Alternative Preservatives SCC Ontario Education Day Alternative Preservatives R. Nunez/ Lonza Inc./ Sept. 2006

Outline Why Preservatives? Conventional Alternatives Preservatives Today: Where are we? Preservative Trends Global Regulatory Overview Conventional Preservatives Profiles Alternative Preservative Approaches Ingredients with Antimicrobial Activity Other Preservative Alternative Approaches Conclusions

Why Preservatives By Definition, Used to Prevent Growth of Microorganisms in a Cosmetic product… A substance intentionally added to a cosmetic product for the primary purpose of inhibiting the development of microorganisms. Help Prevent Microorganism Growth During Manufacturing…But Not a Substitute for GMP Primarily Designed to Prevent Microorganism Growth After Product Sale to Consumers Therefore… Preservatives Must be Toxic to Microorganisms but Be Safe for Humans

Without Preservatives Risky Business Product Spoilage, Recalls Health, Infection Issues Formulating Without a “Safety Net”

With Preservatives Preserved Formulations Low Cost “Insurance” Tradeoff between Preservation and Formulating Issues Need Preservative Potency, Compatibility and Stability

Cosmetic Preservatives History Pre-1900: Sodium Benzoate, Phenol, Cresol 1920’s: Parabens, Formaldehyde 1940’s: Alcohols, Phenoxyethanol 1960’s: Staph Outbreak from Hospital Hand Lotions - Changed Attitude towards Preservatives 1960’s: Formaldehyde Studies, Concerns 1970’s: Imidazolidinyl Urea, DMDMH, Bronopol 1970’s: FDA Surveyed Cosmetics, Found 24% Contaminated 1980’s: Diazolidinyl Urea, Isothiazolinones 1990’s: Blends Introduced, e.g. DMDMH/ IPBC 2000’s: Blends, Naturally-Derived Today: Acute Perception Issues, Fragmented Market

What Preservatives Do We Use Today? 2003 2001 Methylparaben 7161 6893 Propylparaben 5809 5621 Butylparaben 2326 2174 Imadazolidinyl Urea 2038 2025 Ethylparaben 1725 1451 Phenoxyethanol 1670 1480 DMDM Hydantoin 993 943 Diazolidinyl Urea 725 701 MCI/ MI 699 595 Quaternium-15 516 505 Triclosan 451 462

“Conventional” Preservative Takeaways All These Commonly Used Preservatives have Limitations All are Classified as “Conventional” Preservatives and Are Approved by Regulatory Bodies Globally All Have Been Used for Many Years…..Long Histories and Experiences All Have Been Found to be Safe and Effective for Use as Directed And Many are Under Some Sort of Pressure

Why “Alternative” Approaches? Attempt to Meet Varied Real and Perceived Needs Address an Increasingly Fragmented and Confusing Cosmetics Preservatives Market Address Customer and Retailer Perception Issues Simplify Formulating – Less Raw Materials/ Testing Required Allow Global Use of Simplified Systems However…..

Is the Perfect “Alternative” Preservative Possible? Water Soluble Colorless and Odorless Cost-Effective Widely Compatible Globally Approved Available for Use Today…..

Why Is It So Difficult? Regulatory Barriers Few Ingredients Acceptable in All Regions Formulation Barriers No Single Technology Works in All Types of Products New Preservative Molecules Unlikely Due to Cost, Time and Data Requirements vs. Market Size INCI-Listed, Multi-functional Approaches are Best Bets “Alternatives” Effectiveness… Are They Potent Enough? Can They Replace “Conventional” Approaches?

Preservatives Today: Where Are We?

