Read-Across at the Crossroads of Chemoinformatics and Regulatory Science: A Case study at Cosmetic Ingredient Review Mostrag-S
Cosmetic Ingredient Review
1Altamira
1 A,
Boyer
2* I ,
3 B,
2 B,
3 T,
Bienfait Heldreth Kleinoder Maruszyk Tarkhov CH3, Vitcheva V1, Rathman JF1,4, Yang C1,2,4
3 A,
Sacher
3 O,
Schwab
[email protected]
LLC, Columbus Ohio USA, 2Cosmetic Ingredient Review, Washington DC USA, 3Molecular Networks GmbH, Erlangen Germany, 4 The Ohio State University, Columbus Ohio USA
BACKGROUND
Differentiation of homologs by properties 40
The Expert Panel considered the extent of dermal absorption and the potential for dermal irritation of certain long-chain, branched alkyl PEG ethers. The Panel concluded that the toxicity data were sufficient and that these 369 ingredients are safe in the present practices of use and concentrations when formulated to be non-irritating.5 The Objective of this work is to demonstrate how a chemoinformatics-based read-across approach can augment expert judgement, focusing on skin irritation and sensitization as target endpoints.
20 10 0
2 2
3
4
3
4
(7) C11-18EO30-50 (solubilizing) 5
7
(1) C12-22EO1-2 (w/o emulsifying)
Name of properties
(4) C13-22EO13-30
Colloidal properties
HLB (hydrophilic/lipophilic balance) Packing parameter (V/aL)
(solubilizing)
Dermal absorption
Jmax (dermal flux) or Kp
Molecular descriptors
ASA (Approximate surface area), Molar volume, TPSA (polar surface area), water solubility (logS), XlogP
(3) C11-22EO5-15 (detergents)
(6) C1EO25-40 (8) C18EO80-100 (9) C1EO100
(2) C11-18EO3-6 (o/w emulsifying)
Reactivity
CAS RN
9002-92-0 (generic) 3055-96-7
Name
Lauryl hexaethoxylate
Phys-chem properties
• Colloid properties • Molecular properties
Reactivity
• Metabolic potential
SS in vivo
C12EO9 (2.68)
C18EO10
C14EO10 C16EO10 (0.95) C18EO10 (1.90)
SS in silico
SI in vivo
Heats of formation (HoF), HOMO, LUMO SI in silico
no data
no data
no data
poor
N/A
N/A
N/A
N/A
N/A
slight sensitizer
slight sensitizer
slight sensitizer
slight sensitizer
slight sensitizer
slight sensitizer
0.81
0.81
0.81
0.81
0.82
0.80
no data
no data
severe irritant or corrosive
mild irritant
no data
Klimisch 2
N/A
N/A
Klimisch 2
Klimisch 2
N/A
slight irritant
slight irritant
slight irritant
moderate irritant
slight irritant
slight irritant
0.94
0.94
0.95
0.88
0.90
0.93
WoE Read Across Prediction of Safety Concern1 Concern
HOMO LUMO
HLB
slight/mod irritant
Reliability
Skyline profile for a compound (C12EO9) logS
no data
Skin Irritation (SI) Experimental Data and In Silico Predictions (Draize test)2,3,4,5,7
PROFILING WITH PROPERTIES (e.g., WITHIN A CLUSTER=3) HLB Packing
no data
Reliability
Data quality
Scatter plot profile of the cluster 3
nonsensitizer
Data quality
Property type6
Jmax
Value
C12EO9 (1.87)
C16EO10
Skin Sensitization (SS) Experimental Data and In Silico Predictions (LLNA)3,5,7
Hierarchical clustering (Ward linkage) based on properties
Target molecule: C12EO7 (no tox data)
Metabolic potential differences are not presented.
References
1 1
124 homologs of CnEOm with well-defined structures ‒ Structure similarity is not useful Source molecule: C12EO9 (have tox data)
Property
C16EO7
30
CASE: ASSESSMENT OF ALKYL-PEG ETHER GROUP
Target endpoints: Skin Irritation and Skin Sensitization
C12EO7
Analog (Skyline profile distance)
(5) C1EO3-10 (solubilizing)
50
The CIR Panel reviewed 369 alkyl PEG ethers, including 221 ingredients not currently used but that could be used in the future, based on expert judgement and inference to fill data gaps.
C1EOm C8EOm C10EOm C11EOm C12EOm C13EOm C14EOm C16EOm C18EOm C20EOm C22EOm
C12EO9
CLUSTERS OF ALCOHOL ETHOXYLATES
The Cosmetic Ingredient Review (CIR) engages an expert-panel approach to review ingredients. Previously conducted reviews of several groups of alkyl (C16C18) PEG ethers were available. Collectively, these reviews suggested that alkyl PEG ethers are generally quite similar structurally, functionally, and toxicologically.
Methyl PEG Capryleths Deceths Undeceth Laureths Trideceth Myreths Ceteths Steareths Arachideths Beheneths
3 J,
A2709/P216
slight
slight
slight
moderate
moderate
moderate
low
low
moderate
low
low
low
Uncertainty
HoF
ASA Molar volume
CONCLUSION
TPSA Packing parameter
logS XlogP
For clusters 3 and 4, LUMO is constant Jmax is highly correlated with ASA, Molar volume, and HoF
1. ECHA Read-Across Framework - http://echa.europa.eu/documents/10162/13628/raaf_en.pdf 2. Leist, et. al. Altex 29, 4/12, 02012 3. ECETOC TR-066 skin irritation report; ECETOC TR-087 skin sensitization report 4. Bagley et. al, Toxicology in Vitro 10 (1996), l-6 5. CIR Alkyl-PEG Ether report http://online.personalcarecouncil.org/ctfa-static/online/lists/cir-pdfs/PR581.PDF
Jmax
XlogP
ASA TPSA
HoF Molar volume HOMO LUMO All properties are calculated from CORINA Symphony.6
Software
A read-across workflow has been applied to mechanistically group alkyl PEG ethers based on molecular and physicochemical properties relevant for assessing dermal safety. This method supports the evaluation of certain ingredients as a group. Taking the detergent category (cluster 3) as an example, the assessment process was applied using skin irritation and sensitization as the target endpoints. Data gaps were filled by read-across in a quantitative WoE assessment. Next step in the WOE assessment will address use concentrations and exposures..
6. CORINA Symphony descriptors - https://www.mn-am.com/products/corinasymphony 7. ChemTunes/ToxGPS toxicity predictions - https://www.mn-am.com/products/chemtunes_studio 8. CIR CAT Database
