RB-2 Root Bark

GINSENOSIDE-RB-2 Rhizome 4500 5700

GINSENOSIDE-RB-2-C Root GINSENOSIDE-RB-3 Root 50

GINSENOSIDE-RB-C Root 14000

GINSENOSIDE-RB-C Root Bark 24000 GINSENOSIDE-RB-GROUP Root

GINSENOSIDE-RC Root 500 25000 GINSENOSIDE-RC Root Bark

GINSENOSIDE-RC Rhizome 4700

GINSENOSIDE-RC-2 Root GINSENOSIDE-RD Root 380 21200

GINSENOSIDE-RD Root Bark

GINSENOSIDE-RD Rhizome 700 1600 GINSENOSIDE-RD-2 Root

GINSENOSIDE-RE Root 680 84800

GINSENOSIDE-RE Rhizome 4700 5700 GINSENOSIDE-RE-2 Root

GINSENOSIDE-RE-3 Root

GINSENOSIDE-RF Root 200 9200 GINSENOSIDE-RF Rhizome 1500

GINSENOSIDE-RG Root 4600 16300

GINSENOSIDE-RG Root Bark 34000 GINSENOSIDE-RG-1 Root 320 58400

GINSENOSIDE-RG-1 Root Bark

GINSENOSIDE-RG-1 Rhizome 3800 4500 GINSENOSIDE-RG-2 Root 100 26700

GINSENOSIDE-RG-2 Rhizome

GINSENOSIDE-RG-3 Root 3 30 GINSENOSIDE-RH Root

GINSENOSIDE-RH1 Root 15 GINSENOSIDE-RH-2 Root

GINSENOSIDE-R-O Root 100 11000

GINSENOSIDE-R-O Rhizome 18,000 34,000 GINSENOSIDES Root 10720 30000

GINSENOSIDE-Z-R-1 Root

GINSENOYNE-A Root 12.8 GINSENOYNE-A-LINOLEATE Root 2.8

GINSENOYNE-B Root 1.5

GINSENOYNE-C Root 1.1 GINSENOYNE-D Root 7.1

GINSENOYNE-E Root 7.1

GINSENOYNE-F Root 2.6 GINSENOYNE-G Root 0.176

GINSENOYNE-H Root 1.47

GINSENOYNE-I Root 2.6 GINSENOYNE-J Root 3.5

GINSENOYNE-K Root 14.1

GINSENOYNES Root GLUCOSE Root 100 9000

GLUTAMIC-ACID Root

GLY-ARG-GAMMA-GLU-VAL-NH2 Root



18



GLYCINE Root GLYCO-CHENODEOXYCHOLIC-ACID Root

GLYCOCHOLIC-ACID Root

GLYCO-DEOXY-CHOLIC-ACID Root GOMSEMPSODE-RB-2 Root

GUANINE Root

GUM Root 27560 130000 HARMAN Root

HENEICOSANOIC-ACID Root

HEPTADEC-1-EN-4,6-DIYN-3,9,10-TRIOL Root HEPTADEC-1-EN-4,6-DIYNE-3,9,10-TRIOL Root

HEPTADEC-1-EN-4,6-DIYNE-3,9-DIOL Root 150

HEPTADECA-1-4-DIENE-6-8-DIYNE-3-10-DIOL Root HEPTADECA-1-8-DIENE-4-6-DIYN-3-10-DIOL Root

HEPTADECA-1-8-DIENE-4-6-DIYN-10-OL-3-ONE Root HEPTADECA-1-8-DIENE-4-6-DIYN-3-10-DIONE Root

HEPTADECA-1-8-DIENE-4-6-DIYNE-3-10-DIOL Root 14.6

HEPTADECA-1-9-DIENE-4-6-DIYN-3-OL Root HEPTADECA-1-EN-4,6-DIYN-3,9-DIOL Root 150

HEPTADECA-1-ENE-4-6-DIYNE-3-9-10-TRIOL Root 1.5

HEPTADECA-1-TRANS-8-DIENE-4-6-DIYNE-3-10-DIOL Root 5.2 HEPTADECAN-1-OL Root Essent. Oil 19000

HEPTADECAN-2-ONE Root Essent. Oil 43000

HEPTADECANOIC-ACID Root HISTIDINE Root 20

HUMULENE Root Essent. Oil 24000

INVERTASE Root IRON Root 180

ISO-BUTYL-PROPIONATE Root

ISOLEUCINE Root ISO-PROPYL-PROPIONATE Root

KARUSAN-A Root

KARUSAN-B Root KARUSAN-C Root

KARUSAN-D Root

KARUSAN-E Root KETOGLUTARIC ACID Root

KILOCALORIES Root 2740 LEUCINE Root

LIGNOCERIC ACID Root

LIGUSTRAZINE Root LIMONENE Root

LIMONENE Root Essent. Oil

LINALOOL Root Essent. Oil LINOLEIC ACID Root 140

LINOLEIN Root

LINOLENIC ACID Root LYSINE Root

LYSOPHOSPHATIDYLCHOLINE Root

LYSOPHOSPHATIDYL-INOSITOL Root MAGNESIUM Root 102 1950

MALEIC ACID Root

MALIC ACID Root MALONYL-GINSENOSIDE-RB-1 Root 2730 13000

MALONYL-GINSENOSIDE-RB-1 Rhizome 6900 13,000

MALONYL-GINSENOSIDE-RB-2 Root 1370 11000 MALONYL-GINSENOSIDE-RB-2 Rhizome 4000 4200

MALONYL-GINSENOSIDE-RC Root 1000 8400

MALONYL-GINSENOSIDE-RC Rhizome 3400 3500



19



MALONYL-GINSENOSIDE-RD Root 400 1200 MALONYL-GINSENOSIDE-RD Rhizome

MALTOL Root

MALTOSE Root 5100 199600 MANGANESE Root 0.4 180

MANNITOL Root

MAYURONE Root Essent. Oil METHIONINE Root

MOLYBDENUM Root

MONOSACCHARIDES Root 15000 MYRISTIC-ACID Root

N-9-FORMYL-HARMAN Root 0.1

NERVONIC ACID Root N-FORMYL-HARMAN Root

NIACIN Root 17 80 NICOTINAMIDE Root

NICOTINIC ACID Root

N-NONACOSANE Root N-NONACOSANE Rhizome

NORHARMAN Root

NOTOGINSENOSIDE-R-1 Root 20 N-PENTADECANE Root Essent. Oil 18000

O-ALPHA-D-GLUCOPYRANOSYL...FRUCTOFURANOSIDE

Root

O-ALPHA-D-GLUCOPYRANOSYL...GLUCOPYRANOSE Root

OLEANOLIC ACID Root 150 700 OLEIC ACID Root

OXALIC ACID ETHYL ESTER Root

PALMITIC-ACID Root Essent. Oil 86000 PALMITOLEIC-ACID Root

PANACENE Root

PANASINSANOL-A Root 2.3 PANASINSANOL-B Root 12.5

PANAXACOL Root

PANAXADIOL Root 700 6500 PANAXAN-A Root

PANAXAN-B Root PANAXAN-C Root

PANAXAN-D Root

PANAXAN-E Root PANAXAN-F Root

PANAXAN-G Root

PANAXAN-H Root PANAXAN-I Root

PANAXAN-J Root

PANAXAN-K Root PANAXAN-L Root

PANAXAN-M Root

PANAXAN-N Root PANAXAN-O Root

PANAXAN-P Root

PANAXAN-Q Root PANAXAN-R Root

PANAXAN-S Root

PANAXAN-T Root PANAXAN-U Root

PANAXATRIOL Root 700 7700

PANAXATRIOL-GLYCOSIDE Root PANAX-GINSENG-20(S)-PROSAPOGENIN Root



20



PANAX-GINSENG-GENIN-F-1 Root PANAX-GINSENG-GENIN-F-2 Root

PANAX-GINSENG-GENIN-F-4 Root

PANAX-GINSENG-GLYCOPROTEIN Root PANAX-GINSENG-GLYCOSIDE-P-1 Root

PANAX-GINSENG-LIPOLYTIC-PEPTIDE Root

PANAX-GINSENG-POLYACETYLENE-C Root PANAX-GINSENG-POLYACETYLENE-D Root

PANAX-GINSENG-POLYACETYLENE-E Root

PANAX-GINSENG-POLYACETYLENE-F Root PANAX-GINSENG-POLYACETYLENE-G Root

PANAX-GINSENG-PROTEIN Root

PANAX GLYCOPROTEIN Root PANAXIC ACID Root

PANAXIN Root PANAXOSIDE-A Root

PANAXOSIDE-A-PROGENIN-I Root

PANAXOSIDE-B Root PANAXOSIDE-C Root

PANAXOSIDE-D Root

PANAXOSIDE-E Root PANAXOSIDE-F Root

PANAX-POLYPEPTIDE Root

PANAX-POLYPHENOLIC-PERMETHYL-ETHER Root PANAX-POLYSACCHARIDE Root 30000 40000

PANAX-POLYSACCHARIDE-GH-1 Root

PANAX-POLYSACCHARIDE-GL-4 Root PANAX-POLYSACCHARIDE-GL-4-II-B-1-II Root

PANAX-PROTEIN Root

PANAX-SAPONIN-A Root PANAX-SAPONIN-C Root

PANAXYDOL Root 357.1 440

PANAXYDOL-CHLOROHYDRIN Root 13.5 PANAXYDOL-LINOLEATE Root 8.1

PANAXYNE Root

PANAXYNE-EPOXIDE Root 1.8 9 PANAXYNOL Root

PANAXYNOL-LINOLEATE Root 1.3 PANAXYTRIOL Root 14.2 250

PANTOTHENIC-ACID Root 6.6

PATCHOULENE Root Essent. Oil 20000 P-COUMARIC-ACID Root

PECTIN Root

PENTADECANOIC ACID Root PERLARGONIDIN-3-O-BETA-D-GLUCOSIDE Root

PERLOLYRINE Root 1.6

PHENOLASE Root PHENYLALANINE Root

PHOSPHATIDIC-ACID Root

PHOSPHATIDYL-CHOLINE Root PHOSPHATIDYL-ETHANOLAMINE Root

PHOSPHATIDYL-GLYCEROL Root

PHOSPHATIDYL-INOSITOL Root PHOSPHORUS Root 112 528

P-HYDROXYCINNAMIC-ACID Root 26

POLYACETYLENES Root POLYSACCHARIDE Root

POLYSACCHARIDE Rhizome

POLYSACCHARIDE-SA Root



21



POLYSACCHARIDE-SB Root POTASSIUM Root 515 10700

PROLINE Root

PRO-RENIN Root PROTEIN Root 23108 109000

PROTOPANAXADIOL Root

PROTOPANAXADIOL-GLYCOSIDES Root PUTRESCINE Root

PYROGLUTAMIC-ACID Root

PYRUVIC ACID Root QUINQUENOSIDE-R-1 Root 20

RHAMNOSE Root

RIBOFLAVIN Root 0.4 1.8 SALICYLIC-ACID Root 3.4

SAPONIN-II Root SAPONIN-III Root

SAPONIN-IV Root

SAPONINS Root 20000 SAPONIN-V Root

SELENIUM Root 0.5 2.5

SELINA-4(14),7(11)-DIENE Root Essent. Oil SENECRASSIDIOL Root

SERINE Root

SESQUITERPENEDIOL Root SILICON Root

SITOSTEROL-6'-LINOLENYLGLUCOSIDE Root

SITOSTEROL-6'-LINOLYLGLUCOSIDE Root SITOSTEROL-6'-OLEYLGLUCOSIDE Root

SITOSTEROL-6'-PALMITYLGLUCOSIDE Root

SITOSTEROL-6'-STEARYLGLUCOSIDE Root SODIUM Root 5 209

SPERMIDINE Root

SPINACINE Root 33.3 STARCH Root 25440 320000

STARCH Rhizome

STEARIC ACID Root STIGMASTEROL Root

STIGMASTEROL-6'-LINOLENYLGLUCOSIDE Root STIGMASTEROL-6'-LINOLYLGLUCOSIDE Root

STIGMASTEROL-6'-OLEYLGLUCOSIDE Root

STIGMASTEROL-6'-PALMITYLGLUCOSIDE Root STIGMASTEROL-6'-STEARYLGLUCOSIDE Root

SUCCINIC ACID Root

SUCROSE Root 1300 226000 SUCROSE Rhizome

SUGARS Root 19080 90000

SUPEROXIDE DISMUTASE Root TARTARIC-ACID Root

TERPINEOL Root

TERPINEOL Root Essent. Oil THIAMINE Root 0.4 1.7

THREONINE Root

THUJ-4(10)-ENE Root TIN Root 3.4 16

TRACE-ELEMENTS Root

TRANS-BETA-FARNESENE Root Essent. Oil 80000 TRANS-CARYOPHYLLENE Root Essent. Oil

TRICOSANOIC-ACID Root

TRIMETHYL-PYRAZINE Root



22



TRIPALMITIN Root TYROSINE Root

URACIL Root

URIDINE Root VALINE Root

VANILLIC-ACID Root 55

VITAMIN-B12 Root WATER Root 788000

XYLOSE Root

ZINC Root 27

Table 5. Chemical constituents of P. quinquefolius root.16

Constituent Plant Part Lo (ppm) Hi (ppm)1-2-9-10-DIEPOXY-3-OXO-HEPTADECA-4-6-DIYNE

Root 1.7

1-HYDROXY-9-10-EPOXY-C-OXO-HEPTADECA-4-6-DIYNE

Root 7.1

2-PHENYL-DODECANE Root Essent. Oil 41500 3-PHENYL-DODECANE Root Essent. Oil 16700 3-PHENYL-UNDECANE Root Essent. Oil 16700 4-PHENYL-DODECANE Root Essent. Oil 15600 6(R),7(S)-EPOXY-TETRADECA-1,3-DIYNE Root 6-7-EPOXY-TETRADECA-1-3-DIEN Root 2.8 8-ACETOXY-9,10-EPOXYHEPTADECA-4,6-DIYN-1-EN-3-OL

Root 2.2

ACETYL-PANAXYDOL Root 2.8 ALPHA-CARYOPHYLLENE-ALCOHOL Root Essent. Oil 1457 23135 ALPHA-CURCUMENE Root Essent. Oil 1626 8677 ALPHA-ELEMENE Root Essent. Oil 3352 19550 ALPHA-FRUCTOSE Root ALPHA-GLUCOSE Root ALPHA-MALTOSE Root ALPHA-MUUROLENE Root Essent. Oil 2007 9855 AMINO-ACIDS Root BETA-BISABOLENE Root Essent. Oil 6251 58670 BETA-CUBEBENE Root Essent. Oil 997 13216 BETA-FARNESENE Root Essent. Oil 260500 BETA-FRUCTOSE Root BETA-GLUCOSE Root BETA-GURJUNENE Root Essent. Oil 4908 78900 BETA-MAALIENE Root Essent. Oil 4938 6134 BETA-MALTOSE Root BETA-N-OXALO-L-ALPHA-BETA-DIAMINOPROPIONIC-ACID

Root 200

BETA-SITOSTEROL Root CAPROIC-ACID Root Essent. Oil 28600 CARYOPHYLLENE Root Essent. Oil 8670 CIS-BETA-FARNESENE Root Essent. Oil 4961 5279 DIBUTYL-PHTHALATE Root Essent. Oil 9860 29274 D-SUCROSE Root ELEMOL Root Essent. Oil 2959 14637 EO Root FALCALINOL Root 558.3 FRUCTOSE Root 3400 GALACTOSE Root GINSENOSIDE-A-1 Root GINSENOSIDE-F2 Root 180 GINSENOSIDE-FRC Root GINSENOSIDE-RB-1 Rhizome GINSENOSIDE-RB-1 Root 270 20900 GINSENOSIDE-RB-2 Rhizome GINSENOSIDE-RB-2 Root 200 1000 GINSENOSIDE-RB-3 Root 300 GINSENOSIDE-RC Rhizome GINSENOSIDE-RC Root 630 3100



23

Table 5. Chemical constituents of P. quinquefolius root.16 Constituent Plant Part Lo (ppm) Hi (ppm)GINSENOSIDE-RD Rhizome GINSENOSIDE-RD Root 950 7700 GINSENOSIDE-RD-1 Root 3400 3700 GINSENOSIDE-RE Root 200 13800 GINSENOSIDE-RE-2 Root GINSENOSIDE-RE-3 Root GINSENOSIDE-RF Root GINSENOSIDE-RG Root GINSENOSIDE-RG-1 Rhizome GINSENOSIDE-RG-1 Root 300 8600 GINSENOSIDE-RG-2 Root 80 GINSENOSIDE-RG-3 Root GINSENOSIDE-RH1 Rhizome 9800 GINSENOSIDE-RH1 Root GINSENOSIDE-RH-2 Rhizome 18600 GINSENOSIDE-RH-2 Root GINSENOSIDE-R-O Rhizome GINSENOSIDE-R-O Root 700 1000 GINSENOSIDES Root 24400 38800 GINSENOYNE-G Root 5.7 GLUCOSE Root 3200 GUAIOL Root Essent. Oil 4649 11276 GYPENOSIDE-F-11 Root GYPENOSIDE-XVII Root 300 HEPTADECA-1-8-DIENE-4-6-DIYNE-3-10-DIOL

Root 15

LEDOL Root Essent. Oil 6831 7680 MALONYL-GINSENOSIDE-RB-1 Rhizome MALONYL-GINSENOSIDE-RB-1 Root MALONYL-GINSENOSIDE-RB-2 Rhizome MALONYL-GINSENOSIDE-RB-2 Root MALONYL-GINSENOSIDE-RC Rhizome MALONYL-GINSENOSIDE-RC Root MALONYL-GINSENOSIDE-RD Rhizome MALONYL-GINSENOSIDE-RD Root MALTOSE Root 3800 MYRISTIC-ACID Root N-HEXADECANE Root Essent. Oil 88900 NONADECADIENOIC-ACID-METHYL-ESTER

Root Essent. Oil 27682 37935

OCTADECADIENOIC-ACID-METHYL-ESTER

Root Essent. Oil 13701 56439

OLEANOLIC-ACID Root 600 980 OLEIC-ACID Root PALMITIC-ACID Root PALMITIC-ACID Root Essent. Oil 6543 41917 PALMITIC-ACID-ETHYL-ESTER Root Essent. Oil 35913 73504 PALMITIC-ACID-METHYL-ESTER Root Essent. Oil 16744 63486 PANAQUILIN-E-1 Root PANAQUILIN-G-2 Root PANAXADIOL Root 3100 9600 PANAXAN-A Root PANAXAN-B Root PANAXAN-C Root PANAXAN-D Root PANAXAN-E Root PANAXATRIOL Root 1500 12540 PANAX-POLYACETYLENE-PQ-1 Root 75.8 PANAX-POLYACETYLENE-PQ-2 Root 6.6 PANAX-POLYACETYLENE-PQ-3 Root 29.1 PANAX-PROTEIN Root PANAXYDOL Root 950 PANAXYTRIOL Root 59.1 PROTEIN Root 80600 102500 PSEUDO-GINSENOSIDE-F-11 Root 70 400 PULEGONE Root Essent. Oil 260500 QUINQUEFOLAN-A Root QUINQUEFOLAN-B Root QUINQUEFOLAN-C Root QUINQUENOSIDE-R-1 Root 100



24

Table 5. Chemical constituents of P. quinquefolius root.16 Constituent Plant Part Lo (ppm) Hi (ppm)SAPONINS Root STIGMASTEROL Root SUCROSE Root 39000 158600 SUPEROXIDE-DISMUTASE Root TRANS-BETA-FARNESENE Root Essent. Oil 9768 63517 XYLOSE Root

