What is the toxic dose of acetaminophen (N-acetyl-p-aminophenol)?

Toxic Dose of Acetaminophen

The toxic dose of acetaminophen is generally 150 mg/kg or approximately 10 grams in a single acute ingestion for most adults, though severe liver injury has been documented with doses as low as 3-4 grams per day in certain circumstances. 1, 2

Acute Single Ingestion Thresholds

For adults, any single ingestion exceeding 10 grams (10,000 mg) within 24 hours is considered potentially toxic and requires immediate medical evaluation. 1, 3

• In pediatric patients under 6 years of age, the threshold is 200 mg/kg or more in a single ingestion 3
• For patients 6 years and older, toxicity risk begins at 10 grams or 200 mg/kg, whichever is lower 3
• The minimum dose likely to cause toxicity is approximately 140 mg/kg, though this varies based on individual glutathione stores 4

Very high aminotransferase levels (AST/ALT >3,500 IU/L) are highly correlated with acetaminophen poisoning and should raise suspicion even without clear overdose history. 2, 5

Repeated Supratherapeutic Ingestion (RSTI)

This scenario is particularly dangerous because toxicity can develop at lower daily doses when taken repeatedly:

For adults without risk factors:

• ≥10 grams or 200 mg/kg (whichever is less) over a single 24-hour period requires evaluation 1, 3
• ≥6 grams or 150 mg/kg (whichever is less) per 24-hour period for 48 hours or longer is potentially toxic 1, 3

For high-risk individuals (chronic alcohol use, prolonged fasting, isoniazid use):

• The threshold drops dramatically to >4 grams or 100 mg/kg per day 1, 3
• Severe hepatotoxicity has been documented with doses as low as 4-5 grams per day in chronic alcohol users, with mortality rates of 20-33% 1
• Multiple case series show severe outcomes in alcoholics taking 2.5-16.5 grams per day (median 6.4 grams per day) 1

Maximum Therapeutic Dose Considerations

The FDA recommends limiting daily acetaminophen intake to a maximum of 4 grams for the general population. 2

However, important caveats exist:

• For chronic administration, providers should consider limiting doses to 3 grams or less per day to reduce hepatotoxicity risk 2
• For patients with risk factors (liver disease, chronic alcohol use), the maximum should be 2-3 grams per day 2, 1
• One randomized trial demonstrated that even therapeutic doses of 4 grams per day for 14 days caused ALT elevations >3 times normal in 31-41% of healthy adults without risk factors 1

Critical Risk Factors That Lower Toxicity Threshold

The following conditions significantly increase susceptibility to acetaminophen hepatotoxicity:

• Chronic alcohol consumption - documented severe hepatotoxicity with doses of 4-5 grams per day 1
• Pre-existing liver disease including cirrhosis 2, 1
• Prolonged fasting or malnutrition (depletes glutathione stores) 3
• Concurrent isoniazid use 3
• Chronic use of enzyme-inducing medications 3

Common Pitfalls and Clinical Pearls

Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if the ingestion was remote, occurred over several days, or timing is uncertain. 2, 5

Patients may present with elevated transaminases days after ingestion with undetectable serum acetaminophen concentrations, particularly in cases of repeated supratherapeutic ingestion. 6

The toxic dose can be substantially lower than 10 grams in vulnerable populations - always consider risk factors when assessing toxicity potential. 1, 3

Combination products containing acetaminophen (with opioids like hydrocodone or codeine) significantly increase the risk of unintentional overdose because patients may not realize they are taking acetaminophen from multiple sources. 2