Testing Information

Testing Status of Agents at NTP

CAS Registry Number: 616-91-1 Toxicity Effects

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Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 1

Names (NTP)

  • ACETYLCYSTEINE
  • N-ACETYLCYSTEINE - ANTIOXIDANT MODEL (TRAMP)
  • L-ACETYLCYSTEINE
  • N-acetylcysteine
  • Antioxidant model (TRAMP) - N-acetylcysteine

Human Toxicity Excerpts

  • SIGNS AND SYMPTOMS: The features of n-acetyl-l-cysteine overdose are similar to the anaphylactoid reactions but more severe. Cardiovascular collapse and death were temporally assocated with the administration of intravenous n-acetyl-l-cysteine in a 4 year old with subtoxic plasma acetaminophen levels. Several fatalities occurred following intravenous n-acetyl-l-cysteine administration, but the contribution of fulminant hepatic failure to mortality limits conclusions about n-acetyl-l-cysteine effects. [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 163]**PEER REVIEWED**
  • CASE REPORTS: A case of serum sickness like illness assoc with acetylcysteine therapy in a 29 yr old man who was admitted with an acetaminophen overdose is reported. Acetylcysteine was started at 5 g orally every 6 hr. Three days after admission, the patient developed fever, diffuse abdominal tenderness, and bilateral, symmetric swelling of the knee and elbow joints. Had a discrete erythematous maculopapular eruption on the chest, abdomen, back and extremities with a few erythematous macules on the palms and face. The platelet count was 233 x 109/l. Twelve hr after antibiotic admin for suspected intraabdominal abscess, his temperature was 40 deg C and he had tender, palpable cervical, axillary and inguinal lymph nodes. a hypersensitivity reaction to acetylcysteine was suspected and the drug was discontinued. ... [Mohammed S et al; Ann Pharmacother 28: 285 (1994) ]**PEER REVIEWED**
  • CASE REPORTS: A healthy 30-month-old girl allegedly ingested acetaminophen at 418 mg/kg. Because the emergency physician feared the time of ingestion might not be accurate, he decided to start the 20.5-hour intravenous N-acetylcysteine protocol 8 hours after ingestion. He mistakenly prescribed the maximum milliliter-per-kilogram volume of the dextrose 5% diluent for the milliliter-per-kilogram volume of N-acetylcysteine 20% to be administered. Five hours after the error was detected (19.5 hours postingestion), the patient started developing myoclonus on the left side of her body, with left eye deviation. This condition persisted intermittently for 3 hours despite treatment with diazepam, lorazepam, and phenytoin. A first computed tomographic scan result was normal. A few hours later, she sustained shorter recurrences of the myoclonus. At 30 hours after ingestion, she started to have irregular breathing and became unresponsive to pain. A repeated computed tomographic scan showed diffuse cerebral edema. A postmortem examination showed the presence of acute anoxic encephalopathy with marked cerebral edema and the beginning of uncal herniation that confirmed the clinical diagnosis of intracranial hypertension and brain death. A cumulative intravenous dose of 2,450 mg/kg of N -acetylcysteine was associated with status epilepticus, intracranial hypertension, and death in a child. [Bailey B et al; Ann Emerg Med 44 (4): 401-6 (2004) ]**PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Paracetamol overdose is a common reason for presentation to the emergency department and N-acetylcysteine is frequently used in the treatment of toxic paracetamol ingestions. Adverse reactions to N-acetylcysteine are common though usually mild and easily treated. Serious reactions to N-acetylcysteine however, are rare and there have been no previous reported fatalities with its therapeutic use. This report describes the case of a 40 year old brittle asthmatic patient who died after treatment with intravenous N-acetylcysteine. Asthma is a risk factor for adverse reactions to N-acetylcysteine and special caution should be exercised in its use in brittle asthmatic patients. [Appelboam AV et al; Emerg Med J 19 (6): 594-5 (2002) ]**PEER REVIEWED** PubMed Abstract
  • CASE REPORTS: Marked elevations in liver function test results (eg, AST (SGOT) and ALT (SGPT), occurred on 2 occasions following administration of high doses (total doses: 106 and 250 g over 3-4 days) of acetylcysteine rectally and via nasogastric tube in a 3 year old by with cystic fibrosis; these abnormalities were noted within a few days of initiation of acetylcysteine therapy and resolved gradually following discontinuance of the drug. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3564]**PEER REVIEWED**