What Drives Preservative Choice? Formulation Type Effectiveness in the Formulation Use Cost in the Formulation Preservative Safety / Perception / Acceptance Compatibility / Stability with Other Ingredients Global Regulatory Approvals

Today’s Preservative Trends Regulatory Changes Driving Preservative Choices Many Traditional Materials Being Challenged Increase in Restrictions, Perception Issues Increase Preservative System “Safety” But… Maintain Efficacy Ensure Formulation Compatibility More Preservative Studies, Publications, “Pressures” Naturally-Derived and Blended Preservatives, Use of Potentiators Confusing Array of “Alternative” Preservative Approaches

Global Regulatory Overview (1) NAFTA Widest Range of Approved Preservatives Parabens, Formaldehyde Donors, Isothiazolinones, Acids, Alcohols, etc. Europe Positive List, Difficult Approval Process,… Plus Green Groups Close to NAFTA in General, But More Constraints Most Preservative “Controversies” Start in Europe Japan Positive List, Longest and Most Difficult Approval Process No Formaldehyde Donors, Other Constraints

Global Regulatory Overview (2) Other Countries Brazil, Australia, Korea, China Many Driven by US or Europe Gets Complicated……Seek Regulatory Assistance

Conventional Preservatives Profiles

Parabens Profile Target Organisms: Fungi Mode of Action: Nutrient Transport Applications: Rinse-offs, Leave-ons Wide Global Acceptance, Long Use History Typically Blended (methyl, propyl, butyl, ethyl) / Combined with Bactericides Recent Controversy – Study Results, Perception Issues Formulating Tips Low Water Solubility Polysorbates/ PE pH range: 3.5 – 6.5 0.1 – 0.8% as Active

Formaldehyde Releasers Profile Target Organisms: Bacteria Mode of Action: Denatures Proteins Applications: Rinse-offs, Most Leave-ons Limited Approval in Japan Imidazolidinyl Urea, Diazolidinyl Urea, DMDM Hydantoin, Quaternium-15 Recent Controversy: Gas vs. Liquid Formaldehyde measurement Formulating Tips Highly Water Soluble High Temperatures, Reducing Agents pH range: 3 - 10 0.1 – 0.5% as Product

Alcohols Profile Target Organisms: Bacteria Mode of Action: Denatures Proteins Applications: Rinse-offs, Leave-ons Wide Global Acceptance Phenoxyethanol, Benzyl Alcohol, Ethyl Alcohol, Usually Combined with Fungicides Formulating Tips Highly Water Soluble May Impact Viscosity May Add Odor pH range: 3 - 10 0.5 - 1% as Active

Isothiazolinone Profile Target Organisms: Bacteria and Fungi Mode of Action: Disulfide Linkage With Cell Wall Proteins Applications: Rinse-offs, Some Leave-ons Wide Global Acceptance (BIT has Limited Approvals) Chloromethlyisothiazolinone, methylisothiazolinone, benzisothiazolinone – CMI/ MI Most Common Blend Formulating Tips Sensitizations Issues Add at <50°C Primary Amines, Sulfites pH range: 2 - 8 Up to 15 ppm Active R/O

Acids Profile Target Organisms: Fungi Mode of Action: Denatures Proteins Applications: Rinse-offs, Leave-ons Wide Global Acceptance Sorbic, Benzoic, Salicylic, Dehydroacetic, Boric, Citric (and salts) Typically used in combination with a bactericide Formulating Tips Low Water Solubility (acid forms) Add at <50°C Primary Amines, Sulfites pH range: <6 Up to 0.5% as Free Acid

IPBC Profile Target Organisms: Fungi Mode of Action: Nucleophilic Reaction with Thiols, Amines in Cell Applications: Rinse-offs, Leave-ons Wide Global Acceptance Available in Surfactant, Water or Solid Carriers – not sold as 100% Typically used in combination with a bactericide Recent Controversy: EU Dosage Levels and Applications Formulating Tips Low Water Solubility Reducing Agents pH range: Up to 9 0.05 – 0.1% as Active

