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    HEALTHFOCUS HEALTHFOCUS HEALTHFOCUS HEALTHFOCUS HEALTH FOCUS

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    J A N U A R Y

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    W W W

    . L I F E S C A P E M A G

    . C O M

    PARABENSSPOTLIGHT ONThe natural versus chemical products debate isbecoming polarized in favour of natural and organicat any cost for many in the West, but this leads to anunnecessary blight on the word chemical. What isnatural may not be safe and what is chemical may well

    be derived from a natural product and no risk at all.We know that we are directly affected by what weeat, drink and breathe, but what we put on our skin hasnot, until recently, been seen to affect us in the sameway. (If we didtake this seriously,perhaps wewould give upeating chocolatefrom countries

    where womenare plaguedwith skin diseasefrom handlingpesticide-coveredcocoa beans.)

    We nd outwhether the hypearound parabens

    is justied, withthe help ofscientist, CurossBakhtiar, directorof Harley StreetCosmetics

    Parabens , which are commonly found in skin creamsand other beauty products, glues and some foods,have been around since the 1930s. Theyre currentlythe most widely-used preservatives in cosmetic,pharmaceutical and industrial products, but recent newsreports linking parabens to breast cancer in women andlab studies that have shown the hormonal effects of thechemical, has lead the Cosmetic Ingredient Review ExpertPanel to reevaluate theyre safety.

    WHAT ARE PARABENS?Methyl and ethyl parabens are the most frequently usedparabens and, with the exception of water, the mostcommonly used ingredients in cosmetic preparations, saysBakhtiar. Parabens are popular because they are inexpensive,colourless, odourless, non-toxic, with a wide spectrum ofantimicrobial activity theyve been used as preservativesfor over 80 years.

    In 1995, the US Environmental Protection Agencygranted GRAS (Generally Recognised As Safe) status toparabens and current European Union cosmetic regulationspermit a total concentration of 0.8% for methyl-, ethyl,propyl- and butylparaben in cosmetic products thats just

    enough to stop your anti-wrinkle cream going off. The Japanese and Australian medical health boards,

    which are the hardest to please, have also accepted parabensas. But could the Cosmetic Ingredient Review Expert Panelreview could change all that?

    EXPOSING THE MYTHIn the USA, the average total paraben exposure per person

    is estimated to be approximately 76mg per day (1.3mg/kg/dfor a person weighing 70kg), says Bakhtiar. Cosmetics andpersonal products provide the bulk of exposure at 50mg perday, whereas drugs (medicines) supply 25mg per day and foodaccounts for approximately 1mg per day. The concentration ofparabens in foods is usually less than 1%.

    In the past, concentrations of parabens in topical over-the-counter products were as high as 5% in the US. Currently,however, the concentrations of parabens in cosmeticsare generally less than 0.3%, but may range up to a totalconcentration of 1%, he continues. Each paraben ester hasa different solubility and spectrum of antimicrobial activity. As the alkyl chain length increases, water solubility decreasesand oil solubility increases. The greater the parabens lipidsolubility, the greater the penetration through the skin sopenetration increases with ester chain length.

    The potential for absorption of parabens through theskin is inuenced by this relative distribution of the oil/waterphases of formulation and this is further altered by theaddition of various surfactants. In oil-based formulations,methylparaben therefore requires a higher concentration tomaintain effectiveness, which is why we might take in morethrough cosmetics than other products. But although parabensare frequently found in cosmetics, they are consideredrelatively weak sensitisers in these formulations.

    What is now more controversial is scientic evidence thathas shown that parabens accumulate in the body and thattheir effects can build up over time. Given they were presentin larger quantities in the past, most of us may well have themin our body.

    ALLERGIC RE ACTION SParabens are, for the most part, non-irritating and non-sensitising. They can, however, cause skin irritation andcontact dermatitis in the allergy-prone amongst us a smallpercentage of the general population.

    Of course, as the cocktail of environmental hazardsincreases, it may well be that the number of sensitised

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    HEALTHFOCUS HEALTH FOCUS HEALTHFOCUS HEALTH FOCUS HEALTHFOCUS

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    J A N U A R Y

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    THERE IS NOSCIENTIFICEVIDENCE TO

    SUPPORT ALINK BETWEENPARABENEXPOSURE ANDANY FORM OFCANCER

    THE LIFESCAPE VERDICTCRUELTY FREE 0/5

    ORGANIC 0/5

    FAIR TRADE 0/5

    HEALTH HAZARD 1/5 WORRY FACTOR 2/5

    PROVEN CANCER RISK 0/5

    These days its not science that drives cosmetic reformulation customers vote with their feet, with the help of the cosmeticindustry and consumer groups. The hype around parabens

    however, when compared to many other far more questionablechemicals, doesnt seem to be that well warranted. To datethere is no scientic proof that exposure causes cancer. There isno proof that ingesting it is less hazardous than smearing it on

    the body, but given the amount of toothpaste we eat, there isreason to err on the side of caution. Many people will still wantto avoid parabens, given they are extensively used on animalsfor research purposes. Scare stories can often distract fromhard facts, but they help us to be cautious. Parabens arentthe worst of the bunch, but if you can nd products with morenatural ingredients, opt for them instead.

    development. However, no causal link with cancer has everbeen proven and so far there is no scientic evidence tosupport any link with any form of cancer.

    A recent review of the data concluded it was biologicallyimplausible that parabens could increase the risk of anyestrogen-mediated disruption, including effects on the malereproductive tract or breast cancer and that the worst-casedaily exposure to parabens would present substantially lessrisk relative to exposure to naturally occurring endocrineactive chemicals (EACs) in the diet, such as daidzein.

    The American Cancer Society has concluded that thereis no good scientic evidence to support a claim that use ofcosmetics such as antiperspirants increases an individualsrisk of developing breast cancer a feeling thats alsoshared by the UK Medical Control Agency (MHRA) and theEuropean Scientic Committee.

    A PARABEN-FREE LIFEDespite the conicting evidence, some manufacturers in theUK are shifting away from using parabens in products.

    Further studies are necessary in order to determine thesafety of parabens, as well as other preservatives, currentlyused in the marketplace, says Bakhtiar. The cosmeticindustry believes that most cosmetic ingredients areperfectly safe due to their long-term use and safety record,but cosmetic campaigns that raise awareness about thesafety concerns of potentially risky ingredients to avoid canonly help us to question this unproven line of thinking.

    The development of new preservatives (both man-madeand natural) has given the cosmetic scientist and consumera choice, which is undoubtedly a step in the right direction.In the meantime, your health is in your hands.

    PARABENS EXPLAINED Parabens are the most commonly used

    preservatives in cosmetic, pharmaceutical and industrial products and foods suchas frozen dairy products, processed vegetables and jams. Natural cosmetics are

    increasingly labelled paraben-free to be seen as better for our health. Are cosmetics

    companies cashing in on our fears, or are they simply more aware of the dangers?

    YOUR PARABENHIT LISTParabens are esters ofpara-hydroxybenzoicacid, which is wherethey get their name.Common parabensinclude methylparaben(E number E218),ethylparaben (E214),propylparaben (E216)and butylparaben. Lesscommon parabensinclude isobutylparaben,isopropylparaben,benzylparaben andtheir sodium salts. Someparabens are naturallyoccurring and found inplant sources such asmethylparaben, fromthe fruit of the blueberryshrub and acts as anantimicrobial agent.

    individuals increase,says Bakhtiar. But

    even paraben-sensitiveindividuals are mostlyable to tolerate paraben-containing cosmeticswhen applied to normalintact skin. They are alsofor the most part non-irritating from patch-teststudies done using humanskin, whereas the samecannot be said for otherpreservatives.

    Parabens also have a broad spectrum of activityagainst yeasts, moulds, and bacteria, says Bakhtiar. Theirantimicrobial activity increases with alkyl chain length sothey are often combined and enhanced to do so.

    THE CANCER CONNECTIONTrials have shown that butylparaben, but not otherparabens, have weak estrogenic activity, acting as xenoestrogens, says Bakhtiar. Butylparaben is around100,000 times weaker than estradiol, but at a dose level25,000 times higher than is used to preserve products.

    Since estrogens are known to drive the growth oftumors, this study has elicited some concern about the useof butylparaben and, to a lesser extent, other parabens incosmetics and antiperspirants. But there is no evidencethat any cosmetics containing parabens pose a health risk,because of the low doses involved and the fact that parabensare still generally thought unlikely to penetrate the tissue orto accumulate, although the jury is still out on this.

    One scientic study reports that parabens were foundin samples of breast tumours, revealed Bakhtiar. But thevalidity of theses conclusions drawn by Dr Darbre, who hasbeen researching in this eld for twenty years, have beenhotly debated. Darbres study has primarily fuelled the beliefthat parabens in underarm deodorants or other cosmeticsmigrated into the breast tissue and contributed to tumour

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    During the last decade there has beenan increase in consumer awarenesswith regard to chemicals used ineveryday life. To this effect the pressurefrom consumers, pressure groups, mediainstitutions and governments around theworld has increased significantly on thesafety of certain groups of raw materialsused in personal care and cosmeticformulations. Fragrances, dyes,preservatives, surfactants and evennaturally derived materials such as thoseof the tea tree have come under scrutiny or so-called attack. The evolving technology and techniques now employedin evaluating the toxicology of existing materials means that the safety of many

    raw materials is being scrutinised,reassessed and in some cases bannedfrom use by regulatory and safety authorities.

