COSMETIC PRODUCT SAFETY

RESEARCH UPDATE

TABLE OF CONTENTS
INTRODUCTION DEFINING ISSUES
Advances in Science
Protecting Human Health 2 Safety Never Stops: Industry Techniques for Ensuring Ongoing Safety 3 Protecting the Environment 4 The Role of Global Industry and Government Regulatory Groups in Review and Regulation of Cosmetic Products 5 Regulation of Cosmetic Products 5

WHAT WORKS
Novel Approaches to Hazard Assessment
Identifying Potential Skin Allergens 13 In Vitro Eye Irritation Models 15 Screening for Endocrine Disruptors 15

Did You Know?

Dr Frank Gerbericks Pioneering Work in Skin Sensitization Hazard Assessment 14

WHATS COMING
Promising New Areas
ToxicogenomicsThe Future of Safety 15 Nanotechnology 16 P&Gs Commitment to Best Practices and Advances in Research 17

Biological Facts
A Sense of Preservation 6 Potential Sources of Microbial Contamination 6 Defining Skin Sensitivity 7

SAFETY Human
INTRODUCTION
The development and marketing of cosmetics and personal care products has come a long way from the days when rose water was made and sold from the back of a covered wagon. Back then, product sales were driven more by promises than by any proven benefits, and there were no regulatory mechanisms in place to guarantee product efficacy or safety. Today, the cosmetics industry is subject to government oversight and consumers have come to expect that the products they use are safe and effective. While technological advances have spurred great innovations in product development and testing, few consumers are aware of the processes that manufacturers employ to ensure that products are safe for humans and the environment. Today, regulatory bodies around the world have set rigorous standards for product safety, while improved technology has made testing more efficient. Ongoing research continues to generate improvements in the way products are developed and evaluated from start to finish. By using the latest scientific advances and good manufacturing practices, manufacturers are putting products through cutting-edge paces designed to maximize safety. Ensuring the safety of cosmetics and personal care products is a top priority in the beauty care industry.

Lab Notes
Standards in Product Testing 8 Skin Safety Claims 9 Substantiating Sensitive Skin Claims: The Case of Head & Shoulders Sensitive Formula 9

REFERENCES CD-ROM

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Images for Presentation 19

Emotional Attitudes and Behaviors

Safety Matters 10 When Public Interest Groups, Media, and Cosmetic Ingredients Mix: The Controversy Over Phthalates 11 Reading the Fine Print: Consumer Perceptions of Product Labels and Labeling Regulations 12 Animal Testing: Myths, Facts, Advancements 12

DEFINING ISSUES Advances in Science

Protecting Human Health
Before a product can appear on store shelves, it must be demonstrated to be safe to use. A key step in ensuring product safety is the process of risk assessment, whereby risk is defined as a measure of the likelihood that an adverse effect will occur under a given set of conditions. The concept of risk assessment incorporates consideration of the likelihood of exposure to a potential hazard, as well as the type and severity of the hazard.

limitations. About 10% carry an insufficient data designation, meaning that there were insufficient published data available to the CIR Expert Panel to make an assessment.1 In many of those cases, companies may have data in their files to substantiate the safety of an ingredient, but may have elected not to share their data publicly (eg, for trade secret reasons). Next in the human health risk assessment process comes hazard identification, wherein any potential adverse effects that could be caused by a new ingredient are identified. Hazard identification may entail the evaluation of a variety of safety endpoints, including (but not limited to) systemic toxicity (short- or longterm), neurotoxicity, developmental and reproductive toxicity, mutagenicity, carcinogenicity, eye and skin irritation, and skin allergy. These data enable identification of an ingredients critical adverse effects, and aid in the design of dose-response studies to calculate a value such as a NOAEL (No Observed Adverse Effect Level) for that ingredient. The NOAEL is the highest dose at which no adverse effects were seen in the safety studies. The next step in the human health risk assessment process is exposure assessment, whereby the use of a product is studied to calculate a consumers actual exposure to the ingredient. The beauty industry goes to great lengths to understand exactly how consumers will use a new product. For most beauty care products, exposure assessment focuses on how much of an ingredient is applied to, penetrates, and is absorbed by the skin. The final step in human health risk assessment is risk characterization, or the integration of information

obtained thus far to determine an acceptable level of human exposure. A common approach to risk characterization is to determine the margin-of-safety (MOS). MOS quantifies the risk and allows toxicologists to make a decision as to whether an ingredient is safe

for use in a particular product, and is calculated via the following equation: MOS = NOAEL/expected human exposure/ uncertainty factor

Safety Never Stops: Industry Techniques for Ensuring Ongoing Safety

Safety vigilance does not stop once a product reaches market. Companies conduct extensive postmarketing surveillance and tracking of consumer comments, including the establishment of toll-free 800 numbers for consumers to report adverse reactions.

Additionally, manufacturers frequently share information to ensure that all companies have full access to relevant safety information. Much of this information sharing takes place at meetings and workshops conducted by organizations such as the CTFA, the Society of Cosmetic Chemists, the International Federation of Societies of Cosmetic Chemists, and the American Society for Microbiology.