Other Conventional Preservatives Bactericides Benzalkonium Chloride Benzethonium Chloride Chlorophenesin Methyldibromo Glutaronitrile Sodium Hydroxymethylglycinate Thimersal Triclosan Triclocarbon Fungicides Glutaral Zinc Pyrithione Zinc Oxide

Top Global Choices Goal: Broad Spectrum, Global As Possible Blends Acids – Benzoic, Citric, Dehydroacetic, Salicylic, Sorbic Alcohols – Phenoxyethanol, Benzyl, Ethyl Formaldehyde Donors – Imidazolidinyl Urea, DMDMH, DI Isothiazolinones – MI, CMI Parabens – Methyl, Propyl, Butyl, Ethyl Many Blends are Patented or Proprietary Phenoxyethanol + IPBC Formaldehyde Donors + IPBC Phenoxyethanol + Parabens Acids + Alcohols + Quats

Examples of Blended Preservative Systems Pert Shampoo (P&G) CMI + MI Herbal Essences Shampoo (Clairol / P&G) DMDMH + IPBC Nivea Visage Cream (Beiersdorf) Phenoxyethanol + Diazolidinyl Urea Plenitude Facial Lotion (L’Oreal) Imidazolidinyl Urea + Parabens Head-to-Toe Baby Cleansing Cloths (J&J) Phenoxyethanol + Parabens + Citric Acid

Alternative Preservative Approaches

Alternative Approaches Alternative Ingredients Naturals Glycols Glycerins Antioxidants Surfactants Potentiators Alternative Non-Ingredient Approaches Water Activity pH Adjustment Raw Material Specifications Plant GMP Package Design A cosmetic Ingredient is NOT a Preservative if: It’s NOT on Europe’s Positive List It’s NOT on Japan’s Positive List It has an INCI Name Claiming Another Function It Helps Create a More Hostile Formulation Environment

Create a Self-Preserving Environment Use Ingredients and Essential Oils that have Antimicrobial Properties but are NOT classified as Preservatives Create an Environment that is Unfavorable to Microbial Growth either through substituting alternative chemistries lowering water activity changing pH increasing alcohol, surfactant, other ingredient levels Ensuring that the product is manufactured under GMP conditions Use a Package that minimizes introduction of microbes into mass Minimize incoming ingredient bioload

Alternative Ingredients with Antimicrobial Activity

Natural Ingredients Many on the market Used in Combinations or with Traditional Preservatives Addresses Growing Natural Trend, but Difficult to Execute Typically Have Multi-Functionality and INCI Listed Often have Odor, Color and Allergen Issues Tend to be Organism-Specific, not Broad Spectrum

Natural Ingredients (2) Grapefruit Seed Extract Bactericide Activity may be due to Other Ingredients introduced during processing Gluconolactone Moisturizer Tea Tree Oil Humectant

Natural Ingredients (3) Usnic Acid Mostly Gram positive Bactericide May impart blue color to products Neem Seed Oil Bactericide May impart color and odor to products Other Oils and Extracts Cinnamon, eucalyptus, lavender, lemon, rosemary, thyme, honeysuckle….. Challenge Test, Ensure Compatibility

Glycols Possess Humectancy and Potentiation Propylene, Butylene Glycol (6.0%) Improves solubility and product stability Reduces oil/water partitioning Assists in preservation, lowers water activity Hexylene, Pentylene Glycol (2.0%) Preservation Efficacy Caprylyl Glycol (1.0%)

Caprylyl Glycol Some Broad Spectrum Activity Often used in Combination with Phenoxyethanol, Other Preservatives Wide Global Approval Compatible with Most Formulation Types Some reports of Irritation when used in combination with other glycols

Ethylhexylglycerin Similar to Other Glycerins Activity against most Gram Positive Species Lowers Water Activity Often used in Combination with Phenoxyethanol Wide Global Approvals Compatible with Most Formulation Types Some reports of Irritation when used in combination with other ingredients Good Humectant Properties