    This article looks at the importance of preservatives in the cosmetics andpersonal care industry and also thehistorical/future trends of preservatives incosmetic applications and how these arebeing influenced by various publicationsand media headlines.

    DefinitionPreservatives are a group of chemicalsused to prevent the growth andproliferation of microorganisms in cosmeticand personal care products which wouldotherwise cause spoilage or contaminationof the finished product.

    Background

    The use of preservatives is nothing new toevery industry globally and mostconsumers would be amazed at the levelof preservative use in common domestic

    and industrial materials 1 such as coatings,concrete, cooling water, detergents, food,fuel, glues, leather, paper, textiles, wood,electronics, plastics, tiles, and even NasaSpace Suits. In fact, without the use of preservatives in all these materials,proliferation of microorganisms would leadto spoilage and safety concerns.

    There are two main reasons for preserving cosmetic and personal careproducts and the reasons are the same for nearly every industry/application: namely health hazards and product spoilage.

    Health hazardsMost cosmetic and personal care productspresent an ideal environment for micro-

    organisms to grow and multiply quiteeasily. All the vital components such astemperature, nutrients, pH, and water arepresent in cosmetic products which makecontamination highly likely if preservativeswere not used.

    In most countries around the world,the use of preservatives in cosmetic andpersonal care formulations is notcompulsory. However there is a duty ofcare and responsibility by the supplier/ manufacturer to ensure that consumer products such as cosmetics and other personal care products do not cause harmto the end user if used under normalconditions.

    Some microorganisms are pathogenic(harmful to humans) and if allowed tocontaminate and proliferate in cosmeticsand personal care products might causesevere harm to the end user. Another safety concern with regard tocontamination is that the toxins releasedby these microorganisms can also beharmful to humans. This cannot beunderestimated since, in most cases, it isthe toxins which actually pose the threat to

    health. Cosmetics are commonly contaminated by four types of microorganisms: gram negative, gram

    Parabens friends or foes?Parabens friends or foes?

    R. D. Itoe UK & Ireland Regional Business Manager, Functional Chemicals,Personal Care Branch, Clariant UK Ltd

    Sonja Klein Technical Manager, Preservatives, Clariant GmbHPeter Klug R & D Manager, Personal Care, Clariant GmbH

    TABLE 2: GLOBAL APPROVAL OF COMMONLY USED PRESERVATIVES

    Preservative USA EU Japan

    Methylparaben SAU 0.4%* 1%**

    Propylparaben SAU 0.4%* 1%**

    Imidazolidinyl urea SAU 0.6% 0.3%***

    Butylparaben SAU 0.4%* 1%**

    Ethylparaben SAU 0.4%* 1%**

    Isothiazolinones 15 ppm 15 ppm 15 ppm***

    Phenoxyethanol SAU 1% 1%

    DMDM Hydantoin SAU 0.6% 0.3%***

    Quaternium 15 SAU 0.2% No

    Diazolidinyl urea 0.5% 0.5% No

    TABLE 1.

    Total preservatives Allowed in Regulationapproved all applications

    EU 56 34 Annex VI Positive Restricted List

    USA 57 CIR reported 40 CTFA/CIR

    Japan 43 16 Positive Restricted List

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    PRESERVATIVES

    TABLE 3.

    Preservative active Advantages Disadvantages

    Paraben Esters. Low toxicity. Low water solubility (except sodium esters)(methyl, ethyl, propyl, isopropyl, butyl , isobutyl) . Used in food and pharmaceuticals. Slightly weak antibacterial activity.

    Typical use concentrations 0.1%-0.3%. Stable and effective over a wide pH range. Incompatible with some proteins and Approved worldwide in personal care in some non-ionic emulsifiers.

    all applications. Used to broaden the spectrum of activity

    of formaldehyde donors.

    Organic acids. U sed in food and pharmaceuticals. Very poor against bacteria.Sorbic acid. Low toxicity. Severe disassociation and loss of activity Benzoic acid. Good against fungi. begins at very low pH (above 5.0).Dehydroacetic acid. Incompatible with proteins, cationics,

    nonionics.

    Bronopol. Excellent bactericidal activity. Poor fungicidal activity. Typical use concentrations 0.01%-0.04%. Excellent in moist cleansing wipes when Associated with nitrosamine formation.Used in combination with parabens or other used in combinations with parabens. Detectable formaldehyde release.anti-fungal agents. Not bounded by fabric. Not globally approved.

    DMDM Hydantoin. Cheap. Formaldehyde donor bad publicity due Typical use concentrations 0.15%-0.4%. Water soluble. to formaldehyde being classified as a

    Used in combination with parabens. Good broad spectrum activity. Class 3 Carcinogen. Active between pH 4-10. Slightly weaker against fungi. Not bounded by fabric.

    Imidazolidinyl Urea. Water soluble. Poor antifungal activity. Typical use concentrations 0.2%-0.5%. Low oil solubility. Formaldehyde donor bad publicity dueUsed in combination with parabens or other Good antibacterial activity. to formaldehyde being classified as aanti-fungal agents. Active between pH 4-9. Class 3 Carcinogen.

    Non-volatile. Relatively expensive. E asier to handle than formaldehyde. Poor heat stability. Low formaldehyde release

    (not activity-dependent).

    Iodopropynyl butylcarbamate (IPBC). Extremely powerful fungicidal activity. Virtually insoluble in water. Typical use concentrations 0.01%-0.05%. Compatible with nonionics and proteins. Very poor bactericidal activity.

    Can be used in combination with Good synergy demonstrated with Can cause discoloration.good bactericides. phenoxyethanol. Not globally approved.

    Contains iodine labelling requirement forleave on products above 0.2%.

    EU being considered for a ban onchildrens products.

    Methylchloroisothiazolinone Broad spectrum activity. Skin sensitiser.& Methylisothiazolinone. Active at very low concentrations. Restrictive concentration limit of 15 ppm.

    Typical use concentrations 7.5 ppm 15 ppm. Compatible with nonionics. Hazardous to handle as supplied. Poor stability above pH 8. Rarely used in moist cleansing wipes

    especially in Europe and Asia due tosensitisation concerns.

    Phenoxyethanol. Good activity against Pseudomonas. High concentrations required Typical use concentrations 0.4%-1%. Low toxicity. if used alone.Used in combination with parabens Compatible with nonionics and proteins.and other actives. Used as solvent in blends to boost overall

    activity of parabens.

    Benzyl alcohol. Good activity against gram +ve and moulds. High concentrations required Typical use concentrations 0.4%-1%. Low toxicity. if used alone.Used in combination with parabens C ompatible with nonionics and proteins.and other actives. Combinations with parabens improves

    efficacy.

    Methyldibromo glutaronitrile. Excellent preservative. Slightly weak against fungi. Typical use concentrations 0.02%-0.06%. Excellent antibacterial activity. Discoloration in presence of iron.

    Used in combination with phenoxyethanol. Compatible with nonionics and proteins. Unstable above pH 8. Sensitisation and irritation issues. EU banned for use in leave on.

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    PRESERVATIVES

    aureus , Candida albicans , and Aspergillusniger commonly contaminate cosmeticproducts around the world.

    A number of leading scientists, safety and regulatory departments would arguerightly that the risk of contamination is also

    just as important as the toxicologicalprofile of the formulation/product and thisshould not be compromised in the search

    for preservatives with brilliant toxicologicalproperties.

    Some scientists also argue that thefact that preservatives have the capability to kill or limit the proliferation of living microorganisms means that they wouldalso have some kind of effect on the cellsof human beings as well. I will start by looking at the consequences of ineffectivepreservation of cosmetic products.

    Incidents of contamination The CDC (Centre for Disease Control) hashad numerous reported incidences wherecosmetic product contamination has beenblamed for health hazards. For instance in1989, 2 a 47 year old woman reportedly scratched her left eye with mascara andthis led to progressive pain, redness, lightsensitivity and swelling. Three days later she had severely impaired vision and wasexamined by an ophthalmologicconsultant. Sadly, following treatment, her

    vision on the left eye did not improve andanalysis of the mascara showed highcontamination by P. aeruginosa . In a very limited search I came across nine old

    cases where mascara had beencontaminated with P. aeruginosa leading toeye problems. 3,4,5

    Another organism commonly found incontaminated cosmetic products is

    Staphylococcus aureus . It is a bacteriumfrequently found living on the skin and inthe nose of healthy individuals. Incompromised patients it can causeillnesses ranging from minor skin infections(such as pimples, boils, cellulotis) andabscesses to life threatening diseasessuch as pneumonia, meningitis andsepticemia. Each year around 500,000

    patients in American hospitals contract astaphylococcal infection. In some cases

    S. aureus has become resistant tocommonly used antibiotics.

    It can be argued that in nearly 99% of these cases, the contamination is likely tocome from poor hygiene and not cosmeticproducts, but nevertheless no supplier or manufacturer will be confident putting a

    product into the marketplace that couldpotentially be contaminated by S. aureus .

    Although very few incidents like theseoccur today, care still needs to be takenwhen formulating to ensure thatformulations are adequately preserved.

    Product spoilage The second reason for preserving cosmeticproducts is to avoid product spoilage. Whenmicroorganisms proliferate in, for instance,a cream, they break down the emulsioncausing thinning, separation, pH changes,malodour, colour change, etc which meansthat the product not only looks and smellsdifferent but also may not function properly when used. Creams usually contaminatedwith moulds go black/grey on the surfaceand although some of these moulds are notharmful, they can be off-putting to thecustomer.