Risk

Hazard

Exposure

In the cosmetics and personal care products industry, risk assessment starts with a review of the available safety data, including previous testing and history of use; information from public online databases, such as those maintained by the US Centers for Disease Control and Prevention (CDC), and the Environmental Protection Agency (EPA); information from suppliers; and results from expert scientific review groups such as the EU Scientific Committee on Consumer Products (SCCP), and the Cosmetic Ingredient Review (CIR) Expert Panel, an independent body of scientists established in 1976 by the Cosmetic, Toiletry, and Fragrance Association (CTFA) in cooperation with the US Food and Drug Administration (FDA). As of 2006, the CIR has reviewed over 1,200 common ingredients that are used in more than 100,000 marketed cosmetic products. According to the CIR, roughly 90% of reviewed ingredients may be used safely, either as currently used or with some

Safety Life Cycle of an Ingredient

Consumer Safety Assessment in the Product Development Process
Refine assessment analytical safety studies consumer insight Refine assessment

Market research
Market

Laboratory evaluations Exploratory experimentation

Small scale consumer testing

Large scale consumer testing

Market testing

Experimental Technology/material identification

Production Formula/product definition

Favorable safety assessment for market Consumer comments

Identify potential safety concerns

Favorable safety assessment for limited exposure

Favorable safety assessment for extended exposure

Potential Hazard ID Exposure assessment

Safety Assessment Cycle: A cosmetic product ingredient goes through several steps in the safety assessment cycle, starting with potential hazard identification and culminating with a series of safety decisions before and after it comes to market. Throughout the development cycle, riskreduction methods including packaging, labeling, and study restrictions may be applied.

Protecting the Environment

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Effect of Solubility on Toxicity

Acute Toxicity (mg/L)

Advances in environmental knowledge have helped improve the field of ecotoxicology, the study of how chemicals affect the environment and the organisms living in it. This discipline typically employs a tiered approach for assessing a cosmetic ingredients chemical structure to predict its fate and effect on the environment. Under the tiered approach, screening-level tools are used initially, and more sophisticated tools are employed as needed. This approach allows companies to eliminate early in the product development cycle those compounds that will never make it to market for environmental safety reasons, and to quickly identify less toxic, more rapidly degradable compounds. Equations known as quantitative structure property relationships (QSPRs) and quantitative structure activity relationships (QSARs) are examples of first-tier tools for estimating exposure and hazard to the environment. In addition to being quick and inexpensive to use, QSPRs and QSARs can enhance the understanding of a molecules toxicity and biodegradability before any data are generated in the laboratory.2,3

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The Role of Global Industry and Government Regulatory Groups in Review and Regulation of Cosmetic Products
Industry trade associations and government regulatory agencies are another key source of safety information for cosmetics and personal care products. These groups disseminate information through activities such as issuing safety standards and reviews, promoting alternative methods to animal testing, and publishing general safety research findings in the peer-reviewed scientific literature. Examples of such groups include: United States Food and Drug Administration (FDA)www.fda.gov Cosmetic, Toiletry, and Fragrance Association (CTFA) www.ctfa.org Cosmetic Ingredient Review (CIR) Europe European Cosmetic Toiletry and Perfumery Association (COLIPA)www.colipa.com EU Scientific Committee on Consumer Products (SCCP) http://ec.europa.eu/health/ph_risk/committees/04 _sccp/sccp_opinions_en.htm European Centre for Validation of Alternative Methods (ECVAM)http://ecvam.jrc.it European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC)www.ecetoc.org Research Institute for Fragrance Materials (RIFM) www.rifm.org
Solubility (mg/L)

QSARs are equations that help to predict the toxicity of a new chemical structure from its similarity in physical or chemical properties to other wellknown compounds. They are quick and inexpensive to use. The graph above shows a correlation between chemical solubility and toxicity for a class of chemicals that can be used to estimate the toxicity of new chemicals from that class.

The highest tier of ecotoxicity testing uses model ecosystems, or mesocosms. Mesocosms, which contain a diverse array of species and are sustainable for long periods of time, enable study of the environment under realistic and carefully controlled conditions, yielding enhanced understanding of a molecules shortand long-term toxicity.

www.cir-safety.org Environmental Protection Agency (EPA) www.epa.gov Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) http://iccvam.niehs.nih.gov/

Regulation of Cosmetic Products

By law, every cosmetic or personal care product on store shelves must be safe. In the US, cosmetics are regulated under the 1938 Food, Drug and Cosmetic Act and its amendments, which is enforced by the FDA. Historically, there has been little need for the FDA to use its
One way that the industry examines environmental safety is to set up model mesocosms, like the experimental stream pictured here. These enable the study of the environment under realistic and carefully controlled conditions, yielding enhanced understanding of a molecule's short- and long-term toxicity.

of the 1976 EU Cosmetics Directive and its amendments. In both the US and the EU, there is no requirement for premarket review or approval by a government regulatory body. However, in both regions, the manufacturer or distributor of a product is responsible for ensuring that it is safe for its intended use. In most countries outside the EU and US, regulatory control for the safety of cosmetics and personal care

regulatory authority over cosmetics, as most companies use safe ingredients and have acted voluntarily to prevent safety problems. Similarly, in the European Union (EU), cosmetics fall under the regulatory purview

products is generally accomplished through premarket registration and approval. A number of countries are transitioning from the premarket registration requirement toward notification and postmarket surveillance systems. Many of these countries have negative (ie, prohibited) and positive (ie, approved) ingredient lists for cosmeticsoften patterned after such lists in the EU, US, and Japan.

