Capacity for safety evaluation of cosmetics in...
Transcript of Capacity for safety evaluation of cosmetics in...
Capacity for safety evaluation of cosmetics in India
Adip Roy
Safety & Environmental Assurance Centre, Unilever R&D, 64 Main Road, Whitefield, Bangalore – 560066
Cosmetic Ingredient Risk Assessment
For any ingredient safety Risk Assessment is a function of:
» Hazard – potential harmful effects • Intrinsic hazard of material • Safety concerns due to functionality
» Exposure – how much will the consumer be exposed to? • Normal habits & practices • Amount of ingredient in product - Cosmetics • Different risk/benefit compared to other sectors e.g. Pharma • Limited controls
Can We Use a New Ingredient Safely?
Will it be safe • For our consumers? • For our workers? • For the environment?
Can we use x% of ingredient y in product z?
How Do We Assure Safety of Ingredients
Legislation (in place in most countries) requires Companies to ensure that any cosmetic products they put on the market do not cause any adverse health effects when applied under normal or reasonably foreseeable conditions of use.
Regardless of whether legislation exists or not, Unilever requires that all products it places on the market must be safe for use
We use scientific evidence-based risk assessment methodologies to ensure that the risk of adverse health and/or environmental effects from exposure to chemicals used in our products is acceptably low.
Unacceptable
risk
Acceptable risk
A Risk-based Approach Facilitates Safe Innovation
Hazard-based • Check-list compliance
• Unnecessary testing
• Doesn’t consider how product is used
• Yes / no decisions
• Overly conservative
We use scientific evidence-based risk assessment methodologies to ensure that the risk of adverse health and/or environmental effects from exposure to chemicals used in our products is acceptably low
Risk-based • Expertise- & evidence-driven
• Essential testing only
• Product use / exposure determines outcome
• Options to manage risks
• Uncertainties explicit
Safety Assessment Process for Ingredients in Cosmetic Products Consider product type
and consumer habits
Determine route and amount of exposure
Identify toxicological endpoints of potential
concern
Identify critical end point(s) for risk
assessment
Identify available toxicology data
Identify supporting safety data (e.g. QSAR,
HoSU)
Evaluate required vs. available support
Conduct risk assessment for each critical endpoint
Conduct toxicology testing as required
Overall safety evaluation for product – define acceptability
and risk management measures
Safety assessments of Cosmetic products and ingredients
● Toxicological product safety assessments are conducted to support human consumer trials and marketing products where:
– A novel ingredient is to be used in an existing product type – An existing ingredient is used in a new product type/format – Levels of ingredients are modified in an existing formulation
Skin: Skin creams Deodorants/APs Soap/cleansers Hair shampoo/ conditioner Shower gel
Ingestion: Toothpaste/ mouthwash Lipsticks
Inhalation: Aerosols Pump sprays Hair shampoo/ conditioner Shower gel
Routes of Consumer exposure
Toxicity Endpoints (Human Health) Relevant toxicity endpoints based on the Scientific Committee on
Consumer Products guidance document “Notes of Guidance for the
Testing of Cosmetic Substances and their Safety Evaluation”
• Acute toxicity
• Corrosivity and irritation
• Skin sensitisation
• Dermal/percutaneous absorption
• Repeated dose toxicity
• Reproductive toxicity
• Mutagenicity/genotoxicity
• Carcinogenicity
• Toxicokinetic studies
• Photo-induced toxicity
Toxicological Evaluation Capability in India
Several institutions and CROs (GLP compliant) have toxicological
assessment capability in India
India Capacity: Non-animal Alternatives
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0.1 1 10 100 1000 10000
% control NRU
Concentration mg/ml
EC50 level
OECD TG432
Phototoxicity
OECD TG437
OECD TG438
Eye Irritation
OECD TG430/431
OECD TG439
Skin Corrosion/Irritation
Window
Receptor solution in
Receptor solution out
Donor chamber
Receptor chamber
Skin position
OECD TG428
OECD TG471
OECD TG473
OECD TG476
Skin Penetration
Genotoxicity
Only some of the OECD test guideline non-animal methods (e.g.
Genotoxicitiy) are routinely carried out in India.
Challenges: Validation Of Alternative Tests (e.g. Skin Irritation) Test method development*: c.1996-1999
• Prevalidation study: 1999-2001
• Optimisation of test protocols: 2001-2003
• Validation study: 2003-2006
• ECVAM peer review & endorsement of EPISKIN: 2007
• Derivation of performance standards and “catch-up” validation study for 2nd
revision of EpiDerm protocol and for Skin Ethic 2007-2008
• EU test method guideline 2009
• OECD test method guideline 439 July 2010
* New in vitro biology made this possible – harnessing state-of-the-art technology for toxicology
Current Scientific Reality: Non-animal Approaches For Safety Decisions
Human Health
Toxicology Endpoint
Timeline for Replacement of Animal
Testing
[Note: Regulatory Acceptance would require
an additional 4-8 years]
Comments
Repeated dose toxicity No timeline for full replacement could
be foreseen Ongoing work still at research stage
Carcinogenicity No timeline for full replacement could
be foreseen
Current in vitro test methods are
inadequate for generating the dose-
response information required for safety
assessment
Skin Sensitisation 2017 – 2019 for full replacement
Several non-animal test methods under
development & evaluation; data
integration approaches for safety
assessment required
Reproductive Toxicity No timeline for full replacement could
be foreseen
Ongoing work still at research stage
>2020 to identify key biological
pathways
Toxicokinetics No timeline for full replacement could
be foreseen
Ongoing work still at research stage
2015 – 2017: prediction of renal &
biliary excretion and lung absorption
Adler et al (2011), Archives in Toxicology, 85 (5) 367-485
Past:
• hazard focus
• emphasis on tests for classification and labelling (‘positives/negatives’)
• direct replacement of a specific animal test
Approaches to Risk Assessment Without Animals
Now
• focus on non-animal approaches for consumer safety risk assessment
• data required for safety decision should be driver
• dose response information is essential
• understanding the underpinning human biology
• Not looking for a way to do the animal test without the animal
US NRC Report June 2007
“Advances in toxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology could transform toxicity testing from a system based on whole-animal testing to one founded primarily on in vitro methods that evaluate changes in biologic processes using cells, cell lines, or cellular components, preferably of human origin.”
