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A global perspective on replacementFrom principle to reality
Troy SeidleDirector of Research & ToxicologyHumane Society International#EndAnimalTesting
hsi.org/endanimaltesting
Case study: skin irritation
Requisites for replacementHealth concern Animal test Replacement strategy
Reversible skin damage (irritation) or irreversible tissue destruction (corrosion)
Chemical/product is applied to the shaved backs of live rabbits for 4 hrs, then washed off; animals observed at defined time points for 2 wks, then killed (OECD Test Guideline 404).
Validated/accepted in vitro tests (OECD TG 431/corrosion & TG 439/irritation) are reconstructed human skin models that assess cell viability using colour-change MTT test. Full replacement in most cases if both tests run in sequence (back to back).
Timeline for scientific validation & regulatory acceptance
Research &development
? yrs
hsi.org/endanimaltesting
Understand the biology underpinning the toxic response
£nve$tm€nt by companies/government in appropriate non-animal models
» EPISKIN™ (L’Oréal)
» EpiDerm™ (MatTek)
» SkinEthic RHE (L’Oréal)
Timeline for scientific validation & regulatory acceptance
Research &development
? yrs
Pre-validation
2 yrs
Vali- dation
1 yr
Peer review
1 yr
hsi.org/endanimaltesting
CVAMs (Centres for the Validation of Alternative Methods)
ICATM (International Cooperation on Alternative Test Methods)
BraCVAM
Timeline for scientific validation & regulatory acceptance
Research &development
? yrs
Pre-validation
2 yrs
OECD (etc.) test guideline
1-4 yrs
Vali- dation
1 yr
Peer review
1 yr
hsi.org/endanimaltesting
Timeline for scientific validation & regulatory acceptance
Research &development
? yrs
Pre-validation
2 yrs
OECD/ICH test guideline
1-4 yrs
National infrastructure, training, regulatory uptake & use
1-10 years
Vali- dation
1 yr
Peer review
1 yr
hsi.org/endanimaltesting
National regulations prescribing testing for skin irritation
Cosmetics Chemicals Pesticides
Australia (✓) ✓ ✓
Brazil (✓) ✓
Canada ✓ ✓
China ✓ ✓ ✓
European Union BANNED ✓ ✓
India BANNED ✓
Japan ✓ ✓
Korea ✓ ✓
New Zealand ✓ ✓
Taiwan ✓ ✓
United States ✓
hsi.org/endanimaltesting
Domestic laboratories & regulators may lack training in conduct & interpretation of non-animal methods
Models or cell culture reagents may not be readily available in all countries (legal barriers/customs delays)
Outsourcing can create an economic barrier, particularly in non-OECD economies
No formal national regulatory acceptance process
Human resistance to change
3Rs for obstinate regulators = Retrain, Reassign, Retire
hsi.org/endanimaltesting
Barriers to regulatory uptake & use
The lo(oooooo)ng road to replacement
Non-animal test method (or strategy) must be…
Available commercially Scientifically validated to confirm its relevance,
reliability, domain of applicability & limitations Accepted as a(n inter)nationally harmonized test
guideline (OECD, ICH, etc.) Understood by companies & national authorities Able to be performed by domestic laboratories Adopted into data requirements in relevant product
sector regulations (cosmetics, chemicals, pesticides, medicines) in key national markets
Ideally, required preferentially by law
… for all relevant toxicological endpoints
hsi.org/endanimaltesting
Standard testing requirements to register a new pesticide chemical1. Toxicokinetics 11. 28-day dermal CR 21. Chronic (1y) dog 31. Avian acute oral*
2. Acute oral* 12. 28-day inhal. CR 22. Carcino rat 32. Avian dietary
3. Acute dermal* 13. 90-day dermal CR 23. Carcino mouse 33. Avian repro
4. Acute inhalation* 14. 90-day inhal. CR 24. Repro 2-gen rat 34. Fish acute x2*
5. Skin irritation* 15. Vitro mutation x3 25. Prenat dev. rat 35. Fish chronic juv.
6. Eye irritation* 16. Vivo micronuc. CR 26. Prenat dev. rabbit 36. Fish early life stg.
7. Skin sensitisation* 17. Mouse spot CR 27. Neurotox henCR 37. Fish lifecycleCR
8. 90-day oral rat 18. Vivo cytogen. CR 28. Dermal absorpt. 38. Fish bio[ ]
9. 90-day oral dog 19. Vivo germ cell CR 29. Addn’l studiesCR 39. MecososmCR
10. 28-day oral CR 20. Chronic (2y) rat 30. Livestock feed* …
* Test required for both active ingredient and finished product CR = Conditional Requirement
hsi.org/endanimaltesting
HSI’s global #EndAnimalTesting campaign
hsi.org/endanimaltesting
#BeCrueltyFree policy scorecard
hsi.org/endanimaltesting
Region Policy measure(s)
Restriction type
StatusTestin
g Sales
Australia End Cruel Cosmetics Bill 2014 ✓ ✓ 1st reading; Labor consult’n
Brazil Bills 6602/13 (D); 70/2014 (S) ✓ (✓) Passed Deputies, in Senate
Canada Food & Drugs Act amendments (✓) (✓) Bill under development
China CFDA reg. Δ for domestic non-SUC Working on import reg. Δ
EU + EFTA Regulation 1223/2009 ✓ ✓ Implementation
India Rules 148-C (testing) & 135-B (import)
✓ ✓ Implementation
Israel Animal Experiment’n Law (testing) & Pharmacists Ordinance (sales)
✓ ✓ Implementation
Japan – Political discussions
Korea MFDS reg. Δ for functionals (✓) (✓) Bill under development
New Zealand Supplemental Order Paper ✓ Re-introduction after election
Russia – Regulatory discussions
Taiwan Cosmetic Hygiene Act amendments
✓ (✓) Bills under development
USA H.R. 4148 Humane Cosmetics Act ✓ ✓ House bill, 55 co-sponsors
Pesticide policy scorecard
hsi.org/endanimaltesting
Endpoint ‘3R best practice’ EU US BR IN
1 yr dog Deletion (replacement) ✓ ✓ ✓
Repro Extended 1-generation rat study (46% reduction) ✓ ✓
Genotox (MNT)
Assess as part of a 90-day rat study (combination approach) rather than 2 separate studies
✓ ✓
Acute dermal
Waive study requirement if substance is unclassified (non-toxic) via oral route (replacement/reduction)
✓(P)
Carcino Waive mouse second species requirement with scientific justification (50% reduction)
✓(P)
Devtox Waive rat second species requirement if no concerns from rabbit developmental or rat extended 1-gen repro
✓(B)
Fish acute
Tiered ‘threshold’ strategy (70% reduction) ✓
Product C&L
Calculation approach based on ingredient toxicity in lieu of conventional ‘acute toxicity 6-pack’
✓
… etc. ✓
REACHing beyond animal testing
hsi.org/endanimaltesting
Last month, the EU took steps to adopt HSI amendments into its chemical safety law, ‘REACH’, which could spare more than 2.6 million animals
Allowing exemptions for skin lethal dose tests on rabbits
Replacing wasteful animal test for reproductive toxicity
Virtually eliminating rabbit eye & skin irritation tests
Paving the way for replacement of mouse & guinea pig skin allergy tests
hsi.org/endanimaltesting