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“The Animal Testing Ban – What is next?” A Retrospective look at the full day In-Cosmetics Hamburg 1. April 2014 Workshop Steven L. Hanft, M.A., President, CONUSBAT & co-organizer of this workshop, et al.

On April 1st, in the Chicago room at Hamburg’s Exhibition Center, the workshop „The Animal Testing Ban – What is next?” occurred. CONUSBAT once again had been asked to organize the full-day (2-sessions) regulatory event for Reed Exhibition, which it had gladly accepted.

The 2 sessions addressed the following issues: Part 1 Session: Why should the Animal Testing Ban be the end of innovation in cosmetics? Learning about new in-vitro, in-silico and in-chemico methods that form the elements of the new toolbox for assessing ingredient safety. Part 2 Session: Gaining insight about multi-tier alternative strategies for the example of skin sensitization. Explore the biochemical mechanisms behind the effect, how these are addressed by alternative methods and see the way information is put together like mosaic pieces for sensitization assessment. What are the consequences for the industry in supporting existing and new ingredients within the European regulatory processes?

The In-Cosmetics Animal Testing Ban’s list of esteemed speakers and panelists with their topics were: Workshop, part 1, morning session O

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Dr. Annelie Struessmann, Technical Director, CONUSBAT, Aachen, Germany and co-organizer of this workshop Animal Q Animal Testing for Cosmetics in a World-wide Perspective

Historical Background for Animal Protection

Dr. Patric Amcoff, Interim Director Science & Research, Cosmetics Europe, Brussels, Belgium Q The EU’s Animal Testing Ban

In order to know where we are headed with the ban on animal testing for cosmetics and cosmetic ingredients in the EU, it is important to know from where the ban gained its origins. Stemming its roots in the Animal Rights Movement, no one can give an exact date as to when this movement was founded.

Dr. Joop de Knecht, Environment Directorate, OECD, Paris, France Q Implementing Altenatives to Animal Testing Dr. Christian Pellevoisin, Scientific Coordinator, SkinEthic Academy (L’Oreal), Lyon, France Q Existing Alternative for Skin Irritation / Corrosion

However, it could be argued that the initial link for the Animal Rights Movement was the link to religion and more specifically to the Hindu religion. After all, the earliest Hindu Veda (meaning ‘knowledge’) scriptural texts show that vegetarianism has always been a mainstream thought. In the Mahabharata, the great warrior Bhishma explains to Yudhisthira, eldest of the Pandava princes, “that the meat of animals is like the flesh of one's own son, and that the foolish person who eats meat must be considered the vilest of human beings.” The Atharva Veda proclaims, ”Those noble souls who practice meditation and other yogic ways, which are ever careful about all beings, who protect all animals, are committed to spiritual practices.“

Mr. Des Caves, Toxicologist & Account Manager Early Development Services, Bioreliance, UK Q 3D Tissue for Genotoxicity – A Validation Scenario

Workshop, part 2, afternoon session O

Dr. Nava Dayan, Nava Dayan LLC, Fairlawn, NJ, USA Skin Toxicology: Biochemical Mechanisms and their Reflection in Toxicological Testing

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Dr. Reinhard Kreiling, Clariant, Sulzbach, Germany Skin Sensitization as Example of a Comprehensive Testing Strategy

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As for Western thought, in 1875, Ms. Frances P. Cobbe (born in Dublin, Ireland, and a leading woman’s suffragist) founded the UKbased National Anti-Vivisection Society (NAVS), which was the world’s first NGO opposing experiments on animals. The NAVS gathered many notable people of the day to support its cause, one was Queen Victoria. Many of the social reformers of the day, working for children's rights and women's rights, supported the aims of the NAVS.

Ms. Ellen Pfrommer, BASF, Ludwigshafen, Germany Animal Testing Ban / Marketing Ban – Consequences for Cosmetic Ingredients

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Dr. Theresa Callaghan, CCI (claims expertise), Hamburg, Germany

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By 1876, the British Parliament passed the first anti-vivisection law, the ‘Cruelty to Animals Act’. In 1883, the readers of ‘Science’, the organ of the American Association for the Advancement of Science (AAAS), were warned that American scientists in the US faced a similar legislation and thus issues of using animals for testing. In view of this threat, the author advised the medical profession to “inform the laity” how and why animal experimentation was used in scientific research. Inspired by Ms. Cobbe, the American Anti-Vivisection Society (AAVS; Philadelphia, Pennsylvania, USA) was founded in 1883 with the goal of regulating the use of animals in science and society.