    Nearly 50% of all recalls andwithdrawals are due to the fact thatproducts have become contaminated by microorganisms. In most cases theoffending product is spotted not by testing but by people in factories, shops,

    warehouses, etc who notice the differencein colour, smell or appearance andsubsequent testing highlightscontamination. In fact the first thing aquality department does when faced with aconsumer/customer complaint is check thenumber of organisms (if any) present.

    From the aforementioned limited citedexamples it is clear that contamination of products must be avoided by all cosmeticmanufacturers. This has led to preservativesbeing the second most common ingredientafter water to be used in cosmeticproducts. Cosmetic manufacturers are

    faced with the dilemma of whichpreservatives to use to solve this problembecause they have to consider safety,efficacy, regulatory, compatibility, and many more factors.

    Methods ofmicrobiological control

    The first point to stress is that

    preservatives should not be added tocosmetic and personal care products toclean the product and kill off micro-organisms already present. Preservativesshould be added to prevent or limit thegrowth of microorganisms which mightcontaminate the product after manufactureeither from air, water or even humancontact. There is a common misconceptionamong many manufacturers who usepreservatives as a fail safe option due topoor plant hygiene and manufacturing systems. This strategy often fails miserably,resulting in many product recalls andcontamination incidents due to thepreservative system being overloaded andused up fighting contamination before theproduct has even left the manufacturing

    vessel. Although this article will not focus on

    plant/manufacturing considerations, it isstill worth mentioning that the use of preservatives should be in conjunction withgood manufacturing practices (GMP) witha few guidelines below:

    Raw materials need to be screened toensure contamination is at a minimum.

    Process water used in manufacturing must also be checked regularly andsterilised before use in products.Mixing vessels, pipes and other plantequipment such as pumps, valves, etcneed to be sterilised and checkedregularly to limit contamination.Methods of manufacture andtechniques used also need to becarefully designed so as to minimisecontamination of product.

    Training of staff and audits need to becarried out to ensure all controls,procedures and processes are fully complied with and relevant to what they are designed to achieve.

    These are just a few summarised points,highlighting the fact that when a product iscontaminated, the root cause is not alwaysan ineffective preservative system.However, the most important controlmechanism is the effectiveness of thepreservative.

    The ideal preservative?Microorganisms vary in type, shape, size,

    make up, mobility, etc and formulations vary in ingredients, water content, pH, viscosity, etc. Some preservatives are only

    TABLE 4: TRENDS IN PRESERVATIVES

    1977 1987 1996 2001 2003

    Methylparaben 5,693 7,306 7,731 6,893 7,161

    Propylparaben 5,329 6,030 6,278 5,621 5,809

    Butylparaben 483 1,072 1,991 2,174 2,326

    Imidazolidinyl Urea 1,254 2,499 2,498 2,025 2,038

    Ethylparaben 31 581 1,240 1,451 1,725

    Phenoxyethanol 17 253 1,143 1,480 1,670

    DMDM Hydantoin 15 318 955 943 993

    Isothiazolinones 0 512 808 595 699

    Diazolidinyl Urea 0 130 690 701 725

    Quaternium- 15 599 673 704 505 516

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    one preservative which will be effectiveagainst all organisms and allformulations? While there arepreservatives which are effective againstmost organisms (broad spectrum) andwould even work in most formulations,effectiveness and application are not theonly criteria to consider.

    Formulators, chemists, and marketing,safety and regulatory managers in allcompanies around the world wouldprobably recognise the list below as itcontains some of the criteria preservativesuppliers are required to meet whendeveloping an ideal preservative (if such athing exists).

    Broad spectrum against allorganisms.Safe at use concentrations (non-irritant,non-sensitising, non-mutagenic, etc).Cost-effective at use concentrations.Global approval, particularly EU, USA,South America, Asia/Japan.Stable and effective throughout productshelf life.

    Easy to use and handle.Effective at target pH of product.Raw material and formulationcompatibility.Readily soluble in water.Heat stable.

    What the customer wants?

    The variety of requirements per customer per formulation varies so much that it issafe to say that the ideal preservative willnever exist because as soon as apreservative is developed, a new importantcriteria will be stipulated by customerswhich the preservative will not meet. In thelate 19 th to early 20 th Centuries,formaldehyde was the ideal preservative

    PRESERVATIVES

    TABLE 5: SENSITISATION POTENTIAL.

    Sensitsing

    Preservative Least Most

    1 2 3 4 5

    Parabens

    Imidazolidinyl urea

    Quaterium- 15

    formaldehydeBronopol

    Sorbic acid

    MI/MCI

    DMDM Hydantoincitric acid

    Benzoic acid

    Mercurials

    Dehydroacetic aci

    Triclosan

    Phenoxyethanol

    Chloroxylenol

    Source: A.C. De Groot Cosmetics &Toiletries Feb 1991.

    Figure 1: Allergic reactions 10 year clinical study SCCNFP 06/2002.

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    PRESERVATIVES

    but now in nearly all cosmetic products, inEurope at least, it is not even consideredas a preservative option any more.

    Having said that, there are somepreservatives which have passed the testof time and I will look into thesepreservatives and consider why they arestill being used in formulations today.Preservatives such as parabens,

    phenoxyethanol and even someformaldehyde donors such as imidazolidinylurea and DMDMH are still being usedextensively in the majority of personal careproducts.

    Even though the above idealpreservative list seems extremely long andnever ending, there are still three key criteria which all preservatives must meetbefore being considered as a preservativeoption by any customer:

    The first criterion to consider is theregulatory status. This is quite simplesince if a preservative is not approvedor banned, it cannot be used.

    The second important criterion to meetis safety. The safety of a preservative isdirectly related to its regulatory statussince this is the most important factor government agencies and scientistsconsider when regulating preservatives.Finally, the third important point tomeet is broad spectrum effectivenessagainst all organisms since it ispointless using a preservative that doesnot work.

    Regulatory approvalOnce again it must be stressed that if apreservative is not approved or banned, itcannot be used. It must also be noted thatpreservatives can also be approved butrestricted so that they cannot be used insome applications such as baby products,eye, mucus membrane, leave on, etc. Alsothe concentration will be limited to amaximum level which needs to beconsidered even if the preservative isapproved

    Various regions and countries havedifferent ways of regulating cosmeticproducts and preservatives. In the EU for

    instance, The 7 th Amendment contains apositive list of preservatives called Annex VIwhich means that all preservatives addedto formulations for the sole purpose of preserving the product must come fromthat list. It is always advisable to check theregulatory status of a particular preservativefor that region/country before making thedecision about which preservative to use.

    Table 1 shows the number of preservatives approved, and from this itcan be seen that the choice of globally approved preservatives is as low as 16, or even less if more Asian countries areconsidered.

    Figure 2: Dissociation of organic acids.

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    As you can see from Table 2 not allglobally approved preservatives are allowedin every application. Parabens andphenoxyethanol have no restriction withregard to all applications.

    Safety The regulatory status of a preservative is agood indication of the safety profile of thatpreservative. In most cases you will noticethat in cases where preservative useconcentrations have been limited to anextremely low level, say ppm, this meansthat their safety in use needs to becontrolled so that customers do notexceed safety margins. A good example is

    the use concentration of iosothiazolinonescompared to parabens or phenoxyethanol.

    This is because at higher concentrationsthey will cause sensitisation in someconsumers hence they need to berestricted to even lower levels. The sameapplies to methyldibromo glutaronitrile andIPBC where they are restricted in someapplications and are not even globally approved in many countries. It is directly related to safety profile or lack of safety information

    This does not mean that thesepreservatives have no place in cosmeticformulations since they can still be usedsafely in many formulations. However withregard to widespread acceptance, they continue to struggle to gain globalacceptance by many customers who wouldprefer to avoid it altogether.

    Broad spectrumeffectiveness

    The effectiveness of a preservative is also very important. Ideally a preservativeshould be effective against all types of organisms such as gram negative, gram

    positive, yeast and fungi. If there are gapsin its activity, then other preservatives willhave to be added to ensure the

    because although parabens have goodbroad spectrum activity, in difficult-to-preserve formulations they are sometimesweak against gram negative bacteria suchas Pseudomonas aeruginosa .Phenoxyethanol on the other hand is very effective against gram negative bacteriaand as such the two preservativescomplement each other when blended.

    Again the question is: Why not use a very powerful preservative and blasteverything within sight of the product?

    This goes back to the safety concern sincethe use of very powerful highly efficientpreservatives also comes at a price of poor safety profile. For instance formaldehyde,

    isothiazolinones and methyldibromoglutaronitrile can do the job in mostformulations but they are either notapproved in all applications or may increase incidence of sensitisation andhence more customer complaints reportedon cosmetic products.

    Having looked at three of the mostimportant factors, let us now look at theadvantages and disadvantages of commonly used preservatives.

    From Table 3 it can be seen that allnearly all preservatives have their limitations and no single active can beconsidered the ideal preservative.

    The only way to move closer to an idealpreservative scenario is to blend variousactives with the hope of achieving thedesired favourable end characteristics.

    Looking at the trend during the lastthree decades it is clear to see thatparabens, phenoxyethanol andimidazolidinyl urea have remainedconsistently in the top six throughout thatperiod. This is quite surprising considering the number of newly claimed, morepowerful preservatives that have been

    launched by suppliers during the last twodecades. The explanation is quite simple safety and regulatory approval is more

    glutaronitrile have poor toxicologicalproperties compared to parabens and assuch have had their use restricted by regulatory authorities around the world.

