Physico-chemical properties
- Log Kow: extension of applicability domain and development of another model based on machine learning (iSafeRat® ALPS)
- Solubility: extension of applicability domain
- Vapour Pressure: extension of applicability domain
Environmental properties
- Bioconcentration factor: BCF method based on the relationship between Critical Body Burden, Ecotoxicity, Bioconcentration and metabolism (extension of applicability domain) (Guideline OECD 305)
- Biodegradability (Guideline OECD 301)
Domain:
The iSafeRat BCF model is based on critical body burden methodology. It is currently a worst case pilot version which has value in providing accurate BCF values only when no metabolism is expected and for highly hydrophylic (e.g. log Kow <2) and hydrophobic (e.g. log Kow >8) substances. The structural domain has currently been limited to providing predictions for MechoA 1.1 substances. Work is in progress to extend the applicability domain of the model for substances expected to metabolise.
Methodology:
The model has been created using the Critical Body Burden Hypothesis:
BCF (Mol/L) = EC10 (Mol/L) / CBB (Mol/Kg fish)
The EC10 values were derived from the MechoA 1.1 chronic fish experimental data in Zones 1 and 2 and QSAR (see QMRF for ecotoxicity QSARs) combined with a CBB value obtained from the log Water solubility value at 0 Mol/L.The water solubility line was correlated with the decreasing BCF as observed for highly hydrophobic substances.
The corresponding 3-regression graph (Zones 1, 2 & 3) was tested against validated BCF data for poorly metabolising substances and found to correlate very well. Metabolising substances were observed to fall below this graphical construct. The model can therefore be considered a worst case predictor of BCF for MechoA 1.1 substances.
Ecotoxicity endpoints
KREATiS is continuously retrieving data to develop new in silico models and to improve the applicability domain of existing ones in ecotoxicology.
Among others, here are the currently on-going tasks:
- update of the acute and chonic toxicity to fish, daphnids and algae for non-polar narcotic compounds (i.e. MechoA 1.1) taking into account main categories of colorants such as anthraquinones, sulfonates, azo and nitro compounds
- update of the acute and chonic toxicity to fish, daphnids and algae for polar narcotic compounds (i.e. MechoA 1.2) taking into account anilines
- update of the acute and chronic toxicity to fish, daphnids and algae for reactive compounds (i.e. MechoA 3.1 and 3.2) like aldehydes, epoxides and acrylates
- new model of the chronic toxicity to fish, daphnids and algae for carboxylic acids (i.e. MechoA 5.2)
Human Health Endpoints
KREATiS is currently working on development of new in silico models to predict these following endpoints in toxicology:
- Sensitisation MIE key event 1, with or without metabolic activation
- Dermal absorption
Endocrine Disruption Potential
KREATiS is currently working on development of new in silico models to predict these following endpoints :
- Molecular Dynamics
- Further
development of ED SAR and SESAME-3D as a part of an NC3Rs project.
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