Using Derek Nexus to assess the safety of raw materials used in cosmetics and as part of a skin sensitisation ITS. Part 1: Using Derek Nexus to assess the safety of raw materials used in cosmetics. Alison Reeves Sales Executive Alison.Reeves@LhasaLimited.org

Agenda Who are Lhasa Limited? Derek Nexus Where are our members based? Derek Nexus What is Derek Nexus? Why should you use Derek Nexus? How does Derek Nexus work? A Derek Nexus Prediction Explained What does a prediction look like? How to interpret a prediction Skin Sensitisation/ EC3 Predictions in Derek Nexus.

Who are Lhasa Limited? Not-for-profit organisation Educational Charity Controlled by our members Knowledge base and database systems Lhasa est. 1983 Used to be right next to Leeds University Still have close ties to the university Not for profit Not a customer – a member Sponsor the continued development of the software As such have a say in what we do - vICGMs etc. This is an important factor, we are not likely to be bought out by other companies Encourages the sharing of data – it’s safe Educational charity Can offer large discounts to educational and government funded organisations etc (of approx 85%) Also sponsor work of PhD students etc. – some of which go on to become members of staff at Lhasa We offer 5 programs at the moment – rewritten recently into Java Eclipse Sarah – NEW – Mutagenicity QSAR Zeneth – 5yrs – forced degradation Vitic – 8yrs – chem database Meteor – 17yrs – metabolism- predicts metabolites Derek – MOST DEVELOPED @ 25yrs – toxicity prediction tool

339 Lhasa Members 332 dx sites Derek users -product with the most uptake, global use Almost 300 users Mostly European and North American Growth in Japan and now China which are sold through software licensing agents. India is also a growing market. 70% pharma users – biotechs/pharma/generics companies Chemical, agrochemical used for REACH Cosmetics and Perfumeries Personal products Tobacco Medical devices Universities Regulatory – ECHA and FDA are users Top 20 pharma use our software, the likes of Pfizer, GSK etc as you can see at the top of this screen

What is Derek Nexus? Toxicity prediction tool Knowledge-based expert system Broad range of toxic endpoints Identifies toxicophores Makes qualitative predictions KB/expert system, the KB is data that has been compiled and processed by Lhasa’s database scientists (human experts) Lhasa certified database of toxicological endpoints, always growing and developing- don’t just focus on mutagenicity ~65 end points at the moment Alerts within the KB recognise the specific patterns of toxicophores in compounds ~810 alerts within KB atm As opposed to making a quantitative prediction such as a percentage conviction etc. gives a qualitative prediction between Impossible and Certain. Impossible – Improbable - Doubted – Equivocal – Plausible – Probable - Certain

Why use Derek Nexus? Implementation of EU Regulation 1223/2009 (Cosmetics Regulation) has led to increased interest in non-animal alternatives Build toxicity profiles Quick & easy to use No limit on number of predictions KB/expert system, the KB is data that has been compiled and processed by Lhasa’s database scientists (human experts) Lhasa certified database of toxicological endpoints, always growing and developing- don’t just focus on mutagenicity ~65 end points at the moment Alerts within the KB recognise the specific patterns of toxicophores in compounds ~810 alerts within KB atm As opposed to making a quantitative prediction such as a percentage conviction etc. gives a qualitative prediction between Impossible and Certain. Impossible – Improbable - Doubted – Equivocal – Plausible – Probable - Certain

How does Derek Nexus work? -Knowledge base search Molecular weight Metabolic activation Skin permeability Presence of toxicophore So taking this same structure we can see that we have highlighted the toxicophore Derek consists of a Knowledge Base and a reasoning engine. The knowledge base contains structure activity relationships. Once a query structure is inputted and constraints set, the program searches the Knowledge Base for any matches between substructures in the query molecule and sub structures it knows are linked to structure-activity relationships. The toxic likelihood is based on absolute reasoning rules which are in turn based on the species you have selected, skin permeability, molecular weight, etc. Log P- generated by external party, C log P The Knowledge base currently consists of over 300 structure-activity relations that have been derived by searching literature, using published databases & collaborative group suggestions or donations. Species

What does a prediction look like? Example compound: ISOEUGENOL Taken from: SCCS (Scientific Committee on Consumer Safety), opinion on fragrance allergens in cosmetic products, 13-14 December 2011

Skin Sensitisation & EC3 Predictions in Derek Nexus. Skin sensitisation alerts will now give an additional EC3 prediction (extending hazard to risk) EC3 values correlate well with human sensitisation induction thresholds EC3 values are then binned into potency categories: the current version containing 88 skin sensitisation alerts. The LLNA gives an EC3 value to give a quantitative potency prediction Skin sensitisation alerts have been expanded to provide positive predictions. Once a compounds fires a skin sensitisation alert an addition tab will now appear (demonstration later). This will now produce an EC3 value to help quantify the skin sensitisation endpoint. As stated the EC3 is a valuable parameter as it comes from the LLNA (end of the line assay etc). Another advantage is that is gives a dose response from multiple points, so rather than being an opinion from a scientist it is a quantitative measure as oppose to a qualitative method (looking at the side of a shaved guinea pig and trying to decide if it is a weak or moderate sensitizer). These EC3 values correlate well with human sensitisation induction thresholds and can be binned into potency categories. *Also worth noting that other potency categories such as the GHS categories exist. If this is the case you can demonstrate how the potency category can be turned off and just the EC3 value generated. GHS classifications are as follows: GHS 1A =< 2%; GHS 1B > 2%; GHS 2 = non-sensitiser

To summarise: What I hope you have gained… An overview of how Derek Nexus can help you to build toxicity profiles for your cosmetic ingredients An insight into how Derek Nexus works An understanding of how to run and interpret a prediction A flavour of EC3 Predictions in Derek Nexus If you would like to arrange a further demonstration of Derek Nexus please do not hesitate to contact me.

Thank you very much for listening. Do you have any questions Thank you very much for listening. Do you have any questions? Info@Lhasalimited.org Next: Part 2: Using Derek Nexus as part of a skin sensitisation ITS.

Part 2: Using Derek Nexus as part of a skin sensitisation ITS. Using Derek Nexus to assess the safety of raw materials used in cosmetics and as part of a skin sensitisation ITS. Part 2: Using Derek Nexus as part of a skin sensitisation ITS. Dr Donna Macmillan Scientist Donna.Macmillan@lhasalimited.org

Work in progress disclaimer This document is intended to outline our general product direction and is for information purposes only, and may not be incorporated into any contract. It is not a commitment to deliver any material, code, or functionality, and should not be relied upon. The development, release, and timing of any features or functionality described for Lhasa Limited’s products remains at the sole discretion of Lhasa Limited.