An evaluation of the implementation of the Cramer classification scheme in the Toxtree software

Abstract

Risk assessment for most human health effects is based on the threshold of a toxicological effect, usually derived from animal experiments. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals below which there would be no appreciable risk to human health. When carefully applied, the TTC concept can provide a means of waiving testing based on knowledge of exposure limits. Two main approaches exist; the first of these is a General Threshold of Toxicological Concern; the second approach is a TTC in relation to structural information and/or toxicological data of chemicals. The structural scheme most routinely used is that of Cramer and co-workers from 1978. Recently this scheme was encoded into a software program called Toxtree, specifically commissioned by the European Chemicals Bureau (ECB). Here we evaluate two published datasets using Toxtree to demonstrate its concordance and highlight potential software modifications. The results were promising with an overall good concordance between the reported classifications and those generated by Toxtree. Further evaluation of these results highlighted a number of inconsistencies which were examined in turn and rationalised as far as possible. Improvements for Toxtree were proposed where appropriate. Notable of these is a necessity to update the lists of common food components and normal body constituents as these accounted for the majority of false classifications observed. Overall Toxtree was found to be a useful tool in facilitating the systematic evaluation of compounds through the Cramer scheme.

Thresholds of Toxicological Concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space

“…Knowledge of tautomers and mesomers becomes important in evaluating certain structures of multiple ring system colorants or hair dyes, which Toxtree does not handle well. Furthermore, the assignments of sodium or calcium salts to Class III by Toxtree has been already documented elsewhere for its interpretation of Rule 4 (Lapenna and Worth, 2011;Patlewicz et al, 2008). Although converting the salts to neutral species when preparing structure files is common practice, caution is recommended since the original Cramer rules are related to the metal salts.…”

“…It has been deemed still fit for purpose by European advisory bodies (EFSA, 2012;SCCS, SCHER and SCENIHR, 2012). However, the fact that it was developed on the basis of toxicological knowledge of several decades ago and because users of the Toxtree software for assignment of Cramer Classes have raised questions about inconsistencies and problems with some of the steps in the Cramer decision tree, the need to revise some aspects of the decision tree has been discussed and certain changes have been proposed Dewhurst and Renwick, 2013;EFSA/WHO, 2016;Lapenna and Worth, 2011;Patlewicz et al, 2008;Roberts et al, 2015). Some of the proposed changes have been implemented in the Toxtree software.…”

Synthesis, Antimicrobial Activity and in silico Studies on Thymol Esters

“…Physico-chemical, pharmacokinetic and toxicological properties of compounds were calculated using the Molinspiration, 44 admetSAR, 45 DataWarrior 46 and Toxtree prediction tools. 47 …”

“…47 Compounds 3a-t showed structural alerts for DNA binding as they were predicted as compounds able to undergo Michael addition. Moreover, compounds 3a-t showed structural alerts for protein binding due to their predicted ability to undergo Michael addition, ability to participate in acyl transfer and ability to undergo S N 2 reactions (results given in Supplementary data, Table S5).…”

Open Source Drug Discovery with Bioclipse

“…Computational toxicology predictions using the OpenTox models. For example we see the results of tools such as SmartCyp [48] and ToxTree [49]; these predictions are accessed remotely over the internet and via the OpenTox infrastructure [21].…”