    As a result of this restriction consumersand customers have been very cautious inusing these new preservatives in many of their formulations. Nevertheless the author strongly believes these preservatives still

    have an important role to play within theindustry. They are still being used inspecial cases where they are eithercost-effective or where some of their effectiveness/properties make them better to use them than parabens, imidazolidinylurea and phenoxyethanol.

    The question on everyones lips is:Will this trend change or will parabensstill dominate the preservative market,particularly in light of recent publicity withregards to certain claimed adverse heatheffects? Before attempting to answer thatcomplex question, it is important look atwhy parabens have been the number oneused preservative globally for over 50 years(Table 4 indicates how trends can change).

    There are three key reasons why parabens have been the number onepreservative during the last 50 years and itis no coincidence that these propertiescoincide with the three factors mentionedpreviously. These are:

    They are globally approved in allapplications even sensitive ones suchas eye, baby, leave on, mucusmembrane, etc.

    They have an excellent safety profilemainly compiled by independentinstitutions around the world.Finally, they have good broad spectrumcapabilities against all organisms.

    Discovery of parabensParabens are esters of p-hydroxybenzoicacid where the ester can be methyl, ethyl,propyl butyl, etc. They were discovered inthe 1920s mainly due to frustrations atthe use of benzoic acid which wasineffective at high pH. Scientistsdiscovered that substituting and forming anester instead of the acid form meant thatthe pH effectiveness could be improved upto 8.5. This was the single most importantdevelopment in the long history of preservatives, and we still use parabenstoday.

    This esterified molecule had the addedadvantage in that the effectiveness wasimproved over a wide pH range while thesafety profile was still similar to benzoicacid. It is not surprising that parabenssoon became accepted globally in not only cosmetic formulations but also food and

    pharmaceutical applications and up to thepresent day they are still approved in allcosmetic, food applications and most

    PRESERVATIVES

    Figure 3: Percentage improvement in effectiveness over single actives vs. combination.

    S o u r c e :

    C l a r i a n

    t I n H o u s e d a

    t a .

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    PRESERVATIVES

    manufactured under the Nipa name, now acquired by Clariant.

    Safety and toxicology summary

    Acute oral - LD 50 R > 2000 mg/kg for all parabens.

    - LD50 R isothiazolinonesmixture 64 mg/kg.

    Subchronic/chronic - Low order of toxicity.Irritancy - Mild negative

    up to 5-12%.

    Sensitisation - Non-sensitising.

    Mutagenicity - Non-mutagenic.

    Carcinogenicity - Non-carcinogenic.

    Teratogenicity - Non-teratogenic.

    Phototoxicity - No evidence.

    By 1984 the Cosmetic Ingredient Review (CIR 1984) reviewed 6 and approved thesafety of parabens citing over 350 safety publications on parabens alone and in2002 Soni 7 also cited more than 350publications. As recently as early 2005parabens were reviewed 8 by the ScientificCommittee of Consumer Products with nochange in status and still approved in allapplications with no further restrictions.

    This is quite significant since this wasrequested by authors of papers claiming adverse health effects of parabens.

    From Table 5 it can be seen that withregard to sensitising potential, parabens,phenoxyethanol and benzoic acid areamongst the least sensitising preservatives

    available today. The most commoncomplaints from cosmetic consumers isirritation and sensitisation and this causesa lot of concern for the cosmetic industry which wants to market products that causelittle or no irritation or sensitisation.

    Another 10 year study 9 involving 50,000 patients in 10 countries alsolooked at the sensitisation potential asrecently as 2002 (Fig. 1). In fact due tothe significant increase in sensitisationreported for methyldibromo glutaronitrile,the material was restricted for rinse off formulations and a recent review by theSCCP stated that there is no safe level,hence there is activity with suppliers andcustomers looking for replacements.

    The above two examples demonstratethe good toxicological profile of parabens,which is why it has global approval eventoday and is still widely used.Efficacy of parabens:

    Overall good broad spectrum.Very good efficacy against yeast andmould MIC 0.05% - 0.1%.Effective but slightly weak againstgram-ve bacteria.

    Often blended with good anti-bacterialpreservatives.Good synergistic/optimum blends with

    Blends with suitable solvents show improved efficacy.Better pH stability than organic acidssuch as benzoic, DHAA, Sorbic acid,etc. (see Fig. 2 and 3).

    Figure 2 shows the dissociation of organicacids. This is why parabens were inventedin the first place since dissociation of acids

    occurs at pH as low as 5.1 while parabensare still 85% active up to pH 8.5.

    Combinations of parabensBlending of parabens also improvesefficacy and this is one of the advantagesof using various blends of parabens toimprove efficacy. As shown below somemixtures of parabens reduce efficacy whileother mixtures show synergisticperformance. This explains why there areso many blends of parabens on the markettoday.

    Are parabens the ideal preservative?Obviously not, but a look at all theadvantages and disadvantages of availablepreservatives today shows that they arethe closest we have within the industry.It is truly amazing that despite new preservatives launched during the last30 years, parabens remains the firstchoice of preservative in the presentclimate.

    Ideal preservative or not?Broad Spectrum (weak against gram negative).

    Safe at use concentrations non-irritat ing, non-sensitising, etc Yes

    Cost-effective Yes

    Global approval, particularly EU,USA and Japan Yes

    Stable and effective overproduct shelf life Yes

    Easy to use and handle Yes

    Effective at target pH of product(pH 4-8.5) Yes

    Raw material and formulationcompatibility (creams, lotions,cleansers, toothpaste, shower gels,

    lipsticks, baby products, etc.) YesReadily soluble in water(low water solubility).

    Heat Stable Yes

    Applications leave on, rinse off,oral, food, pharmaceutical Yes

    Recent safety concernson parabensUnfortunately, the time has come withinthe chemical industry where any publication in any journal or on the internetmay be seized on and used by the media,

    pressure groups and even governments tofurther their own profile or interests.Chemicals from everyday life have come

    individuals. It appears that authors andresearchers are looking at areas wherethey could generate the maximum publicity by highlighting implausible and sometimesexaggerated risks.

    In the UK for instance, if you consider the negative publicity surrounding MMRcreated by a single doctor involving very few patients, and even after 10 years of

    sound scientific counter arguments withmore credibility and involving analysis of data from millions of children around theworld, there are still doubts in parentsminds about using the triple vaccine.Parents have become so concerned thatsome of them cannot comprehend andbalance both sets of risks. On the onehand there is a higher risk of catching diseases which, until the vaccine wasfound, crippled millions of children in Third

    World countries and on the other hand theconcerns about a report published where itmay not even have been statistically significant.

    Some parents sadly put their children atgreater risk by either not allowing them tobe given the vaccine or preferring thesingle vaccine alternative that has notbeen proven nor tried and there is noguarantee that after 30 years use theeffect will not be worse than what they have just switched from which is provenworldwide.

    It looks like I am digressing but thereare similarities. If parabens are banned or restricted there are no effective options

    which are safer and in fact customers willmove to unsafe and untried options only tofind out that they were better off notswitching in the first place. The increase insensitisation with regards tomethyldibromo glutaronitrile demonstratesthis fact where parabens were replaced by this new preservative in sunscreens only toencounter numerous incidents of sensitisation and irritation as the usageincreased.

    Many preservatives have been bannedby some regulatory authorities or governments where the science does notquite add up. However, it is of greatbenefit that with regard to parabens safety,all sections of the industry customers,manufacturers, suppliers, industry associations (such as Collipa, CTFA, CTPA)and even regulatory bodies andgovernments have continued to defend theuse of parabens in all applications and insome cases reviewing and dismissing misleading articles such as the Darbrepaper. 8 (This paper published misleading research linking parabens in underarmcosmetics to breast cancer which does not

    make any sense when 95% of allunderarm applications do not containpreservatives and the author completely

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    meantime but unfortunately there will stillbe individuals and institutions who willcontinue to carry out research claiming adverse effect on not only parabens but allcosmetic raw materials as well.

    The future of preservativesIt is looking likely that all preservatives willbecome scrutinised against todays safety

    requirements and that new research,however implausible will be considered anddecisions made by regulatory bodiesaround the world.

    Seen already has been the effect of key preservatives such as IPBC andmethyldibromo glutaronitrile being threatened with extinction, a situationmade worse by the fact they are not being defended as vigorously as parabens.

    Another review in 2005 by the SCCPstated that parabens are safe for use in allcosmetics and personal care applicationsand the use concentrations should remain.

    There is still data required for butyl andisobutyl but these are more likely to havetheir use concentrations reduced rather than an outright ban.

    Here are a few other examples of whatis happening within SCCP in Europe:

    IPBC-based formulations iodineconcerns due to effect on thyroid gland. In 2004 SCCNFP opinion concluding

    limitation on concentration and alsoban on childrens products. This islooking likely.

    DBDCB (MDGBN) sensitisation and

    irritation issues following clinical trialsand safety experiments. Already banned on leave-on products

    by EU in 2003. In 2005 another SCCNFP opinion

    concluded that a safe limit could notbe established for rinse-off hencepossible ban on all products.

    Tea Tree oil concerns over sensitisation/irritation. In 2005 SCCP opinion recommended

    not to be used neat.Isothiazolinones concerns over sensitisation already addressed by limiting concentration to 15 ppm but

    still reluctance for use in leave-onformulations by consumers.Formaldehyde donors concerns over carcinogenicity of free formaldehyde. Not substantiated but SCCP now

    debating the ban on all Cat 3 CMRsubstances including formaldehyde.Formaldehyde donors will probably not be affected but free formaldehyde

    might need tightening.

