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Why do methods get stuck?

The process of implementing alternatives for authorisations. Failure to keep up with updates to regulatory use is complicated by a number the pharmacopoeias and other medical legislation Implementing alternatives of factors; regulatory reassurance usually has, in our experience, been one reason why needs to be given for each specific alternative some of these tests are still commissioned. method for each specific sector (e.g. , to pharmaceuticals or chemicals), several regulatory Finally, there needs to be improvements in the bodies may need to be involved and legislative harmonisation of testing requirements between The RAT (Replace Animal Tests) list and other documents may need to be updated. EU and non-EU countries. We believe that Failure by regulatory bodies to recognise these companies and regulators should not permit Over the last 30 years there have been great as skin irritation, acute and various batch steps and take responsibility for them has, in our animal testing for regions that do not accept the developments in the replacement of tests on safety tests have taken years to be completely opinion, been a major reason for some of the alternative if the alternative has been recognised animals for regulatory purposes. Alternatives accepted and in many cases the animal test is delay in the implementation of these methods. in at least one region and there is no scientific have been developed that can now replace still being conducted for regulatory purposes. reason why the other region should not accept it. wholly, or in part, a number of animal tests for Everyone will agree that this is something that Companies may also need to perform in-house several product sectors. should be avoided, both in the interests of validation studies - particularly for alternatives to and good regulatory science, as batch tests and will need to update their market However, our experience has been that these alternative methods are usually cheaper, faster methods can become ‘stuck’ in the process and and more accurate than the animal tests they can take much longer to actually replace animals replace. What regulators can do than most people think. Our experience is that there are a number of Ensure there is a mechanism for continual dialogue on the acceptability of these In recent years alternatives to animal tests such reasons why methods may become ‘stuck’. For alternatives between the regulatory agencies in your region that are responsible Communicate for chemicals, medicines, , biocides, cosmetics and food as well as those responsible for authorising animal . example, companies may need reassurance from their relevant regulatory authority that these methods Identify and map the reasons for the continued use of these tests and take action will be acceptable for regulatory purposes. Failure to provide this reassurance, or delay in doing so, can Analyse where possible. mean that animal tests are still conducted when an alternative method is actually scientifically acceptable and available. Additional validation on a product by product basis may be required for alternatives for Promote Make sure those that use animals are aware of these alternatives or waiving options. quality control testing and there may be insufficient for companies to do this.

Furthermore, lack of communication between regulatory sectors can mean that information about the What companies can do availability and acceptability of new alternative methods simply falls through the gaps.

We have created the RAT list to draw regulatory and industrial attention to this issue. We have selected just Perform in–house validation of the alternative for your product, where necessary Validate 10 animal tests that are still being conducted in Europe despite evidence that they are either redundant or and update your licences. have valid replacements. We have estimated that half a million animals are being used in these tests in Analyse Proactively evaluate the need for animal testing and take your results to the regulators.

Make sure those that throughout your business there is awareness of - and Use Cruelty Free International commitment to use - these alternatives or waiving options. Europe alone despite the fact that EU law (Directive them moving again. 2010/63) states that “Member States shall ensure Cruelty Free International is the leading that, wherever possible, a scientifically satisfactory organisation working to create a world where For change to happen it is important that a desire to minimise animal testing is matched with actual method or testing strategy, not entailing the use of nobody wants or believes we need to policy and resource. Both regulators and companies need to invest in people who will look out for live animals, shall be used instead of a procedure”. on animals. and assess alternatives as they come on board, as well as the science to ensure that new alternatives continue to be developed. We highlight where these 10 tests are ‘stuck’ in We are widely respected as an authority on the process and provide some practical solutions animal testing issues and are frequently called that regulators and companies can employ to get on by governments, the media, corporations and