Perturbation of Toxicity Pathways
Biologic Inputs
Normal Biologic Function
Adaptive Stress Responses
Early Cellular Changes
Exposure
Tissue Dose
Biologic Interaction
Perturbation
Low Dose Higher Dose
Morbidity and
Mortality
Cell Injury
Higher yet
(From Andersen & Krewski, 2009, Tox Sci, 107, 324)
Exposure & Consumer Use Assessment
High-content information in vitro assays in human cells & models
Dose-response assessments
Computational models of the circuitry of the relevant toxicity pathways
PBPK models supporting in vitro to in vivo extrapolations
Risk assessment based on exposures below the levels of significant pathway perturbations
Chemistry-led alerts & in vitro screening
TT21C
Adverse Outcome Pathways (AOP)
• Proposal for a template and guidance on developing and assessing the Completeness of Adverse Outcome Pathways
Adapted from OECD (2012)
Adverse Outcome Pathway (AOP)
• An adverse outcome pathway (AOP) is the sequence of events from the chemical structure of a target chemical through the molecular initiating event to an in vivo outcome of interest.
• It is the ‘capture’ of the mechanistic processes that initiate and progress through the levels of biology to give rise to toxicity in living organisms for given chemical toxins.
• Each AOP represents the existing knowledge of the linkage(s) between a molecular initiating event, intermediate events and an adverse outcome at the individual or population level.
Epidermis Lymph
Node
Induction
Epidermis
Elicitation
AOP-based risk assessments Example: Skin Allergy
AOP-based risk assessments Example: Skin Allergy
Induction of skin allergy is a multi-stage process driven by toxicity pathways
- mechanistic understanding is captured in Adverse Outcome Pathway (AOP)
- non-animal test methods have been developed; each aims to predict impact of a chemical on one key event
- how can we make risk assessment decisions by integrating this scientific evidence?
Modified from ‘Adverse Outcome Pathway (AOP) for Skin Sensitisation’,
OECD report
1. Skin Penetration
2. Electrophilic substance:
directly or via auto-oxidation or
metabolism
3-4. Haptenation: covalent modification of epidermal proteins
5-6. Activation of epidermal
keratinocytes & Dendritic cells
7. Presentation of haptenated protein by
Dendritic cell resulting in activation & proliferation
of specific T cells
8-11. Allergic Contact Dermatitis: Epidermal
inflammation following re-exposure to substance
due to T cell-mediated cell death
Key Event 1 Key Event 2 + 3 Key Event 4 Adverse Outcome
India Capacity: Research on Animal Alternatives in India
Research on Animal Alternatives in India
Research on Animal Alternatives in India: Future Directions The symposium ended with a panel discussion chaired by Dr. KC Gupta (Director, Indian Institute of Toxicology Research) - addressed topics on current status on research on alternatives (current projects, gaps, funding), Education & Training in alternatives, and Policy & Regulations. Key points: • Learn from the experience we have from many years of research that has been carried out in the EU on animal alternatives. • Need to develop a roadmap and academia and STOX can help. • Academia – Industry and Industry-Industry partnerships are critical in addressing this issue. • There is a need to build capability and upgrade skills especially in areas of modelling. • Training in toxicology is not enough; experts from various disciplines need to work together in developing novel methodologies for risk assessment.
Summary / Conclusions
• Pathways based approaches are gaining widespread acceptance as the
conceptual framework under which novel risk assessment techniques
will be developed
• There are challenges of AOPs for using in Chemical Risk Assessment
• How many AOPs are there? • How to extrapolate from in vitro to in vivo concentrations? • Which AOPs are relevant for which chemicals? • How will regulators view AOPs? • How can AOPs be catalogued for use by risk assessors? • How conserved are AOPs across species and life stages? • Which AOPs should be focused on? • How detailed do AOPs need to be? • How should interactions among AOPs be assessed? • What is the best approach for linking exposure (ADME) to AOPs?
Challenges for the Future
1. Maximise use of existing validated non-animal methods for safety decision-making (e.g. skin irritation, skin penetration etc.)
2. For those toxicity pathways where we currently rely on animal studies, continue to develop new risk-based approaches for consumer safety assessment linked to understanding toxicity pathways
3. Importance of collaborative multi-disciplinary research to generate new ideas, working with the best scientists globally
Thank you