Acetaminophen

Other Uses -> Pharmaceuticals

Pharmaceutical

Pharmaceuticals -> Used in Switzerland

Pharmaceutical

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Analgesics

Pharmaceuticals

Drug

log Kow = 0.46

0.46

0.49

0.51

1.293 at 70 °F (NTP, 1992) - Denser than water; will sink

1.293 g/cu cm at 21 °C

1.3 g/cm³

1 to 5 mg/mL at 72 °F (NTP, 1992)

very slightly soluble in cold water but greater solubility in hot water

In water, 14,000 mg/L at 25 °C

Very slightly soluble in cold water, soluble in boiling water

Freely soluble in alcohol; soluble in methanol, ethanol, dimethylformamide, ethylene dichloride, acetone, ethyl acetate; slightly soluble in ether; practically insoluble in petroleum ether, pentane, benzene

14 mg/mL at 25 °C

Breast Feeding; Lactation; Milk, Human; Analgesics, Non-Narcotic

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

This chemical does not meet GHS hazard criteria for 1.2% (5 of 432) of reports.

Warning

H302 (98.1%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P273, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P332+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 432 reports by companies from 47 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H401: Toxic to aquatic life [Hazardous to the aquatic environment, acute hazard]

Chemical: Acetamide, N-(4-hydroxyphenyl)-

Commission Regulation No 844/2012

Status: Active Update: 28-10-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/12532

Paracetamol (4-hydroxyacetanilide): Does not have an individual approval but may be used under an appropriate group standard

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

Combustible.

SYMPTOMS: Symptoms of overexposure to this compound include nausea, vomiting, cyanosis from methemoglobinemia, injury to the liver, kidneys, central nervous system and heart, circulatory collapse, drowsiness, confusion, liver tenderness, low blood pressure, cardiac arrhythmias, jaundice, acute renal failure, death due to liver necrosis, metabolic acidosis, hepatic damage and cirrhosis. Other symptoms include changes in exocrine pancreas, diarrhea, irritability, somnolence, general anesthesia, fever and hepatitis. Diaphoresis and general malaise may occur. Exposure may lead to hematological reactions and, occasionally, skin rashes and other allergic reactions. The rash is usually erythematous or urticarial, but sometimes it is more serious and may be accompanied by drug fever and mucosal lesions. Exposure to large amounts may lead to pallor, anorexia, abdominal pain, abnormalities of glucose metabolism and hepatic encephalopathy. It may also lead to epigastric pain, sweating, paresthesias of distal extremities, muscular aching, weakness, dizziness, central nervous system depression (rare), pain in the upper right quadrant, enlarged liver, oliguria, anuria, coagulation defects and myocardiopathy characterized by ST segment abnormalities, T-wave flattening and pericarditis. This compound can cause purpura, generalized bleeding and hypoglycemia. It can also cause neutropenia, pancytopenia, leukopenia, thrombocytopenia and nephrotoxicity. Other symptoms may include wheezing, general discomfort, blood changes including many anemias (aplastic anemia), central nervous system stimulation, swollen tongue, rapid pulse, skin eruptions, chills, excitement, delirium, vascular collapse and convulsions. Irritation of the skin, eyes, mucous membranes and upper respiratory tract may occur.

Ingestion may cause injury to the liver and kidneys; [ICSC] Histopathological changes of the liver, kidney, reproductive organs, thymus, and lymph nodes observed in 13-week feeding study of rats at 25,000 ppm; No evidence of carcinogenicity in male rats, male mice, or female mice; Equivocal evidence in female rats; [NTP] High oral doses produce testicular toxicity in rats and impaired spermiogenesis and testicular atrophy in mice and rats; [REPROTOX] A skin and strong eye irritant; Harmful by ingestion; Targets the liver and kidney; [Sigma-Aldrich MSDS]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed over-the-counter drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

IPCS; Poisons Information Monograph 396: Paracetamol. (1998).[Available from, as of May 24, 2007: http://www.inchem.org/documents/pims/pharm/pim396.htm]

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, Vol 73 (1999). PARACETAMOL (Group 3)[Available from, as of May 24, 2007: http://monographs.iarc.fr/ENG/Monographs/vol73]

WHO; Environmental Health Criteria 119: Principles and Methods for the Assessment of Nephrotoxicity Associated with Exposure to Chemicals (1991)[Available from, as of April 4, 2003: http://www.inchem.org/documents/ehc/ehc/ehc119.htm]

DHHS/NTP; Toxicology & Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 394 (1993) NIH Publication No. 93-2849[Available from, as of April 4, 2003: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr394.pdf]

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

Use powder, alcohol-resistant foam, water spray, carbon dioxide.

