What is the toxic dose of acetaminophen (paracetamol)?

From the Guidelines

The toxic dose of acetaminophen is generally considered to be more than 150 mg/kg or 7.5-10 grams in a single dose for adults, and chronic ingestion of more than 4 grams per day can also lead to toxicity, as supported by the most recent study 1. When considering the toxic dose of acetaminophen, it's essential to take into account the patient's individual factors, such as alcohol use, malnutrition, and certain medications that induce liver enzymes, which can lower the toxic threshold.

• The study published in 2022 1 suggests that amounts of less than 4 g per day are very unlikely to cause clinically significant hepatotoxicity, but it's crucial to limit the dose of acetaminophen to ≤325 mg per dosage unit when combined with other analgesics.
• Acetaminophen toxicity occurs in stages, with initial symptoms including nausea, vomiting, and abdominal pain, followed by liver damage that can develop 24-72 hours after ingestion, as described in the 2005 study 1.
• The toxicity results from the production of a harmful metabolite called N-acetyl-p-benzoquinone imine (NAPQI) when the liver's normal detoxification pathways become overwhelmed, leading to glutathione depletion and liver cell damage.
• Treatment for acetaminophen overdose includes activated charcoal if within one hour of ingestion and N-acetylcysteine (NAC) administration, which is most effective when given within 8 hours but can be beneficial up to 24 hours after ingestion, as supported by the 2005 study 1.
• It's also important to note that patients with liver cirrhosis are at risk of metabolic disorder and prolonged half-life of acetaminophen, and a daily dose of 2–3 g is generally recommended for these patients, as suggested by the 2022 study 1.

From the FDA Drug Label

The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. The toxic dose of acetaminophen is 150 mg/kg or greater.

• This dose may result in hepatic toxicity. 2

From the Research

Toxic Dose of Acetaminophen

• The toxic dose of acetaminophen is typically considered to be around 12g or more for most adults, before the risk of serious hepatotoxicity becomes a concern 3.
• However, the exact toxic dose can vary depending on several factors, including the individual's weight, liver function, and the presence of other health conditions.

Factors Affecting Toxicity

• The time of ingestion and the amount of drug ingested are crucial factors in determining the risk of liver injury and the need for treatment 3.
• Peak serum transaminase activities usually occur 48-96 hours after acute ingestion, and patients can present with liver failure days after ingestion with undetectable serum acetaminophen concentrations 3.
• Chronic ingestion of excessive acetaminophen doses can also lead to hepatotoxicity, with renal failure being more common in this population 3.

Treatment Options

• N-acetylcysteine (NAC) is the current treatment of choice for acetaminophen overdose, and it works by maintaining intracellular glutathione stores to detoxify the electrophilic acetaminophen metabolite, NAPQI 3, 4, 5, 6, 7.
• Activated charcoal can also be used as an adjunct in the management of acetaminophen overdose, although its effectiveness when administered more than four hours after ingestion is still being studied 4, 5, 6.
• Co-administration of NAC and acetaminophen has been shown to efficiently block acetaminophen toxicity in preclinical studies, suggesting a potential for a co-formulation of acetaminophen and NAC as a safe over-the-counter alternative 7.