• Selected lowest NOAELs from reliable studies

• Effects considered for NOAEL/LOAEL

• Non-neoplastic systemic effects

• Developmental effects included if critical

• Toxicologically significant, human relevant endpoints

when mechanism is known

• Data record reliability confirmed by database QC

• Study results reliability confirmed by NOAEL review

sessions on the high impact portion of the database

- The lowest 10% and records varying greatly across

the data sources

- Studies for 150 chemicals reviewed by ILSI experts

during 2012-2015

• NOAEL values were adjusted by uncertainty factors,

e.g., duration.

Toxicity Profiles of Cosmetics Data

• COSMOS Database has expanded the data model to

include skin permeability, safety evaluation, and TTC

databases.

• The safety evaluation database now includes all

updated Margin of Safety data from

SCCNFP/SCCP/SCCS. It also includes RfP, MOE, ADI

available from other regulatory bodies.

• COSMOS TTC database established and can export

the full dataset as well as combination of the current

Munro database.

• COSMOS DB workflow includes TTC database export

as well as TTC Decision Tree (Kroes 2004)* and the

Oral-to-dermal exposure tiered workflow (ILSI EG2).

Introduction and Objectives

C Yang1,2, DP Hristozov1, A Tarkhov2, T Kleinöder2, I Boyer3, MTD Cronin4, E Fioravanzo5, JH Kim6, B Heldreth3, A

Mostrag-Szlichtyng1, JF Rathman1, A Richarz4, CH Schwab2, V Vitcheva1,2, AP Worth7

COSMOS DB as an international share point for exchanging regulatory and

toxicity data of cosmetics ingredients and related substances

chihae@altamira-llc.com

The funding from the European Community’s 7th Framework Program (FP7/2007-2013) COSMOS Project

(grant agreement n°266835) and Cosmetics Europe, and support from EPAA are gratefully acknowledged.

We also thank ILSI Europe and the expert groups 1 and 2 in support of COSMOS project.

COSMOS DB houses the building blocks of

sources useful for safety evaluation

As one of the practical alternatives to repeated

dose toxicity testing, COSMOS consortium has

established databases and in silico tools. To

enable the pragmatic methods, the COSMOS

database has been expanded to include safety

evaluation data as well as the TTC (threshold of

toxicological concern) databases.

Objectives

• Expand the COSMSO DB data model to

include safety evaluation data as well as TTC

database

• Provide workflow tools to run TTC trees

• Lay foundation to interface with institutions with

cosmetics related issues

1 Altamira LLC, Columbus OH, USA; 2Molecular Networks, Erlangen, Germany; 3Cosmetic Ingredient Review, Washington DC, USA; 4Liverpool John Moores

University, England; 5Soluzioni Informatiche srl, Vicenza, Italy; 6Korean Cosmetics Institute of Industries, Seoul Korea; 7EC Joint Research Centre, IHCP Systems

Toxicology, Ispra, Italy

www.cosmostox.eu

Building Blocks of COSMOS Share Point

• Point of departure

• NOAEL (or BMDL) decisions

• Critical Study and effects/sites

• Evaluation Methods:

• Margin of Safety (SCCNFP/SCCP/SCCS)

• Margin of Exposure (EU EFSA)

• Oral Reference Dose RfD (US EPA IRIS)

Safety Evaluation Database

COSMOS DB v2.0

• Process (arrows): Red = automatic; Black dotted = manual harvesting• TTC database stores the full history of NOAEL decisions and rationales.

Compilation Process:

COSMOS DB – Safety Evaluation and TTC

Study Inclusion Criteria

Summary

SCCNFP/ SCCP/ SCCS

US FDA

CFSAN

CIR (US)KCII (Korea)

COSMOS

Share PointPublic data sharing

Public data sharing

Users

HESS (Japan)

Data update by COSMOS Share Point

EFSA

COSMOS TTC Database

Rat

LiverKidneyGIReproductiveEndocrineSpleen

• A total of 793 compounds in cosmetics inventory was associated with

1150 unique in vivo studies

‒ Other short-term and special toxicology studies are not included.

• Rat is the single most tested species and liver is the top target organ

‒ Most common pathological findings include steatosis phenotypes.

• Subchronic studies have the lowest average NOAEL values

Analysis of NOAEL Distribution

TTC databases and decision tree

Select decision tree

Skin permeability data

• A total of 470 test substances: EDETOX (285),

Kent University update (154), Cosmetics addition

by COSMOS partners (108)

US FDA CFSAN OFASFood contact substances (over 90

substances)

SCCNFP/SCCP/SCCS Cosmetics and consumer products

Registered Substances Database

at ECHA

REACH high tonnage chemicals

US EPA ToxREFDB, IRISIndustrial chemicals, agrochemicals,

etc.

US National Toxicology ProgramNominated substances for safety

concern potential

EFSA (European Food Safety

Agency)

Food/feed related test substances

(opinions in EFSA journals)

Toxicity data sources

• US FDA PAFA legacy database

‒ Food direct and indirect additives, Colorants

• oRepeatTox DB

JRC (EU)

• Cosmetics alone have higher thresholds in general than Munro.

• The thresholds for Munro (Class I = 3.0; Class II = 0.91; Class III

= 0.15 mg/kg-bw/day) are not affected much by the inclusion of

additional 360 cosmetics-related chemicals. (ILSI EG1)

Species/Duration Target organs

Safety evaluation record of butyl

paraben in COSMOS DB

NOAEL summary and QC records

COSMOS DB

- provides TTC

database export

- runs TTC decision

trees*

Export TTC database

* Kroes et. al. 2004 Food and Chemical

Toxicology 42 (2004) 65–83

PCPC†

33393,512 INCI names*(3,713 CAS)

19,390 INCI names* (9,275 CAS)

CosIng

Cosmetics inventory

A look-up table for cosmetics ingredients and related chemicals

used in formulations

† In v2.0 the US list (voluntary cosmetic registration program) is provided by CIR

(cosmetic ingredient review). The current v1.0 counts are from “Compilation of

Ingredients Used in Cosmetics in the United States“, 1st Edition, JE Bailey, Ed.

The Personal Care Products Council, Washington D.C. 20036-4702. The v1.0

and 2.0 counts therefore will be different.

*INCI: International Nomenclature for Cosmetics Ingredients

MOS NOAEL