Fresh air, rest.

Rinse and then wash skin with water and soap.

Rinse with plenty of water (remove contact lenses if easily possible).

Give one or two glasses of water to drink.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.

Ofirmev should be stored at 20 °C to 25 °C (68 °F to 77 °F). ... Do not refrigerate or freeze.

Acetaminophen preparations should be stored at a temperature less than 40 °C, preferably between 15-30 °C; freezing of the oral solution or suspension should be avoided.

Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Sweep spilled substance into covered containers. If appropriate, moisten first to prevent dusting. Do NOT let this chemical enter the environment.

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of the work day.

Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

In adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. Gastric lavage, better known as stomach pumping, may be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion. Acetylcysteine, when used early in the course of treatment, reduces morbidity and virtually eliminating mortality associated with even a massive acetaminophen overdose. (L1712) In patients who develop fulminant hepatic failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation.

Acetaminophen causes dose-dependent decrease in concentration of hepatic glutathione. Agents such as diethyl maleate, which depletes hepatic glutathione, potentiate /hepatic & renal tubular/ necrosis. Conversely, administration of cysteine, glutathione precursor, protects against damage.

At certain dose levels ... pretreatment with phenobarbitone stimulated disappearance of paracetamol from tissues, but markedly potentiated hepatic necrosis. By contrast, pretreatment with piperonyl butoxide inhibited both metabolism and disappearance of paracetamol from tissues, and ... afforded protection against hepatic necrosis.

Rate & extent of absorption of per oral dosed paracetamol is reduced by ... concomitant doses of caffeine, by propantheline & metoclopromide, & also by ... cholestyramine.

A preliminary study in four subjects indicated that acetaminophen (3.0 g/day for 5 days) somewhat reduced the 96 hour urinary excretion of diazepam and its metabolites following a single 10 mg dose of diazepam. The effect was greater in the two female subjects, but additional study is needed to confirm these results and to define the magnitude of the interaction.

For more Interactions (Complete) data for ACETAMINOPHEN (24 total), please visit the HSDB record page.

Chronic therapy with acetaminophen in doses of 4 grams daily has been found to lead to transient elevations in serum aminotransferase levels in a proportion of subjects, generally starting after 3 to 7 days, and with peak values rising above 3-fold elevated in 39% of persons. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage, and in some instances resolve even with continuation at full dose (Case 1).

LC50; Species: Anas platyrhynchos (Mallard duck) age 9 days; diet >5900 ppm for 8 days

LC50; Species: Colinus virginianus (Northern Bobwhite Quail) age 14 days; diet >5900 ppm for 8 days

LD50; Species: Colinus virginianus (Northern Bobwhite Quail) age 22 weeks; oral via capsule >2250 mg/kg

EC50; Species: Xenopus laevis (African clawed toad) Blastula; Conditions: freshwater, renewal, 23 °C; Concentration: >100000 ug/L for 96 hr; Effect: increased developmental deformation /99.1% purity/

