FoodCosme csToxicol16,p255-276,1978

NOEL/NOAELdatabase

MunroFoodCos…,1996

Toxdata–NOEL/NOAELLOEL/LOAEL

StructurecategoriesClassI,II,III

Pragma cTTC

approach

7

Thedosemakesthepoison

Thresholddosebelowwhichnorelevanteffectsareexpected,regardlessofthesubstance

CancerEndpoints:TD50lowdoselinearextrapola on>700substances

Databasewithtoxicityinforma ononasmanysubstancesas

possible

OtherEndpoints:RepeateddoseNOAEL/100>600substances

Thresholdbasedonvirtuallysafedose(10-6)

3CramerstructureclassesðThresholdsat5thpercen leofeachclass

ClassI

Munro1996

MunroRevisited2014

COSMOS2014

N=136 N=28

ClassII ClassIII

N=443

N=130 N=28 N=439

0.15mg/kgbw/day0.97mg/kgbw/day3.25mg/kgbw/day

ClassInoparabens/phthalates

N=123

N=128

3.03mg/kgbw/day

N=237 N=36 N=281 N=226

TTC

dataset

NOAELdatabase

Munro1996

7itera onsofdatasetevalua onand2QCsessions

ofstudyreviews

• Studyinclusioncriteria• NOAELselec oncriteria

AllcompoundsinCOSMOSTTCdatasethavetoxicitydataeitherinoRepeatToxDBv1.0ordatainFDAPAFA,orEPAToxRefDBunlessthecompoundsareineitherMunroorEPAIRIS.

• Studyinclusioncriteria • Studyrelevance• NOAELdecision

V1.7currentinterimversion

2.NOAELdatabase 3.TTCdataset1.Toxicitydatabase

Development of Non-Cancer Threshold of Toxicological Concern (TTC) Database to Support Alternative

Assessment Methods for Cosmetics Related Chemicals

1. US FDA CFSAN OFAS, College Park, MD, United States. 2. Imperial College, London, United Kingdom, 3. Independent consultant, Brighton, United Kingdom. 4. Procter & Gamble, Cincinnati, OH, United States. 5. Dow Europe

GmbH, Horgen, Switzerland. 6. Henkel, Dusseldorf, Germany. 7. EC Joint Research Center, Ispra, Italy., 8. Altamira LLC, Columbus, OH, United States.

INTRODUCTION AND OBJECTIVES

Disclaimer: This study does not reflect the policies of US FDA nor does it endorse products used in the analysis. Acknowledgements: The research leading to these results has received funding from the European Community’s 7th Framework

Program (FP7/2007-2013) COSMOS Project under grant agreement n° 266835 and from Cosmetics Europe.

www.cosmostox.eu

kjacobs@fda.hhs.gov

BUILDING THE DATASET – COSMOS TTC DB

As one of the practical alternatives

to repeated dose toxicity testing,

the Threshold of Toxicological

Concern (TTC) approach is now

being expanded to include

cosmetics-related chemicals. TTC

supports exposure-based safety

assessment with a threshold for

chemicals below which there is a

low probability of a risk to humans.

Relevant Chemicals CosIng database (ca 9,800 CAS) +

US FDA VCRP (ca 3,700 CAS)

COSMOS ‚Cosmetic Inventory‘

Toxicity data

SCCS, FDA PAFA/CERES,

IRIS, EPA TOXREFDB, NTP,

ECHA, MUNRO NOAELS

• Oral repeated dose studies 28d

• Non-neoplastic effects incl. DART

• Rat, mouse, dog, monkey, rabbit (only for DART)

COSMOS Oral Repeated Dose Toxicity Database

Target organ, effect etc. per dose group for 230 cosmetic related chemicals

• Defined organic • No proteins, inorganics, metals • lipid-soluble vitamins and essential

amino acids exclued • EU BAN chemicals included

COSMOS NOAEL Database

Contains NOAEL information from different

sources per substance

NOAEL Determination Algorithm • lowest NOAEL with clear LOAEL • Free Standing NOAELS were excluded

when ever possible • Chronic studies were preferred when

availble • Guideline studies were preferred

NOAELs Adjusted for Duration

• Subchronic Chronic AF = 3 • Subacute Chronic AF = 6

• NOTE : Reproductive/Developmental effects were not adjusted for duration

NOAELs derived from LOAELs

• LOEAL NOAEL AF = 3

COSMOS TTC Dataset v. 1.5

One NOAEL per substance

Database QC #1 • 60 substances reviewed • Most potent 10% of each Cramer class • Large discrepancy of NOAELs across different

sources • Relevance of NOAELs selected by curation

COSMOS TTC Dataset v. 1.6

One NOAEL per substance

Database QC #2 • 60 substances reviewed by toxicologist

group in May-Aug 2013

COSMOS TTC

Dataset v. 1.7

One NOAEL per substance

• All counts are subject to version number and inclusion criteria.

• Each version was distributed to EG1

Muldoon-Jacobs, Kristi1; Boobis, Alan R.2; Barlow, Sue3; Felter, Susan P.4; Hollnagel, Heli M.5; Keller, Detlef6; Vitcheva, Vessela1; Arvidson, Kirk1; Worth, Andrew P.7; Yang, Chihae8

Compilation Process: Building the COSMOS TTC Dataset

COMPARING DIFFERENT TTC DATASETS

NEXT STEPS

Hair dyes: mostly belong to Class III and tend to be more potent. However the effect on 5th

percentile was not significant

Re-evaluate Unreliable data within 5th percentile: (e.g Isopropyl alcohol)

Parabens and phthalates: Munro in general less conservative than COSMOS. They may affect 5th

percentile of the Cramer Class I. EG1 is currently evaluating.*

Expand the Dataset to incorporte Munro and COSMOS

Cramer Class assignment – discrepancy between Munro and ToxTree. Class II is not a viable

group. Consider combining with Class III.

• Total of 120 substances reviewed by toxicologist group in 2012/2013

The base of v1.7 includes 562 chemicals. About 20% of the NOAELs were determined by study reviews in two QC. It also reflects EFSA QC of Munro dataset.

OBSERVATIONS

COSMOS TTC dataset is enriched for skin

care, moisturizer, humectant, hair dye,

perfume/fragrance, antimicrobials,

emulsifiers, surfactants, and plasticizers.

Munro is known to cover a diverse set of

compound classes. Compound classes

lacking in Munro are non-ionic surfactants,

organosilicon compounds, and hair dyes.

Compound descriptions COSMOS TTC v1.7 Munro

Total unique structures 558 607

Cosmetics Inventory 503 190

Impurities (from food contact substances) 55 Not applied

Cramer Class I: Class II: Class III 239: 36: 281 136: 28: 443

Nutrients

- Lipid soluble vitamins

- Essential amino acids

A, D, E, K Removed

Removed

retinol

phenylalanine

Hair dyes (direct and oxidative) 110 13

Parabens (preservatives) 10 7

Phthalates (plasticizers) 7 5

EU BAN (cosmetics use) 27 95

COSMOS TTC vs. Munro

VCRP: Voluntary Cosmetics Registration Program

• COSMOS minimum study (MINIS) criteria

- e.g., no single dose studies,

Munro 1996

Munro Revisited

2014

COSMOS 2014

607 597 558 # unique

structures

Dataset

description

Dataset QC

Adjustment

factors

Parabens and

Phthalates

5th percentile

estimation

• Munro dataset reflects the

minimum NOEL approach

• Data records up to 1990’s

• Many studies are from US EPA

IRIS, JECFA…

• Removed EFSA lowest 10% QC

rejections (6 compounds)

• Munro revisited also did not include

isopropyl alcohol due to data

reliability, possible QC rejection).

Ethanol (Class I), and dinocap and

linamarin (Class III) are removed due

to hamster studies.

• Data compiled from existing sources by manual

harvesting Exception: data from US FDA PAFA

data and US EPA ToxRefDB

• 20% of dataset, including the lowest 10%

followed a “most appropriate” NOEAL

approach.

• Remainder of dataset represents a mixture of

NOEL from PAFA and ToxRefDB and

NOAELs reported in IRIS, SCCS, and REACH

• EFSA lowest 10% QC for Cramer Class

I and Class III (2011)

• Rejected 4% of the Class III data in

the lowest 10% (2 out of 50)

• Rejected 30% of the Class I data in

the lowest 10% (5 out of 16)

• The COSMSO TTC v1.6 dataset and the full NOAEL database, on which COSMOS TTC v1.6 was based, were distributed to EG1 in May 2013.

• COSMOS TTC v1.5 was distributed to EG1 on April 2013.

• Two QC sessions of lowest 10% of the database

and the widely varying data across the sources

• COSMOS QC: QC1 increased the Class 1

fifth percentile by 30%; Class 3 decreased by

30%; QC2 did not change the fifth percentiles

of all class.

• 21% of the whole dataset have been manually

QC’d by toxicology experts.

• About 20% of the resulting dataset contains

NOAELs from the two QCs.

• Data used as is after adjusted for

subchronic to chronic

• DART adjustment did not make

any difference.

• NOAELs normalized for duration and effects.

28 day studies included (subacute to chronic)

• DART adjustment was not included.

• Duration adjusted for subchronic to

chronic

• DART adjustment did not make any

difference.

• Removal of the classes decreased the

potency, hence increasing the 5th %

(Class I) by 20%.

• Removal of the classes from Munro

1996 results in a slight decrease of

the 5th percentile of the Class I.

• Removal of the classes from Munro

1996 results in a decrease of the 5th

percentile of the Class I.

• Data may not be normally distributed.

parametric/ non-parametric analysis

significantly differ for the 5th percentile

of Class I

• Munro preferred logNormal

curve fitting