contain preservativesingredients that help to prevent or inhibit microbial growth. Many consumers are unaware of the potential risks of contamination from unintended uses of cosmetic products. For example, diluting shampoos with tap water can compromise preservative efficacy while introducing potentially harmful microbial contaminants into the product.4 Regardless of whether a cosmetic becomes contaminated during manufacture or consumer use, the hazard is twofold, namely, (1) the

wide variations of temperature and humidity, in distribution, and ultimate consumer acquisition and storage (eg, from hot cars to damp and wet bathrooms and showers). Preservatives also play an important role in preventing oxidation, which can compromise cosmetic efficacy and aesthetics. That is why it is important to discard products that change color or smell, and to heed any expiration dates that may appear on product packaging (Note: In the US, expiration dates are not required on cosmetic products, only on products that are classified as cosmetic drugs, such as antidandruff shampoos and antiperspirants).

that are self-diagnosed by consumers vs those diagnosed by physicians.8 Sensitive skin, also referred to as sensory skin irritation, chemosensory irritability, cosmetic intolerance syndrome, or status cosmeticus, is a condition that can generally be defined as a heightened intolerance to topically applied substances, such as cosmetics or personal care products. Neurosensory symptoms such as itching, burning, stinging, tingling, and tightness are characteristics of the condition and frequently are experienced on the face. Typically, these symptoms are apparent immediately after product use; however, they can be delayed minutes to days after product use, and exacerbated by wind, sun, excessive heat, humidity, or cold temperatures.9 Roughly 50% of patients with sensitive skin demonstrate such uncomfortable symptoms without accompanying visible signs of inflammation.10 The diagnosis of sensitive skin depends upon many factors, including inherited factors, gender, age, and race. Nevertheless, it is clear that individuals with sensitive skin appear to have several unique skin attributes that affect their immune system and the skin barrier, making them more susceptible to irritation. Dermatologists define sensitive skin as reactions characterized by redness, pustules, bumps, and, at times, erosions. Those suffering from atopic dermatitis, eczema, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, rosacea, acne, and psoriasis may have a predisposition to this condition.11,12 As a result, over the past 10 years, there has been an increase in the demand for (and manufacture of) cosmetics and personal care products formulated for individuals with sensitive skin. While there are a large

Biological Facts
A Sense of Preservation

direct effect of microorganisms on human health, and (2) the indirect effect on human health due to the potential for product contamination and spoilage, product separation, or formation of harmful microbial metabolites.

Defining Skin Sensitivity

A key consideration when evaluating the safety of a cosmetic product is whether it irritates the skin or eyes, and why that irritation occurs. The issue is complicated by differences in how individuals react to ingredients and in the type of responses. Some responses are objective in nature and can be measured via instrumentation or visual grading. However, many responses are purely subjective and are more difficult to measure. A prime example is what consumers may describe as sensitive skin. Far from being a rarity, consumer studies in all races suggest that from 25% to 50% of the global adult population may experience heightened skin sensitivity.7 However, there is usually considerable disparity between the incidence and severity of sensitive skin conditions
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Potential Sources of Microbial Contamination

The complexity of processes by which cosmetic ingredients are developed, combined, packaged, and dispensed has given rise to the field of cosmetic
Manufacturers must develop products that are not only safe as manufactured and sold, but also once a consumer takes them home and begins to use them. Preservatives help keep products safe to use whether they have been stored in a hot car or a damp shower.

microbiology. This scientific discipline is dedicated to finding and preventing the growth of microorganisms in beauty products, and focuses primarily on (1) production hygiene to protect products during manufacturing, and (2) preservative ingredients to ensure product microbial safety in the hands of consumers.5 The great diversity of intended cosmetic uses requires a holistic approach to preservation, one that considers all aspects of product development from concept and design through manufacturing to the last consumer use before disposal. Once packaged in final product form, cosmetic units are expected to remain stable through

Any cosmetic or personal care product that contains water has the potential to support the growth of microorganisms (eg, bacteria and fungi such as molds and yeasts). While some cosmetics (ie, those containing more than about 10% ethanol, propylene glycol, glycerol, etc, and cosmetics in self-pressurized containers) are self-preserving, most other products

number of sensitive skin products on the market today, there is currently no industry-wide or government standard for characterizing the condition or for substantiating sensitive skin product claims. This may be attributed to the lack of full understanding of the underlying mechanisms leading to sensitive skin.13 While great strides have been made in the study of sensitive skin, more research is needed to fully explain this condition. An example of how P&G Beauty has approached this issue can be viewed in the sidebar discussion of Head & Shoulders Sensitive Formula on

While in vitro (ie, test tube or in glass) test methods may be used in the initial evaluation process to predict skin irritation potential, clinical testing with human subjects is often conducted in the final stages to confirm the products mildness to skin. Most finished product formulas are clinically tested in humans to ensure safety and efficacy under normal conditions of use. However, in order to ensure an adequate margin of safety, testing may be conducted under conditions that exaggerate potential exposure. Another important part of product safety assessment is the need to confirm the absence of any potential for development of an allergic response (also known as sensitization). A sensitization reaction is more serious

Skin Safety Claims

In addition to ensuring that their products are safe from skin irritation and sensitization, companies often make safety claims that can be found on a product label. Although the cosmetics industry is highly regulated, there is no consistent set of guidelines or definitions governing the use of claims such as hypoallergenic, safe for sensitive skin, or mild on skin. Moreover, manufacturers are not required to substantiate such claims with the FDA.15,16 Nevertheless, most companies have internal guidelines for validating product claims through processes such as human clinical studies, or through consumer-panel testing under highly controlled conditions.

the next page.