For more Ecotoxicity Values (Complete) data for ACETAMINOPHEN (18 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 21(SRC), determined from a log Kow of 0.46(2) and a regression-derived equation(3), indicates that acetaminophen is expected to have very high mobility in soil(SRC). Volatilization of acetaminophen from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 8.9X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.29X10-5 mm Hg(4), and water solubility, 1.4X10+4 mg/L(5). Acetaminophen is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days(6), respectively, suggesting that biodegradation may be an important environmental fate process in soil given acclimation(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 21(SRC), determined from a log Kow of 0.46(2) and a regression-derived equation(3), indicates that acetaminophen is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 8.9X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.29X10-5 mm Hg(5), and water solubility, 1.4X10+4 mg/L(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days(8), respectively, suggesting that biodegradation may be an important environmental fate process in water given acclimation(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acetaminophen, which has an estimated vapor pressure of 6.3X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase acetaminophen is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hrs(SRC), calculated from its rate constant of 1.8X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase acetaminophen may be removed from the air by wet and dry deposition(SRC). Acetaminophen absorbs light at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Common adverse effects associated with oral or rectal administration of acetaminophen may include skin rash, hypersensitivity reactions, nephrotoxicity characterized by elevations in blood urea nitrogen (BUN) and creatinine, and hematological abnormalities such as anemia, leukopenia, neutropenia, and pancytopenia. In addition, it may cause metabolic and electrolyte imbalances, which may manifest as decreased serum bicarbonate, reduced concentrations of sodium and calcium, hyperammonemia, hyperchloremia, hyperuricemia, increased serum glucose, and elevated levels of bilirubin and alkaline phosphatase.

The substance can be absorbed into the body by ingestion.

Oral, rapid and almost complete.

EXPERIMENTAL: In 12 nursing mothers (nursing 2-22 months) given a single oral dose of 650 mg, peak levels of acetaminophen occurred at 1-2 hours in the range of 10-15 ug/mL. Assuming 90 mL of milk were ingested at 3-, 6-, and 9-hour intervals after ingestion, the amount of drug available to the infant was estimated to range from 0.04% to 0.23% of the maternal dose.

EXPERIMENTAL: While studies with Ofirmev have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 - 2% of the maternal dose. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Caution should be exercised when Ofirmev is administered to a nursing woman.

IDENTIFICATION AND USE: Acetaminophen is an odorless compound with a slightly bitter taste. It is a common analgesic and antipyretic agent used for the relief of fever as well as aches and pains associated with many conditions. HUMAN EXPOSURE AND TOXICITY: Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression, stupor, hypothermia, marked prostration, rapid shallow breathing, rapid weak irregular pulse, low blood pressure, and circulatory failure. When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage and/or cardiotoxic effects usually do not become apparent until 2-4 days after ingestion of the drug. Other symptoms of acute poisoning include cerebral edema and nonspecific myocardial depression. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days. Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Hypoglycemia, which can progress to coma have been reported in patients ingesting toxic doses of acetaminophen. Low prothrombin levels and thrombocytopenia have been reported in patients with acetaminophen poisoning. Skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions also have been reported. For use anytime during pregnancy, 781 exposures were recorded, and possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found. There is inadequate evidence in humans for the carcinogenicity of acetaminophen. ANIMAL TOXICITY STUDIES: There is inadequate evidence in experimental animals for the carcinogenicity of acetaminophen. In rats fasted 24 hours and given a single dose of acetaminophen (2 g/kg) by gavage, liver necrosis around the central vein was noted at 9-12 hours and was much more extensive at 24 hours after treatment. In mice after dietary exposure to acetaminophen up to 6400 mg/kg daily for 13 weeks hepatotoxicity, organ weight changes and deaths were observed. Cats are particularly susceptible to acetaminophen intoxication, developing more diffuse liver changes, while hepatic centrilobular lesions found in dogs. High doses of acetaminophen caused testicular atrophy and delay in spermiogenesis in mice. Furthermore, reductions in the fertility and neonatal survival in mice were seen in the F0 generation and decreases in F1 pup weights were found at acetaminophen dose 1430 mg/kg. Acetaminophen was not mutagenic in Salmonella typhimurium assay with or without metabolic activation in six strains: TA1535, TA1537, TA1538, TA100, TA97 and TA98. In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis in cases of overdose. Excipients found in liquid formulations of acetaminophen may decrease its liver toxicity. ECOTOXICITY STUDIES: Daphnia magna was the most susceptible among the test organisms to the environmental effects of acetaminophen. Acetaminophen has recently been identified as a promising snake toxicant to reduce brown tree snake populations on Guam, while posing only the minimal risks to non-target rodents, cats, pigs and birds.

