Acute Toxicity Studies - Study Design of OECD Guideline 425: Acute oral toxicity – up and down procedure

The OECD Guideline 425 outlines the study design for the Acute Oral Toxicity – Up-and-Down Procedure, another method for assessing the potential harm of a substance following a single oral administration. Here’s a breakdown of its key aspects:

Objectives:

  • Estimate the median lethal dose (LD50) of a substance, which is the dose at which 50% of the test animals die.
  • Classify the substance according to its acute oral toxicity based on the GHS criteria.
  • Provide initial information for further safety testing, if necessary.
Acute Toxicity Studies - Study Design of OECD Guideline 425: Acute oral toxicity – up and down procedure

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 Progression:

  • The test starts with a dose level estimated to be below the LD50.
  • Animals are dosed one at a time, with the dose for the next animal determined based on the previous animal’s response:
    • If the previous animal survives, the dose for the next animal is increased by a predetermined factor (e.g., 3.2 times).
    • If the previous animal dies, the dose for the next animal is decreased by the same factor.
  • This up-and-down procedure continues until a statistically valid estimate of the LD50 is obtained.

Observation Period:

  • Similar to the fixed dose method, 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:

  • Statistical methods are used to calculate the LD50 and its confidence interval based on the observed responses.
  • Classification of the substance is based on the estimated LD50 and GHS criteria.

Benefits:

  • Compared to the fixed dose method, this procedure requires fewer animals and provides a more precise estimate of the LD50.
  • It avoids administering unnecessarily high doses that cause severe suffering.

Limitations:

  • Requires more complex statistical analysis compared to the fixed dose method.
  • May not be suitable for substances with very steep dose-response curves.
  • Still relies on animal use, raising ethical concerns.

Additional Resources:

 

 

img1
Please visit our blog at linkedin

Solverwp- WordPress Theme and Plugin

Scroll to Top