Antioxidants BHA, BHT, Propyl Gallate, t-Butyl Hydroquinone, Tocopherol All Provide Varying Benefits, Mainly as Formulation Stabilizers Sodium Sulfites Technically are Preservatives Strong Reducing Agents Stabilizer for Other Ingredients Sodium Erythorbate Isomer of Vitamin C Strong Reducing Agent GRAS, wide use in food industry

Other Ingredients with Antimicrobial Activity Lauricidian Surfactant Effective Against Gram Positive Bacteria Sometimes combined with Lactic Acid and EDTA Biosurfactants Activity against Pseudomonas Fragrances and Fragrance Mixtures Enzymes, Phospholipids, Mono-Esters

Potentiators: Multifunctional EDTA Chelating Functionality Improves Preservative Performance Has Activity against Pseudomonas Helps Prevent Resistance to Antimicrobials Helps Stabilize Color and Fragrance, Control Fading Other Chelators/ Potentiators Include: HEDTA, DTPA, Etidronic Acid

Other Preservative Alternative Approaches

Water Activity Definition: A measure of water’s energy status in a system, aw. “Bound” water is not available for microorganism growth. Microorganisms need “free” water within a product to survive and proliferate Water activity and not water content is a better measure of the free water Pure water has aw of 1.0, typical shampoo 0.96 Goal: lower water activity = less preservative!

Water Activity Requirements 0.95 - 1.0 Gram Negatives 0.90 - 0.95 Staphylococci 0.87 - 0.90 Common Yeast 0.80 - 0.87 Common Mold 0.65 - 0.75 Xerophilic Mold 0.60 - 0.65 Osmophilic Yeast Therefore…lower aw, create a more hostile microbe environment

Water Phase pH Knowing the optimum pH for each of your preservatives is important in using preservatives effectively Extreme pH’s can have an inhibitory affect on bacteria, yeast and mold By using a combination of pH and Water Activity control, you are creating an environment which is hostile to microbial growth

Water Phase pH Impact on Preservatives Methyl Paraben Optimum pH 3.5 - 6.5 Generally poor activity >7.0 Organic Acids Optimum pH <6.0 Phenoxyethanol, Formaldehyde Releasers Not affected by pH

Raw Material Specifications Ensure that incoming raw materials are as clean as possible to minimize bioburden Recommended <100 cfu per gram Ensure that the water system is checked frequently and is free of bacteria Consider it a critical “raw material” with specifications Beware of biofilm buildup in your holding tank, pipes and valves Use hot water when possible

Good Manufacturing Practice (GMP) Ensure that the manufacturing tanks and filling lines are properly cleaned and sanitized All transfer lines and storage tanks are properly cleaned and sanitized That stored product is tested before filling and that partial drums are not returned to the warehouse

Product Package Design Package design can play a big role in minimizing contamination once in the hands of the consumer It can act as a physical barrier to the external environment Examples include: One way valves Pressurized components Airless tubes, sealed tops Unit dose packaging

Conclusions The Cosmetic Preservative Market Will Continue to Fragment Regulations and Perception Will Continue to Drive Conventional Preservative Choices, Particularly as More Studies are Published There is No Conventional or Alternative Preservative “Holy Grail”. The Market Will Mix and Match Preservatives to Meet Product Needs. “Alternative Approaches” Should Focus on Creating as Hostile and Self-Preserving an Environment as Possible There are Many Alternative Ingredients Available in the Market, as Reviewed. Most Have Unique, But Limited, Applicability. There are Many Non-Ingredient Approaches Possible, Such as Water Activity Reduction, Which Can be Used Widely to Improve the Self-Preserving Environment

Acknowledgements My Thanks to the Following Colleagues and Groups for Their Input and Support in Creating this Presentation Lonza Teammates: Carl Cappabianca, Crystal Arlea David Steinberg: Steinberg & Associates Steve Schnittger: Estee Lauder SCC Ontario Chapter The CTFA Microbiology Committee