uncertainty read across ii
TRANSCRIPT
Decreasing Uncertainty in Assessments:
Read-Across
Hans Plugge Senior Toxicologist
15 June 2016
• LD50 values distribution • Data Uncertainty vs Curation • 3E Green Score • Aldehydes vs Ketones • Read Across • Skin Sensitization
Index
Oral LD50 Cumulative Frequency
Log LD50 Cumulative Frequency
Study Design
•Guidelines Study Protocol
•GLP Study Execution
•Curation Study Interpretation
Inherent Uncertainty
Benzothiazole-2-thiol
Methacrylonitrile
2-(2-ethoxyethoxy)ethanol / diethyleneglycol monoethyl ether
(1-Hydroxyethylidene) bisphosphonic acid, sodium salt
Data Analytics
Data Gaps
•Homologues •Analog(ue)s •Structural
similarities •Metabolic pathways
Read Across
Inter/Extrapolation
3E Green Score
Scores
Pre-regulatory input
Drill-Down
Mixtures
• Actual data • Continuous data
analytics
• Anticipate future regulatory restrictions
• Multiple tiers
• Down to ppm
Data: 3E Green Score
Scal
e
Scor
es
Valu
es PCTEC+
Literature data Customer data Read-across QSAR
Health Eco 1- 1000
3E Green Score: HEALTH
CAAS Scoring System
Aldehyde vs Ketone structures
Aldehydes 3E Green Score
ORAL DERMAL INHALATION OVERALL
PENTANAL 793 747 600 708
HEXANAL 798 MISSING 536 654
HEPTANAL 907 750 597 741
OCTANAL 793 776 272 551
Ketones 3E Green Score
ORAL DERMAL INHALATION OVERALL
PENTANONE 701 906 659 748
HEXANONE 738 746 missing 742
HEPTANONE 701 851 587 705
OCTANONE 701 719 missing 710
Aldehyde vs Ketone: Acute Oral
PENTANAL 793 2-PENTANONE 701 3-PENTANONE 727
HEXANAL 798 2-HEXANONE 738 3-HEXANONE 748
HEPTANAL 907 2-HEPTANONE 701 3-HEPTANONE 749
OCTANAL 793 2-OCTANONE 701 3-OCTANONE 800
2-Hexanone Metabolism
1-Hexanal Metabolism
Aldehyde vs. Ketone: Acute Dermal
PENTANAL 747 906 2-PENTANONE
HEXANAL missing 746 2-HEXANONE
HEPTANAL 750 851 2-HEPTANAL
OCTANAL 776 719 2-OCTANAL
Aldehyde vs. Ketone: Inhalation Inhalation
PENTANAL 600 659 2-PENTANONE
HEXANAL 536 missing 2-HEXANONE
HEPTANAL 597 587 2-HEPTANONE
OCTANAL 272 missing 2-OCTANONE
• Oral Route – 2-Ketones significantly more toxic , 3-Ketones
intermediate
• Dermal route – Ketones less toxic/equivocal
• Inhalation Route – Ketones equivocal to aldehydes
Aldehyde vs. Ketone
Aldehyde isomers
n- 2-methyl 3-methyl 2-ethyl
793 Pentanal 828 796
798 Hexanal 822
907 Heptanal
793 Octanal 744
Ketone isomers
n-2-Ketone 3-methyl 4-methyl 5-methyl
701 PENTANONE 758
738 HEXANONE 724
701 HEPTANONE 762
701 OCTANONE 749
• 4-methylpentanone = 2-hexanone • 5-methylheptanone = 2-octanone
READ-ACROSS: inhalation I
PENTANAL 600 659 2-PENTANONE
HEXANAL 536 529 2-HEXANONE
HEPTANAL 597 587 2-HEPTANONE
OCTANAL 272 577 2-OCTANONE
• n-heptanal> n-octanal> 2-octanone
READ-ACROSS: inhalation II
PENTANAL 600 659 2-PENTANONE
HEXANAL 536 529 2-HEXANONE
HEPTANAL 597 587 2-HEPTANONE
OCTANAL 587 577 2-OCTANONE
READ-ACROSS: Dermal
PENTANAL 747 906 2-PENTANONE
HEXANAL 746 746 2-HEXANONE
HEPTANAL 750 851 2-HEPTANAL
OCTANAL 776 719 2-OCTANAL
Aldehyde Read-Across ORAL DERMAL INHALATION OVERALL
PENTANAL 793 747 600 708
HEXANAL 798 MISSING 536 654
HEPTANAL 907 750 597 741
OCTANAL 793 776 272 551
PENTANAL 793 747 600 708
HEXANAL 798 746 536 683
HEPTANAL 907 750 597 741
OCTANAL 793 776 587 712
Skin sensitization
ALDEHYDES2-ketone 5-methyl 4-methyl 3 ketone
nonsens
ambig C5 missing nonsens
sens
missing C6 missing nonsens
nonsens C7 missing nonsens
sens C8 missing
KETONES
Curate your data
Geometric mean
Stick to homologues
Analogues should be
“calibrated” across several
matrices of homologues
and analogues
One-to-one probably does
not make a good initial read-across
Uncertainty remains
huge
Lessons learned