Each year, approximately 500 fatalities and 50,000 emergency department admissions in the United States are linked to acetaminophen. In 2021, US poison control centers recorded over 80,000 cases. Acetaminophen is the most prevalent drug-related cause of acute liver failure, with hepatic injury occurring as a consequence of the drug's metabolism properties. After reaching therapeutic concentrations of oral acetaminophen, 60% to 90% of the drug undergoes metabolism in the liver, forming glucuronic acid- and sulfate-conjugate metabolites. A smaller fraction, approximately 5% to 15%, undergoes metabolism via the cytochrome P450 system (CYP450)—metabolism primarily through CYP2E1 results in the formation of the toxic intermediate NAPQI.

Paracetamol toxicity is one of the most common causes of poisoning worldwide. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine – also known as NAPQI), not acetaminophen itself nor any of the other major metabolites. Cytochromes P450 2E1 and 3A4 convert approximately 5% of paracetamol to NAPQI. This toxic metabolite reacts with sulfhydryl groups on proteins and with glutathione (GSH). NAPQI depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs. More specifically, oxidation by NAPQI of GSH to GSSG (oxidized glutathione) and the reduction of GSSG back to GSH by the NADPH-dependent glutathione reductase appear to be responsible for the rapid oxidation of NADPH that occurs in hepatocytes incubated with NAPQI. Risk factors for toxicity include excessive chronic alcohol intake, fasting or anorexia nervosa, and the use of certain drugs such as isoniazid. At usual doses, paracetamol is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. The toxic dose of paracetamol is highly variable.

/AQUATIC SPECIES/ ... In this study, the four most abundantly used pharmaceuticals in Korea, namely acetaminophen, carbamazepine, cimetidine, and diltiazem, and six sulfonamide related antibiotics, including sulfamethoxazole, sulfachlorpyridazine, sulfathiazole, sulfamethazine, sulfadimethoxine, and trimethoprim were examined for their acute aquatic toxicity employing a marine bacterium (Vibrio fischeri), a freshwater invertebrate (Daphnia magna), and the Japanese medaka fish (Oryzias latipes). In general, Daphnia was the most susceptible among the test organisms. The most acutely toxic among the chemicals tested in this study was diltiazem, with a median lethal concentration of 8.2 mg/L for D. magna. The resulting acute toxicity of these pharmaceuticals was reasonably predicted by physicochemical descriptors such as pH-dependent distribution coefficient and E(HOMO)-E(LUMO) gap. Predicted environmental concentrations (PECs) derived for the test pharmaceuticals in Korea ranged between 0.14 and 16.5 ug/L. Hazard quotients derived from PECs and predicted no effect concentrations (PNECs) for sulfamethoxazole and acetaminophen were 6.3 and 1.8, respectively, suggesting potential environmental concerns and a need for further investigation.

/AQUATIC SPECIES/ The increasing presence of pharmaceutical drugs in nature is cause of concern due to the occurrence of oxidative stress in non-target species. Acetaminophen is widely used in human medicine as an analgesic and antipyretic drug, and it is one of the most sold non-prescription drugs. The present study aimed to assess the toxic effects of acetaminophen (APAP) in Oncorhynchus mykiss following acute and chronic exposures in realistic levels. In order to evaluate the APAP effects in the rainbow trout, gills and liver were analyzed with biochemical biomarkers, such as catalase (CAT), total and selenium-dependent glutathione peroxidase (GPx), glutathione reductase (GRed) and glutathione-S-transferases (GSTs) activity and also lipid peroxidation levels (TBARS). The results obtained in all tests indicate that a significant response of oxidative stress was established, along with the increase of APAP concentrations. The establishment of an oxidative stress scenario occurred with the involvement of all tested biomarkers, sustaining a generalized set of pro-oxidative effects elicited by APAP. Additionally, the occurrence of oxidative damage strongly suggests the impairment of the antioxidant defense mechanism of O. mykiss. It is important to note that the occurrence of oxidative deleterious effects and peroxidative damages occurred for concentrations similar to those already reported for several freshwater ecosystems. The importance of these assumptions is further discussed under the scope of ecological relevance of the assessment of effects caused by pharmaceuticals in non-target organisms.

