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The purpose of this study was to determine if, and how far, risk-benefit-evaluations were already performed at the time of the introduction of the first synthetic drugs in the 19th century. While for natural products or compounds derived therefrom more or less information about toxicity and even efficacy was available. But the totally new synthetic entities were not related to anything formerly known. This led to new challenges of drug safety evaluation. Exploring the three examples chloroform introduced as an inhalation narcoritc in 1847, antipyrin introduced as an antipyretic and analgesic in 1883 and sulfonal a completely new sedative available from 1888. It could be shown that the physicians of the 19th century already followed a quite sophisticated system for testing new substances. It comprised practical testing with a realistic patient collective and a broad reporting in trade publications and conference presentations. The primary aim was to investigate the real benefit for practical therapies and their associated risks. The first uses of new synthetic compounds in clinics were restrained and always took place in full awareness that serious unexpected adverse drug reactions (ADR) could occur. New substances were just administered in cases where conventional therapies had failed, or diseases were very severe. Antipyrin and sulfonal were tested even before a wide marketing of these drugs started. Manufactures sponsored studies with the new products by providing drugs free of charge. Physicians used them in their daily practice approximately for one year. Within this time it was possible to treat around 300 patients which are, according to modern stistics, enough to make statements about common (1/100 to <1/10) ADRs. After almost three years the number of patients was sufficient to detect even rare (1/10,000 to <1/1,000) ADRs. A prominent example is the toxic epidermal necrolysis (TEN) under antipyrin treatment. Toxic epidermal necrolysis (TEN) is a rare but serious drug adverse reaction. It is also known as Lyell syndrome (ICD-10 L51.20–L51.21), named after the British dermatologist Alan Lyell (1917–2007), who described the syndrome in 1956 and some followingpublications. However, it could be shown that TEN has already been described in the medical literature in 1887 by the Jewish physician Baruch Spitz (1818–1897), i.e. several decades earlier than Lyell. Consequently, the eponym “Lyell syndrome” was assigned incorrectly. To justify the treatment with synthetic agents the risk of the illness had to be greater than that of the drug administration. So in mild disease patterns, synthetic agents were rarely used. To determine the risk to human health, animal tests, self-experiments, multicentre clinical trials, side-effect-reports, but also statistical surveys were conducted. Early attitudes towards balancing benefits and risks are also reflected by recommendations of risk reducing methods of administration or dose limitations. Thus, some form of benefit-risk evaluation clearly existed in the early days of synthetic drug substances. Physicians in the late 19th century obviously acted with considerable care using the new substances keeping in mind the obligation of “primum nil nocere”, which dates back to the times of Hippokrates.