Substantiating Sensitive Skin Claims: The Case of Head & Shoulders Sensitive Formula
Consumer research indicates that many dandruff sufferers with self-perceived sensitive scalp do not regularly use antidandruff shampoos because of a perceived harshness of these products to the scalp. Consequently, Procter & Gamble (P&G) Beauty developed the Head & Shoulders (H&S) Sensitive formula as a variant to the dry scalp formulation, and put it through the following steps to ensure that it could meet the sensitivity claims: 1) The new formula, which incorporates the active ingredient zinc pyrithione (ZPT) (recognized under the FDAs over-the-counter [OTC] monograph process as safe and effective for the treatment of dandruff) was further modified to improve the mildness profile and reduce potential irritants such as colorants and perfumes. 2) A number of clinical studies were conducted to demonstrate that the formulation does not exhibit skin irritation or sensitization among consumers with self-perceived sensitive skin/scalp. These included 48-hour patch tests on normal subjects and on subjects sensitive to lactic acid (a clinical marker for sensitive skin), a safety-in-use study on 3) These data were reviewed by two international expert panels on products intended for application on sensitive scalps. The panels concurred with the assessment that the H&S Sensitive Formula was well tolerated by subjects with self-perceived sensitive scalp, had the same skin tolerance profile as a control with established clinical and in-market skin mildness, and would not be expected to induce skin sensitization in the general population (including those with self-perceived sensitive skin).17 self-perceived sensitive skin subjects, and HRIPT tests on both normal subjects and self-perceived sensitive skin subjects. No skin irritation or sensitization was observed in any of these studies.

Lab Notes
Standards in Product Testing

than a transient irritation reaction, as the development of an allergy is irreversible. Clinical models, such as the human repeat insult patch test (HRIPT), are widely used to confirm the absence of skin sensitization potential. Additionally, as sunlight is known to exacerbate allergic responses in some instances, companies often employ
The human repeat insult patch test (HRIPT) is widely used to confirm the absence of skin sensitization potential.

photosensitization test protocols that combine exposure to an ingredient or product with exposure to light under controlled conditions. All of these testing methods conform with international ethical standards for clinical testing to ensure: (1) that protocols involving human use are reviewed by independent third parties, such as institutional review boards or an independent ethics committee; (2) that medical oversight of the research is appropriate and conducted by scientifically qualified persons; and (3) that all volunteers understand the benefits and risks of the study before deciding whether to participate.14

Occasionally, ingredients that are safe by themselves may interact with another ingredient to produce effects that may be deleterious. New combinations of ingredients, even when all the ingredients are well known, may need to be tested for skin irritation or sensitization potential. A large number of testing protocols have been developed specifically to test ingredients for such endpoints.

Emotional Attitudes and Behaviors

Safety Matters
Consumer Confidence in Product Safety Around the World
US Canada 18% 18% 39% 47% 33% 43%
20% 40% 60% 80%

ingredients that can harm their health.19 Such allegations are not supported by scientific evidence. Yet, media coverage can be negative and sensational, often appealing to consumers fears by focusing on toxicity potential (ie, hazard) alone, without any regard to actual risk (which must also consider potential for exposure, as discussed earlier in this document). It therefore behooves the beauty industry to be more proactive and transparent in the sharing of information on the safety of cosmetics and personal care products and their ingredients and the processes we use to ensure their safety. To that end, the CTFA has instituted a Consumer Commitment Code for its members. Highlights of the new code, which formally took effect on January 1, 2007, include :
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When Public Interest Groups, Media, and Cosmetic Ingredients Mix: The Controversy Over Phthalates
Phthalates are ingredients that are sometimes used at low levels in cosmetics and personal care products because they deliver benefits that are difficult to achieve otherwise. For example, adding some dibutyl phthalate (DBP) provides just enough give to make nail polish flexible and chip-resistant. Also, when perfume fragrance ingredients are dissolved in diethyl phthalate (DEP), they evaporate more slowly, allowing the scent to linger longer on the skin. In 2000, a CDC report suggested that phthalate levels in human urine samples were higher than expected and that levels of DBP were higher in women of childbearing age than in women who were not.21,22 Although the authors cautioned that the size of the sample was small and not representative of the general population, and that the mere presence of these ingredients in the bodies of consumers did not imply a biological risk, the report was seized upon by public interest groups in a media campaign denouncing the use of DBP in cosmetics and personal care products. However, the campaign produced no evidence that human exposure to DBP even approached what would be considered dangerous levels. In a 2003 follow-up report, the CDC showed that levels of exposure to DBP and DEP were not only within predicted levels but also well within the safety Despite the fact that there is no reliable evidence that phthalates found in cosmetics have ever caused harm in any human, many companies have eliminated DBP from their products in order to comply with the new EU ban on its use in cosmetics (which does not take into account exposure conditions). This example demonstrates how misleading reporting by the media and activist groups can ultimately deprive consumers of potentially useful cosmetic ingredients. levels set by the EPA. In fact, the data showed that the average exposure levels for DBP remained more than 100 times below government safety levels.23 A separate analysis of data from women aged 20 to 39 years showed that their levels of exposure to DBP were slightly lower than for other women, not higher.24 The US National Toxicology Programs Center for the Evaluation of Risks to Human Reproduction concluded that DBP poses minimal risk to reproduction or fetal development.25,26 In addition, the FDA concluded that it does not have compelling evidence that phthalates, as used in cosmetics, pose a safety risk and that there is no reason for consumers to be alarmed at the use of cosmetics containing phthalates.27 Finally, a comprehensive re-review of all available safety data on phthalates by the CIR Expert Panel in 2003 pronounced DEP and DBP safe for use in cosmetics.28

