VNCI Royal Association of the Dutch Chemical Industry

Chemicals are developed for their useful functions, for example in medicine, clothing, toys and food. Sometimes they also appear to have characteristics that may pose a risk to humans and the environment. “Not enough is known about the dangers to the environment of a wide range of chemical substances, so the problems often only emerge after the substances have been in use for a long time,” says Joanke van Dijk, PhD student at Copernicus. Department of Sustainable Development at the University of Utrecht. “New drugs are coming on the market at a rate that is much faster than the rate at which we can identify and assess hazardous properties.” The problem has been identified by the European Commission in the Chemicals Strategy for Sustainability. Safe and sustainable by design is recommended as a solution, a multidisciplinary design process that guarantees the safety and durability of a substance at an early stage.

But how do you do that in practice? To answer this question, the University of Amsterdam (UvA) and Utrecht University (UU) went in search of a method to (re) design chemical substances for safety and sustainability. Triisobutyl phosphate (TiBP), an organophosphate widely used as a flame retardant, was chosen as the case study. UvA PhD student Hannah Flerlage researched it for her master’s internship. “Flame retardants protect against fire and increase safety, but their widespread use means they are found in many European waters,” she says. “During washing, these substances are washed out of our clothes and end up in the environment via wastewater. As this is unavoidable, we have chosen to redesign TiBP and improve the degradability of the substance in the environment. ” At the end of last year, she won her exam report on a system approach to the production of organophosphate flame retardants suitable for the circular economy Student Recycling Award from the Dutch trade association BRBS Recycling.

parameters

Multilayer was supervised in the research by two PhD students: Joanke van Dijk from the group of prof. Dr. Annemarie van Wezel, scientific director at the Department of Biodiversity and Ecosystem Dynamics at UvA, and Steven Beijer from the group of Dr. Chris Slootweg from the Van ‘t Hoff Institute of Molecular Science at UvA. “We deliberately chose this multidisciplinary approach,” Slootweg says. “To create a method for (re) designing molecules in relation to their use, in this case flame retardancy, as well as safety for humans and the environment and full circularity.”

Workflow for the systematic computer-assisted approach to safe and sustainable substances.

The research used in silico methods: chemical ‘tests’ in computer calculations. Using a modified computer program, the researchers generated more than 6.3 million chemical structures, somewhat reminiscent of the original substance TiBP. They then used Quantitative Structure Activity Relationship (QSAR) models to filter these structures on the parameters persistence, mobility, bioaccumulation (accumulation in organisms) and toxicity. Van Dijk: “In silico methods approach reality to some degree, but always remain an estimate. Some models are also better validated than others. But the big advantage is that you do not have to test everything in the laboratory, which is right “Time consuming and expensive. You can already pre-filter. In the end, you always need experiments in the laboratory to confirm things. Especially towards the end we ran into the fact that you can not model everything.”

Van Wezel: “There are good models in terms of behavior, for example, but we have noticed that there are very few models available in terms of functionality in products. It could be further developed in close collaboration with materials researchers. ”

Raw material

A ranking was then made based on both the predicted properties of the substances and the ease with which they can be synthesized in the laboratory. This resulted in a top 500 of the most promising structures. A manual analysis based on the expertise of the Van ‘t Hoff Institute for Molecular Sciences subsequently identified di-n-butyl (2-hydroxyethyl) phosphate as a suitable alternative to TiBP. Van Dijk: “Here, too, silico models have been used as an indication, but in the end you also have to make your own estimate.”

“Regulators are following this study with interest, both nationally and internationally.”

Within the framework of the faculty theme Zero Waste – to promote a world where waste no longer exists – concrete search was made for structures based on phosphate. “Ideally, you make compounds from residual materials, which become the raw materials,” says Van Wezel. “In this way, you not only make a substance that is not harmful to the environment, but you also make the production and the raw materials circular.” Thereafter, di-n-butyl (2-hydroxyethyl) phosphate was still to be synthesized. “We used well-known synthesis routes for this,” says Slootweg. “You have to master these in the lab, and it takes some time.” There is still a world of difference between a small amount in the laboratory and large-scale production, but the possibilities for upscaling have not yet been looked at. “That’s the next step. That parameter will be included in the future.”

After synthesis, it was tested in the laboratory whether the properties match the QSAR predictions. “We’re in a positive mood,” Van Wezel says. “Tests are currently being conducted to confirm the flame retardant function, but initial results show that performance has been maintained and possibly even improved.” Several tests are also needed to determine the exact biodegradability. Slootweg: “For example, we also look at the influence of light. Not only on the molecule itself, but also on the degradation products. These can, under the influence of light, fall apart into substances that are not desired. You want to rule that out. “

Regulators

“There is a lot of interest in this work from the regulators,” Van Wezel says. “Both nationally and internationally, people see this research with interest.” Van Dijk: “Within the chemicals strategy for sustainability, the European Commission sees safety and sustainability in design as one of the main themes for protecting people and the environment from chemical substances. But exactly what we mean by safe and sustainable by design is not yet clearly defined. Hence the interest in our work. We showed the framework within which you can make a fabric safely and sustainably. ”

Slootweg believes that it is important as a scientist to use interdisciplinary research to propose solutions and methods to the industry for the design of safe and sustainable molecules. “By realizing more shop windows, safe and sustainable design will be available to the industry.”

Van Dijk himself has no room for further research within his PhD. »But several proposals are being written, which build on this work. Hannah has also started a PhD. and will, among other things, continue with this research. She will test different properties in the laboratory. And then she will look at other potential drugs and how we can further optimize the process. ”


Safe and sustainable design: A computer-based approach to redesigning chemicals to reduce environmental risks

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