    Summary and conclusionDespite all the bad press associated withpreservatives, they still play a vital rolewithin all cosmetic formulations. Someformulations claim to be self-preserved buteven these have those properties becausesome of the raw materials used havepreservation properties in their own right.

    The beginning of this article highlightedthe pitfalls of micro-contamination of cosmetic products and the risk of contamination needs to be balanced withthe overall safety of the product. Althoughthankfully very few incidents like theseoccur today, care still needs to be takenwhen formulating to ensure thatformulations are adequately preserved.

    There is no doubt that the increasedawareness and use of effectivepreservatives in todays cosmetic andpersonal care formulations have led tothese incidents being extremely rare andthis is a credit to not only the productmanufacturers but also to preservativesuppliers who have developed safe,

    effective preservatives for use in allformulations today. Parabens have beenleading the way since their discovery in the1920s in ensuring that cosmetic productsare less likely to be contaminated and alsoless likely to cause adverse health effectsand this should be praised and not seenas a weakness or target because of itsdominating position within the industry.

    Fortunately common sense still prevailsand despite all the adverse publicity thereis still global acceptance and support fromall parts of the industry including governments around the world. It is stillwidely accepted that in the future

    parabens will still be the most commonly used group of preservatives globally.

    Alternatives developed or being developed do not have the historical in useproven safety in actualformulations/consumer feedback. Just toreiterate this point, new preservative activessuch as IPBC and methyldibromoglutaronitrile developed only 10-15 years

    ago are now being banned or severely restricted as historical in use data is being compiled. Customers have no option but tocontinue and support parabens with aproven safety record going back to the1920s. If with all the wealth of safety information and in use historical datacompiled since then, parabens are stillbeing questioned, then no cosmeticmaterial let alone preservative is exemptespecially when most have only just beendeveloped with little or no historical safety profile.

    References1 Microbiocides for the protection of materials

    A handbook by Wilfried Paulus. First Ed. 1993.2 CDC MMWR Weekly , Jan 26, 1990/39(3):47-48.3 Wilson L.A., Ahern D.G. Pseudomonas-induced

    corneal ulcer associated with contaminated eyemascaras. Am J Ophthalmol , 1977;84:112-9.

    4 Thomas E.T., Barton S.N. The role of eyecosmetic contaminants in the pathogenesisof eye infection: an epidemiologic investigation.

    Ala J Med Sci , 1978;15:246-51.5 Reid F.R., Wood T.O. Pseudomonas corneal ulcer.

    Arch Ophthalmol , 1979;97:1640-1.

    6 Elder R.L. 1984 (Cosmetic Ingredient Review Panel) Final Assessment on the Safety of

    Methyparaben, Ethylparaben, Propylparaben andButylparaben.

    7 Soni M.G. Food and Chemical Toxicology 40

    (2002) 1335-1373 Evaluation of Health Aspects of Methylparaben (including other

    parabens).8 SCCP Opinions No. 0874/05 and No. 0873/05

    March 2005 Toxicological review of parabens

    following claims associated with breast cancer article by Darbre.

    9 SCCNFP 06/2002 Opinion on 10 year

    clinical study on allergic reactions of commonly used preservatives.

    P C

    PRESERVATIVES

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    skin 20. It was concluded that:-

    "All respiring vegetable and animal species require 4-hydroxybenzoic acid. Without it there areno ubiquinones and hence no respiration. 4-hydroxybenzoic acid is a natural vital ingredient ofaerobic life, it is no foreign substance to them."

    Bose 21 reported that 4-hydroxybenzoic acid exhibited marked synergy with auxins, in promotingroot growth of chrysanthemums, tomatoes and marigolds. Another interesting report byKickuth 22 isolated and identified nine aromatic compounds from the rhizomes of bullrushes S.lacustris which had microbiocidal activity (especially against E. coli and Salmonella spp.) andtherefore would make these plants important in maintaining water quality and protecting against

    pollution from disease producing organisms. The nine compounds identified were derivatives of benzaldehyde, 4-hydroxybenzoic acid and cinnamic acid (0.025 wt % of rhizomes). Thearomatic acid function had the greatest activity and had bactericidal activity against E. coli atconcentrations as low as single ppm levels.

    Da & Vialle 23 studied the flavour components of natural vanilla extracts. They showed that,unlike the Bourbon vanilla, the Tahiti vanilla contained methyl paraben as one of the four majorflavour components. Harbourne 24 found methyl paraben a constituent of lignin in somegymnosperms and woody dicotyledons.

    Aldrich 25,26 , studying the 7th-8th ventral abdominal gland secretions of adult males of the leaf-footed bugs, Leptoglossus and related species, found a preponderance of aromatic compounds,contrasting sharply with the aliphatic compounds which comprise the metathoracic glanddefensive secretions of male and female leaf-footed bugs. It was later found that methyl parabenwas a major component of the ventral abdominal gland secretion.

    Perkins 27, investigating the major components of the rectal glandular secretions of male fruit fliesfound methyl, ethyl and propyl parabens. He found that the glandular extracts of the S.E. Asianfruit fly ( Dacus albistrigatus ) was rich in methyl paraben. In another Dacus zeugodacus sp. (alarge unidentified Malaysian fruit fly) the glandular extract contained 66% ethyl paraben. Dacuscucurbitae , the melon fly, is the major fruit fly pest of melon and other cucurbits. Analysis of therectal gland secretions showed ethyl paraben as the major component and propyl paraben as aminor one. Hancock 28, studying African cucurbit pests, found Dacus vertebratus Bezzi to behighly attracted to methyl paraben. This discovery was initially observed when the fly wasattracted to a locally manufactured cosmetic product.

    Methyl paraben has now joined three other previously identified fruit fly attractants, "Cue-lure"[4-(4-acetoxyphenyl)butan-2-one], "Willison's lure" [4-(4-hydroxyphenyl) buutan-2-one] andmethyl eugenol. Methyl paraben has been called "Vert-lure".

    The article continues with a discussion of the biodegradability and the 4-hydroxybenzoic acid biocycle.

    It was concluded that 4-hydroxybenzoic acid and derivatives have a well reported and proven biocycle and are intrinsic and fundamental to all respiring and anaerobic life.

    See the reference list in the data sheet.

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    2. Niels K. Veien, Thais Hattel and Grete Laurbergg: Oral challenge with parabens in paraben-sensitive patients. Short communications: Contact Dermatitis 1996, 34, 433.

    Parabens used to preserve medicaments and cosmetics may sensitise and cause contact dermatitisat the site of application. It has been suspected that persons sensitised to parabens may

    experience flares of dermatitis from parabens in food and systemic medicaments.

    From 1.1.90 to 31.12.94 we performed a placebo-controlled oral challenge with a mixture of 100mg methyl p-hydroxybenzoate and 100 mg propyl p-hydroxybenzoate in 14 patients with leasta+ positive patch test to the paraben mixture in the European Standard Series. 7 of the patientshad hand eczema; 1 also had dermatitis of the face and 1 also had axillary eczema. 3 patients haddermatitis of the lower legs, 3 had dermatitis of the face and/or scalp, and 1 had dermatitis of theforearms.

    The capsules containing the paraben mixture or a placebo were given an interval of 1 week. Thisinterval was longer if there was a flare of dermatitis after the 1st. capsule. The sequence ofcapsules was randomised. The oral challenge was carried out when the dermatitis was quiescent.The patients themselves recorded whether or not aggravation occurred following the oralchallenge.

    2 of the 14 patients had flares of their usual dermatitis after challenge with the paraben mixture but not after the placebo. Both had hand eczema of the recurrent, vesicular type. Both had asevere erutpion of vesicles on the sides of the fingers within 24 hours of ingesting the parabencapsule. 1 of the patients also has a flare at a paraben patch test site on the back. 1 patient haddoubtful reactions to both the paraben mixture and the placebo, while 11 patients did not haveany reaction to the oral challenge.

    The 2 patients with specific reactions to the challenge were informed about food andmedicaments that may contain parabens. These preservatives are permitted in amounts up to 300mg/kg of foods such as mayonnaise and ready-to-serve salads containing mayonnaise, water-

    based ice cream, preserved fish, preserved vegetables, including ketchup and mustard,marmalade, fruit and vegetable juices and cider as well as candy and cakes.

    At follow-up visits after the patients had attempted to avoid the above-mentioned food items fora period of 1 to 2 months, neither patient of physician could see that the dermatitis had improvedas a result of the diet.

    Using the method described in the current study, we have not found oral challenge with parabensto be a useful test procedure in patients sensitive to the paraben mix. Although specific reactionswere seen in 2 paraben-sensitive patients with recurrent vesicular hand eczema, the significanceof this finding remains uncertain.

    The European Cosmetic Toiletry and Perfumery Association COLIPA stated that theRoutledge work was 'irrelevant' as 'Parabens are hydrolysed in the skin and we have data toshow that none are entering the blood stream', and said that the Industry had no plans tofollow up the work.

    Further information is attached for a considered opinion

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    Safety of Parabens

    We are aware of the new research published by Dr Phillippa Darbre and the concern this maycause to consumers (1). The research does not find a causal link between underarm cosmeticscontaining parabens and breast cancer.

    Parabens are preservatives that are used in cosmetics because of their excellent safety profile.They are very rarely used in deodorant and antiperspirant products because these productsare, essentially, self-preserving. However, where parabens are used in cosmetic products theyare declared in the ingredient listing by the name paraben.