55% 56%

25% 24% 54% 48% 59% 54%

100%

Europe 6% UK 5% Germany 7% Sweden 3%

0%

Incorporating and strengthening some practices already in place for most companies, such as the current voluntary reporting of product formulas and manufacturing establishments to the FDA Establishing new practices such as a safety information summary program that makes information relevant to cosmetic product and ingredient safety readily available to the FDA upon request and creating a cosmetic ingredient information website for consumers Continuing close collaboration with the FDA and state regulatory agencies to provide as much information regarding cosmetic safety as consumers want and need in order to make fully informed choices when purchasing cosmetic products

I actively seek out information from outside sources about the safety of the products I buy. I am concerned about safety in products, but I generally feel confident that the products I buy are safe. I dont pay much attention to the ingredients and am very confident that products that I buy are safe.
Most consumers around the world feel confident that the cosmetic products they use and the ingredients in these products are safe.

Research indicates that the vast majority of consumers feel that the cosmetics and personal care products they use are safe.18 There is an ongoing attempt by certain activist groups, however, to erode this confidence with media coverage that would have consumers believe that the products they use contain large numbers of

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Reading the Fine Print: Consumer Perceptions of Product Labels and Labeling Regulations
Reading the labels of cosmetic products, with their long ingredient names, leaves many consumers perplexed. By law, the cosmetic labels must carry a listing of the International Nomenclature for Cosmetic Ingredients (INCI) chemical names of a products ingredients. The INCI, an international system for naming ingredients used in cosmetic products, helps to minimize confusion that might arise if various synonyms for chemical names are used. By standardizing the ingredient nomenclature, the INCI also assists physicians in the diagnosis of possible cosmetic-related skin conditions and facilitates the patch testing procedures that may be needed to identify suspect ingredients early in patient evaluations. While the FDA does not require premarket approval of cosmetic product labeling, it is the manufacturers and/or distributor's responsibility to ensure that products are labeled properly. The FDA does require safety warnings on product labels when problems become apparent through misuse, as well as warnings that certain products are for external use only and should not be applied to broken, irritated, or itchy skin.29

Animal Testing: Myths, Facts, Advancements

In the past, scientific and legal requirements meant that safeguarding consumers health invariably involved the use of animal research. Today, governments tell us that it remains impossible to avoid all research involving animals and maintain the same levels of health protection. At the same time, some of our consumers tell us they want to see more progress on alternatives to animal research. The beauty industry, therefore, works with interested partners in the scientific and academic communities to develop alternatives that offer the same level of health protection as current animalbased research, and helps to promote their acceptance. Manufacturers are also working with governments around the world to challenge the remaining legal requirements for research involving animals and to find other options wherever possible. In this way, the industry will work to limit and ultimately eliminate animal research for cosmetic and personal care product ingredients. Consequently, many manufacturers strive to use alternative methods such as computer models, in vitro cell culture tests, advanced chemistry methods, published scientific studies, and the information consumers provide about the products they use, and conduct limited research involving animals only as a last resort. In the rare cases in which animal tests are considered necessary, or are requested by regulatory bodies, companies work closely with animal welfare agencies and go to great lengths to ensure that the animals receive the best available care.

One of the most potentially misleading claims in consumer marketing today is the phrase Not Tested on Animals. When this phrase appears on a product package, the consumer has no way of knowing if the statement applies to the product, its ingredients, tests by the manufacturer or its suppliers, or even if the claim applies only to tests conducted after a certain date. It is important to note that the safety information for most ingredients that are commonly used in cosmetics or personal care products today was developed, at some point in time, from previously conducted animal studies. Currently, most countries have no regulations or guidelines that stipulate the conditions that must be met in order to make a valid not tested on animals claim.

The exception is in Europe, where in 2006 the EU issued a set of guidelines that provided the following clarifications: no animal tests have been carried out means that no animal test whatsoever was carried out in relation to the development or safety evaluation of a cosmetic product or its ingredients. Only the full replacement of the animal tests by an alternative method, and therefore not a reduction or a refinement of animal tests, allows the claim to be made. Furthermore, it does not matter where the test (including re-testing) is performed (in the EU Community or in third party countries) or when the test has been performed.30

WHAT WORKS Novel Approaches to Hazard Assessment

Identifying Potential Skin Allergens
As discussed above, a key step in the human safety risk assessment process for cosmetics or personal care products is identifying ingredients that may cause skin sensitization, the allergic response of the skin to an ingredient following repeated exposure. In recent years, the mouse local lymph node assay (LLNA) has become one of the preferred methods for assessing skin sensitization potential, as it allows for a considerable reduction in the number of animals required compared to the traditional guinea pig test.31

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Did You Know?

