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The new and improved QSAR Toolbox
The third version of the QSAR Toolbox was launched in October 2012, ending the second four-year development phase of the joint toolbox programme of the Organisation for Economic Cooperation and Development (OECD) and ECHA. The new release provides a more complete tool to reliably predict the hazardous properties of chemicals.
"With the launch of version 3.0, we now have a tool, which contains a very large database of around 55 000 organic chemicals and over one million data points, including study results from ECHA's registered substances database. The users have the possibility to benefit from this data to make more reliable predictions," says Dr Joop de Knecht from the OECD. In addition to ECHA's database, the toolbox includes two large in vivo databases compiled by the Frauenhofer Institute and Japanese NEDO containing all the historical studies on repeated-dose toxicity and three new in vitro databases for skin sensitisation.
The QSAR Toolbox 3.0 has also been expanded to provide information on tautomers and mixtures as well as on the metabolism of chemicals. Some improvements have been made to increase the user-friendliness of the rather complex application. "We have added an interactive help to guide users within the tool. The users can use the help function at any stage of their workflow and see supporting information related to their situation," says Dr de Knecht.
New concept of adverse outcome pathways
The new release introduces an approach to predict skin sensitisation based on a new concept of adverse outcome pathway (AOP). This pathway approach is based on the concept that toxicity results from a chemical reach ing, and then interacting, with an initial key target in the organism. An AOP is the sequential progression of events in the biological system starting from the molecular initiating event, intermediate events and ultimately ending in the final adverse effect relevant to human or ecological risk assessment.
"As demonstrated in version 3.0, for protein binding leading to skin sensitisation, AOPs can be used to develop and refine chemical categories by providing a more solid mechanistic reasoning for using alternative methods," Joop de Knecht explains. In the coming years, the OECD intends to implement more AOPs in the toolbox, for endpoints such as reprotoxicity. "Our biggest challenge is to get correct predictions for chronic endpoints like repeated dose toxicity or carcinogenicity. This is where the AOPs will, in the future, help the users to build their weight of evidence by reducing uncertainty. Hopefully, they will also play a role in reducing animal testing, which is one of our aims."
Industry appreciates efforts made
"It is a very impressive development that has surpassed the initial promise by far," says Dr Rene Hunziker from the Dow Chemical Company. He is particularly excited about the fact that the toolbox now includes more information on chemicals. His company uses the toolbox mainly for three purposes: research and development; classification of research samples; and REACH. "The most important use is to evaluate candidate chemicals that our research and development team provides. The team gives us a series of molecules for further development and we give them advice as to which of the molecules would be more sustainable from the hazard profile point of view. We also use commercial tools, but the toolbox gives us more in-depth information," says Dr Hunziker.
For classifying its research samples, Dow uses the toolbox in a similar way. A classification shows the potential hazards related to the use of the product. "Basically, we try to make a prediction for a series of endpoints and derive the classification based on that information," Dr Hunziker explains. For REACH, the toolbox is used mostly in the weight of evidence context. Dr Hunziker hopes that the toolbox keeps on improving while the science behind it develops. "I expect that the 2018 registration deadline will be a good opportunity to use the system. By then, even more data will be available. There will be a genuine opportunity for read across," he concludes.
Hülya Genc-Fuhrman from the DHI Group says her company uses the toolbox for REACH registrations. "We normally start with an analysis and identify some endpoints where we are missing experimental data or publications. Then we see if we can generate data and make predictions to fill these data gaps using the toolbox," she says. Another purpose for using the toolbox is to identify chemicals for testing for their customers. "Our customers come up with a list of chemicals for testing. For practical and financial reasons, they need to prioritise, which chemicals to start the testing with. So, we do preliminary predictions for them to identify the group of chemicals which is more likely to have hazardous properties to help them decide," she explains.
Ms Genc-Fuhrman says that one of the improvements in the third version of the toolbox is that the databases have been cleaned from multiple search results for one chemical. "Now that you do not get a long list of chemicals by entering one CAS number, the tool is easier to use." As a tip for the toolbox users, Ms Genc-Fuhrman recommends to invest time in learning how the toolbox functions. "I think the best way is to combine tutorials and background reading with a real life hands-on approach. If you are using the toolbox for REACH registration, it is important to study the Guidance documents published by ECHA. Together, they make a lot more sense," she says.
