Acute Toxicity Studies - Study Design of OECD Guideline 420: Acute Oral Toxicity – Fixed Dose Method

The OECD Guideline 420 outlines the study design for the Acute Oral Toxicity – Fixed Dose Method, an in vivo test used to assess the potential harm of a substance following a single oral administration. Here’s a breakdown of its key aspects:

Objectives:

  • Identify the dose level at which a substance produces evidence of toxicity without causing severe effects or mortality.
  • Classify the substance according to its acute oral toxicity based on the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).
  • Provide initial information for further safety testing, if necessary.
OECD

Test System:

  • Healthy young adult animals of a single sex (usually female) are utilized.
  • Rodents (rats or mice) are the most common choices, but other species may be used in exceptional cases.

Dose Levels:

  • Four fixed doses are administered sequentially: 5, 50, 300, and 2000 mg/kg body weight.
  • An additional higher dose (5000 mg/kg) may be considered in specific situations.

Observation Period:

  • Animals are observed for at least 14 days after dosing.
  • Detailed observations are made at least hourly during the first 24 hours and at specific intervals thereafter.

Endpoints:

  • Mortality and time to death.
  • Signs of toxicity, including gross behavioral changes, tremors, convulsions, salivation, and respiratory distress.
  • Body weight changes.
  • Clinical observations, including physical appearance, skin and fur condition, eyes, mucous membranes, and excreta.
  • Necropsy findings (at termination of the study).

Data Analysis:

  • The dose at which evident toxicity (not causing severe effects or mortality) is observed is identified as the “evident toxicity dose” (ETD).
  • Classification of the substance is based on the ETD and GHS criteria for acute oral toxicity categories (e.g., Category 1: highly toxic, Category 5: practically non-toxic).

Benefits:

  • Relatively simple and cost-effective compared to other acute oral toxicity methods.
  • Provides a quick initial assessment of a substance’s toxicity potential.
  • Utilizes a standardized protocol for international harmonization.

Limitations:

  • Doesn’t provide a complete dose-response relationship or information on specific target organs.
  • Only uses a single sex, potentially missing sex-specific differences in toxicity.
  • Cannot detect all types of toxic effects (e.g., delayed effects, reproductive toxicity).
  • Requires animal use, raising ethical concerns.

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