Dr Frank Gerbericks Pioneering Work in Skin Sensitization Assessment
In the field of skin allergy, few scientists are as highly regarded as P&Gs Frank Gerberick. One of the worlds foremost experts on skin sensitization and hazard assessment, Dr Gerberick pioneered the use of the LLNA,32 dendritic cells, 33 and a peptide reactivity assay for screening contact allergens.34 His development and validation of the LLNA has won him numerous awards, including the 2000 SmithKline Beecham Laboratory Animal Welfare Prize and the 2003 Society of Toxicology Award for the Enhancement of Animal Welfare. Dr Gerbericks groundbreaking work in skin sensitization revolutionized the way ingredients are cleared for human use, and continues to influence thinking among government regulators and dermatologists.35

junction, form a network designed to trap foreign antigens that have entered the skin, including chemical allergens. By extracting LC from humans, or by developing cell lines that could be used as DC surrogates, scientists hope to develop cell culture test systems that measure changes in gene expression induced by topical exposure to contact allergens or irritants. Additionally, microarray gene chip technology can be used to identify new gene candidates as potential markers of allergen-induced changes in DC. Such novel approaches may someday make it possible to exploit DC responses in vitro not only to identify chemical allergens, but also to characterize the type of allergic response they will likely induce.36

In Vitro Eye Irritation Models

Researchers also report advances in developing alternatives to the standard eye irritancy test. These alternatives include the use of isolated whole eyes and cornea models obtained from remnant slaughterhouse carcasses, as well as in vitro three-dimensional tissues constructed from human epidermal or corneal cells. The human cell-derived models can differentiate degrees of irritancy between mild test substances, and are useful for assessing both water-soluble and water-insoluble products and ingredients.
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WHATS COMING Promising New Areas

ToxicogenomicsThe Future of Safety
Recent advances in molecular biology have fueled a dramatic increase in knowledge of gene structure and function, contributing to the growth of a new subdiscipline of toxicology known as toxicogenomics. Toxicogenomics uses tools such as DNA microarrays that provide an unprecedented opportunity for complete, concurrent analysis of thousands of genes. The global analysis of the response of genes to a toxic insult, as opposed to the historical method of examining a few select genes, provides a more complete picture of toxicologically significant events. One such application of this technology is providing mechanistic insights into the response of cells to DNA damage (genotoxicity). Array-based expression profiling may be useful for differentiating compounds that interact directly with DNA from those that are genotoxic via a secondary mechanism.41 Much of the excitement surrounding toxicogenomics lies in its potential to facilitate identification of potential human and environmental toxicants, and to improve monitoring of the effects of exposures to these toxicants. Possibilities include the discovery of new families of safety biomarkers, increased understanding of the influence of genetic variation on toxicological outcomes, and definition of environmental causes of genetic alterations and their relationship to human disease, all of which should make the process of cosmetic ingredient safety assessment more efficient and precise.

Screening for Endocrine Disruptors

Other novel approaches involve development of a series of in vitro receptor binding and reporter gene assays that are used to assess the ability of agents to interfere with hormonal function in humans and wildlife.39 Another alternative assay is the extended fish early-life stage test, which focuses on assessing ingredients effects on endpoints such as sexual differentiation, early gonadal development and reproduction, and which takes less time and is simpler to run.40

Gene chip technology (left) and skin equivalent cultures (right) are two major methods helping to eliminate testing on animals.

Another approach to skin sensitization and irritation testing involves the use of skin-equivalent culture systems, which provide an in vitro, three-dimensional model of the skin with the major structural components intact, and have very similar structural features as intact skin. A key advantage of these cultures is the ability to test anything that can be applied to and tested on intact human skin, including toxic materials.
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However, there is still a need to develop nonanimal test methods for skin sensitization. One promising area of research is focusing on dendritic cells (DC), a distinct group of leucocytes that can initiate immune responses by processing and presenting antigens, which are widely distributed throughout the body. A type of DC known as Langerhans cells (LC), located near the dermal-epidermal

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Nanotechnology
Although nanoscale particles have attained only limited use in cosmetics and personal care products to date, nanotechnology has become a hot topic in the field (a nanometer [nm] is one thousand millionth of a meter [ie, 10-9 m]; for comparison, a single human hair is about 80,000 nm wide). Engineered nanomaterials typically possess nanostructure-dependent properties (eg, chemical, mechanical, electrical) that make them desirable for commercial or medical applications. However, some fear that those same properties may lead to nanostructure-dependent biological activity that differs from, and is not directly predicted by, the bulk properties of the constituent chemicals and compounds. A wide variety of academic institutions, government agencies, non-government organizations, and private industries are engaged in research to ensure that nanotechnology applications are both effective and safe.
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P&Gs Commitment to Best Practices and Advances in Research

Sunscreen products containing these small particles are not only better able to block UV rays, but they provide a clear protective barrier that consumers find easier to apply and more aesthetically pleasing than that found in other sunscreens. This ultimately leads to enhanced consumer acceptance and compliance. Nanoparticles are therefore providing a tremendous public health benefit by helping to reduce skin cancer and other detrimental effects of sun exposure. With a long history of safe use in FDA-regulated products and a demonstrated lack of dermal absorption, there is extensive confirmatory evidence that nanoscale zinc oxide and titanium dioxide may be safely used in cosmetics and OTC drug products.44 Consequently, the potential benefits of nanotechnology will likely encourage increased use in consumer products together with more advanced methods to evaluate the human safety of such products. Globally, more than 400 P&G employees work fulltime to ensure the safety and regulatory compliance of the products that we sell. Additionally, the company extensively studies consumer behavior so that we can obtain the best estimates of exactly how our products will be used, and we provide consumers with 24-hour hotlines to answer any product questions. We are constantly working on development and application of new technologies to the science of safety assessment. For example, we have conducted research on the application of genomics to genetic toxicology, skin sensitization, reproductive toxicology, For a detailed discussion of P&G Beauty procedures for developing and evaluating the safety of our products and their ingredients, visit our website: P&G is committed to adhering to best practices and to promoting research that enhances understanding of product safety. This commitment is not only a requirement for conducting responsible business, but is also an essential element for building and maintaining consumer trust. All ingredients used in P&G Beauty products are thoroughly evaluated and approved as safe before they go to market. If there is reasonable scientific evidence that an ingredient could be unsafe for people or the environment, or where there is significant scientific uncertainty about its safety, the company will not use that ingredient, but instead will find a safe and technically/economically viable alternative. As for animal testing, P&G Beautys position is clear: We do not test our beauty products on animals; nor do we ask suppliers to test them on our behalf. We do not test beauty ingredients on animals, except in rare cases when needed to meet regulatory or safety obligations. As a company, P&G is a global leader in supporting alternatives to animal research, having invested more than $200 million to date in helping to develop more than 50 proven alternative methods, and sharing those discoveries so that others can benefit from our progress. At P&G Beauty we have consistently supported transparency of information for consumers wherever it enables them to make knowledgeable decisions. P&G was among the companies that promoted European legislation on full ingredient labeling in the 1990s, and was possibly the very first company to implement full ingredient labeling across Europe. and aquatic toxicology. Also, our scientists have frequently been invited to present their work at key scientific meetings in toxicology and before the National Academy of Sciences.

One of the most common uses of nanoscale particles in cosmetics or personal care products today is in sunscreens that contain microfine or ultrafine grades of titanium dioxide and zinc oxide. While in reality such products may not contain true nano-sized particles (due to processing and product formulation conditions), but much larger aggregates of particles, these microfine particles have been thoroughly evaluated and found to be safe for use in sunscreens and cosmetics. Scientific studies have confirmed that these particles do not penetrate the skin.43

