Product Information Anti-Dandruff Agent

Zinc-Pyrion®

7th Issue: 01.07.2001

PYRION™ Biocides

Zinc-Pyrion®

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TABLE OF CONTENTS 1. Characteristics ..................................................................................... 2

Structural formula .............................................................. 2

2. Physical data ................................................................................................ 3

Melting range .......................................................................... 3 Solubility .......................................................................... 3 Stability .......................................................................... 3 Stability against light ............................................................... 4 Compatibility .......................................................................... 4 Density .......................................................................... 4 3. Toxicology ................................................................................................ 5

Oral Toxicity ......................................................................... 5 Teratogenicity ......................................................................... 5 Dermal Toxicity ......................................................................... 5 Ecotoxicity ......................................................................... 5 4. Effectiveness ................................................................................................ 6 5. Form of delivery .......................................................................................... 8 Zinc-Pyrion 48% aqueous suspension ....................................... 8 Zinc-Pyrion micronized 48% aqueous suspension ............................ 9 Zinc-Pyrion NF 48% aqueous suspension ....................................... 9 Zinc-Pyrion technical powder ....................................... 10 6. Formulations ............................................................................................... 11 7. Formulation principles of Zinc-Pyrion .................................................. 15 8. Analysis ............................................................................................... 16 Titration ......................................................................... 16 Preparation of samples .................................................. 16 Analytical method 2227-23 ....................................... 16 Analytical method 2227-22 ....................................... 17 Analytical method 2227-22 ....................................... 17 Determination of Zinc by AAS ................................................... 18 9. Storage ................................................................................................ 18 10. Precautions ................................................................................................ 18 11. Literature ................................................................................................ 18 1 CHARACTERISTICS

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Name: Zinc pyrithione; Zinc pyridinethione INCI-name: Zinc Pyrithione CTFA-name: Zinc Pyrithione Chemical names: Zinc-2-pyridinethiol-N-oxide Bis-(2-pyridylthio)zinc-1,1`-dioxide Bis-(1-hydroxy-2[1H]-pyridine-thionato-O,S)zinc. CAS-Nr.: 13463-41-7 EINECS-Nr.: 23 66 713 Total formula: C10H8N2O2S2Zn Molecular weight: 317,7 g/mol Structural formula:

N O

ZnS

SZn

O N

Appearance: off-white dry powder or white to cream aqueous suspension Odour: weak, characteristic Application: Anti-dandruff agent Suggested concentration in shampoos: 0,5 - 1 % based on active 2 PHYSICAL DATA

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2.1 Melting range

The pure and solid Zinc-Pyrion will melt above 240°C (464°F) with decomposition. 2.2 Solubility

Zinc-Pyrion is nearly insoluble in water. At pH 7 and 20°C (68°F) it is soluble to 10 - 20 ppm. The solubility increases to 35 - 50 ppm at pH 8. This is the reason why Zinc-Pyrion is exclusively used as a suspension in shampoos and lotions.

The solubility of Zinc-Pyrion in organic solvents is only slightly better as it is shown with the following data1:

Diethylether < 1 ppmBenzene 3-5 ppmCastoroil 10 ppmIsopropyl-palmitate 10 ppmPropylene glycol 200 ppmEthanol 300 ppmIsopropanol 300 ppmEthylene glycol 500 ppmMethanol 600 ppmAcetone 700 ppmChloroform 3400 ppmDimethylformamide 8100 ppmDimethylsulfoxide 5,13 %

Table 1 (100 ppm = 0,01 %)

The addition of amines or amino acids lead to complete solubility of Zinc-Pyrion2 . 2.3 Stability

Zinc-Pyrion suspension shows excellent stability against heat. It can be stored at 100°C (212°F) for four days without loosing its effectiveness. The aqueous suspension can be stored for a minimum of three years if the pH is between 4 and 8 and the temperature is above 10°C (50°F). Do not freeze. The stability of Zinc-Pyrion in shampoos should be evaluated, especially when cationic or amphoteric surfactants are present (see also compatibility).

2.4 Stability against light

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Formulations containing Zinc-Pyrion develop a weak yellowish colour on exposure to light. Either direct sunlight or UV-light can contribute to this decoloration. There is no data indicating that this color development reduces the efficacy of Zink-Pyrion. We suggest to store Zinc-Pyrion formulations in light-proof containers. If translucent containers are used a stability or activity determination should be done before use.

2.5 Compatibility

Zinc-Pyrion is compatible with most raw materials used in cosmetics. In the presence of cationic or amphoteric surfactants an insoluble precipitate can be formed. Because this phenomenon also depends on the pH and other ingredients (cationic conditioners) a compatibility test is highly recommended.

Zinc-Pyrion is compatible with many preservatives and can be used together with them.

If heavy metal ions (for example iron or copper) are present dark colored chelate complexes can be built. Even traces of heavy metals can lead to discoloration, because these complexes are usually stronger than the zinc complex (the complex building constant is higher). For this reason it is absolutely necessary to minimize the content of heavy metals. Strong complexing agents like phosphonates or an excess of zinc-ions could prevent discoloration. Considering that heavy metal pyriones still have a strong bacteriostatic and fungistatic effect, the effectiveness of Zinc-Pyrion is not influenced by these discolorations.

2.6 Density

Specific density of the powder: approx. 1.76 g/cm³ (at 25°C, 77°F) Bulk density of the powder: approx. 400 - 500 kg/m³ Density of the 48% suspension: approx. 1,27 - 1,30 g/cm³

3 TOXICOLOGY

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Zinc-Pyrion containing shampoos have been used worldwide for more than 30 years. The safety shown by many studies is confirmed by the long history of its use.

3.1 Oral Toxicity

The LD50 of the acute oral toxicity of the pure dry Zinc-Pyrion is 774 - 1300 mg/kg for rat. More than 75 % of orally dosed Zinc-Pyrion will be excreted by urine. Less than 25% will be metabolized2.

3.2 Teratogenicity

Application of a Zinc-Pyrion containing shampoo to the back skins of pregnant rabbits (20 and 50 mg zinc pyrion /kg) showed no effects of embryotoxicity or teratogenicity3. Even when the concentrations where raised so high that skin irritations occurred no teratogenicity was detectable. An increased incidence of skeletal abnormalities was found with rats at oral concentrations so high that toxic effects became visible4.

3.3 Dermal Toxicity

The LD50 of the acute dermal toxicity of the pure dry Zinc-Pyrion is greater than 2000 mg/kg for rat. There is no evidence that skin irritation occurs in the use of shampoos containing up to two percent Zinc-Pyrion.

3.4 Ecotoxicity

Despite the fact that Zinc-Pyrion is nearly insoluble in water it is possible to detect acute toxicity's for fish and daphnia. The data are:

daphnia magna EC50 (48 h): 50 µg/l rainbow trout LC50 (96 h): 150 µg/l

New studies prooved that highly diluted Zinc-Pyrion is degraded in aqueous environment by photolyses. The half life at various pH is less than 7 minutes5.

4 EFFECTIVENESS

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Zinc-Pyrion is active against many gram positive and gram negative bacteria as well as against many fungi and yeasts. The detailed mechanism of its activity is still unknown. It is suspected that Zinc-Pyrion is effective in many ways, because its field of activity is extremely broad. One theory is that the activity may be due to the chelating property of the 2-mercapto-pyridine-N-oxide, another theory is that the dipole structure of the molecule may act like a pseudoquarternic ammonia. Since the activity increases at lower pHs, it is assumed that Zinc-Pyrion is involved in the ionic exchange of living cells or cell membranes. This indicates that the effectiveness of Zinc-Pyrion as an anti-dandruff agent is due to its antimicrobial activity. This hypothesis is supported by experiments that proved that Zinc-Pyrion has no influence on the epidermal renewal6. Further examinations proved that the blight of the scalp with the dandruff-fungi pityrosporum ovale is strongly decreased by Zinc-Pyrion7. In view of the fact that Zinc-Pyrion adsorbs on the surface of the hair its antimicrobial effectiveness continues between the applications. Crystalline Zinc-Pyrion is more effective against the dandruff-fungi pityrosporum ovale than amorphous powder8.

The following tables of the minimal inhibition concentrations give an overview over the broad activity of Zinc-Pyrion:

4.1 Antibacterial Spectrum of the Active Ingredient

Method: Series dilution of suspensions, Calculation: Maximum likelihood method (MIC = minimal inhibition concentration)

BACTERIA MIC in mg/l (ppm) A Pseudomonas aeruginosa 350 B Klebsiella pneumoniae 87 C Micrococcus epidermidis 78 D Salmonella typhimurium 66 E Bacillus subtilis 65 F MIcrococcus aureus 62 G Streptococcus pyogenes 59 H Shigella sonnei 57 i Proteus vulgaris 45 J Bacillus stearothermophilus 45 K Enterobacter cloacae 23

Table 2

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350

8778

66 65 62 59 5745 45

23

0

50

100

150

200

250

300

350

A B C D E F G H I J K

MIC

[mg/

L]

Antibacterial Spectrum of the Active Ingredient 4.2 Antifungal Spectrum of the Active Ingredient

Method: Series dilution of suspensions, Calculation: Maximum likelihood method (MIC = minimal inhibition concentration)

FUNGHI MIC in mg/l (ppm) L Trichophyton mentagrophytes 67 M Aspergillus fumigatus 59 N Cryptococcus neoformans 56 O Aspergillus niger 55 P Saccharomyces cerevisiae 55 Q Penicillium notatum 50 R Candida albicans 46 S Fusarium oxysporum cub. 36

Table 3

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67

5956 55 55

5046

36

0

10

20

30

40

50

60

70

L M N O P Q R S

MIC

[mg/

L]

Antifungal Spectrum of the Active Ingredient 5 FORM OF DELIVERY 5.1 Zinc-Pyrion 48% Aqueous Suspension

A ready to use form of Zinc-Pyrion for shampoos which yields a stable homogenous dispersion and good aesthetics. White to beige aqueous suspension containing a dispersing agent and a viscosity control agent.

Typical product data

Particle size 2-6 µm Assay of active 48 - 52 % Assay of zinc 9,3 - 11,3 % pH-value 6.5 - 8.0

Packaging

Combi containers 5 kg or 25 kg net open top plastic drums 25 kg net

Special container volumes on request For further information see our current Material-Safety-Data-Sheet

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5.2 Zinc-Pyrion micronized 48% Aqueous Suspension

A ready to use Zinc-Pyrion micronized for shampoos which yields a stable homogenous dispersion and good aesthetics. White to beige aqueous suspension. Particle size about 1 µm in microscopical examination.

Typical product data

Particle size 80% < 1,5 µm Assay of active 48 - 52 % Assay of zinc 9,3 - 11,3 % pH-value 6.5 - 8.0

Packaging

Combicontainers 5 kg net open top plastic drums 25 kg net

Special container volumes on request For further information see our current Material-Safety-Data-Sheet

5.3 Zinc-Pyrion NF 48% Aqueous Suspension

New Formulated ready to use Zinc-Pyrion for shampoo. Light cream to yellowish aqueous suspension containing a dispersing agent and a viscosity control agent.

Typical product data

Particle size 2 - 6 µm Assay of active 48 - 52 % Assay of Zinc 9,3 - 11,3 % pH-value 6.5 - 8.0

Packaging

Combi containers 5 kg net Open top plastic drums 25 kg net

Special container volumes on request For further information see our current Material-Safety-Data-Sheet

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5.4 Zinc-Pyrion technical powder

In most cosmetic applications Zinc-Pyrion is used as an aqueous suspension. These suspensions are easy to formulate and give good aesthetics. Some applications require a Zinc-Pyrion powder, for example where water is not needed or can be undesirable. Anhydrous applications where water resistant long-term fungistatic and bacteriostatic efficacy is required are the main uses. The major fields of application are:

Antifouling marine paints:

Antimicrobial efficacy against barnacles, algae and other marine organisms to protect ship hulls. 4-5 % of Zinc-Pyrion combined with 35-40 % of cuprous oxide (calculated on dry film weight) has proven to be the optimal level. A list of patents is available.

Paint:

Biocidal efficacy to be applied in exterior paints, latex or alkyd types e.g. outdoor household paints, industrial and commercial paints.

Plastics:

Fungicide in thermoplastics, recommended for use in polyolefins, urethanes and other polymerics, natural latex and synthetic rubber. Protects from attack by microorganisms, especially mildew and mold. Reduces premature product degradation usually accompanied by discoloration. Application may include carpet underlay, vinyl or urethane flooring, coatings, insulation materials, adhesives, caulks, grouts and sealants.

Zinc-Pyrion technical powder is a beige colored, freeflowing material.

Typical product data

Particle size: 80 % < 6 µm Assay: Not less than 97% active Loss on drying: Not more than 2,0 % Bulk density: 400 - 500 kg/m³

Packaging

25 kg net Fibredrum 50 kg net Fibredrum

For further information see our current Material-Safety-Data-Sheet.

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6 FORMULATIONS

The following shampoos have been tested in our laboratory. This information is intended for use by persons having technical skill and at their own discretion and risk. Nothing contained herein is to be considered as permission to practice any patent invention without permission of the patent owner.

6.1 Anti-Dandruff Shampoo 1 Ingredient Function Weight,%

A Glycol Distearate (Tegin G 1100*) Opacifier, Conditioner 3,00 Sodium laureth sulfate (28 %) Surfactant 25,00 TEA lauryl sulfate (47 %) Surfactant 12,00 Cocoamidopropyl Betaine Foam Enhancer 12,00 Zinc-Pyrion (48%, aq. soln.) Anti-Dandruff Agent 2,00

B Tego Carbomer 134* (1,5 %) Thickener 9,00 Water Diluent 37,00

C Preservative, Color, Fragrance, Sodium Hydroxide, Sodium Chloride q.s. *Th. Goldschmidt AG, Essen, D

Preparation:

Parts A and B are mixed separately and heated to 70°C (158°F). Then Part B is added to Part A and the mixture is cooled to room temperature under stirring. Adjust the pH to 5,5 with sodium hydroxide. Then add the preservative, fragrance and color. The viscosity can be adjusted with small increments of sodium chloride. A viscosity between 6000 and 12000 mPas is recommended (see diagram).

Properties:

medium to high viscosity opaque shampoo pH: 5,5 - 6 Actives: 12,6 % Viscosity: see diagram

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6.2 Anti-Dandruff Shampoo 2 Cold formulation

(Neu ZPT-ST-89/4)

Ingredient Function Weight,% A Water Diluent 48,80 Acrylates/C10-30Alkyl Acrylate Crosspolymer 1 Thickener 1,20 Sodium Hydroxide (10 %) Neutralizer 0,10 B Sodium Lauryl Ether Sulfate (ca. 30 %)2 Surfactant 20,00 Disodium Undecylenamido MEA-

Sulfosuccinate3 Surfactant 8,00

Cocamidopropyl Betaine (ca. 30 %)4 Foam Enhancer 6,00 Water Diluent 15,00 C NaOH (20%) pH-Regulator pH = 5,5 (ca. 4,0) Zinc pyrion (48 %) Anti-Dandruff Agent 2,00 FD&C Blue #1 (0,1 %) Color q.s. Fragrance Fragrance q.s. DMDM Hydantoin Preservative q.s. NaCl Thickener q.s.

1 Carbopol ETD 2020, BF Goodrich Co, Cleveland, USA 2 Neopon LOS/H, Witco Corp., Steinau a. d. Str., Germany 3 Rewocid SB U 185, Witco Corp., Steinau a. d. Str., Germany

4 Tego Betain F, Th. Goldschmidt AG, Essen, Germany

Procedure: A Mix Carbopol ETD 2020 in water, stirr for 3 h and neutralize partly with NaOH until a gel

has formed. It is highly recommended to prepare bigger amounts and store them in the lab. B Mix surfactants and water in order until homogenius. Avoid foam. Add Part A and stirr

overnight. C Adjust pH to 5,5 with NaOH. The mixture will become viscous. Add all ingredients and

stirr until homogenius. If the shampoo has not the right viscosity, it can be adjusted with NaCl.

Properties: Light blue and opake shampoo with medium to high viskosity pH: approx. 5,5 Actives: ca 12 %

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6.3 Anti-Dandruff Shampoo 3 Ingredient Function Weight,% A Water Diluent 55,00 Zinc Pyrion Anti-Dandruff Agent 2,00 B Ammonium lauryl sulfate (28%) Surfactant 22,00 Sodium laureth sulfate (70%) Surfactant 10,00 C Cocamide MEA Foam Enhancer 1,50 Stepan SAB-2* Thickener 4 - 5 D NaOH, Preservative, Dye Fragrance, NaCl q.s. * STEPAN Co., Northfield, Ill, USA

Preparation Mix Part A, then add Part B ingredients and heat to 70-75°C.

Add Part C and stir until homogeneous. Cool to room temperature and add desired pearlizing agent, dye, preservative, fragrance and adjust pH to 5,5 with NaOH.

Add conc. NaCl solution until desired viscosity is reached.

Properties: Light blue opaque shampoo with medium viscosity pH: 5,5 Actives: approx. 13% Viscosity: see diagram

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6.4 Anti-Dandruff Shampoo 4 Cold formulation

Ingredient Function Weight,% A Water Diluent 48,00 Natrosol 250 HR1 Thickener 2,00 B Neopon LOS H2 Surfactant 20,00 Sulfopon 101 Spezial3 Surfactant 15,00 Tego Betain F4 Foam Enhancer 5,00 Water Diluent 5,00 C Zinc pyrion (48 %) Anti-Dandruff Agent 2,00 Citric Acid pH-Regulator q.s. FD&C Blue #1 (0,1 %) Color q.s. Fragrance Fragrance q.s. DMDM Hydantoin Preservative q.s.

1 Hydroxyethylcellulose, Herkules BV, Holland 2 Sodium Lauryl Ether Sulfate, Witco Corp., Steinau a. d. Str., Germany 3 Sodium Lauryl Sulfate, Henkel, Düsseldorf, Germany 4 Cocamidopropyl Betaine, Th. Goldschmidt AG, Essen, Germany

Preparation: A Mix Hydroxyethylcellulose in cold water and stirr until a clear gel has formed (ca. 3 h. It

is highly recommended to prepare a preserved stock 4 % solution for use in formulating). B Add Part B ingredients and stirr until homogeneous (overnight). Avoid foam. C Add Part C ingredients with stirring to batch and adjust pH to 5,5. Properties: Light blue opague shampoo with high viscosity pH: approx. 5,5 Actives: ca 11% Visosity: see diagram

7 Formulation principles of Zinc-Pyrion

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During our long experience with Zinc-Pyrion, many questions concerning Zinc-Pyrion formulations have been answered. The following summary may be helpful for our customers to overcome possible formulation difficulties:

− Zinc-Pyrion can be added during all steps of formulation. − Add Zinc-Pyrion while stirring with high speed. Do not allow the Zinc-Pyrion to

settle to the bottom. − Do not combine Zinc-Pyrion with cationic or amphoteric substances (surfactants,

conditioners or thickeners). If these substances are necessary, Zinc-Pyrion should be added at the very end of the compounding process.

− Use thickeners with a high pseudoplasticity. − Eliminate heavy metals.

7.1 What to do if sedimentation occurs:

− Increase viscosity at low shear rates (higher pseudoplasticity). − Stir for a long time at medium to high shear rates (be aware of foam!). − Eliminate cationic or amphoteric substances. − Make a suspension of Zinc Pyrion in water before adding the surfactants (see also

shampoo-formulation #3). − Filter the shampoo (is the precipitate Zinc Pyrion ?).

8 ANALYTICAL METHODS:

Zinc-Pyrion can be analyzed by titration or atomic absorption spectroscopy (AAS). The following methods are used frequently in our laboratory.

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8.1 Titration 8.1.1 Preparation of samples The method described hereafter is applicable for all Zinc-Pyrion preparations as well as finished shampoo formulations. 1. Disperse a weighed sample of the shampoo or the Zinc-Pyrion formulation in water. This sample must be large enough to achieve a quantity of about 500 mg Zinc-Pyrion precipitate. 2. Allow the solids to settle totally. Remove the supernatant liquid. Disperse the solids with water and centrifuge. 3. Dry the solids using the analytical method 2227-23 (see below). 4. Titrate the dried sample according to the method 2227-22 (determination of free pyridinethione) or 2227-22 for zinc.. 5. Calculate the result in terms of the shampoo or formulation. 8.1.2 Analytical method 2227-23 (Loss on drying) Procedure: Weight the sample into a suitable dish and let dry in a dryer at recommended temperature and

air pressure. The drying process is finished when the weight of the sample is constant. Sample weight: 3-5g (tolerance 0,1 mg) Drying conditions: 105°C (221°F) at ambient pressure Equipment: Dryer, vacuum dryer or desiccator Calculation of results: Percent loss on drying =

100 x (weight before drying - weight after drying)

weight before drying

Percent residue =

100 x (weight after drying)

weight before drying

8.1.3 Analytical method 2227-22 (Iodometric titration of free pyridinethione) Procedure:

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The sample is dissolved in hydrochloric acid and then diluted with water (turbid solutions must be filtrated). After addition of the indicator titrate with the iodine solution. Equipment: Burette, standard glassware Sample weight: ca. 300 mg ( tolerance 0,1 mg) Solvents: 15 ml concentrated hydrochloric acid 150 ml distilled water Indicator: 2 ml starch solution Titration solution: 0,1 n Iodine solution Calculation: 1 ml of titration solution is equivalent to 15,88 mg Zinc-Pyrion 8.1.4 Analytical Method 2227-22 (zinc) (Complexometric titration of zinc) Procedure: The sample is mixed with hydrochloric acid and perhydrol and boiled until the hydrochloric acid has almost evaporated. Then the residue is diluted with 50 ml water. Ammonia is added until the early precipitate has dissolved (turbid solutions must be filtered). The clear solution is mixed with buffer and indicator. The mixture is heated to 40 °C (104°F) and titrated with EDTA until the color changes from red to blue. Equipment: Burette, standard glassware Sample weight: ca. 300 mg ( tolerance 0,1 mg) Solvents: 15 ml concentrated hydrochloric acid 50 ml distilled water Reagents: 1 ml perhydrol (30%, p.a.) ammonia (2n) 2 ml buffer (pH 10) Indicator: Erio T : NaCl = 1: 99 Titration solution: 0,1 n EDTA solution Calculation: 1 ml of titration solution is equivalent to 6,537 mg zinc. 8.2 Determination of Zinc by AAS

The method described here is also applicable to Zinc-Pyrion preparations and finished products.

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1. Dissolve 50 -100 mg of the sample of shampoo or other formulation in 3-5 ml hypochloric acid. 2. Determine the assay of zinc using AAS ( 100% Zinc-Pyrion = 20, 58% zinc) 3. Calculate the result in terms of the principal shampoos or formulations.

9 STORAGE

− Always store between 10° C (50° F) and 30°C (86°F)in well closed containers protected from light.

− Do not freeze. − Before any handling and sampling, homogenize well. − Keep away from metals, metal salts and strong oxidizers. − Do not contaminate water, waste water, food or feed with the material.

10 PRECAUTIONS

Zinc-Pyrion should be handled with the precautions used in handling industrial chemicals.

Keep container closed when not in use. Do not take internally. May be fatal if swallowed. Avoid contact of the pure ingredient with skin. Causes eye irritation. In case of contact flush with plenty of water.

11 LITERATURE

1 J. Soc. Cosmet. Chem. 23 (1972) 99 - 114 2 Fiedler, Lexikon der Hilfsstoffe, 3. Aufl. 1989 3 Nolen et al, Toxic. Appl. Pharmacol. 31(1975) 430 4 C.A. 100 (1984) 12-91124 5 Studies done by RÜTGERS Organics GmbH 6 C.A. 102 (1985) 9-72855 7 J. Soc. Cosm. Chem. 33 (1982) 27-37 8 C. A. 100 (1984) 6-39616