Category analysis of the substituted anilines studied in a 28-day repeat-dose toxicity test conducted on rats: Correlation between toxicity and chemical structure

Abstract

In order to establish methods for estimating the repeat-dose toxicity of chemicals on the basis of their chemical structure, an analysis of a category formed for 14 substituted anilines was conducted. This analysis was based on the results of a 28-day repeat-dose toxicity test conducted on rats in which these 14 chemicals were studied. The intensities of the toxicological effects of the 14 substituted anilines on each target organ at specific dosages were described using the values and histopathological findings of the test. The results clarified the characteristics of the chemical structure that induced specific toxicological effects on specific targets at a particular dosage. Hemolysis was the most frequently observed finding in the test reports in the case of the 14 substituted anilines. Strong linear correlations between the dosage and proportion of decrease in the erythrocyte count were found in the case of chemicals that induced strong hemolytic effects. In particular, for dimethylanilines, strong linear correlations were found between the calculated hemoglobin-binding index and the proportion of decrease in the erythrocyte count at a particular dosage. Thus, the results of our analysis demonstrate that it is possible to correlate the values obtained for substituted anilines from 28-day repeat-dose toxicity tests with their quantitatively determined molecular properties. The intensity of hemolysis and the effects on the liver tended to be low in the case of chemicals with a high water solubility, such as aminophenols and benzene sulfonic acids. However, a similar trend was not observed in the case of the effects of these chemicals on the kidney.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…An example of the application of "manual" read-across to predict the 28-day NOAELs of substituted anilines has been illustrated by Sakuratani et al (2008). This can be performed without any computational tools but is facilitated by using a tool such as the OECD QSAR Toolbox.…”

Thesaurus for histopathological findings in publically available reports of repeated-dose oral toxicity studies in rats for 156 chemicals

“…As part of the NEDO project, we have had an opportunity to analyze 28-day RTS data for existing chemicals under the Japanese Chemical Substances Control Law in order to establish a category approach for the RTS database Sakuratani et al, 2008). Since it is important to compare histopathological findings of RTS of chemicals with similar structural features in using the category approach, it is necessary to develop a pathology thesaurus containing technical terms that commonly appear in RTS reports.…”

“…Bitsch et al (2006). Recently, we have had an opportunity to analyze 28-day RTS data for existing chemicals under the Japanese Chemical Substances Control Law in order to establish a category approach for the RTS database Sakuratani et al, 2008) as a part of the New Energy and Industrial Technology Development Organization (NEDO) grant funded project called Development of Hazard Assessment Techniques Using Structure-Activity Relationship Methods. To facilitate efficient searching for important information in the RTS database, it is necessary to develop a pathology thesaurus containing technical terms that appear in these reports.…”

Formation of mechanistic categories and local models to facilitate the prediction of toxicity

“…these various types of read-across and QSARs built on chemical groupings or category can be thought of as a significant source of local models. they have become more important as predictive toxicology takes on the challenges of issues such as ReACH, especially where data may be sparse, and for the more complex toxicological endpoints such as chronic human health effects (Sakuratani et al, 2008;Johannsen et al, 2008). In addition, as the freely available tools described in this paper (i.e.…”