    Dr Darbre reports finding parabens in samples of human breast tumour tissues but she alsofound quantities of parabens in blank samples that did not contain any tissue at all. Thus,the significance of her results is not easy to ascertain. Extensive independent research has

    previously shown that any traces of parabens that might enter the skin are completely brokendown by skin cells to harmless substances that cannot pose any risk of breast cancer.

    According to a number of leading cancer research organisations, there is no plausible biological mechanism by which antiperspirants and deodorants could cause breast cancer.Other risk factors, including smoking, drinking and obesity, are well known to have animpact on the rising incidence of breast cancer.

    Dr Chris Flower of the CTPA said Extensive research available to our members continues toindicate that there is no proven link between rising breast cancer rates and the use ofantiperspirants or deodorants. Dr Darbres research is based on an extremely small sample of20 breast tumour cases and does not include any reference samples from normal tissues.

    Safety is the number one priority for CTPA members who manufacture antiperspirants anddeodorants. Parabens are officially approved for use under the Cosmetics Directive(76/768/EEC), the European legislation that regulates all cosmetics and toiletries. We canreassure the public that all cosmetic and toiletry products containing parabens may continueto be used safely.

    CF/eoce/state/ingr/parabens 12.1.04

    1 Concentration of Parabens in Human Breast Tumours. P.D. Darbre, A. Aljarrah, W.R. Miller, N.G.Coldham,M.J.Sauer and G.S.Pope. J. Appl. Toxicol. 24 : 5-13 (2004)

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    Expert comment regarding latest reports on parabens and breast cancer

    The findings of parabens in tumour samples are additional results in line with the generalhypothesis that there may be a link between oestrogenic compounds commonly used inunderarm cosmetics and other consumer products and breast cancer. The results alone,

    however, do not suggest that these chemicals caused the tumours in these patients. Darbre etal.s findings invite several questions: how did the parabens get into the breast, are they

    persistent and could they do harm? The answers require further research.Philip W. Harvey and David J. EverettGeneral considerations and conclusion from the Editorial of the Journal of AppliedToxicology where the research was published

    We are all exposed to all kinds of chemicals but it doesnt mean that they all cause cancer.The question is here whether the chemicals would have an impact on the hormones, and alsowhat level you would see in a healthy breast tissue. A causal link has by no means been

    proved.Karol Sikora, Professor of Oncology at Imperial College LondonThe ObserverSunday, 11 th January 2004

    Although this is an interesting study the sample size is very small. No causal link has been found between underarm cosmetics containing parabens and breast cancer. There is also norobust population-based evidence to suggest a link. Should any notional risk exist it wouldbe insignificant when compared to other avoidable environmental risks for the disease, suchas obesity.

    Dr Richard Sullivan, Head of Clinical Programmes at Cancer Research UKThe Sun, The Star, Daily Mail, The Independent, The ObserverMonday, 12 th January 2004

    This extremely small study does not demonstrate a direct or causal link between deodorantor anti-perspirant use and developing breast cancer. Further research is needed to establishthe source of the chemicals found in the breast tumour samples and what, if any, therelationship is to breast cancer.Delyth Morgan, Breakthrough Breast CancerDaily Mail, Daily MirrorMonday, 12 th January 2004

    We conclude from our results that the above mentioned paraben esterase III ofkeratinocytes (a skin enzyme that breaks down parabens) is sufficient to completely hydrolysethe traces of parabens that may enter the skin from topically applied ointments.C. Lobermeier, C. Tschoetschel, S. Westie and E. Heymann.Hydrolysis of parabens by extracts from differing layers of human skin.Biol.Chem. 377(1): 647-651 (1996)

    The Cosmetics Directive 76/768/EECAnnex VI specifically permits 4-hydroxybenzoic acid and its salts and esters (the parabens)

    for use as preservatives in all cosmetic products. The maximum authorised concentration is0.4% (as the acid) for any one ester and no more than 0.8% (as the acid) for mixtures of

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    esters.

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    Safety of Parabens

    We are aware of the new research published by Dr Phillippa Darbre and the concernthis may cause to consumers (1). The research does not find a causal link between

    underarm cosmetics containing parabens and breast cancer.

    Parabens are preservatives that are used in cosmetics because of their excellent safety profile. They are very rarely used in deodorant and antiperspirant products becausethese products are, essentially, self-preserving. However, where parabens are used incosmetic products they are declared in the ingredient listing by the name paraben.

    Dr Darbre reports finding parabens in samples of human breast tumour tissues but shealso found quantities of parabens in blank samples that did not contain any tissue atall. Thus, the significance of her results is not easy to ascertain. Extensiveindependent research has previously shown that any traces of parabens that mightenter the skin are completely broken down by skin cells to harmless substances thatcannot pose any risk of breast cancer.

    According to a number of leading cancer research organisations, there is no plausible biological mechanism by which antiperspirants and deodorants could cause breastcancer. Other risk factors, including smoking, drinking and obesity, are well known tohave an impact on the rising incidence of breast cancer.

    Dr Chris Flower of the CTPA said Extensive research available to our memberscontinues to indicate that there is no proven link between rising breast cancer ratesand the use of antiperspirants or deodorants. Dr Darbres research is based on anextremely small sample of 20 breast tumour cases and does not include any referencesamples from normal tissues.

    Safety is the number one priority for CTPA members who manufactureantiperspirants and deodorants. Parabens are officially approved for use under theCosmetics Directive (76/768/EEC), the European legislation that regulates allcosmetics and toiletries. We can reassure the public that all cosmetic and toiletry

    products containing parabens may continue to be used safely.

    CF/eoc

    e/state/ingr/parabens 12.1.041 Concentration of Parabens in Human Breast Tumours. P.D. Darbre, A. Aljarrah,W.R. Miller, N.G.Coldham, M.J.Sauer and G.S.Pope. J. Appl. Toxicol. 24 : 5-13(2004)

    Expert comment regarding latest reports on parabens and breast cancer

    The findings of parabens in tumour samples are additional results in line with thegeneral hypothesis that there may be a link between oestrogenic compounds

    commonly used in underarm cosmetics and other consumer products and breastcancer. The results alone, however, do not suggest that these chemicals caused the

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    tumours in these patients. Darbre et al.s findings invite several questions: how didthe parabens get into the breast, are they persistent and could they do harm? Theanswers require further research.

    Philip W. Harvey and David J. Everett

    General considerations and conclusion from the Editorial of the Journal of AppliedToxicology where the research was published

    We are all exposed to all kinds of chemicals but it doesnt mean that they all causecancer. The question is here whether the chemicals would have an impact on thehormones, and also what level you would see in a healthy breast tissue. A causal linkhas by no means been proved.Karol Sikora, Professor of Oncology at Imperial College LondonThe ObserverSunday, 11 th January 2004

    Although this is an interesting study the sample size is very small. No causal linkhas been found between underarm cosmetics containing parabens and breast cancer.There is also no robust population-based evidence to suggest a link. Should anynotional risk exist it would be insignificant when compared to other avoidableenvironmental risks for the disease, such as obesity.

    Dr Richard Sullivan, Head of Clinical Programmes at Cancer Research UKThe Sun, The Star, Daily Mail, The Independent, The ObserverMonday, 12 th January 2004

    This extremely small study does not demonstrate a direct or causal link betweendeodorant or anti-perspirant use and developing breast cancer. Further research isneeded to establish the source of the chemicals found in the breast tumour samplesand what, if any, the relationship is to breast cancer.

    Delyth Morgan, Breakthrough Breast CancerDaily Mail, Daily MirrorMonday, 12 th January 2004

    We conclude from our results that the above mentioned paraben esterase III of

    keratinocytes (a skin enzyme that breaks down parabens) is sufficient to completelyhydrolyse the traces of parabens that may enter the skin from topically appliedointments.C. Lobermeier, C. Tschoetschel, S. Westie and E. Heymann.Hydrolysis of parabens by extracts from differing layers of human skin.Biol.Chem. 377(1): 647-651 (1996)

    The Cosmetics Directive 76/768/EEC

    Annex VI specifically permits 4-hydroxybenzoic acid and its salts and esters (the parabens) for use as preservatives in all cosmetic products. The maximum authorisedconcentration is 0.4% (as the acid) for any one ester and no more than 0.8% (as theacid) for mixtures of esters.

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    MORE PARABEN ISSUES

    Dear Tony,

    Whilst Professor Morganti specifically requested a reply on the parabens questionfrom someone from Nipa Laboratories (which no longer exists), I would like to replyin my capacity as an ex-Nipa employee!

    Firstly a general comment. I think that the Board of Directors of Avon are to becongratulated on their calm and sensible response to the current scare. Too often inthese cases a knee-jerk reponse is given without any careful thought or considerationof the facts. It seems to me to be a great shame that some "scientists" feel that theyhave to publicise their theories before they have any proof, especially in these timeswhen the media delight in seizing on any "scare" or "scandal".

    Good science is the formulation of a theory, then testing to prove the theory, then publication of the results with conclusions. The current concerns over the safety of parabens is just sensationalism using an unproven theory.

    I question the validity of the use of some of the papers used in support of Dr. Darbre'scase, notably the Routledge et al paper (Tox. Appl. Pharm 153 (1998) 12 - 19). This

    paper has been used many times to justify the statement that "parabens areoestrogenic". I think it is important to place this paper in context before addressingDr. Darbre's own work. Whilst the workers did find some oestrogenic activity incertain paraben esters, the dose levels used and the strength of oestrogenic responsemust be bourne in mind. Routledge's in vitro study showed comparitive actitivities of

    parabens with oestradiol ranging from 10,000 (butylparaben) to 1,000,000(methylparaben), and the in vivo study showed no oestrogenic activity formethylparaben and the activity for butylparaben was 100,000 times weaker thanoestradiol. The lowest observed effect level of butylparaben (200mg/kg/bw/day) inthis study was acheived using a subcutaneous dose approximately 50,000 timesgreater than is ever likely to be employed by the consumer. A further study byHoussaini et al ((Food & Chem. Tox. 38 (2000) 319 - 323) repeated the subcutaneousapplication used by Routledge et al and found only a weak response with

    butylparaben at 400mg/kg/bw/day and a clear reponse at 600mg/kg/bw/day - muchhigher than that observed by Routledge. I think the telling part of the Houssaini study

    was part of the conclusion - "owing to...rapid metabolism and excretion it isconceivable that concentrations high enough to produce an oestrogenic effect in targettissues will not be reached unless excessive doses are used". In the case of

    butylparaben, the excessive dose required to exhibit an oestrogenic effect was150,000 times the highest typical application rate in humans - surely an excellentmargin of safety!

    Many papers have been published demonstrating that parabens are rapidly absorbedthrough skin, metabolised and excreted - mostly within 24 hours. The huge dosesemployed in these studies, plus the dosing method employed further distort the

    picture, resulting in more of the dose added actually reaching target organs intact.

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    Dr. Darbre's study itself raises some interesting questions, having put to one side thedubious question of oestrogenic activity of parabens. I have read this paper and findsome of the aspects of the work rather questionable. I ignore the results for

    benzylparaben as this compound is hardly ever used in personal care preservation, ifat all. In the results table many of the blank samples showed a paraben presence -

    which is questionable in itself, and I find it difficult to accept the explanation that theycarried over from the detergents used to wash the glassware employed in the study -when the figure for the blank was subtracted from the test sample a negative figureresulted. This occured in 26 out 120 data points, leaving us with the interestingconcept of "minus parabens". To have so many meaningless data points (over 20%)must surely throw a question mark over the validity of the data?

    Part of the claims for this study is that it demonstrates bioaccumulation of parabens.Even if it is accepted that the parabens were found in breast tissue, it is not possible toclaim any form of accumulation from a single data point, and the findings could be

    background levels present during the metabolic process. Dr. Darbre draws comparison between parabens and PCB's and OCP's, quoting mean levels of 20, 267 and 707 ng/gtissue respectively, claiming this as evidence of bioaccumulation. I would argue thatthis proves precisely the opposite. Human exposure to parabens must be severalorders of magnitude greater than exposure to PCB's and OCP's, yet the latter havesignificantly higher residual levels than parabens. If parabens were bioaccumulative,surely this would be reflected in mean levels much higher than those of PCB's andOCP's?

    One of the most questionable aspects of this work is the use of a "corrected averagelevel of parabens" on the basis that 4 of the 20 tumours contained more than twice theaverage level of total parabens, and she then allows for only a 50% recovery of

    parabens through the analytical procedure. The "corrected average level" of 100ng/gonly uses the data from the 4 tumours with the highest levels of parabens, so this isnot a corrected figure at all, but a gross distortion which is then used as a comparisonwith data from other studies. The true "corrected average level" of parabens should be41.2ng/g if it is accepted that only 50% of parabens are recovered by analysis. I notethat there was no justification or demonstration of the basis for the 50% recoveryclaim. The distorted average was used for comparison with a study that found levelsof 150ng/ml of propyl, butyl and isobutylparaben to stimulate growth of MCF7human breast cancer cells. However, 62% of the total paraben found in the breasttumours was methylparaben and almost 10% was ethylparaben, for which there are no

    data on their capacity to stimulate MCF7 human breast cancer cells, so only 28% ofthe total parabens found were relevant to the comparison actually made, which surelycalls into question the validity of the comparison?

    The comments about the reasons for the detection of higher levels of methylparabenare very interesting. The initial conclusion is probably correct in part, ie. thatmethylparaben is the more widely used in consumer products (but it is also used inhigher concentrations), but this is followed by the astonishing claim thatmethylparaben has a greater ability "to be absorbed into body tissues and to resisthydrolysis by esterases of human skin and subcutaneous fat tissue". Basic chemistrytells us that longer chain esters are increasingly resistant to hydrolysis, therefore

    methylparaben is much more likely to be hydrolysed than the higher esters, and lesslikely to be absorbed by fatty tissue.

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    Dr. Darbre has been told on more than one occasion that the vast majority ofunderarm products contain neither parabens, nor any other preservatives, but shechooses to ignore this fact and to continue to court publicity for her cause. To

    paraphrase Phillip Day's comments - " I applaud Phillipa Darbre's intentions, but her

    scientific approach is highly questionable". I take great issue with Mr. Day'scomments as it is clearly scaremongery to publicise Dr. Darbre's theories across theworld without any scientific proof that her theory is correct as this study onlydemonstrates that parabens appear to be present in breast tumours - it does not provethat they are the cause. I also take equal issue with his assertion that "chemical

    products (are) being sold without a care in every supermarket around the world". Thisis complete rubbish, and deserves no further comment.

    I admit that I have no ready explanation for the possible finding of parabens in breasttumour tissue, as it appears to conflict with the many studies that have claimedcomplete metabolism and excretion. It may be that parabens remain stable withintumour tissue for some reason, but this would not prove that they are responsible forthe tumour itself, as the tumour would need to be present before the parabensmigrated there! Dr. Darbre should have tested normal breast tissue to provide acontrol for her study, and she should use a more reliable method of analysis as it iseasy to achieve much greater than 50% recovery of parabens in analytical studies. Iwould also like to see the basis for the claim of only 50% recovery in her method.

    I am not a toxicologist and the above observations have been made on the basis ofdiscussions with expert toxicologists, past experience and basic common sense, but Ihope that I have clarified my point that the study in question has some very importantfailings, and more work is required, possibly by someone less evangelical and morerational about the subject of breast cancer, in order to finally put this to rest.

    I live in hope that, should it ever be proven unequivocally that parabens do notcontribute to breast cancer, I hope the media give it the same degree of attention thatthey have to the alleged negative aspect of their use.

    I shall now go and lie down for a while!

    Best regards

    Dene GodfreySales & Technical DirectorMGS MicroPure Ltd.

    ANOTHER ANSWER FROM MY USA FRIEND

    1. I am not aware of any underarm antiperspirant or deodorant that contains parabens.The use of the CIR report was taken without any understanding of the data. All of thisis junk science.

    2. The major use of parabens as food preservatives is in Soy Sauce in Japan. (The US

    does not use parabens in US made soy sauce). For the paper to have a snow ballschance in hell of any truth, than All Japanese's women should have breast cancer! We

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    rarely use parabens in foods because they really screw up our taste buds. Not a goodidea for foods!

    David C. SteinbergSteinberg & Associates, Inc.

    16 Mershon LanePlainsboro, NJ 08536Phone 1-609-799-1575Fax 1-609-799-5271www.SteinbergConsult.com MORE ON PARABENS

    Hi Tony,

    Parabens & breast cancer

    Thanks for highlighting this emotive subject (I had also seen reports in the UK press).While I believe that this is a study worthy of our attention, I think this is another caseof poorly conducted or half-done science. The researchers have forgotten one thing,that was strongly stressed to me throughout my university career: 'correlation DOES

    NOT prove causation' - just because 2 events are linked, this is no proof that onecauses the other!

    While the postulated link is interesting, I'm sure that many of us can see weaknesses -the primary one for me, is that the majority of AP/deo products do not contain

    parabens. As you know from formulating, most varieties of stick and aerosol don'thave any preservatives at all. I have just searched 2 online sources of information -drugstore.com (which handily gives ingredient listings for products) and GNPDMintel, a marketing company we use that has a searchable online database of new

    personal care products from around the world. Of the 3,324 'deodorants' productslaunched in the last 6 months (includes AP), only 12 contain any parabens! These are5 varieties of wipes, 1 powder, 4 roll-ons, 1 cream and 1 spray (some deo, some AP).

    Therefore, it should be very easy for an epidemiological study to find people usingdifferent formats of deodorant, and monitor their cancer levels. Also, since men aresupposed to be more oestrogen sensitive, shouldn't we be seeing many more cases of

    breast cancer in men?

    They say debate is a good thing, but I am worried that most consumers are notscientists, and take all of these studies as 'gospel', without ever looking at theirscientific rigour.

    Kind regards

    Heather

    http://www.steinbergconsult.com/http://www.steinbergconsult.com/
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    CONTACT DERMATITIS CLINIC

    DEPARTMENT OF DERMATOLOGYUNIVERSITY HOSPITAL OF WALES

    PARABENS Information for patients allergic to PARABENS.

    What causes allergy?

    Although many people may have contact with chemicals, only a very few develop an allergy to them. In these people the body's defence mechanisms learn to recognise this chemical. They therefore develop a reactionwhen the chemical contacts the skin again. The allergy is 'remembered' by the body for many years.

    What are 'Parabens'?

    Parabens are a group of closely related chemicals which are 'esters' of p-hydroxybenzoic acid. They are used

    widely as preservatives for cosmetics, foods and drugs. They work as preservatives by inhibiting the growthof organisms. As different esters inhibit different organisms, they are often used as a combination of differentesters.

    The most commonly used 'parabens' are methylparaben, ethylparaben, p-hydroxybenzoic acid, propylparabenand butylparaben.

    Parabens sensitivity is usually caused by medicaments used to treat eczema. Although parabens are found inmany cosmetics, they are used in low concentration, insufficient to cause an allergy.

