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Acute Toxicity Studies - Study Design of OECD Guideline 402: Acute Dermal Toxicity Study in Rats

The OECD Guideline 402 outlines the study design for assessing the acute dermal toxicity of chemicals in rats. This information is crucial for ensuring the safety of chemicals before they enter the market. Here’s a breakdown of the key aspects:

Objectives:

Determine the dose of a test substance applied to the skin that causes evident toxic effects without severe toxicity or mortality.
Classify the substance according to its acute dermal toxicity based on the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).
Provide initial information for further safety testing, if necessary.

Test System:

Healthy young adult rats of both sexes are used.
A minimum of 3 animals per dose group are required, unless a statistically justified alternative is chosen.

Dose Progression:

The initial dose is selected based on preliminary information or default starting values.
The test substance is applied to a shaved or clipped area of intact skin on the back of the animals.
Typically, three or more dose groups are used, with doses spaced logarithmically.
Occlusive dressings may be used for substances with potential volatility or rapid absorption.

Observation Period:

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

Endpoints:

Mortality and time to death.
Signs of toxicity, including local skin reactions (e.g., erythema, edema, eschar formation), systemic effects (e.g., lethargy, tremors, convulsions), and behavioral changes.
Body weight changes.
Clinical observations, including physical appearance, fur condition, eyes, and excreta.
Necropsy findings (at termination of the study).

Data Analysis:

The dose at which evident toxicity is observed (without causing severe effects or mortality) is identified as the “evident toxicity dose” (ETD).
Classification of the substance is based on the ETD and GHS criteria for acute dermal toxicity categories (e.g., Category 1: highly toxic, Category 5: practically non-toxic).

Benefits:

Standardized protocol for international harmonization.
Provides a quick initial assessment of a substance’s dermal toxicity potential.

Limitations:

Requires animal use, raising ethical concerns.
Only assesses acute effects and may miss delayed toxicity.
Does not provide a complete dose-response relationship or information on specific target organs.
May not be suitable for all types of substances (e.g., volatile or corrosive chemicals).