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

0

10

20

30

40

50

60

70

80

90

100

110

120

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