Background to the Animal Test Ban in Europe for Cosmetics The 11. March 2013 deadline ‘came and went’ for the final implementation of the animal testing ban for cosmetics products in the EU. The last step for the ban applied towards marketing of cosmetic products and their ingredients when tested on animals for the most complex human health effects: skin sensitization, carcinogenicity, repeated-dose systemic toxicity, reproductive toxicity and toxicokinetics. At the time of final implementation, the EU Commissions stated, ‘The testing and marketing bans in the Cosmetics Regulation apply even in case alternative methods to animal testing are not yet available’.

The ideology continuously evolved over millennia, but many animal activists point to the publication of “Animal Liberation” by Professor Peter Singer in 1975 as the catalyst for the modern American animal rights movement. Singer, whose family hails from Vienna (due to Nazi persecution, the family left Austria in 1938 to Australia) now heads up a bioethics chair at Princeton University, Princeton, NJ, USA.

On that day, the animal test ban news even made into the New York Times, which is considered America’s most widely read newspaper. Considering that Europe (incl. Switzerland and Norway) possesses the world’s largest share of the cosmetic sector at € 72billion (US$ 91billion), the newspaper was citing global cosmetics manufacturers, stating, that increasing efforts exist in the companies seeking global acceptance for products with proof of safety not relying on animal tests. However, the NY Times also cited representatives of the European cosmetics industry, who were criticizing the EU Commission for putting a ban into effect before alternatives existed for some of the most complex tests.

NGOs as drivers of the Animal Test Ban Many animal rights protection agencies/organizations espouse a number of approaches, and are bitterly divided on the issue of direct action and violence, with very few activists or writers publicly advocating the latter tactic as a justified method to use. It should be also noted, that the animal rights movement has other cause célèbre, which included stopping the sale of animal furs (seals, mink, etc.) or to end humans waging bets in cock (roosters) or dog fighting. Each NGO has n organization structure, staff and its own campaign to support; thus, monetary donations are their key source to achieving their goals.

As such, these representatives were contributing to an already ‘hot topic’, as in their view, the ban would mean jeopardizing the cosmetic industry’s ability towards innovation. Accordingly, consumers in Europe would not have access to new products because the industry cannot assure the safety for some of the ingredients without having access to suitable and adequate testing.

Whether liked or disliked, the NGOs and their members are the main drivers for the Animal Test Ban, some of whom hail from rock star status (i.e., Paul McCartney) to VIP’s from the entertainment world (TV, film, etc.). The following Animal Right’s NGOs are considered as the being mostly in the main stream: O

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NAVS - National Anti-Vivisection Society; founded in 1875, London, UK

While the discussions are often emotional or narrowed in their objectivity, certainly hurdles do exist. However, it is often overlooked how many impressive alternative approaches to proving the safety of ingredients and products exist already. Based on extensive efforts and money being put into the research of alternatives for this nascent science area of human toxicology, an array of new in-silico, in-chemico and in-vitro methods has evolved. Also, tools for new multi-tiered testing strategies were designed, which are based on the awareness that one alternative test cannot cover the complexity of human biochemical mechanisms. Presenting key results obtained from past year’s research and depicting strategies for assessing cosmetics by alternative approaches was the goal of the regulatory workshop in Hamburg.

AAVS - American Anti-Vivisection Society; founded in 1883, Jenkintown, Pennsylvania, USA The Humane Society, also sometimes referred to as the Society for the Prevention of Cruelty to Animals (SPCA); founded in 1954, Washington, DC, USA (European office: London, UK) WWF - World Wildlife Fund (directed more towards protecting endangered species and concern towards pollution, climate change); found in 1961, Gland (near Geneva), Switzerland PETA - People for the Ethical Treatment of Animals; founded in 1980, Norfolk, Virginia, USA

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Cruelty Free International (claims to be ‘the only global organization working solely to end animal testing for cosmetics and consumer products’); offices in London/UK, Boston, Massachusetts/ USA & Singapore

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Animal Test Ban – Implementation Deadlines

