Acute toxicity
Acute toxicity refers to the adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within a 24-hour period, or an inhalation exposure of 4 hours.[1] This concept is central to toxicology and hazard assessment, distinguishing it from chronic toxicity, which involves prolonged or repeated exposures over extended periods.[2] Acute toxicity evaluates the immediate potential for harm from chemicals, pharmaceuticals, pesticides, and other agents, guiding regulatory classifications for safe handling and emergency response.[3] The Globally Harmonized System (GHS) of Classification and Labelling of Chemicals provides a standardized framework for categorizing acute toxicity into five hazard levels based on median lethal dose (LD50) for oral and dermal routes or median lethal concentration (LC50) for inhalation.[1] Category 1 represents the highest toxicity (e.g., oral LD50 ≤ 5 mg/kg), escalating to Category 5 for the lowest (e.g., oral LD50 > 2000 mg/kg), with specific thresholds varying by exposure route—such as dermal LD50 ≤ 50 mg/kg for Category 1 or inhalation LC50 ≤ 100 ppm (gas) for the same category.[1] These categories inform pictograms, signal words like "Danger" or "Warning," and precautionary statements on labels, ensuring global consistency in communicating risks.[4] In the United States, the Environmental Protection Agency (EPA) aligns with GHS but uses four toxicity categories for pesticides, where Category I denotes the most toxic products (e.g., oral LD50 ≤ 50 mg/kg) and Category IV the least (e.g., oral LD50 > 5000 mg/kg).[5] Acute toxicity testing typically involves animal models to determine LD50/LC50 values, though with regulatory agencies like the FDA now accepting alternative methods such as in vitro assays and computational models under the FDA Modernization Act 2.0 to replace traditional animal testing, including plans announced in 2025 to phase out requirements for certain pharmaceuticals.[6][7] For pharmaceuticals, the Food and Drug Administration (FDA) defines acute toxicity as effects from one or more doses within 24 hours, emphasizing endpoints like mortality, behavioral changes, or organ damage observed over 14 days.[8] Key routes of exposure—oral, dermal, and inhalation—determine the relevant tests, with factors such as dose, substance structure, and individual susceptibility influencing outcomes.[9]Definition and Classification
Core Definition
Acute toxicity refers to serious adverse health effects occurring following a single exposure or multiple exposures to a substance within a 24-hour period, with effects typically manifesting within 14 days of exposure.[10][8] These effects can arise through various routes, including oral ingestion, dermal contact, or inhalation, and may range from mild irritation to severe outcomes such as organ damage or death.[11] The scope of acute toxicity encompasses immediate physiological disruptions caused by high-dose exposures, distinguishing it from chronic toxicity, which involves prolonged or repeated low-level exposures over weeks or months.[12] It focuses on the rapid onset of harm from substances like chemicals, pharmaceuticals, or pesticides, excluding cumulative effects from ongoing environmental or occupational exposures.[6] The concept of acute toxicity originated in early 20th-century toxicology studies on poisons, with the development of standardized tests like the LD50 assay in the 1920s to quantify lethal doses in animal models.[13] It was formalized in U.S. regulations through the 1947 Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), which mandated acute toxicity data for pesticide registration to assess risks to humans and the environment.[14][15] Due to ethical prohibitions on direct human testing, acute toxicity assessments rely on animal models or in vitro alternatives, as established by the 1938 Federal Food, Drug, and Cosmetic Act, which required safety demonstrations without endangering human subjects.[6][8] This approach prioritizes the 3Rs principle—replacement, reduction, and refinement—of animal use to minimize suffering while ensuring reliable hazard identification.[16]Hazard Categories
The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) provides a standardized framework for categorizing acute toxicity hazards based on the median lethal dose (LD<sub>50</sub>) for oral and dermal routes or median lethal concentration (LC<sub>50</sub>) for inhalation, using data from animal studies or equivalent estimates.[4] Categories range from 1 (most severe) to 5 (least severe), with severity decreasing as the dose or concentration required to produce lethality increases; Category 5 is optional and not implemented in all jurisdictions.[4] These categories guide the use of pictograms (e.g., skull and crossbones for Categories 1-3), signal words ("Danger" for Categories 1-3, "Warning" for Category 4), and hazard statements such as "Fatal if swallowed" for oral Category 1.[4] The following table summarizes the GHS acute toxicity categories for key exposure routes, based on approximate LD<sub>50</sub>/LC<sub>50</sub> values in rats or equivalent species:| Route | Category 1 | Category 2 | Category 3 | Category 4 | Category 5 (optional) |
|---|---|---|---|---|---|
| Oral (LD<sub>50</sub>, mg/kg body weight) | ≤ 5 | > 5 and ≤ 50 | > 50 and ≤ 300 | > 300 and ≤ 2000 | > 2000 and ≤ 5000 |
| Dermal (LD<sub>50</sub>, mg/kg body weight) | ≤ 50 | > 50 and ≤ 200 | > 200 and ≤ 1000 | > 1000 and ≤ 2000 | > 2000 and ≤ 5000 |
| Inhalation - Gases (LC<sub>50</sub>, ppmV/4 hours) | ≤ 100 | > 100 and ≤ 500 | > 500 and ≤ 2500 | > 2500 and ≤ 20,000 | Not established |
| Inhalation - Vapors (LC<sub>50</sub>, mg/L/4 hours) | ≤ 0.5 | > 0.5 and ≤ 2.0 | > 2.0 and ≤ 10.0 | > 10.0 and ≤ 20.0 | > 20.0 and ≤ 50.0 |
| Inhalation - Dusts/Mists (LC<sub>50</sub>, mg/L/4 hours) | ≤ 0.05 | > 0.05 and ≤ 0.5 | > 0.5 and ≤ 1.0 | > 1.0 and ≤ 5.0 | Not established |