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REFERENCES
1. Bergfeld WF, Belsito DV, Marks JG, Andersen FA. Safety of ingredients used in cosmetics. J Am Acad Dermatol. 2005;52: 125-132. 2. Walker JD, Jaworska JS, Comber MH, Schultz TW, Dearden JC. Guidelines for developing and using quantitative structure-activity relationships. J Environ Toxicol Chem. 2003;22(8):1653-1665. 3. Cronin M, Walker JD, Jaworska JS, Comber M, Watts CD, Worth AP. Use of QSARs in international decision-making frameworks to predict ecological effects and environmental fate of chemical substances. Environ Health Perspectives. 2003;111:1376-1390. 4. Geis PA, editor. Preservation strategies. Cosmetic Microbiology: A Practical Handbook, Second Edition. New York & London: Taylor & Francis; 2006. 5. Heid SE, Kanti A, McNamee PM, Apel WA. Consumer safety considerations of cosmetic preservation. In: Geis PA, editor. Cosmetic Microbiology: A Practical Handbook, Second Edition. New York & London: Taylor & Francis; 2006. 6. Robinson MK. Age and gender as influencing factors in skin sensitivity. In: Berardesca E, Fluhr J, Maibach HI, editors. Sensitive Skin Syndrome. New York: Informa Healthcare; 2006. p.169-180. 7. Amin S, Engasser P, Maibach HI. Sensitive skin: what is it? In: Baran B, Maibach H, editors. Textbook of Cosmetic Dermatology, Second Edition, London: Martin Duntz Ltd.; 1998. 8. Bowser A. Sensitive skin a dilemma for derms: how do you treat what you cant see? Dermatology Times. 2004 May 1. 9. Davis JA and Wickett RR. New directions for sensitive skin research. Cosmetics & Toiletries. 2006;121(12):55-60. 10. American Academy of Dermatology. Sensitive about your skin? Solving problems related to the use of cosmetic & skin care products. Press release, 2002 Aug 2. 11. Davis JA, Wickett RR. New directions for sensitive skin research. Cosmetics & Toiletries. 2006;121(12):55-60. 12. Marriott M, Holmes J, Peters L, Cooper K, Rowson M, Basketter DA. The complex problem of sensitive skin. Contact Dermatitis. 2005;53(2):93-99. 13. Marriott M, Holmes J, Peters L, Cooper K, Rowson M, Basketter DA. The complex problem of sensitive skin. Contact Dermatitis. 2005;53(2):93-99. 14. Stitzel KA. The use of clinical data to confirm the safety of consumer products for use on the skin. In: Ball M, van Zeller A-M, Halder M, editors. Progress in the Reduction, Refinement and Replacement of Animal Experimentation. Amsterdam: Elsevier; 2000. p. 587-600. 15. US Food and Drug Administration, Center for Food Safety and Applied Nutrition. Hypoallergenic cosmetics: Office of Cosmetics and Colors fact sheet. Dec 19, 1994; revised Oct 18, 2000. 16. Cunningham RJ. Antiwrinkle products. In: Barel AO, Paye M, Maibach HI, editors. Handbook of Cosmetic Science and Technology. New York: Marcel Dekker; 2001. p. 543-549. 17. Shiel S, Gray J, Engasser P. Dandruff and the sensitive scalp: cosmetic considerations. International Congress and Symposium Series 2004; 255:34-37. 18. Procter & Gamble Beauty. Data on file. 19. Procter & Gamble Beauty. Data on file. 20. The CTFA News, Issue 20, Vol. 106, 2006 Nov 27. 21. Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect. 2000;108(10): 979-982. 22. First National Report on Human Exposure to Environmental Chemicals. Atlanta, GA: US Centers for Disease Control and Prevention, National Center for Environmental Health, 2001. 23. Second National Report on Human Exposure to Environmental Chemicals. Atlanta, GA: US Centers for Disease Control and Prevention, National Center for Environmental Health, 2003. 24. Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. Urinary levels of seven phthalate metabolites in the US population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ Health Perspect. 2004;112(3):331-338. 25. NTP-CERHR Expert Panel Report on Di-n-butyl phthalate. 2000 Oct. Report No.: NTP-CERHR-DBP-00. 26. McKee RH, Butala JH, David RM, Gans G. NTP center for the evaluation of risks to human reproduction reports on phthalates: Addressing the data gaps. Reprod Toxicol. 2004;18:1-22. 27. US Food and Drug Administration, Center for Food Safety and Applied Nutrition (homepage on the Internet). Phthalates and cosmetic products. [updated 2005 Mar 31; cited 2006 Dec 18]. Available from http://www.cfsan.fda.gov/~dms/cos-phth.html 28. CIR Expert Panel. Dibutyl Phthalate, Diethyl Phthalate, and Dimethyl Phthalate Re-review Summary, 2003 Feb 7. 29. US Food and Drug Administration. Cosmetic labeling: an overview. Center for Food Safety and Applied Nutrition, Office of Cosmetics and Colors, 2006 Apr 25. 30. Commission recommendation establishing guidelines on the use of claims referring to the absence of tests on animals pursuant to Council Directive 76/768/EEC (OJ L 158 of 7.6.2006 p 18). 31. Gerberick GF, Ryan CA, Kimber I, Dearman RJ, Lea LJ, Basketer DA. Local lymph node assay: validation assessment for regulatory purposes. Am J Contact Dermat. 2000;11(1):3-18. 32. Gildea LA, Ryan CA, Foertsch LM, Kennedy JM, Dearman RJ, Kimber I, et al. Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing. J Invest Derm. 2006;126:1813-1822. 33. Gerberick GF, Ryan CA, Kimber I, Dearman RJ, Lea LJ, Basketer DA. Local lymph node assay: validation assessment for regulatory purposes. Am J Contact Dermat. 2000;11(1):3-18. 34. Gerberick GF, Vassallo JD, Bailey RE, Chaney JG, Morrall SW, Lepoittevin JP. Development of a peptide reactivity assay for screening contact allergens. Toxicol Sci. 2004;81:332-343. 35. Procter & Gamble. Frank Gerberick: A Profile in Innovation. In: Forward Focus: A P&G Update on Innovation in Alternative Testing and Care, Issue II, 2005. 36. Ryan CA, Gerberick GF, Gildea LA, Hulette BC, Betts CJ, Cumberbatch M, et al. Interactions of contact allergens with dendritic cells: opportunities and challenges for the development of novel approaches to hazard assessment. Toxicol Sci. 2005;88(1):4-11. 37. Robinson MK, Osborne R, Perkins MA. In vitro tests for skin irritation. In: Barel AO, Paye M, Maibach HI, editors. Handbook of Cosmetic Science and Technology. New York; Marcel Dekker, 2001. p. 95-106. 38. Bruner LH, Curren RD, Harbell JW, Osborne R, Maurer JK. Eye irritation testing. In: Barel AO, Paye M, Maibach HI, editors. Handbook of Cosmetic Science and Technology. New York; Marcel Dekker, 2001. p. 119-144. 39. Carney EW, Hoberman AM, Farmer DR, Kapp RW, Nikiforov AI, Bernstein M, Hurtt ME, Breslin WJ, Cagen SZ, Daston GP. Estrogen modulation: tiered testing for hazard evaluation. Reprod Toxicol. 1997;11:879-892. 40. Panter GH, Hutchinson TH, Hurd KS, Bamforth J, Stanley RD, Duffell S, et al. Development of chronic tests for endocrine active chemicals. Part 1: an extended fish early-life stage test for oestrogenic active chemicals in the fathead minnow (Pimephales promelas). Aquat Toxicol. 2006;77:279-290. 41. Aardema MJ, MacGregor JT. Toxicology and genetic toxicology in the new era of toxicogenomics: impact of -omics technologies. Mutat Res. 2002;499:13-25. 42. US Food and Drug Administration. FDA forms internal nanotechnology task force. Press release, 2006 Aug 9. 43. Gamer AO, Leibold E, van Ravenzwaay B. The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol in Vitro. 2006;20:301-307. 44. Cosmetic, Toiletry, and Fragrance Association. Nanotechnology white paper: the use of nanotechnology in personal care products. 2006 Oct.

COSMETIC PRODUCT SAFETY | RESEARCH UPDATE

AN ADDITIONAL TOOL
The Cosmetic Product Safety Research Update CD-ROM holds a PowerPoint presentation of the charts and illustrations in this toolkit. Feel free to use these images. Please credit P&G Beauty.

FPO

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CONTACT INFORMATION To talk with a P&G scientist or to learn about ongoing research at P&G Beauty, contact: Lauren Thaman P&G Beauty Science 513-626-1370 Heather Cunningham P&G Beauty Science 513-626-2606
2007 P&G Beauty