/OTHER TERRESTRIAL SPECIES/ The brown tree snake (Boiga irregularis) is a significant ecological, agricultural and economic invasive pest on Guam. Acetaminophen has recently been identified as a promising snake toxicant. Earlier experimentation has shown acetaminophen mouse baits are readily consumed and are acutely toxic to these snakes. Before implementing an island wide acetaminophen baiting program for the reduction of brown tree snake populations, the potential risks for non-target wildlife must be evaluated. Quantification of non-target hazards by comparing potential exposure levels to toxicity values suggested a significant level of concern for rodents, cats, pigs and birds. For these species subsequent calculations and field and laboratory experiments, which quantified the consumption under field conditions indicated the acetaminophen consumption was minimal. Results indicate that the advantage of acetaminophen to reduce brown tree snake populations on Guam out weigh the minimal risks to non-target feral wildlife species.

Cough.

Redness.

When taken at the recommended dose, side-effects of paracetamol are rare. Skin rashes, blood disorders and a swollen pancreas have occasionally happened in people taking the drug on a regular basis for a long time. The signs and symptoms of paracetamol toxicity occur in three phases. The first phase begins within hours of overdose, and consists of nausea, vomiting, pallor, and sweating. Rarely, after massive overdoses, patients may develop symptoms of metabolic acidosis and coma early in the course of poisoning.The second phase occurs between 24 and 72 hours following overdose and consists of signs of increasing liver damage. In general, damage occurs in hepatocytes as they metabolize the paracetamol. The individual may experience right upper quadrant pain. Acute kidney failure may also occur during this phase, typically caused by either hepatorenal syndrome or multiple organ dysfunction syndrome. The third phase follows at 3 to 5 days, and is marked by complications of massive hepatic necrosis leading to fulminant hepatic failure with complications of coagulation defects, hypoglycemia, kidney failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed over-the-counter drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N02BE01

N - Nervous system

QN - Nervous system

Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the _salicylate_ drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use.

According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (non-steroidal anti-inflammatory drugs) due to its ability to inhibit the cyclo-oxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclo-oxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge. Although further investigation is warranted, the active metabolite of acetaminophen (AM404) was shown to interact with several molecular targets, including the Ca_v3.2 calcium channel, the cannabinoid CB1 receptors, TRPV1 receptors, and Na_v1.8 and Na_v1.7 channels.

Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow.

The effects of acetaminophen on cyclooxygenase activity have not been fully determined. Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, /the researchers/ hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.

Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with acetaminophen intoxication. A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically. The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher (p < 0.001). Results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments.

For more Mechanism of Action (Complete) data for ACETAMINOPHEN (9 total), please visit the HSDB record page.

The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.

The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.

Acetaminophen is the major metabolite of _phenacetin_ and _acetanilid_. Acetaminophen is mainly metabolized in the liver by first-order kinetics and its metabolism of comprised of 3 pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation through the cytochrome P450 enzyme pathway, mainly CYP2E1, to produce a reactive metabolite (N-acetyl-p-benzoquinone imine or NAPQI). At normal therapeutic doses, NAPQI undergoes fast conjugation with glutathione and is subsequently metabolized to produce both cysteine and mercapturic acid conjugates. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to the depletion of glutathione and of binding of high levels of reactive metabolite (NAPQI) to important parts of liver cells. The abovementioned damage to the liver can be prevented by the early administration of sulfhydryl compounds, for example, methionine and N-acetylcysteine.

About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.

In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis and that high doses of acetaminophen may deplete glutathione so that inactivation of this toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternative pathways. In addition, it also has been suggested that in fasting individuals conjugation of high doses of acetaminophen with glucuronic acid may be reduced, secondary to decreased hepatic carbohydrate reserves and microsomal oxidation may be increased, resulting in increased risk of hepatotoxicity.

