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

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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 ✓

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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

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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

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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

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HSI’s global #EndAnimalTesting campaign

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#BeCrueltyFree policy scorecard

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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

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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

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