Table 6. Chemical constituents of P. japonicus root.16 Constituent Part Lo (ppm) Hi (ppm) Arabinose Rhizome Beta sitosterol Rhizome Calcium Rhizome 7000 Campesterol Rhizome Campesterol-6’-linolenylglucoside Rhizome Campesterol-6’-linoylglucoside Rhizome Campesterol-6’-oleylglucoside Rhizome Campesterol-6’-palmitylglucoside Rhizome Campesterol-6’-stearylglucoside Rhizome Chikusetsusaponin-I-A Rhizome Chikusetsusaponin-I-B Rhizome Chikusetsusaponin-III Rhizome Chikusetsusaponin-IV Rhizome Chikusetsusaponin-IV-A Rhizome 1900 Copper Rhizome 6 Ginsenoside-R-O Rhizome Ginsenoside-RD Rhizome 6700 Ginsenoside-RG-2 Rhizome Glucose Rhizome Glucuronic acid Rhizome Iron Rhizome 360 Magnesium Rhizome 2400 Majonoside-R1 Rhizome 700 Majonoside-R2 Rhizome 1100 Manganese Rhizome 43 Notoginsenoside-R2 Rhizome 300 Oleanolic acid Rhizome Panatoxin Rhizome Potassium Rhizome 11000 Saponins Rhizome 70000 Sitosetrol-6’-stearylglucoside Rhizome Sitosetrol-6’-linolenylglucoside Rhizome Sitosetrol-6’-linolylglucoside Rhizome Sitosetrol-6’-oleylglucoside Rhizome Sodium Rhizome 499 Stigmasterol-6’-linolenylglucoside Rhizome Stigmasterol-6’-linolylglucoside Rhizome Stigmasterol-6’-oleylglucoside Rhizome Stigmasterol-6’-palmitylglucoside Rhizome Stigmasterol-6’-stearylglucoside Rhizome Zinc Rhizome 20



25

Table 7. Chemical constituents of P. pseudoginseng root.16 Constituent Plant Part Lo (ppm) Hi (ppm) (20)-Protopanoxadiol Root (20)-Protopanoxatiiol Root Beta sitosterol Root Daucosterol Root Ginsenoside RA Root Ginsenoside RA Root Ginsenoside RB Root Ginsenoside RB-1 Root Ginsenoside RB-2 Root Ginsenoside RE Root Ginsenoside RG-1 Root Ginsenoside RG-2 Root Ginsenosides Root 87000 Notogenisnosides Root Panaxynal Root Quercetin Root

Table 8. Comparison of saponin content between white (dried, unsteamed) and black (steamed and dried 9 times) ginseng extract.8

Saponin White ginseng extract (mg/g) Black ginseng extract (mg/g) Rg1 7.81 ± 4.83 Not detected Re 9.30 ± 0.88 Not detected Rh1 0.74 ± 0.31 0.67 ± 0.15 Rb1 14.14 ± 1.35 2.96 ± 1.60 Rc 12.62 ± 3.02 1.61 ± 0.71 Rb2 6.97 ± 1.48 0.63 ± 0.21 Rd 2.88 ± 1.37 0.53 ± 0.44 Rg3(R) Not detected 5.80 ± 1.42 Rg3(S) Not detected 1.97 ± 0.53 Total 54.45 ± 5.08 14.17 ± 4.33

Table 9. Comparison of saponin content by extraction technique.10,12 Saponin Content (%)

3 batches of hydro-glycolic extract Ultrahypothermia biotic extract Rg1 0.004-0.02 4.17 Re Below 0.031 18.99 Rf NR 1.87 Rb1 0.05-0.06 34.49 Rg2 NR 2.30 Rh1 NR 13.31 Rc Below 0.021 - Rb2 0.02-0.04 5.08 Rb3 NR 3.37 Rd Below 0.021 14.89 Rg3 NR - Rh2 NR 1.52 1 Detection limit. NR – Not reported



26

Table 10. Current frequency and concentration of use according to duration and type of exposure provided in 2011.40,41 There was no use reported for panax ginseng root powder, hydrolyzed ginseng root, hydrolyzed ginseng

root extract, hydrolyzed ginseng saponins, panax ginseng root powder, panax ginseng water, panax ginseng root oil, panax ginseng root protoplasts, panax japanicus root extract, panax nonotginseng root extract, or panax notoginseng

root powder. The Council also conducted a survey of use by white and red ginseng root extract.

Use type Uses

Maximum Concentration

(%) Uses


(%) Uses


(%) Uses


(%)

Panax ginseng root extract1 Panax ginseng root Panax notoginseng root Panax quinquefolium root

extract Total/range 149 0.000002-0.5 21 NR NR 0.0004 467 0.0005-0.002

Duration of use Leave-on 102 0.000002-0.5 15 NR NR NR 317 NR Rinse-off 42 0.00000-0.3 6 NR NR 0.0004 146 0.0005-0.002

Diluted for (bath) use

5 0.00004-0.0004

NR NR NR NR 4 NR

Exposure type Eye area 7 0.00001-0.1 2 NR NR NR 32 NR

Incidental ingestion

NR 0.0001-0.1 NR NR NR 0.0004 9 NR

Incidental Inhalation-sprays

9 0.00005-0.1 2 NR NR NR 17 NR

Incidental inhalation-powders

3 0.0004-0.01 NR NR NR NR 8 NR

Dermal contact 123 0.000003-0.5 17 NR NR NR 350 0.002 Deodorant (underarm)

NR 0.02 2 NR NR NR 2 NR

Hair-noncoloring 26 0.000002-0.32 4 NR NR NR 98 0.0005 Hair-coloring NR 0.0002-0.005 NR NR NR NR 7 NR

Nail NR 0.00001-0.1 NR NR NR NR 2 NR Mucous

Membrane 14 0.00004-0.1 1 NR NR 0.0004 43 0.0005-0.002

Baby NR NR NR NR NR NR 1 NR

White Panax ginseng root

extract Red Panax ginseng root

extract

Total/range NS 0.00009-0.04 NS 0.00004-0.003 Duration of use

Leave-on NS 0.0003-0.04 NS 0.00004-0.003 Rinse-off NS 0.0003 NS 0.003

Diluted for (bath) use

NS 0.00009 NS NR

Exposure type Eye area NS 0.002 NS NR

Incidental ingestion

NS NR NS NR

Incidental Inhalation-sprays

NS NR NS 0.00004

Incidental inhalation-powders

NS 0.0003 NS NR

Dermal contact NS 0.00009-0.04 NS 0.00004-0.003 Deodorant (underarm)

NS NR NS NR

Hair-noncoloring NS 0.0003 NS 0.003 Hair-coloring NS NR NS NR

Nail NS NR NS NR Mucous

Membrane NS 0.00009 NS NR

Baby NS NR NS NR 1 The VCRP listed Panax ginseng root extract and ginseng extract as separate ingredients. These were combined under Panax ginseng root extract. 2 0.3% in a rinse-off non-coloring other hair preparation. NR – None reported. NS – Not surveyed. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses.



27

Table 11. Pharmacokinetic studies of selected saponins in rats, dogs or human plasma (after Lu et al 2009)17

Saponin Species model, route Dosage Absolute

bioavailability Reference

25-OH-PPD Rat, oral 10 mg/kg 64.8% 65 Rh2 Rat, oral 100 mg/kg 0.25% 116 Rh1, Rg1 Rat, i.v., or i.g. 100 mg/kg 1.33% 117 20(R)-, 20(S)-Rg2 Rat, i.v 25 mg/kg - 118 Rd Human, in vivo 10 mg/kg - 119 R1, Rg1, Rd, Re Rat, oral 10 mg/kg 9.29%, 6.06%, 2.36%,

7.06% and 1.18%120,121

Rd Dog, i.v., oral 2 mg/kg (oral) 0.2 mg/kg (i.v)

0.26% 122

Rg Rat, oral, in vivo 50 mg/kg 1.52%–6.60% 64 Rg3 Rat, oral 50 mg/kg 2.63 123,124 Multiple Rat, oral 300 mg/kg - 121

Rg1, Rb1 Rat, oral 50 mg/kg 18.4% (Rg1) 4.35% (Rb1)

125

Compound K Rat, oral 20 mg/kg 35.0% 126 i.v.: intravenous administration; i.g.: intragastric gavage.

Table 12. Pharmacokinetic parameters of saponins administered to rabbits.74 Saponin Dose (Exposure route) t1/2 (min) t1/2 abs (min) f (%) Semi-purified A1 500mg in 10% ethanol (iv) 68.8 - 39 Semi-purified A1 500mg in 10% ethanol (iv) 79.9 - 68 Semi-purified A1 500mg in 10% ethanol (iv) 136 - 79 A1 500 mg in propylene glycol/ethanol/NaCl (ip) 25.3 9.90 39 A1 500 mg in propylene glycol/ethanol/NaCl (iv) 59.9 - - A1 250 mg in 10% ethanol (iv) 20.2 - 44 A1 500 mg in 10% ethanol (ip) 104 11.3 68 Semipurified A2 500 mg in 10% ethanol (ip) 24.7 363 61 Semipurified A2 500 mg in 10% ethanol (iv) 69.5 - 61 B2 500 mg in 10% ethanol (iv) 49.8 - 17 B2 500 mg in 10% ethanol (ip) 69.9 324 18 C 250 mg in 10% ethanol (iv) 478 - 41 C 500 mg in 10% ethanol (ip) 412 318 41 t1/2 = elimination half life t1/2abs = absorption half life f = fraction excreted unchanged in the urine

Table 13. Acute toxicity of various forms of ginseng.127 Compound Species Exposure route LD50 (mg/kg) Panax ginseng root Rat Oral 750 Panax ginseng root Mouse Oral 200 Panax ginseng root Mouse ip 54 Ginseng root extract Mouse ip 545 Saponin No. 3 Mouse ip 910 Ginseng, saponin extract Mouse ip 637 Panabolide (TRIS-buffer extract of P. ginseng)

Rat Oral > 12,000

Panabolide (TRIS-buffer extract of P. ginseng)

Rat ip 550


Mouse Oral >2500


Mouse ip >1050



28

Table 14. Reproductive and developmental studies of panax ginseng root extract. Species (n) Dose Details Results Reference

White Wistar rats (10) 20 mg/kg Days 6-15 of gestation by gavage

No signs of toxicity or behavior changes. No differences between controls and treatment group for embryo and fetal abnormalities.

128

Sprague-Dawley Rats (15) 0, 1.5, 5, 15 mg/kg/d in corn

oil mixed in feed

Mated after 3 weeks treatment; females continued treatment

through gestation; at weaning, F1 started on treatment feed and

mated at 13 weeks; F2 raised to 21 days. All rats killed and

necropsied.

F1 males and females had no treatment-related effects (i.e., body weight, feed consumption, hematology, clinical chemistry, ophthalmic, necropsy). Necropsy of F0 and F2 rats were unremarkable.

129

Table 15. Reproductive and developmental studies of saponins. Species Dose Details Results Reference

Rb1

Sprague-Dawley rats (27, 29, 25)

0, 5, 15, 30, 40, 50 μg/ml

9-day-old embryos were extracted from womb and cultured in equal volumes of rat serum and Dulbecco's modified Eagle's medium; penicillin; and streptomycin sulfate with Rb1. Embryos were examined after 48 h. Mean yolk sac diameter and crown-rump length were measured. Embryonic morphologies were given a numerical score (of 0-5) to 17 morphological features depending on their stage of development. Only viable embryos were included.

There were no morphological changes at 5 and 15 µg/ml. There were morphological changes to the flexon, forelimb, and hindlimb in the 30 µg/ml group with a lower total morphological score compared to controls. There were additional morphological changes to the heart and eye in the 40 µg/ml group. There was additional morphological changes to the CRL and somite number. There were no effects to the yolk sac diameter. Authors concluded teratogenic effect on rat embryos.

130

ICR mice (20-21) 0, 5, 15, 30, 40, 50 μg/ml

Same as above

There were no morphological changes at 5 and 15 µg/ml except for yolk sac diamenter in the later. There were morphological changes to the yolk sac diameter and circulation, midbrain, forebrain optic system, and total score in the 30 and 40 µg/ml groups with a lower total morphological score compared to controls. There were additional morphological changes to the CRL, head length, somite number, allantosis, flexon, brachial arch, forelimb bud, and hindlimb bud in the 50 µg/ml group. There was additional morphological changes to the CRL and somite number. There were no effects to the yolk sac diameter. Authors concluded teratogenic effect on rat embryos.

131

Rc

Rats (23-25) 0, 5, 50 μg/ml Same as above

There were no differences in yolk sac diameter, CRL, number of somites, and total morphological score among control and embryos exposed to 5.0 and 50.0 µg/ml Rc

132

Re

Rats (23-25) 0, 5, 50 μg/ml Same as above

Embryos exposed to 50.0g/ml Re had lower morphological scores for all parameters measured (see above) compared to controls. There was no difference between embryos exposed to 5.0 g/ml Re and controls.

132

CRL – crown-rump length



29

Table 16. Reported effects in studies comparing ginseng and placebos (after Coon & Ernst 200255).

Patient Population

n Preparation &

daily dose Duration

Reported effects

Reference Ginseng Placebo Post-menopausal women

384 G115® 200mg 16wk 7 SAEs and 124 AEs Most frequent: flu/cold (36), headache (10), gastrointestinal (13)

9 SAEs and 133 AEs Most frequent: flu/cold (36), headache (10), gastrointestinal (13). Most frequent: flu/cold (35), headache (9), gastrointestinal (22)

133

Healthy men 36 G115® 200 and 400 mg

8 weeks Diarrhea (3) None reported 134

Healthy Volunteers

83 G115® 200mg 4 mo Nausea (1) Nausea, dizziness, headache, stomach problems (5)

135

Healthy Volunteers

227 G115® 200mg 12 weeks Nausea, vomiting, anxiety, insomnia, epigastralgia (10)

Insomnia (1) 136

Healthy Volunteers

28 G115® 200mg 3 weeks Diarrhea (2) – no treatment group specified

137

Patients with psycho-asthenic syndromes

60 G115® [dose not stated]

2 yr Itching, eye burning (2) Urticaria, itching, stomach pain, giddy feelings (4)

138

Patients with Hypertension

34 Red ginseng 4.5g root (300mg ginseng) ± other antihypertensive treatment

12wk Upper abdominal discomfort (2) Also reported: diaphoresis, tiredness, constipation/dyspepsia (9) – no treatment group specified. Only 12 patients had ginseng alone

None reported 139

Healthy Volunteers

22 Korean ginseng 1000mg

30 d Stimulation, improved motor efficiency, increased appetite, diarrhea, skin eruptions, sleeplessness, sleepiness (11)

Depression, improved motor efficiency, increased appetite sleeplessness (7)

140

Elderly patients 49 Korean red ginseng 1.5g

10 d Diarrhea (1) – no treatment group specified

141

Women with postmenopausal osteoporosis

45 Red ginseng 50 mg/kg/d

12 mo Digestion problem (3) Digestion problem (1) 142

Patients with psychogenic impotence

35 Korean red ginseng 2700mg

2 mo Digestive problem, diffuse itching (2)

None reported 143

Healthy Volunteers

64 Red ginseng/white ginseng 11.25g

10 d Hyper- or hypothermia, hot flushes, diarrhea, headache, insomnia, constipation, lip dryness, dizziness, loss of appetite – no treatment group specified

144

Healthy radio operators

32 Liquid ginseng root extract 2ml

Single dose Lighter hand and increased appetite (number of patients not reported)

None reported 145

G115® = standardized ginseng extract, 4% saponins (Ginsana®, Pharmaton SA, Lugano, Switzerland) AE = adverse event SAE = serious adverse event



30

Table 17. Placebo-controlled trials of ginseng in which no adverse effects were reported (after Coon & Ernst 200255). Patient Population n Daily dose Duration Comments Reference Healthy females 19 G115® 200mg 8 wk None 146 Healthy females 19 G115® 200mg 8 wk None 147 Healthy males 16 G115® 200mg 12 wk None 59 Patients with bronchitis

40 G115® 200mg 8 wk Adverse effects not specified

148

Healthy subjects 112 400 mg Ginseng extract

8-9 wk Six patients discontinued the study due to illness

149

Healthy males 41 Standard ginseng extract 300mg

8 wk None 150

Patients with unsettled complaints

30 Korean red ginseng powder 2.7g

6 wk None 151

Patients with erectile Dysfunction

90 Korean red ginseng 1800mg

3 mo None 152

Athletes 30 Chinese ginseng 1200 mg

6 wk None 153

Healthy nurses 12 Korean ginseng 1200 mg

3 d None 154

Middle to old aged subjects

358 Panax ginseng 150 mg 2 mo No vomiting and/or long-term toxic effects observed

154

Patients with diabetes mellitus

36 Ginseng 100 or 200 mg

8 wk None 155

G115® = standardized ginseng extract, 4% saponins (Ginsana®, Pharmaton SA, Lugano, Switzerland)

Table 18. Effects reported in comparative trials comparing ginseng to another treatment (after Coon & Ernst 200255).

Patient Population n Daily dose Duration

Effects reported (no. of patients)

Reference Ginseng Other treatment(s)

Patients with chronic bronchitis

75 G115® 200mg/

antibacterial Treatment

9 d

Not specified; Nine patients withdrew from the study spontaneously (no treatment group specified)

Not specified 156

Sportsmen 20 G115® 200mg/G115s 9 wk None reported None reported 157 Patients with heart failure

45 Red ginseng [dose not stated]/ digoxin/both

15 pills None reported None reported 158

Regular users of ginseng

18 doses]/ginseng and

other stimulants 12 wk

Contact urticarial reaction (1) stimulation, wellbeing, nervousness

Allergic reactions (2), ginseng abuse syndrome (1), stimulation, wellbeing

159

G115® = standardized ginseng extract, 4% saponins (Ginsana®, Pharmaton SA, Lugano, Switzerland); G115s = standardized ginseng extract, 7% saponins (Pharmaton SA, Lugano, Switzerland); n = number of study participants.



31

Table 19. Effects reported in uncontrolled trials of ginseng (after Coon & Ernst 200255). Patient Population n Daily dose Duration Adverse effects reported (no. of patients) Reference Patients with oligospermia

17 G115® 400mg 90 d None reported 160

Patients with chronic respiratory disease

15 G115® 400mg 3 mo None reported 161

Postmenopausal women

49 G115® 200mg 3 mo None reported 162

Postmenopausal women with and without climacteric symptoms

20 Korean red ginseng

6 g 30 d None reported 163

Male athletes 10

Pure ginseng extract 105 mg

2 d None reported 164

Patients with essential hypertension

35 Ginseng extract

1000 mg Up to 10 wk None reported 165

Healthy women

20

Epicutaneous extract of ginseng containing 14%

gensenosides

30 d 3 patients withdrew after 12-15 days due to

skin feeling “too tight” 166

Patients with essential hypertension

19 Red ginseng powder 3 g

12 wk None reported 167

Patients with hypertension

17 Korean red ginseng

4.5 g 21-27 mo None reported 168

Patients with mild proteinaemia and hypertension

24 Red ginseng 900

mg 2 mo Digestive problem (1) 169

G115® = standardized ginseng extract, 4% saponins (Ginsana®, Pharmaton SA, Lugano, Switzerland);



32

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64. Han M and Fang XL. Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models. Acta Pharmacol Sin. 2006;27:499-505.

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35

74. Chen, S. E., Sawchuk, R. J., and Staba, E. J. American ginseng. III. Pharmacokinetics of ginsenosides in the rabbit. Eur.J Drug Metab Pharmacokinet. 1980;5:(3):161-168.

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36

97. Kim, H. S., Kim, D. H., Kim, B. K., Yoon, S. K., Kim, M. H., Lee, J. Y., Kim, H. O., and Park, Y. M. Effects of topically applied Korean red ginseng and its genuine constituents on atopic dermatitis-like skin lesions in NC/Nga mice. Int.Immunopharmacol. 2011;11:(2):280-285.

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116. Qian T, Cai Z, Wong RN, and Jiang ZH. Liquid chromatography/mass spectrometric analysis of rat samples for in vivo metabolism and pharmacokinetic studies of ginsenosided Rh2. Rapid Commun Mas Spectrom. 2005;19:3549-3554.

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118. Gui FJ, Yang XW, Li LY, and Tian JM. Simultaneous enantiomer determination of 20 (R)- and 20 (S)-ginsenoside-Rg2 in rat plasma after intravenous administration using HPLC method. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;850:1-6.

119. Yang L, Deng Y, Xu S, and Zeng X. In vivo pharmacokinetic and metabolism studies of ginsenoside Rd. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;854:77-84.

120. Li X, Sun J, and Wang G. Simultaneous determination of panax notoginsenoside R1, ginsenoside Rg1, Rd, Re and Rb1 in rat plasma by HPLC/ESI/MS: platform for the pharmacokinetic evaluation of total panax notoginsenoside, a typical kind of multiple constituent traditional Chinese medicine. Biomed Chromatogr. 2007;21:735-746.