Cruelty Free International www.CrueltyFreeInternational.org Website: www.CrueltyFreeInternational.org Email: [email protected] Twitter: @CrueltyFreeIntl Tel: +44 (0) 20 7700 4888 Test and number Options for What needs to of animals used Description of test replacement happen The RAT list annually Eye irritation The substance is left in one ’s eye for Eyes from dead hens Regulators need to promote – at least one hour before it may be washed and cows can be used in the alternatives and ensure out. The eyes are then examined for signs validated tests to identify licences are not issued for Test and number What needs to 2,080 rabbits were used in eye of irritation and damage over 3 days. If there severe irritants and non- testing unless absolutely of animals used Description of test Options for replacement are no signs of severe irritation in the initial irritants. Reconstituted necessary. happen irritation tests across Europe in annually 2011. test, two more rabbits are used. Rabbits are human eye models have forced to suffer restraint whilst being dosed also now been accepted. Companies need to ensure Sector: C and examined and can experience painful they use the alternatives Pyrogen test Rabbits are restrained in boxes for up This has been replaced by a test Regulators need to ensure damage in their eyes that can cause blindness. and continue to develop the – Rabbits to eight hours per test, with food and which uses blood from horseshoe that the rabbit test is no being methods for mild irritation. water restriction prior to this. Rabbits crabs, and more recently with a conducted when the relevant 3,167 pyrogen tests were can suffer a fever reaction (in the rare more sensitive test based on cryo- pharmacopeia specifies occasion the batch is contaminated), preserved human blood. otherwise. Skin irritation The product is rubbed onto a 6cm area of a The test can now be Regulators need to promote done in the UK alone in 2014. rabbit’s shaved skin on their backs and held completely replaced with the alternatives and ensure Across the EU the number and damage to ears from repeated – Rabbits injections. Temperature probes are Companies need to be in place with a bandage for four hours. The reconstituted human skin licences are not issued for is thought to be around rabbit is then examined for signs of skin models, which are validated testing unless absolutely 200,000. inserted deep into their rectums during encouraged to validate the 3,151 rabbits were used in skin the test. Rabbits may be housed singly human blood test for their irritation tests across Europe in damage for 14 days. If there are no signs of and widely accepted. They necessary. irritation in the initial test, two more rabbits are more predictive than the Sector: HP, VP during their lives and are typically re- product and update their 2011. used several times. licence. are used in a ‘confirmatory test’. Rabbits are rabbit test. Companies need to ensure Sector: C singly housed and can suffer from painful skin they use the alternatives. reactions and rashes. Botulinum toxin test This is an LD50 (Lethal Dose 50%) test Some toxin manufacturers have Regulators need to ask all – Mice aimed at determining the dose that kills now developed a cell-based test companies to validate the cell- exactly half of the animals used. The to replace the batch test, but they based test. Skin sensitisation In the GPMT guinea pigs are injected six times The GPMT was replaced by Regulators need to promote in their backs with a substance that increases the LLNA in 1999; but the the alternatives and ensure 220,544 mice were used in mice are injected into their abdomens continue to use the mouse test for – Guinea pigs & mice their body’s immune response to the test LLNA itself is now replaced. licences are not issued for LD50 tests in Europe in 2011 with the botulinum toxin and over the other purposes. Companies need to be chemical. Six and then 20 days later the test Chemical based (DPRA) and testing unless absolutely alone. A large proportion of next three days become increasingly encouraged to validate 15,214 guinea pigs were used chemical is rubbed onto their shaved skin. The cell based tests (ARE-Nrf2 necessary. these tests were botulinum paralysed. If left, mice in the higher the cell-based test for their in maximisation test animal is observed daily for allergic reactions -KeratinoSens) have been toxin (botox). dose groups will suffocate to death product. (GPMT) and 16,846 mice were within approximately three days. used in LLNA (Local Lymph for 23 days. The guinea pigs may be killed and formally accepted by the Companies need to ensure dissected to confirm any unusual reactions. OECD in 2015. Currently, at they use the alternatives. Sector: HP Node Assay) skin sensitization tests in Europe in 2011. They may be singly housed and suffer from least two alternative tests painful skin reactions and rashes. need to replace the LLNA, test Animals are exposed to very high doses, This test is redundant in many Regulators need to assess the Sector: C however this strategy has – Rats which can cause irritation, difficulty cases as companies use the need for the oral test across all In the LLNA the test substance is painted onto been shown to consistently breathing, weight loss, convulsions, repeated dose test for their safety sectors. the ears of mice every day for three days. The predict 90% of human skin mice are then killed three days later and their reactions. 