Date

Testing ban on finished cosmetic products Testing ban on ingredients or combination of ingredients Marketing ban when tested for human health effects with the exception of the specific effects of repeated-dose toxicity, reproductive toxicity and toxicokinetics Marketing ban when tested on the specific effects The ban applies irrespectively on the availability of alternative non-animal tests

11. Sept. 2004 11. March 2009

Key Results from the Workshop in Hamburg Contents and Quotations from the Esteemed Speakers Dr. Annelie Struessmann opened the day by looking into the status worldwide on existence of animal testing bans for consumer product areas. She concluded that the EU took the lead and banning of animal testing for cosmetics is under review worldwide. During the past years, major moves happened in various countries, including, the implementation of animal testing bans and the introduction of programs for research of test alternatives. Dr. Struessmann predicted that with alternatives becoming completely available animal testing

11. March 2009 11. March 2013

on cosmetics will be phased out on a worldwide scale. A main hindrance at this time are outstanding replacement methods for complex toxicological endpoints, the REACH testing requirements and the European Chemicals Agency’s (ECHA) role in interpretation of the compliance criteria towards these, as well as, still existing different views in some major markets on the needs for testing of cosmetics. The second speaker was Dr. Patric Amcoff from the industry association Cosmetics Europe (Brussels, Belgium), formerly known as Colipa. He provided an overview of the EU Commission’s and the cosmetic industry’s goals and programs on research for testing alternatives. The joint program under the Steering Committee on

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project and toolbox, which is attempting to identify similarities in structural characteristics and mechanisms for chemicals and subsequent use of existing experimental data in read-across approaches. Finally, Joop de Knecht reported on the OECD’s activities in the area of Adverse Outcome Pathways (AOPs) with a current work plan of about twenty AOP projects for the different assays, endpoints or databases, including the implementation of AOPs into the (Q)SAR Toolbox.

Alternatives to Animal Testing (AAT)’s for the time phase from 20082016 will be followed up by a long range science strategy 2016-20 via the European Partnership for Alternative Approaches to Animal Testing (EPAA), the International Cooperation on Cosmetic Regulation (ICCR), and other sector organisations. The new approach will focus exclusively on test replacements, while before the 3R principal of replacement, refinement and reduction formed the base for research. His conclusions were, that new internationally agreed tools and testing approaches such as AOP (Adverse Outcome Pathway), ITS (Integrated Testing Strategies), IATA (Integrated Approaches to Testing and Assessment), etc., will form the basis for reseach and a conceptual change in performing safety assessments based on mechanistical understanding will be the consequence. An issue in his view is the time required for validation of methods and their regulatory acceptance, e.g. for the SCCS’ ingredient evaluation process. This issue will considerably increase the total time period until availability of the completed new toxicology toolbox. Another part of Dr. Amcoff’s speech covered the EC’s Interpretation on use of animal testing data after the 2013 deadline. Accordingly, tests performed after March 2013 on ingredients exclusively used in cosmetics trigger the ban. Animal data generated for third country cosmetics regulations cannot be used for EU safety assessments; however, use of non-cosmetics data generated for EU- and non-EU regulatory regimes is allowed with an interpretation from the European Court of Justice still pending. No derogative scheme exists for new cosmetics-unique ingredients, but current Member State derogation schemes for existing ingredients remain valid.

Dr. Christian Pellevoisin introduced two existing alternative and fully validated methods, OECD TG 431 is an in vitro method for skin corrosion and OECD TG 439 is an in vitro method for skin irritation. Using reconstructed human epidermis (RhE) as a biological model, both tests are accepted as full replacement methods. Predictive methods have been developed for efficacy and toxicity testing of ingredients and validation was achieved for safety testing. RhE predictivity methods with can also be used for determining the skin irritation potential of finished cosmetic products. The last speaker for the morning session was Des Cave, who depicted the validation scenario in progress for the 3D skin micronucleus assay, a promising and relevant new non-animal approach for genotoxicity evaluation of cosmetics. In the three-step validation process, the method showed usefulness for following up chemicals which are positive in the standard in-vitro genotoxicity assays. Results from the validation steps showed that the test can be readily transferred to new laboratories, it is robust enough for standard GLP testing, and it allows establishing inter and intra-laboratory reproducibility. At this point global validation of the method appears as being very promising.

