Bisphenols represent a prominent class of chemical compounds used in production of polymeric materials with excellent thermal, mechanical, and optical properties. Bisphenol A (BPA) is the most widely-used member of this class of compounds, and is currently produced on multi-million ton scale per year. BPA is used in manufacturing of materials for consumer products, such as packaging in food industry and epoxy resins in construction and furniture industries. 8 It has been known for a long time that BPA can activate estrogen receptors (ER), mimicking the biological activity of endogenous estrogens, such as 17β-estradiol (E2), and a number of studies have linked BPA to adverse effects on both human health and the environment. The use of BPA in food contact materials (FCM) is therefore highly regulated, with a complete ban for use in nursing bottles since 2011 in the EU. The adverse effects of BPA have initiated a wide quest for the development of benign alternatives. 11 Despite extensive efforts, the majority of the proposed BPA substitutes display similar endocrine disruptive effects 12 with only a few exceptions. Notably, introduction of methoxy groups onto the aryl backbone of BPA analogues was recently shown to significantly reduce the adverse exposure effects, while maintaining applicability of such compounds for the production of highperformance polymeric materials. 14 Another advantage of this class of compounds stems from the high abundance of methoxylated phenols in lignina widely available side-stream product from the pulp and paper industries, generated on multi-million ton scale per year. Renewable phenolic compounds, such as guaiacol and syringol, can be derived from lignin, making them the ideal candidates for selection of safe and sustainable BPA analogs. Herein, we showcase a Safe-and-Sustainable-by-Design approach for the development of nontoxic bisphenol-based polymers. This multidisciplinary work demonstrates how in silico assessment can reliably predict toxicological profiles of the envisioned bio-based monomers, thereby minimizing the synthetic efforts towards assembling compound libraries for in vitro toxicological assessments. The in vitro toxicological studies are then used as a primary guide for selection of suitable monomers to yield sustainable polymeric materials with suitable consumer properties, minimized hazards during production and environmental impact.