What is the toxic dose of paracetamol (acetaminophen)?

Toxic Dose of Paracetamol (Acetaminophen)

The toxic dose of paracetamol is generally considered to be above 10 grams (10,000 mg) in a single ingestion or above 4 grams per day in repeated supratherapeutic ingestions, with risk factors such as chronic alcohol use potentially lowering this threshold. 1

Acute Single Ingestion Toxicity

The risk of hepatotoxicity varies based on the amount ingested and time to treatment:

• Adults: Most adults must ingest approximately 12g or more of acetaminophen before serious hepatotoxicity becomes a concern 2
• Children under 6 years: Toxic dose is ≥200 mg/kg in a single ingestion 3
• Individuals 6 years and older: Toxic dose is ≥10g or ≥200 mg/kg, whichever is lower 3

Repeated Supratherapeutic Ingestion Toxicity (RSTI)

Repeated excessive doses can lead to hepatotoxicity at lower daily amounts:

• Children under 6 years:

  • ≥200 mg/kg over a single 24-hour period
  • ≥150 mg/kg per 24-hour period for 48 hours
  • ≥100 mg/kg per 24-hour period for 72+ hours 3

• Individuals 6 years and older:

  • ≥10g or ≥200 mg/kg (whichever is lower) over a single 24-hour period
  • ≥6g or ≥150 mg/kg (whichever is lower) per 24-hour period for 48+ hours 3

Risk Factors That Lower Toxic Threshold

Several factors can increase susceptibility to paracetamol toxicity at lower doses:

• Chronic alcohol use: Cases of severe hepatotoxicity have been reported with doses as low as 4-5 g/day in patients with chronic alcohol use 1
• Fasting/malnutrition: Depletes glutathione stores, increasing vulnerability to toxicity 4
• Liver disease: Patients with pre-existing liver disease have reduced capacity to metabolize paracetamol 5
• Medications inducing cytochrome P450 2E1: Can increase production of the toxic metabolite NAPQI 4

Clinical Evidence of Toxicity at Various Doses

The evidence shows varying toxicity thresholds:

• Standard therapeutic dose (≤4g/day): Generally safe in healthy adults, though a 2006 study showed 31-41% of subjects taking 4g/day had ALT elevations >3x normal after 14 days 1
• 5-8.75g/day: Case series showed severe hepatotoxicity and 33% mortality in patients with chronic alcohol use 1
• 9-10g/day: Multiple case reports document fatal hepatotoxicity at this dose range 1
• >20g/day: Acute intentional overdoses at this level have high rates of severe hepatotoxicity 1

Management of Paracetamol Toxicity

For suspected toxic ingestions:

1. Activated charcoal if within 1-4 hours of ingestion 6, 3
2. N-acetylcysteine (NAC) treatment for:
   • Acute ingestions with paracetamol levels above the treatment line on the nomogram
   • Any patient with suspected ingestion of ≥10g or ≥200 mg/kg
   • Modified release formulations ≥10g or ≥200 mg/kg
   • Massive overdoses (≥30g or ≥500 mg/kg) require increased doses of acetylcysteine 6, 7

Pitfalls and Caveats

• Unreliable history: Patient reports of time and amount of ingestion are often unreliable 2
• Undetectable levels: Patients may present with liver failure days after ingestion when paracetamol is no longer detectable in serum 2
• Combination products: Many over-the-counter and prescription medications contain paracetamol, leading to unintentional overdose 5
• Modified release formulations: Require different management approaches and may need higher doses of NAC 6
• Alcohol use: Chronic alcohol users may develop toxicity at lower doses but evidence is somewhat inconsistent 4

Understanding these thresholds and risk factors is crucial for early identification and management of paracetamol toxicity to prevent severe hepatotoxicity, liver failure, and death.