Title
Development of a QSAR for worst case estimates of acute toxicity of chemically reactive compounds
Author
Freidig, A.P.
Dekkers, S.
Verwei, M.
Zvinavashe, E.
Bessems, J.G.M.
van de Sandt, J.J.M.
TNO Kwaliteit van Leven
Publication year
2007
Abstract
Future EU legislations enforce a fast hazard and risk assessment of thousands of existing chemicals. If conducted by means of present data requirements, this assessment will use a huge number of test animals and will be neither cost nor time effective. The purpose of the current research was to develop methods to increase the acceptability of in vitro data for classification and labelling regarding acute toxicity. For this purpose, a large existing database containing in vitro and in vivo data was analysed. For more than 300 compounds in the database, relations between in vitro cytotoxicity and rat or mouse intravenous and oral in vivo LD50 values were re-evaluated and the possibilities for definition of mechanism based chemical subclasses were investigated. A high in vitro-in vivo correlation was found for chemicals classified as irritants. This can be explained by a shared unspecific cytotoxicity of these compounds which will act as the predominant mode of action for both endpoints, irritation and acute toxicity. For this subclass, which covered almost 40% of all compounds in the database, the LD50 values after intravenous dosing could be predicted with high accuracy. A somewhat lower accuracy was found for the prediction of oral LD50 values based on in vitro cytotoxicity data. Based on this successful correlation, a classification and labelling scheme was developed, that includes a hazard based definition of the applicability domain (irritants) and a prediction of the labelling of compounds for their acute iv and oral toxicity. The scheme was tested by an external validation. © 2007 Elsevier Ireland Ltd. All rights reserved.
Subject
Biology
Analytical research
Biomedical research
Acute rodent toxicity
In vitro-in vivo correlation
QSAR
chemical compound
acute toxicity
article
clinical research
hazard assessment
in vitro study
in vivo study
LD 50
mouse
nonhuman
prediction
priority journal
quantitative structure activity relation
rat
reference database
validation study
Algorithms
Animals
Data Interpretation, Statistical
Endpoint Determination
European Union
Forecasting
Hazardous Substances
Humans
Legislation
Lethal Dose 50
Quantitative Structure-Activity Relationship
Reproducibility of Results
Animalia
Rattus
Rodentia
To reference this document use:
http://resolver.tudelft.nl/uuid:348aecf7-2fdb-4c3b-94f7-0a5dddacbdd3
DOI
https://doi.org/10.1016/j.toxlet.2007.03.008
TNO identifier
239980
ISSN
0378-4274
Source
Toxicology Letters, 170 (3), 214-222
Document type
article