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

2. 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

3. 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

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

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

6. 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

7. What Preservatives Do We Use Today?
Methylparaben
Propylparaben
Butylparaben
Imadazolidinyl Urea
Ethylparaben
Phenoxyethanol
DMDM Hydantoin
Diazolidinyl Urea
MCI/ MI
Quaternium
Triclosan

8. “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

9. 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…..

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

11. 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?

12. Preservatives Today: Where Are We?

13. 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

14. 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

15. 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

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

17. Conventional Preservatives Profiles

18. 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

19. 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:
0.1 – 0.5% as Product

20. 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:
% as Active

21. 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:
Up to 15 ppm Active R/O

22. 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

23. 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

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

25. 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

26. 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

27. Alternative Preservative Approaches

28. 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

29. 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

30. Alternative Ingredients with Antimicrobial Activity

31. 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

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

33. 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

34. 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%)

35. 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

36. 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

37. 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

38. 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

39. 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

40. Other Preservative Alternative Approaches

41. 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!

42. Water Activity Requirements
Gram Negatives
Staphylococci
Common Yeast
Common Mold
Xerophilic Mold
Osmophilic Yeast
Therefore…lower aw, create a more hostile microbe environment

43. 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

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

45. 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

46. 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

47. 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

48. 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

49. 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