4,431 rats were used in acute bleeding and death. Death is still used purposes. This was demonstrated ears are dissected. tests across Europe in 2011. as the ‘endpoint’ in tests via the dermal for pharmaceuticals in 2008. A Regulators need to promote or inhalation route. In tests where the humane simple cell-based test was the use of the cell-based test animals are force-fed, the researchers to waive testing. Sector: HP, VP, C validated in 2013 for chemicals and 2nd species repeated or monkeys are used as a second species conducted by Regulators need to assess may kill the animal before they die but now can be used to demonstrate dose toxicity test after mice or rats to test the safety of human Cruelty Free International the justification for this test in only if they are extremely ill and they are absence of toxicity but is not yet in Companies need to be aware medicines. Animals are dosed every day for has recently provided more collaboration with industry. found before they die. common use. of changes to the requirements – Dogs & monkeys between two weeks to nine months with drugs evidence that this test does for this test in all sectors. that might lead to harmful side effects that can not help show whether a Companies need to work 2,785 dogs were used in include vomiting, diarrhoea, internal bleeding drug is likely to be toxic to with regulators to assess repeated dose tests along with and organ damage, seizures, paralysis and humans. Cell based tests the need for this test. Ecotoxicity Young fish are exposed to the test The Embryo Acute Toxicity Regulators need to promote 1,306 monkeys in Europe 2011. substance dissolved in their tanks for Test Method (ZFET) and the Short- the use of the embryo-based even death. They are also subjected to other and computer models are – Fish stressful tests such as repeat blood sampling in use but are not currently 96 hours. The acute test is a lethal test term Toxicity Test on Embryo and test. Sector: HP and daily gavage. Monkeys are usually considered adequate by 71,406 fish were used in - 50% of the fish are expected to die. Sac-Fry Stages are replacements of imported from Africa or SE Asia for these regulators or companies. acute and chronic toxicity Fish tend to be found dead and are not the acute and chronic fish toxicity Companies need to be aware tests and may have been born to parents or tests in Europe in 2011. humanely killed. Chronic tests can also tests respectively, and use fish of these alternatives and use cause death. embryos rather than young fish. them. grandparents that were taken from the wild. The ZFET has been shown to agree Sector: HP, VP, C with acute fish test results 2nd species prenatal Rabbits or monkeys may be used in an There is little evidence Regulators need to assess 90% of the time. toxicity test additional ‘second species’ test after similar that testing on a second the justification for this test in – Rabbits & monkeys tests in rats. The animals are force-fed the test species adds to the safety collaboration with industry. Carcinogenicity Mice or rats are given a substance Because of its unreliability and Regulators need to speed chemical during most of their pregnancy and of chemicals. Several are killed the day before they are due to give studies have indicated that Regulators need to ensure either in their diet, drinking water or expense, this test is losing popularity up their analysis of the 2,560 rabbits and 281 monkeys – Rats & mice birth. Their pups are extracted by caesarean the test in rabbits may be there is consistency are force-fed every day for two years. and is rarely required in practice for redundancy of this test and were used in developmental section and examined before being killed. unnecessary and should between sectors in the 11,826 rats and mice were All of the animals are then killed and chemicals and cosmetics and is make sure it is removed from toxicity tests in Europe in 2011. dissected to see if the substance leads being examined for replacement all requirements. Due to the high doses used, the chemicals not be conducted, but waiving options. used in carcinogenicity tests may cause the mother to become ill and some regulators are inconsistent across Europe in 2011. to signs of . Animals often suffer for pharmaceuticals. However, it is Sector: HP, VP, C from spontaneous during the still a requirement in the legislation Companies need to continue chemicals could lead to deformities, stillbirths in their rules. Companies need to work experiment that may not be due to the and guidance. to encourage regulators to or miscarriages. with regulators to assess Sector: HP, VP, C substance. end the requirement for this the need for this test. test. HP - Human pharmaceuticals, VP - Veterinary pharmaceuticals, C - Chemicals including biocides, , cosmetics, industrial chemicals