    What are parabens in?a] Pharmaceutical preparations, including:

    Alphosyl HC cream Locoid LipocreamAureocort ointment Mildison LipocreamBarquinol HC cream Neo-medrone creamBetnovate lotion Nerisone creamBetnovate N lotion Synalar gel and lotionCarbo-cort cream Synalar C creamCobadex cream Synalar N cream and lotionDome-cort cream Siladerm creamEfcortelan lotion Synalar forte creamEpifoam Tarcortin creamEurax-Hydrocortisone cream Temtex creamFucidin H gel TerraCortril Nystatin creamGenticin HC ointment and cream Timodine creamHaelen-C cream Tridesilon creamLedercort cream and ointment Ultradil creamLocoid cream Ultralanum plain cream

    b] Barrier creams.

    c] Cosmetics. Many cosmetics contain parabens.

    d] Many drugs given by injection.

    How can I prevent further problems?

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    REFERENCES

    PropylparabenNIPASOL M

    In a material safety data sheet from Nipa Laboratories Ltd .

    It is N-Propyl-4-hydroxybenzoate or propyl paraben. It is a fine, white, crystalline powder.

    Toxic hazard

    Practically non-harmful by ingestion (Acute oral toxicity in rat LD 50 above 8g/Kg).

    Tasteless, but producing a slight burning sensation in the mouth and tongue, followed by a localnumbness.

    Non-irritant to the skin. Slightly irritant to the eyes.

    First aid

    Skin contact: Wash thoroughly with soap and waterEye contact: Irrigate with water for 10 minutesInhalation: Remove to fresh air.

    Martindale. The Extra Pharmacopoeia. 29th. Edition. 1989. The Pharmaceutical Press. ISBN. No.0-85369-210-6.

    Martindale adds no further to the information above.

    Merck. The Merck Index 11th Edition. An encyclopaedia of chemicals drugs and biologicals. 1989 ISBN. 911910-28-X. published Merck.

    It is slightly soluble in boiling water, freely soluble in alcohol, soluble in 2000 parts of water. Itis used as a pharmaceutic aid (antifungal). Preservative in foods.

    COSMETICS & TOILETRIES - March 1994, Vol 109.

    W.P. Jordan reported that hand eczema may be contact dermatitis. The prognosis is not good if- after avoidance of offenders identified by patch test - eczema does not clear. As a rule, preservatives contribute to hand eczema. In his opinion, the safest preservatives are the parabens. Psoralen-UVA(PUVA) therapy of palm eczema can be very effective.

    G.A. Nowak: Cosmetic Preparations. Vol.1. Process Technology of Cosmetics, Microbiology,GMP, Preservation, Data on skin, Special active agents and adjuvants. Verlag fur chem.

    Industrie H. Ziolkowsky KG, Augsburg (Germany).1985. ISBN No. 3-87846-118-6.

    The action is predominantly fungistatic. Solubility in water is lower at 0.05% at 20 C than that of

    the methyl ester.

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    Merck. The Merck Index. 12th edition. Merck & Co. Inc. 1996 Whitehouse Station, NJ,USA. ISBN No. 0911910-12-3.

    Propylparaben.

    4-Hydroxybenzoic acid propyl ester; propyl p-hydroxybenzoate; Nipasol M (Nipa);Solbrol P (Bayer); Propyl Parasept (Tenneco). C 10H12O3; mol wt 180.20. C 66.65%, H6.71%, O 26.64%. Prepn: Stohmann, J. Prakt. Chem. 36, 368 (1887); L. Nobli, Giorn. Farm.Chim. 84, 168 (1935), C.A. 30, 34239 (1936).

    White crystals, mp 96-97 deg. Sol in 2000 parts water; freely sol in alcohol, ether; slightlysol in boiling water.

    USE: Pharmaceutic aid (antifungal). Preservative in foods.

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    PROPOSAL 7RESOLUTION REQUESTING REPORT ON PARABENS

    The Company is informed that Domini Social Investments LLC, whose address andshare ownership will be furnished promptly upon receipt of any oral or written requesttherefore, together with another shareholder co-proponent, whose name, address and

    share ownership will be furnished promptly upon receipt of any oral or written requesttherefore, intend to introduce at the Annual Meeting the following resolution:

    WHEREAS:

    According to Avon Products website, 82 products, including Auto Focus LightAdjusting Foundation, Beyond Color Illuminating Radiance Vitamin C Foundation,Beyond Color Vertical Lift Foundation, Perfect Wear Total Coverage Concealer, ClearFinish Great Complexion Pressed Powder contain parabens.

    Parabens are preservatives that have been identified as estrogenic and disruptive of

    normal hormone functions.1

    Estrogenic substances are chemicals foreign to the body thatmimic the function of the naturally occurring hormone, estrogen. 2 Estrogen has beenshown to control the growth of breast cells, 3 and exposure to external estrogens has beenshown to increase the risk of breast cancer. 4

    According to a report by the National Research Council, some estrogenic substancesare associated with adverse reproductive and developmental effects in wildlife and otheranimals. 5 The US National Toxicology Program lists steroidal estrogens as knownhuman carcinogens. 6 Although parabens are not steroidal estrogens, studies haveshown that they can mimic steroidal estrogens in animal studies, including in mammals(see, e.g., Pedersen et al. (2000) and Routledge et al. (1998), cited above).

    There is substantial scientific evidence to suggest that increased exposure to substancesthat behave like estrogen in the body may elevate an individuals risk of developingcancer. 7 Parabens are among these substances. 8

    BE IT RESOLVED

    The shareholders request that the Board of Directors prepare a report (at reasonablecost and omitting proprietary information), available to shareholders by October 2003evaluating the feasibility of removing, or substituting with safer alternatives, all parabensused in Avon products.

    The proponents have furnished the following statement in support of the resolution:

    Our company deserves high praise for its commitment to womens health. Avon hasraised approximately $190 million for womens health programs in 30 countries througha variety of fundraising programs. Avon states on its web site, No other company hascommitted as much money to the cause of womens health. Our Company has donemore in the breast cancer fight than any other company.

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    Chemicals that may pose higher-than-average risk to human health, and particularly

    those that may increase the risk of breast cancer, could undermine our Companys goodefforts to support womens health, especially in the breast cancer arena. We believe thatthey do not belong in our products.

    ________________________

    1 Pedersen, K.L. et al., The preservatives ethyl-, propyl-and butylparaben are oestrogenic in anin vivo fish assay, Pharmacology & Toxicology (Vol. 86(3), pp 110-13, March 2000);Routledge, E.J., et al., Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic,Toxicology and Applied Pharmacology (Vol. 153(1), pp. 12-19 (Nov. 1998) and Kang, K.S. et al,Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben), Journal of Veterinary Medical Science (Vol. 64(3), pp.227-35 (March 2002).

    2 National Research Council, Hormonally Active Agents in the Environment (Washington DC, National Academy Press (1999) (NRC Report).

    3 US Department of Health and Human Services, National Toxicology Program, 10th Report onCarcinogens, pp. 116-19 (2002).

    4 NRC Report, cited above.

    5 Id.

    6 US Department of Health and Human Services, National Toxicology Program, 10th Report onCarcinogens, pp. 116-19 (2002).

    7 NRC Report, cited above.

    8 See Pedersen at 110-13, Routledge at 12-19, and Kang at 227-35.

    Board of Directors Statement on Proposal 7

    Consumer safety is Avons number one priority. As a responsible cosmeticsmanufacturer, the Company has an extensive formal process for review of the safety andintegrity of all of our products and ingredients. Toxicologists at Avon thoroughly

    evaluate safety data for all ingredients before they are approved for use in any of our products. Also, the Companys scientists participate in industry-wide and professionalscientific organizations in order to access and evaluate the latest information to ensure thecontinued safe use of all our product ingredients. In addition, Avon microbiologists striveto ensure that our products do not present potential health risks from contamination byharmful microorganisms by using preservative systems such as parabens.

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    REFERENCES

    MethylparabenNIPAGIN M

    In a material safety data sheet from Nipa Laboratories Ltd .

    It is sodium methyl-4-hydroxybenzoate or sodium methyl paraben. It is a white hygroscopic powder, readily soluble in water and having a pH (0.1% solution) in water of 9.5-10.5.

    Toxicity hazard

    Slightly harmful by ingestion (acute oral toxicity in mouseLD50 2g/Kg). Tasteless, but producing a slight burning sensation of mouth and tongue, followed

    by local numbness.

    Non-irritant to the skin. Slightly irritant to the eyes and to nasal passages.

    First aid

    Skin contact: Wash thoroughly with soap and water.Eye contact: Irrigate with water for 10 minutes.

    Merck. The Merck Index 11th Edition. An encyclopaedia of chemicals drugs and biologicals. 1989 ISBN. 911910-28-X. published Merck.

    The solubility in water is given as 0.25% w/w at 20o

    C and as 0.3% w/w at 25o

    C. It is used as a preservative in foods, beverages and cosmetics.

    Martindale. The Extra Pharmacopoeia. 29th. Edition. 1989. The Pharmaceutical Press. ISBN. No.0-85369-210-6.

    gives no further information to reference 1.

    COSMETICS & TOILETRIES - March 1994, Vol 109.

    W.P. Jordan reported that hand eczema may be contact dermatitis. The prognosis is not good if- after avoidance of offenders identified by patch test - eczema does not clear. As a rule,

    preservatives contribute to hand eczema. In his opinion, the safest preservatives are the parabens. Psoralen-UVA (PUVA) therapy of palm eczema can be very effec