Yields 4-acetamidocatechol in rat; yields s-(5-acetamido-2-hydroxyphenyl)-l-cysteine probably in man. Yields p-acetamidophenyl-beta-d-glucuronide in rabbit; yields p-acetamidophenyl-beta-d-glucuronide in rat, in guinea pig, & in ferret; yields p-acetamidophenyl-beta-d-glucuronide in man & in dog; yields p-acetamidophenyl sulfate in rabbit, guinea pig, & ferret; yields p-acetamidophenyl sulfate in rat & in man; yields p-methoxyacetanilide in guinea pig; yields quinol probably in rat. /From table/

Children have less capacity for glucuronidation of the drug than do adults. A small proportion of acetaminophen undgoes n-hydroxylation to form n-acetyl-benzoquinoneimine, a highly reactive intermediate. This metabolite normally reacts with sulfhydryl groups in glutathione. However, after large doses of acetaminophen the metabolite is formed in amounts sufficient to deplete hepatic glutathione; under these circumstances reaction with sulfhydryl groups in hepatic proteins is increased and hepatic necrosis can result.

For more Metabolism/Metabolites (Complete) data for ACETAMINOPHEN (7 total), please visit the HSDB record page.

Drugs that are used to reduce body temperature in fever.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS.

Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL). The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration.

Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as free (unconjugated) acetaminophen and at least 90% of the administered dose is excreted within 24 hours.

Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.

Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).

Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses. Food may delay slightly absorption of extended-release tablets of acetaminophen. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively. In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH. Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance. Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours. The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.

Following rectal administration of acetaminophen, there is considerable variation in peak plasma concentrations attained, and time to reach peak plasma concentrations is substantially longer than after oral administration.

Registered for use in the US for control of brown tree snakes; [NPIRS] Used to make azo dyes, photographic chemicals, and pharmaceuticals, as a stabilizer for hydrogen peroxide, and as a therapeutic analgesic and antipyretic; [HSDB]

Manufacture of azo dyes, photographic chemicals.

Stabilizer for hydrogen peroxide

An analgesic used as an aspirin substitute

Analgesics, Non-Narcotic; Antipyretics

For more Uses (Complete) data for ACETAMINOPHEN (6 total), please visit the HSDB record page.

(1972) 9.1X10+7 GRAMS (PRINCPL CUSTMS DISTS)

(1975) 3.46X10+8 GRAMS (PRINCPL CUSTMS DISTS)

(1975) 4.5X10+9 GRAMS (INCL PHENACETIN)

(1976) GREATER THAN 2.27X10+6 GRAMS

Acetaminophen was one of the most used pharmaceuticals in England during 2002, at an amount used per year of 390,954.26 kg and has been detected in the environment.

Production volumes for non-confidential chemicals reported under the Inventory Update Rule.[Table#4345]

For more U.S. Production (Complete) data for ACETAMINOPHEN (6 total), please visit the HSDB record page.

PRINCIPALLY USED AS A MEDICINAL (1976).

Acetaminophen. Analgesic, 75%; exports, 25%.

CHEMICAL PROFILE: Acetaminophen. Demand: 1987: 30 million lb; 1988: 30.5 million lb; 1992 /projected/: 31.5 million lb (Includes exports, but not imports, which totaled about 5 million lb last year.)

p-Nitrophenol is reduced and the resulting p-aminophenol is acetylated by means of heating with a mixture of acetic anhydride and glacial acetic acid. The crude product may be purified by recrystallization from an ethanol-water mixture.

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80 °C, with acetic anhydride in pyridine at 100 °C, with acetyl chloride and pyridine in toluene at 60 °C, or by the action of ketene in alcoholic suspension. 4-Hydroxyacetanilide also may be synthesized directly from 4-nitrophenol. The available reduction-acetylation systems include tin with acetic acid, hydrogenation over Pd-C in acetic anhydride, and hydrogenation over platinum in acetic acid.

Preparation: ... Wilbert, De Angelis, United States of America patent 2998450 (1961 to Warner-Lambert).

Table: Acetaminophen Preparations [Table#4343]

Ofirmev: (acetaminophen) injection: 1000 mg/100mL (10 mg/mL)

Common combination products containing acetaminophen include the following: Darvocet, Excedrin ES, Lorcet, Norco, NyQuil, Percocet, Unisom dual relief formula, Sominex 2, tylenol with Codeine, Tylenol PM, Tylox, Vicks formula 44-D, and Vicodin.

Proprietary Preparation: Crocin (India)

Cosmetics -> Stabilizing

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan