development of non-cancer threshold of toxicological concern (ttc… · 2014. 3. 29. · the...
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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
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