37

121. Li X, Wang G, and Sun J. Pharmacokinetic and absolute bioavailability study of total panax notoginsenoside, a typical multiple constituent traditional chinese medicine (TCM) in rats. Biol.Pharm.Bull. 2007;30:847-851.

122. Wang W, Wang GJ, and Xie HT. Determination of ginsenoside Rd in dog plasma by liquid chromatography-mass spectrometry after solid-phase extraction and its application in dog pharmacokinetics studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;852:8-14.

123. Xie HT, Wang GJ, and Sun JG. High performance liquid chromatographic-mass spectrometric determination of ginsenoside Rg3 and its metabolites in rat plasma using solid-phase extraction for pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;818:167-173.

124. Cai Z, Qiana T, Wongb RNS, and Jiang Z-H. Liquid chromatography–electrospray ionization mass spectrometry for metabolism and pharmacokinetic studies of ginsenoside Rg3. Appl Liquid Chromat coupled to Mass Spectrom Pharma. 2003;492:283-293.

125. Xu QF, Fang XL, and Chen DF. Pharmacokinetics and bioavailability of ginsenoside Rb1 and Rg1from Panax notoginseng in rats. J Ethnopharmacol. 2003;84:187-192.

126. Paek IB, Moon Y, and Kim J. Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm Drug Dispos. 2006;27:39-45.

127. National Toxicology Program (NTP). Ginseng and ginsenosides (50647-08-0). 10-8-2009. http://ntp.niehs.nih.gov/?objectid=03DB22AE-938D-8EBE-5FAF28638D68FCCF. Date Accessed 5-3-2011. Report No. TR-567.

128. Elsaieed, E. M. and Nada, S. A. Teratogenicity of hexavalent chromium in rats and the beneficial role of ginseng. Bull Environ Contam Toxicol. 2002;68:(3):361-368.

129. Hess, F. G., Jr., Parent, R. A., Cox, G. E., Stevens, K. R., and Becci, P. J. Reproduction study in rats or ginseng extract G115. Food Chem.Toxicol. 1982;20:(2):189-192.

130. Chan LY, Chiu PY, and Lau TK. An in-vitro study of ginsenoside Rb1-introduced teratogenicity using a whole rat embryo culture model. Human Reproduction. 2003;18:(10):2166-2168.

131. Liu P, Xu Y, Yin H, Wang J, Chen K, and Li Y. Developmental toxicity research of ginsenoside Rb1 using a whole mouse embryo culture model. Birth Defects Res (Part B). 2005;74:207-209.

132. Chan, L. Y., Chiu, P. Y., and Lau, T. K. Embryotoxicity study of ginsenoside Rc and Re in in vitro rat whole embryo culture. Reprod.Toxicol. 2004;19:(1):131-134.

133. Wiklund IK, Mattsson L-A, Lindgren R, and Limoni C. Effects of a standardised ginseng extract on quality life and physiological parameters in symptomatic postmenopausal women: a doupble blind, placebo controlled trial. International Journal of Clinical Pharmocological Research. 1999;19:(3):89-99.

134. Engels H-J and Wirth JC. No erogenic effects of ginseng (Panax ginseng C. A. Meyer) during graded maximal aerobic exercise. Journal of the American Diatetic Association. 1997;97:1110-1115.

135. Gianoli AC and Riebenfeld D. A double blind study to assess the tolerability and efficacy of the standardised ginseng extract G115 with specific regard to its effect on the resistance of the organism to external influences. Cytobiology Review. 1984;8:177-186.

136. Scaglione F, Cattaneo G, Alessandria M, and Cogo R. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Under Experimental and Clinical Research. 1996;22:(6):65-72.

137. Allen JD, McLung J, Nelson AG, and Welsch M. Ginseng supplementation does not enhance healthy young adults' peak aerobic exercise performance. Journal of the American College of Nutrition. 1998;17:462-466.

138. Mulz D, Scardigli G, Jans G, and Degenring FH. Long term treatment of the psycho-asthenia in the second half of the life. Pharmazeutische Rundschau. 1990;12:86.

139. Han KH, Choe SC, Kim HS, Sohn DW, Nam KY, Oh BH, Lee MM, Park YB, Choi YS, Seo JD, and Lee YW. Effect of red ginseng on blood pressure in patientswith essential hypertension and white coat hypertension. The American Journal of Chinese Medicine. 1998;26:(2):199-209.

140. Cartwright L. You and ginseng: recent human trials. Australian Journal of Pharmacology. 1982;62:47.

141. Fulder S, Kataria M, and Gethyn-Smyth B. A double blind clinical trial of Panax ginseng in aged subjects. Proceedings of the 4thInternational Ginseng Symposium. 1984.

142. Kim NH, Lee HM, and Choi CH. Clinical effect of Korean red ginseng on osteoporosis. Journal of Ginseng Research. 1998;22:114-121.



38

143. Kim YC, Hong YK, and Shin JS. Effect of Korean red ginseng on sexual dysfunction and serum lipid level in old aged men. Korean Journal of Ginseng Science. 1996;20:(2):125-132.

144. Kim S-H, See S-R, and Do J-H. Effects of Korean red ginseng and western ginseng on body temperature, pulse rate, clinical symptoms and the hematological changes in human. Korean Journal of Ginseng Science. 1995;19:1-16.

145. Medvedev MA. The effect of ginseng on the working performance of radio operators. Papers on the study of ginseng and other medicinal plants of the Far East. Vladivostok. 1963;237-239.

146. Engels H-J, Said JM, and Wirth JC. Failure of chronic ginseng supplementation to affect work performance and energy metabolism in healthy adult females. Nutrition Research. 1996;16:1295-1305.

147. Smith K, Engels H-J, Martin J, and Wirth JC. Efficacy of a standardised ginseng extract to alter psychological function characteristics at rest and during exercise stress. Medicine and science in sports and exercise. 1995. 27: pp.S147

148. Scaglione F, Cogo R, Cocuzza C, Arcidiacono M, and Beretta A. Immunomodulatory effects of Panax ginseng C.A.Meyer (G115) on alveolarmacrophages from patients suffering with chronic bronchitis. International Journal of Immunotherapy. 1994;10:(1):21-24.

149. Sorensen H and Sonne J. A double masked study of the effets of ginseng on cognitive functions. Current Therapeutic Research. 1996;57:(12):959-968.

150. Cherdrungsi P and Rungroeng K. Effects of standardised ginseng extract and exercise training on aerobic and anaerobic exercise capacities in humans. Korean Journal of Ginseng Science. 1995;19:93-100.

151. Chang YS and Park CI. The effect of Panax ginseng on the postoperative radiation complication in cervical cancer patients. Seoul Journal of Medicine. 1980;21:187-193.

152. Choi HK, Seong DH, and Rha KH. Clinical efficacy of Korean red ginseng for erectile dysfunction. International Journal of Impotence Research. 1995;7:181-187.

153. McNaughton L, Egan G, and Caelli G. A comparison of Chinese and Russian Ginseng as erogenic aids to improve various facets of physical fitness. International Clinical Nutrition Review. 1989;9:32-35.

154. Hallstrom C, Fulder S, and Carruthers M. Effects of ginseng on the performance of nurses on night duty. Comparative medicine East and West. 1982;4:277-282.

155. Sotaniemi EA, Haapakoski E, and Rautio A. Ginseng therapy in non-insulin dependent diabetic patients. Diabetes Care. 1995;18:1373-1375.

156. Scaglione F, Weiser K, and Alessandria M. Effects of the standardised ginseng extract G115 in patients with chronic bronchitis. Clinical drug investigation. 2001;21:41-45.

157. Forgo I and Kirchdorfer AM. The effect of different ginsenoside concentrations on physical work capacity. Notabene Medici. 1982;12:721-727.

158. Ding D, Shen T, and Cui Y. Effects of red ginseng on the congestive heart failure and its mechanism. Chinese Journal of Integrated Traditional and Western Medicine. 1995;15:(6):325-327.

159. Siegel RK. Effects of red ginseng on the congestive heart failure and its mechanism. Proceedings of the 3rd International Ginseng Symposium. 1980.

160. Lee HY, Paick JS, and Lee SW. Efficacy of ginseng extract on patients with oligospermia. Korean journal of urology. 1988;29:950-960.

161. Gross D, Krieger D, Efrat R, and Dayan M. Ginseng extrakt G115 for the treatment of chronic respiratory diseases: a pilot study investigating the effects of ginseng extract G115 on pulmonary functions, general functions and oxygenation. Schweiz Zschr Ganzheits Medizin. 1995;1:29-33.

162. Reinold E. Der Einsatz von Ginseng in der Gynakologie. Natur Ganzheits Medizin. 1990;4:131-134.

163. Tode T, Kikuchi Y, Hirata J, Kita T, Nakata H, and Nagata I. Effect of Korean red ginseng on psychological functions in patients with severe climacteric syndromes. International Journal of Gynecology and Obstetrics. 1999;67:169-174.

164. Wyss V, Gribaudo C, and Ganzit GP. Effetti del ginseng su alcuni aspetti della performance fisica in atleti. Medicina dello Sport. 1982;35:383-389.

165. Sohn E-S, Huh B-Y, and Lee D-H. The effect of korean ginseng on blood pressure in essential hypertension by oral administration. Journal of the Korean Medical Association. 1980;23:227-233.



39

166. Curri SB and Gezzi A Longhi MG. Dermocosmetic activity of ginsenosides. Note III: long term evaluation of the moisturising and tonifying effect on the face skin. Filoterapia. 1986;57:217-222.

167. Imamura Y and Kuwashima K. The effects of red ginseng on blood pressure and the quality of life in essential hypertensives. Proceedingsof the 4th International Ginseng Symposium Sept.18-20. 1984.

168. Sung J, Han K-H, and Zo J-H. Effects of red ginseng upon vascular endothelial function in patients with essential hypertension. American Journal of Chinese Medicine. 2000;28:205-216.

169. Kim HK, Choi WY, and Cho WY. Effect of ginseng on renal function in patient with renal injury. Korean Journal of Ginseng Science. 1997;21:49-52.



November 11, 2011

MEMORANDUM

To: CIR Expert Panel and Liaisons From: Lillian C. Becker, M.S.

Scientific Analyst and Writer Subject: Unpublished data for panax ginseng root and other ginseng root derived

ingredients used in cosmetics The Personal Care Products Council submitted unpublished data on panax ginseng root ingredients. These include:

1) Supplier information on products/production of panax ginseng root extract; 2) Supplier information on Panax Ginseng root extract including: impurity analysis,

drug effects, safety evaluation, and effectiveness evaluations; 3) An analysis of a ginseng root product for constituent content and impurities (in

German); 4) A HRIPT of a product containing panax ginseng root extract; and 5) The concentration of use survey results.



TO:

FROM:

DATE: July 6,2011

Products CouncilCommitted to Safety,Quality & Innovation

Personal Care

Memorandum

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

John Bailey, Ph.D. I IIndustry Liaison to the CIR Expert Panel

SUBJECT: Supplier Information on Panax Ginseng Root Extract

1101 17th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.persenalcarecouncil.org

a



Panax Ginseng Root ExtractSummary of Information Received From Suppliers

July 6, 2011

Dried raw material extracted with the following solventsPropylene GlycolPropylene Glycol + WaterPropylene Glycol Dicapryylate[DicaprateButylene GlycolEthanolEthanol + WaterGlycerin + WaterCaprylic/Capric TriglycerideHelianthus Annuus (Sunflower) Seed Oil

One supplier reports the extraction solution (in aqueous 70% Ethanol and Butylene Glycol) is“aged” for 6 weeks before filtering and evaporation of ethanol. This extract contains a total of4.61 ±0.98 mg/g dry weight ginsenosides (2.75 ±0.7 triol, 1.86 ±0.3 diol, 0.73 ±0.11 diol/triol)

Panax Ginseng Root Extract in trade name products: 0.1-10%%solids: 0.5-2% with ginsenoside content 0.2-0.3%%solids: 1.1-2.5%

Measurement of ginsenosides in three batches of hydro-glycolic extract from one supplierresulted in the following:

ginsenoside Rbl: 0.05-0.06%ginsenoside Rb2: 0.02-0.04%ginsenoside Rc: not measurable (up to 0.02%)ginsenoside Rd: not measurable (up to 0.02%)ginsenoside Re: not measurable (up to 0.03%)ginsenoside Rgl: 0.004-0.02%

May contain low concentrations of preservatives such as: 0.5-0.7 % Bactiphen 2506 G(Phenoxyethanol, Methylparaben, Ethylparaben, Propylparaben, Butylparaben)



Personal Care’ Products CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: John Bailey, Ph.D.Industry Liaison to the Cifi Expert Panel

DATE: July 6, 2011

SUflUJECT: Information on Panax Ginseng Root Extract

Biospectrum, Inc. 2011. HerbEx Korean Ginseng ExtractTM.

Radiant. 2011. Planoxia-RG (Panax Ginseng Root Extract).

11011 7th Street, N.W, Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



Last Update: April 12, 2011

HerbEx Korean Ginseng ExtractTM (P)

Anti-Wrinkle, Anti-Oxidation, UV Protection

BioSpectrum, Inc.hF Eines Platz Bldg., 442-13 Sangdaewon-dong, Jungwon-gu, Seongnam-si

Gyeonggi-do 462-120, Republic of Korea

Tel: +82-31-750-9400-4, Fax: +82-31 -750-9797

Homepage: www.biospectrum.com

E-mail: infobiospectrum.com

DO NOT COPY ©BioSpectrum, Inc.



Dr BIOSPECTRUMAdvanoc biotohnoIoqy

TABLE OF CONTENTS

1. GENERAL PRODUCT INFORMATION 4

1.1. Korean Ginseng (Panax ginseng CA. Meyer) 4

1.2. What is HerbEx Korean Ginseng ExtractTM (P)7 4

2. PRODUCT LINE 5

2.1. HerbEx Korean Ginseng ExtractTM (B) 5

2.2. HerbEx Korean Ginseng ExtractTM (P) 5

3. COMPOSITION OF HerbEx Korean Ginseng ExtractTM (P) 6

4. ANALYTICAL STUDY ON HerbEx Korean Ginseng ExtractTM (P) 7

4.1. Quantitative Analysis by HPLC 7

4.2. GC/SIM Quantitation of Fragrance Allergens 8

5. EFFICACY OF HerbEx Korean Ginseng ExtractTM (P) 10

5.1. The Effects of Each Ginsenoside 10

5.2. Anti-Inflammation 12

5.3. Anti-wrinkle Effect 16

5.4. Anti-inflammatory Effect 17

5.5. UV Protection Effect 18

6. CLINICAL SAFETY EVALUATION OF Korean Ginseng ExtractTM (P) 19

7. CLINICAL EFFICACY EVALUATION OF Korean Ginseng ExtractTM (P) 21

8. PUBLICATIONS ON Korean Ginseng ExtractTM (P) 24

8.1. Publication 24

8.2. Domestic Patent 25

9. PRACTICAL HINTS 26

DO NOT COPY 2 ©BioSpectrum, Inc.



ij BIOSPECTRUMAdvnc S< r biotechnoloqy

9.1. Recommended Use Level .26

9.2. How to Get the Most of HerbEx Korean Ginseng ExtractTM (P) 26

9.3. Guide Formula 27




l BIOSPECTRUMAclvancec S.< n botochroIoqy

1. GENERAL PRODUCT INFORMATION

1.1. Korean Ginseng (Panax ginseng CA. Meyer)

Panax ginseng C.A., Meyer, Korean ginseng, the most commonly

used type, belongs to the Araliacease family. Widely cultivated, Korean

Ginseng is now used as a natural preventive, restorative remedy and

valued for its adaptogenic properties. KOREA Ginseng is not only a

species different from those of American ginseng or Chinese Sanchi

ginseng but is grown in an optimal geographical environment and

climatic conditions suitable for the growth of superior quality ginseng.

Used for centuries in China, Korean Ginseng was believed to be and

anti-aging herb. Today, Ginseng is a favorable herb because of its

ability to be used long-term without toxic effects on the body. Korean

Ginseng contains adaptogens that have been known to return the body’s system levels back to normal. By

equalizing the system levels in the body, Korean Ginseng has been used to lower cholesterol, balance the

metabolism, increase energy levels, and stimulate the immune system. It has also been used to alleviate fatigue

and reduce nervousness & stress on the body. Korean Ginseng also increases oxygenation to the cells and

tissues, promoting detoxification, and stimulating the regeneration of damaged cells. For this reason, Korean

Ginseng is the popular choice because it enhances the feeling of overall well being by stimulating the nervous

system, brain, and heart, as well as healthy liver functions.

1.2. What is HerbEx Korean Ginseng ExtractTM (P)?

HerbEx Korean Ginseng Extract was exploited and rectified from natural fresh ginseng using advanced

ultrahypothermia biotic extraction techniques. The extracts have been analyzed qualitatively and quantitatively to

valuate yield and selectivity of extractions of ginsenosides. HerbEx Korean Ginseng Extract (P) has a lot of

biological effect such as anti wrinkle, anti oxidant, anti inflammatory effects on the human skin. Also HerbEx

Korean Ginseng Extract (P) maintained the saponins of ginseng root. (Figure 1.)




i BIOSPECTRUMAvancec Sk n biotechoIoqy

2. PRODUCT LINE

2.1. HerbEx Korean Ginseng ExtractTM (B)

• Panax Ginseng Root Extract in butylene glycol (Natural)

• INCI Name: Panax Ginseng Root Extract, Water, Butylene Glycol (Natural)

• % Breakdown:

FDA Code (Contents) INCI Name (Product: HerbEx Korean Ginseng ExtractTM(B))

A (50%) Butylene Glycol (Natural)

B (25 50%) Water

C (10 25%)

U (5 10%)

E (1 5%) Panax Ginseng Root Extract

F_(0.1 - 1%)

G (<0.1%)

2.2. HerbEx Korean Ginseng ExtractTM (P)

• Panax Ginseng Root Extract in propanediol

• INCI Name: Panax Ginseng Root Extract, Water, Propanediol (Natural)

• % Breakdown:

FDA Code (Contents) INCI Name (Product: HerbEx Korean Ginseng ExtractTM(P))

A (50%) Propanediol (Natural)

B (25 50%) Water

C (10 25%)

D (5 - 10%)

E (1 5%) Panax Ginseng Root Extract

F (0.1 - 1%)

G (<0.1%)




? BIOSPECTRUMAdvancoc S< n motochnoloqy

3. COMPOSITION OF HerbEx Korean Ginseng ExtractTM (P)

The important constitutes of Korean ginseng are Ginsenoside saponin: ginsenoside Rx (x=o, a, bi, b2, c, d, e, f,

gi, g2) (Fig. 1.), Ginsenosides possess a steroidal backbone reminiscent of hormones. Ginsenoside has been

known to be effective on inflammation, anticancer, wrinkle and so on. It has been reported that the components

have strong effectiveness to cell migration, collagen synthesis, anti-oxidation and so on.

Rb1: R1zglu21glu

Rc: R1=glu21glu

Re: R1=H

Rf: RIH

Rgi: R11-I

Rg2: R1H

Rg3: Rlglu-2-1-glu

Rh1: RIH

R2=H

R2=H

R2glu-2-1 -rham

R2=glu-2-1 -glu

R2g1u

R2g1u-2-1 -rham

R2=H

R2glu

R3g1u-6-1 -glu

R3g1u-6-1 -ara

R3g1u

R3=H

R3g1u

R3=H

R3=H

R3=H

Fig. 1. HPLC Profile and Structure of a ginsenoside mixture in HerbEx Korean Ginseng Extract (P).

DO NOT COPY 6 ©Biospectrum, Inc.



‘ BIOSPECTRUMAdvancec 3< n botocbnoIoqy

4. ANALYTICAL STUDY ON HerbEx Korean Ginseng ExtractTM (P)

4.1. Quantitative Analysis by HPLC

1I% 1 )1 I$ 4&S4e4e SM*autei

Ginsenosides (%)

Rgl Re Rf Rbl Rg2 Rhi Rc Rb2 Rb3 Rd Rg3 Rh2

> 80%4.17 18.99 1.87 34.49 2.30 13.31 - 5.08 3.37 14.89 - 1.52

Ginsenosides

• Analytical Condition

Instrument : Waters HPLC PDA System, 600E System controller, 600Q pump, 717 autosampler

Column : Runa C18(2) (4.6 X 150 mm, 5 pm)

Mobile Phase : Solvent: H20 (A), MeCN (B)

gradient system : 0-5 mm (20% B), 5-35 mm (20-40% B),

35-40 mm (40-100% B), 40-50 mm (100% B)

Flow Rate: I mUm in

Injection Volume:10 pL(l000ppm Korean Ginseng Extract (P) (as 800ppm Ginsenosides)




“ BIOSPECTRUM-

Avnced S’ n biotoch*oloqy

4.2. GCISIM Quantitation of Fragrance Allergens

In the European Union, the allergenicity of some consumer products has recently come to the forefront. The

adoption of the 7th amendment of the European Cosmetic Directive 76/768/EEC requires any cosmetic product

containing any of 26 raw materials (30, including isomers) identified by the Scientific Committee on Cosmetic

Products and Non-Food Products intended for Consumers as likely to cause a contact allergy when present

above certain trigger levels to be declared on the package label. Of these 26, 24 are volatile and can be analyzed

by GC/MS.

GC-SIM analysis was carried out on a Hewlett-Packard 589011 PLUS gas chromatography fitted with a fused

silica capillary column (HP-5MS, 30 m x 0.25 mm x 0.25 .im film thickness) coupled to a 5972 mass spectrometer

(Electron impact ionization, 70 electron voltage). Oven temperature was maintained at 60°C for 2 mm, elevated

to 260°C at a rate of 10°C 1mm, and then hole at 260°C. Helium was used as the carrier gas, at a flow rate 1

mL/min and initial gas velocity was 36.6 cm/sec. As the result of GC-SIM analysis, no fragrance allergens were

detected in Korean Ginseng ExtractTM (P)..

Table 1. Analysis of Fragrance Allergens in Korean Ginseng Extract (P)

No. Substance CAS No. GC-Rt Prominent IonsAmountDetected

I (R)-(+)-Limonene 5989-27-5 6.14 136, 93, 68* Not detected

2 Benzyl alcohol 100-51-6 6.21 108, 91, 79° Not detected

3 Phenylacetaldehyde 122-78-1 6.38 120, 91°, 65 Not detected

4 Linalool 78-70-6 7.26 136, 93, 71° Not detected

5 1,4-Dibromobenzene 106-37-6 8.69 236°, 155, 75 Not detected

6 Allylanisole(Estragole) 140-67-0 8.80 148°, 133, 121 Not detected

7 Methyl 2-octynoate 111-12-6 8.82 123, 95°, 75 Not detected

8 Citronellol 106-22-9 9.20 156, 95, 69° Not detected

9 cis-Citral (neral) 5392-40-5 9.42 109, 94, 69° Not detected

10 Geraniol 106-24-1 9.59 154, 123, 69° Not detected

11 trans-Citral (geranial) 5392-40-5 9.84 109, 94, 69° Not detected

12 Cinnamaldehyde 104-55-2 9.87 131*, 103, 77 Not detected13 4-Methoxybenzyl alcohol 105-13-5 10.02 138°, 212, 109 Not detected

14 Hydroxy-citronellal 107-75-5 10.06 157, 139, 59° Not detected15 Methyl 2-nonynoate 111-80-8 10.24 153, 137, 79° Not detected

16 Cinnamyl alcohol 104-54-1 10.34 134, 105, 92° Not detected

17 Eugenol 97-53-0 11 06 164*, 149, 103 Not detected

18 Methyleugenol (4-Allyl-1 ,2-dimethoxybenzene) 93-1 5-2 11.65 178*, 163, 147 Not detected

19 cis-lsoeugenol 97-54-1 11.73 164°, 149, 131 Not detected

20 Coumarin 91-64-5 12.18 146*, 118, 90 Not detected

21 lsoeugenol 97-54-1 12.27 164°, 149, 131 Not detected

22 a-lsomethylionone 127-51-5 12.68 206, 150, 135° Not detected

23 2-(4-tert-Butylbenzyl)propinaldehyde (BMHCA) 80-54-6 13.26 204, 189, 147 Not detected

24 a-Amylcinnamaldehyde 122-40-7 14.67 202, 145, 129° Not detected

25 Hydroxy-methylpentyl-31906-04-4 14.77 192, 136, 59° Not detectedcyclohexenecarboxaldehyde (HMPCC (Lyral))




. BIOSPECTRUMAdvnceC S< r botochnoIoqy

26 Hydroxymethylpentyl-31906-04-4 14.85 192, 136*, 59 Not detectedcyclohexenecarboxaldehyde (HMPCC)

27 a-Amylcinnamyl alcohol 101-85-9 15.09 204, 133, 91* Not detected

28 a.Amylcinnamyl alcohol 101-85-9 15.32 204. 133, 91* Not detected

29 Farnesol 106-28-5 15.47 136. 81, 69* Not detected

30 Hexylcinnamaldehyde 101-86-0 15.78 216. 145. 129* Not detected

31 Benzyl benzoate 120-51-4 16.00 212, 194. 105* Not detected

32 Hexylcinnamaldehyde 101-86-0 16.06 216, 145, 91* Not detected

33 Benzyl salicylate 118-58-1 17.11 228. 121, 91* Not detected

34 4,4’-Dibromobiphenyl 92-86-4 18.46 312*, 310, 152 Not detected

35 Benzyl cinnamate 103-41-3 19.25 238, 131, 91* Not detected




. BIOSPECTRUMAdvanced SK.n biotochnoloqy

5. EFFICACY OF HerbEx Korean Ginseng ExtractTM (P)

5.1. The Effects of Each Ginsenoside

Name Contents

Ginsenoside-Rbi antiamnesic, antipsychotic, antistress, antitumor, antiulcer calcium antagonist, CNS sedative,corticosteroidogenic, hypothermic, neurogenic, tranquilizer, vasodilator

Ginsenoside-Rb2 Epidermis proliferative effect, anticarcinogen, corticosteroidogenic, hypocholesterolemic,hypoglycemic, hypotriglyceridemic, lipolytic, proteinogenic

Ginsenoside-Re corticosteroidogenic, lipogenic, vasodilator, calcium antagonist

Ginsenoside-Rd corticosteroidogenic, neurogenic

Ginsenoside-Re calcium antagonist, corticosteroidogenic, vasodilator, increase lipase activity

Ginsenoside-Rf Antitumor calcium antagonist, inhibit lipid peroxidation

Ginsenoside-Rgi antiaggregant, antifatigue, antistress. antitumor, aphrodasiac, calcium antagonist. CNSstimulant, homeostatic, hypoglycemic, estrogen-like activity, vasodilator

Ginsenoside-Rg2 antiaggregant

Ginsenoside-Rg3 Hepatoprotectant, inhibit COX-2

Ginsenoside-Rh1 Hepatoprotectant, reduce PLC activity (3T3), anti-inflammation, antiallergy

Ginsenoside-Rh2 Anticarcinogenic effect, reduce PLC activity (3T3), Cell cycle arrest




Fig. 2. The effectiveness of HerbEx Korean Ginseng Extract (P)

. BIOSPECTRUMAcIvanc.cc Sc rc botechnoIoqy

200% 192%

160%

120%0I

4-’

0C-)II0 80%

129%

40%

(10/V 10

60%

Free radicalscavenging Superoxide

activity anion MMP-1scavenging activity

activity inhibitionCollagensynthesis Eotaxin

productioninhibition

DO NOT COPY 11 ©BoSpectrum, Inc.



5.2. Anti-Inflammation

5.2.1. Biological effect of oxidative stress

Oxidative stress

.. BIOSPECTRUMAdvanced S’ n biotechnology

uvIrradiation

N11øIOus

: COX .1jAJteraUonof

Pathogen

Metabolism4

Darnageto Membrane

AgingApoptosisCancerAutoimmune diseaseInflammation

Organisms living in an oxygen atmosphere are constantly exposed to reactive oxygen free radicals, which gives

rise to destructive effects on DNA, proteins and lipids. A major target of free radical damage is the cellular

membrane that contains abundant unsaturated lipids. These unsaturated lipids may be transformed into lipid

radicals by bond dissociating reaction and then undergo lipid peroxidation. The result of such membrane

peroxidation is increased membrane permeability, loss of ion-gradients and controlled signal transductions, loss

of controlled energy transformations, and loss of functional properties.

Cellular damage can result in diseases, such as cancer, inhibit enzyme activity and produce mutations in

genetic material that makes aging go faster.

Inflammation fOxidative Stress Lipid peroxidation

Collagen synthesis

MMP activity t

Wrinkles occur when skin loses its elasticity. The loss of elasticity is caused by extensive formation and

accumulation of collagen cross-links. Collagen cross-linking is a result of a chemical process that starts with

nonenzymatic attachment of glucose to a collagen molecule.

Skin cancerWrinkle

,Skin damage




i BIOSPECTRUMAdvr,ncec S.< n bochroIoqy

When enzymes attach glucose to collagen, there is a reason for it and a purpose. Nonezymatic attachment, on

the other hand, is random. Collagen cross-linking in this case is uncontrollable and more often than not -

unnecessary. Once cross-linking occurs, it is irreversible.

By inhibiting enzyme production, free radicals lead to chaotic collagen cross-linking.

Metabolism, environmental toxins and pollution are the main reasons why free radicals exist. Metabolism is a

part of life, sun and toxins are hard to escape. The only way to counteract free radical damage is to neutralize

them as they appear.

5.2.2. ROS & Photo aging

-.IL

Exposure to ultraviolet light, UVA or UVB,

from sunlight accounts for 90% of the

symptoms of premature skin aging. Most of

the photoaging effects occur by age 20.

The amount of damage to the skin caused

by the sun is determined by the total

lifetime amount of radiation exposure and

the person’s pigment protection.

Changes in the epidermis caused by the

sun include thinning of the epidermis and

the growth of skin lesions such as actinic

keratoses, basal cell carcinomas, and

In the dermis, sun effects cause collagen to break down at a higher rate than with just chronologic aging.

Sunlight damages collagen fibers and causes the accumulation of abnormal elastin. When this sun-induced

elastin accumulates, enzymes called metalloproteinases are produced in large quantities. Normally,

metalloproteinases remodel sun-injured skin by manufacturing and reforming collagen. However, this process

does not always work well and some of the metalloproteinases actually break down collagen. This results in the

formation of disorganized collagen fibers known as solar scars. When the skin repeats this imperfect rebuilding

process over and over wrinkles develop.

V\_______

______

Cytokine

squamous cell carcinomas.




BIOSPECTRUM4, AcIvancEc S< r bothnoIoqy

The photoaging is closely related to:

• The photoaging process induced by sunlight or artificial UV-exposure, which has the major

impact on skin appearance through an obvious free radical generation in the skin. [Ed.-

Referring to Dr. Kyriazis article in this issue of the Bulletin, remember that as much as 90%

of skin damage could be caused by photoagingj.

• Toxic environmental exposure via smoking, industrial exhausts, heavy metals, detergents,

all of which are known to be potent free radical inducers.

• Chronic infection! inflammatory states associated with an increased free radical attack,

(superoxide, peroxinitrite, hypochlorite).

• Inappropriate nutrition, (excess of refined carbohydrates, fats, food additives, alcohol, low

water intake) and last, but not least;

Sleep deficiency and stress. Photoaging and photodamage of skin may be at least partially reversible with

antioxidants treatment. An increase in cellular antioxidants can be achieved by exogenous administration of

antioxidant compounds. In the case of the skin, the most appropriate route of administration seems to be the

topical application, because it allows reaching higher tissue levels with high tissue specificity and diminishes

potential side effects to other organs.

5.2.3. Reactive oxygen species scavenging test

Superoxide dismutase (SOD) catalyzes the dismutation of the superoxide anion into hydrogen peroxide and

molecular oxygen. The scavenging activity of superoxide anion can be determined by a colorimetric method

(SOD assay kit; Dojindo Laboratories, Japan)

RadicalSCavGnflGrs

500‘ H202 )< ‘ •QH < . Lipid

GSSO /IGSH /j %\

42H20 H20+02

A rapid, simple and inexpensive method to measure antioxidant capacity of ingredients involves the use of the

free radical, 2,2-Diphenyl-1-picrylhydrazyl (DPPH).

The HerbEx Korean Ginseng Extract solution (20-640 pg/mL) was mixed with 400 pM DPPH (Sigma Chemical

Co.. St Louis Ml.) methanol solution at a ratio of 1:3. The mixture was left in the dark at room temperature for 90




BIOSPECTRUMAdeanea S< r botoohnoIoqy

mm. The absorbance of the resulting solution was measured by a spectrophotometer at 517 nm. The capability of

scavenging DPPH radicals was then calculated by the following equation:

Scavenging effect % = [1 -(A51 7 of sam pleIA5I 7 of control)]

01N N0

yN0

Purple

+ RH + R.

NO

Ye 110w

A

>

UCa

ba

a)

C)Ca

a)

CC

C(12

B

100%80%

a)

C-)

80%

DC °

C

60%

40%

40%

20%

0% — — -—-—— 0%

0.1% 0.25% 0.5%

Fig. 3. HerbEx Korean Ginseng Extract (P) shows superoxide anion (A) and free radical (B)

scavenging activities.

0.1% 0.25% 0.5%




5.3. Anti-wrinkle Effect

i BIOSPECTRUMAr.ivncec 3K fl boteohno)oqy

Proline

Glysine

Hydroxyproilne

Hydroxylysne

— ActivatIon

nI,ibtknTriple

_ ProcoHagen Collagen • > Aniinoherix

V

V

0L)0I-.

0

IAnti

Wrinkle

Aff— WzthkIWt

Collagen Synthesis‘

MMP Activity4

5.3.1. Korean Ginseng Extract (P) induces pro-collagen synthesis

Human dermal fibroblast cells were confluently7

cultured and treated with HerbEx Korean6

Ginseng Extract (P) for 1 day. Pro-collagen

were measured by Procollagen Type I C

peptide ELISA kit (DAKARA, Japan). HerbEx

Korean Ginseng Extract (P) 2% increased

collagen synthesis by 29% (2%) compared with 1

untreated control.

() RA(uM) 0.5% 1% 2%




i BIOSPECTRUMAdvancoc 3K ri htohr1oIoqy

5.3.2. HerbEx Korean Ginseng Extract (P) inhibits MMP-1 activity

Human dermal fibroblast cells were

confluently cultured and treated with 0. 2o

HerbEx Korean Ginseng Extract (P) for0 2

1 day. MMP-activity was measured by •

0.15 -Type I Collagenase assay kit I

o.i L(Amersham, USA). 1-lerbEx Korean

Ginseng Extract (P) reduced MMP-1 0.00

activity by 40% (2%) compared with 0 —

________

C-) TNF-a 0.5% 1% 2%untreated control.

5.4. Anti-inflammatory Effect

Skin inflammation is associated with increased eotaxin production in acute skin lesions.

Inflammation and allergic effect on skin

0.4

Eotaxin 0.3 Iri:: I i. — HMast cell () TNFa 0.5% 1% 2%

Mouse NIH3T3 fibroblast cells were confluently cultured and treated with TNF-a only or HerbEx Korean Ginseng

Extract (P) in the presence of TNF- a for 1 day. HerbEx Korean Ginseng Extract (P) inhibited ectaxin production

induced by TNF- a by 38% (2%) compared with untreated control.




c,z>

C-)

Fig. 4. HerbEx Korean Ginseng Extract (P) protects skin cell from UVB-induced damage

HaCaT cell were treated for 24 h with HerbEx Korean Ginseng Extract (P) 1% (Gs) and were then exposed to

UVB radiation. At 24 h after UVB irradiation, viability was assessed by MTT assay. Phase-contrast microscopy 24

h after irradiation showed enhanced survival in HerbEx Korean Ginseng Extract (P) treated cells.

. BIOSPECTRUMAcIvncec S. r, botochnooqy

5.5. UV Protection Effect

150% -

100%

50%

0%

UV B

UVB+Gs

(-) UVB UVB+Gs




6. CLINICAL SAFETY EVALUATION OF Korean Ginseng ExtractTM (P)

. BIOSPECTRUMAdvcn. SK r bioohrioIoqy

REPORT SUMMARYTitle Clinical safety evaluation by single patch test of 1-lerbEx Korean Ginseng

Purpose To evaluate the irritation potential of cosmetics and its ingredients on human skin

Test center DerrnaproiSkin Research Center Test period 11 May. — 14 May. 2009

Jae-sook Kol-i, PhD.

Authentication Scientific Director of Oerrnapro/Skin Research centerDERMAPRO was vahdated QUALITY MANAGEMENT SYSTEM CERTIFICATE

of Test Center(Cenificate No. 5855) by KOTRIC Certification Center on the contract research andconsulting service on human skin safety and efficacy.

BioS pectnimSponsor SK vention’ 101-701, Dangjung Dorig. Gunpo City. Gyunggi-Do, Rep. of Korea

Eunsun Jung I Team Manager

Subiects: 30 healthy women (mean age 39.73±6.86)Procedure: 48 hours single closed patch test on the upper back

Method Reodu7r ond ,nteroret3non: Reactions were assessed at 30 minutes and 24 hoursafter patch removal by the dermatologist and principal researcher according to themodification of Frosch & Klgman (1979) and CTFA safety guidelines (1981). Allassessments were performed under standard lighting conditions.

Result This material (#32) did not show any skin reaction at 24 hr and 48 hr in ali subjects.

Conclusion This material (#32) did not show a significant evidence of primary irritation on humanskin and were classified in the non-irritating range,

27 May. 20091 DSA-Pl-914

Safety Test Seung-joo Kang. M.D.. Ph.D.Assessor Scientific Director of Dermapro! Skin Research Center




. BIOSPECTRUMAduncc SK n botchnoIoqy

RESULTS OF SAFETY CLINICAL EXAMINATIONS

- None of the 30 subjects experienced a reaction based on the 30 mm and I day readings.

- No adverse reactions such as erythema, burning, or pruritus in the study subjects that was

related to the topical treatment of HerEx Korean Ginseng Extract (P) (KGE).

48h 72h Reactiongrade’)No Test material — — — — — — — —

+ 1+ 2+ 3+ 4+ + 1+ 2+ 3+ 4+ 48h 72h Mean

i Squalane - - - - - - - - - - 0 0 0

2 KGE1’(%) - - - - - - - - - - 0 0 0

3 KGE(5%) - - - - = - - - - - 0 0 0

a> No reachon. b) KGE HerbEx Korean Ginseng Extractc) Reachor grade=j{Grade X No. of Responders}I{4 (Maximum grade) X 30 (Total Subjects)}J X 100 X(112)




. BIOSPECTRUMAdvnod Sc r botochnoleqy

7. CLINICAL EFFICACY EVALUATION OF Korean Ginseng ExtractTM (P)

REPORT SUMMARY

Title A clinical :tudy of the anti-wnnkle effect ofG eno:ide: on human ..kin

Te:t Center Der pro Skin Reearch Center Tet Period Nov. iS. 2009 Jan 15. 200

Objective To evaluate ann-wrinkle effects and :aferv on human kii

Report Date Mar. 1. 2010

DERMAPRO wa: vahdated by receivui a “QUALITY NACYEMENT SYSTEMAuthentication CERTIFICATE” (KS A 9001:2001 /150 9001:2000:C ijcw 5S55) fiotn theof Te:t Center KOTRIC Cern&ation Center for pzovidin contract ieearch and coru1nng :ervice:

on human ..kin .afetv and efficacy.

Frfteen heaithy ubject participated in thi+: tudy. Skin condztzon of the :ubjectwere evaluated before treatnient. 4 week and S week: after teamient, Skin vrir.lcle

Method wa: evaluated by vr:ual pade. ku roughne: (R-parameter). derural denity andelf-quetuonn.me:. AU obtained data were ana’yzed by uzug the paired r-te.t of

SPSS 11.5 packageproram -

I Vr:ualCompared to pre-treatmern. the vr:u.al grade of wrinkle wa: improved aikei Sweek.

2. Skin 2ougbne: a:eznent (Rparanieter)Compared to pre-treatmeat, Ra paranietex wa :rgiufcant1y improved after Sweeks (p 0.05). Rmax. Rz and Rp parameter: were :igm&antly reduced after 4and S week: (p 0.05).

3. Dennal dea:zrv a::e::zneiitReu1t: Compared to pre-treatineut, the de:mal deaity wa :izuficantly improved after 4

andSweek: (p 0.05).

4. A:r:meut of que:tronnaireIii the re:iilt of :elf-que ionnaire: on efficacy, more than 70. of :ubject: offeredpoitave anwer: on ‘Moizruie’. Soe:’ md ‘Fee1m ofmzner: at S week:,In the re:ult of f-quetzonnmue on ir:age. more than SGe of ject offeredpoatzve an.wer: on all item: except l’erfume’ at S week:.

5. Safety evaluationNo advere reaction wa: oberved danng the coure of the :rudy.

The Gin:eno:ide: :howed the ann-wrinkle effect a: irn’e:ngated by chricalConclu:ion ebr.ervatzon. ui:trumenral a:.e::uient: and :eIf-que:onaaire:.

Appendix Data table:. Statinc:. Image data. R.eearcb :t,aff and facthtie:




I ó4

140

V

rou2hness parameters

4.)

‘ BIOSPECTRUMAcI’cncec Scn botechnoloqy

Definition

Arithmetic average value of profile peaks within the total measuringlengthMaximum of all peak-to-valley values Rt. measured over the assessmentlength

Maximum profile peak height

Average maximum height of the profile

• RESULTS OF SKIN ROUGHNESS

24G

t

V 00

1IGe

flG0ww

963%£00

0

E

40

4G 0

Definition ofParameter

Ra

Rinax

Rp

Rz




. RESULTS OF DERMAL DENSITY

. BIOSPECTRUMI Advncec BK r hotehnaIoqy

Week N Me2n SD SEM p-value Increment (%)OW 15 16.36 0.43 0.11 - -

4W 15 16.61 0.57 0.15 OOO1* 5ASW 15 12 0.6S 0.IS OOOO* 2.S2A

Sigm&rn1v diiferei: atp 0.05 cotnp3red topre-rreaern1aemt of the aean value repreeuts the ipovement of deni1 dewy,

16.80

1640

16.00

1.604,

15.20

14.80

14.40

14.00

ow

*

4W 8W




8. PUBLICATIONS ON Korean Ginseng ExtractrM (P)

8.1. Publication

ij BIOSPECTRUMAcivanooc Sc n biotochnoloqy

Panax ginseng induces human Type I collagen synthesis through activation of Smad signaling

(Publication in <Journal of Ethnopharmacology> in 2007)

ELSEVIER

PUIUX giI?eIIg induces human Type I collagen synthesisthrough activation of Smad signaling

iongsung Leett. Eunsun ijinga. Jiyoung Lee’. Sungran huh1.Jicun Kini’. Mijung ParkJungwuon So’. Youneeeun Hama. Kwangscon Jung. Chang-Gu hlyun

Ycong Shik Kim ‘. Deokhuon Park

Alrslrnct

tn I 1. ‘it 10 .i,v.si F i.’irI ‘iA I I lit II, t’ I ,rc’or,t, IH..rtr. or a Cii t00C, In IF 1,t,i.i,,‘Pit krtoto ItISIC.,! r.oti’ir. ,,sr.,St Itnr,rr.i t’nCt.rtiRpttJntr. n’iA.’,t,,

IF’t tort IF ‘il.r.h iW’. r arts_i ,n tart so.J r,ot,r 0 Irma Ptik- ao.’prrt 4 itt 2)1)’,‘isiahie.itrir ‘i, 1 t 2111),

Skin aging appearc to’ he principally rattled l&r a raise in leek ofTy pa I collagen, the puritan cat prinsent of the derail layer 1 skin. ItIs niponain Lii tinidilve an attn ren .01011 her clitOric rfl.tniagtrIrs’tii iii skit $IIIP: Otis pen st01LiIrI have the (trr.est pa’.sriile side eftiacts .ti1d

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Avatiabie orlrne at www,sciencectnrect,com

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8.2. Domestic Patent

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ICERTIFICATE OF PATENT




. BIOSPECTRUMAds’anc S n borochnooqy

9. PRACTICAL HINTS

9.1. Recommended Use Level

We are confident in recommending HerbEx Korean ginseng extractTM (P) as an effective ingredient of cosmetics

to anti-aging. In addition, HerbEx Korean ginseng extractTM (P) can be an ingredient of cosmetics for a wide

range of product types, from skin care to shampoos and from creams to gels etc. Usage levels may vary from 1%

to 5%, depending on the formulation, the typical usage level averages around 2%.

9.2. How to Get the Most of HerbEx Korean Ginseng ExtractTM (P)

Do not add HerbEx Korean ginseng extractTM (P) to the formulation at temperature above 55CC, where there is a

heating stage it is recommended to add after the cooling process.

If possible, avoid any strong oxidizers and UV or direct light.




9.3. Guide Formula

9.3.1. Toner

i BIOSPECTRUMAdvncec SK n biotochnoloqy

Wt(%)Ingredient

A. Deionized Water To 100

Disodium EDTA 0.05

Allantoin 0.10

HerbEx Hyaluron 1.50

(sodium hyaluronate 0.5%)

D-Panthenol 3.00

Sodium PCA 2.00

Methyl Paraben 0.10

B. Alcohol 5.00

PEG 60 Hydrogenated Castor Oil 0.50

Fragrance q.S

C. Imidazolidinyl Urea 0.05

Citric acid q.s

Trisodium Citrate q.s

D. HerbEx Korean ginseng extract (P) 2.00

HerbEx Green Tea Extract 2.00

+ Procedure

Heat A and B separately to 75°C.

Stir until complete dispersion.

Add B into A and mix for 3mm.

Cool to 50°C and add C

Then add D at 40°C while stirring




9.3.2. Lotion

iJ BIOSPECTRUMAcivancec S r botechnooqy

Ingredient Wt(%)

A. Deionized Water TolOO

Carbomer94l 0.05

B. Allantoin 0.10

HerbEx Hyaluron 1.00

Methyl Paraben 0.10

Glycerin 1.10

Disodium EDTA 0.05

C. Polysorbate 60 1.00

Sorbitan Sesquioleate 1.00

Stearic acid 1.00

Glyceryl Stearate/PEG-1 00 Stearate 1.50

Cetyl Alcohol 1.30

Propylparaben 0.05

Butylparaben 0.05

Macademia Nut Oil 0.50

Dimethicone 0.50

Caprylic and Capric Triglyceride 1.00

Mineral Oil 4.50

D. Triethanolamine 0.10

Imidazolidinyl Urea 0.05

E. Fragrance q.s

HerbEx Korean ginseng extract (P) 2.00

MultiEx Hydro Soother 2.00

+ Procedure

HeatAto 75°C and disperse completely

Add B into Awith mixing.

Separately, heat C to 75°C and mix to disperse.

Pour C intoAand homogenize for 5mm.




9.3.3. Shampoo

BIOSPECTRUMAdvt,cec 6-c-fl boteChflOIOqy

Ingredient Wt(%)

A. Deionized Water To 100

TEA lauryl Sulfate 30.00

Sodium laureth Sulfate 15.00

Cocamidopropyl Betain 3.00

Cocamide DEA 2.00

Citric Acid 0.20

Methyl Paraben 0.10

B. PEG-7 Glyceryl Cocoate 1.50

Disodium Laureth Sulfosuccinate 3.00

Sodium Chloride 1.00

Imidazolidinyl Urea 0.05

Fragrance q.s

C. HerbEx Korean ginseng extract (P) 2.00

BSASM Plus 2.00

+ Procedure

Heat A to 75°C and disperse completely.

Add B into Awith mixing.

Cool to 50°C and add C while stirring.




.)kj 3//

DKSH North America Inc. 100 Stierli Court Suite 102 Mount Arlington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

PLANOXIA-RGFor promotion ofhair growth

RADIANTRm 207 Bioindustry Innovation center

Hi-Tech Venture Town. 198-53

Hupyeng, Chuncheon. Gangwon

Republic of Korea 200-957

Email:[email protected]

Based on the SoulofNature

DKSH North America Inc.



DKSH North America nc. 100 Stierli Court Suite 102 Mount Arlington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

CONCEPT

Hair loss is a distressing condition for an increasing number of men and

women. It is of great importance; therefore, to develop new therapies for the treatment of

hair loss.

Korean Red Ginseng is an important crude drug that has been used from ancient times to

improve constitutional tendencies to poor body condition, to promote appetite, to increase

vitality and to reduce over-sensitivity to cold. Pharmacological evidence shows that ginseng

improves blood circulation and accelerates both metabolism and digestion.

PLANOX1A-RG is a Korean Red Ginseng extract as a hair growth agent, based on its

abilities to induced earlier telogen to anagen conversion than did the minoxidil and negative

control. itd ginseng extract markedly increase the depth and size of the hair follicles, it is

from red ginseng extract effect that help of hair growth factor expression such as VEGF,

PCNA, Substance P

2

•ANoxL4i:—-4.

U — — — aS





CoNTENT

PART? General Information

1. About PLANOXIA-RG (Red Ginseng extract) 5

2. Research data of Red Ginseng extract 8

3. Hair Structure and Hair Life Cycle 12

4. Hair Loss 14

PART? Technical Data

1. Explain of PLANOXIA-RG 16

2. Stability study 18

3. Safety study 21

PART? Efficacy Data

1. Hair growth effect 28

PART? Conclusion

1.Summary 34

2. Application 35

3




DKSH North America Inc. 100 Stierli Court Suite 102 Mount Arlington, NJ. 07856 (973) 810-5511 tax (973) 810-5520

Part ? • General Information

1. About PLANOXIA-RG (Red Ginseng extract)

2. Research data of Red Ginseng extract

3. Hair Structure and Hair Life Cycle

4. Hair Loss

4





1.About PLANOXIA-RG (Red Ginseng extract)

Ginseng, the root ofPanax ginseng, has been used frequently in traditional Oriental medicine

and is now widely used around the world. Ginseng is one of the most famous herbal

medicines used as a dietary supplement in recent years. There are various types of

commercial ginseng products, the most popular being red ginseng.

Ginsenosides, the ginseng saponins, are the major components having pharmacological and

biological activities, including antidiabetic and antitumor activities. More than 30 different

ginsenosides have been isolated and characterized, and they have different pharmacological

effects. Ginsenosides can be divided into 20(S)-protopanaxadiol (ginsenoside Rbl, Rb2, Rb3,

Rc, Rd, and Rg3) and 20(S)-protopanaxatriol (ginsenoside Re, Rgl, Rg2, and Rhi) groups

based on their aglycone moieties

5

Ginsenoside Rl R2

Rgl Gic Glc

Re G1c2-Rha Glc

Rf G1c2- GIc H

Rhi GIc H

Rg2 G1c2-Rha H

Common name (7 7 , 7 7 , ginseng steamed redKorean red ginseng)

Latin name Panax ginseng

INCI name Panax Ginseng Root Extract

CAS Number 90045-38-8

ETNECS Number 289-898-5

Main ingredient B- sitosterol, ginsenosides, Campesterol,Vitamin Bi, B2, B3, B5, C

Gf

2 Dis: proopaxtrioIR=R,=N





R?OOH .-

I_ 2O(S)protopanaxadolR1=R2:rH

Ginsenoside Ri R2

Rbl Gic2-Glc Gic6-Glc

Re Glc2-Glc G1c6-Ara(f)

Rb2 G1c2-Gic Glc6-Ara(p)

Rb3 Gic2-Glc Glc6-Xyl2Rd Gic -Glc Gic

Korean red ginseng is made by steaming andRg3 Gic2-Glc H

diying fresh ginseng by a traditional method,Rh2 Glc H

whereas white ginseng is made by simply

drying the fresh ginseng. The processed red ginseng contains some distinct constituents such

as the ginsenosides Rg3, Rg5, and Rkl, which are not found in white ginseng. There are

several reports that these unique compounds have potent biological activities, such as

anticancer and anti-inflammatory activities (Ref Simultaneous quantification of 14

ginsenosides in Panax ginseng CA. Meyer (Korean red ginseng) by HPLC-ELSD and its

application to quality control, Journal ofPharmaceutical and Biomedical Analysis 45 (2007)

164—170)

6





coo (A) (C1

iooo

00goo a400

200

iJiL LRjitpntjcui tIme (mm) Retention time (mirl)

1200 (fl) 1100 fl)

E 1000 1coa

EoD ;800a

aU, —400 400

200

_____________________

1•0 —

Retention timc (mini Retention time (mm)

Representative HPLC chromatograms of mixed standards and extracts of finished ginseng

products. Column: Agilent Zorbax SD-Aq C18 column (4.6mmx 150 mm, 5m), d etector:

ELSD. (A) Mixed standards with internal standard, (B) extract of white ginseng powder, (C)

extract of red ginseng powder, (D) extract of red ginseng concentrate. 1, Rgl; 2, Re; 3, Rf 4,

Rhi; 5, Rg2; 6, Rbl; 7, Re; 8, Rb2; 9, Rb3; 10, Rd; 11, Rg3; 12, Rkl; 13, Rg5; 14, Rh2; IS,

internal standard (digoxin).

7




DKSH North Amenca nc. 100 Stierli Court Suite 102 Mount Arlington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

2.Research data of Red Ginseng extract

Anti-oxidant effect & anti-tumor effect

Antioxidant and anti-tumor promoting activities of the methanol extract of heat-

processed ginseng. c’a,zcer Le#. 2000 Mar 13;150(]):41 -8.

Abstract; Heat treatment of Panax ginseng C.A. Meyer at a temperature higher than

that applied to the conventional preparation of red ginseng yielded a mixture of saponins

with potent antioxidative properties. Thus, the methanol extract of heat-processed

neoginseng (designated as NGMe’) attenuated lipid peroxidation in rat brain

homogenates induced by ferric ion or ferric ion plus ascorbic acid. Furthermore, the

extract protected against strand scission in phiX 174 supercoiled DNA induced by UV

photolysis of H202, and was also capable of scavenging superoxide generated by

xanthine-xanthine oxidase or by 12-O-tetradecanoylphorbol- 13-acetate (TPA) in

differentiated human promyelocytic leukemia (HL-60) cells. Topical application of

NGMe onto shaven backs of female ICR mice 10 mm prior to TPA, significantly

ameliorated skin papi Ilomagenesis initiated by 7,12- dimethylbenz[a] anthracene.

Moreover, TPA-induced enhancement of epidermal ornithine decarboxylase (ODC)

activity and ODC mRNA epression was abolished by a topical dose (0.68 mg) of

NGMe. Likewise, TPA-induced production of tumor necrosis factor- in mouse skin was

inhibited by NGMe pretreatment.

NGMe(mg/ml) % Inhibition of TBARS formation

NGMe(mg/ml) Fe3 Fe3 + ascorbic acid

0.25 2.7 ± 1.5 56.0 ± 16.7

0.5 30.0± 13.7 89.8± 2.6

1.0 93.5 ± 1.0 97.2 ± 0.5

2.0 97.7 ± 0.6 99.8 ± 0.2

Inhibitory effects of NGMe on lipid peroxidation in rat brain homogenates in vitro

8





250

C 200

150 i

z50

0’ —

Suppression of TNF-a production in mouse skin by Me. NGMe (0.68 mg) was

topically applied to the shaven backs of female ICR mice 30 mm prior to TPA (10 mg) in

acetone.

TNF-a is a major pro-infammatory cytokine that has been considered to be an

endogenous tumor promoter. NGMe treatment did not affect the basal level of TNF-a.

Based on these finding it is likely that the inhibitory effect of NGMe on mouse skin

tumor promotion is associated with its anti inflammatory as well as anti-oxidative

activity.

9

Acetone NGMe Acetone NGMe+ 1 + +

Acetone Acetone TPA WA





Wound healing effect

Effects of ginseng saponins isolated from Red Ginseng roots on burn wound healing

in mice. Br J Pharinacoh 148(6,:860 -70. 2006

Abstract; We recently demonstrated that ginsenoside Rbl (C54H92023, molecular

weight 1108) isolated from ginseng, when intravenously infused into rats with permanent

middle cerebral artery occlusion, reduced cerebral infarct volume and ameliorated place

navigation disability of the animals, through an anti-apoptotic action and possibly

promotion of vascular regeneration. To investigate the ginsenoside Rb 1-mediated

vascular regeneration in vivo in a more easily accessible experimental systems, we made

a bum wound on the backs of mice and topically applied either Vaseline (vehicle) alone

or Vaseline containing low doses of ginsenoside Rbl to the wound. 2. Surprisingly, we

found that ginsenoside Rbl at low concentrations (100 pg g(-1), 1 pg g(-1) and 10 fg g(

1) ointment) exhibited the strongest bum wound-healing action. Furthermore,

ginsenoside Rbl (100 fg-1 ng per wound) increased neovascularization in the

surrounding tissue and production of vascular endothelial growth factor (VEGF) and

interleukin (IL)-lbeta from the burn wound, compared to those mice with bum wounds

treated with vehicle alone. 3. In human keratinocyte cultures (HaCaT cells), ginseroside

Rbl (100 fg ml(- 1) to 1 ng ml(- 1)) enhanced VEGF production induced by IL- ibeta and

expression of hypoxia -inducible factor (HIF)- 1 alpha. 4. These findings suggest that the

promotion of bum wound healing by ginsenoside Rbl might be due to the promotion of

angiogenesis during skin wound repair via the stimulation of VEGF production, through

the increase of HIF -1 alpha expression in keratinocytes, and due to the elevation of IL

ibeta resulting from the macrophage accumulation in the burn wound.

10




DKSH North AmerIca Inc 100 Stierli Court Suite 102 Mount Arlington, NJ. 07856 (973) 810-5511 fax (973) 810-5520

Emmunohistochemical analysis of the effect of ginsenoside Rb I treatment on wound

healing in mice

b Xi (4? staining c N1aUrtIpFIto1 tainim:4 .•./

• .--cmA. i• ‘-a.-,

4 “‘‘.ft 2 •

:4;?‘. ?_i,, •-:. .

t.•‘. ttp

• a4•. ) ..-• * - , r -

t..’ t11.. - ‘ S

a •

SOtun 4’• •

Vcliic Ic- treated bum wound mice (Control)*

*,ff

0

4,- - 4

44 44*

%.tt’ -‘ ‘4

+ bEUF 2.5 pg per wound)— . . . .

. •i.•—•-,

E ‘F.

+ Ginscnosidc Rb1 (100 ig per wound)

34.4 .

+ (iinsenosjdc Rh1 (It) P8 P wound)

Light micrographs of cells stathed with hematoxylin—eosin (HE) (a), anti-mouse Ki-67(a well-

known marker of cellular proliferation) rat monoclonal antibody to show the keratinocyte

proliferation (b) or stained with anti-macrophage mouse monoclonal antibody to show the

macrophage migration (c) From this result, ginsenoside Rb) had found that keratinocyte

11





proliferation effect and migration of macrophages into the wound exudates was increased by the

application of ginsenoside Rbl

3.Hair Structure and Hair Life Cycle

Hair Structure

Hair is composed of strong structural protein called keratin. This is the same kind of

protein that makes up the nails and the outer layer of skin.

Each strand of hair consists of three layers.

1. An innermost layer or medulla which is only present in large thick hairs.

2. The middle layer known as the cortex. The cortex provides strength and both the color

and the texture of hair.

3. The outermcst layer is known as the cuticle. The cuticle is thin and colorless and

serves as a protector of the cortex.

Structure of the hair root

Below the surface of the skin is the hair root, which is enclosed within a hair follicle. At

the base of the hair follicle is the derrnal papilla. The dermal papilla is feed by the

bloodstream which carries nourishment to produce new hair.

The dermal papilla is a structure very

important to hair growth because it

contains receptors for male hormones

and androgens. Airogens regulate

hair growth and in scalp hair

Androgens may cause the hair follicle

to get progressively smaller and the

hairs to become finer in individuals

who are genetically predisposed to this

type of hair loss.

12

j.




DKSH North America Inc. 100 Stierli Court Suite 102 Mount Arlington, NJ. 07856 (973) 810-5511 fax (973) 810-5520

The Hair Growth Cycle

Ref htip:/’’niwföl/ic/e.corn

Hair follicles grow in repeated cycles. One cycle can be broken down into three phases.

independent of the neighboring hairs.

Anagen Phase - Growth Phase Approxhnately 85% of all hairs are in the growing phase at

any one time. The Anagen phase or growth phase can vary from two to six years. Hair

grows approximately 10cm per year and any individual hair is unlikely to grow more than

one meter long.

Catagen Phase - transitional phase At the end of the Anagen phase the hairs enters into a

Catagen phase which lasts about one or two weeks, during the Catagen phase the hair

follicle shrinks to about 1/6 of the normal length. The lower part is destroyed and the

dermal papilla breaks away to rest below.

Telogen Phase - resting phase The resting phase follows the catagen phase and normally

lasts about 5-6 weeks. During this time the hair does not grow but stays attached to the

follicle while the dermal papilla stays in a esting phase below. Approximately 10-15

percent of all hairs are in this phase at an one time.

At the end of the Telogen phase the hair follicle re-enters the Anagen phase. The dennal

papilla and the base of the follicle join together again and a new hair begins to form. If

13

cTAJEN

Each hair passes through the phases

F —-H





the old hair has not already been shed the new hair pushes the old one out and the growth

cycle starts all over again.

4.Hair Loss

The number of men and women who suffer hair loss and/or hair thinning is increasing in

accordance with clRnges in lifestyle and nutritional balance. Therefore, it is of great

importance to develop new therapies to prevent hair loss and to enhance hair growth

Hair LOSS CaUSeS

Common causes of hair loss Uncommon causes of alopecia

Male pattern baldness Poor blood flow

Trauma Infections such as syphilis

Chemicals Skin diseases such as lupus

Medications such as allopurinol, warfarin Cancers

Poor nutrition Hormone problems

Stress, for example, during a major illness Kidney failure / Liver failure

Hair Loss and DHT

The speed at which hair loss occurs in androgenic alopecia is dependant on by three

things:

1) Progression in age.

2) Heredity tendency to have hair loss

3) The prevalence of dihydrotestosterone (DHT) within the hair follicle

- rdudac

DHT is a highly active form of testosterone, which influences many aspects of manly

behavior, from sex drive to aggression. DHT which is produced in the prostate, various

adrenal glands, and the scalp is produced from testosterone by two 5-a reductase

14

DKSFI North America Inc.




isoenzymes

Part ? Technical Data

1. Explain of PLANOXIA-RG

2. Stability study

3. Safety study

15




DKSH North America nc. 100 Stierli Court Su[te 102 Mount Arlington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

1. Explain of PLANOXIA-RG

Overall Procedure for the preparation of PLANOXIA-RG

Extraction Solvent; 70% EtOH(natural origin)

Extraction time ; l2hr

Extraction temperature; 20-25?

Produce of final product and sterilization

Yes jQuality control

Yes

residual solvent (EtOH)less than 1%

Extraction and then 1st Filtration

(remove the extracted red ginseng)

Evaporation (remove the EtOH)

Centrifugation(4SOOrpm. 30mm) and then 2nd Filtration

(remove the predpitat

measurement of dry content on 110?

ReexfractionJ Dryc±ntsW:

No

16





PLANOXIA-RGS p e c I fi c a t i o nLatin Name Panax ginseng

INCI Name Water / Butylene glycol / Panax Ginseng Root Extract

Colour Pale yellow

Odor Typical

pH (10% solution) 4.0—7.0

Specific Gravity 0.980-1.100

Heavy Metal = 20ppm

Arsenic (As) = 2ppm

Dry residue (1 10? ) 0.2% (+ 0.02)

Distillated water less than 40%

1,3 - Butylene glycol contents 60%

Preservative Non-added

Residual solvent (EtOH) less than 1%

EINECS (Butylene glycol) 203-529-7

CAS (Butylene glycol) 107-8 8-0

Microbiology

Total Aerobic Count Less than 100 cfu!g

E. coli Not detected

Salmonella Not detected

Storage Sealed containers should be Stored at a temperature of lO—30?

CO fl d it 10 II (50—86? ), Quality might be affected after opening packing, pleaserefer to MSDS for more informations. After opening the drums,sterilization is no more guaranteed

Packaging unit 5kg! lokg/2Okg

Recom mendationdosageE x p1 ration Date 2 years in sealed original packing. stored in due

conditions

17





A p p1 i c a t ion Hair Care; Hair Conditioner, Shampoo, Hair Rinse, etc

2. Stability study

Stability as a function of pH

We have evaluated the stability of PL.47V0X1,4-RG at different pH. temperature, ethanol, at its

recommended dosage 1% to 5°/o in final products.

Function of pH of PLANOXIA-RG solution was measured using the potentiometric method.

Measurements were made at room temperature within a pH range of 2 to 10.

\pH

\\ 2 3 4 5 6 7 8 9 10

v’v

1% -t + + + + + + + +

2% + + + + + + + -t +

3% + + + + + + + + +

+ stable, ±; slightly unstable

PLANOXJA-RG shows good stability within the tested range of pH. Accordingly, it allows the use in

any formulations, PLANOXIA-RG can be formulated at any desired pH and shows efficacy

independently of the pH, however it is recommended to prepare formulations at the same pH of the

scalp

18





Stability as a function of temperature

This study was made at the pH of the solution (pH close to 5.0) at temperatures ranging from 40 to

80? , for 2 hours.

Temp

40? 60? 80?

VN

‘\30mm 60mm 120mm 30mm 60mm 120mm 30mm 60mm 120mm

1% + + + + + H- H- + +

3% + + + + + + + + +

5% + + + + + H- + + +


PLAN OXIA-RG shows good stability within the tested range of temperature. Therefore, it allows

the use in any formulations. PLANOXIA -RG does not show limitations during production processes

like heat.

19




DKSH North America Inc. 100 Stierli Court Suite 102 Mount Aiiington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

Stability in the presence of ethanol

The study of solubility in various water/ethanol mixtures was made at room temperature at the pH

of the solution (pH close to 5.0)

Ethanol / H20 (V/V)

(V/V)

10/90 20/80 30/70 40/60 50/50 60/40

1% + + + + + +

3% + + + + ± ±

5% + + + ± ± ±


PLANOXJ.4-F3 shows good stability within 10/90 (v/v) -. 60/40(v/v) the 1% tested concentration

and also shows good stability within 10/90 (v/v) 40/60(v/v) the 3% tested concentration. The 5% tested

concentration shows slightly unstable above 30/70(v/v). Therefore, PLANOXIA-RG is suitable in

formulations containing up to 40% ethanol. Higher concentrations of ethanol might affect the stability of

the product.

20





3. Safety study

Repeated insult patch test (RIPT)OBJECTIVE

To determine the irritation and/or sensitization potential of a test material after repeated application

under occlusive, semi-occlusive or open patches to the skin of human subjects.

TEST MATERIAL

PLANOXJA-RG 10% solution in distillated water

STUDY DATES

This study was initiated on June 25th, 2007 and was completed on July 20 ih 2007

PANEL SELECTION

Panels of human subjects, male and female, randomly selected. No individuals were empanelled if they

exhibited or had a history of acute or chronic dermatologic, medical, or physical conditions that could

interfere with dermal scoring.

TEST METHOD

Patches were applied to the same site on Monday, Wednesday, and Friday for a total of 9 applications

during the Induction period. The subjects remove the patches 24hours after each application. 24hour rest

periods follow each removal. Prior to each reapplication, site(s) were graded for dermal irritation and

sensitization

Dermal scores

0 No visible skin reaction

± Barely perceptible erythema (minimal)

1+ Mild erythema (diffuse)

2+ Well defined erythema

3+ Erythema and oedema

4+ Erythema and oedema with vesiculation

Ten to 21 days after application of the final induction patch, challenge patch(es) are applied to previously

unpatched sites, adjacent to the original induction patch sites. The challenge sites 24-72hours after

application.

REFERENCE

21





Standard Operating Procedures, Clinical Trials 930.00, Repeat Insult Patch Test (RIPT)

RESULT

Induction Scores Challenge Scores

Subject Subject 1 2 3 4 5 6 7 8 9 24hr 48hr 72hr

Number Initials

1 KIY 0 0 0 0 0 0 0 0 0 0 0 0

2 JKJ 0 0 0 0 0 0 0 0 0 0 0 0

3 CHC 0 0 0 0 0 0 0 0 0 0 0 0

4 PDO 0 0 0 0 0 0 0 0 0 0 0 0

5 UJK 0 0 0 0 0 0 0 0 0 0 0 0

6 SHC 0 0 0 0 0 0 0 0 0 0 0 0

7 LKS 0 0 0 0 0 0 0 0 0 0 0 0

8 CYS 0 0 0 0 0 0 0 0 0 0 0 0

9 YYJ 0 0 0 0 0 0 0 0 0 0 0 0

10 LHS 0 0 0 0 0 0 0 0 0 0 0 0

CONCLUSION

Based on the test population of 10 subjects and under the conditions of this study, the PLANOXIA-RG

10% solution identified did not demonstrate a potential for eliciting dermal irritation on sensitization.

22




DKSH North America mc. 100 Stierli Court Suite 102 Mount Arlington, N.J. 07856 (973) 810-5511 fax (973) 810-5520

Ames test for mutagenicity

OBJECTIVE

To screen for mutagens through the simple and inexpensive procedure that uses a bacterial test organism.

It is a biological assay used in genetics, generally genetic toxicology, to test for mutagenic properties of a

chemical compound.

STUDY DATES

This study was initiated on July 2. 2007 and was completed on July 29th, 2007

TEST ORCANISMS

The test organism is a histidine-negative (his) auxotrophic strain ofsalinonel/a tvphiniuriurn that will not

grow on a medium deficient in histidine unless a back mutation to his (histidinepositive) has occurred.

PRINCIPLE OF TEST METHOD

It is recognized that the mutagenic effect of a product is frequently influenced by the enzymatic pathway

of an organism, whereby non-mutagens are transformed into mutagens and vice versa when introduced

into human system.

REFERENCE

K. Mortelmans. E. Zeiger., Mutation Research 455 (2000) 29-60. The Ames Salmonella. Microsome

mutagenicity assay.

RESULT

His+ revertants/plate

Test samplesTA98 TA100

Spontaneous test 20 146

4-NQO 3000 4000

PLANOXJA-RG3O% 31 108

PLANOXIA-AG 50% 39 127

PLANOXJA-RG 70% 47 140

CONCLUSION

Based on the test procedure and under the conditions of this study, the FLANOXJA-RG from 30% to 70%

23





solution identified did not demonstrate a potential for mutagenicirv.

MATERIAL SAFETY DATA SHEET

DATE April 30, 2007 WRITTEN BY:

SIGNATURE:

1. PRODUCT AND COMPANY IDENTIFICATION

Product name: PLANOXIA-RG

Productcode: RAO19

Use: Raw material for cosmetic

Manufacturer: RADIANT Rm 207 BIOINDUSTRY FOUNDATION, 188-53

Hupyeong-Dong, Chunchon-city, Gangwon-Do, ROK

Tel : +82- 33-244-1 243

Fax : +82-33-244-1367

E — mail [email protected]

Emergency call +82-33-244-1 243

G2. COMPOSITION AND IMFORMATION OF INGREDIENTS

Chemical Name: None

Molecular weight N.A

CAS Number (1.3 Butylene 107-88-0

glycol) 203-529-7

EINECS(1.3 Butylene glycol) Panax Ginseng Root Extract and Water and Butylene glycol

INCI Name: None

Hazardous ingredients:

3. HAZARDS

Information provided on the health effects of this product is based on individual components. All ingredients

are bound and potential for hazardous exposure as shipped is minimal. However, some vapours may be

released upon heating and the end-user (fabricator) must take the necessary precautions (mechanical

ventilation, respiratory protection, etc) to protect employees from exposure.

Main hazards No Known Health hazards

24





Health risks

Environment risks

Routes of exposure

4. FIRST AID

Skin:

Eyes:

ingestion

Inhalation

Experience shows no acute irritancy or toxic effects.

Handle the product with good working practice avoiding dispersion into

the environment.

InIation, Ingestion, Skin/Eye contact.

Wash off with soap and plenty of water.

Immediately irrigate with water.

Do not induce vomiting without medical advice.

Move to fresh air in case of accidental inhalation of fumes from

overheating or combustion. When symptoms persist or in all cases of

doubt seek medical advice.

5. FIRE FIGHTING

Suitable extinguishing media

Unsuitable extinguishing media

Special fire-fighting procedures

Unusual fire/explosion hazads

6. ACCIDENTAL RELEASE

Water spray, dry powder,

Carbon monoxide (CO),

Carbon dioxide (C02)

None known

Full-face self-contained breathing apparatus (SCBA) used in positive

pressure mode should be worn to prevent inhalation of vapour/fumes.

May emit irritant/toxic vapour/fumes under fire conditions.

Remove heat and sources of ignition. Drums and packing in danger should be cooled by pulverized water,

as heating could provoke a rise in pressure with explosion or deflagration risks.

Prevent entry into watercourses and pipeworks.

Immediately mop up with suitable absorbant equipment for subsequent correct disposal according to

current legislation.

7. HANDLING AND STORAGE

Store in a dry place and away from light to insure the quality. Keep the drums well closed in a well aired

place. Keep away from heat and sources of ignition. Do not smoke. In case of important heating of the

25





liquid, there is a risk of formation of explosive mixtures with air. Risk of fire in case of contact with hot area,

sparks or flames.

8. EXPOSURE CONTROL AND PERSONAL PROTECTION

Appearance: Liquid

Colours: Pale yellow

Odour: Typical

Specific Gravity at 20? : 0.980-1 .100

Solubility in water: Soluble

pH(10% soln.): 4.0-7.0

Vapour prsure N.A.

Vapour density N.A.

10. STABILITY AND REACTIVITY

Respiratory protection

Hand Protection

Eye Protection

Skin and body protection

Engineering measures

Facial mask

Protective gloves

Glasses with air-tight protection

Long sleeved clothing and safety shoes

Heat only in areas with appropriate exhaust ventilation. Provide

appropriate exhaust ventilation at machinery.

9. PHYSICAL AND CHEMICAL PROPERTIES

Thermal decomposition: Distillation without decomposition at normal pressure, No thermal decomposition in

case of correct storage and hidling.

Dangerous decomposition products: No dangerous decomposition products if storage and handling

conditions are respected. In case of fire or thermal decomposition, release of carbon monoxide and

carbonic anhydride.

Dangerous reactions : Reacts viobntly with powerful oxidising agents.

Hazardous decomposition products :May emit irritant/toxic vapour/fumes under fire conditions.

11. TOXICOLOGY

26





Acute toxicity: No toxical effect known

Sensitisation : Not sensitizing

Inhalation : Inhalation is possible only under aerosol conditions, and vapour/fumes

might be irritant/toxic.

12. ECOLOGICAL INFORMATION

No ecologic effect known

13. DISPOSAL

Recommended method to dispose the product without danger: Dispose in accordance with the current

legislation preferably using high temperature incineration or In a biological purification station in accordance

with the current legislation.

14. TRANSPORT INFORMATION

Not dangerous for transport. (ROAD -RAIL, SEA, AIR)

15. REGULATORY INFORMATION

Labelling according E.E.C. directives : Not submitted to labelling

16. OTHER INFORMATION

This information is furnished without warranty, except that it is accurate to the best knowledge of RADIANT

INC. The data on this sheet relates only to the specific material designated herein.

Remarks column

To the best of our knowledge PLANOXIA-RG is not made from nor containsGMO statement

any ingredients derived from GMO sources.

27





Part ? . Efficacy Data

28




DKSH North America nc. 100 Stiert Court Suite 102 Mount Arhngton, N.J. 07856 (973) 810-5511 fax (973) 810-5520

Hair growth effectOblective

Hair loss is a distressing condition for an increasing number of men and women. It is of great

importance; therefore, to develop new therapies for the treatment of hair loss. We examined

the effects of Red Ginseng extracts that have been traditionally used for treating hair loss in

oriental medicine in order to identif’ potential stimulants of hair growth.

Reference

1. The hair growth promoting effect of Asiasari radix extract and its molecular regulation,

Journal ofDermatological Science (2005) 38, 89—97

2 Promotion of hair growth by ginseng radix on cultured mouse vibrissal hair follicles,

Phytother Res. 2003 Aug;17(7,):797-800

Positive (‘ontrol

1. 5% Minoxidil (Minoxidil is a vasodilatory medication known for its ability to slow hair

loss and promote hair regrowth)

Positive (‘ontrol

1. Red Ginseng extract concentrate

2 1% Rg2

Test Method (Animal tests were required by medical devices and not cosmetic enquiries)

q’ Animals Five-week-old female C57BL/6 mice were allowed to adapt to their new

environment for one week, with food and ater provided adlibitum. The backs of the

mice were shaved with hair removal tape at seven weeks of age, at which time all of the

hair follicles were synchronized in the telogen stage. Starting the following day (day 1),

0.2 ml of test materials include positive controls were applied topically, on a daily basis,

for 14 days. Hair growth promotion was evaluated simply by observing the darkening of

the skin color, which indicated telogento-anagen conversion

29

DKSH North America nc.




V Immunohistochemistrv The mounted mouse skin tissie preparations were cut at a

thickness of 5 m, placed on microscope slides, and incubated for three miiutes each

serially in xylene, 99.5% ethanol and 70% ethanol for the removal of paraffin. The

sections were then washed in gently running tap water for 3 minutes, and immersed in

distilled water for 1 minute. H-E stainingtwas then performed for the sections from each

group of mouse.

t Haematoxylin & Eosin (HE) Staining; H&E stain, or hematoxylin and eosm stain, is a popular staining

method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist

looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E jj is a

fluorescent red dye resulting from the action of bromine on fluorescein. It can be used to stain cytoplasm,

collagen and muscle fibers for examination under the microscope. Haematoxylin can be used to stain cell

nuclei prior to examination under a microscope.

V Western blot analysis of hair growth factors Protein quantification of the samples was

performed by the method of Bradford using bovine serum albumin as a standard. After

boiling for 5 mm in sample buffer (50 mM Tris-HCI, pH 7.6, 0.1 M EDTA, 2%

bacitracin), 20 ig of each sample was loaded and electrophoretically size-separated with

a discontinuous system consisting of a 8% polyacrylamide resolving gel and a 5%

polyacrylamide stacking gel. The proteins were then electrophoretically transferred to a

nitrocellulose membrane at 20 mA overnight. The membranes were washed with Tris

buffered saline (pH 7.6) containing 0.1% Tween-20 (TBST) and were blocked for 1 h

with 5% skim milk in TBST. The membranes were then incubated for 2 h at room

temperature with affinity-purified, anti-human polyclonal antibodies against PCNA,

VEGF, Substance P diluted in TBST with 5% skim milk. The membranes were then

incubated for 1 h with second antibody in TBST with 5% skim milk. The bound antibody

was detected by enhanced chemiluminescence with Hyperfilm.

V Immunofluorescence Staining fr hair growth factor For immunofluorescence staining,

frozen tissue was fixed in cold acetone and chloroform, washed with PBS, and incubated with

primary and secondary antibodies.

PCNA(Proliferating Cell Nuclear Antigen) is a protein that acts as a processivity factor

for DNA polymerase delta in eukaryotic cells, cell-cycling marke r

VEGF(Vascular Endothelial Growth Factor) is a hair growth factors

Substance P induces transition of hair from telogen to anagen phase30




DKSH North America mc. 100 Stierli Court Suite 102 Mount Artngton. N.J. 07856 (973) 810-5511 fax (973) 810-5520

RESULT

1. Hair growth —promoting effects ofthe red ginseng extract

Visual score

+ +++ +++

25—5O% growth (+), 5O--75% growth (++), 75--I OO% growth (+++)

Immunokistochemistry (WE stainin)

After topical application onto the backs of mice for up to 14 days, the red ginseng extract

and Rg2 induced earlier telogen to anagen conversion than did the minoxidil and

negative control. Immunohistochemistry studies showed that the red ginseng extract and

Rg2 markedly increase the depth and size of the hair follicles, as compared to the

negative control and minoxidi I

Rg2 > Red Ginseng extract> Minoxidil > 1120

31

Test samplesVisual score for the hair growth

Day 7 Day 11 Day 14

H20 + + +

5% Minoxidil ++ II ++

1% Rg2 +++ +++ +++

Red Ginseng extract

DKSH North America nc.




2. Effect of the red ginseng extract on growth factor expression

Western blot analysis of hair rowtla factors

Lane 1,7: H20 / 2,8; Minoxidil /3.9; ?? I 4,10; ? ? / 5,11; Red ginseng extract /6,12; Rg2

Recently, several growth factors related to the hair growth cycle have been reported. In this

experiment, we used western blotting to search for growth factors that were affected by the rel

ginseng extract and Rg2. We measured the expression levels of PCNA, Substance P, VEGF

(stimulating effect on hair growth). From this data we know that Rg2 has very strong promotion

effect of Substance P expression. Immunofluorescence Staining studied showed that the Rg2, Red

ginseng extract markedly increased the expression of VEGF, PCNA as cunpared to the negative

control(H70)

32

Immunofluorescence Staining for hair growth factor





[Reference data]

Promotion of hair growth by ginseng radix on cultured mouse vibrissal hair follicles, Phytother Res.

2003 Aug;17(7):797-800

Hair growth effect of Red ginseng (RG-ext) or white ginseng (WG-ext) on organ culture of

mouse vibrissal hair follicles

After 48h After 72h

Sample Conc (? /ml)Length(? ) Activation(%) Length(? ) Activation(%)

Control - 476±34.8 - 625±48.7 -

20 522.2±26.1 9.7 663.0±31.1 5.9RG-ext

50 559.3±21.8 17.5 736.3±29.5 19.2

Control 574.9±32.2 - 728.4±55.1 -

20 539.7±38.3 Non active 732.262.3 4.1WG-ext

50 628.4±47.3 9.2 885.7±51.5 21.1

Ginseng Radix extracts are also found in such hair care agents. Increased blood

circulation around the head dermis may provide hair loss with additional energy thereby

stimulate hair growth. The results presented here indicated that Ginseng Radix possesses

hair growth promoting activity in mouse vibrissal hair follicle organ culture model.

33





Part ? Conclusion

1. Summary

2. Application of Cosmetics

34





1. Summary

PLANOXIA-RG is a Korean Red Ginseng extract as a hair growth agent based on its

abilities to induced earlier telogen to anagen conversion than did the minoxidil and negative

control.

Red ginseng extract markedly increase the depth and size of the hair follicles, it is from red

ginseng extract effect that help of hair growth factor expression such as VEGF, PCNA,

Substance P

35

ANAGEN CATAGEN TELOGEN

‘ PLANOXIA-RG ‘.




DKSH North America Inc. 100 Stierli Court Suite 102 Mount Arlington. N.J. 07856 (973) 810-5511 fax (973) 810-5520

2. Application of Cosmetics — Hair care product

36




DKSH North America nc. 100 Stierli Court Suite 102 Mount Arlington. N.J. 07856 (973) 810-5511 fax (973) 810-5520

Certifications

• May. 2005 Received an ISO 900 1/ 14001

• August. 2005 Certified clean manufacturing company

• Member of International Trade Association

• Member of Cosmetic, Toiletry and Fragrance Association

• Selected as the promising small or medium sized business

enterprise designated by Gang won Province

37

•

.: 4q KAB Zu I2LTFE

Rm 207 Bioindustry Innovation center

Hi-Tech Venture Town, 198-53

Hupyeng, Chuncheon, Gangwon

Seoul, Korea 200-957

Email :ra d ian tern ochoI.com

www.eradiant.co.kr




Personal Care iProducts CouncilCommitted to Safety,Quality & Innovation

TO:

FROM:

DATE: July 13, 2011

Memorandum

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CR)

John Bailey,Ph.D_3___01--%__\Industry Liaison to the CR Expert Panel

SUBJECT: Certificate of Analysis: Panax Ginseng Root

Cosmetochem International AG. 2009. Analyzenzertifikat (Certificate of Analysis) Ginseng PheurRadix conc.

1101 17th Street, N.W., Suite 3OO Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



CosmetochemIntemationol AGSennweidstrcisse 44/46CH-631 2 Steinhousen

Datum 25.03.09Analysenzertifikat Analyse Nr. AZ39244Auftragsnr./Datum 552505117.03.09

Ginseng PHEUR &stellung 09-1119Radix conc . Artikel Nr./FD 0342.07.20.001719

him Art -Nr 707450.00.0Ginsengwurzeln PhEur geschnitten Lot Nr. 3419301

Ursprung CNFreigaba. 12.03,08ZuQberprufenbis 12.03.11Untersucthtnacfi Ph.Eur. 6.0

Beschrelbung Mathode Spezifikationen Resu (tat

DEFINiTIONGinsengwurzel besteht aim den genzen oder geschnittenen,getrockneteten Wurzeln von Panax Ginseng CA. Meyer,(Weisser Ginseng)

PROFLJNGAUF IDENTITATA Makroskoptscbe PrfJfung Ph.Eur. Monographie Entspricht EntsprichtB. Mikroskopische PrOlong Ph.Eur. Monographie Entspricht EntsprichtC. DUnnschichtchrornatographie Ph,Eur, 2.2.27 Entspricht Entspricht

PROFLING AUF REINHEITFrende Bestandteile Ph.Eur. 2.8.2 max. 2.0% 0.0 %Fanax Quinquefouum Ph.Eur. Monographie Abwesend AbwesendTrocknungsverlust Ph.Eur. 2.2.32 max. 10.0 % 9.8 %Asche Ph.Eur. 2.4.16 max. 7.0 % 3.2 %salzsureundsliche Asche Ph.Eur. 2.8.1 max. 1.0% 0.1 %

GEM ALTGinsenosid Rgl + Gneenosid Rbl bereohnetaufdie Ph.Eur, 2.2.29 rriin. 0.40% 0.83%getroclinete IDroge

MIKROSIOLOGIEAerobe mesophile Keime Ph.Eur, 2,6.12 a max. 50’OOO’OOO KEEJ9 45000 KBE/gPiize Ph.Eur. 2.6.12 b max. 500.000 KBE/g 20 KBE/gEscherichiaColi Ph.Eur. 2.6.13 max. 500 KBE/g <10 KBE/g

• SCHWCRMETALLEBlei MS <0.040 mg/kgCadmium AAS 0.051 mg/kgQuecksilber. ME <0.010 mg/kg

I rnior’r JIMA F,IIIrAr’rIIn,.’c I



Seite 2Datum 25.03.09Analyse Nr. P239244Auftragsnr./Datum 552505/17.03.09Analysenzertifakat Sestellung 09-1119ArtikelNr, /10 0342,07.20.00/7w

Ginseng PHEUR ThreArt.-Mr, 707450.00.0Radix cairn Lot Mr 3419301

Ursp rung ONGinsengwurzeln PhEur geschriitten Freigabe 12.03.08

Zu ObeiprOfen b/s 12.03.11Untersucht neck Ph. Eur. 6.0

AFLATOXINEAflatoxin Si HPLC max. 2,0 p1kg <0.3 p/kgAfLatoxln 82 I-I PLC <0.3 p/kgAflatoxin Cl HPLC <0.3 p/kgAfiatoxinG2’ HPLC <0.3 p/kgAflatoxin 81tB2÷G1÷G2 Berechnet max 4.0 p/kg EntsprLcht

- I rnrirpArT IJSrijIIpArTIIp[r,jfl



eire 3Datum 25.U3.09Analyse Nit P239244

RuekstandsanaJyti k 552505/ 17.03.09

Artikel Nit lID 0342.07.20.00 / 719Ginseng PHEURIbm Art.-Nr, 707450.00.0Radix cone(Jrsprung CN

Ginsengwurzeln PhEur geschnftten Fr&gabe 12.03,08Zu UberprUfen bis 12.03.11Untersuclitnach Ph.Eur 6.0

Resuitat Resu!tatWirkstotf [mg!kg] DO Wirkstotf [mglkgj

PHOSPHORESTER - PESTIZIDE Phenkapton n.n,Acephat n.n. Phenthoat en.Azrnphos-ethyl n.e. Phorat (Surnme) n.n.Broreophos - ethyl n.n. Phosalon n.e.Bromophos - methyl n.e. PhosfolaneCarbophenothioe n.e. Ptrimiphos - ethyl n.e.Chiorpyrifos - ethyl en. Pirimiphos - methyl n.e.Chiorpyrifos - methyl n.e. Profenofos en.Chlorthiophos n n Prothiofes ,Coumaphos n.e. Pyrazophos en.’Cyanofeephos n.e. Pyridaphenthion enCyanophos

, n.e. Parathion - methyl n.e.Chiorfenviephos cia (E) n.e. Phosphaniidon-E n.n. , .

,Chlorfenvinphos-tJ-ansR) n,n. Phosphamidon-Z n.n.‘ ‘ -Chiorfenviephos (Summe) n.e. Phosphamidon (Summe) . n,n,

Diazinon n.e.‘ Quinaiphos n.n.

Diohiofenthion n.e. Saiithion (Dioxabeezophos) n.n.• Dichlorvos n.e. Sutfotep An.

Dioxathion n.e. Tetrachiorvinphos n.e.Ditalimphos . en. Tololotosmetyl

. n.e.Dimethoat n.e.

, Triazophos n.e.• Omethoat n.n. TrichIorOnat flit

-Dimethoat (Summe) n.e. TEPP• Edifenphos n.n. Terbufos n.e.

Eth]on n.e. Terbufos (Summe) n.e.• Ethoprophos we. Zinophos (Thionazin) n.e.

Etrimfos en. ORGANOCHLCR - PESTIZIDEEPN n.n. Benliuralin n.e.Fenamiphos en.

. Binapacryl n.e.• Fenchlorphos en. . Bromoxynil-ocancat n.e.• Fenitrothion n.e. Brornoxynil, einschl. Seize und Ester en.

• Perithion (Summe) en. Chiorfenapyr n.e.Fonophos n.e. Chiorfenson n.n.Formoihion n.e. Chiorothal-dirnetyl n.e.

• Fensuifothion (Summe) n.n. Chiorothalonil Itfl.Heptenophos n.e. Chiorthion

• iprobenfos n.e. Chiordan, tie ito.isocarbofos n.e. Chlordan, trans n.e.lsofenphos (Summe) n.e. oxy - Chiordari n.n.

• Jodphenphos en. Chiordari (Sunime cis-, trans-S and oxy-Chi n.e.• Leptophos n.e. Dichiobenil n.e.

Mecarbani n.e. Dicloran n.n.Mephosfofan n.e. Dicofol n.e.Methacrifos n.e. o,p- DDD n.e.• Methamidophos n.e. p,p - DDD n.e.Methidathion n.e. op-DDE n.n.Monocrotophos ito. pp - DDE 0.02.Malathion n.e. o,p - DDT en.Mevinphos-E n.e. p,p - DDT 0.01Movie phos-Z n.e. DDT (Sijmme) 0,03Mevinphos (Summe) n.e. Dieldrin n.n.Parathion - ethyl n.e. Aidrin fl;fl.



Ginseng PHEURRadix cant

Ginsengwurzeln PhEur geschnitten

Aidrin und Dieldrin (Summe)EndiinEndosulfan. alphaEndosulfan, betaEndosulfansulfatEndosulfän (Summa)FlubenziminèFluohioralinFlumetralin1-lalfenproxI-ICEHCH-alphsF-Id-I- betaHCH-deltal-$CH - epsilonHCI-I (Summe ohne Lindan)Heptach Forl-ceptachlorepoxid, cia1-leptachiorapoxid, transHaptachior (Summe)lsobenzanIsodrirtloxynri - Octanoatloxynli, einschl. Salas und EaterKetoefldrifl - deltaLindan (HCH - gamma)

• Methoxychior• Mirex

NitrapyrifiNitrofen

• Octachiorstyrol• oxyfluofen•

. pendimethalinPentachiorarisolpentachlorbenzolQuintozen

• Pentachloranitfl• . Methylpentachlorpheflylsuifld

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• PYRETHROIDEBifenthrinCyfluthrinCyhalothrin, lambda

• Cypermethrln (Summe)Deltamethrin (Summe)Fenpropathrin

• FluoythrlnatFenvalerat RR)SSFenvalerat RSISRFerrvalerat (Summe)Perniethrin (Summe)N-HALTIGE IJND WEITERE PESTIZIDEAlach ForAllethrinAzinphos - methylBrompropylatBuprofezlnDiflubenzu ranFipronilFiproniF-desutfinylFipronil (Summe)PhosmetPiperonylbutoxidProcymldonPropargitPropiconazolPyrethrine (Summe)Pyridaben

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TO:

iProducts Council

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (Cifi)

Committed to Safety,Quality & Innovation

FROM:

DATE:

Halyna Breslawec, Ph.D.Industry Liaison to the CIR Expert Panel

September 30, 2011

SUBJECT: HRIPT of a Product Containing Panax Ginseng Root Extract

Consumer Product Testing Co. 2010. Repeated insult patch test of a cuticle serum containing 0.1%Panax Ginseng Root Extract. Study Number: C 10-1072.04

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org

Personal Care

Memorandum



Consumer Product Testing Co.EST I75

CLIENT:

ATTENTION:

FINAL REP ORT

TEST:

Licensed Cosmetologist

Repeated Insult Patch TestProtocolNo.: 1.01

TEST MATERIAL;

EXPERIMENTREFERENCE NUMBER:

Reviewed by:

Approved by:

Approved by:

Serum ENG044980-O.1.1.16,

Cl 0-1072.04

,kA 4Richard R. Eisenberg, M.D.Medical DirectorBoard Certified Dermatologist

mMichael Caswell, Ph.D., C.C.R.C., C.C.R.A.Director, Clinical Evaluations

Joy rExecutive Vice President, Clinical Evaluations

This report is submitted for the exclusive use of the person, partnership, or corporation to whom it is addressed, and neither the report nor thename of these Laboratories nor any member of its staff, may be used in connection with the advertising or sale of any product or processwithout written authorization.

O I°/o

LrsuvjCL4

70 New Dutch Lane • Fairfield, New Jersey 07004-25 14 • (973) 808-71 11 • Fax (973) 808-7234



Consumer Product Testing Co.Em: 1975

QUALITY ASSURANCE UNIT STATEMENT

Study Number: C1O-1072.04

The Consumer Product Testing Company, Incorporated (CPTC) Quality Assurance Unit (QAU) isresponsible for monitoring the conduct, content and reporting of all clinical laboratory studies that areconducted at CPTC.

This study has been conducted in accordance with ICH Guideline E6 for Good Clinical Practice, therequirements of 21 CFR Parts 50 and 56, other applicable regulations, CPTC Standard OperatingProcedures, and the approved Study Protocol.

The CPTC QAU has reviewed all data, records, and documents relating to this study and also this FinalReport. The following QAU representative signature certifies that all data, records, and documentsrelating to this study and also this Final Report have been reviewed and are deemed to be acceptable, andthe study conforms to all of the requirements as indicated above.

Quality Assurance Representative ate

70 New Dutch Lane Fairfield, New Jersey 07004-2514 • (973) 808-71 11 • Fax (973) 80S-7234Clinical • Toxicology • Analytical Chemistry • Microbiology



C 10-1072.04Page 3 of 13

Objective: To determine by repetitive epidermal contact the potential of a test materialto induce primary or cumulative irritation andlor allergic contactsensitization.

Participants: One hundred thirteen (113) qualified subjects, male and female, ranging inage from 17 to 70 years, were selected for this evaluation. Ninety-nine (99)subjects completed this study. The remaining subjects discontinued theirparticipation for various reasons, none of which were related to theapplication of the test material.

Inclusion Criteria; a. Male and female subjects, age 6 and over.b. Absence of any visible skin disease which might be confused with a skin

reaction from the test material.e. Prohibition of use of topical or systemic steroids andlor antihistamines

for at least seven days prior to study initiation.d. Completion of a Medical History form and the understanding and

signing of an Informed Consent form.e. Considered reliable and capable of following directions.

Exclusion Criteria: a. Ill health.b. Under a doctor’s care or taking medication(s) which could influence the

outcome of the study.e. Females who are pregnant or nursing.d. A history of adverse reactions to cosmetics or other personal care

products.

Test Material: — ENG044980-0.1.l.16,

Study Schedule: Panel # Initiation Date Completion Date

20100126 Mareh22,2010 April29,201020100127 March24,2010 April29,2010

aWith parental or guardian consent



C 10-1072.04Page 4 of 13

Methodology: The upper back between the scapulae served as the treatment area.Approximately 0.2 g of the test material, or an amount sufficient to cover thecontact surface, was applied to the 1” x 1” absorbent pad portion of a clearadhesive dressing and allowed to volatilize for several minutes. This wasthen applied to the appropriate treatment site to form a semi-occlusive patch.

Induction Phase:

Patches were applied three (3) times per week (e.g., Monday, Wednesday,and Friday) for a total of nine (9) applications. The site was marked to ensurethe continuity of patch application. Following supervised removal andscoring of the first Induction patch, participants were instructed to remove allsubsequent Induction patches at home, twenty-four hours after application.The evaluation of this site was made again just prior to re-application. If aparticipant was unable to report for an assigned test day, one (1) makeup daywas permitted. This day was added to the Induction period.

With the exception of the first supervised Induction Patch reading, if any testsite exhibited a moderate (2-level) reaction during the Induction Phase,application was moved to an adjacent area. Applications were discontinuedfor the remainder of this test phase, if a moderate (2-level) reaction wasobserved on this new test site. Applications would also be discontinued ifmarked (3-level) or severe (4-level) reactivity was noted.

Rest periods consisted of twenty-four hours following each Tuesday andThursday removal, and forty-eight hours following each Saturday removal.

Challenge Phase:

Approximately two (2) weeks after the final Induction patch application, aChallenge patch was applied to a virgin test site adjacent to the originalInduction patch site, following the same procedure described for Induction.The patch was removed and the site scored at the clinic twenty-four andseventy-two hours post-application.



dO- 1072.04Page 5 of 13

Methodology(continued): Evaluation Criteria (Erythema and additional Dermal Segnelae):

o = No visible skin reaction E = Edema0.5 = Barely perceptible U = Dryness

1 = Mild S = Staining2 = Moderate P = Papules3 = Marked V = Vesicles4 = Severe B = Bullae

U = UlcerationSp — Spreading

Eryrthema was scored numerically according to this key. If present, additionaLDermal Sequelae were indicated by the appropriate letter code and anumerical value for severity.

Results: The results of each participant are appended (Table 1).

Observations remained negative throughout the test interval.

Subject demographics are presented in Table 2.

Summary: Under the conditions of this study, test material, 2uticle SerumENG044980 did not indicate a potential for

dermal irritation or allergic contact sensitization.



Table 1Panel #20100126

Cl 0-1072.04Page 6 of 13

Individual Results

Virgin ChallengeSubject Induction Phase SiteNumber 24*hr 1 2 3 4 5 6 7 8 9 24*hr 72 hr

23

456

789101112

1314

1516

171819

20

21

2223

24

2526

2728

29

0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 DID

0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0, 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 00 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0

0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0

0 0 0

0 0 00 0 00 0 00 0 00 0 0

COMPLETE STUDY

0 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 0

0 0 00 0 00 0 00 0 00 0 00 0 00 0 00 0 0

00

0

00

0NOT

00

0

0

00

00

000

000

00

0

0

00

0

0

24* Supervised removal of I Induction and Challenge Patch



Table 1(continued)

Panel #20100126

Individual Results

C10-1072.04Page 7 of 13


30 DID NOT COMPLETE STUDY31 0 0 0 0 0 0 0 0 0 0 0 032 0 0 0 0 0 0 0 0 0 0 0 033 0 0 0 0 0 0 0 0 0 0 0 034 0 0 0 0 0 0 0 0 0 0 0 035 0 0 0 0 0 0 0 0 0 0 0 036 0 0 0 0 0 0 0 0 0 0 0 037 0 0 0 0 0 0 0 0 0 0 0 038 0 0 0 0 0 0 0 0 0 0 0 039 0 0 0 0 0 0 0 0 0 0 0 040 0 0 0 0 0 0 0 0 0 0 0 041 0 0 0 0 0 0 0 0 0 0 0 042 0 0 0 0 0 0 0 0 0 0 0 043 0 0 0 0 0 0 0 0 0 0 0 044 0 0 0 0 0 0 0 0 0 0 0 045 0 0 0 0 0 0 0 0 0 0 0 046 0 0 0 0 0 0 0 0 0 0 0 047 0 0 0 0 0 0 0 0 0 0 0 048 0 0 0 0 0 0 0 0 0 0 0 049 0 0 0 0 0 0 0 0 -DID NOT COMPLETE STUDY50 0 0 0 0 0 0 0 0 0 0 0 051 DID NOT COMPLETE STUDY52 0 0 0 0 0 0 0 0 0 0 0 053 0 0 0 0 0 0 0 0 0 0 0 054 0 0 0 0 0 0 0 0 0 0 0 055 — DID NOT COMPLETE STUDY —---------—-------------

56 0 ---- —----- DID NOT COMPLETE STUDY------------- —----

57 0 0 0 0 0 0 0 0 0 0 0 0

24* = Supervised removal of l Induction and Challenge Patch




Individual Results

C10-1072.04Page 8 of 13


1 0 0 0 0 0 0 0 0 0 0 0 02 0 0 0 0 0 0 0 0 0 0 0 03 0 0 0 0 0 0 0 0 0 0 0 04 0 0 0 0 0 0 0 0 0 0 0 05 0 0 0 0 0 0 0 0 0 0 0 06 0 0 0 0 0 0 0 0 0 0 0 07 0 0 0 0 0 0 0 0 0 0 0 08 0 0 0 0 0 0 0 0 0 0 0 09 0 — — - —----DID NOT COMPLETE STUDY — —------

10 0 0 0 0 0 0 0 0 0 0 0 011 0 0 0 0 0 0 0 0 0 0 0 012 0 0 0 0 0 0 0 0 0 0 0 013 0 0 0 0 0 0 0 0 0 0 0 014 0 0 0 0 0 0 0 0 0 0 0 015 0 0 0 0 0 0 0 0 0 0 0 016 0 0 0 0 0 0 0 0 0 0 0 017 0 0 0 0 0 0 0 0 0 0 0 018 0 0 0 0 0 0 0 0 0 0 0 019 0 0 0 0 0 0 0 0 0 0 0 020 0 0 0 0 0 0 0 0 0 0 0 021 0 0 0 0 0 0 0 0 0 0 0 022 0 0 0 0 0 0 0 0 0 0 0 023 0 0 0 0 0 0 0 0 0 0 0 024 0 0 0 0 0 0 0 0 0 0 0 025 0 0 0 0 0 0 DID NOT COMPLETE STUDY26 0 0 0 0 0 0 0 0 0 0 0 027 0 0 0 0

28 0 0 0 029 0 0

0 0 0 0 0 00 0 0 0 0 0 0 0

•—----------DID NOT COMPLETE STUDY -

0 0

24* Supervised removal of l Induction and Challenge Patch



Table 1(continued)

Panel #20100 127

dO- 1072.04Page 9 of 13

Individual Results


0

33 0 0 0 0 0 0 0 0 0 034 0 0 0 0 0 0 0 0 0 035 0 0 0 0 0 0 0 0 0 036 ‘0 0 0 0 0 0 0 0 0 0

44 0

45 046 047 048 049 050 051 052 053 0

0 0 0 0

0 0 0 00 0 0 0

54 0 0 0 0 055 0 0 0 0 0

o o 0 0

NOT COMPLETE STUDYDID NOT COMPLETE STUDY-

o 0 0 0 0

24* = Supervised removal of l Induction and Challenge Patchm = Additional makeup day granted at the discretion of the clinic supervisor

31 032 0

30 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 om 0 0

DID NOT COMPLETE STUDY0 0

37 0 0 0 0 038 0 0 0 0 0

o o 0 0 0o 0 0 0 0

0 00 00 0

0 00 00 0

39 0 0 0 0 0 0 0 0 0 0 0 040 0 0 0 0 0 0 0 DID NOT COMPLETE STUDY41 0 0 0 0 0 0 0 0 0 0 0 042 0 0 0 0 0 043 0 0 0 0 0 0

0 0 0 0 0 00 0 0 0 0 0

0 0 0 0 0 0 0 0-DID NOT COMPLETE STUDY.

0 0 0 0

0 0 0 0

0 0 0

L

0 0

0 0

0 0

0 0

0 0 00 0 00 0 0

0 00 00 0

0 0 0 0 00 0 0 0 00 0 0 0 00 0 0 0 0

.-0 -0-- 0 O -

0 00 00 00 00 00 0



Table 2Panel #20 100126

Subject Demographics

C10-1072.04Page 10 of 13

SubjectNumber Initials Age Sex

I JK 49 M2 AV 63 F3 LH 47 F4 VDP 48 F5 DAM 54 F6 BT 47 p

7 GD 69 M8 MD 66 F9 JR 26 M10 TDE 45 F11 ALM 31 F12 JS 34 F13 CMP 25 F14 00 33 F15 MRK 69 F16 1MM 34 F17 MJD 27 F18 RID 67 F19 JIC 43 M20 RM 33 F21 SC 52 F22 GV 37 F23 ELP 69 F24 DAW 45 F25 TSB 38 F26 CIZ 33 F27 EM 43 F28 GO 54 F29 M---- ...



Table 2(continued)

Panel #20100126


C 10-1072.04Page 11 of 13

Subj eelNumber Initials Age Sex

30 JS 18 M31 DES 32 F32 DN 50 F33 ZC 59 F34 A13 61 F35 JPT 19 F36 MR 32 F37 PC 45 F38 .FVR 64 F39 CGZ 45 F40 CM 45 F41 MAE 42 F42 DJO 47 M43 LAD 18 F44 PRL 42 M45 BMP 26 M46 MP 50 F47 MV 49 F48 LMV 58 M49 MRM 19 M50 LMR 44 F51 SDC 23 F52 DAM 51 M53 PMP 55 F54 CAL 69 F55 DF 55 F56 CET 36 F57 CJM F.





dO- 1072.04Page 12 of 13


1 NL 61 F2 WHH 69 M3 RMS 59 F4 MAH 63 F5 DLP 55 F6 FP 70 F7 EEH 65 F8 KMG 30 F9 RJG 19 M10 LSC 55 F11 EJE 66 F12 AM 40 F13 KI 39 M14 AS 61 M15 AG 49 M16 0’! 33 M17 AN 52 F18 CC 47 F19 MJG 41 F20 PAB 62 F21 CBR 59 F22 PRO 47 F23 FF1 56 F24 BAP 66 F25 DMS 39 F26 CLD 51 F27 CR 57 F28 CMM 44 F

29..-._



Table 2(continued)

Panel #20100 127


ClO- 1072.04Page 13 of 13


30 50 57 F31 RNO 36 M32 RMD 52 F33 DD 49 M34 JMB 57 M35 RIB 47 F36 JRS 53 M37 MAll 54 F38 SBO 63 F39 LAK 39 F40 500 39 F41 KIVIF 44 F42 SLH 22 F43 MH 40 F44 JTA 42 M45 DSS 29 F46 JDL 20 F47 AMP 19 F48 FND 68 F49 JAR 23 M50 JML 32 F51 JLS 30 F52 DLC 53 F53 BEM 56 F54 RMF 41 F55 SMT 34 M56 STS 19 M



Halyna Breslawec, Ph.D.

‘Products CouncilCommitted to Sofety,Quality & Innovation

Industry Liaison to the CR Expert Panel

DATE: October 26, 2011

SUBJECT: Concentration of Use by FDA Product Category: Panax-Derived Ingredients


Personal Care

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CR)

FROM:



Concentration of Use by FDA Product Category*Panax Ginseng Root Extract Panax Ginseng Root OilHydrolyzed Ginseng Root Panax Ginseng Root ProtoplastsHydrolyzed Ginseng Root Extract Panax Japonicus Root ExtractHydrolyzed Ginseng Saponins Panax Notoginseng Root ExtractPanax Ginseng Root Panax Notoginseng Root PowderPanax Ginseng Root Powder Panax Quinquefolium Root ExtractPanax Ginseng Root Water

Ingredient Product Category MaximumConcentrations ofUse

Panax Ginseng Root Extract Bath oils, tablets and salts 0.00004%

Panax Ginseng Root Extract Bubble baths 0.0001%

Panax Ginseng Root Extract Other bath preparations 0.0004%

Panax Ginseng Root Extract Eye shadow 0.002-0.02%

Panax Ginseng Root Extract Eye lotion 0.0003-0.1%

Panax Ginseng Root Extract Mascara 0.00001%

Panax Ginseng Root Extract Other eye makeup preparations 0.002%

Panax Ginseng Root Extract Colognes and toilet waters 0.0001%

Panax Ginseng Root Extract Hair conditioners 0.000002-0.1%

Panax Ginseng Root Extract Rinses (noncolonng) 0.002%

Panax Ginseng Root Extract Shampoos (noncoloring) 0.00001-0.3%

Panax Ginseng Root Extract Tonics, dressings and other hair 0.000002-0.3%grooming aids

Panax Ginseng Root Extract Other hair preparations 0.3%(noncoloring)’

Panax Ginseng Root Extract Hair dyes and colors (all types 0.0002-0.005%requiring caution statement andpatch test)

Panax Ginseng Root Extract Blushers (all types) 0.0001%

Panax Ginseng Root Extract Face powders 0.0004-0.01%

Page 1 of 4



Panax Ginseng Root Extract Foundations 0.0001-0.05%

Panax Ginseng Root Extract Lipstick 0.0001-0.1%

Panax Ginseng Root Extract Makeup bases 0.05%

Panax Ginseng Root Extract Makeup fixatives 0.00002%

Panax Ginseng Root Extract Other makeup preparations 0.05%

Panax Ginseng Root Extract Basecoats and undercoats 0.00001%(manicuring preparations)

Panax Ginseng Root Extract Cuticle softeners 0.05-0.1%

Panax Ginseng Root Extract Nail creams and lotions 0.05%

Panax Ginseng Root Extract Nail polish and enamel 0.002%

Panax Ginseng Root Extract Bath soaps and detergents 0.0001-0.001%

Panax Ginseng Root Extract Deodorants (underarm) 0.02%

Panax Ginseng Root Extract Other personal cleanliness products 0.00004%

Panax Ginseng Root Extract Aftershave lotions 0.0003-0.02%

Panax Ginseng Root Extract Beard softeners 0.002%

Panax Ginseng Root Extract Shaving cream (aerosol, brushless 0.1%and lather)

Panax Ginseng Root Extract Skin cleansing (cold creams, 0.0001-0.1%cleansing lotions, liquids and pads)

Panax Ginseng Root Extract Depilatories 0.0002-0.04%

Panax Ginseng Root Extract Face and neck creams, lotions and 0.0001-0.1%powders

Panax Ginseng Root Extract Body and hand creams, lotions and 0.0002-0.5%powders

Panax Ginseng Root Extract Foot powders and sprays 0.00005%

Panax Ginseng Root Extract Moisturizing creams, lotions and 0.000003-0.03%powders

Panax Ginseng Root Extract Night creams, lotions and powders 0.04-0.1%

Panax Ginseng Root Extract Paste masks and mud packs 0.005-0.05%

Page 2 of 4



Panax Ginseng Root Extract Other skin care preparations 0.0001-0.5%

Panax Ginseng Root Extract Suntan gels, creams and liquids 0.006-0.1%

Panax Ginseng Root Extract Other suntan preparations 0.0001%

Panax Ginseng Root Extract Bath oils, tablets and salts 0.00009%(WHITE)

Panax Ginseng Root Extract Eye lotion 0.002%(WHITE)

Panax Ginseng Root Extract Hair conditioners 0.0003%(WHITE)

Panax Ginseng Root Extract Shampoos (noncoloring) 0.0003%(WHITE)

Panax Ginseng Root Extract Tonics, dressings and other hair 0.0003%(WHITE) grooming aids

Panax Ginseng Root Extract Face powders 0.0003%(WHITE)

Panax Ginseng Root Extract Foundations 0.0003%(WHITE)

Panax Ginseng Root Extract Makeup bases 0.0003%(WHITE)

Panax Ginseng Root Extract Skin cleansing (cold creams, 0.0003%(WHITE) cleansing lotions, liquids and pads)

Panax Ginseng Root Extract Face and neck creams, lotions and 0.04%(WHITE) powders

Panax Ginseng Root Extract Body and hand creams, lotions and 0.002%(WHITE) powders

Panax Ginseng Root Extract Moisturizing creams, lotions and 0.009%(WHITE) powders

Panax Ginseng Root Extract Paste masks and mud packs 0.0003%(WHITE)

Panax Ginseng Root Extract Perfumes 0.00004%(RED)

Panax Ginseng Root Extract Shampoos (noncoloring) 0.003%

Page 3 of 4



(RED)

Panax Ginseng Root Extract Skin cleansing (cold creams, 0.003%(RED) cleansing lotions, liquids and pads)

Panax Ginseng Root Extract Face and neck creams, lotions and 0.001%(RED) powders

Panax Ginseng Root Extract Moisturizing creams, lotions and 0.002-0.003%(RED) powders

Panax Notoginseng Root Dentifrices (aerosol, liquid, pastes 0.0004%Extract and powders)

Panax Quinquefolium Root Shampoos (noncoloring) 0.0005%Extract

Panax Quinquefolium Root Bath soaps and detergents 0.002%Extract

*Ingredients included in the title of the table but not found in the table were included in theconcentration of use survey, but no uses were reported.‘0.3% in a rinse-off noncoloring other hair preparation

Information collected in 2011Table prepared October 26, 2011

Page 4 of 4



Persona Care iProducts CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REViEW (CIR)

FROM: John Bailey, Ph.D. r7_.s.__QL_____\ 3—il— IIndustry Liaison to the CIR Expert Panel

DATE: July 11, 2011

SUBJECT: Comments on the Scientific Literature Review on Panax Ginseng Root Extract andOther Ginseng Root-Derived Ingredients as Used in Cosmetics

Cover - Is Wilbur Johnson really the author of this report (as indicated on the cover of the report)?NTP report, reference 82 - The 2009 NTP report is a Board draft that says “Not for distribution or

attribution” on every page. If this NTP report is cited in the CIR safety assessment, it should bemade clear everywhere the NTP report is cited that this is Board draft. Perhaps C]R staffshould contact NTP to see when this report is expected to be finalized. If it is soon, this CRreport should be delayed until the final NTP report is available (or at least until the Councilconcentration of use survey is complete (sometime after the September 2011 CR Expert Panelmeeting)). If the NTP studies are left in the report, the extract studied should be made clear.The draft NTP report indicates that they used 3 lots of 80% ethanol extracted Panax ginsengroot. The ginsenoside content was 7.4% in two lots and 10.9% in the third lot.

p.1, 10 - Please change “cosmetic uses” to “cosmetic functions”. In the functions, “skin-conditionagents - miscellaneous” is listed twice.

p.1 - Jojoba oil is a fixed oil and not an essential oil and should not be given as an example of a “non-triglyceride” oil.

p.1 - The following is not correct: “The term water refers to the instance wherein the water has come incontact with the named material (ie, panax ginseng root water is water that in some way hascome into physical contact with P. ginseng root).” Under the chemical class “Essential Oilsand Waters” the Dictionary states the following: “The water soluble fraction from the steamdistilled plant material is identified by the term ‘Water” in the INCI name.” It goes on to states:“Different names are assigned to “Waters” that are prepared by steam distillation from thosethat are prepared by adding water to materials isolated by solvent extraction of plant materials,i.e., extracts, or other by processes. The latter are named as mixtures. For example, if a plantmaterial is prepared by the addition of water to a plant extract the INCI name would include thename of the extract followed by the term water. For example, if water is added to LavandulaAngustifolia (Lavender) Flower Extract the INCI name assigned is: Water (and) LavandulaAngustifolia (Lavender) Flower Extract. If a material is prepared by steam distillation the watersoluble fraction from Lavandula Angustifolia (Lavender) Flowers the INCI name assigned is:




Lavandula Angustifolia (Lavender) Flower Water. If a material is prepared by the addition ordissolution of an essential oil such as Lavender Oil in water the INCI name assigned is: Water(and) Lavandula Angustifolia (Lavender) Oil.”

Plants in cosmetics (reference 7 of this report) provides the following definition of a water:“Aromatic distilled waters of plants or waters of plants are aqueous solutions containingessential oils of these plants. They are obtained by condensation of the water steam used whenobtaining these essential oils by steam distillation.”

pA. - Rather than the properties of cosmetic ingredients, please state that Table 8 provides theproperties of saponins found in ginseng.

p.4 - In the Non-Cosmetic use section, it would also be helpful to state that ginseng is found in someenergy drinks.

p.6 - Unless the mice were exposed to a mixture of water extracts of herbs, it is not necessary toinclude all the other species. If a mixture was used, please make that clear when summarizingreference 80.

p.6, 10 - Please used “ginseng root-derived” rather than “ginseng root-related” when describing theingredients in this report.

p.6 - How was G1 15 obtained? What was the level of ginsenosides in this extract?p.7 - In the text of the Human oral exposure section, it would be helpful to provide some indication of

the doses used. What is a typical human dose of ginseng root extract that is not associated withadverse effects in humans?

p.7, 10 - As exposure was only during gestation in reference 166, the Reproductive and DevelopmentalToxicity section should indicate that there was one developmental toxicity study and onereproductive and developmental toxicity study (or one-two-generation study). The highest doseused in the reproductive and developmental toxicity study was 15 mg/kg/day. The high dose of20 mg/kg/day was used in the developmental toxicity study.

p.7, 8 - Please use the heading “Ginseng Saponins” rather than “Saponins”p.7 - In the summary of the Genotoxicity section please indicate the types of assays in which the

ginseng root preparations were not mutagenic.p.7 - As the summary of reference 89 indicates that Panax Ginseng Root Extract was provided in feed,

this study is not an in vitro study. Either the in vitro heading needs to be removed, or an in vivogenotoxicity section needs to be added to the report. How long were the rats treated with PanaxGinseng Root Extract in this study (reference 89)?

p.7, 11 - The conclusion of the NTP study (no evidence of carcinogenicity in mice or rats) should beincluded in the Carcinogenicity section and in the Summary.

p.7-8 - The information currently in the Carcinogenicity section concerns cancer prevention propertiesand should be in a separate section.

p.8 - Has the format of CJR reports changed again? Generally, sections are divided into non-humanand human subsections. This is not done in the Irritation sections. The studies showing thatPanax Ginseng Root Extract alleviate dermal effects of other substances should be in a separatesection. What was the vehicle used in the human patch test study of Panax Ginseng RootExtract (reference 79)?

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p.9 - The studies that suggest that Panax Ginseng Root Extract provides protection from adverse effectsof UV radiation should not be presented in the Phototoxicity section.

p.9, 10 - If it is not possible to distinguish between subjects taking Panax ginseng and subjects takingSiberian ginseng, perhaps reference 107 should be removed from the report as Siberian ginsengis Eleutherococcus senticosus which is not a subject of this CIR report.

p.10 - In the summary, it is not clear what is meant by: “There were no dermal, percutaneous, orinhalation data discovered.” There was some dermal safety data summarized in the report.Does this sentence only apply to absorption or pharmacokinetic data?

p.12, Figure 2 - Please provide a reference for Figure 2.p.13-21, Table 2, p.21-23, Table 3, p.23-24, Table 4, p.24, Table 5 - These tables would be more useful

if the ingredients were grouped by plant part, so that all of the ingredients in the root oils weretogether. The ubiquitous compounds, such as aluminum and amino acids should either beremoved from the tables or placed in separate tables.

p.25, Table 8, p.27, Table 11 - The title of the tables should indicate that these saponins are derivedform ginseng.

p.26, Table 10 - As the title of the table indicates that all the measurements were in plasma, “plasma” isnot needed in the column titled “Species model, route.” What was the route of exposure usedin the human study (it currently says “in vivo”)? What was the route of exposure in the lastfour rat studies? It is not clear what is meant by “Absolute bioavailability” if the study wasdone in vitro.

p.27-28, Table 13, p.28, Table 14, p. 29, Table 15 - As there were ginseng treated and placebo treatedsubjects or another treatment, what does “n” represent? It would be helpful to provide thenumber of treated versus placebo treated subjects, or indicate if the subjects served as their owncontrols.

p.30, Table 17 - If available, please describe the Panax Ginseng Root Extract used in references 166and 167. What was the extraction solvent? Was the level of saponins provided?

p.30, Table 18 - The title of this table should be changed to “In Vitro Developmental Studies ofSaponins Derived from Panax Ginseng” (or another source if appropriate).

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green ginseng root

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