ECHA

A new version of the QSAR Toolbox was launched in December 2014. Are you making full use of it? Companies and authorities are increasingly using it to group chemicals into categories and to fill data gaps by read-across or trend analysis – thereby avoiding the need to test substances on animals, and saving money. You can use the wealth of data in the Toolbox completely free of charge. ECHA Newsletter spoke with three data donors to find out how their data can help you.

The QSAR Toolbox was built by the Organisation for Economic Co-operation and Development (OECD). However today, there are a number of actors involved in its further development. For the latest version of the Toolbox, data and knowledge has been contributed, for example, by Procter and Gamble, Environment Canada and the National competence centre for Industrial Safety and Environmental Protection (INERIS) in France.

Comparing chemical structures to find developmental and reproductive toxicants

Procter and Gamble, a multinational manufacturer of consumer goods, has developed a developmental and reproductive toxicity (DART) decision tree and has worked with the OECD to implement the tree in the latest version of the QSAR Toolbox. "The decision tree allows users to identify whether or not a chemical shares structural features with chemicals that are known to be developmental and reproductive toxicants," Dr Karen Blackburn Research Fellow at Procter and Gamble explains. The DART decision tree was first published in 2013 but it took some time to apply it to the QSAR Toolbox software.

The great advantage of the DART decision tree is that a weight of evidence assessment to evaluate the probability that a certain substance may be a developmental or reproductive toxicant can be done without developing new data using animal testing.

However, showing a similar chemical structure with DART does not necessarily mean that the chemical is a DART toxicant. "The results can be used in the overall weight of evidence assessment or as part of an initial screening programme. We think more importantly, the tree provides a structure to organise information on DART toxicants that can be further expanded and used to develop additional testable hypotheses about modes of action," Dr Blackburn says.

Procter and Gamble is committed to developing alternatives to animal testing, and so, bringing the DART decision tree to the QSAR Toolbox seemed like a natural step. "The commitment of the European Commission, ECHA and the OECD to the development of open access tools is extremely important in making methods available to all interested parties, without bias to their ability to purchase proprietary software," Dr Blackburn emphasises.

Dr Blackburn believes that the importance of the QSAR Toolbox and other computer based methods will grow in the future. "Toxicology is going through an unprecedented reinvention both to reduce our reliance on animal testing and to ultimately produce models with improved predictability compared to historical animal tests." She also points out that there is a clear need to continue developing computer based tools that can be used as part of the weight of evidence for endpoints with well understood modes of action, in the generation of testable hypotheses and in predicting effects for the more complex endpoints.

Model to assess explosive properties of a chemical

INERIS is a public research institute that provides scientific and technical assistance to the French Ministry of Environment. Together with Chimie ParisTech, INERIS has created a Quantitative Structure-Property Relationship (QSPR) model that is used to estimate the impact sensitivity of nitroaliphatic compounds. This model is now available in the QSAR Toolbox.

Impact sensitivity is related to the explosive properties of a substance and helps to predict its explosiveness. "This property, characterising the tendency of a material to react under the effect of a mechanical impact, is one of the most important to classify explosive substances according to the Classification, Labelling and Packaging of substances and mixtures," Dr Patricia Rotureau, Scientific Manager at the Accidental Risks Division of INERIS points out.

The model can help companies to fulfil their REACH obligations. Entirely characterising physical-chemical properties is both costly and time consuming. "For example, up to now, experimental characterisation is used by laboratories to gather data on the physico-chemical hazardous properties of energetic substances. Due to the fact that these tests are complex, costly and require a large amount of substance and dedicated facilities, QSPR methods are extremely important," Dr Rotureau explains. QSPR models can also be useful for research and development purposes and computer based modelling can help eliminate potentially hazardous compounds.

According to Dr Rotureau, the model is easy to use. "The model presents remarkable predictive power and it has the advantage of being easy to use for new predictions, since no advanced computational tools are needed."

INERIS is and will be using the Toolbox as a data mining tool, a profiler for characterising chemically-induced toxicities and for building read-across predictions. The institute is committed to continuing their cooperation with the OECD on the Toolbox and is also planning to donate other models dedicated to the endpoint of explosivity and flammability in the future, to help fulfil existing data gaps. "For several years, we have actively worked on the development of new QSPR models dedicated to the prediction of explosive properties. One of INERIS' missions is to provide methods and predictive models to identify and mitigate industrial risks," Dr Rotureau says.

Estimating organic chemical half-life in humans and mammals

Environment Canada has been a long-term partner in donating data to the OECD QSAR Toolbox. Since 2006, they have been involved in the Toolbox development and a few years ago donated databases related to bioaccumulation factors and fish metabolism rates and half-lives. Recently, Environment Canada helped fund a team of experts in Canada and Germany to develop a screening level half-life database for humans based on rodent and human adult studies. This database is now included in the latest version of the Toolbox.

The most recent screening level human and mammalian half-life database helps Toolbox users estimate the extent to which a chemical could bioaccumulate in a human or a mammal. "It will help us to make better estimates of bioaccumulation as this database helps us to make the necessary corrections," Mr Mark Bonnell, Senior Science Adviser at Environment Canada explains. He adds that the database is still relatively limited to certain chemical classes but it will continue to grow.

The information available in the database can be put into a model that estimates the accumulated quantities in humans and can be scaled for other mammals as well. It can also be very useful for building read-across and generating additional weight of evidence. Overall, the database will bring users significant savings since time consuming and costly testing can be avoided or reduced. It could also offer possibilities to avoid additional animal testing on rodents and mammals.

Mr Bonnell also believes that it is important to keep developing the Toolbox further. Working with the OECD QSAR Management Group, plans have been introduced for contributing additional data and knowledge to the Toolbox in the coming years. "It has been proposed that a mechanistic profiler be developed with key experts to better understand how weak acids can have excess toxicity to non-human organisms. As a member of the Management Group, we are also likely to contribute ADME (absorption, distribution, metabolism and elimination) and ionising chemicals expertise in the next couple of years," he says and continues, "the Toolbox is probably the most comprehensive chemical property database or collection of databases in the world. In some respects, it is a one-stop-shop for empirical data for chemicals. This is very useful for data gap filling in risk assessment."

Further information:

• Procter and Gamble – Animal welfare and alternatives
• INERIS
• Environment Canada – Chemical substances
• QSAR Toolbox website
• QSAR Toolbox support on ECHA's website
• Terminology – in 23 languages

Text and interviews by Päivi Jokiniemi

Top image: Fotolia

If you liked this article, you may also like: Continuous development of the QSAR Toolbox, Newsletter 3/2014 The new and improved QSAR Toolbox, Newsletter 1/2013