Symrise AG, a global supplier of fragrances and cosmetic ingredients, also makes use of the toolbox in its research and development work, says Cécile Mignatelli from the company. "For the regulatory work, like REACH registrations, we only use it as a support for read across justifications or as additional evidence to existing studies. Unfortunately, we can't use it yet as a full replacement for experimental studies, due to the fact that the underlying databases do not sufficiently correspond to our chemical domains," she says. Ms Mignatelli hopes that ECHA can in the future provide industry with examples of sufficiently acceptable predictions, in the hope of developing the use of the OECD QSAR Toolbox for the 2018 registrations.
ECHA is committed to the Toolbox development
The ECHA Executive Director, Geert Dancet, announced at the end of 2012, that ECHA is committed to the continuing development of the QSAR Toolbox at least until the last REACH registration deadline in 2018. It will also put resources into the development of alternative methodologies and new databases. The main aim of the work is to also make the toolbox more user friendly and accessible to smaller companies, so that it can be used to fulfil the REACH information requirements of the 2018 deadline.
"This is very challenging for us," says Dr Tomasz Sobanski from ECHA, "on one hand we need to move forward with the scientific content, cover higher endpoints and introduce higher complexity, while on the other, we want to make sure that the toolbox itself is ever easier to use."
ECHA has already started work on making the prediction process more straightforward for certain simple endpoints. "We are trying to find ways of incorporating experience and higher level mechanistic understanding into the more straightforward approach for some of the lower-tier endpoints."
"We have already done the IT review of the tool and we will soon proceed with the scientific review. An important part of this scientific review will be to have interviews with users of the toolbox to know how they perceive the tool and what they would like to see in the tool in the future. This will be for us the starting point for further development," says Dr Sobanski.
Helping registrants to fulfil their obligations under REACH
Dr Sobanski says that the toolbox is already quite good at predicting physicochemical properties and some short term effects for human health and the environment, and that the registrants can benefit from this in fulfilling their various obligations under REACH. "However, we do not yet have enough understanding on long term effects. For that we need to gain additional toxicological knowledge, implement it in the form of AOPs and add AOP related data to the toolbox," he says.
The toolbox can also support registrants with their read across argumentation for higher tier human health endpoints, such as the 90-day repeated dose toxicity or carcinogenicity. These endpoints are often covered with read across from a similar substance. However, the argumentation provided in dossiers for the read across is often poor. "Providing argumentation for higher tier human health endpoints which is based on the structural similarity is not enough," says Tomasz Sobanski, "we would like to develop the toolbox so that registrants can better justify their read across cases by providing similarity measures which are based on mechanistic understanding. This approach combined with implementation of new AOPs will provide registrants with very powerful tool to support their read across hypothesis."
Dr Sobanski reminds that the QSAR Toolbox cannot do the work for the registrant. "Using alternative methods always requires a solid strategy, reasoning and a certain level of expertise. In the future, we want to make sure that toolbox users who know what they want to achieve, will be able perform their actions without struggling with the complexity of the toolbox," he concludes.
Did you know?
The QSAR Toolbox is an OECD tool developed for filling data gaps in (eco)toxicity data needed for assessing the hazards of chemicals and for grouping chemicals into categories. It can also be used for the development of integrated testing strategies. REACH registrants can use the QSAR Toolbox to generate an alternative method to animal testing in order to fulfil their information requirements.
The toolbox currently has 2 243 registered users. The majority of the users are from Germany, the United States, India and the United Kingdom. The main user group is the chemical industry, followed by universities and research organisations as well as governments.
The first update to third generation of the Toolbox (version 3.1) was released on 30 January 2013.
Visits to the QSAR Toolbox download page for different versions of the QSAR Toolbox.
Interviews by Hanna-Kaisa Torkkeli
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Biocidal Products Committee:
30 November-4 December (tentative)
Committee for Risk Assessment:
6-8 October (RAC-52B);
30 November-4 December (tentative);
7-11 December (tentative)
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