Acute Toxicity Categories

Overview

Acute Toxicity module performs rapid and accurate predictions of the tested compounds' LD50 values in rodents after various administration routes. In addition to the statistical model, ACD/Percepta contains a classification system that assigns the most likely OECD hazard categories (important for risk assessment) and an expert system that identifies structural elements typical for toxic compounds known from the literature.

Features

• All predictions are supported by Reliability Index (RI) values that represent a quantitative evaluation of prediction confidence. High RI shows that the calculated value is likely to be accurate, while low RI indicates that no similar compounds with consistent data are present in the training set.
• Experimental LD50 value and similarity to test compound is shown for 5 most similar structures from the training set.
• Categories module defines possible “Oral Acute Toxicity Hazard Categories” for a compound and displays experimentally assigned categories for similar compounds.
• The chemicals are assigned to one of the five toxicity categories according to the numeric criteria expressed as LD50 (oral administration to rats). The categories were defined by OECD (Organization for Economic Cooperation and Development. A Guide to The Globally Harmonized System of Classification and Labeling of Chemicals (GHS))
• Predicted logLD50 values are converted to the probability of compound to have LD50 value in defined range by binomial regression. Probabilities were further corrected according to the presence of known “toxicophores” and to reliability index of LD50 prediction. The most probable acute toxicity hazard categories are defined.

Interface

1. Possible “Oral Acute Toxicity Hazard Categories” and corresponding oral acute toxicity labels. Chemicals can be allocated to one of five toxicity categories based on acute toxicity by oral route of administration according to numeric criteria expressed as LD50 (oral administration to rats).
   File:acute toxicity categories table.png
   Hover over the label to see it more detailed:
   File:acute toxicity categories hint.png
2. Probability table describes the probability that LD50 value is lower (greater) that the defined limit. This table is the basis for the definition of oral hazard categories.
3. Up to 5 similar structures from training set with experimental LD50 values (oral administration to rats), corresponding oral acute toxicity categories and similarity indices to tested compound are provided by the model.

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Technical information

Calculated quantitative parameter

A standard measure of acute toxicity is LD50 (lethal dose 50) defined as a dose that is lethal to 50% of the treated animals. It can be viewed as a “cumulative potential” to cause various acute effects and death of animals. To obtain a linear relationship with structural properties these data were converted to logarithmic form (pLD50) for modeling, but the final prediction results returned to the user are converted back to LD50 value (mg/kg).

In Tox Boxes LD50 is calculated for two different rodent species: toxicity for mice is estimated under oral, intraperitoneal, intravenous, subcutaneous administration, and for rats - under oral and intraperitoneal administration.

Model Features & Prediction Accuracy

Acute Toxicity predictor was built using critically evaluated experimental data for more than 100,000 compounds extracted from RTECS and ESIS databases.

Fragmental QSAR (quantitative structure-activity relationship) was used for the development of baseline LD50 prediction model. The predictions are corrected according to the analysis of experimental LD50 values for similar compounds. Predictions are supported by reliability estimation that takes into account:

• Similarity of tested compound to the training set
• Difference between predicted LD50 for tested compound and experimental values for similar compounds
• Consistence of experimental values for similar compounds.

Predictive models of LD50 in various systems have been validated on external data sets. Validation results show that the accuracy of prediction is proportional to the reliability index. The predictions with a high or moderate reliability index are accurate (average prediction error is about 0.5-0.7 log units). A high/moderate reliability index was reported for 20-50% of compounds in the validation sets.

OECD Ranges

Chemicals are assigned to one of the five Oral Acute Toxicity Hazard Categories according to the numeric criteria expressed as LD50 (oral administration to rats). Categories were defined by OECD (Organization for Economic Cooperation and Development. A Guide to The Globally Harmonized System of Classification and Labeling of Chemicals (GHS)):

• V – LD50 2000-5000 mg/kg (may be harmful if swallowed)
• IV – 300-2000 mg/kg (harmful if swallowed)
• III – 50-300 mg/kg (toxic if swallowed)
• II – 5-50 mg/kg (fatal if swallowed)
• I < 5 mg/kg (fatal if swallowed).

Toxicity hazards

Toxicity Hazards is a knowledge-based expert system that identifies and highlights structural elements that may be responsible high acute toxicity of compounds in rodents. Tox Hazards system contains a list of 86 predefined 'toxicophores' compiled after thorough analysis of toxicological literature. Significance of the defined hazardous fragments was verified on acute toxicity data set (more than 100,000 compounds).