Dr. Joop de Knecht introduced the OECD’s tools and programs in the area of testing alternatives and started with available guidelines for in-vitro tests, which include, but are not limited to skin corrosion, phototoxicity, skin absorption, eye corrosion, genotoxicity and endocrine disruption. Further efforts address integrated approaches; draft OECD guidance, which is in the reviewing phase, exists on how to integrate all existing information on corrosion and irritation potentials for final decisions on classification and labelling of chemicals. Another alternative approach uses grouping of chemicals for read-across, promoting use of data from analogue substances to fill data gaps. Existing guidance has recently been augmented with examples encountered in the OECD Cooperative Chemicals Assessment Program; publication of the update is anticipated for 2014. The eChemPortal is a global portal with information on chemical substances and provides direct links to information from a large number of data sources. Another alternative OECD approach is the (Q)SAR

Dr. Nava Dayan opened up the afternoon session by exposing the complexity of the human body’s largest immune response organ, the skin, and the difficulty of addressing the toxicological responses in testing procedures. She evaluated the biochemical mechanisms leading to the induction of skin sensitization reactions and the various types of hypersensitization and their attributes. While looking into the functionality of cosmetic ingredients in inducing sensitization reactions it was reminded that the risks determined do not consider the final cosmetic formulations. Gaps for risk assessment result also from current skin sensitization testing approaches which do not address all different biochemical responses sufficiently and also, most often, do not consider accumulation for chemical exposure. Animal testing is limited due to the differences between

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animal and human skin which is easily expressed by the difference in number of follicles. Finally, in addressing replacement for animal test she emphasized to further investigate the use of gene expression and proteomics, methods frequently used in pharmaceutical testing. As an example of a comprehensive testing strategy, Dr. Reinhard Kreiling addressed AOPs for skin sensitization. Traditionally, quantitative potency estimates for contact dermatitis were based on the in-vivo Local Lymph Node Assay (LLNA). Current integrated evaluation methods use a stepwise process integrating all relevant information and approaches on a case-by-case basis to reach science-based decisions in a weight-of-evidence (WoE) assessment. Adverse outcome pathways (AOPs) reflect the shift towards knowledgedriven approaches to toxicological hazard & risk assessment. Important for establishing AOPs are the identification of key targets and events for a given endpoint, the development of assessment tools (alternative assays) and the development of extrapolation tools to translate mechanistic data into reliable predictions of in vivo outcomes. According to Dr. Kreiling, skin sensitization strategies need to address both, the potential and the potency for a skin sensitizer. Integrated Testing Strategies (ITS) in form of combination(s) of (test) methods may allow the identification and classification of skin sensitization hazard but lack to date the information on potency. Including addressing this gap in an IATA, he generally sees the need for an OECD wide agreed guidance on the significance and application of IATA (Integrated Approaches to Testing and Assessment) for all relevant regulatory objectives.

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Ellen Pfrommer spoke from the ingredient supplier’s perspective about consequences from the animal testing ban / marketing ban. For Europe, ingredient suppliers need to address two key regulatory areas, one is chemicals’ legislation and consequently compliance with REACH. At the same time, support for cosmetic product manu-

facturers in their compliance with the Cosmetic Product Regulation is requested. Therefore, two different sets of testing requirements exist, with REACH requiring defined testing standards. Issues arising from this situation include the status on availability of alternative test methods, as such the questions if tests are accepted under REACH. Also critical is in case of animal tests performed, how to document in the PIF that they were generated for non-cosmetic purposes, etc. Ms. Pfrommer concluded, that for break-through innovations animal testing so far is not avoidable and serious risks exist for ingredient manufacturers in developing long-term R&D strategies for these. Therefore, her statement and general conclusion was: ‘avoiding animal tests is key; however, no general rule exists and strategies need to be developed in case-by-case decision’. The workshop concluded with a panel discussion interacting with a highly energetic audience. The outlook for the industry included that the Animal Testing Ban will not vanish. The presence depicts an interim phase where extensive input into research on still missing alternatives is made. The future will provide alternative approaches for all toxicological endpoints – new tools and testing approaches will lead to a conceptual change in performing safety assessments. While amazing progress for test alternatives has been made, and further results are in the pipeline, existing key issues remain, as such: O

a lack of methods for complex toxicological endpoints

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long time frames for validation processes

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reluctant approach towards alternative data by authorities

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extensive requirements on professionals while gaining experience with the complex new methods.

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