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Non-Human Toxicity Excerpts

  • LABORATORY ANIMALS: Acute Exposure: Although adequately tolerated when applied as drops to alkali burned corneas (as a collagenase inhibitor), a 20% solution was severely damaging when injected into the corneal stroma. In rabbits receiving drops, corneal epithelial wound healing was not retarded. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 45]**PEER REVIEWED**
  • LABORATORY ANIMALS: Subchronic or Prechronic Exposure: In the dog, rabbit, & rat, exposure to a chamber atmosphere produced by 30 sec of nebulization of 20% soln of acetylcysteine has been evaluated. These animals were exposed to this atmosphere for 15 min twice daily for 35 consecutive days. Addnl groups of animals were exposed for 1 hr daily, 5 times a wk for 12 wk. No clinical or histophathologic changes were found that could be assoc with the exposure of the animals to acetylcysteine. [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 683]**PEER REVIEWED**
  • LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity: No evidence of oncogenic activity was observed in rats given oral acetylcysteine in dosages up to 1000 mg/kg daily (5.2 times the human mucolytic dose) for 12 months. ... [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: A slight reduction in fertility wa observed in a reproductive study in rats given oral acetylcysteine dosages of 500 or 1000 mg/kg daily (2.6 or 5.2 times the human mucolytic dose, respectively. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ... Pregnant ICR mice were ip injected with 25 mg/kg of 5-fluorouracil on day 11 of gestation (vaginal plug = day 0). Pregnant mice were pretreated with N-acetylcysteine at dose levels of 80, 160 and 320 mg/kg injected iv 2 hr before dosing with 5-fluorouracil. Pregnant mice were /sacrificed/ on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with 160 and 320 mg/kg of N-acetylcysteine decr the incidence and severity of oligodactyly induced by 5-fluorouracil. There was little difference in maternal body weight gain, fetal mortality, fetal weight gain between the 5-fluorouracil group and the 5-fluorouracil plus N-acetylcysteine groups. Pretreatment with phorone, a glutathione depleting agent, at dose levels of 160 and 320 mg/kg ip, 4 hr before dosing with 5-fluorouracil, incr the incidence and severity of oligodactyly induced by 5-fluorouracil. Cotreatment with N-acetylcysteine 160 mg/kg could not suppress the augmentative effect of phorone on 5-fluorouracil teratogenicity under the severe condition, that is, the excess amount of phorone such as 320 mg/kg. ... The teratogenicity of 5-fluorouracil is mitigated with N-acetylcysteine pretreatment, and also the level of endogenous glutathione is one of the factors which significantly affects teratogenicity of 5-fluorouracil. [Naya M et al; Senten Ijo 33: 77-84 (1993) ]**PEER REVIEWED**
  • LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Reproductive studies in rabbits using oral acetylcysteine dosages of 500 mg/kg daily (2.6 times the human mucolytic dose) on days 6 through 16 of gestation revealed no teratogenicity. Studies in rabbits exposed for 30-35 minutes twice daily to a nebulized solution containing acetylcysteine and isoproterenol hydrochloride on days 16 through 18 of gestation revealed no teratogenicity. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**
  • GENOTOXICITY: No evidence of acetylcystein-induced mutagenicity was seen with an in vitro microbial test system (Ames test) with or without metabolic activation. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**

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Human Toxicity Values

  • None found

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Non-Human Toxicity Values

  • LD50 Dog oral 1 g/kg [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 683]**PEER REVIEWED**
  • LD50 Rat oral 3 g/kg [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 683]**PEER REVIEWED**
  • LD50 Mouse oral > 3 g/kg [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-380]**PEER REVIEWED**
  • LD50 Rat oral > 6 g/kg [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-380]**PEER REVIEWED**
  • LD50 Dog ip 700 mg/kg [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 683]**PEER REVIEWED**

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Absorption, Distribution and Excretion

  • Following oral administration (e.g., when used as an antidote for acetaminophen overdosage), acetylcysteine is absorbed from the GI tract. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**
  • Oral acetylcysteine is rapidly absorbed, but the bioavailability is low (10-30%) due to significant first-pass metabolism. Intact acetylcysteine has a relatively small volume of distribution (0.5 L/kg). Serum concentrations after intravenous administration of an initial loading dose of 150 mg/kg over 15 minutes are about 500 mg/L. A steady state plasma concentration of 35 mg/L (10-90 mg/L) was reached in about 12 hours following the loading dose with a continuous infusion of 50 mg/kg over 4 hours and 100 mg/kg over the next 16 hours. [Goldfrank, L.R., Flomenbaum, N.E., Lewin, N.A., Weisman, R.S., Howland, M.A., Hoffman, R.S., Goldfrank's Toxicologic Emergencies 6th Ed. (1998)., McGraw-Hill, New York, N.Y., p. 566]**PEER REVIEWED**

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Metabolism/Metabolites

  • Following oral inhalation or intratracheal instillation, most of the administered drug appears to participate in the sulfhydryl-disulfide reaction; the remainder is absorbed from the pulmonary epithelium, deacetylated by the liver to cysteine, and subsequently metabolized. [McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 3565]**PEER REVIEWED**
  • Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcystine. [Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 19]**PEER REVIEWED**

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TSCA Test Submissions

  • None found

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Footnotes

1 Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.

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Web page last updated on May 14, 2008