Capacity for safety evaluation of cosmetics in India - Adip Roy Safety & Environmental Assurance Centre, Unilever R&D, 64 Main Road
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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 Acceptable
risk risk
A Risk-based Approach Facilitates Safe
Innovation
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
Hazard-based Risk-based
• Check-list compliance • Expertise- & evidence-driven
• Unnecessary testing • Essential testing only
• Doesn’t consider how • Product use / exposure
product is used determines outcome
• Yes / no decisions • Options to manage risks
• Overly conservative • Uncertainties explicit
Safety Assessment Process for
Ingredients in Cosmetic Products
Consider product type
and consumer habits
Identify available Identify supporting
toxicology data safety data (e.g. QSAR,
Determine route and HoSU)
amount of exposure
Identify toxicological
Evaluate required vs.
endpoints of potential
available support
concern
Identify critical end
Conduct toxicology
point(s) for risk
testing as required
assessment
Overall safety evaluation for
Conduct risk assessment
product – define acceptability
for each critical endpoint
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
Routes of Consumer exposure
Skin: Inhalation:
Skin creams Aerosols
Deodorants/APs Pump sprays
Soap/cleansers Hair shampoo/
Hair shampoo/ conditioner
conditioner Shower gel
Shower gel
Ingestion:
Toothpaste/
mouthwash
Lipsticks
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
Only some of the OECD test guideline non-animal methods (e.g.
Genotoxicitiy) are routinely carried out in India.
OECD TG473
Donor
Skin chamber
position
Skin
Genotoxicity Receptor
solution in Penetration
Receptor
chamber Window
Receptor
solution
OECD TG471
OECD TG428 out
OECD TG476
OECD TG438
OECD TG432
% control
NRU
120
110
100
90
OECD TG430/431 80
70
60 EC50 level
OECD TG439 50
40
30
OECD TG437 20
10
0
0.1 1 10 100 1000 10000
Concentration mg/ml
Eye Irritation
Skin Corrosion/Irritation
PhototoxicityChallenges: 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
Timeline for Replacement of Animal
Human Health Testing
Comments
Toxicology Endpoint [Note: Regulatory Acceptance would require
an additional 4-8 years]
No timeline for full replacement could
Repeated dose toxicity Ongoing work still at research stage
be foreseen
Current in vitro test methods are
No timeline for full replacement could inadequate for generating the dose-
Carcinogenicity response information required for safety
be foreseen
assessment
Several non-animal test methods under
development & evaluation; data
Skin Sensitisation 2017 – 2019 for full replacement integration approaches for safety
assessment required
Ongoing work still at research stage
No timeline for full replacement could
Reproductive Toxicity >2020 to identify key biological
be foreseen
pathways
Ongoing work still at research stage
No timeline for full replacement could
Toxicokinetics 2015 – 2017: prediction of renal &
be foreseen
biliary excretion and lung absorption
Adler et al (2011), Archives in Toxicology, 85 (5) 367-485Approaches to Risk Assessment Without Animals Past: • hazard focus • emphasis on tests for classification and labelling (‘positives/negatives’) • direct replacement of a specific animal test 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
Exposure
Tissue Dose Low Dose
Higher Dose
Biologic Interaction Higher yet
Perturbation
Normal
Biologic
Biologic
Inputs Function
Early Cellular
Changes
Adaptive Stress
Cell Morbidity
Responses Injury and
Mortality
(From Andersen & Krewski, 2009, Tox Sci, 107, 324)TT21C
Exposure & Consumer Use
Assessment
Chemistry-led
alerts & in vitro
High-content information in vitro
assays in human cells & models screening
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 perturbationsAdverse 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.
AOP-based risk assessments
Example: Skin Allergy
Epidermis Epidermis
Lymph
Node
Induction ElicitationAOP-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?
1. Skin
Penetration 8-11. Allergic Contact
7. Presentation of
3-4. Haptenation: 5-6. Activation of Dermatitis: Epidermal
haptenated protein by
covalent modification epidermal inflammation following
2. Electrophilic Dendritic cell resulting in
of epidermal proteins keratinocytes & re-exposure to substance
substance: activation & proliferation
Dendritic cells due to T cell-mediated
directly or via of specific T cells
cell death
auto-oxidation or
metabolism
Key Event 1 Key Event 2 + 3 Key Event 4 Adverse Outcome
Modified from ‘Adverse Outcome Pathway (AOP) for Skin Sensitisation’,
OECD reportIndia 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
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